Rituximab, Bendamustine and Cytarabine (RBAC500) As Induction Therapy in Elderly Patients with Mantle Cell Lymphoma: Final Results of a Phase 2 Study from the Fondazione Italiana Linfomi

Carlo Visco, Annalisa Chiappella, Luca Nassi, Caterina Patti, Simone Ferrero, Daniela Barbero, Andrea Evangelista, Michele Spina, Anna Lia Molinari, Luigi Rigacci, Monica Tani, Alice Di Rocco, Graziella Pinotti, Alberto Fabbri, Renato Zambello, Silvia Finotto, Manuel Gotti, Angelo Michele Carella, Flavia Salvi, Stefano A Pileri, Marco Ladetto, Giovannino Ciccone, Gianluca Gaidano, Marco Ruggeri, Maurizio Martelli and Umberto Vitolo


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Background: The combination of rituximab (R, 375 mg/m2 intravenously [IV], day 1), bendamustine (B, 70 mg/m2IV, days 2 and 3), and cytarabine (800 mg/m2, IV on days 2 to 4) was highly active in patients with mantle-cell lymphoma (MCL) in a phase 2 study [R-BAC; Visco et al, JCO 2013]. This regimen was well tolerated, but hematologic toxicity was quite relevant, especially in terms of transient grade 3 to 4 thrombocytopenia (76% of cycles). Aiming at reducing hematologic toxicity, the Fondazione Italiana Linfomi (FIL) designed a phase 2 trial adopting the R-BAC schedule, but lowering cytarabine dose to 500 mg/m2 (RBAC500).

Materials and Methods: Patients with newly diagnosed MCL, aged 61 to 80 years, not eligible for autologous transplant and fit according to the comprehensive geriatric assessment, were enrolled. Patients presenting with non-nodal leukemic disease were excluded. The primary endpoints were complete remission rate (CR) measured by FDG-PET according to Cheson criteria 2007, and safety. Secondary endpoints included rate of molecular response (MR) by nested-PCR using patient specific IGH or BCL1 based targets, progression-free (PFS) and overall survival (OS). The study was conducted according to the Bryant and Day two-stage design.

Results: From May 2012 to February 2014, 57 patients with MCL from 29 centers were recruited and treated. Central pathology revision was performed in 87% of cases. Median age was 71 years (range 61-79), 75% were males, and 91% had Ann Arbor stage III/IV disease. Mantle Cell International Prognostic Index (MIPI) was low in 15%, intermediate in 40%, high in 45%, Ki-67 was ≥30% in 31%, and 9% had the blastoid cytological variant. Overall, 53 patients (91%) received at least 4 cycles, while 36 (63%) had 6 cycles (median 5.3 cycles per patient). Fifteen patients (26%) discontinued treatment before reaching cycle 6 because of toxicity/adverse events, that mainly consisted of prolonged hemato-toxicity between cycles. Only one patient discontinued due to progressive disease. Grade 3 or 4 neutropenia and thrombocytopenia were observed in 49% and 52% of administered cycles, respectively. Febrile neutropenia occurred in 6% of cycles. Extra-hematologic toxicity was mainly cardiac (5%). Overall response rate was 96%, and CR was 93%. The MR rate at the end of treatment was 76% on peripheral blood and 55% on bone marrow (BM) samples. With a median follow-up of 34 months (28-52), the 2-years PFS (± confidence interval) was 81%±5% and the OS 85%±4%. Elevated Ki-67 (≥30%), and the blastoid variant were the strongest independent predictors of adverse PFS. Patients with either of these two features (33%), had a significantly inferior PFS (41% vs 97% after 34 months) compared to patients with classical/pleomorphic variants and low proliferative index (p<0.0001, Figure 1).

Conclusions: The R-BAC500 regimen can be safely administered as first line therapy to elderly patients with MCL. Hematologic toxicity is substantially reduced compared to our previous experience. With 93% of FDG-PET negative CR, and a 2-years PFS of 81% without maintenance therapy, the R-BAC500 regimen is a highly effective treatment for patients with MCL, and compares favourably with previously reported regimens in this patient population, including R-bendamustine.

Disclosures Visco: Gilead: Speakers Bureau; Lundbeck: Consultancy; Mundipharma: Research Funding; Celgene: Speakers Bureau. Spina: Mundipharma: Membership on an entity's Board of Directors or advisory committees, Other: Speaker Fee; Teva Pharmaceuticals Industries: Membership on an entity's Board of Directors or advisory committees, Other: Speaker Fee. Di Rocco: Celgene: Honoraria. Carella: Millenium: Speakers Bureau; Genentech: Speakers Bureau. Vitolo: Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; Gilead: Honoraria; Celgene: Honoraria.

  • * Asterisk with author names denotes non-ASH members.

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