Abstract
This prospective phase II trial (Nov 2011- Dec 2012), supported by the LYSA group, aimed to evaluate the impact on PFS of the RiBVD regimen in newly diagnosed, previously untreated, elderly MCL patients (>65 years or not eligible for ASCT) (NCT01457144). Inclusion criteria were: WHO 2008 MCL not previously treated, CD20 positive, ECOG 0-2, AA stage II-IV, no CNS involvement or active HBV/HCV/HIV infection. Patients were scheduled to receive a total of 6 cycles of the RiBVD regimen, if they responded (IWG criteria) after 4 cycles. The regimen was administered every 4 weeks with Rituximab 375 mg/m² IV on day(D)1, Bendamustine 90 mg/m² IV on D1 and 2, Dexamethasone 40 mg/m² IV on D2 and bortezomib (Velcade®) 1.3 mg/m² subcutaneously on D1, 4, 8 and 11. Primary prophylaxis with acyclovir was mandatory for Herpes virus reactivation, but there was no recommendation for bacterial prevention. Herein we present preliminary analysis of the trial after 4 RiBVD cycles. Results: A total of 76 patients were included, one was excluded because of HBV active disease and 5 had insufficient data reported in the database. To date we analyzed 70 patients. Patients characteristics: sex ratio M/F 49/21, median age 72 years (y) [64-83] (2 patients were 64 y old), AAstage II/III-IV 5/65, ECOG 0-1/2 59/11, MIPI score low/intermediate/high 3/19/48. Response: 61 responded (ORR=87%), with 19 in PR (26%) and 42 in CR/CRu (60%). Four patients died from pneumonia (n=1), cardiac arrest (n=2) and one following Progressive Multifocal Leukoencephalopathy. Three patients have progressed after 3 cycles. Sixty one patients were analysed by PETscan after 4 cycles, 39 (64%) reached a CR (30 were in CR/CRu and 9 in PR) and 22 remained PET positive (11 patients were in CR/CRu, 10 in PR and 1 stable). RiBVD cycles: 271 cycles were administered out of 280 planned (97%). Twenty four (9%) were delayed, 10 for toxicity. All but one planned Bendamustine doses (n=542) were administered with dosing modified 17 times (3%), mostly for hematological toxicity (n=14). Regarding Bortezomib, 79% (1028/1084) of planned doses were administered, it was prematurely stopped (56, 4%) for neurotoxicity (10 instances) or hematological side effects (46). Rituximab was not administered in 4 instances. Hematologic toxicities: Over the 271 cycles administered, neutropenia was reported in 104 cycles [56 grade 3/4 (g3/4) (21%)], 2.5% with fever; thrombopenia in 181 cycles [41 g3/4 (15%)]; anemia in 210 cycles, [6 g3/4 (2%)]. Non-hematologic toxicities:Reported in >10% of the cycles were : allergic reactions (10.3%, g3/4 <1%), fatigue (40%, g3/4 5%), fever without neutropenia (12%, g3/4 none), weight loss (12%, g3/4 0%), cutaneous rash (12%, g3/4 1.5%), gastrointestinal (40%, g3/4 1.5% ; diarrhea 8%, constipation 17% or emesis 15%), elevated transaminases (14%, g3/4 1%), creatinin (13%, g3/4 none), or glucose (18%, g3/4 1%) ; neuropathy (sensitive or pain) (25%, g3/4 4%). Serious adverse events (SAE) additional to the 4 deaths, were 12 infections including 3 pneumonias (no pneumocystosis), one listeriosis and 2 herpes zoster. Four febrile neutropenia and 3 cutaneous hypersensitivity episodes were also reported.
Despite 4 toxic deaths (6%), toxicity appears acceptable and manageable. In particular, subcutaneous bortezomib shows markedly decreased neurotoxicity compared to the IV form. This interim analysis shows that four cycles of RiBVD are very effective for untreated elderly MCL patients (ORR 87%) with a high response rate (CR/CRu 60%) which has been shown to be predictive of a long duration of response. An update of these results will be presented at the ASH meeting together with the molecular response rates after 4 cycles.
Gressin:Pfizer: Consultancy; Mundipharma: Consultancy. Cartron:Roche: Membership on an entity’s Board of Directors or advisory committees.
Author notes
Asterisk with author names denotes non-ASH members.
