Abstract
Introduction: Patients with aggressive B cell lymphomas carrying concomitant c-Myc and Bcl-2 and/or Bcl-6 gene rearrangement (DHL/THL) have a poor outcome when treated with standard R-CHOP regimen. Better results were reported in patients treated with more intensive programs, currently used in highly proliferative diseases such as Burkitt lymphoma. In particular, R-DA-EPOCH obtained the best result in a retrospective study comparing different intensive regimens (Oki et al. BJH 2014). We report the experience with this program of two hematologic centres in Northern Italy in patients with dysregulation of c-Myc gene associated with Bcl-2 and/or Bcl-6 abnormalities.
Methods: From January 2014, all consecutive fit patients aged less than 80 years, with diffuse large B cell lymphoma (DLBCL) or lymphoma with intermediate features between DLBCL and Burkitt (BCLU), including 10 patients with histological features suggesting transformation from follicular lymphoma, and showing DHL or THL by fluorescent in situ hybridization (FISH), were treated with R-DA-EPOCH and central nervous system prophylaxis with intrathecal methotrexate +/- cytarabine . Patients with c-Myc amplification (more than 4 signals) plus Bcl-2 and/or Bcl-6 gene rearrangement or amplification were also included (AMPL). Pre-treatment with one cycle of R-CHOP was allowed in patients in need of urgent treatment, pending the results of FISH analysis. Autologous stem cell transplantation (ASCT) was planned in one of the two centres for patients who reached at least a partial remission after six R-DA-EPOCH courses. Cell of origin (COO) was defined by immunohistochemistry (IHC) according to Hans's algorithm.
Results: Thirty-five patients (30 DLBCL and 5 BCLU) were treated. They received a median of 6 courses of R-DA-EPOCH (range 1-6) administered either to inpatients or to outpatients using a single portable infusion pump. Six patients were pre-treated with R-CHOP and 10 patients received consolidation with ASCT. According to FISH analysis, 18 cases were DHL, 6 THL and 11 AMPL. The median age of the whole group was 63 years (range 34-79). Twenty-nine patients were male (83%). Thirty-two patients (91%) had Ann-Arbor stage III/IV and 25 (71%) had high-intermediate/high risk score according to International Prognostic Index (IPI), with extranodal presentation in 74%, mainly in bone and gastrointestinal tract. According to Hans's algorithm, 85% of patients were of germinal center COO. By IHC double expression of myc (>40%) and of bcl-2 protein (>50%) was reported in 75% of patients. Median lymphoma cells proliferation fraction assessed by Ki-67 IHC was 80% (range 35-100%). Three patients died of infectious complications during chemotherapy. The overall response rate for the entire cohort was 71%. Of seven refractory patients, five have died of lymphoma, one is disease free after allogeneic transplantation and one is still on treatment. Among 25 patients who achieved a response to front-line therapy, one died of suicide and 24 are still in remission after a median of 15 months. The 1-year PFS and OS rates were 69% and 73%, respectively. There was no significant association of PFS or OS with age, COO, type of histology, transformation from FL, extranodal involvement, Ki-67. THL had significant worse survival comparing to DHL and AMPL (20% vs 88% vs 68% p 0.03) (Fig.1).
Conclusions: These results confirm R-DA-EPOCH as a feasible program in unselected fit patients up to the age of 80. Short-term efficacy was high, considering the poor prognosis of double or triple-hit aggressive B-cell lymphoma. Few data are available to define the role of consolidative ASCT and its utility is still unclear. Treatment response seems to favourably impact on patient survival. A longer follow-up on larger number of patients is ongoing to confirm these promising results.
Corradini: Takeda: Honoraria; Sanofi: Honoraria; Novartis: Honoraria; Roche: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Amgen: Honoraria; Gilead: Honoraria. Rossi: Teva: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees.
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