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RiBVD regimen as first-line treatment for older MCL patients
52 months, the 24-month progression-free survival rate was 70%, hence the primary objective was reached. After six cycles of treatment, 91% (54/59) of responding patients were analyzed for peripheral blood residual disease and 87% of these (47/54) were negative. Four-year overall survival rates of the patients who did not have or had detectable molecular residual disease in the blood at completion of treatment were 86.6% and 28.6%, respectively (P<0.0001). Neither the mantle cell lymphoma index, nor fluorodeoxyglucose-positron emission tomography nor Ki67 positivity (cut off of ≥30%) showed a prognostic impact for survival. Hematologic grade 3-4 toxicities were mainly neutropenia (51%), throm- bocytopenia (35%) and lymphopenia (65%). Grade 3-4 non-hematologic toxicities were mainly fatigue (18.5%), neuropathy (15%) and infections. In conclusion, the tested treatment regimen is active as front- line therapy in older patients with mantle cell lymphoma, with manageable toxicity. Minimal residual disease status after induction could serve as an early predictor of survival in mantle cell lymphoma. ClinicalTrials.gov: NCT 01457144.
Introduction
Mantle cell lymphoma (MCL) is a rare subtype of B-cell non-Hodgkin lymphoma characterized by the genetic hallmark t(11;14)(q13;q32) chromosomal translocation which leads to overexpression of cyclin D1.1 The stan- dard-of-care for the treatment of older MCL patients (>65 years), has been eight cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and pred- nisone) given at 21-day intervals (R-CHOP-21), followed by maintenance therapy which has been shown to improve response duration and overall survival (OS) in patients who reach the maintenance phase.2 Complete response rates do, however, remain low with R-CHOP (30-35%) and the median progression-free survival (PFS) is in the range of 14-18 months.3,4 After R-CHOP and main- tenance therapy, the 4-year OS rate was 87%.2 Although dose-intensive and high-dose cytarabine-containing regi- mens, with or without autologous stem cell transplanta- tion consolidation in younger patients, has improved out- comes (the median PFS is now well in excess of 5 years), such approaches are frequently not feasible, given that the median age at diagnosis of MCL is in the mid to late 60s.1
Bortezomib was the first novel agent to be approved for the treatment of patients with relapsed/refractory MCL.5,6 The addition of bortezomib to rituximab-anthracycline- based regimens has improved the results, compared to those achieved by R-CHOP, for frontline therapy in MCL, leading to a complete response rate of 50% and a median PFS of 25 months albeit with increased hematologic toxi- city.7,8 Two phase III trials have shown the superiority of bendamustine-rituximab combination therapy over R- CHOP or R-CHOP/R-CVP (rituximab, cyclophos- phamide, vincristine, prednisolone) with respect to overall and complete response rates and reduced toxicity.9,10 However, superior PFS was observed in only one of the latter phase III studies.9 More recently, combining geno- toxic agents (such as cytarabine) or targeted agents (such as bortezomib or lenalidomide) with bendamustine and rituximab (BR) has shown efficacy in both first-line and salvage therapy in MCL.1,11-13
In anticipation of the above findings, our group initiated a phase II trial to assess the efficacy of a new regimen combining rituximab, bortezomib, bendamustine and dexamethasone (RiBVD) for first-line therapy of older MCL patients. Specifically, for the trial design, associating RiBVD, we took into account the interim results of the BR regimen, for which the reported overall response rates
were 90% in relapsing MCL patients,14,15 and the promis- ing results (32% overall response rate) of bortezomib monotherapy in relapsing MCL patients (PINNACLE study).6 Pre-defined secondary objectives of our study included assessment of molecular complete response rates in blood and bone marrow and evaluation of their prog- nostic impact on survival.
Methods
Study design and patients
The RiBVD multicenter phase II trial enrolled newly diagnosed MCL patients ≥65 years or <65 years if ineligible or unwilling to undergo autologous stem cell transplantation. The study was con- ducted in 37 centers of the Lymphoma Study Association (LYSA) (NCT 01457144) and was approved by institutional review boards and ethics committees at all sites, and conducted according to the Declaration of Helsinki. The diagnosis of MCL was established according to the World Health Organization (WHO) 2008 criteria. Ki67 staining and scoring were performed centrally, according to European MCL Network recommendations.16 All pathology results were reviewed centrally by the LYSA pathology commis- sion. Eligible patients gave written, informed consent, as per stan- dard guidelines. Inclusion and exclusion criteria are summarized in Online Supplementary Table S1.
The RiBVD regimen consisted of a maximum of six cycles of 28 days each for all enrolled patients, as described in the Online Supplementary Methods and Online Supplementary Table S2.
Response and safety assessments
The International Working Group (IWG) 1999 and 2007 criteria were used to define responses after four and six cycles, respective- ly. [18F]fluorodeoxyglucose (FDG)-positron emission tomography (FDG-PET) responses were evaluated in each center with the five- point scale, visual method of Deauville.17 Hematologic and non- hematologic toxicity was monitored continuously during treat- ment and at follow-up visits and graded according to the National Cancer Institute criteria (Common Terminology Criteria for Adverse Events, version 3.0) (see the Online Supplementary Methods for details).
Molecular minimal residual disease
Molecular responses were evaluated centrally by real-time quantitative polymerase chain reaction targeted to patient-specif- ic, IGH V(D)J clono-specific rearrangements, to quantify tumor B cells, according to EURO-MRD guidelines, as previously described.18 Minimal residual disease (MRD) analysis was per-
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