Audience Response Question? Non-Hodgkin s Lymphomas: Optimizing Therapeutic Choices for Initial Management. Presenter Disclosure Information

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1 Welcome to Master Class for Oncologists Session 4: 10:00 AM - 10:45 AM Miami, FL December 18, 2009 Non-Hodgkin s Lymphomas: Optimizing Therapeutic Choices for Initial Management Speaker: Arnold S. Freedman, MD Presenter Disclosure Information The following relationships exist related to this presentation: Initial management issues in lymphoma Dr Arnold S. Freedman has no relationships to disclose. Off Label/Investigational Discussion In accordance with Pri-Med Institute policy, faculty have been asked to disclose discussion of unlabeled or unapproved use(s) of drugs or devices during the course of their presentations. Follicular lymphoma Diffuse large B cell lymphoma Mantle cell lymphoma T-cell lymphomas 3 4 Audience Response Question? What is the optimal initial chemotherapy for a 60 y.o. patient with symptomatic follicular lymphoma, FLIPI score of 3? 1. CVP (or CHOP) + rituximab 2. CHOP-R followed by maintenance rituximab 3. Fludarabine + rituximab 4. Chemotherapy followed by radioimmunoconjugate R-CVP vs CVP International study 8 cycles of therapy TTF primary endpoint Approx. 45% patients FLIPI Marcus R, et al. Blood. 2005;105(4):

2 4167 patients Prognosis in follicular NHL follicular lymphoma IPI (FLIPI) Follicular Lymphoma International Prognostic Index (FLIPI) Age > 60, Stage III/IV, > 4 nodal sites, LDH, Hgb < 12 Low risk 0-1 Intermediate risk 2 High risk 3-5 Low risk 0-1 Intermediate risk 2 High risk Solal-Céligny P, et al. Blood. 2004;104(5): Solal-Céligny P, et al. Blood. 2004;104(5): Event-free survival median follow-up 53 months FLIPI 0, 1 FLIPI 2 Overall Survival median f/u 53 months FLIPI >3 9 Marcus R, et al. J Clin Oncol. 2008;26: Marcus R, et al. J Clin Oncol. 2008;26: Phase III trials of chemo vs R chemo in previously untreated follicular NHL Marcus CVP vs CVP-R Improved OS Hiddemann CHOP vs CHOP-R Improved OS Herold MCP vs MCP-R Improved OS Foussard CHVP vs CHVP-R Improved OS in + interferon high FLIPI only Maintenance rituximab or observation after CVP E1496 (ECOG, CALGB) 6-8 cycles of CVP Maintenance rituximab (4 doses q 6 m x 2 y) Approx. 37% patients FLIPI

3 Progression-free Survival Overall Survival 13 Hochster H, et al. J Clin Oncol. 2009;27: Hochster H, et al. J Clin Oncol. 2009;27: Radioimmunotherapy as Consolidation of First Remission Therapy in Follicular NHL Progression-free Survival All patients PR to induction CR to induction 15 Morschhauser F, et al. J Clin Oncol ;26: Morschhauser F, et al. J Clin Oncol ;26: Fludarabine and Rituximab for Previously Untreated Patients Is maintenance rituximab justified? 27 patients, 50% IPI 0,1 Phase II study ORR 90% CR 80% Grade 3, 4 neutropenia (27%) Herpes infections 15% Yes No Following induction chemotherapy (ECOG 1496) Improves PFS Borderline improvement in OS MRD associated with longest PFS Following induction R + chemotherapy Currently no data 17 Czuczman MS, et al. J Clin Oncol. 2005;23:

4 Will maintenance rituximab improve outcome following induction R + chemotherapy? PRIMA trial (2 years R at 1 dose q 3 months) following R + chemotherapy induction therapy (non-randomized) Perhaps if one treats. A high risk population at risk of early relapse, and/or with therapy with median time to progression < 30 months (CVP-R) Will maintenance rituximab improve outcomes following induction R + chemotherapy? Perhaps not with more aggressive initial treatment (R-CHOP) Median time to progression > 4 year Few events during the 2 years of maintenance therapy Audience Response Question? Which Regimen? CHOP vs CVP What is the optimal initial chemotherapy for a 60 y.o. patient with symptomatic follicular lymphoma, FLIPI score of 3? 1. CVP (or CHOP) + rituximab 2. CHOP-R followed by maintenance rituximab 3. Fludarabine + rituximab 4. Chemotherapy followed by radioimmunoconjugate 21 Jones SE, et al. Cancer. 1983;51(6): Update on Diffuse Large B Cell Lymphoma Many diseases Relevance of the IPI Cell of origin (GC vs ABC) Impact of current therapy New entities Diffuse Large B Cell Lymphoma (DLBCL) DLBCL NOS (not otherwise specified) T-cell/histiocyte-rich rich large B cell lymphoma Primary mediastinal large B-cell lymphoma Intravascular large B cell lymphoma Lymphomatoid granulomatosis (EBV+ large B-cell lymphoma Primary cutaneous DLBCL, leg type EBV positive DLBCL of the elderly 4

5 Diffuse Large B Cell Lymphoma DLBCL associated with chronic inflammation Large B cell lymphoma arising in HHV8-associated multicentric Castleman s disease Primary effusion lymphoma B cell lymphoma, unclassifiable, with features intermediate between DLBCL and Burkitt s lymphoma B cell lymphoma, unclassifiable, with features intermediate between DLBCL and Hodgkin s lymphoma IPI Age > 60 LDH > nl* PS > 1* Stage III/IV* EN sites > 1 * for aa IPI IPI CHOP-based Therapy 26 N Engl J Med. 1993;329(14): Modification of the IPI following CHOP+R Cell of Origin and Prognosis CHOP Low 0,1; Low-Int 2; High-Int 3; High 4,5 Very good 0; Good 1,2; Poor > 3 CHOP-R Treatment of Early Stage Disease Update of SWOG 8736 CHOP x 3 + RT v CHOP x 8 Treatment of Stage I/II DLBCL: Impact of Rituximab % CHOP x 3 + RT or CHOP x 8 Age > 60, LDH > nml, PS > 2, Stage II CHOP-R R x 3 + RT > 1 risk factor 5

6 R-CHOP Alone for Early Stage DLBCL MiNT Study CHOP-R + Radiotherapy for Bulky Early Stage DLBCL (MiNT) Patients < 60, bulky stage I, stages II-IV IV IPI 0, 1 q 21 d cycles x 6 PFS OS No randomized study +/- RT CHOP-R R x Gy to bulky sites EFS For low volume, early stage disease CHOP-R R x 6 has excellent outcome Bulky disease unfavorable even with RT. Still unclear whether RT is beneficial. Treatment of Advanced Stage DLBCL Patients < 60 or > 60, CHOP-R R higher DFS and OS than CHOP alone. No advantage of adding etoposide to CHOP-R. No role for maintenance R following CHOP-R. CHOP-R R 14: 6 cycles equivalent to 8 cycles. Is CHOP-R R 14 better than CHOP-R R 21? R-CHOP 21 vs R-CHOP 14 R-CHOP 21 x 8 vs R-CHOP 14 x 6 2 more doses rituximab + G-CSF) G Primary endpoint overall survival 1080 patients randomized, median age 61 More grade III/IV neutropenia in R-CHOPR CHOP-21 More thrombocytopenia in R-CHOPR CHOP-14 No difference in CR/Cru, limited follow-up More info at ASH 2009 CNS Prophylaxis High risk associated with: testicular, breast, epidural, or sinus involvement, high IPI, multiple EN sites, B symptoms, and BM involvement. Only 2.8-5% of patients develop CNS disease. R-CHOP may decrease risk (RICOVER trial), but not seen in R-CHOP R GELA trial. CNS Prophylaxis SWOG study (no rituximab) 80% of CNS relapses on therapy or < 6 months following therapy Intraparenchymal/intraspinal > leptomenigeal I.T. methotrexate probably insufficient I.T. and high dose MTX probably better (GELA ACVBP vs CHOP, no rituximab) Benefit and method remains uncertain 6

7 B Cell Lymphoma, Unclassifiable, with Features Intermediate between DLBCL and Burkitt s Lymphoma B Cell Lymphoma, Unclassifiable, with Features Intermediate between DLBCL and Burkitt s Lymphoma Atypical immunophenotype c-myc: : typical and atypical rearrangements. Some previously called Burkitt-like lymphoma, BLL not in new WHO classification. Frequently has c-myc and bcl-2 2 rearrangements ( double-hit lymphoma ). bcl-2 2 protein expressed, Ki-67 high. Nodal, EN disease, BM and CNS involvement. Uncertain how best to treat (CHOP-R R or Burkitt s regimens?) Audience Response Question? Clinical factors and biologic markers are of prognostic relevance. The IPI is still useful. Update on DLBCL The challenge is adjusting therapy based on new prognostic factors. 2. What is the treatment approach for a previously healthy 66 yo man with stage IVB mantle cell lymphoma,? 1. CHOP-R 2. Induction therapy and ASCT 3. Hyper CVAD/cytarabine/methotrexate + rituximab Survival of MCL What should be the initial therapy for mantle cell lymphoma? vs Prognostic factors Chemotherapy Autologous SCT Herrmann A, et al. J Clin Oncol. 2009;27:

8 Deferred Initial Therapy in MCL Mantle Cell Lymphoma: MIPI OS observed vs early Rx OS observed vs early Rx following first Rx Martin P, et al. J Clin Oncol ;27: Hoster E, et al. Blood. 2008;111(2): Prognostic factors: age, PS, LDH, WBC Prognosis of MCL: Ki-67 Chemo vs R-Chemo in MCL (GLSG) CHOP CHOP-R: Improved RR, CR rate, TTF No difference in OS CHOP-R R-HyperCVAD, mtx, ara-c Meta-analysis (3 studies) improved DFS, trend for improved OS with rituximab 46 Lenz G, et al. J Clin Oncol. 2005;23(9): Hyper CVAD/cytarabine-methotrexate + rituximab Hyper CVAD/cytarabine-methotrexate + rituximab MD Anderson MD Anderson SWOG CR 87% 58% PFS 64% (3 y) 89% (1 yr) OS 82% (3 y) 91% (1 yr) Off-study 29% 42% FFS OS 47 Romaguera JE, et al. J Clin Oncol. 2005;23(28): Romaguera JE, et al. J Clin Oncol. 2005;23(28):

9 Auto SCT in First Remission (HOVON Group) Auto SCT vs INF-α in 1st CR/PR following CHOP (European MCL Network) 49 Dreyling M, et al. Blood. 2005;105(7): PFS OS R-CHOP x 3, CR or PR >> HiDAC + BEAM + ASCT This leads to long-term, but probably not durable, remissions. van t Veer MB et al. Br J Haematol. 2009;44: Audience Response Question? Future options in upfront treatment? Bortezomib Bendamustine Lenalidomide Cyclin D1 kinase inhibitors 2. What is the treatment approach for a previously healthy 66 yo man with stage IVB mantle cell lymphoma? 1. CHOP-R 2. Induction therapy and ASCT 3. HyperCVAD/cytarabine/ methotrexate + rituximab What is the optimal initial therapy for T-cell lymphoma? T-cell Lymphoma Subtypes Subtypes Prognosis Therapy Rizvi MA, et al. Blood. 2006;107(4):

10 T-cell Lymphomas: Prognosis by Subtype T-cell lymphomas: Do anthracyclines matter? PTCL-NOS Angioimmunoblastic TCL Treatment of PTCL: Alternatives to CHOP CHOP + alemtuzumab 71% CR Opportunistic infection, EBV lymphoma In phase III trial Upfront Autologous SCT for PTCL 83 patients 51% high-int, high IPI Rx with CHOP 65 (79%) had CR or PR 55 (66%) underwent ASCT No randomized trials. ASCT in CR1 reasonable option. T-cell Lymphomas Many different diseases, different prognosis Current treatment limited benefit for majority One size (Rx) does not fit all Thank you for attending Master Class for Oncologists Autologous transplant reasonable in CR

11 Questions & Answers Prognostic value of early restaging PET scanning? Haioun C, et al. Blood. 2005;106(4): Age > 50 EBV+ DLBCL of the Elderly Is maintenance rituximab justified? Yes, in relapsed, rituximab-naïve patients following chemotherapy or R-chemotherapy Improved PFS Improved OS But this group no longer exists No prior immunodeficiency 9% of cases of DLBCL in Asia, seen more now in Western countries 70% extranodal disease 50% high or high intermediate IPI 63 Median survival 2 years 11