Improved outcome of adult Burkitt lymphoma/leukemia with rituximab and chemotherapy: report of a large prospective multicenter trial

Abstract

This largest prospective multicenter trial for adult patients with Burkitt lymphoma/leukemia aimed to prove the efficacy and feasibility of short-intensive chemotherapy combined with the anti-CD20 antibody rituximab. From 2002 to 2011, 363 patients 16 to 85 years old were recruited in 98 centers. Treatment consisted of 6 5-day chemotherapy cycles with high-dose methotrexate, high-dose cytosine arabinoside, cyclophosphamide, etoposide, ifosphamide, corticosteroids, and triple intrathecal therapy. Patients >55 years old received a reduced regimen. Rituximab was given before each cycle and twice as maintenance, for a total of 8 doses. The rate of complete remission was 88% (319/363); overall survival (OS) at 5 years, 80%; and progression-free survival, 71%; with significant difference between adolescents, adults, and elderly patients (OS rate of 90%, 84%, and 62%, respectively). Full treatment could be applied in 86% of the patients. The most important prognostic factors were International Prognostic Index (IPI) score (0-2 vs 3-5; P = .0005), age-adjusted IPI score (0-1 vs 2-3; P = .0001), and gender (male vs female; P = .004). The high cure rate in this prospective trial with a substantial number of participating hospitals demonstrates the efficacy and feasibility of chemoimmunotherapy, even in elderly patients. This trial was registered at www.clinicaltrials.gov as #NCT00199082.

© 2014 by The American Society of Hematology.

Figures

Figure 1

Consort diagram depicting enrollment, exclusion, and treatment realization. Overall chemoimmunotherapy realization: 86% of all patients received the complete number of treatment cycles, either 6 in stage III-IV or 4 of the planned cycles in stage I-II. A tumor lysis syndrome was observed in only 3 patients, which is less than 1%. Auto-SCT, autologous stem cell transplant; EN, extranodal involvement; MedTu, mediastinal tumor; PR, partial remission.

Figure 2

Treatment scheme and the detailed treatment application for patients aged 15 to 55 years. CNS prophylaxis (**) started with a single intrathecal administration of methotrexate (MTX) on day 1 of prephase treatment, followed by triple intrathecal therapy with MTX, cytarabine, and dexamethasone in cycles A and B, twice per cycle. The second application in cycle A on days 12 and 33 was later omitted because triple intrathecal therapy may have aggravated cytopenia, particularly neutropenia, due to a systemic effect; furthermore, the patients increasingly complained about the number of intrathecal injections. Patients with documented CNS involvement received intrathecal chemotherapy twice weekly during induction until the cerebrospinal fluid cell count was normalized and the cytological examination was negative, and then followed the prophylactic scheme described above. Prophylactic application of granulocyte colony-stimulating factor after each cycle was part of the protocol. The aim was the application to therapy cycles at 21-day intervals. Before each cycle, hematologic regeneration with granulocytes >1000/mL, platelets >50 000/mL, the absence of grade 3/4 mucositis, or other severe organ toxicities was required. In Burkitt patients with stage I-II disease achieving a CR already after 2 cycles, chemotherapy could be stopped after 4 cycles if they had no initial extranodal involvement or a mediastinal tumor. The protocol for older patients (>55 years) consisted of cycles A and B alternatively repeated up to 6 total cycles (supplemental Figure 1). To reduce toxicity, HD-MTX was reduced to 500 mg/m2, cycle C with high-dose cytarabine was omitted, and intrathecal therapy with MTX was reduced to single to triple intrathecal therapy. c.i., continuous infusion; G-CSF, granulocyte colony-stimulating factor; h, hour; HD, high-dose; i.th., intrathecal; p.o., by mouth; s.c., subcutaneously; tu, tumor; VM26, teniposide.

Figure 3

A+B 5-year probability of OS and PFS in Burkitt lymphoma/leukemia patients. (A) Five-year probablitity of OS in Burkitt lymphoma/leukemia patients (N = 363): 0.80 ± 0.02. (B) Five-year probability of PFS in Burkitt lymphoma/leukemia patients (N = 363): 0.75 ± 0.03. (C) Five-year probability of OS in Burkitt lymphoma/leukemia patients ≤55 years old (n = 265): 0.86 ± 0.02; >55 years old (n = 98): 0.62 ± 0.05 (P < .0001). (D) Five-year probability of PFS in Burkitt lymphoma/leukemia patients ≤55 years old: 0.82 ± 0.03; >55 years old: 0.60 ± 0.05 (P < .0001).

Figure 4

Five-year probability of OS in Burkitt lymphoma/leukemia patients according to risk factors. (A) Five-year probability of OS according to IPI score: 0-2 (n = 140), 0.90 ± 0.03; 3-5 (n = 146), 0.75 ± 0.04 (P = .0005). (B) Five-year probability of OS according to aaIPI score; 0-1 (n = 111), 0.93 ± 0.03; 2-3 (n = 192), 0.74 ± 0.03 (P < .0001). (C) Five-year probability of OS according to age: 15 to 25 years (n = 69), 0.90 ± 0.04; 26 to 55 years (n = 196), 0.84 ± 0.03; >56 years (n = 98), 0.62 ± 0.05 (P < .0001). (D) Five-year probability of OS according to age >55 years: 55 to 59 years (n = 19), 0.56 ± 0.12; 60 to 65 years (n = 34), 0.71 ± 0.08; 66 to 70 years (n = 30), 0.68 ± 0.09; >70 years (n = 15), 0.43 ± 0.14 (P = .3). (E) Five-year probability of OS according to gender: male (n = 253), 0.84 ± 0.02; female (n = 110), 0.70 ± 0.05 (P = .004).