Rituximab, Bendamustine and Cytarabine (R-BAC) Is a Very Active Regimen In Patients with Mantle Cell Lymphoma Not Eligible for Intensive Chemotherapy or Autologous Transplant

Bendamustine (B) and rituximab (R) in combination have relevant clinical activity in mantle cell lymphoma (MCL), and a favorable toxicity profile. We recently demonstrated that B and cytarabine, a key drug in the treatment of younger patients with MCL, are strongly synergistic when added to MCL cell lines in-vitro. In the present study we combined cytarabine with B and R (R-BAC) in previously untreated patients with MCL aged >65, and in patients relapsed or refractory (R/R) to one previous line of immunochemotherapy.

This prospective safety/efficacy phase 2 study started with a dose-finding stage based on three stepwise dose-escalations of cytarabine. After the first 6 patients (3+3) were enrolled and concluded their whole treatment, the first dose level of cytarabine (800 mg/m2) was validated for the extension of the study. Therefore, all patients received 4 to 6 cycles of R 375 mg/m2 on day 1, B 70 mg/m2 on day 2 and 3, cytarabine 800 mg/m2 on Day 2, 3, and 4. Cycles were administered every 4 weeks, mostly on outpatient basis. The primary objectives were the safety of R-BAC, and assessment of overall and complete response rates (ORR and CRR).

Thirty-seven patients have been enrolled, of whom 20 were previously untreated, and 34 were evaluable for response. Median age was 71 years (range 55–88), and 60% were males. Ann Arbor stage was III-IV in 92%, 44% had bulky disease, and MIPI was low/interm/high in 28/18/54% of patients, respectively. Cytologic subtype was blastoid in 17%, and mean ki-67 was 25% (range 5–80). All R/R patients had received rituximab containing regimens as first line. Six of them (35%) were refractory to induction therapy. Overall, R-BAC was very well tolerated. The dose limiting toxicity was hematological, with 60% and 90% of patients experiencing transient grade 3–4 neutropenia and/or thrombocytopenia, respectively (median duration 2 days, range 1–5). Grade 2 anemia was also frequent, with 60% of patients that were transiently treated with erythropoetin. Hematologic toxicity was significantly more frequent in R/R patients than in treatment naive. Three patients (8%) had febrile neutropenia with pneumonitis in one. Thirteen patients (35%) had grade 1–3 elevation of gamma-GT. No other significant toxicity was observed. Considering all patients, ORR was 88%, and CRR was 74% (CR 53%, unconfirmed CR 21%). CRR was 82% for previously untreated and 67% for R/R patients. According to the recently revised PET-including response criteria (Cheson BD et al, JCO 2007), CRR was 88% for previously untreated patients, and 73% for R/R. At a median follow-up from the start of therapy of 13 months (range 1–28) the 1-year progression-free survival was 76% ± 8% (87% ± 8% for previously untreated, and 62% ± 13% for R/R, Figure 1).

R-BAC combination is a well tolerated and active regimen in the treatment of older patients with MCL.

Figure 1:

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Figure 1:

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Visco:Mundipharma International Ltd: Research Funding. Off Label Use: Bendamustine has no formal indication in Italy for the treatment of mantle cell lymphoma.