The Berlin‐Frankfurt‐Münster Protocol for the Upfront Treatment of Aggressive Lymphomas: the Bologna Experience

To the Editor: High Grade B-Cell Lymphoma Double Hit (HGBL-DH), diffuse large B cell lymphoma-double expressor (DLBCL-DE) and Burkitt's lymphoma (BL) represent a subset of highly aggressive B-cell lymphomas. Unlike standard-risk DLBCL, HGBL-DH have shown poor responses when treated with standard-dose combination immunochemotherapy approaches. Even the addition of consolidative autologous stem cell transplant (ASCT) has demonstrated no improvement in outcome of patients with HGBL-DH, while in a recent study patients affected by DLBCL-DE have shown a favorable trend.1 To improve outcomes of patients with HGBL-DH and to prevent early progression, dose-escalation immunochemotherapy regimens have been adopted and recent trials are incorporating novel agents, as lenalidomide into first line treatment regimens.2 BL can be successfully managed with intensive multiagent chemotherapy regimens and an advantage was demonstrated with the addition of anti-CD20 monoclonal antibody rituximab which has become an integral part of treatment strategies of BL.3 Berlin-Frankfurt-Münster (BFM) protocols are intensive chemotherapeutic regimens which were firstly developed in pediatric acute lymphoblastic leukemia and Non Hodgkin lymphomas. Recently, modified BFM regimens have been adopted in adult patients affected by BL, with the obtainment of high rates of complete response (CR) and durable responses. Moreover, an improvement was observed with the addition of rituximab, given before each of the 6 cycles and twice as maintenance (R-BFM).4 To date, no studies were conducted concerning the use of R-BFM protocols in HGBL-DH or DLBCL-DE. Aim of present retrospective study was to evaluate the effectiveness and safety of adapted R-BFM regimen in adults affected by BL, HGBL-DH, and DLBCL-DE followed by consolidation with ASCT. The study, approved by local Ethical Committee, has been performed in accordance with Declaration of Helsinki and patients provided written informed consent. A total of 50 patients with a diagnosis of BL (n = 37), HGBL-DH (n = 12) or DLBCL-DE (n = 1) underwent R-BFM regimen from February 2004 to October 2016. Median age at diagnosis was 41 years (range 16–74 years), 11 patients were ≥60 years old and 37 patients were males. Thirty-eight patients had Ann-Arbor stage III-IV disease and 24 presented with bulky disease. Central nervous system (CNS) involvement was uncommon (4%). Bulky disease occurred in 24 patients and extranodal involvement in 37, mainly at the gastrointestinal tract (59%). Twelve patients required a preliminary surgical approach, mainly because of bowel occlusion. Patients’ characteristics are summarized in Table 1. Each patient was planned to receive 6 cycles of chemoimmunotherapy according to the BFM protocol, which consisted of initial cytoreduction followed by 3 blocks: A (iphosphamide, vincristine, methotrexate, etoposide, cytarabine), B (vincristine, cyclophosphamide, methotrexate, doxorubicin), C (vindesine, methotrexate, etoposide, cytarabine), each repeated twice, every 28 days, with rituximab at day 1 each block. All patients were planned to receive CNS prophylaxis with intrathecal methotrexate, cytarabine, and dexamethasone. Autologous stem cells harvest was performed after 4 cycles, and consolidation with ASCT was planned at the end of the 6-blocks after BEAM (carmustine, etoposide, cytarabine, melphalan) conditioning. For patients aged ≥60 years, an age-adjusted dose reduction was performed according to institutional guidelines. Responses and time-to-point events were determined using the Revised Response Criteria for Malignant Lymphoma.5 Overall, 28 patients (56%) completed the therapeutic program receiving the 6 scheduled cycles of chemo-immunotherapy and subsequent ASCT. Seven patients interrupted treatment early due to disease progression, 4 for toxicity, 4 due to a premature death and 2 for other reasons. Among patients who did not complete all 6 cycles of R-BFM treatment, 5 received ASCT, 4 after 5 cycles and 1 after 4 cycles, respectively. Overall, CR rate was 72% (36 patients, 30 with BL and 6 with HGBL-DH) and overall response rate (ORR) was 76%. The CR rate was 81% and 50% in patients affected by BL and HGBL-DH, respectively. Among the 33 patients who underwent ASCT, 27 (82%) achieved a CR and 2 (6%) a partial response (PR), with an ORR of 88%. The patient affected by DLBCL-DE achieved a PR after receiving ASCT. With a median follow-up of 50 months, median OS was not reached and the estimated 124-months overall survival (OS) was 71% for the whole population. The diagnosis of BL vs. HGBL-DH and age (< 60 years vs. ≥ 60 years) had no statistically significant influence on outcome in terms of OS; the lack of influence of a diagnosis of HGBL-DH on prognosis could be affected by the small number of patients with HGBL-DH included in our analysis. At the latest available follow up, all the responder patients are still in CR leading to a 100% disease free survival at 9.8 years. For the whole population, the estimated 124-months progression free survival (PFS) was 71% (median not reached). Diagnosis of BL vs. HGBL-DH and age <60 years were not associated with a significant advantage in terms of PFS. Patients who underwent ASCT appeared to have a better outcome in terms of OS and PFS; nevertheless, these results could be affected by a selection bias, as most of patients received ASCT in CR or PR. The most common adverse events (AE) were hematological: almost all patients experienced grade III-IV neutropenia (48 patients), 26 patients had anemia (12 grade III-IV), and 23 a decreased platelet count (21 grade III-IV). Among extrahematological toxicities, the most common AEs were infections, which occurred in 29 patients. Overall, most grade III-IV events were hematologic; extrahematologic grade III-IV toxicities were uncommon and mostly infectious. All AEs both hematological and extrahematological were easily manageable and reversible with a median time of resolution of two weeks with no differences in elderly patients. Two secondary malignancies occurred: one myelodysplasia and one acute myelocytic leukemia 1 and 6 years after ASCT, respectively. In our study, we evaluated for the first time the effectiveness of R-BFM regimen in the setting of HGBL-DH. We observed promising results in terms of response rates and in terms of OS (58% at 89 months) and PFS (55% at 89 months), which are comparable or even higher than those observed with other intensive regimens. Regarding BL, the results of our study are consistent with those observed by Hoelzer and colleagues6; indeed, in the BL subgroup, we observed a CR rate of 81% and a 124-months OS and PFS of 76%, confirming previously reported outcomes. In our study, only one patient with DLBCL-DE was included and no conclusion can be reached; thus, further studies are needed to investigate efficacy of R-BFM in this subset of patients. The main limitation of this study is represented by its retrospective design; its main strengths are the relatively large number of patients enrolled, the long follow-up and the population and treatment homogeneity. In conclusion, R-BFM represents an effective and tolerable therapeutic regimen, which could be adopted as first line strategy for the treatment of aggressive lymphomas as BL and HGBL-DH. Adding ASCT could be a strategic tool to achieve a long term disease control, giving physicians the chance to cure patients affected by HGBL-DH and BL. The results we obtained should be validated in a larger prospective multicentric study. The authors declare that they have no conflict of interest.