FIVE‐YEAR UPDATE OF THE FIRST‐LINE IMCL‐2015 GELTAMO STUDY. PROLONGED MOLECULAR AND CLINICAL RESPONSES WERE OBSERVED AFTER MRD‐DRIVEN IBRUTINIB DISCONTINUATION

Abstract

Introduction: A frontline tailored treatment for indolent clinical forms of mantle cell lymphoma (MCL) with ibrutinib in combination with rituximab was evaluated. A high rate of complete remissions (CR) with undetectable minimal residual disease (MRD) was reported, with predictable toxicity (Giné, JCO 2022). We herein present an updated analysis focusing in the data of treatment discontinuation. Methods: This was an open-label, phase II trial conducted in 14 Spanish GELTAMO sites (NCT02682641). Centralized histology, PET-CT review, MRD studies (qPCR and NGS in peripheral blood) and biological studies were 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. Results: Fifty patients (Male 66%; median age 65 years) were enrolled in the study (June 2016 to December 2019, data cut-off 18 October 2022, median follow-up 54 months and next cut-off is planned in March 2023). The overall response (OR) and CR rates at 12 months of treatment were 84% and 80%, respectively (including 4 early discontinuations). Undetectable MRD was reached in 40 (87%) of 46 evaluable cases (sensitivity 10−5). After 24 months, 42 of 44 patients were in response, with OR and CR rates of 86% and 84%, respectively. Undetectable MRD was observed in 35 (80%) of 44 cases. Thirty-two patients discontinued ibrutinib as per protocol (64% of initial series). Twelve patients continued on ibrutinib. Median time on ibrutinib treatment was 29 months (1.7–51+ months). The median duration of undetectable MRD, achieved in 41 cases, was 60 months (95% CI: 29–92), and has not been reached in the 32 cases that stopped ibrutinib as per protocol. Six patients progressed from the disease between 12 and 72 months of follow-up and three of them eventually died of disease progression. Overall, PFS and OS at 48 months were 86% (95% CI: 75–96) and 88% (95% CI: 79–98), respectively. At current follow-up, 6 patients remain on treatment, and up to 13 patients discontinued ibrutinib because of adverse events, including 7 associated to ibrutinib with a hemorrhagic cardiac tamponade being the most severe. Five secondary neoplasms in 4 patients have been reported. Whole-genome sequencing of paired tumor/normal samples from 34 patients was obtained and will be presented. The research was funded by: The funding for the IMCL-2015 was obtained through unrestricted 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, Milteny Honoraria: Janssen, Genmab, Gilead Research funding: Janssen Educational grants: Janssen A. Medina-Herrera Research funding: Janssen Educational grants: Invivoscribe F. de la Cruz Honoraria: Roche, Takeda, Eusa Pharma, Abbvie, Janssen, Beigene, Kiowa Kirin, Astrazeneca and Gilead J. López Jiménez Honoraria: Roche, Abbvie, Janssen and Gilead Research funding: Roche Educational grants: Gilead, Janssen, Abbvie A. Martín García- Sancho Consultant or advisory role: Roche, Celgene/BMS, Morphosys, Kyowa Kirin, Clinigen, Eusa Pharma, Novartis, Gilead, Servier, Incyte Honoraria: Roche, Celgene, Janssen, Servier, Gilead Research funding: Janssen Educational grants: Roche, Servier, Celgene, Janssen, KernPharma M. J. Terol Research funding: Gilead Educational grants: Janssen, Gilead/Kite, Roche, Abbvie A. de la Fuente Honoraria: Abbvie, Astellas Pharma, BMS, incite, JazzPharma, Novartis, Roche and Pfizer Research funding: Janssen, Novartis Educational grants: Abbvie, Astellas Pharma, BMS, Incyte, Janssen, JazzPharma, Mundipharma, Roche, Pfizer A. Marín Niebla Consultant or advisory role: Janssen, Gilead, Kiowa Kirin, Takeda, Beigene Honoraria: Gilead/Kite, Janssen, Genmab Educational grants: Takeda, Janssen, Kiowa Kirin T. J. González López Honoraria: Novartis, Amgen, Sobi, Grifols and Mome Research funding: Novartis, Amgen X. Setoain Honoraria: Roche, Gilead, General Electric Educational grants: General Electric, Takeda R. García Sanz Honoraria: Janssen, Beigene Research funding: Janssen A. López Guillermo Consultant or advisory role: Roche, Gilead/Kite, Celgene, Novartis, Janssen, Abbie, Spectrum Honoraria: Roche, Celgene, Gilead/Kite Research funding: Roche, Celgene, Gilead