1. 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

2. clinicaloptions.com/oncology Current and Emerging Treatment Options in Cutaneous T-Cell lymphoma About These Slides  Our thanks to the presenters who gave permission to include their original data  Users are encouraged to use these slides in their own noncommercial presentations, but we ask that content and attribution not be changed. Users are asked to honor this intent.  These slides may not be published or posted online without permission from Clinical Care Options –Contact: permissions@clinicaloptions.com Disclaimer The materials published on the Clinical Care Options Web site reflect the views of the authors of the CCO material, not those of Clinical Care Options, LLC, the CME providers, or the companies providing educational grants. The materials may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and Drug Administration. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or using any therapies described in these materials.

3. 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

4. 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;105:3768-3785 Willemze R, et al. Blood. 2005;105:3768-3785. 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)

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

6. 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

7. 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;350:1978-1988. Copyright © 2004 Massachusetts Medical Society. All rights reserved. Insights Into the Pathogenesis of Mycosis Fungoides

8. 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;110:1713-1722. Early-Stage Disease (No Change) Clinical StageTNMB Stages IAT1N0M0B0-1 IBT2N0M0B0-1 IIAT1-2N1-2M0B0-1

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

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

11. clinicaloptions.com/oncology Current and Emerging Treatment Options in Cutaneous T-Cell lymphoma Olsen E, et al. Blood. 2007;110:1713-1722. Late-Stage Disease (Small Change) Clinical StageTNMB Stages IIBT3N0-2M0B0-1 IIIAT4N0-2M0B0 IIIBT4N0-2M0B1 New ISCL Staging for Mycosis Fungoides and Sézary Syndrome

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

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

14. clinicaloptions.com/oncology Current and Emerging Treatment Options in Cutaneous T-Cell lymphoma Olsen E, et al. Blood. 2007;110:1713-1722. 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

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

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

17. 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;9:1011-1019.

18. 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

19. 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. 2008.

20. 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;16:303-310. Phototherapy for MF

21. 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; 9:1077-1088. PUVA Phototherapy for MF

22. 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, 2002Bex54484 1. Kempf W, et al. Hematol Oncol Clin N Am. 2003;17:1405-1419. Bexarotene Capsule Monotherapy in CTCL [1]

23. clinicaloptions.com/oncology Current and Emerging Treatment Options in Cutaneous T-Cell lymphoma BaselineWk 12 Wk 28 Bexarotene Pivotal Trial: L1069-24 (282) Patient 544, Lesion 1X, Forearm

24. 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;16:322-330. Kempf W, et al. Hematol Oncol Clin N Am. 2003;17:1405-1419. Bexarotene Capsules for MF/SS

25. 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 –1.5-2.0 Gy per fraction over 9-10 wks – Total dose: 30-36 Gy  Method: localized electron beam therapy –Tumors: 9-12 MeV with 2-cm margins –Total dose: 20-30 Gy Hoppe RT. Dermatol Ther. 2003;16:347-354. Jones G, et al. Hematol Oncol Clin N Am. 2003;17:1421-1434. Radiation Therapy for MF

26. 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% 35-40 1. Jones GW, et al. Hematol Oncol Clin N Am. 1995;9:1057-1076. 2. Jones G, et al. Hematol Oncol Clin N Am. 2003;17:1421-1434. TSEB Radiation Therapy for MF Efficacy (N = 561 combined analysis, ORR 100%) [1] CR Rates, %Relapse-Free Rates at 2.5 Yrs, % IA84-9664-73 IB56-8135-40 IIA63-7421-37 IIB24-537-26 III26-5010-23

27. 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;16:347-354. Jones G, et al. Hematol Oncol Clin N Am. 2003;17:1421-1434. TSEB Radiation Therapy for MF

28. 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;104:2437-2441. –Phase II trial; N = 32 untreated CTCL (7 [22%] CRs, 17 [53%] PRs) –Pegylated liposomal doxorubicin –Wollina U, et al. Cancer. 2003;98:993-1001. –Retrospective analysis; N = 34 CTCL (15 CRs [DFS: 13.3 mos], 15 PRs) Kuzel TM. Dermatol Ther. 2003;16:355-361. Pichardo DA, et al. Leuk Lymphoma. 2004;45:1755-1765.

29. 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.

30. clinicaloptions.com/oncology Current and Emerging Treatment Options in Cutaneous T-Cell lymphoma Quereux G, et al. Arch Dermatol. 2008;144:727-733. Used with permission. Liposomal Doxorubicin for CTCL Mos Figure 2 10203040500 0 40 20 60 80 100 Survival Probability, % Mos 10203040500 0 40 20 60 80 100 Survival Probability, % Figure 1

31. 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;25:3109-3115. Vorinostat for CTCL

32. 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;25:3109-3115.

33. 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;25:3109-3115.

34. 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;19:376-388. Denileukin Diftitox for CTCL

35. 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;19:376-388.

36. clinicaloptions.com/oncology Current and Emerging Treatment Options in Cutaneous T-Cell lymphoma ReferencePatients, N (Age) Conditioning Regimen GVHD Prophylaxis Outcome Soligo 20033 (51-60 yrs)Fludarabine, TBICSA, MMF3 CRs: 18 & 24 mos, 1 dead d+73 Molina 2003, 2005 8 (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 (33-106 mos), 2 dead (sepsis) Guitart 20023 (27-39 yrs)Cyclophos/mesna, TBI CSA, steroid, ± MMF 3 CRs: 15, 52, 60 mos Masood 20021 (37 yrs)Cyclophos, TBIMTX, CSACR: 24 mos Koeppel 19941 (21 yrs)Cyclophos, TBIMTX, CSA, steroid CR: 72 mos Allogeneic Stem Cell Transplantation Series Pichardo DA, et al. Leuk Lymphoma. 2004;45: 1755-1764. Peripheral Stem Cell Transplantation for CTCL

37. 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

38. clinicaloptions.com/oncology Current and Emerging Treatment Options in Cutaneous T-Cell lymphoma Photopheresis for MF/SS StagePatients, NORR, %CR, % IB256428 IIA255624 IIB195326 III283618 IVA865120 IVB11279 Skin stage T175743 Skin stage T2686228 Skin stage T3443216 Skin stage T42245815 Sézary syndrome1054310 Zic JA. Dermatol Ther. 2003;16:337-346.

39. 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. 2008.

40. 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;15:1496-1503. 2. Leitenberger JJ, et al. J Am Acad Dermatol. 2008;58:480-484.

41. 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;109:4655-4662. 2. Zinzani PL, et al. J Clin Oncol. 2007;25:4293-4297. 3. Korycka A, et al. Mini Rev Med Chem. 2007;7:976-983.

42. clinicaloptions.com/TCell Go Online for More Detailed Information on T-Cell Lymphomas! Interactive Virtual Presentations PTCL CTCL Text-Based Module