|

 

Sezary syndrome: immunopathogenesis, literature review of therapeutic options, and recommendations for therapy by the united states cutaneous lymphoma consortium (usclc)

Sezary syndrome: Immunopathogenesis, literature review of therapeutic options, and recommendations for therapy by the United States Cutaneous Lymphoma Consortium (USCLC) Elise A. Olsen, MD,a Alain H. Rook, MD,b John Zic, MD,c Youn Kim, MD,d Pierluigi Porcu, MD,e Christiane Querfeld, MD,f Gary Wood, MD,g Marie-France Demierre, MD,h Mark Pittelkow, MD,i Lynn D. Wilson, MD, MPH,j Lauren Pinter-Brown, MD,k Ranjana Advani, MD,d Sareeta Parker, MD,lEllen J. Kim, MD,b Jacqueline M. Junkins-Hopkins, MD,m Francine Foss, MD,j Patrick Cacchio, BS,a and Madeleine Duvic, MDn Durham, North Carolina; Philadelphia, Pennsylvania; Nashville, Tennessee; Palo Alto and Los Angeles, California; Columbus, Ohio; Chicago, Illinois; Madison, Wisconsin; Boston, Massachusetts; Rochester, Minnesota; New Haven, Connecticut; Atlanta, Georgia; Baltimore, Maryland; and Sezary syndrome (SS) has a poor prognosis and few guidelines for optimizing therapy. The USCutaneous Lymphoma Consortium, to improve clinical care of patients with SS and encourage controlledclinical trials of promising treatments, undertook a review of the published literature on therapeuticoptions for SS. An overview of the immunopathogenesis and standardized review of potential currenttreatment options for SS including metabolism, mechanism of action, overall efficacy in mycosisfungoides and SS, and common or concerning adverse effects is first discussed. The specific efficacy ofeach treatment for SS, both as monotherapy and combination therapy, is then reported usingstandardized criteria for both SS and response to therapy with the type of study defined by amodification of the US Preventive Services guidelines for evidence-based medicine. Finally, guidelines forthe treatment of SS and suggestions for adjuvant treatment are noted. ( J Am Acad Dermatol 2011;64:352-404.) Key word: Sezary syndrome.
This review on Sezary syndrome is dedicated to one of the co- Millennium (I), Therakos (C). Dr Querfeld: Celgene (I), Eisai authors, Marie-France Demierre, MD, who died unexpectedly (S), Eli Lilly (I), Therakos (I, C). Dr Wood: BioCryst Pharmaceu- on April 13, 2010. Dr Demierre's research, teaching, publica- ticals (I), Gloucester (C), Merck (RG), Therakos (C), Yaupon (I).
tions, and dedication to patient care in the area of cutaneous T- Dr Demierre: Celgene (C), Eisai (I), GenMab (I), Gloucester (I, S, cell lymphoma enriched the lives of colleagues and patients AB), Merck (I, S, AB), Novartis (I), Schering (I), Therakos (I). Dr Pittelkow: Gloucester (C). Dr Wilson: Merck (RG). Dr Pinter- From Duke University Medical Center, Durhama; University of Brown: Eisai (AB, S), GenMab (I), Merck (AB, S). Dr Parker: Pennsylvaniab; Vanderbilt University, Nashvillec; Stanford BioCryst Pharmaceuticals (I), Eisai (I), Genmab (I), Gloucester University, Palo Altod; Ohio State Universitye; University of (C), Merck (I). Dr E. J. Kim: BioCryst Pharmaceuticals (I), Centocor (I), Eisai (C), Eli Lilly (I), Genmab (I), Gloucester (I), School of Medicineh; Mayo Clinic, Rochesteri; Yale Univer- Ten-X (I), Yaupon (I). Dr Foss: Allos (S), Eisai (C), Gloucester sity, New Havenj; University of CaliforniaeLos Angeles (C), Merck (S). Dr Duvic: Allos (I, C, AB), BioCryst Pharmaceu- Medical Centerk; Emory University, Atlantal; Johns Hopkins ticals (I), Eisai (I, C), Eli Lilly (I, C), GenMab (I), Merck (C), Roche University, Baltimorem; and M.D. Anderson Cancer Center, (I, C), Therakos (I, AB), Yaupon (I). Drs Advani and Junkins- Hopkins and Mr Cacchio have no conflicts of interest to Funding sources: None.
Disclosure: Abbreviations are as follows: I (investigator), C (con- Reprints not available from the authors.
sultant), AB (advisory board), H (honoraria), S (speaker), RG Correspondence to: Elise A. Olsen, MD, Duke University Medical (research grant, unrestricted, fellowship, etc).
Center, Box 3294, Durham, NC 27710. E-mail: Dr Olsen: BioCryst Pharmaceuticals (I, S), Eisai (I), Gloucester (C), Johnson & Johnson (I, C), Merck (I, C), Yaupon (I). Dr Rook: Published online December 10, 2010.
GenMab (I), HyBioPharma (C), Merck (C), Therakos (C). Dr Zic: Eisai (AB), GenMab (I), Gloucester (C), Therakos (I). Dr Y. Kim: ª 2010 by the American Academy of Dermatology, Inc.
Allos (I, C), BioCryst Pharmaceuticals (I), Celgene (C), Eisai (AB), GenMab (I), Kyowa (I, C), Merck (I, AB), Seagen (C),Yaupon (I). Dr Porcu: Eisai (H), Eli Lilly (I), GenMab (I), J AM ACAD DERMATOL VOLUME 64, NUMBER 2 TABLE OF CONTENTS Abbreviations used: acute promyelocytic leukemia Therapeutic options antithymocyte globulin all-trans-retinoic acid Immunomodulating agents chemokine receptor 4 chronic lymphocytic leukemia complete response cutaneous T-cell lymphoma Bexarotene (Targretin) Retinoic acid receptor retinoids deoxycytidine kinase erythrodermic mycosis fungoides Etretinate (Tegison)/acitretin (Soriatane) EORTC: European Organization for the Research All-trans-retinoic acid (Vesanoid) and Treatment of Cancer Food and Drug Administration Denileukin diftitox histone deacetylase Chemotherapeutic agents hematopoietic stem cell transplantation half maximal inhibitory concentration Purine analogs (fludarabine monophosphate, 2-chlorodeoxyadenosine, and deoxycoformy- International Society for CutaneousLymphomas monoclonal antibody Gemcitabine (Gemzar) mean duration response mycosis fungoides median response duration Alkylating agents Chlorambucil (Leukeran) Nitrogen mustard (Mustargen) NBUVB: narrowband ultraviolet B National Comprehensive Cancer Network National Cancer Institute Temozolomide (Temodar) Topoisomerase inhibitors objective response VP-16 (etoposide) Pegylated liposomal doxorubicin (Doxil) purine nucleoside phosphorylase Histone deacetylase inhibitors Vorinostat (Zolinza) psoralen plus ultraviolet A quality of life questionnaire Monoclonal antibodies retinoic acid receptor Alemtuzumab (Campath-1H) Bortezomib (Velcade) retinoid 3 receptor Antithymocyte globulin (Thymoglobulin) stromal cell-derived factor Multiagent chemotherapy Hematopoietic stem cell transplantation erythrodermic skin stage in MF or SS thymus and activation- regulated Topical and systemic steroids transforming growth factor Topical mechlorethamine (nitrogen mustard) tumor necrosis factor regulatory T-cells Total skin electron beam radiation total skin electron beam therapy Antipruritic therapy US Cutaneous Lymphoma Consortium Recommendations for therapy visual analog scale Table I: Monotherapies in Sezary syndrome 358 J AM ACAD DERMATOL lymphomatous involvement. However, the blood of patients with benign inflammatory dermatoses may also show CD26 or CD7 deletionIn addition, the correlation of the blood tumor burden by flow Table IV: Treatment recommendations for Sezary cytometry and by SC preparation is inexact and may offer differing results from center to center unless a Table V: Principles of therapy for Sezary single observer or a panel of experts is used to read the slides. Expansion of a clonal T-cell population assessed by polymerase chain reaction or Southern blotting to demon- A review of the published literature on The origin of the term potential treatments of Sezary syndrome receptor (TCR) gene rear- (SS) has merit for clinical practice and dates back to a series of re- rangement in the blood, al- future clinical research.
ports from 1938 to 1949 in though also not specific for which Sdescribed Efficacy of treatments for SS, both patients who presented with monotherapy and combination therapy, supportive evidence for sig- erythroderma and very large is presented here in a standardized nificant blood involvement in fashion using defined criteria for both the presence of an increased monstreuses) in the blood the definition of SS and objective number of atypical lympho- that he ascribed to a new cytes or SCs by cytopatho- malignant cutaneous reticu- logic or immunophenotypic The type of study performed is reported losis, different but related to, evaluation, especially if the based on evidence-based guidelines.
clonal T-cell population is Suggested guidelines for therapy of SS, Since then, there has been the same in skin and blood.
including adjuvant agents, are given.
substantial disagreement re- A consensus statement of garding the distinction be- the ISCL was published in tween erythrodermic MF (E-MF), which may evolve 2002 to define and to draw a distinction between slowly through patch/plaque disease and have var- variants of cutaneous T-cell lymphoma (CTCL) that ious levels of blood involvement, and SS, which manifest with erythrodermaBlood involvement in usually presents with erythroderma and significant MF and SS was categorized into prognostically signif- blood involvement, and whether these are variants icant categories, ie: B0 = no involvement; B1 = low of the same Erythroderma was given a more tumor burden; and B2 = leukemic, high tumor burden.
precise definition by the International Society for The criteria for this blood classification were further Cutaneous Lymphomas (ISCL) in 2007 as erythema refined in the 2007 proposed revisions to the staging and classification of MF and SS prepared by the ISCL A standardized definition of neoplastic lymphocytes and the European Organization for the Research and in the blood and how to quantify them has been Treatment of Cancer (EORTC).The definition of B2 more difficult.
was defined as evidence of a dominant T-cell clone by A method of quantifying the blood tumor burden in polymerase chain reaction or Southern blot plus one MF and SS was initially published in 1979 by noting the or more of the following findings of: (1) an absolute SC percentage of ‘‘atypical'' peripheral lymphocytes with count of 1000 cells/mm3 or higher; (2) expanded hyperconvoluted or cerebriform nuclei, now known CD31 or CD41 cells with a CD4/CD8 ratio of 10 or as ‘‘Sezary cells, on a peripheral buffy coat smear.' higher; and (3) expanded CD41 T cells with abnormal Despite attempts over the years to provide objective immunophenotype including loss of CD7 ( $ 40%) or definitions for these morphologically defined neo- CD26 ( $ 30%). Furthermore, SS was defined as pa- plastic lymphocytethe Sezary cell (SC) preparation tients with both erythroderma and B2 blood involve- remains today a subjective test with high potential for ment and as such, would now be staged as IVA disease interobserver variability. Moreover, such cells in the using the new 2007 staging revision blood are not specific for MF or SS but may be seen inhealthy individuaand in those with benign skin conditions.Flow cytometry has introduced a more As many therapies for SS, such as interferons, objective measure of atypical lymphocytes in MF and produce at least a portion of their clinical benefit SS but relies on ascribing deletion of certain cell through modification of the host immune response, a surface markers, primarily CD7and CDto rigorous understanding of the disordered immune J AM ACAD DERMATOL VOLUME 64, NUMBER 2 response associated with SS is useful for the devel- and plasmacytoid DCs, which produce IFN-a.
opment of a sound therapeutic approach to this Consequently, production of DC-dependent cyto- malignancy. SS is associated with significant immune kines, including IFN-a, IL-12, and IL-15, all critical for abnormalities characterized by dysregulation of both normal antitumor and antiviral immunity, becomes cellular and humoral immunitThe vast majority progressively impaired with an increasing blood of cases are associated with the proliferation of a tumor burden. Direct examination of individual malignant population of CD41 T cells that exhibit DCs by flow cytometry has demonstrated decreased high expression of the chemokine receptor 4 (CCR4) intracellular concentrations of IL-12 within the cells and typically coexpression of cutaneous lymphocyte obtained from patients with SS in comparison with Another identifying feature is the typical DCs derived from the peripheral blood of age- and absence of expression of CD26 or CD7 or loss of both sex-matched healthy volunteerThus, DC cyto- kine production appears to be abnormal on an A progressive impairment of cellular immunity is individual cell basis and an overall decline in num- quite typical of advancing SS. Expansion of the bers of circulating DCs does not fully account for the malignant T-cell population appears to correlate entirety of the DC defects observed.
with the progressive decline in normal cell-mediated Emerging evidence suggests that soluble factors immuniWysocka et alhave demonstrated a produced by the malignant population likely play an direct relationship between the magnitude of the important role in the observed abnormalities of circulating burden of malignant T cells and abnormal- cellular immunity. In the majority of cases, the ities in multiple arms of the cellular immune response.
malignant population exhibits a T-helper (Th) 2 cell Functions of natural killer (NK) cells, including cellu- phenotype with the production of IL-4, IL-10, and in lar cytotoxicity and production of interferon (IFN)-g, some cases IL-5.Moreover, gene expression pro- become increasingly impaired as circulating tumor files of isolated SCs have demonstrated high expres- burden increases. An inverse correlation exists be- sion of the Th2 transcription factor GATA-3.Both tween circulating tumor burden and activation status IL-4 and IL-10 can exert effects to blunt NK cell and of both NK cells and CD81 T cells with a diminishing CD81 T-cell functions and suppress Th1 cell immu- number of these cells expressing the activation nity. Inhibition of IL-12 production from myeloid DCs markers CD69 and CD25, and decreased expression and IFN-g by NK cells by IL-10 likely also plays an of intracellular IFN-gBecause these cells are important role in the decline of cellular immunity thought to be critical for direct antitumor responses, among patients with SS. Excess IL-10 production presumably a decline in their functions can lead to may also impede the normal differentiation of DCs.
further acceleration of growth of the malignant pop- Impaired expression of CD40 ligand on the ma- ulation.Another consequence of the decline in lignant T cells, observed by French et is another cytotoxic T-cell and NK cell functions is impaired factor that may impede differentiation of DCs. The activity against opportunistic infectious pathogens.
normal up-regulation of CD40 ligand during T-cell A noticeable increase in severity of herpes viral activation and its interaction with the constitutively infections in advanced SS and cases of progressive expressed CD40 on antigen-presenting cells is cru- multifocal leukoencephalopathy as a result of polyo- cial for optimal activation of the latter cell types.
mavirushave been reported among patients with SS Without this interaction, there is marked impairment who have never been treated with chemotherapeutics of activation of DCs with depressed production of or other immune-suppressing agents. Defective neu- IL-12. Thus, expansion of the circulating burden trophil function as a result of the abnormal cytokine of malignant T cells leads to a larger population of milieu may also account for enhanced severity of T cells that are incapable of activating DCs during an bacterial infections and, perhaps, for the increase in immune response as the body is populated with an skin colonization with Staphylococcus aureus. It is increasing number of helper T cells that are incapa- ble of expressing CD40 ligand at the cell surface.
Staphylococcus may be a result of impaired produc- French et has also demonstrated that provision of tion of skin cathelicidin in a manner similar to that an appropriate stimulus for CD40 by using soluble observed among patients with atopic dermatit recombinant CD40 ligand in vitro can provide the The number of peripheral blood dendritic cells necessary signal for activation of DCs from patients (DCs) and the functions of these cells also declines with SS and the resultant reconstitution of IL-12 significantly in concert with an increasing peripheral production. The implications of such an approach blood tumor burdBoth major populations of for therapy are quite significant.
DCs are affected including myeloid DCs, which are Increased numbers of regulatory T cells (Tregs) known to produce interleukin (IL)-12 and IL-15, have also been implicated in the immune deficiency J AM ACAD DERMATOL accompanying SS.Several groups have reported important implication of these observations is that that the malignant CD41 T cells can behave, in some the malignant CD41 T cells are likely responsible cases, like Tregs in that they express Foxp3 and may for the numerous abnormalities of cellular immunity.
produce increased levels of IL-10 and transforming If these cells can be cleared using an immune- growth factor (TGF)-beta. Both of these cytokines potentiating regimen, immune reconstitution is pos- can exert profound depressive effects on DCs, NK sible. Moreover, the ability to respond to microbial cells, and CD81 T cells.
pathogens will likely improve as well.
Loss of the normal T-cell repertoire may also impair the ability of patients with SS to respond to a THERAPEUTIC OPTIONS diversity of antigens.Yawalkar et using beta The overall prognosis of patients with SS is poor spectratyping, demonstrated that a loss of the normal with few lasting remissions and responses that may repertoire can be observed in cases of early CTCL but not address the disabling pruritus that so affects is typically quite profound among patients with SS.
quality of life. The most relevant information avail- The loss of the normal T-cell repertoire could able today on the survival of patients with SS comes potentially complicate the already compromised from patients seen at Stanford University Medical immune response against microbial pathogens.
Center between 1958 and 1999 with a histologic Importantly, induction of clinical remission in SS diagnosis of MF/SS and SC counts of either more than with immune therapies has been associated with 1000/mm3 or more than 20% of peripheral blood recovery of T-cell diversity.
lymphocytes, 80% of whom also had erythrodermic A peculiar feature of SS is the less frequent skin disease.Median survival was 2.9 years in this occurrence of epidermotropism in comparison with subgroup of primarily patients with SS according to early MF. Although the basis for this observation has current criteria. Much has changed since 1999 in- not been clearly determined, it may be related to cluding the creation of additional objective criteria alterations in chemokine gradients that occur with for the definition of SS,the regular use of immuno- the leukemic phase of CTCL. The skin-derived che- modulatory agents in and the availability of new mokines of thymus and activation-regulated chemo- chemotherapeutic drugs or monoclonal antibodies kine (TARC) and stromal cell-derived factor (SDF)-1, (mAb) with documented activity in There are ligands for CCR4 and fusin (CXCR4), respectively, are few publications that address what effect on survival produced at increased levels by the skin of patients these changes have wrougThere also are few with CTCL. This would be expected to lead to data on the relative efficacy of the therapeutic recruitment of malignant T cells that highly express options for patients with SS for a variety of reasons: CCR4 and fusin (CXCR4)Nevertheless, the report- (1) there is a small number of patients with SS edly high serum levels of TARC and SDF-1 that occur compared with patients who have MF (5%-6% to- in SS could compete with cutaneous gradients of (2) patients with SS are commonly excluded chemokines and, thus, could alter the migratory from clinical trials of MF; (3) the majority of articles patterns of the malignant cells away from the epi- have been published before both international con- dermis. Once the malignant cells arrive within the sensus definitions of SS and the incorporation of cutaneous environment, a relevant issue in regard to blood into the staging of MF and SS and, hence, the proliferation of malignant T cells within the skin is response in patients with E-MF with no or low levels the observation by Yamanaka et althat skin- of blood involvement and patients with SS have derived IL-7 may be an important stimulus for often been grouped together; (4) many studies perpetuation of growth of the abnormal CD41 group the efficacy results in those with ‘‘aggressive'' or ‘‘late stage'' or stage IIB or greater MF/SS together Importantly, most, if not all of the described versus separating out the results in patients with SS immune abnormalities associated with SS have separately; and (5) the definition of endpoints has been observed to normalize after clinical remission often varied between studies.
induced by immune modulatory therapies including Despite these limitations and because of a dire photopheresis, interferons, and systemic retinoids.
need to improve the treatment and prognosis of On clearance of the malignant cells, repopulation of these patients, we have undertaken a literature the peripheral blood with NK cells, CD81 T cells, and review of the current therapeutic options for SS.
DCs that all function normally is quite characteris- Each therapeutic option has been evaluated in a tic.Although chemotherapeutic regimens may standard format in an attempt to control for as many induce transient remission, their immunosuppres- variables as possible and allow for a comparison of sive effects impede immune reconstitution. One the various agents on a single plane. We have first J AM ACAD DERMATOL VOLUME 64, NUMBER 2 provided information on the mechanism of action, is also a pegylated form of interferon alfa-2b overall efficacy in MF/SS (to provide a point of (PegIntron) although neither of the pegylated forms comparison with those patients with SS), and ad- has published efficacy reports in clinical trials of MF verse effects of each agent. We have then reported on or SS. The pegylated forms differ quite a bit in their the results for each agent used as a monotherapy size and structure with pegylated interferon alfa-2a (or as part of combination therapy specifi- being a much larger molecule (40 vs 12 kd) and cally in SS ), noting the definition of SS, the having a longer elimination half-life (80 [50-140] vs response criteria used, and type of study in each 40 [22-60] hours) than pegylated interferon alfa-2b, publication. There are no published trials in SS with which acts primarily as a prodrug with slow inter- an active control group and most data on efficacy are feron release.There is also another Food and Drug from individual patients so designated within a study Administration (FDA)-approved interferon alfa, in- of patients with MF/SS. Nonetheless, we assigned a terferon alfacon-1 (Infergen), which is a recombi- hierarchy of research design using a modification of nant, nonnaturally occurring type-1 IFN derived the US Preventive Services guidelines for evidence- from several natural IFN-a subtypes and differing based medicine: level I is evidence obtained from from interferon alfa-2b at 20/166 amino acids and at least one properly randomized controlled trial; with identity of 30% or more of amino acid positions level II-1 is evidence obtained from at least one well- of interferon beta.It is FDA approved for the designed controlled trial without randomization; treatment of hepatitis C and, to date, there have level II-2 is evidence obtained from at least one been no published clinical trials using it in CTCL.
prospective, well-designed cohort or case-control Interferons as a class have cytotoxic, antiprolifer- study, preferably from more than one center or ative, and antiviral properties. Interferon alfa in- research group; level II-3 is evidence obtained creases class I molecules on lymphocytes and has a from at least one retrospective, well-designed cohort variable effect on NK activity and antibody produc- or case-control study, preferably from more than one tion by B cells.Importantly as pertains to CTCL, center or research group; level III is evidence interferon alfa inhibits production of IL-4 and IL-5 by obtained from multiple time series with or without normal T cells and SCs, thus suppressing the Th2 the intervention; and level IV includes opinions of cytokine secretion pattern.Development of re- respected authorities, based on clinical experience, sistance to interferon alfa has been obserand descriptive studies, and case reports or reports of has been hypothesized to be related to the presence expert committees. The results of bone-marrow of neutralizing antibodies (dose/duration/route re- transplantation in SS are given in down-regulation of IFN receptors,or Guidelines for the treatment of SS proposed by the more recently, a lack of STAT1 expressio US Cutaneous Lymphoma Consortium (USCLC) are Interferon alfa has efficacy across all stages of MF given in : these are modified from the and Papa et showed that 80% of patients National Comprehensive Cancer Network (NCCN) with patch/plaque disease and 70% of patients with guidelines published in 2009 of which several mem- stage III/IV disease (including SS) treated with 18 bers of the USCLC participate million units (MU) interferon alfa-2a daily for 3months and then 3 times per week (tiw) had an IMMUNOMODULATING AGENTS objective response (OR) (OR = complete response [CR] [100% clearing] plus partial response [PR] [at least There are two forms of recombinant interferon 50% clearing]). This was very similar to that of the alfaeinterferon alfa-2a (Roferon) and interferon alfa- Duke University Medical Center and Northwestern 2b (Intron)ethat have been studied in the treatment University Medical Center study with 73% and 60% of MF/SS for more than 20 years although neither is OR in those with similar stages of diseasbut on 3 specifically approved for this indication. Interferon to 18 MU daily of interferon alfa-2a. The maximally alfa-2a and -2b differ in structure by one amino acid tolerated dose of interferon alfa is 9 to 18 MU daily at position 23 and in their method of purification with most patients being treated in practice with 3 to but bind to the same type I IFN receptor with 6 MU tiw to daily. However, there may be an purportedly the same biologic specific activity.
advantage to higher doses of interferon alfa espe- Subcutaneous (SQ) or intramuscular injections of cially with waning response to low-dose inter- interferon alfa are equivalent with an elimination feron.Reports of patients with SS treated half-life of 2 to 3 hours for interferon alfa-2b and 3 to with interferon alfa are limited. Several studies failed 8 hours for interferon alfa-2Interferon alfa-2a is to give criteria for the diagnosis of SS but reported no longer available in the United States but has been responses. Dallot et alreported improvement in 3 supplanted by its pegylated form (Pegasys). There of 5 patients with SS treated with 5 MU interferon Table I. Monotherapies in S Level of evidence: II-2 0.05-0.15 mg/kg 3 cohortstudy (1 site) Level of evidence: II-2 plea caseseries (2 sites) cells/mm3 1WBC [32,000 Phase II trial and Level of evidence: II-2 Phase II-III study Level of evidence: II-3 prednisone,maintenancechlorambucil2-4 mg 1prednisone5-10 mg/d Denileukin diftitox Level of evidence: II-3 Denileukin diftitox Decadron8 mg/d 3 5 dq 3 wk Denileukin diftitox 5 days first cycle then 18-27 g/kgqd 3 5 1 Decadron8 mg q 3 wk Level of evidence: II-2 qowk 3 6 wkthen monthly Level of evidence: II-2 flow orchromosomalabn cohort study(1 site) T4 1 [5% atypical ECP 2 consecutive d q 4 wk 3 at least ECP 2 consecutive d either q 4 wk 3 either PB clone or Level of evidence: II-2 Level of evidence: II-2 Level of evidence: II-2 8 patients treatedoff-studyat 150 mg/m2 Level of evidence: II-2 Interferon alfa-2a tolerated dose tiw Interferon alfa-2a 11/51 (SS 11 T4 1 $ 5% All patients l CR Level of evidence: II-2 At least 2/16 T4 1 PB SC Level of evidence: II-2 cohort study(8 sites) Liposomal doxorubicin Level of evidence: II-2 20 mg q 4 wk 27/34, also receivedinterferon alfa Overall PFS 5 mo, SNBM Level of evidence: II-2 1-1.5 mg bid or2 mg over slowinfusion to courseof 0.4 mg/kg Methotrexate, high dose Level of evidence: II-2 leucovorin rescue;escalating doseq 5 d; maintenanceoral dose Methotrexate, low dose Level of evidence: II-3 if definition SS is Level of evidence: II-2 on d 1, 8, and15 q 28 d forup to 6 cycles Level of evidence: II-2 3 d/wk 3 4 wk,then 5 d/wk or300 mgbid 3 14 d with7-d rest abn, Abnormal; B, blood; B1, [5% SC per ISCL/European Organization for the Research and Treatment of Cancer (EORTC) clasB2, high blood tumor burden per ISCL/EORTC ;bid, twice a day; BM, bone marrow; CR, complete response; DFS, disease-free survival; ECP, extracorporeal photopheresis; FFTR, freedom from treatment failure; IM, intramuscularly; ISCL, InternationalSociety for Cutaneous Lymphomas; IV, intravenous; LCT, large cell transformation; M, viscera; MRD, median response duration; MU, million units; N, nodes; NA, not applicable; NG, not given; OR,objective response (CR 1 PR); PB, peripheral blood; PFS, progression-free survival; PR, partial response; q, every; qd, once daily; qowk, every other week; S, skin; SC, Sezary cells; SQ, subcutaneous; SS,Sezary syndrome; T4, erythrodermic stage (mycosis fungoides or SS); TCRGR, T-cell receptor gene rearrangement; tiw, 3 times weekly; UNK, unknown; WBC, white blood cell.
Levels of evidence: I = evidence obtained from at least one properly randomized controlled trial; II-1 = evidence obtained from at least one well-designed controlled trial without randomization; II-2 = evidence obtained from at least one prospective, well-designed cohort or case-control study, preferably from more than one center or research group; II-3 = evidence obtained from at least oneretrospective, well-designed cohort or case-control study, preferably from more than one center or research group; III = evidence obtained from multiple time series with or without intervention;IV = includes opinions of respected authorities, based on clinical experience, descriptive studies, and case reports or reports of expert committees.
Publications included must have described Food and Drug Administrationeapproved treatment, definition of SS used, dosing regimen used, and had definition of response as $ 50% clearancefrom baseline. In cases where definition of SS was not specifically given, extrapolation could be made from history that subjects likely met current criteria of SS.
*These publications reported only evaluable patients who completed minimum number of treatments.
Table II. Combination therapies in S ECP 2 consecutive d q 3 wk 1 interferon ECP 2 consecutive d q 4 wk; interferon alfa up to 36 MU qd Interferon alfa-2b T4 1 CD4/CD8 4:1 1 Interferon alfa-2b alfa 3-18 MU tiw; ECP 2 consecutive Interferon alfa-2b T4 1 [1000 SC/L 1 2 consecutived q 4 wk 11/12 T4 1 [15% PBSC 1 Interferon alfa 1 either clone, abn 4 1 ISCL criteria B2 Interferon alfa-2a q 2-4 wk, PUVA tiw, 2/63 T4 1 [5% PBSC 3 MU escalated to 1 mo then continuous dosing 1 PUVA tiw 28/28 T4 1 one or more ECP 2 consecutive d interferon alfa 1.5 MU 3-53/wk 1 bexarotene 40-100 g 3-53/wk, acitretin, GMCSF,PUVA 1 topical NM 1topical BCNU, UVB T4 1 [ 1000 PBSC/L ECP 2 consecutive d bexarotene 300 mg/m2 T4 1 [1000 SC/L 1 300-650 mg/d 1 ECP Interferon alfa 6 MU tiw 1 alfa 1 prednisone prednisone 20 mg/d 1 ECP monthly X 3 yrs 1addition bexarotene450 mg/d ECP 1 interferon alfa, 1 MTX 1 topical NM et regimens not specified T4 1 CD4/CD8 66 1 ECP d 1 1 interferon alfa-2a 4.5 MU 3 7 d then tiw 3 3 wk 1 IL-2 18 MU IV d 1,9 MU d 2-5 in 3 wkcycle 3 6 cycles 4.2 MU SQ 43/wk 1 150 mg/d 1PUVA biw bexarotene150-225 mg/d 1 PUVA Interferon alfa-2b 1 Interferon alfa-2b 75-300 mg/d 1 PUVA ECP 1 bexarotene 1 40 g SQ tiw added to ECP 1 bexarotene 150 mg/d post-TSEBT ECP 2 consecutive d q 4 wk 3 at least T4 1 74% CD41/CD26e Interferon gamma vorinostat 400 mg TSEBT 1 interferon regimen of interferon Fludarabine 25 mg/m2 Phase II study II-2 Fludarabine 18 mg/m2 Chlorambucil 10-12 mg 1 fluocortolone 75/50/25 mg treatment 1 interferonalfa (dose NG) Chlorambucil 10-12 mg 1 fluocortolone 75/50/25 mg interferon alfa 1 Chlorambucil 10-12 mg 1 fluocortolone 75/50/25 mg treatment 1 interferonalfa 1 PUVA McEvoy et al11/11 T Chlorambucil 4 mg/d 1 prednisone 20 mg/d 1 leukopheresis 2-33/wk MTX 60-120 mg/m2 IV 1 MTX 10 mg/wk orally; 1, Plus; 1/-, with or without; abn, abnormal; B, blood; BCNU, bis-chloronitrosourea; BRM, biologic response modifier; CR, complete response; ECP, extracorporeal photopheresis; FU, fluorouracil;GMCSF, granulocyte monocyte colony-stimulating factor; IL, interleukin; IV, intravenous; MRD, median response duration; MTX, methotrexate; MU, million units; N, nodes; NA, not applicable; NG, notgiven; NM, nitrogen mustard; OR, objective response; PB, peripheral blood; PD, progressive disease; PFS, progression-free survival; PR, partial response; PUVA, psoralen plus ultraviolet A; q, every; qd,once daily; qod, every other day; qowk, every other week; S, skin; SC, Sezary cells; SQ, subcutaneous; SS, Sezary syndrome; T4, erythrodermic stage (mycosis fungoides or Sezary syndrome); tiw,3 times weekly; TSEBT, total skin electron beam radiation; UNK, unknown; UV, ultraviolet; V, viscera.
Levels of evide: I = evidence obtained from at least one properly randomized controlled trial; II-1 = evidence obtained from at least one well-designed controlled trial without randomization; II-2 = evidence obtained from at least one prospective, well-designed cohort or case-control study, preferably from more than one center or research group; II-3 = evidence obtained from at least oneretrospective, well-designed cohort or case-control study, preferably from more than one center or research group; III = evidence obtained from multiple time series with or without intervention;IV = includes opinions of respected authorities, based on clinical experience, descriptive studies, and case reports or reports of expert committees.
Publications included must have described Food and Drug Administrationeapproved treatment, definition of SS used, dosing regimen used, and had definition of response as $ 50% clearancefrom baseline. In cases where definition of SS was not specifically given, extrapolation could be made from history that subjects likely met current criteria of SS.
FEBRUARY DERMATOL2011 Table III. Allogeneic bone-marrow transplantation in study transplantation 21, 58/F; Retinoid, 1 liver orGI GvHD 50, 53/F; Retinoid, 1, 13, 14 mo 67% CR 36, 61/M; $ 4 Systemic liver, skinGvHD, 2/3chroniccutaneousGvHD, 1/3no GvHD 48-55/M Retinoid, GvHD, 1 deadat 5 mo withacute/chronicskin GvHD alfa, ECP, Ontak, Table III. Cont'd in study transplantation molecularremission inskin, blood,nodes,BM, andcytogenetic) CR at $ 23 mo(clinical,molecularremission;skin, blood) FEBRUARY DERMATOL2011 Flu 25 mg/m2 3 No Flu 30 mg/m2 3 No alkylating agents, molecularremission inskin andblood) Allo, Allogeneic; ATG, antithymocyte globulin; BM, bone marrow; BMT, bone-marrow transplantation; Bu, busulfan; CD341, CD34-enriched PBSCT; CDA, chlorodeoxyadenosine; CHOP, Cy, Adriamycin,vincristine, and prednisone; CR, complete response; CSA, cyclosporine; Cy, cyclophosphamide; DLI, donor lymphocyte infusion; ECP, extracorporeal photopheresis; F, female; Flu, fludarabine; FTBI,fractionated total body irradiation; f/u, follow-up; GI, gastrointestinal; GN, glomerulonephritis; GvHD, graft-versus-host disease; HDACi, histone deacetylase inhibitor; IV, intravenous; LCT, large celltransformation; M, male; Mel, melphalan; MTX, methotrexate; MUD, matched unrelated donor; NR, no response; PB, peripheral blood; PD, progressive disease; PR, partial response; PUVA, psoralenplus ultraviolet A; q, every; qd, once daily; SCT, stem cell transplantation; SS, Sezary syndrome; TBI, total body irradiation; TSEBT, total body electron beam radiation.
1Fourteen patients with SS in tables (presented here), 11 patients with SS in text.
Studies included only if they reported dosing regimen, definition of SS, and definition of response as $ 50% improvement from baseline.
*Response lasting at least 1 mo.
zInternational Society for Cutaneous Lymphomas/European Organization for the Research and Treatment of Cancer definition SS, ie, T4B2.
yMycosis Fungoides Cooperative Group staging SS, ie, T4B1 $ 5% SC.
J AM ACAD DERMATOL Table IV. Treatment recommendations for S Secondary treatment (after inadequate response, refractory disease, Primary treatment or progression despite primary treatments) d Category A systemic therapies (monotherapies) d Category B systemic therapies (decision as to what order to use must take into account o Interferon alfa blood tumor burden, patient age and overall health, prior therapies) o Low-dose methotrexate ( # 100 mg/wk) o Denileukin diftitox (plus corticosteroid) o Chlorambucil 1 corticosteroido Liposomal doxorubicin d Category A combination therapies o HDAC inhibitors o Systemic 1 SDT* n Interferon alfa or gamma 1 PUVA or topical nitrogen mustard n Methotrexate (low dose) 1 o Deoxycoformycin topical nitrogen mustard o High-dose methotrexate ([100 mg/wk) n Bexarotene 1 PUVA o Fludarabine 6 cyclophosphamide n Immunomodulators o Mechlorethamine (ECP, interferon alfa or gamma, o Consider allogeneic transplantation bexarotene singly or in combination) 1 TSEBT o Systemic 1 systemic n Interferon alfa 1 bexarotene n ECP 1 other immunomodulators (bexarotene, interferon alfa, interferongamma, low-dose methotrexate singlyor in combination) n Methotrexate (low dose) 1 interferon alfa ECP, Extracorporeal photopheresis; HDAC, histone deacetylase; PUVA, psoralen plus ultraviolet A; SDT, skin-directed therapy; TSEBT, total skinelectron beam radiation.
Modified from National Comprehensive Cancer Network guidelinThe only treatments included here are those that are Food and DrugAdministration approved and have published data demonstrating at least 20% response rate in Sezary syndrome.
*Topical corticosteroids are reasonable SDT used with any systemic therapy.
alfa-2b tiw but scant data preclude more specific studies where the combination is compared with comments on response. Nicolas et alreported monotherapy alone and none where the results in improvement in patients with SS treated with inter- SS are specifically addressed. Patients with SS feron alfa 40 MU/wk for 6 months. Dreno et al treated with a combination of interferon alfa and reported on 13 cases of SS treated with interferon alfa pentostatinor interferon alfa and fludarabi 6 to 9 MU once daily (qd) for 2 to 3 months then tiw demonstrated ORs but the overall response rate (RR) for 10 months with an OR in 25% (3 of 12) of these in all patients with MF thus treated (41% and 51%, compared with 60% (12 of 20) with early-stage MF.
respectively) was not higher than that seen in other Other publications of patients with SS (where criteria studies with interferon In the case of was specifically defined) treated with interferon alfa patients treated with interferon alfa and extracorpo- are presented in real photopheresis (ECP), there has been an overall Interferon alfa in combination with psoralen plus excellent response to combination therapy in those ultraviolet (UV) A (PUVA) has shown efficacy in with and an improvement in response to E-MF (blood involvement unspecified)but ongoing ECP with the addition of interferon alfa in there was not been a uniform response in the two individual patients with SS.The only prospec- patients with SS Interferon in combi- tive study comparing interferon alfa alone with nation with retinoids (isotretinoin, etretinate, bex- combination interferon alfa/ECP in various stages arotene) has been noted to be effective in late-stage of MF/SS, however, failed to show any improvement but, to our knowledge, there are no J AM ACAD DERMATOL VOLUME 64, NUMBER 2 monotherraising the question of whether generally mild and does not generally require dose there is truly an additive or synergistic effect of adjustment. Myelosuppression is also common with combination ECP and interferon alfa and calling for the nadir at 1 to 3 weeks for leukocytes and 4 weeks a prospective randomized clinical trial to address for platelets but absolute neutropenia is rare and Positive results have been reported in patients changes do not usually require intervention other with SS treated with multimodality immunomodu- than dose reduction. All changes are reversible off latory therapy with interferon alfa 3 to 9 MU tiw drug. There are no long range cumulative dose (maximum tolerated dose), ECP on 2 consecutive effects and no increased incidence of second malig- days every 2 to 4 weeks, PUVA tiw, and topical nancies with interferon alfa so that long-term treat- steroids with a RR of 42% (5 of 12) including a CR in ment is reasonable.
It is of value to highlight the results of a large single-site trial of interferon alfa and methotrexate (MTX) that included patients with SS but did not Recombinant interferon gamma-1b (Actimmune) selectively present their results and thus are not is a type 2 interferon that acts as a biological response presented in Aviles et altreated 158 modifierSimilar to type 1 interferons, IFN-g plays patients with stage IIB to IVA MF/SS with MTX 10 an important role in immunoregulation. It is cur- mg/m2 twice a week (biw) plus interferon alfa-2a rently FDA approved for chronic granulomatous 9 MU tiw 3 6 months: those with PR continued for disease and osteopetrosis but its use in CTCL was another 6 months on interferon and MTX and those first reported in 1990.In CTCL, IFN-g enhances with a CR at 6 or 12 months continued only on cell-mediated cytotoxicity of CD81 T cells and NK interferon. The results were impressive: 49% CR at 6 cells, primes DCs, inhibits tumor cell proliferation months and 49% additional CR at 12 months for a and Th2 cytokine production, and inhibits Tregs.
total of 74% CR. Mean duration of response (MDR) Unlike interferon alfa, publications of the use of was not given but the 10-year estimated survival was interferon gamma in CTCL and SS are extremely 69%. Toxicity was mild, grade 1 in most cases, and limited. Kaplan et alreported 16 patients with CTCL only 3 of 158 patients had any hepatic enzyme and stage IB to IVB treated with interferon gamma elevations (all mild). This paucity of adverse effects with a RR in 31% of patients including one of two was all the more unusual given both the relatively with SS Publications citing the use of high dose of interferon and MTX and no folic or interferon gamma in combination with other bio- folinic acid given in conjunction with the latter. All logic response modifiers is shown in publications using interferon alfa in combination Shapiro et alreported a patient with SS who had with other therapies for the treatment of SS are progressive disease on interferon gamma and ECP who went on to a durable CR with the addition of Acute side effects of interferon alfa include fever, bexarotene and PUVA. McGinnis et also showed chills, myalgias, and headache that usually dissipate a long-lasting clearing of disease in a patient with SS over the first week of therapy and are minimized by treated with a combination of interferon gamma, pretreatment with acetaminophen. The common ECP, and bexarotene. More recently, adenovirus- chronic side effects seen with interferon alfa include mediated intralesional interferon gamma gene trans- fatigue, anorexia, weight loss (generally 5-10 lb), fer in CTCL and cutaneous B-cell lymphoma was depression, or change in cognitive fuThe studied in phase I and II clinical Three latter is generally more severe in the elderly. The patients with MF and two with SS were treated in a adverse effects are generally dose related and may dose escalation trial of 3 3 109 to 3 3 1011 intramus- decrease over time. Thyroid dysfunction, primarily cularly 3/4 weeks per monthly cycle: two of 3 hypothyroidism, may develop in up to 20% of patients with MF had a response in the lesion treated patients receiving interferon alfa and may be the but neither of the patients with SS responded.
cause of some of the fatigue, especially if it escalates Shimauchi et altreated 12 patients with MF (4 during therapy. Cardiac toxicity has been reported with erythroderma, rest with plaque disease) with with higher doses of interferon alfa than generally interferon gamma e0.25 to 0.5 MU qd 5/7 days per used for CTCL but patients with a history of coronary week 3 1 to 4 weeks in conjunction with narrow- artery disease, especially those with any recent acute band UVB (NBUVB) tiw. All but one patient was a events, should be carefully monitored. Less com- responder and 4 of 12 (25%) had a CR. There was no mon effects include loose stools, peripheral neu- information on median response duration (MRD).
ropathy, and altered (metallic) taste. An increase in Clinical responses to interferon gamma have been liver function test results is very common but is observed in interferon alfa nonresponders.
J AM ACAD DERMATOL Adverse effects of interferon gamma are similar to OR (including 2% [one of 56] with a CR) compared those observed for interferon alfa but are notably with 55% (21 of 38) OR in those patients begun on milder: low-grade fever, flu-like symptoms, head- more than 300 mg/m2/d (including 13% [5 of 38] CR).
ache, myalgias, fatigue, nausea, weight loss, cogni- There was a RR of 24% (4 of 17) in those with SS. The tive effects, dose-dependent cytopenia (usually St Johns Hospital group in London, England reported neutropenia), hepatic transaminitis, nonscarring on 28 patients with stage IB or higher MF/SS who alopecia, and less commonly, triggering of autoim- were treated with bexarotene monotherapy 150 to mune phenomenon (eg, thyroiditis, hepatitis, ne- 300 mg/m2/d escalating to 300 mg/m2/d: the RR was phritis, psoriasis). An urticarial reaction to interferon 46% (13/28) including 14% (4/28) CR and was gamma has been documElderly patients highest in those with The patients with SS appear to tolerate interferon gamma better than treated with bexarotene monotherapy are reported interferon alfa in terms of cognitive effects (depres- sion, confusion). Two of the authors (E. Kim, MD, Tsirigotis et noted a 100% RR in 3 patients and A. Rook, MD, unpublished data) have noted lot- with MF and two with SS treated with a combination to-lot variation in regard to the adverse effect of fever of ECP and bexarotene, and Rankinoted a PR in seen with interferon gamma: it is possible that some one patient with SS treated with a combination of lots may contain higher levels of endotoxin after the interferon alfa and bexarotene. Richardson et production process.
noted an 89% RR rate in 28 patients treated with ECP,interferon alfa, andein 24 of 28 casesebexarotene.
McGinnis et altreated two patients with SS with a Bexarotene (Targretin). Bexarotene is a novel combination of ECP, interferon gamma, bexarotene, synthetic rexinoid that binds selectively to the reti- and PUVA with resulting one CR and one PR. They noid X receptor (RXR) isoforms (RXR a, b, and g).
also reported on two patients with SS treated with a The RXRs form heterodimers with various other combination of ECP, interferon alfa-2b, and bexar- nuclear hormone receptors including retinoic acid otene who went on to a CR (A. Rook, MD, unpub- (RA) receptors (RARs), the vitamin-D receptor, thy- lished data) and one patient with SS treated with a roid hormone receptor, peroxisome proliferator ac- combination of interferon gamma, ECP, and bexar- tivator receptor, liver X receptor, and farsenoid otene who went onto a CR only on the addition of X receptor, which in turn act as ligand-inducing PUVA, highlighting again the efficacy of PUVA in transcription regulatory facRetinoids have MF/SS, even in systemic disease. Although there are been shown to affect the malignant cells by inhibi- several case reports of patients with all stages of MF tion of tumor cell proliferation, promotion to termi- who have had an OR to a combination of bexarotene nal differentiation, and induction of ap and PUVA,there are no reports to date of Bexarotene may also work through the down- efficacy in SS. There have been several reports, regulation of Th2 cytokines,by inhibiting malig- primarily in patients with SS, of acute worsening or nant cell trafficking to the skin through an ability more aggressive disease (large cell transformation, to suppress CCR4 expression among malignant extracutaneous disease, CD81 lymphoma) after lymphocor through down-regulation of E- starting bexarotene: the causality is not clear in these selectin on endothelial cells, thus causing the en- cases.Also noted has been an im- trapment of cutaneous homing T lymphocytes in the provement in the skin with bexarotene treatment circulThe exact mechanism of action in while either no change or worsening of the blood CTCL is unknown. Bexarotene was FDA approved in tumor burden has occurred.Publications 1999 as 75-mg soft gelatin capsules for the treatment of refractory CTCL. It is highly protein bound, elim- therapies in the treatment of SS are shown in inated primarily through the hepatobiliary system, and appears to be metabolized to oxidative forms by The two most common side effects of bexarotene the cytochrome p450 3A4 isozyme, the latter of include hyperlipidemia and central (secondary) hy- which could lead to an increase or decrease in blood pothyroidism.In patients taking 300 mg/m2/d or levels of bexarotene when taken with other drugs more of bexarotene, 60% developed cholesterol that are inhibitors or inducers of CyP 4503A, more than 300 mg/dL and 70% developed more than 2.5 times the normal level of triglycerides Bexarotene has been studied in late-stage CTCL in including 55% with triglycerides over 800 mg/dL.
a large multicenter phase II to III triaOf 94 Central hypothyroidism occurred in ;40% of pa- patients with stage IIB or higher MF/SS, 45% (25 of tients during the clinical trials but is observed in 56) of those patients begun on 300 mg/m2/d had an nearly all patients in clinical practice. Expectant J AM ACAD DERMATOL VOLUME 64, NUMBER 2 treatment for these two side effects is necessary and erythroderma with 1 to 3 mg/kg/d of isotretinoin treatment with antilipid agents 6 thyroid supple- with an OR in all. Kessler et altreated an additional ments begun before or concomitant with bexarotene 25 patients with MF, 7 whom had erythroderma and is necessary in most cases with close monitoring and 5 with more than 5% SC but no documented SS, with adjustment of doses of ancillary drugs over the first 4 isotretinoin 1 to 2 mg/kg/d: there was a 44% OR to 8 months of treatment. Certain antilipid agents including 4 of 7 with erythroderma. Three of the (atorvastatin or fenofibrate) are preferable: gemfi- 25 had a CR (stage unspecified) and MRD was greater brozil is to be avoided secondary to increased levels than 8 (1-25) months. The Scandinavian Mycosis of bexarotene and thus triglycerides. Dose-related Fungoides Group treated at least 39 patients leukopenia occurs in more than 10% of patients and with isotretinoin (reported in two different publica- neutropenia can be dose limiting. Other side effects tions)the OR in MF/SS to isotretinoin 0.2 to 2 include fatigue, asthenia, headache, anemia, nausea, mg/kg/d was 59% including one of 5 SS (blood peripheral edema, photosensitivity, diarrhea, dry involvement not noteBecause of the uncer- skin, and rash. Hypoglycemia has been noted espe- tainty of the definition of SS used in reports, the cially in patients on insulin-secreting medications or efficacy of isotretinoin in SS is unknown.
insulin sensitizers. Infections are uncommon with Common side effects of isotretinoin include bexarotene. All retinoids are pregnancy category X dry skin, cheilitis, dry eyes, arthralgias, myalgias, and women of childbearing potential must use two elevated liver function test results, and mild alope- effective methods of contraception for a month cia.Elevation of triglycerides is common (gener- before, during, and 1 month after discontinuation ally mild but marked elevations have been reported) of drug. Male patients should use condoms during and lipids must be monitored during therapy.
sexual intercourse while on bexarotene and for Pseudotumor cerebri; mood changes, especially de- 1 month after stopping the drug.
pression; changes in bones (including diffuse idio- RAR retinoids. The retinoids isotretinoin, etret- pathic skeletal hyperostosis); hearing problems; and inate, acitretin, and all-trans-RA (ATRA) all work decrease in night vision have been reported. As with through transcriptional changes induced in the all retinoids, the use of isotretinoin is contraindicated RARs.The RARs, including the isozymes RAR a-1 in pregnancy. Women of childbearing potential and and -2, b-1 to -4, and g-1 and -2, form heterodimers men with sexual partners of childbearing potential with each other and with RXRs: these bind to RA are mandated to take special contraceptive precau- response elements in the cell nuclei, which in turn tions including monthly pregnancy tests for women bind to DNA and interact with other transcription at risk of pregnancy.
RARs do not bind to the other nuclear Etretinate (Tegison) and Acitretin (Soriatane).
hormone receptors as does bexarotene and their Etretinate was FDA approved for the treatment of side-effect profile is, not surprisingly, different from psoriasis and was also used in several pre- that of bexarotene. RAR retinoids can induce IFN-g, bexarotene trials of MF/SS. It was withdrawn from partially through IL-12, which may produce a shift the market in 1998 but its metabolite, acitretin, was from a Th2 to Th1 cell predominance, up-regulate approved in its place, again for psoriasis. Etretinate Langerhans cell antigen presentation and surface was replaced by acitretin because of its long half-life, expression of HLA-DR and CD11 involved in T-cell protracted tissue storage time, and thus prolonged activation, and enhance cytotoxic activity of NK risk of teratogenicity in women. After oral absorp- cells.RAR retinoids have antiproliferative, tion, which is increased with food, acitretin is antiangiogenic, and immunomodulatory effects and interconverted to its 13-cis form (cis-acitretin) and modulate cellular differentiation.
both further metabolized to short chain conjugates Isotretinoin (Amnesteem, Claravis, Sotret). Iso- and breakdown products that are eliminated in the tretinoin (13-cis-RA) was the first retinoid used in feces and urine. The terminal elimination half-life of MF/SS: it is FDA approved for the indication of acitretin is 49 hours. When taken with alcohol, severe recalcitrant nodular acne. Its absorption is acitretin undergoes transesterifcation to etretinate.
increased with food or milk and it is metabolized to Etretinate has shown efficacy as monother- both RA, with which it is reversibly interconverted, in the treatment of MF and SS. Claudy and oxidized forms. Terminal elimination half-life is et alused etretinate 0.8 to 1 mg/kg/d to treat 21 hours with excretion in the urine and feces.
6 patients with MF (3 with erythroderma, one with Isotretinoin has shown efficacy as monother- SS, one with extensive plaque, one with tumors apyin both tumor- and plaque-stage MF at and blood involvement [[10% SCs]). Five of the doses of ;1 to 3 mg/kg/d. Kessler et altreated 6 patients clinically ‘‘cleared'' including the one 4 patients with MF and either extensive plaque or patient with SS but there was no histologic clearance J AM ACAD DERMATOL in the skin. Molin et alreported on 7 patients with decrease seen in plasma levels with chronic dosing.
advanced disease (5 tumor-stage MF, one with nodal Of note, ATRA blood levels have been shown to be disease, and one SS) who were treated with etreti- higher with concomitant interferon alfa dosing than nate 0.2 to 1 mg/kg/d: there was an OR in 4 of ATRA monotherapy.
7 patients with MF but no response in the patient The biologic effects of ATRA were reported in with SS. When they compared all stages of patients 33 patients with MF/SS (12 stage IB or IIA and 21 stage with MF/SS treated with either etretinate (n = 29) or IIB-IVA) with an overall RR of 12% including one of isotretinoin (n = 39), there was no significant differ- 33 Seventeen of these patients had SS by T4B1 ence in overall RR (66% vs 59%, respectively) be- Mycosis Fungoides Cooperative Group with tween the two retinoids.Acitretin has also shown 24% OR including one of 17 CR (C. Querfeld, MD, usefulness in all stages of MF as monotherapy.
unpublished data). The MRD is unknown.
Mahrle et saw a response in 3 of 4 patients with Common reported adverse effects of ATRA in- MF treated with acitretin but not in the patient clude dry skin and mucous membranes, and consti- identified as having SS (no information on blood tutional symptoms such as fatigue, arthralgias, and involvement given). As with other retinoids, acitretin myalgias that often require dose reduction.
has been shown to be less effective than interferon Irritability and mild to moderate headaches including alfa when used in combination with PUVA to those secondary to pseudotumor cerebri have also treat patients with MF.Since the approval of been seen with ATRA. The most common laboratory bexarotene for MF, there have been few additional changes are reversible, dose-dependant, asymptom- studies using these RAR retinoids in MF/SS.
atic hypertriglyceridemia and elevated liver function Common side effects of etretinate/acitretin in- test findings. In patients with acute promyelocytic clude elevated liver function test results, increase in leukemia (APL), but so far not in patients with MF, an serum lipids (especially triglycerides), dry eyes, dry RA-APL syndrome characterized by fever, pulmonary skin, cheilitis, alopecia, nail abnormalities including infiltrates, and potential multiorgan failure has been paronychia, ‘‘sticky skin,'' arthralgias, and hyperos- seen in as many as 25% of patients.As with other tosis. As with all retinoids, the use of acitretin is retinoids, ATRA is a teratogen and precautions to contraindicated in pregnancy. Women of childbear- prevent pregnancy in women of childbearing ing potential and men with sexual partners of child- potential should be undertaken.
bearing potential are mandated to take specialcontraceptive precautions during and for 3 years Denileukin diftitox after therapy for the women at risk.
Denileukin diftitox is a recombinant DNA-derived ATRA (Vesanoid). The natural retinoids such as fusion protein containing the peptide sequences for ATRA (tretinoin) and its isomers 9-cis-RA (alitreti- the enzymatic activity and membrane translocatory noin) and 13-cis-RA (isotretinoin) are nonselective domains of diphtheria toxin followed by sequences agonists.Although ATRA binds only with RAR, from human IL-2. The drug brings the cytocidal and 9-cis-RA binds with both RAR and RXR, all action of diphtheria toxin to cells with expression of 3 ligands activate RAR and RXR as a result of the medium and high affinity IL-2 receptors isomerization. ATRA is a natural retinol metabolite (CD122/132 and CD25/122/132). After interaction formed by enterocytes from B-carotene and from with the receptor, the drug is internalized, the toxin is tissue metabolism of vitamin A (retinol) and retinal- released to the cytosol after cleavage in the endo- dehyde in an enzymatic process that requires some and inhibition of protein synthesis (via aden- osine diphosphate ribosylation of elongation factor Cytochrome P450 enzymes have been implicated in 2) leads to the cell's death.Denileukin diftitox is the oxidative metabolism. Its metabolites include approved for the treatment of CD251 CTCL.
13-cis-RA, 4-oxo-trans-RA, 4-oxo-trans-RA glucuro- In a multicenter phase I dose escalation trial of nide, and 4-oxo-cis-RA. The in vitro biologic action 35 patients with CTCL (30 with MF, 4 with large cell of ATRA includes induction of apoptosis, induction CTCL, and one with T-cell lymphoma not otherwise of IFN-g, and IL-12 production and enhancement of specified), denileukin diftitox 6 to 31 g/kg/d was cell-mediated immunity.ATRA is FDA approved given in a 5- to 15-minute intravenous (IV) infusion for acute promyelocytic leukemia as a 10-mg capsule repeated every 3 weeksThe overall RR for stages I formulated in an oil suspension with absorption to IV was 37% (14% CR, 23% PR) with a lower OR in primarily through the portal route. ATRA is rapidly advanced-stage patients (2/7 [29%] stage III and 0/10 metabolized to a variety of oxidized or conjugated stage IV): no patients with SS were specifically metabolites and does not accumulate in any tissue.
reported. In the phase III multicenter study of 71 The terminal half-life is under 1 hour with a gradual patients with MF/SS where the dose of denileukin J AM ACAD DERMATOL VOLUME 64, NUMBER 2 diftitox was randomized to 9 or 18 g/kg/d 3 5 days symptoms including nausea, vomiting, and/or diar- repeated every 3 weeks, there was an overall 10% CR rhea. Delayed toxicities include a vascular leak and 20% There was also a higher RR in those syndrome (hypoalbuminemia and/or edema and with early (stage IB-IIA) compared with advanced orthostatic hypotension) that occurs in up to 25% (stage $ IIB) disease (RR of 43% vs 10%) treated with of patients, transient transaminase elevation and the lower 9-g/kg/d dose of denileukin diftitox but lymphopenia, rash, thromboses, rarely hyperthy- increased RR in advanced disease with the 18- roidism, possible elevated risk of infection,and g/kg/d dose (RR of 33% in stage IB-IIA and 38% uncommon visual impairmentThere is a de- RR in $ stage IIB). Although there were patients in creased incidence of side effects, especially dyspnea this study who had erythrodermic (T4) skin disease and edema, seen with steroid premedication.It is and blood involvement as defined by more than 20% advised that the infusion of the drug should be CD41/CD7e peripheral blood cells, patients with SS undertaken over 60 minutes to minimize infusion were not specifically identified or noted among the reactions. Consideration should be given to treating responders. In a phase III multicenter placebo- severe edema associated with severe hypoalbumi- controlled study of 144 patients with MF/SS stage nemia with albumin replacement.
IA to III (using TNM staging system) where the doseof denileukin diftitox was randomized to 9 or 18 g/kg/d 3 5 days repeated every 3 weeks, there was ECP is an apheresis procedure that targets the a CR/OR rate of 9.1%/49.1%, 11.1%/37.8%, and circulating malignant clone in patients with CTCL.
2.3%/15.9% for the 18-g/kg/d dose of denileukin The procedure currently performed uses liquid 8-me- diftitox versus 9-g/kg/d dose of denileukin diftitox thoxypsoralen injected directly into a collection bag versus placebo, respecPatients with SS containing an enriched white blood cell (WBC) were not specifically identified or results reported fraction. After photoactivation of the WBC fraction in this publication.
with UVA energy, all treated and untreated blood Higher RRs were noted in trials where corticoste- products are returned to the patient. Patients with MF roids were used as premedication: as these were the or SS are usually treated on two consecutive days at 4- only studies where patients with SS were specifically week intervals. The immunomodulatory mechanism noted, they are listed in The phase I underlying patient responses to ECP is still unfolding.
dose escalation trial of denileukin diftitox reported However, evidence currently supports the following by Chin and Fosused 4 to 9 g/kg/d 3 5 days the two simultaneous and synergistic processes occurring first cycle then escalated to 18 to 27 g/kg/d there- during ECP: induction of apoptosis in malignant T after along with premedication with Decadron 8 mg.
cells and a conversion of blood monocytes to DCs.
The 29 patients with advanced-stage MF ( $ IIB) had Together these processes induce an immune re- a RR of 48% compared with 63% of patients with sponse against the malignant clon earlier disease stages. Foss et alreported on a Efficacy in treating certain clinical stages (IB, IIA, retrospective review of 7 patients with MF and 8 with III, and IVA) and skin stages (patch/plaque [T2] and SS (T4 skin disease plus circulating CD41/CD7e erythroderma [T4]) of MF and SS with ECP is favorable, lymphocytes) treated at two institutions with 9 or although randomized trials comparing ECP with other 18 g/kg/d denileukin diftitox for the first cycle then standard therapies are neeThe overall RR 18 g/kg/d in subsequent cycles plus either 20 mg for ECP monotherapy has ranged from 36% in an prednisone or 8 mg Decadron with each infusion. An intention-to-treat analysto 10%, 17%, 50%, 80%, OR was seen in 5 of 7 (71%) patients with MF and 4 of and 83% in those patients with MF/SS who have been 8 (50%) patients with SS. The combination of on ECP for at least 3 months.Edelson denileukin diftitox 18 g/kg/d and Decadron 8 mg et alreported a response ( $ 25%) in 83% (24 of 3 3 days every 21 days along with cohort escalations 29) of patients with E-MF (blood involvement not of bexarotene from 75 to 300 mg every day was used given). Those studies in which SS has been clearly to treat 14 patients with MF stages I to IVA with a RR defined and an OR defined as at least 50% clearing are of 67% (4/14 CR, 4/14 No patient with SS was shown in However, there are identified in the latter study.
notable publications where response in patients with Acute side effects of denileukin diftitox include SS to ECP (given as 2 consecutive days monthly) is hypersensitivity reactions such as dyspnea, chest defined only as at least 25% clearing. Not surprisingly, tightness, hypotension, chills, fever, pruritus, flush- the RR is higher in these cases: de Misa et al ing, rash, tachycardia, dysphagia, and/or back pain; reported on 60% response in the skin in 10 patients a flu-like reaction characterized by fever, asthenia, with SS (defined as T 1 [ 5% peripheral blood SC 1 myalgia, and/or arthralgia; and gastrointestinal (GI) clonal involvement) and Evans et noted a J AM ACAD DERMATOL response in skin in 57% of patients with SS (defined reduced to 3 MU qd 3 9 months (9 patients) versus stringently as T4, $ 10% peripheral blood SC, and interferon alone (11 patients): there was RR of 22% clonality TCR gene rearrangement). Duvic et (two of 9 PR) on the combination arm versus 36% (4 of used an accelerated protocol for ECP (9 vs 6 cycle 11 with one CR [the lone patient with SS] and 3 PRs) on collection and increased frequency from the standard the interferon alone arm (E. Olsen, MD, unpublished two treatments per month in the case of nonre- data). The effect of ECP has not appeared to add sponders) and noted inclusion of 20 of 34 patients additional value when given with chemotherapy: with peripheral blood SCs (not specifically SS) with an there was a PR in 4 of 10 patients with stage IIA to OR in 50% of all patients including a CR in 18%.
IV (no CR) to a combination of standard ECP plus A recent consensus statement from the United various chemotherapeutic agents (chlorambucil, Kingdom recommends that all patients with erythro- MTX, combination chemotherapy, doses and dosing dermic CTCL, either stage III or IVA (major criteria), regiments not specified).Whether ECP would be of who have one or more minor criteria of a peripheral value after a remission from chemotherapy induction blood T-cell clone, more than 10% SCs, and/or remains to be determined.
CD4/CD8 ratio higher than 10 should be considered ECP is well tolerated with few complications or for ECP therapThere are data to suggest that adverse effects.Uncommon adverse reactions are response is better in those who have not been usually vascular related and include the following: immunosuppressed by chemotherapy (A. Rook, fluid-responsive hypotension, venipuncture-site he- MD, unpublished data) and among those who have matomas, rare exacerbation of congestive heart fail- a lower blood tumor buror the absence ure or arrhythmias, superficial thrombophlebitis, of bone-marrow involvement.There is also catheter-related sepsis, rare herpes infections, and evidence to show a potential disconnect between rare disseminated fungal infection clearance of disease in the skin and bloFraser-Andrews et have questioned whether there is an CHEMOTHERAPEUTIC AGENTS increase in survival with ECP monotherapy.
A majority of reports of patients with MF and SS MTX works by blocking cell division in the S treated with ECP have, however, included the use of phase. It inhibits dihydrofolate reductase that con- adjuvant therapy verts dihydrofolate to tetrahydrofolate, which is especially interferon alfa, and the RRs have in general required for synthesis of thymidylate and purine been higher with the combination versus monother- nucleotides involved in DNA and RNA synthesis. It apy. A combined analysis of more than 400 patients also inhibits thymidylate synthetase. In addition, treated with ECP and adjunctive therapies showed an MTX has anti-inflammatory effects. It inhibits methi- overall RR for all stages of CTCL of 55.7% (244 of 438) onine synthetase and aminoimidocarboxyamido- with 17.6% (77 of 438) achieving a CR.Duvic et ribonucleotide transformylase thereby reducing reported a 40% OR in patients with stage III to IV S-adenyl methionine and increasing adenosine.
MF/SS treated with at least 6 cycles of ECP therapy The reported RR of low-dose MTX (defined as alone versus 57% OR in those treated in combination doses 100 mg/wk) in MF/SS ranges from 9 of with interferon alfa, bexarotene, or granulocyte mon- 16 ‘‘definite improvement'' in the first report using ocyte colony-stimulating factor. Arulogun et 2.5- to 10-mg dose to reports by Zackheim performed a retrospective review of patients with SS et of RR of 58% (17 of 29) in patients with E-MF (defined as at least two of the following: [5% SCs, to 33% (20 of 60) in patients with plaque-stage MF CD4/CD8 $ 10, and/or clonal TCR gene rearrange- given median weekly doses of 25 mg. Winkelmann ment) treated with ECP 2 times per week for the first et did not note a response in the 4 patients with week, weekly 3 6 weeks, every 2 weeks for 6 weeks, SS he treated with MTX (regimen not specified). The then monthly in combination with various systemic RR to high-dose MTX (60-240 mg/m2 IV) with therapies (steroid, MTX, interferon alfa, bexarotene) leucovorin rescue as reported by McDonald and in 10 of 13 patients versus 3 of 13 patients treated with Bertino,however, is impressive with more than monotherapy ECP. There were 7 of 10 responders in 80% clearing in 9 of 11 patients, the majority with those treated with combination therapy versus 1 of 3 lymphadenopathy, and including 7 of 11 with a CR.
treated with ECP alone. There has only been one An overall RR to single-agent MTX in SS is difficult to prospective randomized trial of ECP in combination estimate because of the small number of well- with interferon alfa-2a versus interferon alone.
documented cases reported.
Twenty patients with MF/SS stages IA to IVB were There are also studies using MTX in combination treated with either ECP two consecutive treatments with another agent for SS ).A small monthly plus interferon alfa-2a 18 MU qd 3 3 months study of IV MTX 60 mg/m2 over a 24-hour infusion J AM ACAD DERMATOL VOLUME 64, NUMBER 2 followed by 5-fluorouracil 20 mg/kg over 36 to 48 it is first dephophosphorylated to 2-fluoroadenine hours with leucovorin rescue showed at least 80% arabinoside triphosphate, which on intracellular dif- clearing in both of two patients with SS and one of fusion is phosphorylated by deoxycytidine kinase two patients with E-MFAnother study of low- (dCykThe accumulation of 2-fluoroadenine ara- dose oral MTX 10 mg/m2 twice weekly and inter- binoside triphosphate curtails DNA synthesis through feron alfa 9 MU SQ tiw was performed among inhibition of ribonucleotide reductase and DNA patients with refractory MF/SS. There were 89 of polymerase alpha. Fludarabine may be particularly 158 stage III cases (unknown how many were SS vs useful in T-cell malignancies because of its apoptotic E-MF) plus 33 of 158 stage IVB, some with T4 skin (probably including All other cases were stage Fludarabine is FDA approved for the treatment of IIB yet overall CR was 74% by 1 year with 10-year chronic lymphocytic leukemia (CLL).
survival of 70%. Hirayama et alreported on a Reports of fludarabine monotherapy in CTCL are single patient with SS who had a durable ([4 year) few: those in SS are shown in Redman PR to combination therapy with low-dose MTX et aldescribed 5 patients with MF (not otherwise 10 mg/wk and etoposide 25 mg/d.
specified) who were treated with 25 mg/m2 fludar- There is a recent study of a MTX-related com- abine 3 5 days every 3 to 4 weeks: there were two of pound in which 15 MF/SS cases (the majority with 5 responders. Von Hoff et alrandomized 33 pa- large cell transformation) were aggregated and tients with MF (SS unknown) to treatment with either showed a 47% RR to IV trimetrexate (200 mg/m2 25 mg/m2 (treatment naive group) or 18 mg/m2 biweekly).Horwitz et alreported on the phase I (prior systemic or radiation therapy) of fludarabine results of pralatrexate, another antifolate analog, daily 3 5 days every 28 days. Of the 31 evaluable used in 20 to 30 mg/m2 doses 3 2 of 3 weeks or patients who averaged over 46 courses of treatment, 3 of 4 weeks to treat 11 patients with MF/SS. There there was a 19% RR including one CR. Quaglino was an OR of 45% including two of 11 CR. MRD and et altreated 27 patients with MF and 17 patients specifics regarding patients with SS were not noted.
with SS with fludarabine alone at the above dose Potential side effects of MTX include GI (nausea, with a RR of 30% including a CR of 9% in the patients vomiting, stomatitis, diarrhea, ulcers), bone marrow with MF and 35% RR including 18% (3/17) CR in those with SS. Other significant untoward effects of (increased transaminases, hepatitis, fibrosis, cirrho- fludarabine are prolonged T-cell dysfunction and the sis, the latter two cumulative dose related), lung potential to introduce secondary neoplasia.
Combination therapy has yielded only slightly abortifacient), and miscellaneous (alopecia, photo- better results (Foss et altreated 35 sensitivity reactivation sunburn, radiation recall, patients with CTCLe24 with MF and 11 with SS oligospermia, anaphylaxis).MTX-induced lym- (T4 plus peripheral SCs)ewith fludarabine 25 mg/m2 phoproliferative disorders have been reported 3 5 days every 28 days along with interferon alfa at including in one patient with Toxicity of MTX 5 to 7.5 MU SQ tiw. CR was seen in 4 of 35 (11%) can be enhanced by drug interactions with other including 3 of 11 patients with SS and 3 of 4 of the folate antagonists (trimethoprim, sulfonamides, dap- CRs were maintained more than 18 months.
sone), hepatotoxins (ethanol, retinoids), conditions Scarisbrick et treated 8 patients with SS (defined that result in elevated blood levels (reduced renal as erythroderma with [10% abnormal circulating excretion and displacement from protein binding), lymphocytes and TCR gene rearrangement clone) or underlying liver disease including metabolic syn- with fludarabine 18 mg/m2 and Cytoxan 250 mg/m2 drome. Oral folic acid supplementation (1-5 mg 3 3 days every month for 3 to 6 months. There was a daily) combats GI symptalthough questions response in 4 of 8 patients with SS including one CR have been raised whether dose or dosing of folic acid but no clear improvement in survival. Publications affects efficacyLeucovorin (folinic acid) rescue is using fludarabine in combination with other thera- used to rescue normal tissue, especially that of the pies in the treatment of SS are shown in .
kidney, when high-dose MTX is used or to counter- Potential side effects of fludarabine include mye- act acute toxicity regardless of dose.
losuppression especially neutropenia and its atten-dant risk of infection, which is generally moderate Purine analogs (fludarabine monophosphate, and reversible; GI symptoms of nausea, vomiting, and diarrhea; infrequent somnolence and fatigue; prolonged T-cell dysfunction; the potential to induce Fludarabine. Fludarabine is a fluorinated ade- secondary neoplasia; and uncommon pulmonary nine nucleoside resistant to deamination. On infusion, Severe neurotoxicity has been seen J AM ACAD DERMATOL with the use of much higher doses of fludarabine hours, much longer in those with renal impairment, than those used to treat CTCL but has been reported with ;90% of the drug excreted in the urinDCF is sporadically at lower levels.
FDA approved as an IV formulation for the treatment 2-Chlorodeoxyadenosine (cladribine). 2-Ch- of hairy cell leukemia.
lorodeoxyadenosine (CDA) is a nucleoside analog DCF has demonstrated clinical activity in all stages that accumulates in the cell as a result of its resistance of CTCL. In an early phase I study of 4 patients with to adenosine deaminase and its phosphorylation by plaque and tumor stage, one patient received 4 dCyk to 2-CDA-triphosphate. The high activity of this mg/m2/d, two received 8 mg/m2/d, and one re- kinase in lymphocytes ensures accumulation of ceived 10 mg/m2/d of DCF for 3 days repeated every toxic concentrations of the drug in these cells. It 28 days.Two of the patients (8 mg/m) achieved a is postulated that 2-CDA-triphosphate inhibits ribo- CR that lasted for 7 to 9 months. The remaining two nucleotide reductase and DNA polymerase leading to patients achieved a PR that lasted 4 to 9 months.
accumulation of deoxynucleotides and DNA strand Three of the 4 patients achieved 100% inhibition of breaks that interfere with DNA repair and accelerate adenosine deaminase. Tsimberidou et alpre- apoptos2-CDA is available in IV form and sented the M.D. Anderson Cancer Center (Houston, approved for the indication of hairy cell leukemia.
TX) experience with 32 patients with stage IIB to IV 2-CDA has shown efficacy in MF and SS with MF/SS who were treated with DCF 5 mg/m2 3 3 days various dosing regimens. O'Brien et alin 1994 every 3 weeks: there was a 31% RR with two of 32 reported on one of 8 patients with MF who had a CR CRs. The Eastern Cooperative Oncology Group with daily infusions of 4 mg/m2 2-CDA 3 7 days presented 4 of 8 patients with CTCL and a global repeated every 28 days. Trautinger et reported PR to the same dosing regimen, with at least one on 8 patients with MF who were treated with low- patient having a response that lasted 1.6 years.
dose 2-CDA 0.06 mg/kg/d for 5 days every 4 weeks: Greiner et altreated 18 patients with MF/SS with there was a PR in two of 8 patients but none among one of 3 dosing regimens of DCF for a median of those with erythroderma. Kong et alpresented the 5 courses of treatment: 4 mg/m2/wk (one patient), Northwestern experience of 24 patients with MF/SS 5 mg/m2 3 3 days every month (3 patients), or 4 (80% $ stage IIB) who were treated with 2-CDA 0.1 mg/m2 every week (14 patients). There was an OR mg/kg/d by continuous infusion over 5 to 7 days rate of 39% with two of 18 CR and 5 of 18 PR and a every 28 days. The RR was 24% with 3 of 24 CR and disease-free survival of 1.5 to 6 months in the patients 3 of 24 PR. OR has been seen in 0% to 50% of the with PR and 4 and 76 months in the patients with CR.
13 reported patients with SSthose patients The response specifically of patients with SS to who have documented T4B2 status are shown in monotherapy with DCF is given in A phase II EORTC trial of DCF was conducted at Side effects of 2-CDA are primarily myelosuppres- 92 centers and included 22 patients with MF and sion, especially effecting neutrophils and platelets, 21 patients with Patients received 4 mg/m2 of and a protracted lymphopenia with a marked de- DCF weekly for 3 weeks then every other week for crease in the CD4/CD8 ratio that lasts 6 to 9 months 6 weeks followed by maintenance treatment with posttreatment.Related to this immunosuppres- 4 mg/m2 monthly for 6 months. There was a 33% RR sion is a high risk of infection. Neurotoxicity is much in the patients with SS (one CR and 6 PRs) and a 23% less common at lower doses and hepatic or renal RR in the patients with MF (5/22 PR, no CR). A dose- toxicity is unusual. Mild nausea and fever may occur.
adapted regimen of DCF was explored by Kurzrock Deoxycoformycin (pentostatin). Deoxycofor- et alin 27 patients with CTCL including 14 patients mycin (DCF) is a potent inhibitor of adenosine with SS (not otherwise defined) and 6 patients with deaminase.DCF blocks the deamination of aden- tumor-stage MF. The starting dose was 5 mg/m2/d for osine to inosine and deoxyadenosine to deoxyino- 3 days every 3 weeks and was increased or decreased sine, resulting in an accumulation of intracellular by 1.25 mg/m2/d on subsequent courses based on deoxyadenosine and deoxyadenosine triphosphate.
toxicity. Patients with SS had an overall RR of 71% These metabolites block DNA synthesis through the (4/14 CR, 6/14 PR) whereas the RR in MF was 66% inhibition of ribonucleotide reductase and are espe- (1/6 CR and 3/6 PR).
cially toxic to lymphocytes. Deoxyadenosine also A combination study of DCF with intermittent inactivates 5-adenylhomocysteine hydrolase in blood high-dose interferon alfa was conducted in 41 pa- cells of DCF-treated patients leading to accumulation tients with advanced or refractory MF/SS.DCF of S-adenosylhomocysteine, an inhibitor of many 4 mg/m2/d for 3 days every 42 days was given along transmethylation reactions.The mean terminal with interferon at a dose of 10 MU on day 22 and elimination half-life after IV infusion of DCF is 5.7 50 MU on days 23 to 26 for at least two cycles. The J AM ACAD DERMATOL VOLUME 64, NUMBER 2 overall RR was 41% with two of 41 CR (both in the treated 20 patients with MF and 11 with SS (the only patients with SS) and 15 of 41 PR. Patients with patients with criteria for SS given in any report) with erythroderma had a higher RR (8/18 or 44%) than gemcitabine 1000 mg/m2 IV on days 1, 8, and those with tumor-stage disease (3/15 or 20%).
15 monthly for at least 6 cycles for an overall RR of The most common side effects of DCF are hema- 65%: this included 3 CR and 9 PR in 20 patients with tologic, GI, nonneutropenic fever, and transient MF and 8 PR in 11 patients with SS.
Overall, gemcitabine was well tolerated in all Infections, including life-threatening pneumonia reports. Hematologic toxicities, including neutrope- and sepsis, have been reported and may occur nia, thrombocytopenia, and anemia, were observed months after stopping DCF. The latter may be related in 20% to 60% of patients: they were mostly grade to the long-term ([1 year) depression of CD4 counts 1 to 2 with rare grade 3 to 4 events. Dose reduction that have been reported.Less common side effects was routine with grade 3 to 4 hematologic toxicities.
include neurologic problems (confusion, seizures, Nonhematologic toxicities included fever (flu-like), nausea/vomiting, interstitial pneumonitis (mild to especially bronchospasm, mild nephrotoxicity, con- severe dyspnea), transient increases of liver function junctivitis/scleritis, and rash.
test results (occasional grade 3), rare renal symptomsincluding hemolytic uremic syndrome, thromboses, Gemcitabine (Gemzar) rare arrhythmias, left ventricle dysfunction, erythema Gemcitabine is a deoxycytidine analog (2', 2'- flare response, diffuse hyperpigmentation in SS, difluorodeoxycytidine), a pyrimidine antimetabolite, alopecia (mild-moderate), radiation sensitivity, and subgroup of nucleoside analogs, with antitumor recall. Specific to patients with SS, two cases of cytotoxic activity. On entering cells via nucleoside hemolytic uremic syndrome and several patients transporter proteins, it is phosphorylated by dCyk to with cutaneous erythema flare and hyperpigmenta- gemcitabine monophosphates, diphosphates, and tion were reported by Duvic et al.
triphosphates. These phosphorylated substrates in-hibit elongation of DNA chain via ‘‘masked chain termination'' and competitively inhibits ribonucleo- Forodesine hydrochloride (BCX-1777, BioCryst tidyl reductase leading to impaired DNA synthesis Pharmaceuticals, Birmingham, AL) is a rationally and induction of apoptosis. Metabolic clearing is by designed small-molecule, transition-state analog in- deamination but gemcitabine-triphosphate inhibits deoxymonophosphate deaminase, possibly provid- (PNP).Under normal physiologic conditions, de- ing one mechanism for the prolonged retention oxyguanosine undergoes phosphorolysis by PNP to phenomenon that distinguishes gemcitabine from guanine and ribose 1-phosphate.When PNP is other pyrimidine analogsGemcitabine is ap- inhibited in lymphocytes, dCyk shunts unmetabo- proved as an IV infusion for ovarian, breast, lized deoxyguanosine into deoxyguanosine triphos- nonsmall cell lung, and pancreatic cancer.
phate that accumulates, inhibits the conversion of Although gemcitabine is widely used in the treat- ribonucleoside diphosphates to deoxyribonucleo- ment of patients with MF or SS, there are limited side diphosphates, which in turn, inhibits DNA published data of efficacy. In CTCL (MF plus SS), the synthesis and cell replication and leads to apopto- overall RRs range from 65% to 73%,although Although PNP is present in all mammalian most are PRs with variable response durations.
cells, human T cells are especially susceptible to the A brief report by Sallah et alshowed a PR in deficiency of this enzyme because they selectively both of two patients with CTCL treated with 1200 have high dCyk activity and/or low nucleotidase mg/m2 on days 1, 8, and 15 of a 28-day cycle. Zinzani activity.Forodesine has been shown to inhibit the et treated 30 patients with tumor-stage or T4 MF proliferation of activated human T lymphocytes and with 1200 mg/m2 IV on days 1, 8, and 15 of a 28-day acute lymphoblastic leukemic T cells in vivo and in schedule for at least 3 courses: there was a cutaneous vitro.Forodesine is currently in phase III RR of 70% including 3 of 30 CR and 18 of 30 PR. The clinical trials for the treatment of MF/SS.
reports that include patients with SS are very limited In a phase I, open-label, multicenter, IV dose- and are mixed among the reports of other patients ranging study of 40, 60, 90, and 135 mg/m2 every with CTCL. Marchi et treated 26 patients with MF 12 hours in 9 doses over 4.5 days repeated at 2-week (all tumor-stage or T4 skin disease) and one patient intervals4 of 13 patients with MF/SS (31%) had with SS (criteria not given) with a 73% RR including an OR and 9 of 13 had either improvement in 6 of 26 CR and 13 of 26 PR in the patients with MF and erythroderma or decrease in the SS cell count or no response in the patient with SS. Duvic et the CD4:CD8 ratio. The activity and bioavailability of J AM ACAD DERMATOL oral forodesine was also demonstrated in a multi- excellent response to chlorambucil. Several case center dose-escalation phase I trial of 40, 80, 160, or reports have shown variable activity of chloram- 320 mg/m2 oral forodesine daily for 4 weeks in bucil as a single-agent therapy in treatment of MF.
patients with stage IB or higher MF/SSThere were Wright et examined chlorambucil 2 to 28 PRs in 3 of 14 patients, all in the 80-mg/m2 cohort. No mg/d (average 10 mg) in 9 patients (6 evaluable) dose-limiting toxicities were observed with the target with MF with some transient responses but no OR.
dose of 320 mg/m2 but based on pharmacokinetics Only 3 other reports have suggested some benefit (PK)/pharmacodynamics results, the 80-mg/m2 dose using chlorambucil for MF: one case report with was identified as optimal.A phase II trial with monotherapy, and 6 cases with chlorambucil and 30 patients with MF/SS treated with 80 mg/m2 rounded to the nearest 100-mg capsule (essentially More extensive trials have been conducted for SS a fixed oral dose of 200 mg/d forodesine) was then using chlorambucil (In all these undertaken with two CRs and 9 PRs for a 37% studies, oral corticosteroid has also been used in conjunction with chlorambucil to maintain re- Forodesine is well tolerated in most patients. The sponses and duration of improvement. In these most common side effects are fatigue, peripheral open trials, all patients had skin and blood involve- edema, nausea, pruritus, dyspnea, and headache.
ment and some had clinical evidence of nodal Grade 3 to 4 lymphopenia has occurred in 70% of disease as well. Continuous treatment with chloram- patients and low CD4 counts in 32% of patients in the bucil (2-6 mg/d) in conjunction with prednisone phase II oral clinical There is little effect on (initially ;20 mg/d, tapering over time) (regimen of hemoglobin, neutrophils, or platelets. Opportunistic Winkelmann et al) resulted in a significant infections are uncommon.
response in patients with SS.In the study reportedby McEvoy et alleukapheresis was also per- Alkylating agents formed concurrently with an OR of 100% including Chlorambucil (Leukeran). Chlorambucil (Leu- two of 11 CR. MRD was 1 to 3 years and mean time to keran) is a bifunctional alkylating agent first death was 6.5 to 8 years versus historical controls of synthesized by Everett et in 1953 based on 3 years. Coors and von den Drieschreported their modification of the parent nitrogen mustard struc- clinical experience with pulse chlorambucil and ture. Alkylation of DNA results in strand breaks and fluocortolone in patients with stage III to IVb treated interstrand cross-linking, disrupting DNA replication with chlorambucil 10 to 12 mg/d and fluocortolone and RNA transcription. It is a cell cycle phase 75-50-25 mg on 3 successive days every 2 weeks. Of nonspecific antitumor agent. Chlorambucil is avail- 13 patients, 7 (54%) achieved CR and 6 (46%) able in tablet form and orally administered, where it achieved PR. MRD was 16.5 months. Publications is rapidly and virtually completely absorbed from the using chlorambucil in combination with other ther- GI tract. Peak plasma levels are observed within apies in the treatment of SS are shown in 1 hour. The terminal elimination half-life is approx- imately 1.5 hours, and it is efficiently metabolized to Low-dose chlorambucil is generally well tolerated phenylacetic acid mustard with limited urinary ex- with few significant side effects. The main toxicity is cretion. The parent agent and metabolites degrade leukopenia, which should be monitored by monthly spontaneously in vivo to the inactive monohydroxy complete blood cell counts. The effectiveness of the and dihydroxy derivatives. Chlorambucil is highly therapy for SS is likely partly a result of this side bound to albumin and there are no known drug-drug interactions with chlor drug fever, and hyperuricemia are early side effects With the early recognition of the use of nitrogen and delayed side effects include amenorrhea, azoo- mustard and derivatives, especially chlorambucil, spermia, infertility, pulmonary interstitial fibrosis, in managing leukemias and lymphomas, studies to cystitis, hepatotoxicity, peripheral neuropathy, and evaluate the effect of chlorambucil in MF and SS the late effects of acute leukemias and solid tumors were performed. Libansky and Tfirst re- that are seen with other alkylating therapies.
ported success in treating 4 patients with ‘‘eryth- Chlorambucil is teratogenic and should not be used rodermia'' (clinical and laboratory evidence for SS) in pregnancy.
with chlorambucil in doses of 4.6 to 5.6 mg/kg for Nitrogen mustard (Mustargen). Karnofsky 4-week cycles. Marked clinical responses were in 1950 reported on 21 cases of MF treated with observed with remissions from 4 to 24 months.
nitrogen mustard 0.1 mg/kg/d 3 10 days: there was a They also reported the initial treatment of a case of rapid and marked response to the first cycle that MF refractory to multiple previous therapies with lasted 5 to 7 months. Subsequent treatments were J AM ACAD DERMATOL VOLUME 64, NUMBER 2 less effective. Because of the efficacy shown with Dobsonin which the main side effects seen in topical nitrogen mustard, Van Scott et in 1975 4 patients treated for 2 to 12 months were alopecia, examined the use of systemic nitrogen mustard again nausea, and vomiting with no leukopenia or throm- in 27 patients with plaque-stage MF and 14 with bocytopenia, leukopehas been the dose- E-MF/SS including 6 with peripheral blood SC counts limiting factor for continuous dosing. The potential greater than or equal to 20% (here termed ‘‘SS'') for hemorrhagic cystitis with oral dosing and, in (). They used various regimens including young patients, germ cell damage, remain as nitrogen mustard by IV push 0.5 to 3 mg daily, 1 to 3 mg tiw, 1 to 1.5 mg twice a day, or a 6- to 8-hour IV Temozolomide (Temodar). Temozolomide, an infusion of 2 mg daily with a total amount of nitrogen imidazotetrazine derivative, is an oral alkylating agent approved for the treatment of glioblastoma multi- Importantly, all patients were also treated with forme and anaplastic astrocytoma. Temozolomide concomitant topical nitrogen mustard. An OR was functions as a prodrug, undergoing rapid nonenzy- seen in 57% of the 14 patients with erythroderma, matic conversion to active 5-(3-methyltriazen-1-yl) including 6 of 11 of those with nodal disease and 4 of 6 of those with SS (T4 plus SCs [20%) including at thought to be a result of alkylation (methylation) of least one response lasting more than a year.
DNA mainly at the 06 and N7 positions of guanine with IV Mustargen may cause thrombosis or thrombo- depletion of the DNA repair protein 06-alkylguanine- phlebitis, myelosuppression with an acute effect on DNA alkyl transferase.Food decreases absorp- lymphocytes, rash, and GI symptoms. It is a probable tion and temozolomide is rapidly eliminated with an carcinogen and mutagen.
elimination half-life of 1.8 hours.
Cyclophosphamide (Cytoxan). Cyclophosph- There have been two studies evaluating the effi- amide is an alkylating agent, a phosphamide ester of cacy of temozolomide in MF. Temozolomide was mechlorethamine that induces intrastrand cross-links evaluated in a phase I study of 42 patients with a during cell division requiring excision repair.
variety of types of advanced cancer in doses of 750, The first report of cyclophosphamide in the treat- 900, 1000, and 1200 mg/m2 3 5 days in a 4-week ment of MF was by Abele and in 1960.
One patient with MF had a CR in the skin of Four patients with biopsy-proven MF (two with 7 months' duration. A prospective single-center exfoliative dermatitis that would probably be qual- phase II study of temozolomide 150 mg/m2/d 3 5 ified as erythroderma today, one with widespread days on first 28-day cycle then 200 mg/m2 3 5 days dermatitis and one with plaque disease) were treated on cycles 2 and was conducted in 9 patients with with 200 mg of IV cyclophosphamide 3 14 to 20 days MF stage IIB or III. There was an OR in 33% of with an OR at the end of induction in all patients and patients including one CR and two PRs with a clearing of skin in 3 of 4 patients including the two duration of response of 6 to 9 or more months.
with erythroderma. Maintenance cyclophosphamide There is no mention of results in SS specifically in therapy was necessary to maintain the response and either report.
the optimum dosing appeared to be single weekly Temozolomide is well tolerated. Myelosuppression dosing of 400 to 700 mg. Van Scott et reported (leukopenia, thrombocytopenia) is the dose-limiting on 10 patients with MF, all tumor or plaque stage, side effect with a predictable nadir at day 22 and mild treated with varying doses of 50 to 175 mg IV nausea and vomiting is reported.Infection is cyclophosphamide until leukopenia or thrombocy- topenia developed at which point drug was stoppedand restarted on recovery. With this dosing regimen, Topoisomerase inhibitors there was a skin PR in two of 10 and CR in two of 10.
VP-16 (etoposide). VP-16 is a semisynthetic de- Mendelson et alreported on a patient with MF rivative of the plant toxin podophyllotoxin used first who failed to respond to 8 courses of 1500 mg/m2 line for the treatment of small cell lung cancer. It is also used for testicular tumors and as combination 3 weeks. Three other case reports of plaque- and therapy for a variety of hematologic malignancies. It tumor-stage MF responding to 100 to 200 mg/d of is available in an IV and oral formulation.
cyclophosphamide have been noted.In gen- Although it induces single-strand and double- eral, cyclophosphamide has been used much more stranded DNA breaks, its major mechanism of action frequently as part of a multiagent chemotherapy appears to be through reversibly binding to DNA regimen, including in SS, versus monotherapy.
topoisomerase II, resulting in the inability of this With the exception of the lower (400-700 mg enzyme to repair double-stranded DNA breaks.
Interference with this enzyme results in disrupted J AM ACAD DERMATOL transcription and, ultimately, cytotoxicity and cell use of VP-16 25 mg/d orally in combination with death. Of the IV dose of VP-16, 30% to 40% is MTX 10 mg every week in a patient with SS: there recovered in the urine unchanged with the remain- was a reduction in the leukocyte count and adenop- der metabolized primarily to glucuronide or hydroxy athy and resolution of erythroderma. Publications acid forms. The terminal half-life is ;5.6 hours with using etoposide in combination with other therapies clearance correlated with creatinine clearance. Oral to treat SS are shown in .
dosing is subject to variable absorption with no effect VP-16 is generally well tolerated. Serious side from food but decreased absorption with increased effects are primarily hematologic (reversible myelo- suppression) and are often dose limiting. Other The first reports on the use of VP-16 for CTCL potential side effects include GI (nausea, vomiting), were in 1975. One patient with tumor-stage MF had a mucositis, alopecia (total), and rarely hypersensitiv- CR to VP-16 60 mg/m2 IV 3 5 days repeated every ity reactions. Increased toxicity has been seen with 2 weeks with maintenance biw injections.
impaired renal function and decreased albumin pre- A second case of a patient with a generalized sumably secondary to increased exposure to un- dermatosis compatible histologically with MF was bound VP-16Chronic VP-16, especially weekly or treated with 60 mg/m2 VP-16 3 5 days every 2 weeks biweekly dosing, has been associated with acute 3 5 courses with a CR maintained for greater than myeloid leukemiPotential advantages for the 1 year on maintenance 60 mg/m2 3 5 days followed use of VP-16 include that it is available in an oral by 100 mg/m2 biw of the remaining 3 weeks of the 4- formulation, it can be given on a chronic dosing week Onozuka et alreported on a patient schedule, and its safety in the elderly has been with E-MF without blood involvement who was treated initially with IV weekly 150 mg/d VP-16 Pegylated liposomal doxorubicin (Doxil). Do- and oral prednisolone 3 3 d/wk for 9 weeks xorubicin HCl is an anthracycline topoisomerase followed by oral VP-16 (25 mg/d 3 21 days every 4 inhibitor approved for the treatment of ovarian cancer, weeks) with a CR of 36 months. Nasuhara et al multiple myeloma, and Kaposi sarcoma with activity reported on a patient with non-E-MF and histolog- also in non-Hodgkin lymphoma. The mechanism of ically confirmed pulmonary involvement who had a action of doxorubicin HCl is thought to be related to its 36-month remission when treated with weekly oral ability to bind DNA and inhibit nucleic acid synthesis.
VP-16 (200 mg) and prednisolone (30 mg) thrice Pegylated liposomal doxorubicin is a formulation of weekly. The Scandinavian Mycosis Fungoides Group doxorubicin encapsulated in liposomes, microscopic treated a total of 9 patients with MF (SS included but vesicles composed of a phospholipid bilayer that are not defined or otherwise identified in results) with capable of encapsulating active drugs. The size of the VP-16 alone 100 mg IV 3 5 days every 2 to 3 weeks liposomes allows selective accumulation in the tumor and oral VP-16 100 mg qd 3 5 days during mainte- vascular bed and the surface-bound methoxy poly- nance every 2 to 3 weeks or in combination with ethylene glycol (pegylation) induces reduced clear- cyclophosphamide 500 mg IV every fourth day ance by the mononuclear phagocyte system thereby during induction and 150 mg qd orally during improving the PK and pharmacodynamics. Once the maintenance.Of the 5 patients with MF (3 skin liposomes distribute to the tissue compartment, the only, two with nodal involvement) treated with encapsulated doxorubicin HCl is released.
single-agent VP-16, there was one CR and one PR.
Adriamycin has previously shown efficacy as In the 4 patients treated with cyclophosphamide in monotherapy in advanced MF/SSand has been combination with VP-16, there were two CR and one an effective agent in multiple combination chemo- PR. Progressive disease generally occurred 4 to 6 therapy regimens as well. Although Doxil is used months after the start of therapy.
increasingly in the treatment of patients with MF or There has only been one case report using VP-16 SS, the published data to support its use in SS are as monotherapy in patients with SS. Miyoshi and limited. In CTCL (MF 1 SS), the overall RR has ranged Nodareported a PR that persisted for 48 months from 30% to 80% with CR rates of 20% to but did not define the criteria used for SS diagnosis In a report of 31 patients with MF/SS, Wollina et al nor the dose of VP-16 used. Olsen and Lai reported used various dosing regimens of liposomal doxoru- on the use of 50 to 100 mg oral VP-16 3 20 days every bicin of 20 or 30 mg/m2 every 2 to 4 weeks (in most month in 4 patients with SS (erythroderma, lym- cases) and 40 mg/m2 (two patients). There was a phadenopathy, diffuse pruritus, and[15% SC): there particularly high RR of 87% including 12 of 30 CR and was a PR in one of 4 patients that lasted 6 months 14 of 30 PR that may have been partly related to the while on therapy (E. Olsen, MD, and E. Lai, BS, definition of PR used (either [50% decrease in the unpublished data). Hirayama et alreported on the size of lesions or [50% change of nodular or plaque J AM ACAD DERMATOL VOLUME 64, NUMBER 2 lesions to macular ones) along with the use of proteins by HDAC inhibitors results in transcription- interferon alfa in two patients. However, Pulini ally active chromatin that alters gene expression and et in a study of 19 patients with CTCL affects protein function, thus, leading to growth (13 with MF, 3 with peripheral T-cell lymphoma, inhibition, apoptosis, and cellular differentiation and 3 with SS) treated with liposomal doxorubicin among other antitumor ef 20 mg/m2 IV every 4 weeks and using a globalresponse criteria, reported a RR of 84% including CRs Vorinostat (Zolinza) in 50% of the patients with MF/SS (7 of 13 MF and one Vorinostat (suberoylanilide hydroxamic acid) is a of 3 SS). Quereux et using similar dosing, pan HDAC inhibitor of HDACs in class I (HDAC1, reported a RR of 56% in 25 patients with MF/SS HDAC2, and HDAC3) and II (HDAC6).Vorinostat including 20% CRs: there was CR in 4 of 15 patients is orally bioavailable with a mean terminal half-life of with MF and one of 10 with SS, and PR in 4 of 15 2 hours. In vitro studies have demonstrated that patients with MF and 5 of 10 with SS. In a study by Di vorinostat selectively induces apoptosis of malignant Lorenzo et althat was restricted to 10 patients with stage IVB MF (SS not defined) who were treated with Vorinostat was FDA approved for the treatment of 20 mg/m2 every 8 weeks, 30% (all heavily pretreated) the cutaneous manifestations of CTCL based on two achieved a PR.
phase II clinical trials. The first was a single-center, Myocardial damage may lead to congestive heart dose-ranging study of 33 patients with CTCL with an failure and may occur as the total cumulative dose of overall RR of 24% (8 of 33 paAn optimal doxorubicin HCl approaches 550 mg/m2 or at lower dose of 400 mg daily was identified based on cumulative doses (400 mg/m2) in patients who are response and dose-limiting toxicity of thrombocyto- receiving concurrent cyclophosphamide therapy.
penia at 300 mg twice a day 3 2 weeks. Four (36.4%) Acute infusion-related reactions including, but not of the 11 patients with SS had clinical responses. One limited to, flushing, shortness of breath, facial patient with a circulating SS count of more than swelling, headache, chills, back pain, tightness in 100,000 cells at baseline had a rapid decrease in the the chest or throat, and/or hypotension have oc- absolute SS count to less than 1000 after receiving curred in up to 10% of patients treated with liposo- 300 mg twice daily for 2 weeks but developed mal doxorubicin. Severe myelosuppression may thrombocytopenia. The pivotal trial was a multicen- occur and liposomal doxorubicin may potentiate ter single-arm phase II trial enrolling 74 patients with the hematologic toxicities of other chemotherapeu- MF/SS at a fixed dose of 400 mg per day given tic agents. Hand-foot syndrome may occur during orally.The overall RR (based on $ 50% reduction therapy with Doxil, generally after 2 to 3 cycles of in modified severity-weight assessment tool score) treatment, and may require dose reduction, delay in was 30% (22/74) and among patients classified as administration, or discontinuation of Doxil. Other having SS (T4B2), 10 of 30 (33%) were responders.
potential side effects include radiation recall, muco- Publications using vorinostat in combination with sitis, alopecia, asthenia, fatigue, and GI symptoms.
other therapies in SS are shown in Liposomal doxorubicin is eliminated in large part by The most common drug-related side effects seen the liver and it is recommended that dosage be during the clinical trials were fatigue, GI symptoms reduced in patients with impaired hepatic function.
(nausea, vomiting, diarrhea, and the potential for Fortunately, the toxicity profile in the CTCL experi- secondary dehydration), hematologic (especially ence of approximately 88 patients treated across thrombocytopenia and anemia), dysgeusia, anorexia, several studies has been excellent and most events weight loss, and muscle spasms.Alopecia, head- reported have been grade 1 or 2 in less than 20% of ache, edema, hyperglycemia, hypophosphatemia, patientsGrade 3 to 4 toxicities have been rare hypomagnesemia, increase in serum creatinine, and and have included anemia, neutropenia, lympho- corrected QT interval prolongation were reported penia, hand-foot syndrome, and capillary leak but generally without sequelae. Prolongation of pro- thrombin time and international normalized ratio(INR) in patients on coumarin-derived anticoagulants HISTONE DEACETYLASE INHIBITORS require close monitoring. Thromboembolism was Histone deacetylase (HDAC) inhibitors are com- seen in 5% of patients. Infection was uncommon.
pounds that target the epigenome and cause pleio-tropic apoptosis. There is increasing evidence of epigenetic Romidepsin is a potent pan-HDAC inhibitor of the cyclic peptide structural It has the greatest Increased acetylation of histone and nonhistone activity against selective HDACs in classes I (HDAC1, J AM ACAD DERMATOL HDAC2, and HDAC8), II (HDAC4, HDAC5, and an OR and 5.9 months in patients with (overall HDAC6), and IV (HDAC 1It is currently un- median time to progression of 6.5 months).There known which isoenzyme(s) may be associated with were 13 treated subjects in the GPI-04-0001 study the antitumor effects of romidepsin. Romidepsin has who met the criteria of SS (defined as erythroderma potent in vitro growth inhibitory action as demon- plus either ISCL definition of B2 or [20% SCs) with a strated in HUT78 cells (CTCL cell line) with the RR of 30.8% (4 of Data for the treated SS half-maximal inhibitory concentration IC50 in the subjects in the GPI-04-0001 study are presented in nanomolar range. Romidepsin was approved in 2009 for the treatment of CTCL in patients who have Overall, romidepsin was well tolerated in both received at least one prior systemic therapy.
studies. Although asymptomatic T-wave flattening Two major independent, international, multicen- was common in the NCI study,the results of an ter phase II single-arm clinical trials of romidepsin in intensive safety analysis revealed no clinically signif- MF/SS were completed: the pivotal study, GPI- icant corrected QT interval prolongation or electro- 04-0001, and the National Cancer Institute (NCI) cardiogram abnormalities that were attributable to 1312 study. The data from these two studies are romidepsin. However, concomitant medications that available for further analysis to assess its efficacy in prolong the QT interval or inhibit CYP3A4 are to be Although the two studies are not identical avoided with romidepsin. The most commonly in their enrollment criteria or efficacy assessment reported drug-related adverse events ([20%) in tool, both used the same dose and schedule of both studies include nausea, fatigue, vomiting, and romidepsin (14 mg/m2 in a 4-hour infusion on days anorexInfection was reported in more than 1, 8, and 15 every 28 days). Both studies used a 45% of cases in both studies, however, most of these global scoring method where skin and extracuta- were attributable to disease and not related to neous sites of involvement were combined in the romidepsin. Drug-related adverse events that oc- assessment of response with the following impor- curred in both studies in 10% to 20% of patients tant differences: in the GPI-04-0001 phase IIB inter- included diarrhea, headache, dysgeusia, thrombo- national, multicenter, registration/pivotal study, a PR cytopenia, and anemia. Most of these related adverse was defined as greater than 50% improvement in the events were grade 1 to 2 and were very manageable.
sum of the 3 assessments (change in skin 1 change Lymphopenia and granulocytopenia, regardless of in lymph node 1 change in peripheral blood causality, occurred in 3% and 8% versus 55% and 52% Sezary) but with at least 30% improvement in the of patients in the GPI-04-0001 versus NCI studies, skin involvement (as determined by severity-weight respectively.In all, 55% of patients with the NCI assessment tool score or in the case of erythro- study were hospitalized for at least the first cycle, derma, by 5-point erythroderma score), no new thus more laboratory assessments were done and all tumors (in skin or otherwise), and no worsening of abnormalities were reported regardless of clinical nodes or blood involvement. In the NCI 1312 phase significance, which may account for the differences II investigator-initiated study, PR was defined as in the hematologic adverse event profiles. Twelve $ 50% improvement in skin (as measured by PGA deaths within 30 days of study administration were toolwithout new tumors and no worsening of reported for both studies together, 3 possibly related nodes (blood involvement not considered here).
to treatment (acute cardiovascular insufficiency Radiotherapy of nonresponding lesions was al- after pneumonia; sudden death in setting pre- lowed in the NCI study, but these lesions were not existing valvular disease and cardiomyopathy; and included in the response assessment. Results in the Escherichia coli sepsis).
intention-to-treat population of patients are remark-ably similar between studies. In the GPI-04-0001 MONOCLONAL ANTIBODIES study of 96 patients with MF/SS (29.2% stage IB-IIA Alemtuzumab (Campath) and 70.8% $ stage IIB), results included an overall Campath (alemtuzumab [United States], MabCam- RR of 34.4% (33/96) including 6.3% CR (6/96), path [European Union]) is a humanized IgG1 kappa median time to response of 1.9 months, MRD of mAb directed against the human CD52 antigen that 14.9 months, and median time to progression of 8.3 is FDA approved for the treatment of patients months.In the NCI study of 71 patients with with CLL.CD52 is a 21- to 28-kd glycosyl- MF/SS (12.7% stage IA-IIA and 87.3% stage $ IIB), phosphatidylinositol-anchored glycoprotein whose results included an overall RR of 34% (24/71) function is unknown.CD52 is abundantly ex- including 7% CR (4/71), median time to response pressed on mature malignant B and T lymphocytes, of 2 months (1-6), MRD of 13.7 months, and median monocytes, DCs, eosinophils, NK cells, a subset of time to progression of 15.1 months in patients with granulocytes and epithelial cells of the epididymis, J AM ACAD DERMATOL VOLUME 64, NUMBER 2 deferens duct and seminal vesicle; hematopoietic tiw IV along with betamethasone each infusion for stem cells, plasma cells, erythrocytes and platelets 4 weeks in 4 patients with MF and tumor or appear to be spared.In vitro evidence shows erythrodermic disease: a PR was seen in 3 of 4 that alemtuzumab induces complement-dependent patients with no grade 3 or 4 hematologic toxicity.
cytotoxicity, antibody-dependent cellular cytotoxic- The results in studies where SS is clearly defined ity, and direct apoptosis in B-CLL along lines of the ISCL criteria and where all or the CD41 cells have about two times the amount of majority of patients are SS have shown an impressive surface CD52 compared with CD81 cells. The overall RR of 86% to 100% with a CR of 21% to 100% amount of surface CD52 determines not only the ).Of particular note is the lower type of cytotoxicity (complement-dependent cyto- dosage of alemtuzumab used in 14 patients with SS, toxicity in CD41 cells, antibody-dependent cellular and lower incidence of side effects, reported by cytotoxicity in CD81 cells) but correlates with the Bernengo et al.They used a low dose (maximum overall sensitivity to killing by alemtuzumab and is 10-15 mg) of alemtuzumab delivered SQ and a inversely proportional to the rate of re-emergence dosing schedule that was individually determined posttreatment: CD81 cells are effected less than based on the patient's SC counts. The overall re- CD41 cells and return to 25% of baseline after sponse (skin, node, and blood) was 86% including 24 versus 52 weeks off therapy with CD41 cell 3 CRs, median reduction of 96% of SC count, and The effect of alemtuzumab on T cells may be through median time to treatment failure was 12 months. In a combination of activation of Tregs and lymphocyte addition, none of the patients given a maximum of 10 depletion.The biodistribution and clearance of mg alemtuzumab developed hematologic toxicity or alemtuzumab during treatment is dominated by the infections. Weder et has proven that alemtuzu- tumor burden and does not fit into any simple PK mab may be successfully used in combination with model.Alemtuzumab may be dosed SQ with chemotherapy. A patient with treatment-refractory better tolerability, similar peak drug concentrations tumor-stage MF (including failure to respond to achieved but at a higher cumulative dose, and gemcitabine and alemtuzumab monotherapies) had with a greater potential for the development of a PR on combination therapy with alemtuzumab anti-alemtuzumab antibodies compared with IV 30 mg SQ tiw and gemcitabine 1000 mg/m2 every week and progression-free survival of more than Unlike most of the other therapeutic options for 1 year off therapy. Porcu et showed that SS, a relatively large number of patients with SS have alemtuzumab may be safely administered with cy- been treated with alemtuzumab, many in studies of clophosphamide, doxorubicin, vincristine, and pred- advanced MF/SS and several in studies of exclusively nisone chemotherapy and growth factor support.
SS. Gibbs et alsuccessfully treated a patient with Infectious complications are the main concern simultaneous SS and B-CLL with alemtuzumab 30 mg with alemtuzumab with the frequency depending on IV tiw. Using the same dosing regimen, Capalbo the dose and dosing regimen: they are markedly et altreated one patient with IVA MF and two reduced with the 10- versus 30-mg tiw dose and with patients with E-MF with improvement in all and a CR SQ dosing.The most frequent observed in one of the patients with E-MF. Kennedy et al opportunistic infection is cytomegalovirus reactiva- treated 6 patients with stage IIB to IV MF and two tion but herpes zoster, generalized herpes simplex, patients with SS (no information on blood criteria and opportunistic fungal and bacterial diseases have other than presence of circulating SCs) with 30 mg IV also been reported. Myelosuppression is common tiw 3 12 weeks with OR in one of 6 of the patients with thrombocytopenia, usually noted during the with MF and both of the two patients with SS. Lundin first 2 weeks, neutropenia weeks 5 to 6, and lym- et conducted a phase II study of alemtuzumab phopenia nadir weeks 3 to 6 with recovery of the in 22 patients with heavily pretreated, CD521, latter delayed for greater than a year postdosing.
advanced-stage MF/SS (10 patients with T4 disease Infusional reactions secondary to cytokine release and 7 with circulating SCs but unclear how many SS) are the most common adverse events during alem- with 30 mg alemtuzumab IV tiw for up to 12 weeks.
tuzumab therapy, particularly IV dosing, and tend to RR was 55% (32% CR, 23% PR) and median time to dissipate over time.The dose of alemtuzumab is treatment failure was 12 months (5- $ 32 months).
generally escalated to help minimize this, beginning Lenihan et treated 8 patients, 3 with MF and at 3 mg on day 1 and 10 mg on day 3, regardless of 5 with SS (criteria for SS not given), with 30 mg target dose. Local reactions may be seen with SQ alemtuzumab IV tiw 3 12 weeks with a PR in dosing. A variety of cardiovascular adverse events 3 patients (37.5%), all designated SS. Zinzani were observed in one study but a causative relation- et alused a lower dose of alemtuzumab 10 mg ship with alemtuzumab has been disput J AM ACAD DERMATOL BORTEZOMIB (VELCADE) 26S proteasome is a multicatalytic protease that is IL-2 is a 15-kd polypeptide produced by activated responsible for most nonlysosomal intracellular CD41 cells (Th1 cells specifically) that results in protein degradation and as such, maintains the activation, proliferation, and maintenance of T appropriate balance of cell survival and apopto- helper lymphocytes.IL-2 is also associated with sis.Bortezomib is a cell-permeable dipeptide release of IFN-a, TNF-alfa, TNF-B, IL-1, IL-5, and IL- 6. It has been shown to be effective in the treatment chymotryptic-like proteolytic activity of the b5 sub- of a variety of cancers and is FDA approved currently unit of the proteasome.It is FDA approved as an for the treatment of metastatic renal cell carcinoma or IV treatment for multiple myeloma and mantle cell lymphoma. Bortezomib has an elimination half-life There have been few studies of IL-2 in MF/SS.
of 9 to 15 hours and it is primarily oxidatively Nagatani et treated a patient with tumor-stage metabolized via cytochrome P450 enzymes 3A4, MF with IL-2 with a CR for 13 months on monthly 2C19, and IA2.
dosing. Marolleau et altreated 3 patients with MF Reports of bortezomib in CTCL are limited to one and 3 patients with SS (criteria not given) with IL-2 study of 10 patients with previously treated MF (no 20 MU/m2 IV on days 1 to 5, 14 to 17, and 28 to 30 and SS noteThere was a 70% OR rate to bortezo- then 1 month later, the same dose 2 d/mo for mib 1.3 mg/m2 IV on days 1, 4, 8, and 11 every 21 5 months. All 3 of the patients with MF had a CR days for 6 cycles: the one CR lasted more than 12 and one of 3 of the patients with SS had a PR. Two of the CRs have lasted for more than 56 and more than The most common dose-limiting side effects with 62 months at last report but the PR lasted only bortezomib are myelosuppressive (neutropenia and 5 months. Gisselbrecht et used the same induc- thrombocytopenia).Other side effects seen tion dose of IL-2 and 20 MU/m2 3 5 d/mo in commonly in the myeloma trials were asthenia, GI 6 patients with MF and one with SS (T4, 30% symptoms, and headache. Sensory neuropathy peripheral blood SC) with a 71% RR including one occurred in 36% of the patients with myeloma and CR in an patient with MF that lasted longer than 50% of the patients with CTCL treated with bortezo- 29 months. Gold et reported on the initial results mib with most patients having improvement or of 0.5 to 4 MU/m2/d SQ 3 5 days for 4 weeks in a resolution off drug. Infection is uncommon.
phase I trial of 4 patients with MF stage IIB to IV withtwo of 4 PR in the skin, one whose adenopathy,however, increased during therapy. Querfeld et al ANTITHYMOCYTE GLOBULIN reported on the use of IL-2 at a dose of 11 MU on 4 consecutive days per week for 6 weeks in 22 patients Antithymocyte globulin (ATG) is commercially with advanced CTCL: there was an 18% RR.
available as a purified gamma immune globulin Side effects of IL-2 have included flu-like illness, obtained by immunization of rabbits with human GI symptoms, weight gain, increased creatinine, thymocytes and is available for IV infusion.
hypotension, cardiac toxicity, vascular leak syn- Mechanism of action in T-cell malignancies is likely drome, anemia, and thrombocytope through T-cell clearance from the circulation andmodulation of T-cell activation, homing, and cyto-toxic activit MULTIAGENT CHEMOTHERAPY Two case reports of ATG 15 mg/kg in SS have Multiple variations of combination chemotherapy been published and do not appear to support the use have been tried in advanced-stage MF/SS but, of ATG in SS.The combination of ATG pre- despite high initial RRs, responses have generally ceded by cyclophosphamide to induce tolerance to been short-lived and without documented effect on ATG produced only transient improvement survival.Unlike immunomodulators, these Potential side effects of ATG include infusione chemotherapeutic regimens cannot be sustained associated reactions with flu-like illness, GI symp- long term because of their side effects. Moreover, toms, changes in blood pressure, rash and headache, given the life-threatening toxicities, which result in serious immune-mediated reactions including ana- hospitalizations in many cases, and long-term se- phylaxis and cytokine release syndrome (both of quelae of many combination chemotherapy regi- which can lead to cardiorespiratory arrest), and mens used even for relatively short periods of time, serum sickness. Leukopenia, particularly T cells but this approach may have a negative impact on the quality of life for many patients so treated. However, because patients with a very high blood tumor J AM ACAD DERMATOL VOLUME 64, NUMBER 2 burden are unlikely to respond to immunomodula- risk of treatment-related morbidity and mortality tors alone and/or may urgently need a reprieve from such as life-threatening infections and graft-versus- severe symptoms leading to secondary complica- host disease. Reduced-intensity nonmyeloablative tions in less time than a treatment with immuno- modulators or single-agent chemotherapy is likely to lymphoma effect with lesser toxicities related to the deliver, multiagent chemotherapy has its place in the conditioning regimen. The published experience of treatment of advanced MF and SS.
allogeneic HSCT in advanced stages of MF/SS have It is difficult to sort out the efficacy of the various combination chemotherapy regimens specifically in A response duration as far as 9 years patients with E-MF or in SS given the small number of posttransplantation in a patient with SS/stage IVA reports where their inclusion or response is specif- disease has been reported.A recent meta-analysis ically noted. However, review of the literature illu- that compared the outcome of allogeneic versus minates some combination chemotherapies or autologous HSCT in patients with advanced MF/SS multimodality regimens that warrant further explo- (97% $ stage IIB) using 39 cases from the literature ration in MF/SS. For SS, it may be fruitful to focus on showed a significantly better outcome for patients those combinations that are able to achieve a near who received allogeneic HSCTFive-year overall 100% RR including a high ([50%) CR without undue survival was 80% in the allogeneic transplantation lasting toxicity and to use these as induction therapy group (n = 20) compared with 23% in the autologous followed by treatment with a lower side-effect pro- transplantation group (n = 19). The incidence of file (eg, immunomodulators) to expand on this graft-versus-host disease was high (90%) in patients response. Such induction regimens include cyclo- with myeloablative and nonmyeloablative alloge- phosphamide, doxorubicin, vincristine, and predni- ; MTX, cyclophosphamide, vincristine, and Review of the literature has identified 22 patients prednis; and etoposide, idarubicin, cyclo- with SS whose disease was clearly defined and who phosphamide, vincristine, prednisone, and bleomy- received allogeneic HSCT. Most were from small case One must consider the powerful effect of series or case reports except for the M.D. Anderson skin-directed therapy, most notably total skin elec- Cancer Center experience that included 14 patients tron beam therapy (TSEBT)but also designated as SS, of which at least 11 fulfilled the topical nitrogen mustard,in any sort of multi- ISCL definition of T4B2 staging. Twenty of the 22 modality regimen.
patients received a reduced-intensity (nonmyeloa-blative) regimen ().Overall HEMATOPOIETIC STEM CELL outcome results are encouraging. Of the 22 SS allogeneic HSCT recipients reviewed, 15 patients The concept of high-dose combination chemo- were alive and disease free at a mean posttransplan- therapy followed by autologous bone-marrow tation follow-up of 44 months (range 18-109 transplantation or peripheral blood stem cell sup- months). The durable remissions were associated port has curative potential in various non-Hodgkin with chronic graft-versus-host disease in all but 5 lymphomas, but experience in CTCL is limited.
patients. Allogeneic HSCT should be a consideration Autologous hematopoietic stem cell transplantations as a potentially curative option in patients with SS (HSCT) have yielded disappointing results in and aggressive and advanced disease resistant to patients with MF. Most cases have been reported standard treatment. However, once patients develop in patients with advanced stages of MF. Despite nodal large cell transformation, overall efficacy may reported effective responses with CR in many be reduced (A. Rook, MD, unpublished data).
treated patients (;75%), 18 of 22 (;80%) haverelapsed within a mean of 5.8 months (2-14 The duration of remission in various Topical and systemic steroids types of CTCL does not seem to be related to the Topical and systemic corticosteroids are main- stage of the disease or absence of a detectable T-cell clone in the harvest.
Corticosteroids may help SS in several ways includ- Allogeneic HSCT are known to achieve much ing a direct anti-inflammatory effect and induction of more durable CRs and provide a potentially curative apoptosis in malignant lymphocytes.The use of treatment option for advanced MF.A proposed these agents has such a positive effect on quality of graft-versus-lymphoma effect is thought to be re- life for patients with SS that it is difficult to withdraw sponsible for higher effectiveness of allogeneic them for the purpose of clinical trials or to prevent transplantations. It does, however, carry a higher long-term toxicity. Unfortunately, in patients with SS J AM ACAD DERMATOL who are long-term users, discontinuation of either but who responded to NBUVB and potent topical topical or systemic steroids is also usually associated steroids with both clearing of the skin and blood.
with a flare of disease. Adverse effects of these agents Thus phototherapy may affect both the skin and may include skin atrophy with chronic use of topical blood tumor compartments in MF/SS. Publications steroids and adrenal suppression and/or osteoporo- using PUVA or NBUVB in combination with sis with either widespread application of topical other therapies in the treatment of SS are shown steroids or the use of systemic steroids.
Side effects of both NBUVB and PUVA include potential pain, sunburn, and an increased risk of PUVA combines the photosensitizing drug psora- nonmelanoma skin cancer. Additional side effects len with long-wave (320-400 nm) UV light. Ingested with PUVA include nausea with psoralen ingestion, psoralen is activated by UVA that then binds cova- potential for eye damage if inadequate protection lently and reversibly to DNA forming bifunctional from UV light for 24 hours postingestion of psoralen, adducts to pyrimidine bases.The net effect in- and an increased risk of melanom cludes inhibition of cellular DNA synthesis, lympho-cytotoxicity, and, with long-term use, decrease in Topical mechlorethamine (nitrogen mustard) circulating helper cells.NBUVB (311 nm), Mechlorethamine in an aqueous or ointment- which does not require the use of sensitizing agents, based formulation has been a mainstay in the treat- has been reported to suppress the function of ment of MF for more than 50 years. This has been Langerhans cells and cytokine production from used as primary therapy with curative potential in early diseasor after TSEBT to prolong remissions Outside of TSEBT, PUVA is the skin-directed in the skin.It has also been used in conjunction therapy most likely to induce a cutaneous CR in all with systemic therapy, including chemotherapy, in skin stages of MF. Combination therapy in MF/SS more advanced disease. The main immediate side effects of topical mechlorethamine are irritancy and PUVhas shown enhanced efficacy but the an allergic contact dermatitis but importantly, its use one randomized trial in this area failed to show an does not cause myelosuppression. There have been improvement of etretinate or isotretinoin in conjunc- several publications about the long-term added risk tion with PUVA (73% OR) over PUVA alone (72% OR) of nonmelanoma skin cancer in patients treated with in 69 patients with early MFNBUVB has been topical nitrogen mustardbut it has been difficult to used in combination with immunomodulators as sort out the effect of other carcinogenic treatments well but no randomized study of monotherapy (phototherapy and/or radiation) also commonly versus combination therapy or comparison of used in the sequential treatment of most patients PUVA versus NBUVB used in combination with with MF. No specific study has addressed the adju- systemic therapy in MF/SS has been performed.
vant use of topical mechlorethamine specifically in Lowe et reported on the use of PUVA with patients with SS. Topical nitrogen mustard has been chemotherapy in a patient with SS with 20,000 WBC: used in combination with ECP, interferon alfa, and on failing prednisone and cyclophosphamide, PUVA MTX in 3 patients with was added leading to clearance of the erythrodermaand pruritus in only 14 PUVA treatments.
There are several reports of PUVA monotherapy There have been a number of older reports of the in SS. Kovary et noted 4 patients with SS use of leukapheresis in the treatment of (erythroderma plus 60%-80% SCs on buffy coat Most of the reports have combined intermittent evaluation): all 4 patients had a good to excellent leukapheresis with various forms of chemotherapy.
skin response but no change in the blood involve- Although there are no controlled trials to compare ment or adenopathy. They noted that efficacy the combination with chemotherapy alone, certain depended on increasing the UVA despite the initial conclusions can be made from the authors' reports.
discomfort that most patients with SS experience First, leukapheresis was well tolerated. Second, it and that continued PUVA was necessary to main- appeared to make a positive impact on the disease, tain the response (as opposed to that seen in early including pruritus and SC counts, even in those with MF). Molin and Voldenused a short course of normal leukocyte count. From the Mayo Clinic systemic steroids to prevent this initial increased experience, McEvoy et felt that the results photosensitivity. Masui et has reported on a with leukapheresis in combination with chlorambu- patient with SS with 23% SCs, CD4/CD8 ratio of 31, cil and prednisone were better than the chemother- adenopathy, and keratoderma who failed PUVA apy alone and affected both quality of life and J AM ACAD DERMATOL VOLUME 64, NUMBER 2 survival (). Other reports indicate that the and ECP in a fourth patient) had a CR in the skin and response to leukapheresis is short-lived with less a marked decrease in the circulating lymphocytes improvement over time.
including the CD41/CD7e and CD41/CD26e popu-lation and CD4/CD8 ratio on treatment with TSEBT.
Total skin electron beam radiation This raises two potential uses of TSEBT in patients Lymphoma cells generally suffer an apoptotic with SS: palliative and debulking of not only the skin, death when exposed to radiation.They are sen- but the blood tumor compartment as well.
sitive to very low doses of radiation given that there is Several other studies have addressed multimodal- typically no shoulder on the cell survival curve, ity therapy using TSEBT. In another series published which in this case is typically linear. There may be by Wilson et a different group of 44 patients other contributing factors in the cutaneous environ- with erythroderma who received TSEBT were retro- ment that are stimulated by radiation exposure that spectively evaluated. All patients received a higher may contribute to lymphocyte demise.
dose of TSEBT (minimum of 32 Gy) and 21 of these It is generally acknowledged that TSEBT should patients also received ECP that was offered neo- be used in conjunction with multimodality therapy if adjuvantly, concomitantly, or after TSEBT for a nodal, blood, or visceral involvement is present median of 6 monthly cycles. A total of 59% of the unless palliation alone is the objective. However, it patients had more than 5% SCs at the time of TSEBT is extremely useful to determine the extent of initiation. The CR rate was 73% (not biopsy con- improvement that TSEBT alone adds to the treatment firmed) for all 44 patients, 71% for those on mono- regimen before considering the results of multi- therapy, and 74% for those with combination modality therapy that include TSEBT. Patients with therapy. The 3-year disease-free survival for CRs SS have not been evaluated separately in any report was 49% for those on TSEBT alone and 81% for those of TSEBT but the experience in E-MF/SS sheds receiving a combination of TSEBT and ECP. After valuable light on its potential effects in this type of adjustment for stage and hematologic involvement, MF skin disease. The largest studies in E-MF/SS have the use of ECP was associated with improvement in been those combined from the Yale and the Ontario cause-specific survival (multivariate P = .048).
Cancer Clinic experience. Jones et alevaluated a Hence, the combination of TSEBT and ECP in group of 45 patients with MF/SS and erythroderma, patients with E-MF/SS appears to potentially en- all of whom were treated in a similar fashion and had hance clinical outcomes compared with TSEBT never received neoadjuvant (pre-TSEBT), concomi- tant, or adjuvant (post-TSEBT) therapies. Twenty- Combination of TSEBT with chemotherapy has two patients received less intensive radiation been addressed in several studies. Duvic et al (9 patients 20 Gy and 13 patients 20-30 Gy) and treated 44 patients with advanced MF/SS with 23 patients received more intensive radiation (32-40 a 4-month induction regimen of isotretinoin and Gy). Blood involvement ([5% SCs) was present in interferon alfa-2b followed by 6 cycles of alternating 21 patients. Although the immediate response did the combination of cyclophosphamide, MTX, eto- not appear to be affected by blood involvement with poside, and dexamethasone with the combination 100% OR on skin evaluation, the median overall and of doxorubicin, bleomycin, and vinblastine or with cause-specific survival (3.4 and 5 years, respectively) the combination of cyclophosphamide, MTX, eto- were negatively effected by blood involvement poside, and dexamethasone alone before TSEBT 28 based on multivariate analysis. In addition, the to 32 Gy in 44 patients with advanced disease. There dose of radiation affected the amount of histologic was an OR rate of more than 60% after induction clearing in the skin: 74% versus 45% with the more with immunomodulators alone and 73% after che- versus less intensive regimen. This confirmed earlier motherapy plus TSEBT with 70% of the CRs coming findings that a dose more than 2500 Gy gives after the TSEBT. Disease-free survival was 7 months.
enhanced results in patients with erythroderma Three studies failed to show any prevention of with more than 3000 Gy giving the best overall relapse by 3 different regimens of chemotherapy response in MFIntrocaso et alhave recently given post-EB in patients with advanced MF, includ- shown impressive responses to TSEBT alone in both ing 6 monthly cycles of mechlorethamine or cyclo- the skin and blood compartment in patients with SS defined according to present ISCL criteria. Four procarbazine, and prednisone (MOPP or COPP) patients with SS who were all already on systemic cyclophosphamide, vincristine, and prednisone immunomodulator therapy for more than 12 weeks or 6 monthly cycles of doxorubicin and cyclophos- (interferon alfa in one patient; interferon alfa plus phamiTwo studies have shown potential ECP in two patients; and interferon alfa, bexarotene, efficacy of combined therapy. Griem et alshowed J AM ACAD DERMATOL a positive prolongation of the disease-free interval pruritus is therefore challenging. The generous use post-TSEBT with the addition of MOPP or COPP.
of moisturizers and nonirritating creams and judicious Bunn et reported on a regimen of relatively use of antihistamines is critical to helping relieve this.
low-dose TSEBT (24 Gy) with concomitant and Patients with SS are known to have a high coloniza- adjuvant multiagent chemotherapy (total 54 weeks) tion by S aureusand antibiotic treatment has been with vinblastin, doxorubicin, bleomycin-cytoxan, shown to result in both clinical improvementand MTX, prednisone (VAB-CMP) in patients with stage diminished pruritus. In some patients, the use of IIB to IVB MF/SS. On comparison with historical gabapentin, a first-line treatment in the management controls at Stanford University Medical Center trea- of neuropathic pain,has helped manage pruri- ted with TSEBT alone (dose of radiation not tus.Titrating the dose of gabapentin upward addressed), there appeared to be increased survival slowly and using doses of 900 to 3600 mg per day in with the combination therapy over TSEBT alone.
two or three divided doses can be effective. The The best results with TSEBT are based on a highly primary adverse effect, sedation, may allow patients fractionated regimen of 32 to 36 Gy with appropriate with SS to sleep and function better in the daytime and shielding as per standard protocol. A fractionated the PK of gabapentin make drug interactions un- regimen over 9 weeks is recommended in an effort to likIf gabapentin is not effective enough at minimize both acute and chronic effects. Given the night, substituting the evening dose with a low dose technically complicated nature of TSEBT, it is rec- of mirtazapine 7.5 to 15 mg will help ensure sleep.
ommended that it be provided at centers with Mirtazapine has a wide therapeutic index and can be experience in the techniqu used safely with other medications.A report of the All patients who receive TSEBT will experience effectiveness of topical naloxfor pruritus in MF skin erythema, hair loss, and hyperpigmentation.
supports the opinergic pathways as potentially re- Nail dystrophy and lower extremity edema occur in lated to this process and opens the door for evaluation approximately 50%, and a minority of patients will of systemic opioid antagonists in the treatment of experience lower extremity edema and bullae when pruritus in MF/SS. Most recently, 3 patients with SS such therapy is administered with a 36-fraction course, were treated with 80 mg a day of aprepitant, an oral 4 days per week. Some patients will experience neurokinin-1-receptor antagonist widely used as an decreased sweating and difficulty with body temper- antiemetic agent in chemotherapy-induced nausea ature control. Late side effects include an increased and vomiting, with more than 75% improvement in incidence of nonmelanoma skin cancers. Both pruritus.The treatment of the disease itself with acute and chronic radiation dermatitis may occur.
targeted therapies will also help manage pruritus.
The effect on pruritus of new therapeutic agents Antipruritic therapy for MF and SS has been addressed and measured in Although patients with early-stage MF generally several recent clinical trials. A relevant aspect of this have pruritus limited to involved areas, patients with evaluation is the definition of ‘‘pruritus relief'' used in more advanced disease, particularly those with SS, two recent reports of MF/SS treated with HDAC commonly report severe, diffuse, and less well- inhibitors. In the phase IIB study of vorinostat in defined pruritus. Pruritus may become so severe stage IB to IV MF and SS, pruritus relief was defined and debilitating that it can result in poor health- as $ 3-point reduction in those with pruritus score of related quality of lifePatients with SS may also $ 3 points at baseline or complete reduction of describe pain, burning, tightness, and sharp pins-and- pruritus, both for $ 4 continuous weeks without an needles sensations similar to established neuropathic increase in antipruritic medication. Treatment with pain syndromes such as diabetic neuropathy, post- vorinostat was associated with pruritus relief in 21 of herpetic neuralgia, and neuropathic cancer pain 65 patients (32%) whose pruritus was 3 or higher at In a recent quality of life survey using the Skindex-29 baseline and in 13 of 30 patients (43%) with severe and EORTC Quality of Life Questionnaire (QLQ)-C30, pruritus (a baseline score of 7 to 10 points); patients with SS had the worst health-related quality antihistamine use was not excluded. In the trial of of life compared with patients with MF or cutaneous romidepsin, significant pruritus relief was defined by a decrease of 30 mm or more from baseline on a The exact pathophysiology of pruritus in SS is not 100-point VAS (similar to the vorinostat study) or a known. It is likely a result of several contributing pruritus score of 0 for two or more consecutive factors, including peripheral blood cytokine imbal- cycles. By this definition and with the exclusion of ance, skin infiltration by neoplastic cells, super- steroid and antihistamine use, 25 of 52 (48%) patients infection, and an impaired epidermal barrier with experienced significant pruritus relief.Of note transepidermal water loss. The management of in an in-depth study of the impact of pruritus on J AM ACAD DERMATOL VOLUME 64, NUMBER 2 health-related quality of life of 20 patients with MF Table V. Principles of therapy for S and SS, the median change (decrease on a 10-pointVAS) in pruritus as reported by patients to represent a d Use disease burden and rapidity of progression as meaningful improvement was 3, in line with what determinants of approach to therapy both vorinostat and romidepsin trials have used (M-F d Preserve immune response whenever possible Demierre, MD and E. Olsen MD, unpublished data).
d Use immunomodulatory therapy before chemotherapy In other trials, it has been reported that the anti-CD52 unless burden of disease or failure of prior such thera- mAb, alemtuzumab, currently used in SS, improves pies warrants otherwise pruritus in responders.
d Always consider combination therapy, particularly sys- What is not yet clear is the degree by which temic immunomodulatory plus skin-directed treatments,which in general has greater efficacy than monotherapy improvement in pruritus correlates with OR. In the d Consider potential Staphylococcus infection as cause of aforementioned vorinostat trial, significant relief worsening disease and maintain low threshold for use of from pruritus was observed in 47.6% of the 21 systemic antibiotics to prevent life-threatening sepsis patients with an OR and in 25.5% of 51 patients d Preserve quality of life by aggressive treatment of without an ORIn the recent romidepsin pivotal trial, clinically meaningful improvement in prurituswas observed in 28 (43%) of 65 patients with mod-erate to severe pruritus at baseline, which included11 patients who did not achieve an objective disease efficacy as monotherapy have not been tested in response.There is a wide number of agents clinical trials with adjuvant skin-directed therapy or commonly used in SS, such as bexarotene, inter- as part of a multimodality therapeutic regimen but of feron, and ECP, in which their impact on pruritus has those that have, there has generally been an increase not been evaluated so that comparative information between treatments is lacking.
There are several important principles that should be considered when selecting therapy for a patient RECOMMENDATIONS FOR THERAPY with SS ). Initially, choice of therapy should With few exceptions, there is a dearth of efficacy be based on the relative burden of disease, impact on data on therapeutic agents used to treat patients with quality of life, and rapidity with which the disease is SS. This is a result of several factors including that progressing. With regard to burden of disease, issues frequently the response for patients with SS is not to note include the degree of infiltration of the reported separately from patients with advanced MF skin, the presence or absence of tumors on the skin, and/or the number of patients with SS in any given the extent of lymphadenopathy, the relative burden trial is small either because of the relative paucity of of circulating malignant T cells, and the rate of patients with SS compared with MF or because increase of the serum lactate dehydrogenase and of patients with SS are specifically excluded from study the peripheral WBC count. Furthermore, when con- inclusion. This review has also highlighted that there sidering the initial therapeutic approach, whenever has not until recently been a consistent definition of possible, preservation of the immune response is SS used by investigators and clinicians nor attention exceedingly important. Because the malignant T cells to the effect on both skin and blood in any given produce soluble factors that are responsible for patient with SS, further narrowing the information endogenous immune suppression leading to height- available on a meaningful response. In this review, ened susceptibility to infection, further suppression we have focused on the literature available where of the immune response can have deleterious effects.
the diagnosis of SS could be confirmed and where Therefore, the use of immune modulatory therapies the response definition was clearly delineated. In that can augment host immunity, such as interferon addition, the collective experience of the authors has alfa or interferon gamma, together with retinoids been taken into consideration in confirming the list and/or ECP should be considered as initial treatment of recommended therapies in choices. The addition of skin-directed therapies can Based on the extensive current review of published lead to further debulking of tumor cells without trials of SS, the following suggestions for treatment of producing a significant adverse impact on the SS are made These suggestions mirror for immune response.
the most part the recently published NCCN guidelines Thus, combination or multimodality approaches but have been modified based on this literature should be encouraged when possible as emerging review, with the acknowledgement that the number evidence suggests that higher RRs may be achievable of patients reported with each treatment may be small.
and that responses may occur in a more accelerated Many of the systemic therapies that have shown manner. For example, use of PUVA with interferon J AM ACAD DERMATOL may enhance RRs in comparison with PUVA alone.
been reported separately that both may not respond Moreover, responses to ECP together with interferon in tandem. Therefore, in future clinical trials of SS, and bexarotene may yield higher RRs when com- the inclusion of an evaluation of blood tumor burden pared with ECP alone. The addition of TSEBT to the determined either by flow cytometry or by periph- latter multimodality regimen will likely further aug- eral blood SCs quantified by a central laboratory and ment responses in the skin and in the peripheral the report of results for SS separately from other blood compartment. Another combination that de- patients with MF would help to determine the serves further exploration is dual therapy with MTX usefulness of various agents in this subtype of CTCL.
and interferon alfa, which as summarized previouslyin this review, may lead to high RRs.
All of the above choices would be suitable for a 1. Sezary A, Bouvrain Y. Erythrodermie avec presence de cellules monstreuses dans le derme et le sang circulant.
patient with a new diagnosis and without signs of Bull Soc Fr Dermatol Syph 1938;45:254-60.
rapid progression of disease. However, should the 2. Sezary A. La reticulose maligne leucemique a histio- patient's progression appear to be rapid, then con- sideration should be given to the use of a therapeutic cedemateuse et pigmentee. Ann Dermatol Syph 1949;8:5-22.
approach that might lead to the accelerated removal 3. Clendenning W, Brecher G, Van Scott E. Mycosis fungoides: relationship to malignant cutaneous reticulosis and the of large numbers of tumor cells. This might include a Sezary syndrome. Arch Dermatol 1964;89:785-92.
chemotherapeutic drug or regimen in category B of 4. Olsen E, Vonderheid E, Pimpinelli N, Willemze R, Kim Y, keeping in mind that many of the chemo- Knobler R, et al. Revisions to the staging and classification of therapeutic approaches in category B tend not to be mycosis fungoides and Sezary syndrome: a proposal of the associated with sustained clinical responses or are International Society for Cutaneous Lymphomas (ISCL) andthe cutaneous lymphoma task force of the European Orga- able to be continued long term for maintenance nization of Research and Treatment of Cancer (EORTC). Blood therapy and are likely to depress the host immune response. Thus, a resumption of immune modula- 5. Lutzner M, Jordan H. The ultrastructure of an abnormal cell in tory therapy should be considered at the earliest Sezary's syndrome. Blood 1968;31:719-26.
possible time. It is noteworthy that immune modu- 6. Bunn PA Jr, Lamberg SI. Report of the committee on staging and classification of cutaneous T-cell lymphomas. Cancer lators may be less effective when used immediately Treat Rep 1979;63:725-8.
after an intensive regimen of chemotherapeutics.
7. Willemze R, van Vloten WA, Hermans J, Damsteeg MJ, Meijer When this approach fails to produce the desired CJ. Diagnostic criteria in Sezary's syndrome: a multiparameter clinical benefit, other agents may be considered that study of peripheral blood lymphocytes in 32 patients with are efficacious and produce short-term immune erythroderma. J Invest Dermatol 1983;81:392-7.
8. van der Loo EM, Meijer CJ, Scheffer E, van Vloten WA. The suppression. An excellent choice for patients refrac- prognostic value of membrane markers and morphometric tory to immunomodulators is the mAb alemtuzumab characteristics of lymphoid cells in blood and lymph nodes used in a low-dose regimen popularized by from patients with mycosis fungoides. Cancer 1981;48: Bernengo et It is extremely effective at debulk- ing the blood and erythrodermic skin of malignant T 9. Duncan SC, Winkelmann RK. Circulating Sezary cells in hospitalized dermatology patients. Br J Dermatol 1978;99: cells. Clinical responses can be quite prolonged, and, with the addition of prophylaxis against infection 10. Vonderheid EC, Bigler RD, Kotecha A, Boselli CM, Lessin SR, with trimethoprim-sulfamethoxazole, voriconazole, Bernengo MG, et al. Variable CD7 expression on T cells in the and acyclovir, serious infection rates can be low. The leukemic phase of cutaneous T cell lymphoma (Sezary fusion protein denileukin diftitox, which is among syndrome). J Invest Dermatol 2001;117:654-62.
11. Harmon CB, Witzig TE, Katzmann JA, Pittelkow MR. Detection agents listed in category A of does not of circulating T cells with CD41CD7e immunophenotype in appear to profoundly suppress the immune re- patients with benign and malignant lymphoproliferative sponse. However, it is best used among patients dermatoses. J Am Acad Dermatol 1996;35:404-10.
with a low circulating burden of malignant T cells as 12. Wood GS, Hong SR, Sasaki DT, Abel EA, Hoppe RT, Warnke a high tumor burden may serve as a ‘‘sink'' for this RA, et al. Leu-8/CD7 antigen expression by CD31 T cells:comparative analysis of skin and blood in mycosis fungoi- drug leading to an inadequate systemic response at des/Sezary syndrome relative to normal blood values. J Am the recommended doses. Refractory patients should Acad Dermatol 1990;22:602-7.
also be considered for clinical trials or allogeneic 13. Jones D, Dang NH, Duvic M, Washington LT, Huh YO.
transplantation before the introduction of prolonged Absence of CD26 expression is a useful marker for diagnosis courses of multidrug chemotherapy.
of T-cell lymphoma in peripheral blood. Am J Clin Pathol2001;115:885-92.
We recommend continued evaluation in clinical 14. Bernengo MG, Novelli M, Quaglino P, Lisa F, De Matteis A, trials of a combination of skin-directed and single or Savoia P, et al. The relevance of the CD41 CD26e subset in multiple systemic therapies for SS. It is also obvious the identification of circulating Sezary cells. Br J Dermatol from studies where the results in skin and blood have J AM ACAD DERMATOL VOLUME 64, NUMBER 2 15. Abel EA, Lindae ML, Hoppe RT, Wood GS. Benign and defective IL-12 and TNF-alpha production in Sezary syn- malignant forms of erythroderma: cutaneous immunophe- drome: circumvention by hexameric soluble CD40L. Blood notypic characteristics. J Am Acad Dermatol 1988;19:1089-95.
16. Bakels V, van Oostveen JW, Gordijn RL, Walboomers JM, 32. Berger CL, Tigelaar R, Cohen J, Mariwalla K, Trinh J, Wang N, Meijer CJ, Willemze R. Diagnostic value of T-cell receptor beta et al. Cutaneous T-cell lymphoma: malignant proliferation of gene rearrangement analysis on peripheral blood lympho- T-regulatory cells. Blood 2005;105:1640-7.
cytes of patients with erythroderma. J Invest Dermatol 1991; 33. Walsh PT, Benoit BM, Wysocka M, Dalton NM, Turka LA, Rook AH. A role for regulatory T cells in cutaneous T-Cell lym- 17. Weinberg JM, Jaworsky C, Benoit BM, Telegan B, Rook AH, phoma; induction of a CD41 CD251 Foxp31 T-cell pheno- Lessin SR. The clonal nature of circulating Sezary cells. Blood type associated with HTLV-1 infection. J Invest Dermatol 18. Posnett DN, Sinha R, Kabak S, Russo C. Clonal populations of T 34. Yawalkar N, Ferenczi K, Jones DA, Yamanaka K, Suh KY, Sadat cells in normal elderly humans: the T cell equivalent to ‘‘benign S, et al. Profound loss of T-cell receptor repertoire complexity monoclonal gammapathy.'' J Exp Med 1994;179:609-18.
in cutaneous T-cell lymphoma. Blood 2003;102:4059-66.
19. Vonderheid EC, Bernengo MG, Burg G, Duvic M, Heald P, 35. Yamanaka K, Fuhlbrigge RC, Mizutani H, Kupper TS. Resto- Laroche L, et al. Update on erythrodermic cutaneous T-cell ration of peripheral blood T cell repertoire complexity during lymphoma: report of the International Society for Cutaneous remission in advanced cutaneous T cell lymphoma. Arch Lymphomas. J Am Acad Dermatol 2002;46:95-106.
Dermatol Res 2010;302:453-9.
20. Kim EJ, Hess S, Richardson SK, Newton S, Showe LC, Benoit 36. Kallinich T, Muche JM, Qin S, Sterry W, Audring H, Kroczek RA.
BM, et al. Immunopathogenesis and therapy of cutaneous Chemokine receptor expression on neoplastic and reactive T T cell lymphoma. J Clin Invest 2005;115:798-812.
cells in the skin at different stages of mycosis fungoides.
21. Ferenczi K, Fuhlbrigge RC, Pinkus J, Pinkus GS, Kupper TS.
J Invest Dermatol 2003;121:1045-52.
Increased CCR4 expression in cutaneous T cell lymphoma.
37. Yamanaka K, Clark R, Rich B, Dowgiert R, Hirahara K, Hurwitz J Invest Dermatol 2002;119:1405-10.
D, et al. Skin-derived interleukin-7 contributes to the prolif- 22. Introcaso CE, Hess SD, Kamoun M, Ubriani R, Gelfand JM, eration of lymphocytes in cutaneous T-cell lymphoma. Blood Rook AH. Association of change in clinical status and change in the percentage of the CD41CD26e lymphocyte population 38. Yoo EK, Cassin M, Lessin SR, Rook AH. Complete molecular in patients with Sezary syndrome. J Am Acad Dermatol 2005; remission during biologic response modifier therapy for Sezary syndrome is associated with enhanced helper T type 23. Wysocka M, Zaki MH, French LE, Chehimi J, Shapiro M, 1 cytokine production and natural killer cell activity. J Am Everetts SE, et al. Sezary syndrome patients demonstrate Acad Dermatol 2001;45:208-16.
a defect in dendritic cell populations: effects of CD40 39. Kim YH, Liu HL, Mraz-Gernhard S, Varghese A, Hoppe RT.
ligand and treatment with GM-CSF on dendritic cell Long-term outcome of 525 patients with mycosis fungoides numbers and the production of cytokines. Blood 2002; and Sezary syndrome: clinical prognostic factors and risk for disease progression. Arch Dermatol 2003;139:857-66.
24. Wysocka M, Benoit BM, Newton S, Azzoni L, Montaner LJ, 40. Horwitz SM, Olsen EA, Duvic M, Porcu P, Kim YH. Review of Rook AH. Enhancement of the host immune responses in the treatment of mycosis fungoides and Sezary syndrome: a cutaneous T-cell lymphoma by CpG oligodeoxynucleotides stage-based approach. J Natl Compr Canc Netw 2008;6: and IL-15. Blood 2004;104:4142-9.
25. Bouaziz JD, Ortonne N, Giustiniani J, Schiavon V, Huet D, 41. Olsen EA, Kim YH, Kuzel TM, Pacheco TR, Foss FM, Parker S, Bagot M, et al. Circulating natural killer lymphocytes are et al. Phase IIb multicenter trial of vorinostat in patients with potential cytotoxic effectors against autologous malignant persistent, progressive, or treatment refractory cutaneous T- cells in Sezary syndrome patients. J Invest Dermatol 2005; cell lymphoma. J Clin Oncol 2007;25:3109-15.
42. Bernengo MG, Quaglino P, Comessatti A, Ortoncelli M, Novelli 26. Lee J, Richardson SK, Melhem ER, Rook AH, Kim EJ. Progress- M, Lisa F, et al. Low-dose intermittent alemtuzumab in the ive multifocal leukoencephalopathy from JC virus in a patient ezary syndrome: clinical and immunologic with advanced mycosis fungoides. J Am Acad Dermatol 2007; findings in 14 patients. Haematologica 2007;92:784-94.
43. Vidulich KA, Talpur R, Bassett RL, Duvic M. Overall survival in 27. Nizet V, Ohtake T, Lauth X, Trowbridge J, Rudisill J, Dorschner erythrodermic cutaneous T-cell lymphoma: an analysis of RA, et al. Innate antimicrobial peptide protects the skin from prognostic factors in a cohort of patients with erythrodermic invasive bacterial infection. Nature 2001;414:454-7.
cutaneous T-cell lymphoma. Int J Dermatol 2009;48:243-52.
28. Vowels BR, Cassin M, Vonderheid EC, Rook AH. Aberrant 44. Willemze R, Jaffe ES, Burg G, Cerroni L, Berti E, Swerdlow SH, cytokine production by Sezary syndrome patients: cytokine et al. WHO-EORTC classification for cutaneous lymphomas.
secretion pattern resembles murine Th2 cells. J Invest 45. Harris RP, Helfand M, Woolf SH, Lohr KN, Mulrow CD, Teutsch 29. Asadullah K, Docke WD, Haeussler A, Sterry W, Volk HD.
SM, et al. Current methods of the US Preventive Services Progression of mycosis fungoides is associated with increas- Task Force: a review of the process. Am J Prev Med 2001;20: ing cutaneous expression of interleukin-10 mRNA. J Invest 46. National Comprehensive Cancer Network. NCCN clinical 30. Kari L, Loboda A, Nebozhyn M, Rook AH, Vonderheid EC, practice guidelines in oncology: non-Hodgkin's lymphoma.
Nichols C, et al. Classification and prediction of survival in V.1, 2009. Available at: Accessed November patients with the leukemic phase of cutaneous T cell lymphoma. J Exp Med 2003;197:1477-88.
47. Olsen EA, Bunn PA. Interferon in the treatment of cutaneous 31. French LE, Huard B, Wysocka M, Shane R, Contassot E, T-cell lymphoma. Hematol Oncol Clin North Am 1995;9: Arrighi JF, et al. Impaired CD40L signaling is a cause of J AM ACAD DERMATOL 48. Lai L, Hui CK, Leung N, Lau GK. Pegylated interferon alpha-2a and Sezary syndrome treated by interferon-alfa. Br J Derma- (40 kDa) in the treatment of chronic hepatitis B. Int J 68. Stadler R, Otte HG. Combination therapy of cutaneous T cell 49. Infergen [package insert]. Warrendale, PA: Three Rivers lymphoma with interferon alpha-2a and photochemother- apy. Recent Results Cancer Res 1995;139:391-401.
50. Dinarello CA, Mier JW. Lymphokines. N Engl J Med 1987;317: 69. Roenigk HH Jr, Kuzel TM, Skoutelis AP, Springer E, Yu G, Caro W, et al. Photochemotherapy alone or combined with 51. Koeller JM. Biologic response modifiers: the interferon alfa interferon alpha-2a in the treatment of cutaneous T-cell experience. Am J Hosp Pharm 1989;46:S11-5.
lymphoma. J Invest Dermatol 1990;95:198S-205S.
52. Olsen EA. Interferon in the treatment of cutaneous T-cell 70. Salvagno L, Bononi A, Cola P, Chiarantano MR, Peila R, lymphoma. Dermatol Ther 2003;16:311-21.
Lorenzi G, et al. Interferon alfa-2A (IFN) and phototherapy 53. Rook AH, Heald P. The immunopathogenesis of cutaneous T- (PUVA) for mycosis fungoides and Sezary syndrome. Ab- cell lymphoma. Hematol Oncol Clin North Am 1995;9: stract No. 131 presented at: 1999 ASCO Annual Meeting; 54. Gottlieb SL, Wolfe JT, Fox FE, DeNardo BJ, Macey WH, 71. Kuzel TM, Gilyon K, Springer E, Variakojis D, Kaul K, Bunn PA Bromley PG, et al. Treatment of cutaneous T-cell lymphoma Jr, et al. Interferon alfa-2a combined with phototherapy in with extracorporeal photopheresis monotherapy and in the treatment of cutaneous T-cell lymphoma. J Natl Cancer combination with recombinant interferon alfa: a 10-year Inst 1990;82:203-7.
experience at a single institution. J Am Acad Dermatol 72. Chiarion-Sileni V, Bononi A, Fornasa CV, Soraru M, Alaibac M, Ferrazzi E, et al. Phase II trial of interferon-alpha-2a plus 55. Olsen EA, Rosen ST, Vollmer RT, Variakojis D, Roenigk HH Jr, psoralen with ultraviolet light A in patients with cutaneous T- Diab N, et al. Interferon alfa-2a in the treatment of cutaneous cell lymphoma. Cancer 2002;95:569-75.
T cell lymphoma. J Am Acad Dermatol 1989;20:395-407.
73. Knobler RM, Trautinger F, Radaszkiewicz T, Kokoschka EM, 56. Kuzel TM, Roenigk HH Jr, Samuelson E, Herrmann JJ, Hurria A, Micksche M. Treatment of cutaneous T cell lymphoma with a Rademaker AW, et al. Effectiveness of interferon alfa-2a combination of low-dose interferon alfa-2b and retinoids.
combined with phototherapy for mycosis fungoides and J Am Acad Dermatol 1991;24:247-52.
the Sezary syndrome. J Clin Oncol 1995;13:257-63.
74. Thestrup-Pedersen K, Hammer R, Kaltoft K, Sogaard H, 57. de Mel WC, Hoffbrand AV, Giles FJ, Goldstone AH, Mehta AB, Zachariae H. Treatment of mycosis fungoides with recombi- Ganeshaguru K. Alpha interferon therapy for hematological nant interferon-alpha 2a2 alone and in combination with malignancies: correlation between in vivo induction of the etretinate. Br J Dermatol 1988;118:811-8.
2',5'oligoadenylate system and clinical response. Br J Hae- 75. Stavrianeas N, Katsambas A, Vareltzides A, Stavropoulos P, Polydorou D, Zika P, et al. Treatment of mycosis fungoides 58. Rajan GP, Seifert B, Prummer O, Joller-Jemelka HI, Burg G, with recombinant alpha 2B interferon in combination with Dummer R. Incidence and in-vivo relevance of anti-interferon etretinate. J Invest Dermatol 1989;93:580.
antibodies during treatment of low-grade cutaneous T-cell 76. Straus DJ, Duvic M, Kuzel T, Horwitz S, Demierre MF, lymphomas with interferon alpha-2a combined with acitretin Myskowski P, et al. Results of a phase II trial of oral or PUVA. Arch Dermatol Res 1996;288:543-8.
bexarotene (Targretin) combined with interferon alfa-2b 59. Kirkwood JM, Ernstoff MS. Interferons in the treatment of (Intron-A) for patients with cutaneous T-cell lymphoma.
human cancer. J Clin Oncol 1984;2:336-52.
60. Sun WH, Pabon C, Alsayed Y, Huang PP, Jandeska S, Uddin S, 77. McGinnis KS, Junkins-Hopkins JM, Crawford G, Shapiro M, Rook et al. Interferon-alpha resistance in a cutaneous T-cell lym- AH, Vittorio CC. Low-dose oral bexarotene in combination with phoma cell line is associated with lack of STAT1 expression.
low-dose interferon alfa in the treatment of cutaneous T-cell lymphoma: clinical synergism and possible immunologic 61. Papa G, Tura S, Mandelli F, Vegna ML, Defazio D, Mazza P, mechanisms. J Am Acad Dermatol 2004;50:375-9.
et al. Is interferon alpha in cutaneous T-cell lymphoma a 78. Foss FM, Ihde DC, Breneman DL, Phelps RM, Fischmann AB, treatment of choice? Br J Haematol 1991;79(Suppl):48-51.
Schechter GP, et al. Phase II study of pentostatin and 62. Bunn PA Jr, Ihde DC, Foon KA. The role of recombinant intermittent high-dose recombinant interferon alfa-2a in interferon alfa-2a in the therapy of cutaneous T-cell lympho- advanced mycosis fungoides/Sezary syndrome. J Clin Oncol mas. Cancer 1986;57:1689-95.
63. Mughal TI. Role of interferon alfa-2b in the management of 79. Foss FM, Ihde DC, Linnoila IR, Fischmann AB, Schechter GP, patients with advanced cutaneous T-cell lymphoma. Eur J Cotelingam JD, et al. Phase II trial of fludarabine phosphate and interferon alfa-2a in advanced mycosis fungoides/S 64. Dallot A, Teyeux C, Gorin I. Interferon treatment in cutaneous syndrome. J Clin Oncol 1994;12:2051-9.
lymphomas. Proceedings of the International Society of 80. Ferenczi K, Yawalkar N, Jones D, Kupper TS. Monitoring the Hematology 22nd Congress; 1988; Milan, Italy; p. 267.
decrease of circulating malignant T cells in cutaneous T-cell 65. Nicolas JF, Balblanc JC, Frappaz A, Chouvet B, Delcombel M, lymphoma during photopheresis and interferon therapy.
Thivolet J. Treatment of cutaneous T cell lymphoma with Arch Dermatol 2003;139:909-13.
intermediate doses of interferon alpha 2a. Dermatologica 81. Haley HR, Davis DA, Sams WM. Durable loss of a malignant T- cell clone in a stage IV cutaneous T-cell lymphoma patient 66. Dreno B, Claudy A, Meynadier J, Verret JL, Souteyrand P, treated with high-dose interferon and photopheresis. J Am Ortonne JP, et al. The treatment of 45 patients with cutane- Acad Dermatol 1999;41:880-3.
ous T-cell lymphoma with low doses of interferon-alpha 2a 82. Vonderheid EC, Bigler RD, Greenberg AS, Neukum SJ, Micaily B.
and etretinate. Br J Dermatol 1991;125:456-9.
Extracorporeal photopheresis and recombinant interferon alfa 67. Jumbou O, N'Guyen JM, Tessier MH, Legoux B, Dreno B.
2b in Sezary syndrome: use of dual marker labeling to monitor Long-term follow-up in 51 patients with mycosis fungoides therapeutic response. Am J Clin Oncol 1994;17:255-63.
J AM ACAD DERMATOL VOLUME 64, NUMBER 2 83. Bouwhuis SA, McEvoy MT, Davis MD. Sustained remission of gamma for treatment of cutaneous T-cell lymphoma. J Natl Sezary syndrome. Eur J Dermatol 2002;12:287-90.
Cancer Inst 1990;82:208-12.
84. Dippel E, Schrag H, Goerdt S, Orfanos CE. Extracorporeal 100. Shapiro M, Rook AH, Lehrer MS, Junkins Hopkins JM, French photopheresis and interferon-alpha in advanced cutaneous LE, Vittorio CC. Novel multimodality biologic response mod- T-cell lymphoma. Lancet 1997;350:32-3.
ifier therapy including bexarotene and long-wave ultraviolet 85. Rook AH, Prystowsky MB, Cassin M, Boufal M, Lessin SR.
A for a patient with refractory stage IVa cutaneous T-cell Combined therapy for Sezary syndrome with extracorporeal lymphoma. J Am Acad Dermatol 2002;47:956-61.
photochemotherapy and low-dose interferon alfa therapy: 101. McGinnis KS, Ubriani R, Newton S, Junkins-Hopkins JM, clinical, molecular, and immunologic observations. Arch Vittorio CC, Kim EJ, et al. The addition of interferon gamma to oral bexarotene therapy with photopheresis for Sezary 86. Cohen JH, Lessin SR, Vowels BR, Benoit B, Witmer WK, Rook syndrome. Arch Dermatol 2005;141:1176-8.
AH. The sign of Leser-Trelat in association with Sezary 102. Gardner JM, Introcaso CE, Nasta SD, Kim EJ, Vittorio CC, Rook AH.
syndrome: simultaneous disappearance of seborrheic kera- A novel regimen of vorinostat with interferon gamma for toses and malignant T-cell clone during combined therapy refractory Sezary syndrome. J Am Acad Dermatol 2009;61:112-6.
with photopheresis and interferon alfa. Arch Dermatol 1993; 103. Dummer R, Hassel JC, Fellenberg F, Eichmuller S, Maier T, Slos P, et al. Adenovirus-mediated intralesional interferon-gamma 87. Zackheim HS. Evidence is lacking for a synergistic or additive gene transfer induces tumor regressions in cutaneous lym- effect of combination extracorporeal photopheresis with phomas. Blood 2004;104:1631-8.
interferon alfa for cutaneous T-cell lymphoma. J Am Acad 104. Shimauchi T, Sugita K, Nishio D, Isoda H, Abe S, Yamada Y, et al. Alterations of serum Th1 and Th2 chemokines by 88. Booken N, Weiss C, Utikal J, Felcht M, Goerdt S, Klemke CD.
combination therapy of interferon-gamma and narrowband Combination therapy with extracorporeal photopheresis, UVB in patients with mycosis fungoides. J Dermatol Sci 2008; interferon-alpha, PUVA and topical corticosteroids in the management of Sezary syndrome. J Dtsch Dermatol Ges 105. Querfeld C, Nagelli LV, Rosen ST, Kuzel TM, Guitart J.
Bexarotene in the treatment of cutaneous T-cell lymphoma.
89. Aviles A, Nambo MJ, Neri N, Castaneda C, Cleto S, Gonzalez Expert Opin Pharmacother 2006;7:907-15.
M, et al. Interferon and low dose methotrexate improve 106. Budgin JB, Richardson SK, Newton SB, Wysocka M, Zaki MH, outcome in refractory mycosis fungoides/Sezary syndrome.
Benoit B, et al. Biological effects of bexarotene in cutaneous Cancer Biother Radiopharm 2007;22:836-40.
T-cell lymphoma. Arch Dermatol 2005;141:315-21.
90. Vonderheid EC, Zhang Q, Lessin SR, Polansky M, Abrams JT, 107. Richardson SK, Newton SB, Bach TL, Budgin JB, Benoit BM, Lin Bigler RD, et al. Use of serum soluble interleukin-2 receptor JH, et al. Bexarotene blunts malignant T-cell chemotaxis in levels to monitor the progression of cutaneous T-cell lym- Sezary syndrome: reduction of chemokine receptor 4-positive phoma. J Am Acad Dermatol 1998;38:207-20.
lymphocytes and decreased chemotaxis to thymus and 91. Ranki A. Bexarotene combination therapy for patients with activation-regulated chemokine. Am J Hematol 2007;82:792-7.
Sezary syndrome. Dermatol Clin 2008;26(Suppl):55-7.
108. Cheng SX, Kupper T. A new rexinoid for cutaneous T-cell 92. Richardson SK, Lin JH, Vittorio CC, Kim EJ, Yoon JS, Junkins- lymphoma. Arch Dermatol 2001;137:649-52.
Hopkins J, et al. High clinical response rate with multi- 109. Physicians' desk reference. 57th ed. Montvale (NJ): Medical modality immunomodulatory therapy for Sezary syndrome.
Economics; 2003.
Clin Lymphoma Myeloma 2006;7:226-32.
110. Duvic M, Hymes K, Heald P, Breneman D, Martin AG, 93. Bagazgoitia L, Perez-Carmona L, Rios L, Munoz E, Harto A, Myskowski P, et al. Bexarotene is effective and safe for Jaen P. Acute hyperkeratotic and desquamative reaction in a treatment of refractory advanced-stage cutaneous T-cell patient with Sezary syndrome treated with bexarotene. J Eur lymphoma: multinational phase II-III trial results. J Clin Oncol Acad Dermatol Venereol 2008;22:389-90.
94. Fritz TM, Kleinhans M, Nestle FO, Burg G, Dummer R.
111. Abbott RA, Whittaker SJ, Morris SL, Russell-Jones R, Hung T, Combination treatment with extracorporeal photopheresis, Bashir SJ, et al. Bexarotene therapy for mycosis fungoides interferon alfa and interleukin-2 in a patient with the S ezary syndrome. Br J Dermatol 2009;160:1299-307.
syndrome. Br J Dermatol 1999;140:1144-7.
112. Bagot M. Treatment of Sezary syndrome with bexarotene 95. McGinnis KS, Shapiro M, Vittorio CC, Rook AH, Junkins- after IFNalpha and methotrexate failure. Dermatol Clin 2008; Hopkins JM. Psoralen plus long-wave UV-A (PUVA) and bexarotene therapy: an effective and synergistic combined 113. Bouwhuis SA, Davis MD, el-Azhary RA, McEvoy MT, Gibson LE, adjunct to therapy for patients with advanced cutaneous T- Knudsen JM, et al. Bexarotene treatment of late-stage cell lymphoma. Arch Dermatol 2003;139:771-5.
mycosis fungoides and Sezary syndrome: development of 96. Introcaso CE, Micaily B, Richardson SK, Junkins-Hopkins JM, extracutaneous lymphoma in 6 patients. J Am Acad Dermatol Yoon JS, Kim EJ, et al. Total skin electron beam therapy may be associated with improvement of peripheral blood disease 114. Ruiz-de-Casas A, Carrizosa-Esquivel A, Herrera-Saval A, Rios- in Sezary syndrome. J Am Acad Dermatol 2008;58:592-5.
Martin JJ, Camacho F. Sezary syndrome associated with 97. Coors EA, von den Driesch P. Treatment of erythrodermic granulomatous lesions during treatment with bexarotene. Br cutaneous T-cell lymphoma with intermittent chlorambucil J Dermatol 2006;154:372-4.
and fluocortolone therapy. Br J Dermatol 2000;143:127-31.
115. Tsirigotis P, Pappa V, Papageorgiou S, Kapsimali V, Giannopou- 98. Rook AH, Junkins-Hopkins JM, McGinnis KS, Wysocka M, lou V, Kaitsa I, et al. Extracorporeal photopheresis in combina- Richardson SK, Budgin JB, et al. Cytokines and other biologic tion with bexarotene in the treatment of mycosis fungoides agents as immunotherapeutics for cutaneous T-cell lym- and Sezary syndrome. Br J Dermatol 2007;156:1379-81.
phoma. Adv Dermatol 2002;18:29-43.
116. Singh F, Lebwohl MG. Cutaneous T-cell lymphoma treatment 99. Kaplan EH, Rosen ST, Norris DB, Roenigk HH Jr, Saks SR, Bunn using bexarotene and PUVA: a case series. J Am Acad PA Jr. Phase II study of recombinant human interferon J AM ACAD DERMATOL 117. Huber MA, Kunzi-Rapp K, Staib G, Scharffetter-Kochanek K.
137. Bollag W, Isnardi L, Jablonska S, Klaus M, Majewski S, Pirson Management of refractory early-stage cutaneous T-cell lym- W, et al. Links between pharmacological properties of phoma (mycosis fungoides) with a combination of oral retinoids and nuclear retinoid receptors. Int J Cancer 1997; bexarotene and psoralen plus ultraviolet bath therapy.
J Am Acad Dermatol 2004;50:475-6.
138. Sacchi S, Russo D, Avvisati G, Dastoli G, Lazzarino M, Pelicci 118. Stern DK, Lebwohl M. Treatment of mycosis fungoides with PG, et al. All-trans retinoic acid in hematological malignan- oral bexarotene combined with PUVA. J Drugs Dermatol cies, an update: GER (Gruppo Ematologico Retinoidi). Hae- 119. Papadavid E, Antoniou C, Nikolaou V, Siakantaris M, Vassila- 139. Newton SB, Yoon JS, Benoit BM, Wysocka M, Rook AH. Apoptotic kopoulos TP, Stratigos A, et al. Safety and efficacy of low- responses to all-trans retinoic acid of Targretin-resistant, malig- dose bexarotene and PUVA in the treatment of patients with nant, CD41 peripheral blood T cells from patients with S mycosis fungoides. Am J Clin Dermatol 2008;9:169-73.
syndrome. Arch Dermatol 2007;143:661-2.
120. Kreuter A, Altmeyer P. Rapid onset of CD81 aggressive T-cell 140. Lazzarino M, Corso A, Regazzi MB, Iacona I, Bernasconi C.
lymphoma during bexarotene therapy in a patient with Modulation of all-trans retinoid acid pharmacokinetics in Sezary syndrome. J Am Acad Dermatol 2005;53:1093-5.
acute promyelocytic leukemia by prolonged interferon-alpha 121. Duvic M. Bexarotene and DAB(389)IL-2 (denileukin diftitox, therapy. Br J Haematol 1995;90:928-30.
ONTAK) in treatment of cutaneous T-cell lymphomas: algo- 141. Querfeld C, Rosen ST, Guitart J, Rademaker A, Fung BB, rithms. Clin Lymphoma 2000;1(Suppl):S51-5.
Posten W, et al. Comparison of selective retinoic acid 122. el-Azhary RA. Bouwhuis SA. Oral bexarotene in a therapy- receptor- and retinoic X receptor-mediated efficacy, toler- ezary syndrome patient: observations on S ance, and survival in cutaneous T-cell lymphoma. J Am Acad cell compartmentalization. Int J Dermatol 2005;44:25-8.
123. Zhang C, Duvic M. Treatment of cutaneous T-cell lymphoma 142. Olsen E, Duvic M, Frankel A, Kim Y, Martin A, Vonderheid E, with retinoids. Dermatol Ther 2006;19:264-71.
et al. Pivotal phase III trial of two dose levels of denileukin 124. Kempf W, Kettelhack N, Duvic M, Burg G. Topical and diftitox for the treatment of cutaneous T-cell lymphoma.
systemic retinoid therapy for cutaneous T-cell lymphoma.
J Clin Oncol 2001;19:376-88.
Hematol Oncol Clin North Am 2003;17:1405-19.
143. Saleh MN, LeMaistre CF, Kuzel TM, Foss F, Platanias LC, 125. Kessler JF, Meyskens FL Jr, Levine N, Lynch PJ, Jones SE.
Schwartz G, et al. Antitumor activity of DAB389IL-2 fusion Treatment of cutaneous T-cell lymphoma (mycosis fun- toxin in mycosis fungoides. J Am Acad Dermatol 1998;39: goides) with 13-cis-retinoic acid. Lancet 1983;1:1345-7.
126. Neely SM, Mehlmauer M, Feinstein DI. The effect of isotret- 144. Prince HM, Duvic M, Martin A, Sterry W, Assaf C, Sun Y, et al.
inoin in six patients with cutaneous T-cell lymphoma. Arch Phase III placebo-controlled trial of denileukin diftitox for Intern Med 1987;147:529-31.
patients with cutaneous T-cell lymphoma. J Clin Oncol 2010; 127. Warrell RP Jr, Coonley CJ, Kempin SJ, Myskowski P, Safai B, Itri LM. Isotretinoin in cutaneous T-cell lymphoma. Lancet 1983; 145. Foss FM, Bacha P, Osann KE, Demierre MF, Bell T, Kuzel T.
Biological correlates of acute hypersensitivity events with 128. Kessler JF, Jones SE, Levine N, Lynch PJ, Booth AR, Meyskens DAB(389)IL-2 (denileukin diftitox, ONTAK) in cutaneous T-cell FL Jr. Isotretinoin and cutaneous helper T-cell lymphoma lymphoma: decreased frequency and severity with steroid (mycosis fungoides). Arch Dermatol 1987;123:201-4.
premedication. Clin Lymphoma 2001;1:298-302.
129. Molin L, Thomsen K, Volden G, Aronsson A, Hammar H, 146. Chin KM, Foss FM. Biologic correlates of response and Hellbe L, et al. Oral retinoids in mycosis fungoides and Sezary survival in patients with cutaneous T-cell lymphoma treated syndrome: a comparison of isotretinoin and etretinate; a with denileukin diftitox. Clin Lymphoma Myeloma 2006;7: study from the Scandinavian mycosis fungoides group. Acta Derm Venereol 1987;67:232-6.
147. Foss F, Demierre MF, DiVenuti G. A phase-1 trial of bexarotene 130. Thomsen K, Molin L, Volden G, Lange Wantzin G, Hellbe L. 13- and denileukin diftitox in patients with relapsed or refractory cis-Retinoic acid effective in mycosis fungoides: a report from cutaneous T-cell lymphoma. Blood 2005;106:454-7.
the Scandinavian mycosis fungoides group. Acta Derm 148. Zic JA. The treatment of cutaneous T-cell lymphoma with photopheresis. Dermatol Ther 2003;16:337-46.
131. Wargon O, Downie D. A case of mycosis fungoides treated 149. Duvic M, Chiao N, Talpur R. Extracorporeal photopheresis for with etretinate. Australas J Dermatol 1984;25:77-9.
the treatment of cutaneous T-cell lymphoma. J Cutan Med 132. Claudy AL, Rouchouse B, Boucheron S, Le Petit JC. Treatment Surg 2003;7:3-7.
of cutaneous lymphoma with etretinate. Br J Dermatol 1983; 150. Knobler R, Jantschitsch C. Extracorporeal photochemoimmu- notherapy in cutaneous T-cell lymphoma. Transfus Apher Sci 133. Tousignant J, Raymond GP, Light MJ. Treatment of cutane- ous T-cell lymphoma with the arotinoid Ro 13-6298. J Am 151. Bouwhuis SA, el-Azhary RA, Gibson LE, McEvoy MT, Pittelkow Acad Dermatol 1987;16:167-71.
MR. Effect of insulin-dependent diabetes mellitus on re- 134. Hoting E, Meissner K. Arotinoid-ethylester: effectiveness in sponse to extracorporeal photopheresis in patients with refractory cutaneous T-cell lymphoma. Cancer 1988;62:1044-8.
Sezary syndrome. J Am Acad Dermatol 2002;47:63-7.
135. Mahrle G, Thiele B, Ippen H. Chemotherapy of cutaneous T- 152. Edelson R, Berger C, Gasparro F, Jegasothy B, Heald P, cell lymphomas with arotinoid [in German]. Dtsch Med Wintroub B, et al. Treatment of cutaneous T-cell lymphoma by extracorporeal photochemotherapy: preliminary results. N 136. Stadler R, Otte HG, Luger T, Henz BM, Kuhl P, Zwingers T, Engl J Med 1987;316:297-303.
et al. Prospective randomized multicenter clinical trial on the 153. Zic JA, Stricklin GP, Greer JP, Kinney MC, Shyr Y, Wilson DC, use of interferon-2a plus acitretin versus interferon-2a plus et al. Long-term follow-up of patients with cutaneous T-cell PUVA in patients with cutaneous T-cell lymphoma stages I lymphoma treated with extracorporeal photochemotherapy.
and II. Blood 1998;92:3578-81.
J Am Acad Dermatol 1996;35:935-45.
J AM ACAD DERMATOL VOLUME 64, NUMBER 2 154. Crovetti G, Carabelli A, Berti E, Guizzardi M, Fossati S, De 171. Zackheim HS, Epstein EH Jr. Low-dose methotrexate for the Filippo C, et al. Photopheresis in cutaneous T-cell lymphoma: Sezary syndrome. J Am Acad Dermatol 1989;21:757-62.
five-year experience. Int J Artif Organs 2000;23:55-62.
172. Schappell DL, Alper JC, McDonald CJ. Treatment of advanced 155. Arulogun S, Prince HM, Gambell P, Lade S, Ryan G, Eaton E, mycosis fungoides and Sezary syndrome with continuous et al. Extracorporeal photopheresis for the treatment of infusions of methotrexate followed by fluorouracil and Sezary syndrome using a novel treatment protocol. J Am leucovorin rescue. Arch Dermatol 1995;131:307-13.
Acad Dermatol 2008;59:589-95.
173. Hirayama Y, Nagai T, Ohta H, Koyama R, Matsunaga T, 156. Stevens SR, Baron ED, Masten S, Cooper KD. Circulating CD41 Sakamaki S, et al. Sezary syndrome showing a stable clinical CD7e lymphocyte burden and rapidity of response: predic- course for more than four years after oral administration of tors of outcome in the treatment of Sezary syndrome and etoposide and methotrexate [in Japanese]. Rinsho Ketsueki erythrodermic mycosis fungoides with extracorporeal photo- pheresis. Arch Dermatol 2002;138:1347-50.
174. Sarris AH, Phan A, Duvic M, Romaguera J, McLaughlin P, 157. Russell-Jones R, Fraser-Andrews E, Spittle M, Whittaker S.
Mesina O, et al. Trimetrexate in relapsed T-cell lym- Extracorporeal photopheresis in Sezary syndrome. Lancet phoma with skin involvement. J Clin Oncol 2002;20: 158. de Misa RF, Harto A, Azana JM, Belmar P, Diez E, Ledo A.
175. Horwitz S, Duvic M, Kim Y, Cance L, Myskowski P, Talpur R, Photopheresis does not improve survival in Sezary syndrome et al. Low dose pralatrexate (PDX) is active in cutaneous T- patients with bone marrow involvement. J Am Acad Derma- cell lymphoma: preliminary results of a multi-center dose tol 2005;53:171-2.
finding trial [abstract]. Ann Oncol 2008;19: iv162.
159. Evans AV, Wood BP, Scarisbrick JJ, Fraser-Andrews EA, Chinn 176. Rodrigues M, Westerman D, Lade S, McCormack C, Prince HM.
S, Dean A, et al. Extracorporeal photopheresis in Sezary Methotrexate-induced lymphoproliferative disorder in a pa- syndrome: hematologic parameters as predictors of re- tient with Sezary syndrome. Leuk Lymphoma 2006;47:2257-9.
sponse. Blood 2001;98:1298-301.
177. Duhra P. Treatment of gastrointestinal symptoms associated 160. Scarisbrick JJ, Taylor P, Holtick U, Makar Y, Douglas K, Berlin with methotrexate therapy for psoriasis. J Am Acad Dermatol G, et al. UK consensus statement on the use of extracorporeal photopheresis for treatment of cutaneous T-cell lymphoma 178. Salim A, Tan E, Ilchyshyn A, Berth-Jones J. Folic acid supple- and chronic graft-versus-host disease. Br J Dermatol 2008; mentation during treatment of psoriasis with methotrexate: a randomized, double-blind, placebo-controlled trial. Br J 161. Knobler E, Warmuth I, Cocco C, Miller B, Mackay J. Extracor- poreal photochemotherapyethe Columbia Presbyterian ex- 179. Chun HG, Leyland-Jones B, Cheson BD. Fludarabine phosphate: perience. Photodermatol Photoimmunol Photomed 2002;18: a synthetic purine antimetabolite with significant activity against lymphoid malignancies. J Clin Oncol 1991;9:175-88.
162. Jiang SB, Dietz SB, Kim M, Lim HW. Extracorporeal photo- 180. Stoetzer OJ, Pogrebniak A, Scholz M, Pelka-Fleischer R, Gullis chemotherapy for cutaneous T-cell lymphoma: a 9.7-year E, Darsow M, et al. Drug-induced apoptosis in chronic experience. Photodermatol Photoimmunol Photomed 1999; lymphocytic leukemia. Leukemia 1999;13:1873-80.
181. Quaglino P, Fierro MT, Rossotto GL, Savoia P, Bernengo MG.
163. Fraser-Andrews E, Seed P, Whittaker S, Russell-Jones R.
Treatment of advanced mycosis fungoides/Sezary syndrome Extracorporeal photopheresis in Sezary syndrome: no signif- with fludarabine and potential adjunctive benefit to subse- icant effect in the survival of 44 patients with a peripheral quent extracorporeal photochemotherapy. Br J Dermatol blood T-cell clone. Arch Dermatol 1998;134:1001-5.
164. Richardson SK, McGinnis KS, Shapiro M, Lehrer MS, Kim EJ, 182. Nikko AP, RutherFord CJ, Pandya AG. Successful treatment of Vittorio CC, et al. Extracorporeal photopheresis and multi- Sezary syndrome with lymphomatous transformation to modality immunomodulatory therapy in the treatment of large cell lymphoma with fludarabine phosphate. Arch cutaneous T-cell lymphoma. J Cutan Med Surg 2003;7: 183. Redman JR, Cabanillas F, Velasquez WS, McLaughlin P, 165. Olsen EA. The pharmacology of methotrexate. J Am Acad Hagemeister FB, Swan F Jr, et al. Phase II trial of fludarabine phosphate in lymphoma: an effective new agent in low- 166. Wright JC, Lyons MM, Walker DG, Golomb FM, Gumport SL, grade lymphoma. J Clin Oncol 1992;10:790-4.
Medrek TJ. Observations on the use of cancer chemothera- 184. Von Hoff DD, Dahlberg S, Hartstock RJ, Eyre HJ. Activity of peutic agents in patients with mycosis fungoides. Cancer fludarabine monophosphate in patients with advanced my- cosis fungoides: a Southwest Oncology Group study. J Natl 167. Zackheim HS, Kashani-Sabet M, Hwang ST. Low-dose meth- Cancer Inst 1990;82:1353-5.
otrexate to treat erythrodermic cutaneous T-cell lymphoma: 185. Scarisbrick JJ, Child FJ, Clift A, Sabroe R, Whittaker SJ, Spittle results in twenty-nine patients. J Am Acad Dermatol 1996;34: M, et al. A trial of fludarabine and cyclophosphamide combination chemotherapy in the treatment of advanced 168. Zackheim HS, Kashani-Sabet M, McMillan A. Low-dose meth- refractory primary cutaneous T-cell lymphoma. Br J Dermatol otrexate to treat mycosis fungoides: a retrospective study in 69 patients. J Am Acad Dermatol 2003;49:873-8.
186. Cohen RB, Abdallah JM, Gray JR, Foss F. Reversible neurologic 169. Winkelmann RK, Perry HO, Muller SA, Schroeter AL, Jordon toxicity in patients treated with standard-dose fludarabine RE, Rogers RS III. Treatment of Sezary syndrome. Mayo Clin phosphate for mycosis fungoides and chronic lymphocytic Proc 1974;49:590-2.
leukemia. Ann Intern Med 1993;118:114-6.
170. McDonald CJ, Bertino JR. Treatment of mycosis fungoides 187. Beutler E. Cladribine (2-chlorodeoxyadenosine). Lancet 1992; lymphoma: effectiveness of infusions of methotrexate fol- lowed by oral citrovorum factor. Cancer Treat Rep 1978;62: 188. O'Brien S, Kurzrock R, Duvic M, Kantarjian H, Stass S, Robertson LE, et al. 2-Chlorodeoxyadenosine therapy in J AM ACAD DERMATOL patients with T-cell lymphoproliferative disorders. Blood cutaneous T-cell lymphoma: experience in 44 patients. J Clin 189. Trautinger F, Schwarzmeier J, Honigsmann H, Knobler RM.
207. Marchi E, Alinari L, Tani M, Stefoni V, Pimpinelli N, Berti E, Low-dose 2-chlorodeoxyadenosine for the treatment of et al. Gemcitabine as frontline treatment for cutaneous T-cell mycosis fungoides. Arch Dermatol 1999;135:1279-80.
lymphoma: phase II study of 32 patients. Cancer 2005;104: 190. Kong LR, Samuelson E, Rosen ST, Roenigk HH Jr, Tallman MS, Rademaker AW, et al. 2-Chlorodeoxyadenosine in cutaneous 208. Sallah S, Wan JY, Nguyen NP. Treatment of refractory T-cell T-cell lymphoproliferative disorders. Leuk Lymphoma 1997; malignancies using gemcitabine. Br J Haematol 2001;113: 191. Saven A, Carrera CJ, Carson DA, Beutler E, Piro LD. 2- 209. Bantia S, Kilpatrick JM. Purine nucleoside phosphorylase Chlorodeoxyadenosine: an active agent in the treatment of inhibitors in T-cell malignancies. Curr Opin Drug Discov cutaneous T-cell lymphoma. Blood 1992;80:587-92.
Devel 2004;7:243-7.
192. Zaucha JM, Lewandowski K, Hellmann A, Pawlik H, Siedlewicz 210. Bantia S, Miller PJ, Parker CD, Ananth SL, Horn LL, Kilpatrick A. 2-Chlorodeoxyadenosine treatment in the Sezary syn- JM, et al. Purine nucleoside phosphorylase inhibitor BCX- drome. Blood 1997;89:1462-4.
1777 (Immucillin-H)ea novel potent and orally active immu- 193. Bouwhuis SA, el-Azhary RA, McEvoy MT, Gibson LE, Haber- mann TM, Witzig TE, et al. Treatment of late-stage Sezary syndrome with 2-chlorodeoxyadenosine. Int J Dermatol 211. Miles RW, Tyler PC, Furneaux RH, Bagdassarian CK, Schramm VL. One-third-the-sites transition-state inhibitors for purine 194. Matsumoto SS, Yu AL, Bleeker LC, Bakay B, Kung FH, Nyhan nucleoside phosphorylase. Biochemistry 1998;37:8615-21.
WL. Biochemical correlates of the differential sensitivity of 212. Kicska GA, Long L, Horig H, Fairchild C, Tyler PC, Furneaux RH, subtypes of human leukemia to deoxyadenosine and deox- et al. Immucillin H, a powerful transition-state analog inhibitor ycoformycin. Blood 1982;60:1096-102.
of purine nucleoside phosphorylase, selectively inhibits hu- 195. Dang-Vu AP, Olsen EA, Vollmer RT, Greenberg ML, Hershfield man T lymphocytes. Proc Natl Acad Sci U S A 2001;98:4593-8.
MS. Treatment of cutaneous T cell lymphoma with 2'- 213. Bantia S, Ananth SL, Parker CD, Horn LL, Upshaw R. Mech- deoxycoformycin (pentostatin). J Am Acad Dermatol 1988; anism of inhibition of T-acute lymphoblastic leukemia cells by PNP inhibitoreBCX-1777. Int Immunopharmacol 2003;3: 196. Grever MR, Bisaccia E, Scarborough DA, Metz EN, Neidhart JA.
An investigation of 2'-deoxycoformycin in the treatment of 214. Duvic M, Foss FM. Mycosis fungoides: pathophysiology and cutaneous T-cell lymphoma. Blood 1983;61:279-82.
emerging therapies. Semin Oncol 2007;34:S21-8.
197. Tsimberidou AM, Giles F, Duvic M, Fayad L, Kurzrock R. Phase 215. Duvic M, Forero-Torres A, Foss F, Olsen EA, Kim YH, Bennett II study of pentostatin in advanced T-cell lymphoid malig- JC, et al. Oral forodesine (BCX-1777) is clinically active in nancies: update of an M.D. Anderson Cancer Center series.
refractory cutaneous T-cell lymphoma: results of a phase I/II study. Blood 2006;108:698a.
198. Cummings FJ, Kim K, Neiman RS, Comis RL, Oken MM, 216. Kim Y, Forero-Torres A, Foss F, Olsen E, Pinter-Brown L, Weitzman SA, et al. Phase II trial of pentostatin in refractory Duvic M. Responses to oral forodesine in refractory cuta- lymphomas and cutaneous T-cell disease. J Clin Oncol 1991; neous T-cell lymphoma (CTCL): final results of a phase I/II study. Presented at the Society of Investigative Dermato- 199. Greiner D, Olsen EA, Petroni G. Pentostatin (2'-deoxycofor- mycin) in the treatment of cutaneous T-cell lymphoma. J Am Acad Dermatol 1997;36:950-5.
217. Everett JL, Roberts JJ, Ross W. Aryl-2-halogenoalkylamines, 200. Ho AD, Suciu S, Stryckmans P, De Cataldo F, Willemze R, part XII: some carboxylic derivatives of N, N-di-2-chloroethy- Thaler J, et al. Pentostatin in T-cell malignanciesea phase II laniline. J Chem Soc 1953:2386-92.
trial of the EORTC: Leukemia Cooperative Group. Ann Oncol 218. Chabner BA, Ryan DP, Paz-Ares L, Garcia-Carbonero R, Calabresi P. Antineoplastic agents. In: Hardman JG, Limbird 201. Mercieca J, Matutes E, Dearden C, MacLennan K, Catovsky D.
LE, editors. Goodman and Gilman's the pharmacologic basis The role of pentostatin in the treatment of T-cell malignan- of therapeutics. 10th ed. New York (NY): McGraw Hill; 2001.
cies: analysis of response rate in 145 patients according to disease subtype. J Clin Oncol 1994;12:2588-93.
219. Libansky J, Trapl J. Chlorambucil in erythrodermia. Lancet 202. Kurzrock R, Pilat S, Duvic M. Pentostatin therapy of T-cell lymphomas with cutaneous manifestations. J Clin Oncol 220. Molin L, Thomsen K, Volden G, Bergqvist-Karlsson A, Hellbe L.
Prednimustine in mycosis fungoides: a report from the 203. Monfardini S, Sorio R, Cavalli F, Cerny TH, Van Glabbeke M, Scandinavian mycosis fungoides study group. Acta Derm Kaye S, et al. Pentostatin (2'-deoxycoformycin, dCF) in patients with low-grade (B-T-cell) and intermediate- and 221. Amante C, Brodkin RH, Cohen F. Chlorambucil in mycosis high-grade (T-cell) malignant lymphomas: phase II study of fungoides: report of a case of successful treatment. Acta the EORTC early clinical trials group. Oncology 1996;53:163-8.
Derm Venereol 1968;48:60-3.
204. Nabhan C, Krett N, Gandhi V, Rosen S. Gemcitabine in 222. Holmes RC, McGibbon DH, Black MM. Mycosis fungoides: hematologic malignancies. Curr Opin Oncol 2001;13:514-21.
progression towards Sezary syndrome reversed with chlor- 205. Duvic M, Talpur R, Wen S, Kurzrock R, David CL, Apisarntha- ambucil. Clin Exp Dermatol 1983;8:429-35.
narax N. Phase II evaluation of gemcitabine monotherapy for 223. Hamminga L, Hartgrink-Groeneveld CA, van Vloten WA.
cutaneous T-cell lymphoma. Clin Lymphoma Myeloma 2006; Sezary's syndrome: a clinical evaluation of eight patients. Br J Dermatol 1979;100:291-6.
206. Zinzani PL, Baliva G, Magagnoli M, Bendandi M, Modugno G, 224. Winkelmann RK, Diaz-Perez JL, Buechner SA. The treatment Gherlinzoni F, et al. Gemcitabine treatment in pretreated of Sezary syndrome. J Am Acad Dermatol 1984;10:1000-4.
J AM ACAD DERMATOL VOLUME 64, NUMBER 2 225. McEvoy MT, Zelickson BD, Pineda AA, Winkelmann RK. Inter- 246. Levi JA, Diggs CH, Wiernik PH. Adriamycin therapy in mittent leukapheresis: an adjunct to low-dose chemotherapy advanced mycosis fungoides. Cancer 1977;39:1967-70.
for Sezary syndrome. Acta Derm Venereol 1989;69:73-6.
247. Wollina U, Dummer R, Brockmeyer NH, Konrad H, Busch JO, 226. Karnofsky DA. Nitrogen mustards in the treatment of neo- Kaatz M, et al. Multicenter study of pegylated liposomal plastic disease. Adv Intern Med 1950;4:1-75.
doxorubicin in patients with cutaneous T-cell lymphoma.
227. Van Scott EJ, Grekin DA, Kalmanson JD, Vonderheid EC, Barry WE. Frequent low doses of intravenous mechlorethamine for 248. Pulini S, Rupoli S, Goteri G, Pimpinelli N, Alterini R, Tassetti A, late-stage mycosis fungoides lymphoma. Cancer 1975;36: et al. Pegylated liposomal doxorubicin in the treatment of primary cutaneous T-cell lymphomas. Haematologica 2007; 228. Abele DC, Dobson RL. The treatment of mycosis fungoides with a new agent, cyclophosphamide (Cytoxan). Arch 249. Quereux G, Marques S, Nguyen JM, Bedane C, D'Incan M, Dereure O, et al. Prospective multicenter study of pegylated 229. Van Scott EJ, Auerbach R, Clendenning WE. Treatment of liposomal doxorubicin treatment in patients with advanced mycosis fungoides with cyclophosphamide. Arch Dermatol or refractory mycosis fungoides or Sezary syndrome. Arch 230. Mendelson D, Block JB, Serpick AA. Effect of large intermit- 250. Di Lorenzo G, Di Trolio R, Delfino M, De Placido S. Pegylated tent intravenous doses of cyclophosphamide in lymphoma.
liposomal doxorubicin in stage IVB mycosis fungoides. Br J 231. Suter DE. Follow-up case mycosis fungoides treated with 251. Piekarz RL, Sackett DL, Bates SE. Histone deacetylase inhibitors cyclophosphamide (Cytoxan). Arch Dermatol 1964;89:616.
and demethylating agents: clinical development of histone 232. Auerbach R. Mycosis fungoides successfully treated with deacetylase inhibitors for cancer therapy. Cancer J 2007;13:30-9.
cyclophosphamide (Cytoxan). Arch Dermatol 1970;101:611.
252. Zhang C, Richon V, Ni X, Talpur R, Duvic M. Selective induction 233. Maguire A. Treatment of mycosis fungoides with cyclo- of apoptosis by histone deacetylase inhibitor SAHA in cuta- phosphamide and chlorpromazine. Br J Dermatol 1968;80: neous T-cell lymphoma cells: relevance to mechanism of therapeutic action. J Invest Dermatol 2005;125:1045-52.
234. Newlands ES, Stevens MF, Wedge SR, Wheelhouse RT, Brock 253. Duvic M, Talpur R, Ni X, Zhang C, Hazarika P, Kelly C, et al.
C. Temozolomide: a review of its discovery, chemical prop- Phase 2 trial of oral vorinostat (suberoylanilide hydroxamic erties, pre-clinical development and clinical trials. Cancer acid, SAHA) for refractory cutaneous T-cell lymphoma (CTCL).
Treat Rev 1997;23:35-61.
235. Newlands ES, Blackledge GR, Slack JA, Rustin GJ, Smith DB, 254. Newbold A, Lindemann RK, Cluse LA, Whitecross KF, Dear AE, Stuart NS, et al. Phase I trial of temozolomide (CCRG 81045: Johnstone RW. Characterization of the novel apoptotic and M&B 39831: NSC 362856). Br J Cancer 1992;65:287-91.
therapeutic activities of the histone deacetylase inhibitor 236. Tani M, Fina M, Alinari L, Stefoni V, Baccarani M, Zinzani PL.
romidepsin. Mol Cancer Ther 2008;7:1066-79.
Phase II trial of temozolomide in patients with pretreated 255. Gloucester Pharmaceuticals. Romidepsin: treatment of cuta- neous T-cell lymphoma (CTCL), including relief of pruritus, in patients who have received at least one prior systemic 237. Hainsworth JD, Johnson DH, Frazier SR, Greco FA. Chronic therapy. Sponsor's background package for the Oncologic daily administration of oral etoposide in refractory lym- Drugs Advisory Committee Meeting; September 2, 2009.
phoma. Eur J Cancer 1990;26:818-21.
256. Piekarz RL, Frye R, Turner M, Wright JJ, Allen SL, Kirschbaum 238. Hainsworth JD, Greco FA. Etoposide: twenty years later. Ann MH, et al. Phase II multi-institutional trial of the histone deacetylase inhibitor romidepsin as monotherapy for pa- 239. Jacobs P, King HS, Gordon W. Epipodophyllotoxin in mycosis tients with cutaneous T-cell lymphoma. J Clin Oncol 2009;27: fungoides [letter]. Lancet 1975;1:111-2.
240. Jacobs P, King HS, Gordon W. Chemotherapy of mycosis 257. Whittaker S, Demierre M, Kim E, Rook A, Lerner A, Duvic M, fungoides [letter]. S Afr Med J 1975;49:1286.
et al. Final results from a multicenter, international, pivotal 241. Onozuka T, Yokota K, Kawashima T, Shimada H, Kodama K, study of romidepsin in refractory cutaneous T-cell lym- Kobayashi H, et al. An elderly patient with mycosis fungoides phoma. J Clin Oncol 2010;28:4485-91.
successfully treated with chronic low-dose oral etoposide 258. Mone AP, Cheney C, Banks AL, Tridandapani S, Mehter N, therapy. Clin Exp Dermatol 2004;29:91-2.
Guster S, et al. Alemtuzumab induces caspase-independent 242. Nasuhara Y, Kobayashi S, Munakata M, Kawakami Y, Fujita M.
cell death in human chronic lymphocytic leukemia cells A case of mycosis fungoides with pulmonary involvement: through a lipid raft-dependent mechanism. Leukemia 2006; effect of etoposide and prednisolone [in Japanese]. Nihon Kyobu Shikkan Gakkai Zasshi 1995;33:1013-8.
259. Lapalombella R, Zhao X, Triantafillou G, Yu B, Jin Y, Lozanski 243. Molin L, Thomsen K, Volden G, Bergqvist-Karlsson A, Hallberg G, et al. A novel Raji-Burkitt's lymphoma model for preclinical O, Hellbe L. Epipodophyllotoxin (VP-16-213) in mycosis and mechanistic evaluation of CD52-targeted immunother- fungoides: a report from the Scandinavian mycosis fungoides apeutic agents. Clin Cancer Res 2008;14:569-78.
study group. Acta Derm Venereol 1979;59:84-7.
260. Zhang Z, Zhang M, Goldman CK, Ravetch JV, Waldmann TA.
244. Miyoshi N, Noda M. Complication of topoisomerase II Effective therapy for a murine model of adult T-cell leukemia inhibitor-related acute promyelocytic leukemia with t(1;10) with the humanized anti-CD52 monoclonal antibody, Cam- (q21;q26) in a patient with Sezary syndrome [in Japanese].
path-1H. Cancer Res 2003;63:6453-7.
Rinsho Ketsueki 2006;47:399-401.
261. Mone A, Puhalla S, Whitman S, Baiocchi RA, Cruz J, 245. Pui CH, Ribeiro RC, Hancock ML, Rivera GK, Evans WE, Vukosavljevic T, et al. Durable hematologic complete re- Raimondi SC, et al. Acute myeloid leukemia in children sponse and suppression of HTLV-1 viral load following treated with epipodophyllotoxins for acute lymphoblastic alemtuzumab in zidovudine/IFN-{alpha}-refractory adult T- leukemia. N Engl J Med 1991;325:1682-7.
cell leukemia. Blood 2005;106:3380-2.
J AM ACAD DERMATOL 262. Alinari L, Lapalombella R, Andritsos L, Baiocchi RA, Lin TS, 279. Ri M, Iida S, Ishida T, Ito A, Yano H, Inagaki A, et al.
Byrd JC. Alemtuzumab (Campath-1H) in the treatment of Bortezomib-induced apoptosis in mature T-cell lymphoma chronic lymphocytic leukemia. Oncogene 2007;26:3644-53.
cells partially depends on up-regulation of Noxa and func- 263. Schroter S, Derr P, Conradt HS, Nimtz M, Hale G, Kirchhoff C.
tional repression of Mcl-1. Cancer Sci 2008;100:341-8.
Male-specific modification of human CD52. J Biol Chem 1999; 280. Fernandez Y, Miller TP, Denoyelle C, Esteban JA, Tang WH, Bengston AL, et al. Chemical blockage of the proteasome 264. Nuckel H, Frey UH, Roth A, Duhrsen U, Siffert W. Alemtuzu- inhibitory function of bortezomib: impact on tumor cell mab induces enhanced apoptosis in vitro in B-cells from death. J Biol Chem 2006;281:1107-18.
patients with chronic lymphocytic leukemia by antibody- 281. Zinzani PL, Musuraca G, Tani M, Stefoni V, Marchi E, Fina M, dependent cellular cytotoxicity. Eur J Pharmacol 2005;514: et al. Phase II trial of proteasome inhibitor bortezomib in patients with relapsed or refractory cutaneous T-cell lym- 265. Lowenstein H, Shah A, Chant A, Khan A. Different mecha- phoma. J Clin Oncol 2007;25:4293-7.
nisms of Campath-1H-mediated depletion for CD4 and CD8 T 282. Fisher RI, Silver BA, Vanhaelen CP, Jaffe ES, Cossman J.
cells in peripheral blood. Transpl Int 2006;19:927-36.
Objective regressions of T- and B-cell lymphomas in patients 266. Hale G, Rebello P, Brettman LR, Fegan C, Kennedy B, Kimby E, following treatment with anti-thymocyte globulin. Cancer et al. Blood concentrations of alemtuzumab and antiglobulin Res 1982;42:2465-9.
responses in patients with chronic lymphocytic leukemia 283. Hunter RF, Roth PA, Huang AT. Cutaneous T cell lymphoma: following intravenous or subcutaneous routes of administra- lymphocyte phenotype analysis after anti-thymocyte globu- tion. Blood 2004;104:948-55.
lin therapy. Am J Med 1985;79:653-8.
267. Gibbs SD, Herbert KE, McCormack C, Seymour JF, Prince HM.
284. Barett AJ, Staughton RC, Brigden D, Byrom N, Roberts JT, Alemtuzumab: effective monotherapy for simultaneous B- Hobbs JR. Antilymphocyte globulin in the treatment of cell chronic lymphocytic leukemia and Sezary syndrome. Eur advanced Sezary syndrome. Lancet 1976;1:940-1.
J Haematol 2004;73:447-9.
285. Rook AH, Kuzel TM, Olsen EA. Cytokine therapy of cutaneous 268. Capalbo S, Delia M, Dargenio M, Liso A, Diomede D, Garofalo T-cell lymphoma: interferons, interleukin-12, and interleukin- L, et al. Mycosis fungoides/Sezary syndrome: a report of three 2. Hematol Oncol Clin North Am 2003;17:1435-48, ix.
cases treated with Campath-1H as salvage treatment. Med 286. Nagatani T, Kin ST, Baba N, Miyamoto H, Nakajima H, Katoh Y.
A case of cutaneous T cell lymphoma treated with recom- 269. Kennedy GA, Seymour JF, Wolf M, Januszewicz H, Davison J, binant interleukin 2 (rIL-2). Acta Derm Venereol 1988;68: McCormack C, et al. Treatment of patients with advanced mycosis fungoides and Sezary syndrome with alemtuzumab.
287. Marolleau JP, Baccard M, Flageul B, Rybojad M, Laroche L, Eur J Haematol 2003;71:250-6.
Verola O, et al. High-dose recombinant interleukin-2 in 270. Lundin J, Hagberg H, Repp R, Cavallin-Stahl E, Freden S, advanced cutaneous T-cell lymphoma. Arch Dermatol 1995; Juliusson G, et al. Phase 2 study of alemtuzumab (anti-CD52 monoclonal antibody) in patients with advanced mycosis 288. Gisselbrecht C, Maraninchi D, Pico JL, Milpied N, Coiffier B, fungoides/Sezary syndrome. Blood 2003;101:4267-72.
Divine M, et al. Interleukin-2 treatment in lymphoma: a phase 271. Lenihan DJ, Alencar AJ, Yang D, Kurzrock R, Keating MJ, Duvic II multicenter study. Blood 1994;83:2081-5.
M. Cardiac toxicity of alemtuzumab in patients with mycosis 289. Gold PJ, Thompson JA, Lindgren C, Kern D, Fefer A. Phase I fungoides/Sezary syndrome. Blood 2004;104:655-8.
trial of subcutaneous, outpatient interleukin-2 for patients 272. Zinzani PL, Alinari L, Tani M, Fina M, Pileri S, Baccarani M.
with advanced mycosis fungoides. Blood 1996;88:191b.
Preliminary observations of a phase II study of reduced-dose 290. Querfeld C, Rosen ST, Guitart J, Rademaker A, Foss F, Gupta R, alemtuzumab treatment in patients with pretreated T-cell et al. Phase II trial of subcutaneous injections of human lymphoma. Haematologica 2005;90:702-3.
recombinant interleukin-2 for the treatment of mycosis 273. Alinari L, Geskin L, Grady T, Baiocchi RA, Bechtel MA, Porcu P.
fungoides and Sezary syndrome. J Am Acad Dermatol Subcutaneous alemtuzumab for Sezary syndrome in the very elderly. Leuk Res 2008;32:1299-303.
291. Bunn PA Jr, Fischmann AB, Schechter GP, Kumar PP, Ihde DC, 274. Gautschi O, Blumenthal N, Streit M, Solenthaler M, Hunziker Cohen MH, et al. Combined modality therapy with electron- T, Zenhausern R. Successful treatment of chemotherapy- beam irradiation and systemic chemotherapy for cutaneous refractory Sezary syndrome with alemtuzumab (Campath- T-cell lymphomas. Cancer Treat Rep 1979;63:713-7.
1H). Eur J Haematol 2004;72:61-3.
292. Rosen ST, Foss FM. Chemotherapy for mycosis fungoides and 275. Querfeld C, Mehta N, Rosen ST, Guitart J, Rademaker A, the Sezary syndrome. Hematol Oncol Clin North Am 1995;9: Gerami P, et al. Alemtuzumab for relapsed and refractory erythrodermic cutaneous T-cell lymphoma: a single institu- 293. Kaye FJ, Bunn PA Jr, Steinberg SM, Stocker JL, Ihde DC, tion experience from the Robert H. Lurie Comprehensive Fischmann AB, et al. A randomized trial comparing combi- Cancer Center. Leuk Lymphoma 2009;50:1969-76.
nation electron-beam radiation and chemotherapy with 276. Weder P, Anliker M, Itin P, Bargetzi M. Familial cutaneous topical therapy in the initial treatment of mycosis fungoides.
mycosis fungoides: successful treatment with a combination N Engl J Med 1989;321:1784-90.
of gemcitabine and alemtuzumab. Dermatology 2004;208: 294. Merlo CJ, Hoppe RT, Abel E, Cox RS. Extracutaneous mycosis fungoides. Cancer 1987;60:397-402.
277. Porcu P, Baiocchi RA, Lee J, Lin TS, Blum K, Grady T, et al.
295. Grozea PN, Jones SE, McKelvey EM, Coltman CA Jr, Fisher R, Phase I trial of subcutaneous (SQ) alemtuzumab (A) and Haskins CL. Combination chemotherapy for mycosis fun- CHOP in T-cell lymphoma: preliminary results [abstract].
goides: a Southwest Oncology Group study. Cancer Treat J Clin Oncol 2006;24(suppl 18S):7594.
Rep 1979;63:647-53.
278. Lundin J, Kennedy B, Dearden C, Dyer MJ, Osterborg A. No 296. Case DC Jr. Combination chemotherapy for mycosis fun- cardiac toxicity associated with alemtuzumab therapy for goides with cyclophosphamide, vincristine, methotrexate, mycosis fungoides/Sezary syndrome. Blood 2005;105:4148-9.
and prednisone. Am J Clin Oncol 1984;7:453-5.
J AM ACAD DERMATOL VOLUME 64, NUMBER 2 297. Fierro MT, Doveil GC, Quaglino P, Savoia P, Verrone A, transplantation for refractory Sezary syndrome and mycosis Bernengo MG. Combination of etoposide, idarubicin, cyclo- fungoides. J Clin Oncol 2005;23:6163-71.
phosphamide, vincristine, prednisone and bleomycin (VICOP- 313. Molina A, Nademanee A, Arber DA, Forman SJ. Remission of B) in the treatment of advanced cutaneous T-cell lymphoma.
refractory Sezary syndrome after bone marrow transplanta- tion from a matched unrelated donor. Biol Blood Marrow 298. Hamminga L, Hermans J, Noordijk EM, Meijer CJ, Scheffer E, Van Vloten WA. Cutaneous T-cell lymphoma: clinicopatho- 314. Guitart J, Wickless SC, Oyama Y, Kuzel TM, Rosen ST, Traynor logical relationships, therapy and survival in ninety-two A, et al. Long-term remission after allogeneic hematopoietic patients. Br J Dermatol 1982;107:145-55.
stem cell transplantation for refractory cutaneous T-cell 299. Duvic M, Apisarnthanarax N, Cohen DS, Smith TL, Ha CS, lymphoma. Arch Dermatol 2002;138:1359-65.
Kurzrock R. Analysis of long-term outcomes of combined 315. Wu PA, Kim YH, Lavori PW, Hoppe RT, Stockerl-Goldstein KE.
modality therapy for cutaneous T-cell lymphoma. J Am Acad A meta-analysis of patients receiving allogeneic or autolo- gous hematopoietic stem cell transplant in mycosis fun- 300. Sentis HJ, Willemze R, Van Vloten WA. Systemic polychemo- goides and Sezary syndrome. Biol Blood Marrow Transplant therapy in patients with mycosis fungoides and lymph node involvement: a follow-up study of 17 patients. Acta Derm 316. Cudillo L, Cerretti R, Baliva G, De Angelis G, Postorino M, Picardi A, et al. Sezary syndrome in relapse after reduced 301. Zakem MH, Davis BR, Adelstein DJ, Hines JD. Treatment of intensity allogeneic transplant successfully treated with do- advanced stage mycosis fungoides with bleomycin, doxoru- nor lymphocyte infusion. Bone Marrow Transplant 2009;43: bicin, and methotrexate with topical nitrogen mustard (BAM- M). Cancer 1986;58:2611-6.
317. Kahata K, Hashino S, Takahata M, Fujisawa F, Kondo T, 302. Zachariae H, Thestrup-Pedersen K. Combination chemother- Kobayashi S, et al. Durable remission of Sezary syndrome apy with bleomycin, cyclophosphamide, prednisone and after unrelated bone marrow transplantation by reduced- etretinate (BCPE) in advanced mycosis fungoides: a six-year intensity conditioning. Acta Haematol 2008;120:14-8.
experience. Acta Derm Venereol 1987;67:433-7.
318. Herbert KE, Spencer A, Grigg A, Ryan G, McCormack C, Prince 303. Zachariae H, Grunnet E, Thestrup-Pedersen K, Molin L, Schmidt HM. Graft-versus-lymphoma effect in refractory cutaneous T- H, Starfelt F, et al. Oral retinoid in combination with bleomycin, cell lymphoma after reduced-intensity HLA-matched sibling cyclophosphamide, prednisone and transfer factor in mycosis allogeneic stem cell transplantation. Bone Marrow Transplant fungoides. Acta Derm Venereol 1982;62:162-4.
304. Bigler RD, Crilley P, Micaily B, Brady LW, Topolsky D, Bulova S, 319. Soligo D, Ibatici A, Berti E, Morandi P, Longhi E, et al. Autologous bone marrow transplantation for advanced Venegoni L, et al. Treatment of advanced mycosis stage mycosis fungoides. Bone Marrow Transplant 1991;7: fungoides by allogeneic stem-cell transplantation with a 305. Olavarria E, Child F, Woolford A, Whittaker SJ, Davis JG, McDonald C, et al. T-cell depletion and autologous stem cell 320. Herrmann JJ, Roenigk HH Jr, Honigsmann H. Ultraviolet transplantation in the management of tumor stage mycosis radiation for treatment of cutaneous T-cell lymphoma.
fungoides with peripheral blood involvement. Br J Haematol Hematol Oncol Clin North Am 1995;9:1077-88.
321. Moscicki RA, Morison WL, Parrish JA, Bloch KJ, Colvin RB.
306. Russell-Jones R, Child F, Olavarria E, Whittaker S, Spittle M, Reduction of the fraction of circulating helper-inducer T cells Apperley J. Autologous peripheral blood stem cell transplan- identified by monoclonal antibodies in psoriatic patients tation in tumor-stage mycosis fungoides: predictors of treated with long-term psoralen/ultraviolet-A radiation disease-free survival. Ann N Y Acad Sci 2001;941:147-54.
(PUVA). J Invest Dermatol 1982;79:205-8.
307. Ingen-Housz-Oro S, Bachelez H, Verola O, Lebbe C, Marolleau 322. Morhenn VB, Benike CJ, Engleman EG. Inhibition of cell JP, Hennequin C, et al. High-dose therapy and autologous mediated immune responses by 8-methoxypsoralen and stem cell transplantation in relapsing cutaneous lymphoma.
long-wave ultraviolet light: a possible explanation for the Bone Marrow Transplant 2004;33:629-34.
clinical effects of photoactivated psoralen. J Invest Dermatol 308. Sterling JC, Marcus R, Burrows NP, Roberts SO. Erythrodermic mycosis fungoides treated with total body irradiation and 323. Masui Y, Sugaya M, Kagami S, Fujita H, Yano S, Nagao M, et al.
autologous bone marrow transplantation. Clin Exp Dermatol Sezary syndrome treated with narrowband ultraviolet B: time-course measurement of serum levels of CCL17/CCL27.
309. Duarte RF, Schmitz N, Servitje O, Sureda A. Hematopoietic Clin Exp Dermatol 2007;32:57-9.
stem cell transplantation for patients with primary cutaneous 324. Thomsen K, Hammar H, Molin L, Volden G. Retinoids plus T-cell lymphoma. Bone Marrow Transplant 2008;41:597-604.
PUVA (RePUVA) and PUVA in mycosis fungoides, plaque 310. Oyama Y, Guitart J, Kuzel TM, Burt RK, Rosen ST. High-dose stage: a report from the Scandinavian mycosis fungoides therapy and bone marrow transplantation in cutaneous T- group. Acta Derm Venereol 1989;69:536-8.
cell lymphoma. Hematol Oncol Clin North Am 2003;17: 325. Lowe NJ, Cripps DJ, Dufton PA, Vickers CF. Photochemo- 1475-83, xi.
therapy for mycosis fungoides: a clinical and histological 311. Duvic M, Donato M, Dabaja B, Richmond H, Singh L, Wei W, study. Arch Dermatol 1979;115:50-3.
et al. Total skin electron beam and non-myeloablative 326. Kovary PM, Frosch P, Macher E. Photochemotherapy of allogeneic hematopoietic stem-cell transplantation in ad- Sezary syndrome. Dermatologica 1981;162:112-7.
vanced mycosis fungoides and Sezary syndrome. J Clin Oncol 327. Molin L, Volden G. Treatment of light-sensitive mycosis fungoides with PUVA and prednisolone. Photodermatology 312. Molina A, Zain J, Arber DA, Angelopolou M, O'Donnell M, Murata-Collins J, et al. Durable clinical, cytogenetic, and 328. Stern RS, Nichols KT, Vakeva LH. Malignant melanoma in molecular remissions after allogeneic hematopoietic cell patients treated for psoriasis with methoxsalen (psoralen) J AM ACAD DERMATOL and ultraviolet A radiation (PUVA): the PUVA follow-up study.
to total skin electron beam therapy. Int J Radiat Oncol Biol N Engl J Med 1997;336:1041-5.
329. Vonderheid EC, Tan ET, Kantor AF, Shrager L, Micaily B, Van 341. Griem ML, Tokars RP, Petras V, Variakojis D, Baron JM, Griem Scott EJ. Long-term efficacy, curative potential, and carcino- SF. Combined therapy for patients with mycosis fungoides.
genicity of topical mechlorethamine chemotherapy in cuta- Cancer Treat Rep 1979;63:655-7.
neous T cell lymphoma. J Am Acad Dermatol 1989;20:416-28.
342. Chen Z, Agostinelli AG, Wilson LD, Nath R. Matching the 330. Price NM, Hoppe RT, Constantine VS, Fuks ZY, Farber EM. The dosimetry characteristics of a dual-field Stanford technique treatment of mycosis fungoides: adjuvant topical mechloreth- to a customized single-field Stanford technique for total amine after electron beam therapy. Cancer 1977;40:2851-3.
skin electron therapy. Int J Radiat Oncol Biol Phys 2004;59: 331. Pineda AA, Winkelmann RK. Leukapheresis in the treatment of Sezary syndrome. J Am Acad Dermatol 1981;5:544-9.
343. Demierre MF, Tien A, Miller D. Health-related quality-of-life 332. Di Guglielmo R, Miliani A, Avanzi G, Cozzolino F, Duminuco assessment in patients with cutaneous T-cell lymphoma.
M, Vannucci R, et al. Exceptionally long disease-free period in Arch Dermatol 2005;141:325-30.
a case of Sezary syndrome after combined treatment with 344. Namaka M, Gramlich CR, Ruhlen D, Melanson M, Sutton I, leukapheresis and chemotherapy. Haematologica 1987;72: Major J. A treatment algorithm for neuropathic pain. Clin 333. Sellins KS, Cohen JJ. Gene induction by gamma-irradiation 345. Sampogna F, Frontani M, Baliva G, Lombardo GA, Alvetreti G, leads to DNA fragmentation in lymphocytes. J Immunol Di Pietro C, et al. Quality of life and psychological distress in patients with cutaneous lymphoma. Br J Dermatol 2009;160: 334. Jones GW, Rosenthal D, Wilson LD. Total skin electron radiation for patients with erythrodermic cutaneous T-cell 346. Talpur R, Bassett R, Duvic M. Prevalence and treatment of lymphoma (mycosis fungoides and the Sezary syndrome).
Staphylococcus aureus colonization in patients with mycosis fungoides and Sezary syndrome. Br J Dermatol 2008;159:105-12.
335. Jones GW, Hoppe RT, Glatstein E. Electron beam treatment 347. Tremont-Lukats IW, Megeff C, Backonja MM. Anticonvulsants for cutaneous T-cell lymphoma. Hematol Oncol Clin North for neuropathic pain syndromes: mechanisms of action and Am 1995;9:1057-76.
place in therapy. Drugs 2000;60:1029-52.
336. Hoppe RT, Fuks Z, Bagshaw MA. Radiation therapy in the 348. Rose MA, Kam PC. Gabapentin: pharmacology and its use in management of cutaneous T-cell lymphomas. Cancer Treat pain management. Anaesthesia 2002;57:451-62.
Rep 1979;63:625-32.
349. Demierre MF, Taverna J. Mirtazapine and gabapentin for 337. Wilson LD, Jones GW, Kim D, Rosenthal D, Christensen IR, reducing pruritus in cutaneous T-cell lymphoma. J Am Acad Edelson RL, et al. Experience with total skin electron beam therapy in combination with extracorporeal photopheresis in 350. Davis MP, Frandsen JL, Walsh D, Andresen S, Taylor S.
the management of patients with erythrodermic (T4) mycosis Mirtazapine for pruritus. J Pain Symptom Manage 2003;25: fungoides. J Am Acad Dermatol 2000;43:54-60.
338. Hallahan DE, Griem ML, Griem SF, Medenica M, Soltani K, 351. Pincus S, Oseroff A, Breneman D, Duvic M, Vonderheid E, Coe Lorincz AL, et al. Combined modality therapy for tumor stage B, et al. Effectiveness of topical naloxone, an opioid antag- mycosis fungoides: results of a 10-year follow-up. J Clin onist, in the treatment of pruritus associated with mycosis fungoides (MF) and Sezary syndrome (SS). J Invest Dermatol 339. Braverman IM, Yager NB, Chen M, Cadman EC, Hait WN, Maynard T. Combined total body electron beam irradiation 352. Duval A, Dubertret L. Aprepitant as an antipruritic agent? N and chemotherapy for mycosis fungoides. J Am Acad Engl J Med 2009;361:1415-6.
353. Kim Y, Whittaker S, Demierre MF, Rook AH, Lerner A, Duvic M, 340. Wilson LD, Licata AL, Braverman IM, Edelson RL, Heald PW, et al. Clinically significant responses achieved with romidep- Feldman AM, et al. Systemic chemotherapy and extracorpo- sin in treatment-refractory cutaneous T-cell lymphoma: final real photochemotherapy for T3 and T4 cutaneous T-cell results from a phase 2B, international, multicenter, registra- lymphoma patients who have achieved a complete response tion study. Blood 2008;112:263.

Source: http://www.usclc.org/files/Olsen_et_al_Sezary.pdf