Consolidation therapy with mitoxantrone, ifosfamide and etoposide with or without rituximab before stem cell transplantation in relapsed diffuse large B-cell lymphoma patients failing second-line treatment

Non-Hodgkin lymphoma (NHL) patients failing secondline regimens have three potential therapeutic avenues; a third-line regimen in the perspective of HDT/ASCT consolidation, a novel drug (if available), or best supportive care. High-dose chemotherapy with autologous stem-cell transplantation (HDT/ASCT) is curative in approximately 50% of patients with relapsed or refractory aggressive NHL. [1] Chemosensitivity is a critical parameter for improving overall survival (OS) in this context, as partial or complete remissions (PR, CR) following reinduction chemotherapy generally allow patients to undergo HDT/ASCT. [1] The role of several critical issues in reinduction therapy yet to be resolved, including therapy type (particularly rituximab in an era when R-CHOP [rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone] is accepted as frontline standard of care), risk stratification according to the second-line ageadjusted International Prognostic Index (aaIPI), and relapse within 12 months of diagnosis. [1] Reinduction therapy consists of salvage regimens that frequently incorporate novel drugs and notably the anti-CD20 antibody rituximab, with response rates around 50% including 15% to 20% CR. [2] Most are based on platinum, cytarabine, ifosfamide, and/or etoposide. DHAP (cisplatin–cytarabine–dexamethasone) or ICE (ifosfamide–carboplatin–etoposide) combinations generally give optimal results, with approximately twothirds of patients reported to respond. [3] Nonetheless, only 40% (R-DHAP) and 36% (R-ICE) of patients achieved CR or unconfirmed CR (CRu) in this study, and only half of them ultimately underwent intensification. Anthracyclines are also one of the most effective classes of drugs in lymphoma, and standard first-line therapy now includes anthracycline-based combinations, notably mitoxantrone. We performed a retrospective analysis evaluating the efficacy of mesna/ifosfamide, mitoxantrone, and etoposide with or without rituximab (MINE ± R) in relapsed/ refractory diffuse large B-cell lymphoma (DLBCL) patients failing second-line treatment with R-DHAX (rituximab plus oxaliplatin–cytarabine–dexamethasone). [4] Response rate, number of patients undergoing HDT/ASCT, and survival were evaluated. Thirty patients with relapsed/refractory DLBCL treated with third-line MINE ± R in a single French center between March 2008 to January 2015 were evaluated. To be eligible, patients had to have histologically-proven DLBCL at diagnosis, have failed two prior treatment lines, specifically first-line R-CHOP [5] and second-line RDHAX (assessed by FDG-PET and CT-scan after two cycles), and be suitable for HDT/ASCT (570 years old and without limiting comorbidities). Histology was reviewed according to the World Health Organization classification. [6] Patients were rebiopsied prior to R-DHAX. When administered, rituximab was given on day 1 at 375 mg/m with acetaminophen (1000 mg) and dexchlorpheniramine (5 mg). MINE was administered as mitoxantrone (12 mg/m, 30 min, day 1) then ifosfamide (1500 mg/m/day, 1 h, day 1) with simultaneous mesna 1000 mg/m 3, days 1–3, and etoposide (150 mg/m, 2 h, days 1–3. Two to six cycles were administered every 21 days. Doses were adjusted according to toxicity. Patients eligible for HDT received the BEAM regimen, composed of carmustine (300 mg/m) on day 6,