John A. Zic, MD Associate Professor of Medicine Division of Dermatology Vanderbilt University School of Medicine Nashville, Tennessee Current and Emerging Treatment Options in Cutaneous T-Cell Lymphoma This program is supported by educational grants from

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clinicaloptions.com/oncology Current and Emerging Treatment Options in Cutaneous T-Cell lymphoma Overview of This Presentation  Review the new EORTC-WHO classification of CTCL variants  Current insights into pathogenesis of mycosis fungoides  Review the new ISCL staging for mycosis fungoides and Sézary syndrome  Prognostic groups in CTCL  Therapeutic overview and treatment algorithm  Approach to the patient with advanced CTCL  Emerging therapies

clinicaloptions.com/oncology Current and Emerging Treatment Options in Cutaneous T-Cell lymphoma Review the New WHO-EORTC Classification of CTCL Variants Willemze R, et al. Blood. 2005;105: Willemze R, et al. Blood. 2005;105: Cutaneous T-Cell and NK-Cell Lymphomas Mycosis fungoides MF variants and subtypes Pagetoid reticulosis Granulomatous slack skin Sézary syndrome Adult T-cell leukemia/lymphoma Primary cutaneous CD30+ lymphoma* Extranodal NK/T-cell lymphoma, nasal type Primary cutaneous peripheral T-cell lymphoma, unspecified Primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma (provisional) Cutaneous  /  T-cell lymphoma (provisional) Primary cutaneous CD4+ small/medium-sized pleomorphic T-cell lymphoma (provisional)

clinicaloptions.com/oncology Current and Emerging Treatment Options in Cutaneous T-Cell lymphoma Insights Into the Pathogenesis of Mycosis Fungoides Skin Homing T Cells

clinicaloptions.com/oncology Current and Emerging Treatment Options in Cutaneous T-Cell lymphoma Epidermotropism and Pautrier’s Microabscesses Langerhans cell Malignant T cell Insights Into the Pathogenesis of Mycosis Fungoides

clinicaloptions.com/oncology Current and Emerging Treatment Options in Cutaneous T-Cell lymphoma Membrane Protein Interactions Girardi M, et al. N Engl J Med. 2004;350: Copyright © 2004 Massachusetts Medical Society. All rights reserved. Insights Into the Pathogenesis of Mycosis Fungoides

clinicaloptions.com/oncology Current and Emerging Treatment Options in Cutaneous T-Cell lymphoma New ISCL Staging for Mycosis Fungoides and Sézary Syndrome Olsen E, et al. Blood. 2007;110: Early-Stage Disease (No Change) Clinical StageTNMB Stages IAT1N0M0B0-1 IBT2N0M0B0-1 IIAT1-2N1-2M0B0-1

clinicaloptions.com/oncology Current and Emerging Treatment Options in Cutaneous T-Cell lymphoma New ISCL Staging for Mycosis Fungoides and Sézary Syndrome Stage IA

clinicaloptions.com/oncology Current and Emerging Treatment Options in Cutaneous T-Cell lymphoma Stage IB New ISCL Staging for Mycosis Fungoides and Sézary Syndrome

clinicaloptions.com/oncology Current and Emerging Treatment Options in Cutaneous T-Cell lymphoma Olsen E, et al. Blood. 2007;110: Late-Stage Disease (Small Change) Clinical StageTNMB Stages IIBT3N0-2M0B0-1 IIIAT4N0-2M0B0 IIIBT4N0-2M0B1 New ISCL Staging for Mycosis Fungoides and Sézary Syndrome

clinicaloptions.com/oncology Current and Emerging Treatment Options in Cutaneous T-Cell lymphoma Stage IIB New ISCL Staging for Mycosis Fungoides and Sézary Syndrome

clinicaloptions.com/oncology Current and Emerging Treatment Options in Cutaneous T-Cell lymphoma Stage IIIA New ISCL Staging for Mycosis Fungoides and Sézary Syndrome

clinicaloptions.com/oncology Current and Emerging Treatment Options in Cutaneous T-Cell lymphoma Olsen E, et al. Blood. 2007;110: Late-Stage Disease (Big Change) Clinical StageTNMB Stages IVA1T1-4N0-2M0B2 IVA2T1-4N3M0B0-2 IVBT1-4N0-3M1B0-2 Sézary Syndrome IVA 1 or 2 or IVBT4N0-3M0-1B2 New ISCL Staging for Mycosis Fungoides and Sézary Syndrome

clinicaloptions.com/oncology Current and Emerging Treatment Options in Cutaneous T-Cell lymphoma Stage IVA1 New ISCL Staging for Mycosis Fungoides and Sézary Syndrome

clinicaloptions.com/oncology Current and Emerging Treatment Options in Cutaneous T-Cell lymphoma Stage IVA2 New ISCL Staging for Mycosis Fungoides and Sézary Syndrome

clinicaloptions.com/oncology Current and Emerging Treatment Options in Cutaneous T-Cell lymphoma Prognostic Groups in CTCL  Low-risk group (most favorable): TNM stages IA, IB, IIA (survival ~ 12 yrs)  Intermediate-risk group: TNM stages IIB, III, IVA1 (survival ~ 3 yrs)  High-risk group (least favorable): TNM stage IVA2, IVB (survival ~ < 2 yrs) Foss FM, et al. Hematol Oncol Clin North Am. 1995;9:

clinicaloptions.com/oncology Current and Emerging Treatment Options in Cutaneous T-Cell lymphoma Overview of Therapy for CTCL Skin Directed  Topical steroids  Topical nitrogen mustard: mechlorethamine  Topical bexarotene gel  Phototherapy –NBUVB –PUVA  Radiation therapy –Total skin electron beam –Localized electron beam Systemic  Bexarotene capsules  Vorinostat capsules  Methotrexate  Interferon  Extracorporeal photochemotherapy  Denileukin diftitox  Single-agent chemotherapy  Combination chemotherapy

clinicaloptions.com/oncology Current and Emerging Treatment Options in Cutaneous T-Cell lymphoma MF/SS Treatment Algorithm Denileukin Diftitox Bexarotene Capsules Topical Corticosteroids (Class I) Electron Beam Radiotherapy Bexarotene Gel PUVA (± IFN or ± Retinoid) Nitrogen Mustard Single-Agent Chemotherapy Photopheresis ± IFN ± Bex Photopheresis NBUVB Vorinostat AlloSCT Stage IAStage IB/IIAStage IIBStage IIIStage IV Zic A, et al. Wintrobe’s Clinical Hematology

clinicaloptions.com/oncology Current and Emerging Treatment Options in Cutaneous T-Cell lymphoma Types of phototherapy for MF  WBUVB  NBUVB  PUVA UVAUVB 290 nm 320 nm400 nm NBUVB 311 nm Baron ED, et al. Dermatol Ther. 2003;16: Phototherapy for MF

clinicaloptions.com/oncology Current and Emerging Treatment Options in Cutaneous T-Cell lymphoma  Efficacy of PUVA (combined analysis CR rates) –IA: 54/60 (90%); 31% relapse –IB: 88/116 (76%); 56% relapse –IIA: 7/9 (78%); 71% relapse –III: 11/18 (61%); ~ 100% relapse Herrmann JJ, et al. Hematol Oncol Clin N Am. 1995; 9: PUVA Phototherapy for MF

clinicaloptions.com/oncology Current and Emerging Treatment Options in Cutaneous T-Cell lymphoma ReferenceDrugPatients, nORR, % CR % PR, n (%) Heald 2000Bex7100 Duvic et al, 2001Bex9445 Relapse rate: 28%Early I, IIA54 Median time to relapse: 43 wks Late ≥ IIB45 Prince et al, 2001Bex7 5 (71) Talpur et al, 2002Bex Kempf W, et al. Hematol Oncol Clin N Am. 2003;17: Bexarotene Capsule Monotherapy in CTCL [1]

clinicaloptions.com/oncology Current and Emerging Treatment Options in Cutaneous T-Cell lymphoma BaselineWk 12 Wk 28 Bexarotene Pivotal Trial: L (282) Patient 544, Lesion 1X, Forearm

clinicaloptions.com/oncology Current and Emerging Treatment Options in Cutaneous T-Cell lymphoma  Adverse effects –Hyperlipidemia (≥80%): usually requires support therapy with lipid lowering agent *Gemfibrozil is contraindicated* –Central hypothyroidism (30% to ≥70%); may require thyroid supplementation –Leukopenia (11%) Zhang C, et al. Dermatol Ther. 2003;16: Kempf W, et al. Hematol Oncol Clin N Am. 2003;17: Bexarotene Capsules for MF/SS

clinicaloptions.com/oncology Current and Emerging Treatment Options in Cutaneous T-Cell lymphoma  Method: total skin electron beam therapy –6-9 MeV electrons via linear accelerator –6 field technique: ant, post, 4 oblique fields – Gy per fraction over 9-10 wks – Total dose: Gy  Method: localized electron beam therapy –Tumors: 9-12 MeV with 2-cm margins –Total dose: Gy Hoppe RT. Dermatol Ther. 2003;16: Jones G, et al. Hematol Oncol Clin N Am. 2003;17: Radiation Therapy for MF

clinicaloptions.com/oncology Current and Emerging Treatment Options in Cutaneous T-Cell lymphoma  Efficacy (N = 561 combined analysis, ORR 100%) [1] : 15-yr PFS [2] : –Early disease (IA, IB, IIA): ~ 25% –Late disease (IIB, III, IV): < 10% Jones GW, et al. Hematol Oncol Clin N Am. 1995;9: Jones G, et al. Hematol Oncol Clin N Am. 2003;17: TSEB Radiation Therapy for MF Efficacy (N = 561 combined analysis, ORR 100%) [1] CR Rates, %Relapse-Free Rates at 2.5 Yrs, % IA IB IIA IIB III

clinicaloptions.com/oncology Current and Emerging Treatment Options in Cutaneous T-Cell lymphoma  Adverse effects –Acute skin effects: burning erythema, edema –Chronic skin effects: xerosis, superficial atrophy, telangiectasia, and dyspigmentation –Alopecia and loss of nails (usually regrow) –Heat intolerance due to the suppression of sweat gland production (6-12 mos) –Increased SCC and BCC (? role of other therapies) Hoppe RT. Dermatol Ther. 2003;16: Jones G, et al. Hematol Oncol Clin N Am. 2003;17: TSEB Radiation Therapy for MF

clinicaloptions.com/oncology Current and Emerging Treatment Options in Cutaneous T-Cell lymphoma Chemotherapy for CTCL  Reserved for relapsed or refractory disease  Response rates modest and duration of response < 6 mos  Agents that show some notable activity –Gemcitabine –Jidar K, et al. Br J Dermatol. 2009;[Epub ahead of print]. –Marchi E, et al. Cancer. 2005;104: –Phase II trial; N = 32 untreated CTCL (7 [22%] CRs, 17 [53%] PRs) –Pegylated liposomal doxorubicin –Wollina U, et al. Cancer. 2003;98: –Retrospective analysis; N = 34 CTCL (15 CRs [DFS: 13.3 mos], 15 PRs) Kuzel TM. Dermatol Ther. 2003;16: Pichardo DA, et al. Leuk Lymphoma. 2004;45:

clinicaloptions.com/oncology Current and Emerging Treatment Options in Cutaneous T-Cell lymphoma Gemcitabine for CTCL  25 patients with CTCL on a phase II open-label trial and 8 patients off study received intravenous gemcitabine 1000 mg/m 2 on Days 1, 8, and 15 for ≥ 6 cycles  17 of 25 (68%) of study patients responded – 2 CRs – 4 of 8 patients (1 CR) off protocol  7 of 13 patients with mycosis fungoides (T3) responded, 10 had tumor burden reductions, and 8 of 11 patients with Sézary syndrome responded  Adverse effects –Myelosuppression (n = 14), hemolytic uremic syndrome (in 2 elderly patients with Sézary syndrome), pulmonary embolism (n = 2), and 1 episode each of congestive heart failure, acute myocardial infarction, and stable angina  Gemcitabine is an effective monotherapy with a 68% ORR in patients with advanced, heavily pretreated CTCL Duvic M, et al. Clin Lymphoma Myeloma. 2006;7:51-58.

clinicaloptions.com/oncology Current and Emerging Treatment Options in Cutaneous T-Cell lymphoma Quereux G, et al. Arch Dermatol. 2008;144: Used with permission. Liposomal Doxorubicin for CTCL Mos Figure Survival Probability, % Mos Survival Probability, % Figure 1

clinicaloptions.com/oncology Current and Emerging Treatment Options in Cutaneous T-Cell lymphoma  HDAC inhibitor  Dosage: 400 mg orally once daily  Pivotal study: N = 74 –82% stage IIB-IVB –Median of 3 previous therapies –30% ORR Olsen EA, et al. J Clin Oncol. 2007;25: Vorinostat for CTCL

clinicaloptions.com/oncology Current and Emerging Treatment Options in Cutaneous T-Cell lymphoma Mechanism of Action of Vorinostat  Excess HDAC results in tightly packaged DNA and gene silencing  HDAC inhibition increases acetylation –Uncoiling of DNA within chromatin –Transcriptional activation of genes  The mechanism of the antineoplastic effect of HDAC inhibition has not been fully characterized  Vorinostat induces cell-cycle arrest and apoptosis in some transformed cells as shown by in vitro studies Olsen EA, et al. J Clin Oncol. 2007;25:

clinicaloptions.com/oncology Current and Emerging Treatment Options in Cutaneous T-Cell lymphoma Vorinostat for CTCL  Kaplan-Meier median time to response: 2 mos  Kaplan-Meier median duration of response not reached; estimate > 6 mos  Adverse effects –Thromboembolism (PE 4.7%) –Fatigue, diarrhea, nausea (40% to 52%) –Lab abnormalities: increased glucose (69%), increased creatinine (47%), proteinuria (51%) –QT prolongation: 5%, 1 patient grade 3 (> 500 msec) Olsen EA, et al. J Clin Oncol. 2007;25:

clinicaloptions.com/oncology Current and Emerging Treatment Options in Cutaneous T-Cell lymphoma  Fusion protein: diphtheria toxin fragments A and B linked to IL-2  Approximately 50% of tumor cells in CTCL express IL-2 receptor  IV infusion daily for 5 days every 3 wks at 9 or 18 mcg/kg/day  Pivotal study: N = 71, 63% stage IIB-IVB, median of 5 previous therapies; 30% ORR Olsen E, et al. J Clin Oncol. 2001;19: Denileukin Diftitox for CTCL

clinicaloptions.com/oncology Current and Emerging Treatment Options in Cutaneous T-Cell lymphoma Denileukin Diftitox for CTCL  Kaplan-Meier median duration of response: 4 mos  Adverse effects –Acute hypersensitivity reactions (69%): acute; hypotension, SOB, rash, chest pain –Vascular leak syndrome (27%): delayed; hypotension, edema, hypoalbuminemia –Infections (48%) –Lymphopenia (34%) Olsen E, et al. J Clin Oncol. 2001;19:

clinicaloptions.com/oncology Current and Emerging Treatment Options in Cutaneous T-Cell lymphoma ReferencePatients, N (Age) Conditioning Regimen GVHD Prophylaxis Outcome Soligo (51-60 yrs)Fludarabine, TBICSA, MMF3 CRs: 18 & 24 mos, 1 dead d+73 Molina 2003, (21-59 yrs)Flud/melph, n = 4 Cyclophos/TBI, n = 3 Cyclophos/busulfan CSA, n = 8 MTX, n = 4 MMF, n = 6 8 CRs: 6 alive ( mos), 2 dead (sepsis) Guitart (27-39 yrs)Cyclophos/mesna, TBI CSA, steroid, ± MMF 3 CRs: 15, 52, 60 mos Masood (37 yrs)Cyclophos, TBIMTX, CSACR: 24 mos Koeppel (21 yrs)Cyclophos, TBIMTX, CSA, steroid CR: 72 mos Allogeneic Stem Cell Transplantation Series Pichardo DA, et al. Leuk Lymphoma. 2004;45: Peripheral Stem Cell Transplantation for CTCL

clinicaloptions.com/oncology Current and Emerging Treatment Options in Cutaneous T-Cell lymphoma Photopheresis Whole blood RBCWBC 8-methoxypsoralen Ultraviolet A Photoactivation Return to patient

clinicaloptions.com/oncology Current and Emerging Treatment Options in Cutaneous T-Cell lymphoma Photopheresis for MF/SS StagePatients, NORR, %CR, % IB IIA IIB III IVA IVB11279 Skin stage T Skin stage T Skin stage T Skin stage T Sézary syndrome Zic JA. Dermatol Ther. 2003;16:

clinicaloptions.com/oncology Current and Emerging Treatment Options in Cutaneous T-Cell lymphoma MF/SS Treatment Algorithm Denileukin Diftitox Bexarotene capsules Topical Corticosteroids (Class I) Electron Beam Radiotherapy Bexarotene Gel PUVA (± IFN or ± Retinoid) Nitrogen Mustard Single-Agent Chemotherapy Photopheresis ± IFN ± Bex Photopheresis NBUVB Vorinostat AlloSCT Stage IAStage IB/IIAStage IIBStage IIIStage IV Zic, et al. Wintrobe’s Clinical Hematology

clinicaloptions.com/oncology Current and Emerging Treatment Options in Cutaneous T-Cell lymphoma Emerging Therapies for CTCL  Romidepsin [1] –Novel intravenous HDAC inhibitor; phase II trial complete –FDA advisory committee recommends romidepsin for approval for cutaneous T-cell lymphoma –Side effect profile similar to vorinostat  Pralatrexate [2] –Investigational intravenous antifolate agent; phase I trial recruiting 1. Woo S, et al. Clin Cancer Res. 2009;15: Leitenberger JJ, et al. J Am Acad Dermatol. 2008;58:

clinicaloptions.com/oncology Current and Emerging Treatment Options in Cutaneous T-Cell lymphoma Emerging Therapies for CTCL  Zanolimumab (HuMax-CD4) [1] –Novel humanized anti-CD4 monoclonal; phase II trial complete –RR: 30% - 40%  Bortezomib [2] –Novel proteasome inhibitor; in vitro data suggest synergistic activity with HDACs  Forodesine [3] –Purine nucleoside phosphorylase inhibitor; specifically targets T cells –Well-tolerated; Phase I and II trials not published yet 1. Kim YH, et al. Blood. 2007;109: Zinzani PL, et al. J Clin Oncol. 2007;25: Korycka A, et al. Mini Rev Med Chem. 2007;7:

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