Efficacy and safety of ibrutinib in combination with rituximab as frontline treatment for indolent clinical forms of mantle cell lymphoma. results of the geltamo imcl-2015 study

Introduction: Mantle-cell lymphoma (MCL) is a heterogeneous disease and the existence of indolent clinical forms is increasingly recognized. The aim of this study was to propose a frontline tailored treatment for indolent clinical forms with ibrutinib in combination with rituximab (IR). Methods: This is a multicenter single-arm, open-label, phase II study with a two-stage design conducted in 14 Spanish GELTAMO sites (NCT02682641). Centralized histology, PET-CT review, minimal residual disease (MRD) studies (qPCR and NGS in peripheral blood [PB] and bone marrow [BM]) and biological studies are conducted. Previously untreated MCL patients with indolent clinical forms were eligible according to the following criteria: no symptoms attributable to MCL, ECOG 0-1, stable disease without therapy need for at least 3 months, non-blastoid variants, Ki-67 <30% and largest tumor diameter ≤3 cm. Both leukemic non-nodal and nodal forms were acceptable. Patients received ibrutinib 560 mg daily and a total of 8 doses of rituximab 375 mg/m2 (4 weekly doses during the first 28-day cycle, followed by day 1 of cycles 3, 5, 7 and 9). Ibrutinib could be discontinued after 2 years of treatment in case of sustained undetectable MRD. The primary endpoint was the rate of complete remissions (CR) achieved after 12 cycles according to the Lugano criteria. Results: Fifty patients (Male 66%; median age 65 years) were enrolled in the study (June 2016 to December 2019, data cut-off 22 Jan 2021, median follow-up 33 months). Efficacy data of the 50 patients included four cases that were discontinued earlier due to adverse events (AE): ORR 84% and CR 80%. Regarding MRD evaluable cases (N = 45), 86% achieved undetectable MRD in PB and 64% also in BM. In CR cases, 72% had undetectable MRD in both PB and BM. After 24 months of treatment, 19 patients were in response with undetectable MRD and discontinued ibrutinib treatment according to protocol. Four patients progressed from the disease at 12, 38, 40 and 52 months of follow-up and two of them eventually died of progression. Overall, PFS and OS estimated at 42 months were 81% (95% CI: 65-98) and 86% (95% CI: 71-100), respectively. Five patients were withdrawn from the study due to serious adverse events (one each), including skin rash, severe aplastic anemia, pancreatic adenocarcinoma, and lumbar fractures, or by decision of the patient. The most common treatment-related adverse events (AE) were diarrhea (38%), neutropenia (36%), fatigue (32%), upper respiratory infection (26%) nausea (22%), and arterial hypertension (20%). AE grades ≥ 3-4 corresponded predominantly to hematologic toxicity (22%). So far 10/50 patients have discontinued ibrutinib due to intolerance. The research was funded by: Janssen Clinical Investigator-Initiated Study (IIS) Research Support Keywords: Aggressive B-cell non-Hodgkin lymphoma, Molecular Targeted Therapies Conflicts of interests pertinent to the abstract E. Giné Consultant or advisory role: Gilead Honoraria: Janssen, Gilead, Roche, Genmab Research funding: Janssen, Gilead, Roche Educational grants: Janssen, Gilead