Phase 2 data highlighted a high complete response rate and undetectable minimal residual disease rate in patients with indolent clinical forms of mantle cell lymphoma who received ibrutinib plus rituximab.
High rates of complete response and undetectable minimal residual disease (MRD) were observed among patients with indolent clinical forms of mantle cell lymphoma (MCL) who were treated with frontline ibrutinib (Imbruvica) plus rituximab (Rituxan), according to results from the phase 2 IMCL-2015 trial (NCT02682641) published in the Journal of Clinical Oncology.
An overall response was observed in 84% (95% CI, 74%-94%) of patients after 12 cycles of treatment with the combination, with 80% (95% CI, 69%-91%) of patients experiencing a complete response. Undetectable MRD in the peripheral blood was achieved in 87% of patients (95% CI, 77%-97%).
“The present study shows that the ibrutinib plus rituximab combination achieves a high rate of complete and molecular responses as up-front treatment for indolent clinical forms of MCL. This is an MRD-driven study that results in a time-limited treatment with the ibrutinib plus rituximab combination for the majority of patients,” the investigators wrote.
Eligible patients needed to be 18 years or older and have a confirmed MCL diagnosis, excluding blastoid variants and/or Ki-67 of more than 30%. Further eligibility criteria required patients to be previously untreated and have an ECOG performance score of 0 or 1.
Patients on the trial received 4 weekly doses of intravenous rituximab at 375 mg/m2 in the first cycle of 28 days on days 1, 8, 15, and 22 followed by 4 additional doses on the first day of every other cycle (cycles 3, 5, 7, and 9) for a maximum of 8 doses. Ibrutinib was administered orally at a fixed continuous dose of 560 mg once daily; treatment was discontinued at 2 years following sustained undetectable MRD.
Complete response rate at 12 months was the trial’s primary end point. Secondary end points included the safety and tolerability of treatment, overall response, undetectable MRD rate, progression-free survival (PFS), duration of response, and overall survival (OS).
A total of 50 patients were enrolled across 12 centers. The median age for the population was 65 years and most patients were male (66%). Forty-six patients were evaluable for response after 12 treatment cycles, and 37 patients received 24 cycles of ibrutinib. Median follow-up was 36 months for survival outcomes.
The estimated PFS rate at 36 months was measured at 93% (95% CI, 86%-100%). MIPI and TP53 mutational status had a significant impact on PFS, although there were no differences by molecular subtype, genomic complexity, or MRD status at cycle 12. The 36-month event-free survival rate was 76% (95% CI, 64%-89%) and OS was 92% (95% CI, 84%-100%).
At the time the study was published, 6 patients had died due to disease progression (n = 4), pancreatic adenocarcinoma (n = 1) and COVID-19 infection (n = 1).
Common treatment-related adverse effects (AEs) of any grade included diarrhea (38%), neutropenia (36%), fatigue (32%), upper respiratory infection (24%), nausea (22%), and arterial hypertension (20%). Grade 3 or higher AEs were mostly hematologic (22%).
“Some patients, particularly those with a TP53 mutation, may not be good candidates for treatment discontinuation, even in the case of molecular response. Future randomized studies are guaranteed to explore the final role of targeted therapies in the frontline treatment of patients with MCL,” the investigators concluded.
Giné E, de la Cruz F, Jiménez Ubieto A, et al. Ibrutinib in combination with rituximab for indolent clinical forms of mantle cell lymphoma (IMCL-2015): a multicenter, open-label, single-arm, phase II trial. J Clin Oncol. Published online January 14, 2022. doi:10.1200/JCO.21.02321