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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
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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)
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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.
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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.
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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.
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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
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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 (%)
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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.
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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
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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.
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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
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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]
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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
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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.
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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
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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.
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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
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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.
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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.
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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.
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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.
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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.
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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.
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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
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