Substantially Improved Outcome of Adult Burkitt Non-Hodgkin Lymphoma and Leukemia Patients with Rituximab and a Short-Intensive Chemotherapy; Report of a Large Prospective Multicenter Trial
Authors: Hoelzer Dieter , Walewski Jan , Döhner Hartmut , Schmid Mathias , Hiddemann Wolfgang , Baumann Anja , Serve Hubert , Dührsen Ulrich , HÃ¼ttmann Andreas , Thiel Eckhard , Dengler Jolanta , Kneba Michael , Schuler Markus , Schmidt-Wolf Ingo , Beck Joachim , Hertenstein Bernd , Reichle Albrecht , Domanska-Czyz Katarzyna , Fietkau Rainer , Horst Heinz-August , Rieder Harald , Schwartz Stefan , Burmeister Thomas , Goekbuget Nicola 
Published: October 2019

Abstract
Abstract 667

Aim.
The aim of this study was to prove in a large prospective multicenter trial the tolerance and efficacy of short-intensive chemotherapy combined with the antibody Rituximab directed against CD20 for patients with Burkitt Non-Hodgkin lymphoma (B-NHL) and Burkitt leukemia (B-L).

Background.
In adult Burkitt lymphoma/leukemia with short-intensive chemotherapy regimen - mostly derived from pediatric protocols - a complete remission (CR) rate of 83% and an overall survival (OS) of 62% (both weighted mean) could be achieved. Further intensification of chemotherapy apparently did not improve the overall outcome. This was the rationale to integrate the monoclonal anti-CD20 antibody Rituximab in B-NHL / leukemia patients with a CD20 expression of >90%.

Patients and Methods.
363 adult patients (229 B-NHL and 134 B-L), 15 years or older (without age limit) were recruited from 98 centers in the German Multicenter Study Group for Adult Acute Lymphoblastic Leukemia (GMALL) B-ALL/NHL 2002 protocol, initiated in 8/2002 until 06/2011. Median age of the Burkitt lymphoma cohort was 40 years (16–79) and for the Burkitt leukemia cohort 47 years (16–85). CNS involvement was observed in 6% / 18%. In the Burkitt lymphoma cohort, 6% had mediastinal tumor, 53% had stage III/IV and IPI>2 of 35%.

Treatment.
The treatment consisted of 6 five-day chemotherapy cycles with high-dose methotrexate (HD-MTX) 1500 mg/m2 (total 6 doses), high-dose cytosine arabinoside (HD-AraC) 2000 mg/m2 (total 4 doses), cyclophosphamide, etoposide, ifosphamide and corticosteroids, and a triple intrathecal therapy (MTX, AraC, Dexa). Elderly patients >55 years received reduced drug doses (500 mg/m2), particularly no C-cycles with HD-AraC among other drugs. Rituximab was given d ⦵1 before each cycle and twice at 4 week intervals thereafter, for overall 8 doses. Total treatment duration was 28 weeks (figure 1).

Results.
CR rate in B-NHL patients was 91% (182/229) and 86% (162/182) in B-L patients. For the B-NHL cohort the results were excellent with an OS of 88%, and a progression-free survival (PFS) of 83% at >7 yrs, with no significant difference in OS for adolescents 15-≤25 yrs with 91%, adults 26-'55 yrs with 91% or elderly >55 yrs with 80%. In Burkitt leukemia the OS for adolescents was also very promising with 90%, for adults OS was 71%, but inferior for elderly patients with 46%. Therefore two cycles C, including high dose AraC, were added for older patients in an amendment.

Prognostic factors.
In B-NHL patients the age adapted International Prognostic Index (aIPI) was the only significant prognostic factor for OS (p = 0.02) whereas in B-L patients the factors age 15-≤25, 26-≤55 and >55 yrs (p = 0.0007) and a lower platelet count <25000/μl (p = 0.01) had an adverse influence on OS. Major toxicity grade III/IV was less pronounced in B-NHL than in B-L, neutropenia 64% vs. 68%, mucositis 31% vs. 54% and infections 23% vs. 49%. Neurotoxicity was low in both cohorts.

Conclusion.
In the largest prospective trial for adult Burkitt NHL/leukemia, overall survival and progression-free survival could be substantially improved by a combination of short-intensive chemotherapy with Rituximab with manageable toxicity. Even with lower doses of HD-MTX outcome of B-NHL was excellent in all age groups, including elderly.

Disclosures:
No relevant conflicts of interest to declare.