Regimen Selection to Optimize Results in CTCL - Educational ...

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Regimen Selection to Optimize Results in CTCL - Educational ...

Regimen Selection toOptimize Results inCTCLJasmine Zain, MDDirector, Bone Marrow Transplant ProgramAssistant Professor, Division of HematologicMalignancies and Medical OncologyNYU Langone Medical CenterNew York, New York12/15/2010 ECG1


WHO-EORTC (2005) WHO (2008)Cutaneous T-cell and NK-cell lymphomasMycosis fungoidesMF variants and subtypesFolliculotropic MFPagetoid reticulosisGranulomatous slack skinSézary syndromeAdult T-cell leukemia/lymphomaPrimary cutaneous CD30 + lymphoproliferativedisordersPrimary cutaneous anaplastic large celllymphomaLymphomatoid papulosisSubcutaneous panniculitis-like T-cell lymphoma *Extranodal NK/T-cell lymphoma, nasal typePrimary cutaneous peripheral T-cell lymphoma,unspecifiedPrimary cutaneous aggressive epidermotropicCD8 + T-cell lymphoma (provisional)Cutaneous/T-cell lymphoma (provisional)Primary cutaneous CD4 + small/medium-sizedpleomorphic T-cell lymphoma (provisional)Mature T-cell and NK-cell neoplasmsMycosis FungoidesSézary syndromeAdult T-cell leukemia/lymphomaPrimary cutaneous CD30 positive T-celllymphoproliferative disordersLymphomatoid papulosisPrimary cutaneous anaplastic large cell lymphomaPrimary cutaneous gamma delta T-cell lymphomaExtranodal NK/T-cell lymphoma, nasal typePrimary cutaneous CD8+ aggressiveepidermotropic cytotoxic T-cell lymphomaPrimary cutaneous CD4+ small/medium T celllymphoma12/15/2010 ECG 2


SKIN STAGINGSKINSTAGECLINICOPATHOLOGICFEATUREST1Patches/plaques lessthan 10% BSAT2T3Patches/plaques greaterthan 10% BSAAt least one tumornodule > 1cm indiameterT4Confluence of erythema(erythroderma) covering> 80% BSA12/15/2010 ECG 3


STAGING OF MF/SS: T SKINSTAGEST1T2T3T4


2007 ISCL/EORTCCLINICAL STAGINGT (skinstage)N (nodes)M(metastases)B- Blood1A T1 N0 M0 B0-11B T2 N0 M0 B0-1IIA T1-2 N1-2 M0 B0-1IIB T3 N0-2 M0 B0-1IIIA T4 N0-2 M0 B0IIIB T4 N0-2 M0 B1IVA1 T1-4 N0-2 M0 B2IVA2 T1-4 N3 M0 B0-2IVB T1-4 N0-3 M1 B0-2IVA1 OR IVB T4 N0-3 M0-1 B2EARLYSTAGELATE STAGESEZARYSYNDROMEOlsen E, et al. Blood. 2007;110(6):1713-1722.


PROGNOSTIC FACTORS FOR CTCL•Skin stage•Blood involvement•Large celltransformation•MF or SS•De novo LCT hasbetter prognosisKim,YH, et al. Arch Dermatol 2003;139:857-866.


OVERVIEW OF THERAPY FOR CTCLSkin DirectedSystemicTopical SteroidsTopical Nitrogen MustardTopical Bexarotene GelTopical CarmustinePhototherapyNBUVBPUVARadiation TherapyTotal skin electron beamLocalized electron beamIsotretinoin capsulesBexarotene capsulesAcitretin capsulesExtracorporealphotochemotherapyVorinostat capsulesMethotrexateRomidepsinInterferonDenileukin diftitoxSingle agent chemotxCombination chemotx


FDA APPROVED THERAPIES FORCTCL• Extracorporeal photopheresis (ECP) 1990• Denileukin diftitox -- accelerated approval in1999, full approval October 2008• Bexarotene capsules -- 1999• Bexarotene gel -- 2000• Vorinostat -- October 2006• Romidepsin -- September 2009• Efforts to get topical nitrogen mustard approvedfor CTCL


EARLY STAGE DISEASEIA, IB, IIAFIRST-LINE THERAPIES – SKIN DIRECTEDOintments ( steroids, topical bexarotene) topical nitrogenmustard, topical carmustine, imiquimod)Light therapy ( PUVA, UVB)Local radiationSECOND-LINE THERAPIESRetinoids/rexinoidsLow dose oral methotrexate (MTX)Histone deacetylase (HDAC) inhibitorsDenileukin diftitoxTotal skin electron beam (TSEB)Novel agents: clinical trials12/15/2010 ECG 9


PRINCIPLES OF TREATMENTFOR ADVANCED STAGE CTCL–Stage–Age–Performance status–Tempo of disease–Risk of immunosuppression/myelosuppression12/15/2010 ECG 10


OVERVIEW OF THERAPY FOR CTCLSkin DirectedSystemicTopical steroidsTopical nitrogen mustardTopical bexarotene gelTopical carmustinePhototherapyNBUVBPUVARadiation TherapyTotal skin electron beamLocalized electron beamIsotretinoin capsulesBexarotene capsulesAcitretin capsulesExtracorporealphotochemotherapyVorinostat (SAHA) capsulesMethotrexateRomidepsinInterferonDenileukin diftitoxSingle agent chemotxCombination chemotx


C24 H28 O2, MW 348REXINOIDS• Vitamin A analogue - bexarotene• RR of 54%• CR 6%• Dose response effects• Hyperlipidemia and hypothyroidism, fatigue• Topical formulation available• Maybe combined with– Denileukin diftitox -IL-2 expression, RR 70% ( Foss et al,Blood 2005)– Vorinostat - phase 1 trial, interim report in 2008, well tolerated– Phototherapy - UVB or PUVA- ongoing clinical trials– ECP– Chemotherapy (MTX, liposomal doxorubicin, CHOP)


EXTRA CORPOREALPHOTOPHORESIS (ECP)• Combination of ECPwith– Immunomodulators– Interferon-α– Bexarotene– GM-CSF• Transimmunization


STAGEECP IN MF/SSTOTALPATIENTSOVERALLRESPONSECOMPLETERESPONSEIB 25 64% 28%IIA 25 56% 24%IIB 19 53% 26%III 28 36% 18%IVA 86 51% 20%IVB 11 27% 9%Skin stage T1 7 57% 43%Skin stage T2 68 62% 28%Skin stage T3 44 32% 16%Skin stage T4 224 58% 15%Sézary Syndrome 105 43% 10%Zic JA. Dermatologic Therapy. 2003;16:337.


BIOLOGIC RESPONSE MODIFIERS• Interferon-alpha: 3-10 million units– First-line therapy: stage IIB, III, and SS– Second-line therapy: IA-IB– Can be combined with PUVA, ECP, retinoids,chemotherapy• Interferon-gamma: limited availability• IL-2• IL-12


DENILEUKINDIFTITOXDiphtheriaIL-2Response compared to placeboORR 44% compared to placebo(P = 0.0026)Higher responses seen at 18 µg/kg37% vs 26%Effect of stageStage had no effect on responseRetreatmentORR of 40% seen with retreatment afterinitial response – TTF 189 days (72-429) Abstract 2863.Approved for the treatment of CD25+ CTCL


DENILEUKIN DIFTITOXPROGRESSION-FREE SURVIVALNegro-Vilar A, et al. J Clin Oncol. ASCO Annual Meeting Proceedings Part I. 2007;vol 25, No. 18S (June 20 supp):8026.


CLASSES OF HDAC INHIBITORSClass / Potency Select Examples Pharmacologic ProfileAliphatic AcidsHydroxamic AcidsBenzamidesValproic AcidPhenylbutyric AcidVorinostatLBH598BelinostatLAQ-824Trichostatin AMS-275CI-994MGCD-0103Longest studied HDACI. Whilewell tolerated, these drugsexhibit a short-half life due torapid metabolism, arerelatively less potent, and arenon-specificPan-HDACI with Class 1 & 2activity. Vorinostat first in classapproved for CTCL. PO andIVIncludes both pan- andisotype selective HDACI(MGCD-0103). μM to nMpotencyCyclic peptidesDepsipeptideApicidin ACHAPStructurally complex pan-HDACI active in nM range.Depsipeptide metabolicallyconverted to active metabolite


VORINOSTATMolecular structure of vorinostat(suberoylanilide hydroxamic acid)Crystallographic image of vorinostatbinding to HDACHNOONHOH• Inhibits both Class I and Class II HDACs atnanomolar concentrations• Small molecule (MW < 300)• Orally bioavailable; half-life < 2 hoursDuvic M, Vu J. Expert Opin Investig Drugs. 2007;16:1111-1120;Finnin MS, et al. Nature. 1999;401:188-193.


CLINICAL ACTIVITY OF VORINOSTAT IN CTCLTIME TORESPONSE(DAYS)DURATION OFRESPONSE(DAYS)TIME TOPROGRESSIVEDISEASE (DAYS)Population N RR (%)Median(Range)Median* (Range)Median* (Range)All patients 74 22 (29.7) 55 (28-171) NR* (34+, 441+) NR † (78+, 470+)Stage IB orIIAStage IIBand higherSézarysyndromePatients withtumordisease13 4 (30.8) 42.5 (30-57) 80.5 (48+, 418+) 136.5 (78+, 448+)61 18 (29.5) 56 (28-171) NR* (34+, 441+) NR † (85, 470+)30 10 (33.3) 56 (28-171) NR* (34+, 244+) NR † (85, 365+)22 5 (22.7) 31 (29-87) 187 (55, 441+) NR † (148, 470+)Olsen EA, et al. J Clin Oncol. 2007;25:3109-3115.


PARTIAL RESPONSE IN STAGE IVB WITHTRANSFORMED MF (6 PRIOR THERAPIES)Baseline Week 8 Week 24


ROMIDEPSIN• Unique structure• Bi-cyclic peptide• Pan-HDAC inhibitor• Potent; active at nMconcentrationsH 3 COCH 3HNHHHNOHS HNO SOHNO CH3OHCH3CH 3


GPI AND NCI STUDIESPARAMETER GPI STUDY NCI STUDYDesignOpen-label, multicenter,internationalSameKey entrycriteriaStage IB to IVA≥ 1 prior systemictherapyStage IA to IVBPrior therapy varied by diseasestageECOG 0 - 1 ECOG 0-2Treatmentregimen14 mg/m 2 4-hr infusion on Day1, 8, 15 of a 28-day cycleSameWhittaker SJ, et al. J Clin Oncol. 2010;28:4485-4481.Piekarz RL, et al. J Clin Oncol. 2009;27:5410-5417.


PATIENT CHARACTERISTICSCHARACTERISTIC GPI STUDY NCI STUDYAge, median (range) 57 (21 to 89) yrs 57 (28 to 84) yrsSex, Men, n (%) 59 (61) 48 (68)ECOG, n (%)0 49 (51) 16 (23)1 47 (49) 41 (58)2 NA 10 (14)Disease stage, n (%)IA NA 1 ( 1)IB 15 (16) 6 ( 9)IIA 13 (14) 2 ( 3)IIB 21 (22) 14 (20)71%III 23 (24) 9 (13)Stage ≥ IIBIVA 24 (25) 27 (38)IVB NA 12 (17)Blood involvement, n (%) 37 (39) 21 (30)Whittaker SJ, et al. J Clin Oncol. 2010;28:4485-4481;Piekarz RL, et al. J Clin Oncol. 2009;27:5410-5417.87%Stage ≥ IIB


PRIOR SYSTEMIC THERAPYPrior systemic therapyGPI STUDYn = 96NCI STUDYn = 71Median (range) 2 (1-8) 2 (0-7)Most frequent prior systemic therapy, n (%)Chemotherapy 74 (77%) 48 (68%)Bexarotene 32 (33%) 31 (44%)Immunotherapy 36 (38%) 24 (34%)Steroids 12 (13%) 17 (24%)Denileukin diftitox 14 (15%) 13 (18%)Median skin-directed / photophoresis (range) 2 (1-6) 2 (1-3)Whittaker SJ, et al. J Clin Oncol. 2010;28:4485-4481;Piekarz RL, et al. J Clin Oncol. 2009;27:5410-5417.


RESULTSAs-treatedN = 96GPI STUDYEvaluableN = 72As-treatedN = 71NCI STUDYEvaluableN = 63ORR, n (%) 33 (34%) 30 (42%) 25 (35%) 25 (40%)95% CI [25, 45] [30, 54] [25, 49] [28, 53]CCR, n (%) 6 (6%) 6 (8%) 4 (6%) 4 (6%)Whittaker SJ, et al. J Clin Oncol. 2010;28:4485-4481;Piekarz RL, et al. J Clin Oncol. 2009;27:5410-5417.


RESPONSES BY CLINICAL STAGEGPINCI STUDYStage N ORR CCR N ORR CCRAll stages 96 33 (34%) 6 (6%) 71 25 (35%) 4 (6%)IA - IIA 28 7 (25%) 1 (4%) 9 5 (56%) 0IIB 21 9 (43%) 2 (9%) 14 6 (43%) 1 (7%)III 23 9 (39%) 1 (4%) 9 4 (44%) 0IV 24 8 (33%) 2 (8%) 39 10 (26%) 3 (8%)≥ IIB 68 26 (38%) 5 (7%) 62 20 (32%) 4 (7%)Whittaker SJ, et al. J Clin Oncol. 2010;28:4485-4481;Piekarz RL, et al. J Clin Oncol. 2009;27:5410-5417.


Median duration of responseGPI study 14.9 moNCI study 11.1 mo12/15/2010 ECG 28


STAGE IVA, PR, PRIOR: METHOTREXATE,ETRETINATE, PUVA, INTERFERON ALPHABaselineCycle 2 Cycle 3


STAGE IVB, PR, PRIOR: CVP,PREDNISONEBaselineCycle 5


OVERALL SAFETY OF HDACI• Toxicities generally mild (grade 1 or 2)and reversible• Safety profile familiar to those treating CTCL– Gastrointestinal disturbances– Hematologic toxicities– Clinical chemistry abnormalities– Asthenic conditions– Infections• Transient ECG changes not associated with functionalcardiovascular changes


BORTEZOMIB AND PROTEASOMEINHIBITION20SAsp/Glu1*7Postglutamyl2*Tryptic3Phe/Tyr/Trp19S RegulatoryComplex + ATP26S Proteasome(four 7 membered rings)65*BortezChymotryptic4Lys/Arg(Hydrolysis mediated by N- terminalThreonine – ie, Threonine Protease)H 3 CRH 2NOHHOB OHOHHH 3 CRNH 3OBOHOHHOH


OverallResponseRateCompleteRemissionPartialRemissionAll patients(n = 12)8 67% 2 17% 6 50%≤ Twopreviousregimens(n = 5)4 80% 1 20% 3 60%≥ Threepreviousregimens(n = 7)4 57% 1 14% 3 43%Mycosisfungoides(n = 10)PeripheralT-celllymphomaunspecified(n = 2)7 70% 1 10% 6 60%1 1 —RESPONSESSEEN WITHBORTEZOMIBZinzani PL, et al. J Clin Oncol. 2007;25:4293-4297.12/15/2010 33


==H 2 NNN1N84 5NHHH9METHOTREXATE(10-Methyl Aminopterin)NH 2-OH = Folic AcidH 3 CCH 2N10O COO -C - N - C - CH 2 - CH 2 - COO -H HH 2 NNN1N84 5NNH 2H 3 CH CHHH9CHHCC1010-Propargyl-10-Deazaaminopterin(PRALATREXATE)OCOO -C - N - C - CH 2 - CH 2 - COO -H HANTIFOLATES


PHASE I/II OF PRALATREXATE IN CTCL• Eligible CTCL types included: progression after ≥ 1 systemic therapy• Mycosis fungoides (MF)• Sézary syndrome (SS)• Primary cutaneous anaplastic large cell lymphoma (ALCL)• Pralatrexate administered as an IV push; doses reduced in sequentialcohorts based on toxicity• 3 out of 4 week schedule• 2 out of 3 week schedule• Phase I - study design was a de-escalation of the dose in sequentialcohorts of 6-9 patients. Response assessed by mSWAT• Phase II – 15 additional patients treated at 15 mg/m 2 weekly on a 3out of 4 week scheduleHorwitz et al., ASH 2008


RESULTSPRALATREXATE IN CTCLN = 54 Median Age 57HistologyMFSSALCLCTCL-NOSSystemicTherapy(30-81)3313114(1-11)Phase IOptimaldose/schedulen = 31 15 mg/m 2weeklyfor 3 /4Phase IIN = 23 15 mg/m 2weekly for3 /4Response61% atoptimaldosing vs8%RR of 29pts at thisdose-ORR 50%ToxicityFatigue,mucositis,nausea,anemia,thrombocytopenialowincidenceof grade 3and 412/15/2010 ECG 36


FORODESINEKicska GA, et al, Proc Natl Acad Sci. 2001;98:4593-4598;Duvic M, et al. Blood. 2007;110. Abstract 122.


LENALIDOMIDE (CC-5013):NEW GENERATION ANALOGSONOHNOONOHNOOThalidomideNH 2Lenalidomide• 4-amino-glutamyl analogue• 10-1000 times more potent• Safety profile: non-neurotoxic,non-teratogenic, non-sedatingStirling D. Semin Oncol. 2001;28:602-606.


LENALIDOMIDE IN CTCL


ALEMTUZUMAB- ANTI CD 52N RESPONSES DURATION OFEFFECTLundin et al 2003 22 ORR 52%CR 32%PR 23%ORR better inerythroderma 69% vs40%Kennedy GA et al200387 MF/SS1 TMFDuvec et al 2004 8 3 PRs1 SDTime to treatmentfailure 12 months(5-32)ORR 38% POD within 4monthsCOMMENTSCMV reactivation n = 4,other infections n = 6Significant infections4 developed cardiactoxicity, arrhythmias,CHFBarengo et al 2007 14 SS ORR 85 %, CR 21% TTF 12 months Infections seen in 28%of patientsQuerfeld et al 2009 19 SS/T4 ORR 84% with 47%CR and 37% PRPFS 6 months OS41 monthsMyelosuppression andinfections12/15/2010 ECG 42


ZANOLIMUMAB• Fully human anti-CD4 monoclonal antibody• Prevents interaction between CD4 and majorhistocompatibility class II molecules• Prevents T-cell activation• Antibody dependent cellular toxicity12/15/2010 ECG 43


•2 identical phase II studies of zanolimumab•Dose was 280-980 mg weekly for 17 weeks•47 pts, MF n = 38, SS n = 9•ORR 56% in the (560-980mg )with median duration of response of 81weeks- No major toxicity12/15/2010 Kim YH, et al. Blood. 2007;109:4655-4662. 44


KW-0761MONOCLONAL ANTIBODY AGAINST CCR4• Phase I/II study in relapsed PTCL and CTCL• Given IV once a week for 4 weeksrest• No DLTS noted so far• No increase in the rate of infections• 38 CTCL – MF n = 23, SS n = 152 week• ORR in CTCL is 39%, SS 47%, MF 35%, 7 CRsin SSDuvic, et al. ASH 2010. Abstract # 962.


SINGLE-AGENT CHEMOTHERAPYAGENT DOSE STAGE RESPONSE COMMENTSLow dose MTX(Zacheim et al 2003,Mc Donald et al 1978)25-75 mg weekly Largest series in T2(60 pts)12% CR22% PRTTF-15 monthsCan be combined withIFN- a, ECP, PUVAGemcitabine (Zinzani etal 2000)1000-1200 mg/m 2 q 3-4weeksRelapsed disease 68%Median duration ofCR/PR 10-15 monthsFrontline therapy inadvanced CTCL - 73%RR (Marchi et al 2005)Pegylated LiposomalDoxorubicin (Wollina etal 2003)20-40 mg/m 2 q 2-3weeksRelapsed MFORR 88% with a CR44% - DFS was 13.3months, OS 17.8monthsClinical trials incombination withbiologic agentsPentostatin(Kurzrock et al 2004)2 CDA(Kuzel et al 1996)Relapsed MF ORR stage IIB 75%Stage III 58%Stage IV 50%Relapsed MF ORR Iia-IV 28%Median duration ofresponse 4.5 monthsBest activity seen inSS, lymphopeniaBone marrowsuppression, infections12/15/2010 ECG 46


PERIPHERAL STEM CELL TRANSPLANTFOR CTCLREFERENCE N CONDITIONINGREGIMENOUTCOMESoligo 2003 3 Fludarabine, TBI 3 CR: 18 & 24 mo, 1dead d+73Molina2003 & 20058 Fludar/Melph n=4CTX/TBI n=3CTX/Busulfan n=18 CR: 6 alive (33-106mo), 2 dead (sepsis)Guitart 2002 3 Cyclophos/Mesna, TBI 3 CR: 15, 52, 60 moDuvic 2010 18 TSEB +Flu/mel ITT 68& CR 58%11/13 CR at 19monthsDuarte et al 2010 60 RIC and fully ablative OS 66% 1 year and54% 3Lechowicz et alASH # 364129 RIC in 64% OS at 2 yrs 44%RIC no diff than fullyablative conditioning


LARGE CELL TRANSFORMATIONTREATMENT CONSIDERATIONS• Local radiation therapyfor unifocal disease• Systemicchemotherapy – ORRof 58% seen withpralatrexate –(abstract #1762)• Clinical trials• Consider SCT inyoung patientsVergier B, et al. Blood .2000;95:2212-2218.


SEZARY SYNDROMETREATMENT CONSIDERATIONSFIRST-LINE• ECP: combine withIFN-α, bexarotene, or lowdose MTX• IFN-α• PUVA +/- IFN-α• MTXSECOND-LINEBexarotene – combinationtherapyVorinostatRomidepsinDenileukin diftitoxAlemtuzumab: high RR in SSNovel agentsChemotherapyHSCT12/15/2010 ECG 49


SUMMARY OF THERAPIES FOR CTCL• Skin-directed therapies: highly effective in theearly stages of MF but relapses are common• The Challenge: develop systemic targetedtherapies with minimal toxicities capable ofinducing meaningful remissions• The Goal (for now): Do no harm and preventprogression


MANAGEMENT OF CTCLIALimitedDiseaseIB/IIAGeneralizedIIBTumorsIIIErythrodermaExtracutaneousDiseaseSkin directed*PhotopheresisSingle-agent chemotherapy †PUVA bexarotene or IFNTotal skin radiationAlemtuzumabCombinationchemoBexarotene, denileukin diftitox, IFN, vorinostat,romidepsin (single / combination chemotherapy)Clinical TrialAllo-HSCT*Topical steroid, retinoid gel, nitrogen mustard, phototherapy.†Methotrexate, liposomal doxorubicin, gemcitabine, pentostatin, chlorambucil, etoposide, temozolomide.


THANK YOU12/15/2010 ECG 52

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