NCI 9177: Risk-Adapted DA-EPOCH-R in Adults With Burkitt Lymphoma New Findings in Hematology: Independent Conference Coverage* of ASH 2015, December 5-8, 2015, Orlando, Florida *CCO is an independent medical education company that provides state-of-the-art medical information to healthcare professionals through conference coverage and other educational programs. DA, dose-adjusted; EPOCH-R, etoposide, prednisolone, vincristine, cyclophosphamide, doxorubicin, rituximab. This program is supported by educational grants from Amgen, Celgene Corporation, Merck, Incyte, Seattle Genetics, and Takeda Oncology.

NCI 9177: Background Burkitt lymphoma: rare, highly aggressive B-cell non-Hodgkin’s lymphoma with very high tumor proliferation Treatment strategies modeled after ALL regimens with multiple agents in high- intensity, alternating cycles[1] Good efficacy but high toxicity in adults, immunosuppressed pts Risk-adapted therapy used to mitigate toxicity CHOP: low efficacy in highly proliferating cells (Burkitt, DLBCL)[2,3] EPOCH-R-based regimens: FFP and OS > 90%[4] NCI 9177: a multicenter phase II study of risk-adapted DA-EPOCH-R in Burkitt lymphoma[5] ALL, acute lymphocytic leukemia; CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; DLBCL, diffuse large B-cell lymphoma; DA, dose-adjusted; EPOCH-R, etoposide, prednisolone, vincristine, cyclophosphamide, doxorubicin, rituximab; FFP, freedom from progression. 1. Mead GM, et al. Ann Oncol. 2002;13:1264-1274. 2. Dave SS, et al. N Engl J Med. 2006;354:2431-2442. 3. Rosenwald A, et al. N Engl J Med. 2002;346:1937-1947. 4. Dunleavy K, et al. N Engl J Med. 2013;369:1915-1925. 5. Dunleavy K, et al. ASH 2015. Abstract 342. Slide credit: clinicaloptions.com

NCI 9177: Study Design Multicenter, prospective phase II study Objective: validation of single center findings Low-Risk Arm* DA-EPOCH-RR 2 cycles (n = 11) Negative DA-EPOCH-RR 1 cycle Routine FU CT/ FDG-PET Untreated pts ≥ 18 yrs old with Burkitt lymphoma (N = 88) Positive Repeat CT/ FDG-PET if + after 2 cycles High-Risk Arm DA-EPOCH-R 2 cycles (n = 77) Negative Routine FU DA-EPOCH-R 4 cycles† CT/ FDG-PET DA, dose-adjusted; ECOG, Eastern Cooperative Oncology Group; EPOCH-R, etoposide, prednisolone, vincristine, cyclophosphamide, doxorubicin, rituximab; EPOCH-RR, etoposide, prednisolone, vincristine, cyclophosphamide, doxorubicin, dose-dense rituximab; FU, follow up; LDH, lactate dehydrogenase; MTX, methotrexate; PS, performance status. *Low-risk: stage I or II disease, normal LDH, ECOG PS 0-1, mass size < 7cm; all other pts high risk. †Intrathecal MTX included in high-risk arm on cycles 3, 4, 5. Slide credit: clinicaloptions.com Dunleavy K, et al. ASH 2015. Abstract 342.

NCI 9177: Baseline Characteristics Baseline characteristics similar to those from other studies in adults, including UK LY06[1] Characteristic,* %[2] All (N = 88) Low Risk (n = 11) High Risk (n = 77) UK LY06[1] Low Risk (n = 12) (n = 40) Median age, yrs (range) 40 yrs or older 60 yrs of older 46 (18-78) 57 25 38 (19-62) 45 9 47 (18-78) 58 27 26 (15-52) 38 (16-60) 48 Male 82 64 84 83 50 Stage III or IV 73 80 Elevated LDH 56 ECOG PS ≥ 2 18 21 - Extranodal disease 23 CNS disease 13 15 17 HIV positive 24 CNS, central nervous system; ECOG, Eastern Cooperative Oncology Group; LDH, lactate dehydrogenase; PS, performance status. *Includes data from 24 sites. 1. Mead GM, et al. Ann Oncol. 2002;13:1264-1274. 2. Dunleavy K, et al. ASH 2015. Abstract 342. Slide credit: clinicaloptions.com

NCI 9177: Outcomes by Subgroup Median follow-up: 25 mos Subgroup PFS, % P Value OS, % Overall 84 86 Risk group Low risk High risk 100 81 .16 .19 HIV infection status Positive Negative 85 .91 88 .77 Age Younger than 40 yrs 40 yrs or older .41 83 91 .33 Slide credit: clinicaloptions.com Dunleavy K, et al. ASH 2015. Abstract 342.

NCI 9177: Safety Main on-treatment toxicity observed: infectious deaths in high-risk arm (n = 3) Cycle 1 Male, 72 yrs of age Male, 59 yrs of age Cycle 4 Female, 52 yrs of age Toxicity profile consistent with previous reports Regimen administered on an outpatient basis where feasible Slide credit: clinicaloptions.com

NCI 9177: Conclusions Phase II study suggests DA-EPOCH-R an effective approach for treating Burkitt lymphoma Treatment-related toxicity markedly reduced compared to standard regimens for Burkitt lymphoma Excellent outcomes in low-risk pts treated with an abbreviated regimen (3 cycles) without intrathecal therapy Study accrual is ongoing Investigators concluded that DA-EPOCH-R is a potential alternative to high-intensity treatment requiring a multicenter setting DA, dose-adjusted; EPOCH-R, etoposide, prednisolone, vincristine, cyclophosphamide, doxorubicin, rituximab. Slide credit: clinicaloptions.com Dunleavy K, et al. ASH 2015. Abstract 342.

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