Safety and Efficacy of Rituximab Plus Bendamustine in Relapsed or Refractory Diffuse Large B-Cell Lymphoma Patients
Authors: Arcari Annalisa , Chiappella Annalisa , Valenti Vanessa , Zanlari Luca , Tani Monica , Marasca Roberto , Cabras Maria Giuseppina , Spina Michele , Santagostino Alberto , Ilariucci Fiorella , Carli Giuseppe , Musto Pellegrino , Savini Paolo , Marino Dario , Ghio Francesco , Gentile Massimo , Cox Maria Christina , Della Seta Roberta , Vallisa Daniele 
Published: October 2019

Abstract
Background:
Diffuse large B-cell lymphoma (DLBCL) relapsed or refractory after chemoimmunotherapy have dismal prognosis; the standard salvage treatment is Rituximab plus high dose chemotherapy with autologous stem cell transplantation (R-HDC). However, no standardized treatment is available for patients not eligible for R-HDC because of age and/or comorbidity. The combination Rituximab plus Bendamustine (R-B) has shown to be non-inferior and with a favorable toxicity profile compared to R-CHOP in indolent B-cell lymphoma. The use of R-B in DLBCL is a matter of debate.
Purpose:
We designed an Italian multicenter retrospective study aimed to evaluate safety and efficacy of R-B as salvage treatment in patients with DLBCL relapsed or refractory after at least one complete course of Rituximab-chemotherapy, who were not eligible for R-HDC because of age and/or comorbidity or in patients with post-HDC recurrence.
Patients and Methods:
We retrospectively reported 43 unselected consecutive patients with relapsed or refractory DLCBL treated with R-B in 15 Italian haematological centers between October 2008 and January 2014. Schedule of R-B were: 6 courses of Bendamustine at 90 mg/mq or 70 mg/mq on days 1 and 2 of each 28-day cycle and Rituximab 375 mg/mq on day 1 of each cycle. They were analyzed for baseline characteristics (age, IPI, ECOG, comorbidity), outcome (ORR, PFS, OS) and toxicity (CTCAE).
Results:
The median age was 76 years (range 56-94). Eighty-three % of patients had advanced-stage disease (III-IV stage) and 67% had IPI score of ≥3. An extranodal involvement was present in 65% of cases (bone marrow, lung, stomach, skin, pleura, pericardium). More than half the patients (51%) presented with poor functional status with ECOG score of ≥2. Comorbidity assessment by CIRS-G revelead 30% of patients with ≥1 severely or very severely (level 3 or 4) affected organs and 27% of patients with moderate or severe (level ≥2) cardiopathy. The mean number of prior therapies was 1,7 (range 1-3). All patients were previously treated with Rituximab-chemotherapy and three patients had already received R-HDC. Twelve patients had a refractory disease and 31 experienced relapse after last treatment. Patients received a median of 5 cycles of planned 6 courses of R-B (range 2-6); 24 patients underwent Bendamustine at 90 mg/mq, 19 at 70 mg/mq. All patients received Rituximab 375 mg/mq. In 38% of patients treatment was stopped because of progression; in 4 patients (9%) progression occurred within the first 2 treatment cycles. The overall response rate was 47%, including 28% complete remission and 19% partial remission. One patient in partial remission after R-B achieved a complete remission after local radiotherapy. The median OS was 16 months (95% CI 10-20). The median PFS was 8 months (95% CI 6-11). The median follow up was 10 months (range 2-60). Nine patients are still alive and in complete remission at last follow up; 7 of these patients had a chemosensitive relapse before R-B (in 5 cases a first relapse) and only 2 had a refractory disease with progression after a previous lenalidomide treatment. Toxicity was moderate, mainly grade 1 and 2. Grade 3-4 adverse events were neutropenia in 14 patients (32%), thrombocytopenia in 5 patients (11%), anemia in one patient, infections in 3 patients (6%), skin rash in one patient, nausea in one patient, diarrhea in one patient. One patient died of septic shock after the third R-B cycle. One patient died of miocardial infarction related to underlying cardiac comorbidity.
Conclusions:
Bendamustine in combination with Rituximab showed promising efficacy results with a low toxicity profile in a poor prognosis population (advanced stage disease and extranodal involvement, high median age, poor functional status, comorbidities), not eligible for R-HDC. The optimal dosage and schedule of Bendamustine and/or combination with novel drugs should be further investigated, in order to improve the duration of response and reduce the rate of early progression.

Disclosures
Off Label Use: Bendamustine in diffuse large B-cell lymphoma. Marasca:Mundipharma: Honoraria.