Hyper-CVAD and Rituximab for De Novo Burkitt Lymphoma/Leukemia
Authors: Thomas Deborah A. , Kantarjian Hagop M , Faderl Stefan , Wierda William G. , Jabbour Elias , Garcia-Manero Guillermo , Ferrajoli Alessandra , Verstovsek Srdan , Burger Jan A. , Fayad Luis , Romaguera Jorge E , Garris Rebecca , Cortes Jorge E. , O'Brien Susan 
Published: October 2019

Abstract
Abstract 2698
Outcomes for Burkitt lymphoma/leukemia have improved significantly with the use of short, intensive, multi-agent chemotherapy regimens. The hyper-CVAD regimen (fractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone alternating with high dose methotrexate (MTX) and cytarabine) was established as an effective first line program for younger patients with de novo Burkitt leukemia (B-ALL) [Thomas D, J Clin Oncol 17:2461, 1999]. An overall complete remission (CR) rate of 81% was influenced by a high infection-related induction mortality rate of 19% in the subset aged 60 yrs or older with 3-yr survival (OS) rate of 17% for older pts versus 77% in younger pts. Supportive care measures such as use of laminar air flow rooms since 1999 has reduced the elderly early mortality rate to < 5%. Standard dose monoclonal antibody therapy with rituximab was also incorporated into the hyper-CVAD regimen in order to exploit the high CD20 expression (total 8 doses of 375 mg/m2 Days 1, 11 of hyper-CVAD and Days 1, 8 of MTX-cytarabine courses). CNS prophylaxis alternated intrathecal (IT) MTX Day 2 with cytarabine Day 7 of each course (total 16 ITs). Encouraging results were observed in the first 31 consecutive non-HIV pts treated with hyper-CVAD and rituximab; in contrast to the hyper-CVAD experience 3-yr OS rates were similar (89% versus 88%) for the elderly and younger pts. An additional 26 patients have been accrued since the previous report [Thomas, Cancer, 106:1569, 2006]. Fifty-seven pts with newly diagnosed non-HIV BL (n=30) or B-ALL (n=27) were treated. Median age was 44 years (range, 17–77); 25% were aged 60 yrs or older. Over 80% of cases were Ann Arbor stage III/IV. The overall CR rate in 47 evaluable pts (10 in CR at start due to one course of prior therapy or resected disease) was 94%; 2 pts achieved partial response and 1 younger pt died during induction. All pts aged 60 yrs or older achieved CR. After a median follow-up of 62 months (range, 5–136+ months), 4 relapses were observed. Nine pts died in CR related to infections (n=3), secondary malignancies (n=3), or other causes (n=3). In comparison with 48 historical BL or B-ALL pts treated with hyper-CVAD alone, the 5-yr rates for OS (74% vs 50%, p=.03), age < 60 yrs (72% vs 70%, p=NS), and age 60 yrs or older (70% vs 19%, p=.002) continue to favor hyper-CVAD with rituximab. Six pts developed secondary dyscrasias (1 with acute myelogenous leukemia [AML] at 7 yrs, 1 with t(8;21) AML at 3 yrs, 1 with monosomy 7 AML at 3 yrs, 3 with myelodysplastic syndrome at 3 or 3–1/2 yrs). Toxicity profile was otherwise similar to hyper-CVAD alone. Incorporation of rituximab into hyper-CVAD appears to improve disease-related outcomes for de novo Burkitt-type lymphoma/leukemia, particularly for the older subset. The relatively high incidence (11%) of secondary blood dyscrasias mandates long-term monitoring even in the younger subset. Incorporation of second or later generation anti-CD20 monoclonal antibodies such as ofatumumab, or anti-CD22 monoclonal antibody conjugates such as inotuzumab into the hyper-CVAD regimen merits investigation as a potential strategy to allow reduction in systemic chemotherapy exposure without sacrificing efficacy.

Disclosures:
Wierda: Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees. O'Brien:Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.