1. Steven M. Horwitz, MD Assistant Attending Physician Lymphoma Service Department of Medicine Memorial Sloan-Kettering Cancer Center New York, New York Clinical Focus: Considerations for Optimal Care of Patients With Anaplastic Large-Cell Lymphoma Jointly sponsored by Postgraduate Institute for Medicine and Clinical Care Options, LLC This program is supported by an educational grant from Image: XVIVO LLC/Copyright©2013 Phototake All Rights Reserved

2. clinicaloptions.com/oncology Considerations for Optimal Care of Patients With Anaplastic Large-Cell Lymphoma WHO 2008 Classification of Mature T/NK- Cell Neoplasms 1. Lim MS, et al. J Hematop. 2009;2:65-73. T-cell prolymphocytic leukemia T-cell large granular lymphocytic leukemia Chronic lymphoproliferative NK cells Aggressive NK-cell leukemia Adult T-cell lymphoma/leukemia Systemic EBV-positive T-cell lymphoma Extranodal NK/T-cell lymphoma, nasal type Enteropathy-type intestinal T-cell lymphoma Hepatosplenic T-cell lymphoma Angioimmunoblastic T-cell lymphoma Anaplastic large-cell lymphoma, ALK positive/ALK negative Peripheral T-cell lymphoma, NOS Mycosis fungoides Sezary syndrome Primary cutaneous CD30+ lymphoproliferative Primary cutaneous anaplastic large-cell lymphoma Lymphomatoid papulosis Borderline lesions Subcutaneous panniculitis-like T cell Primary cutaneous gamma-delta T cell Hydroa vacciniforme lymphoma Primary cutaneous aggressive epidermotropic CD8+ cytotoxic T cell Primary cutaneous small/medium CD4+ T-cell lymphoma (provisional)

3. clinicaloptions.com/oncology Considerations for Optimal Care of Patients With Anaplastic Large-Cell Lymphoma International PTCL Study: NHL Types by Region Subtype, %North AmericaEuropeAsia PTCL, NOS34.434.322.4 Angioimmunoblastic16.028.717.9 ALCL, ALK+16.06.43.2 ALCL, ALK-7.89.42.6 NK/T cell5.14.322.4 ATLL2.01.025.0 2. Vose JM, et al. J Clin Oncol. 2008;26:4124-4130.

4. clinicaloptions.com/oncology Considerations for Optimal Care of Patients With Anaplastic Large-Cell Lymphoma Overview of the Characteristics of ALCL  ALCL mainly affects lymph nodes, although extranodal sites may be involved; the most commonly involved extranodal sites include skin, bone, soft tissues, lung, and liver [4-6]  ALCL is characterized by large lymphoid cells with abundant cytoplasm and pleomorphic—often horseshoe- shaped—nuclei [5]  Cells express CD30 and either TcR or no specific antigens (null cell) [4,5]  TcR rearrangements are common (70% to 90% of patients), with β loci rather than  loci more commonly affected [4,6]  ALK expression status is important for the diagnosis of ALCL [6] CD30+ 4. Rizvi MA, et al. Blood. 2006;107:1255-1264. 5. Swerdlow SH. WHO classification of tumours of haematopoietic and lymphoid tissues. 2008. 6. Savage KJ, et al. Blood. 2008;111:5496-5504.

5. clinicaloptions.com/oncology Considerations for Optimal Care of Patients With Anaplastic Large-Cell Lymphoma ALK and ALCL FeaturesALK+ Systemic ALCL ALK- Systemic ALCL Primary Cutaneous ALCL T-cell phenotypeCD4+/null ALK protein+-- CD30+++ Clusterin++- EMA+-/+- Cytotoxic proteins+ (80%)+ (50%)+ (70%) Median age, yrs< 35> 50 SexM > FM = FM > F 7. Swerdlow SH. WHO classification of tumours of haematopoietic and lymphoid tissues. 2008. 8. Savage KJ, et al. J Hematology. 2005;111:5496-5504. 9. Rizvi MA, et al. Blood. 2006;107:1255-1264.

6. clinicaloptions.com/oncology Considerations for Optimal Care of Patients With Anaplastic Large-Cell Lymphoma Prognosis: OS in a Subset of Lymphomas  PTCL, if CD30+ in > 80% of cells = worse prognosis  HTLV-1/ATLL, NK may be CD30+  MF with large-cell transformation will be CD30+ 10. Vose J, et al. J Clin Oncol. 2008;28:4124-4130. 15. Savage KJ, et al. Blood. 2008;111:5496-5504. ALCL, ALK- 14 ALCL, ALK+ Primary Cutaneous ALCL PTCL-NOS Lymphomatoid papulosis Yrs PTCL-CD30? 0 0.2 0.4 0.6 0.8 1.0 024681012 Proportion

7. clinicaloptions.com/oncology Considerations for Optimal Care of Patients With Anaplastic Large-Cell Lymphoma Dutch Cutaneous Lymphoma Group: Primary Cutaneous CD30+ Lymphomas LyP Cut ALCL + local LN Secondary cut ALCL Primary cut ALCL 18. Bekkenk MW, et al. Blood. 2000;95:3653-3661. TypePts, n5-Yr OS, %10-Yr OS, %5-Yr Disease- Specific Survival, % 10-Yr Disease- Specific Survival, % LyP1189895100 PC-ALCL79837896 PC-ALCL + reg LN1176 91 0 25 50 75 100 0510 15 Follow-up (Yrs) Cumulative Survival (%)

8. clinicaloptions.com/oncology Considerations for Optimal Care of Patients With Anaplastic Large-Cell Lymphoma Primary Cutaneous CD30+ LPD  Lymphomatoid papulosis ‒ Characteristic mixed infiltrate in a wedge-shaped configuration, mixed with large CD30+ cells ‒ Type A (histiocytic), type B (MF ‒ like), and type C (ALCL ‒ like) ‒ Skin lesions that always spontaneous regress, usually over 4-10 wks ‒ Clinical correlation ‒ Association with other lymphomas?  PC-ALCL ‒ Skin only at presentation ‒ Often localized but can be disseminated ‒ CD30+, ALK negative ‒ Usually indolent course with frequent relapses in skin, with rare progression to extracutaneous sites (10% to 15% risk) ‒ Nodules or tumors, less tendency for regression than LyP 19. Bekkenk MW, et al. Blood. 2000;95:3653-3661.

9. clinicaloptions.com/oncology Considerations for Optimal Care of Patients With Anaplastic Large-Cell Lymphoma 100 80 60 40 20 0 Prognosis in ALCL According to ALK Expression Status 20. Vose JM, et al. J Clin Oncol. 2008;26:4124-4130. ALK+ ALCL ALK- ALCL 5-yr OS% All7049 IPI 0/19074 IPI 4/53313 5-yr FFS % All6036 IPI 0/18062 IPI 4/52513 Yrs Patients (%) ALCL, ALK+ ALCL, ALK- 0 2 4 6 8 10 12 14 16 18 P <.001 Overall Survival

10. clinicaloptions.com/oncology Considerations for Optimal Care of Patients With Anaplastic Large-Cell Lymphoma Adding Etoposide to CHOP: German Prospective High-Grade NHL Studies Mos EFS, aged < 60 yrs Benefit 020406080100 80 60 20 0 40 Patients (%) P =.003 6 x CHOP-14/21 (n = 41) 6 x CHOEP-14/21 (n = 42) Mos 020406080100 80 60 20 0 40 Patients (%) P =.012 Non-etoposide (n = 12) Etoposide (n = 34) EFS, ALCL, ALK+ Benefit Mos EFS, other subtypes No Benefit Non-etoposide (n = 29) 020406080100 80 60 20 0 40 Patients (%) Etoposide (n = 69) P =.057 PTCL Subtypen ALCL, ALK+78 ALCL, ALK-113 PTCL-NOS70 AITL28 Other31 Total320 21. Schmitz N, et al. Blood. 2010;116:3418-3425.

11. clinicaloptions.com/oncology Considerations for Optimal Care of Patients With Anaplastic Large-Cell Lymphoma Nordic Lymphoma Group: CHOEP-ASCT HDT/ASCT* N = 115 90 CRs 3 mos post ND PTCL N = 160 Median age: 57 yrs ALK+/ALCL excluded CHOEP x 6 CR PR *Cycle 5-6 used as stem-cell mobilizing chemotherapy 23. d’Amore F, et al. J Clin Oncol. 2012;30:3093-3099. 0 0.2 0.4 0.6 0.8 1.0 0 122436486072 Mos PFS, Largest Subtypes P =.26 (log-rank test) Proportion of Patients PTCL-NOS AILT ALCL, ALK ‒ EATL

12. clinicaloptions.com/oncology Considerations for Optimal Care of Patients With Anaplastic Large-Cell Lymphoma ASCT at Relapse (PTCL)  Response to ICE: 70% (28/40)  Received ASCT: 68% (27/40) 24. Horwitz SM, et al. ASH 2005. Abstract 2670. 25. Smith SM, et al. J Clin Oncol. 2013;31:3100-3109. 12366084108132 PFS ICE Mos 0 0.2 0.4 0.6 0.8 1.0 Proportion of Patients All, N = 40 0 PFS [24] 100 80 60 40 20 0 0 12 24 36 48 MOS Adjusted Progression-Free Survival (%) Auto, 3-year PFS = 47% (n = 115) Allo, 3-year PFS = 36% (n = 126) P = NS PFS [25]

13. clinicaloptions.com/oncology Considerations for Optimal Care of Patients With Anaplastic Large-Cell Lymphoma Approved Agents in Relapsed/Refractory PTCL Pralatrexate [24] (N = 109) OutcomesRomidepsin [25] (N = 131) 29ORR, %25 11CR, %15 18PR, %11 10.1Median DOR, mos16.6 3.5Median PFS, mos4 26. O’Connor OA, et al. J Clin Oncol. 2011;29:1182-1189. 27. Coiffier B, et al. J Clin Oncol. 2012;30:631-636.  Median number of previous treatment regimens –Pralatrexate study: n = 3 –Romidepsin study: n = 2

14. clinicaloptions.com/oncology Considerations for Optimal Care of Patients With Anaplastic Large-Cell Lymphoma PROPEL (Pralatrexate) Study: Adverse Events Adverse Events (N = 111), %Any GradeGrade 3Grade 4 Mucosal inflammation*71184 Thrombocytopenia † 411419% § Nausea4140 Fatigue3652 Anemia † 34162 Neutropenia † 25148 Dyspnea1970 Hypokalemia † 1641 Abnormal LFTs*1350 Abdominal pain1240 Leukopenia † 1144 Febrile Neutropenia550 Sepsis532 Hypotension531 *Includes 6 MedDRA preferred terms. † Includes 2 MedDRA preferred terms. † Includes 3 MedDRA preferred terms. § Only 5 patients had platelet count < 10,000 μL. 28. O’Connor OA, et al. J Clin Oncol. 2011;29:1182-1189.

15. clinicaloptions.com/oncology Considerations for Optimal Care of Patients With Anaplastic Large-Cell Lymphoma Romidepsin Study: Adverse Events At least 1 TEAE Nausea Fatigue Thrombocytopenia Diarrhea Pyrexia Neutropenia Constipation Anorexia Anemia Dysgeusia ≥ Grade 3 Infection Events with a missing toxicity grade are included. 29. Coiffier B, et al. J Clin Oncol. 2012;30:631-636. 020406080100 Percent Overall Vomiting

16. clinicaloptions.com/oncology Considerations for Optimal Care of Patients With Anaplastic Large-Cell Lymphoma Phase II Study: Brentuximab Vedotin for R/R Systemic ALCL Multicenter, Open-Label Study (N = 58) Administration1.8 mg/kg every 3 wks Patient Characteristics Median of 2 previous systemic lines ResponsesORR: 86% CR: 57% Median DOR: 13.2 mos* * For those patients who achieved CR. 30. Pro B, et al. J Clin Oncol. 2012;30:2190-2196.

17. clinicaloptions.com/oncology Considerations for Optimal Care of Patients With Anaplastic Large-Cell Lymphoma Phase II Study: Brentuximab Vedotin for R/R Systemic ALCL 31. Pro B, et al. J Clin Oncol. 2012;30:2190-2196. -100 -50 50 100 0 Individual Patients (N = 57) Tumor Size (% Change From Baseline) CR PR SD PD Histologically ineligible Best clinical response

18. clinicaloptions.com/oncology Considerations for Optimal Care of Patients With Anaplastic Large-Cell Lymphoma Phase II Brentuximab Vedotin Study: AEs Adverse Events in >20% of patients All GradesGrade 3Grade 4 Pts, n (N = 58) % % % Peripheral sensory neuropathy 244171200 Nausea23401200 Fatigue22382312 Pyrexia20341200 Diarrhea17292300 Rash14240000 Constipation13221200 Neutropenia122171259 32. Pro B, et al. J Clin Oncol. 2012;30:2190-2196.

19. clinicaloptions.com/oncology Considerations for Optimal Care of Patients With Anaplastic Large-Cell Lymphoma BENTLY Study: Bendamustine in T-Cell Lymphoma T-cell lymphoma subtypes:  AILT (n = 32)  PTCL-NOS (n = 23)  ALCL (n = 2)  EATL (n = 1)  MF (n = 2)  Primary endpoint: ORR  ORR: 50%; 28% CR/CRu  Median PFS: 3.6 mos  Median OS: 6.3 mos  Most frequent grade 3/4 AEs: neutropenia, infection, thrombocytopenia R/R T-cell lymphoma; ≤ 3 previous lines of chemotherapy (N = 60) Bendamustine 120 mg/m 2 IV on Days 1,2 every 3 wks for 3 cycles If no PD, additional 3 cycles 33. Damaj G, et al. J Clin Oncol. 2013;31:104-110.

20. clinicaloptions.com/oncology Considerations for Optimal Care of Patients With Anaplastic Large-Cell Lymphoma Phase II Trial: Lenalidomide for R/R TCL  ORR: 30% (7/23)  Median PFS: 96 days (range, 8- 696 days)  Common AEs –Grade 4: thrombocytopenia (33.0%) –Grade 3: neutropenia (20.8%), febrile neutropenia (16.7%), pain NOS (16.7%) R/R T-cell lymphoma (other than MF); WHO PS ≤ 3; includes those previously treated and untreated unsuitable for standard therapy (N = 24) Lenalidomide 25mg PO QD for Days 1-21 of a 28-day cycle Tx continued until PD, death, or unacceptable toxicity Primary endpoint: ORR Secondary endpoints: PFS, OS, Safety HistologynCR, nPR, nORR, % ALCL50240 AITL70229 EATCL1000 HSTCL1000 PTCL90333 34. Dueck G, et al. Cancer. 2010;116:4541-4548.

21. clinicaloptions.com/oncology Considerations for Optimal Care of Patients With Anaplastic Large-Cell Lymphoma Phase I Study: Crizotinib for R/R ALK+ Pediatric Tumors  9 ALCL patients enrolled, ALK+ by FISH or IHC  All received previous multiagent chemotherapy, 1 patient had previous SCT  7 CRs –Rx with doses 165-280 mg/m 2 BID –CR onset: C1 (n = 2), C2 (n = 3), C3 (n = 1), C5 (n = 1)  5 patients remain on Rx: 7+ to 30+ cycles  3 patients removed from Rx to receive SCT: 4-9 cycles 35. Mossé YP, et al. Lancet Oncol. 2013;14:472-480.

22. clinicaloptions.com/oncology Considerations for Optimal Care of Patients With Anaplastic Large-Cell Lymphoma Clinical Trials: Phase I Study With Brentuximab Vedotin for Tx of ALCL  Open-label, multicenter phase I study  Arm 2 designed to determine recommended dose of brentuximab vedotin in combination with CHP (CHOP without vincristine) to be further evaluated in arm  Maximum tolerated dose was not exceeded at 1.8 mg/kg every 3 wks Brentuximab vedotin 1.8 mg/kg + standard-dose CHP every 3 wks x 6 cycles Single-agent Brentuximab Vedotin 1.8 mg/kg every 3 wks x 10 cycles 16 total cycles 36. Fanale MA, et al. ASH 2012. Abstract 60.

23. clinicaloptions.com/oncology Considerations for Optimal Care of Patients With Anaplastic Large-Cell Lymphoma Phase I Study With Brentuximab Vedotin in the First-line Setting: Results sALCL (n = 19) Other Diagnoses (n = 7) Total (N = 26) ORR, n (%)19 (100)7 (100)26 (100) CR, n (%)16 (84)7 (100)23 (88) PR, n (%)3 (16)--3 (12) Median PFS-- NR Median OS-- NR 37. Fanale MA, et al. ASH 2012. Abstract 60.

24. clinicaloptions.com/oncology Considerations for Optimal Care of Patients With Anaplastic Large-Cell Lymphoma ALCL: Conclusions  ALCL has 3 different subtypes with different prognoses and treatment approaches  Systemic ALCL is curable with combination chemotherapy –Etoposide –ASCT in CR1  Relapse ALCL treatment options –Limited data with SCT –New approved agents include pralatrexate and romidepsin –Other promising treatments include brentuximab vedotin, bendamustine, lenalidomide, and crizotinib  Brentuximab vedotin + CHP is being tested in an international phase III study for first-line treatment of ALCL