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The combination of ibrutinib and rituximab produced a high overall response rate and durable survival in elderly patients with mantle cell lymphoma.
The combination of ibrutinib (Imbruvica) and rituximab (Rituxan) produced a high overall response rate (ORR) and durable survival in elderly patients with mantle cell lymphoma (MCL), according to data from a phase 2 ENRICH trial (NCT0180567) published in the Journal of Clinical Oncology.1
The combination elicited an investigator-assessed best ORR of 96% among 48 patients, including a complete response (CR) rate of 71%, a partial response rate of 25%, and a stable disease rate of 4%. Within the intent-to-treat population (n = 50), the best ORR achieved with the doublet was 92%; this included a CR rate of 68%.
“Ibrutinib plus rituximab is an effective, easily administered, and chemotherapy-free option in elderly patients with nonblastoid MCL,” lead study author Preetesh Jain, MD, DM, PhD, of MD Anderson Cancer Center, and colleagues, wrote in the paper. “New onset atrial fibrillation was observed in 9 patients. We recommend that pretreatment assessment of cardiovascular risk factors is beneficial before ibrutinib/rituximab therapy.”
Patients older than 65 years with MCL treated with systemic chemotherapy tend to have inferior outcomes compared with younger patients with the disease. Standard treatment for elderly patients with MCL is rituximab-based chemoimmunotherapy followed by rituximab maintenance. However, a high incidence of grade 3 to 4 myelosuppression, hospitalization rates, infectious complications, and second cancers following this approach represent significant complications in this population.
The investigator-initiated, institutional review board–approved, open-label, single-institution, single-arm trial stemmed from a study originally designed to investigate the safety and efficacy of ibrutinib plus rituximab in relapsed or refractory MCL.
In 2015, another cohort was added to investigate the effects of ibrutinib and rituximab on elderly patients. The study enrolled 50 patients who were aged 56 years of age or older with previously untreated MCL. These patients had nonblastoid or pleomorphic histology, and/or a Ki-67% less than 50%, and an ECOG performance status of 2 or less. Notably, patients with a history of controlled atrial fibrillation were permitted.
Patients were administered oral ibrutinib 560 mg once daily in 28-day cycles with rituximab, which was given via an intravenous infusion at 375 mg/m2 once weekly for 4 weeks in the first cycle, followed by a dose on day 1 of every cycle starting in cycles 3 through 8. After cycle 8, rituximab was given on day 1 of every 2 months for up to 2 years. After 2 years, Ibrutinib was administered in continuous cycles until disease progression, toxicity, or other factors caused discontinuation.
The primary objective of the study was to estimate ORR, and key secondary objectives included progression-free survival (PFS) and overall survival (OS). Safety was also evaluated.
Participants were enrolled to the trial between October 2015 and November 2019. The median age of patients was 71 years (range, 69-76), and 71% were men. Bone marrow involvement was observed in 94% of patients, and gastrointestinal tract involvement was noted in 79% of evaluable patients. Additionally, 16% of patients had a high MCL international prognostic index (MIPI) risk score, and 28% had a high biologic MIPI score including Ki-67%. Furthermore, 3 of 18 patients had TP53 aberrations detected in the bone marrow. Twenty-three percent of patients had a history of atrial fibrillation.
At a median follow-up of 45 months (range, 24-56), 45 patients were still alive and 5 had died. A total of 4 patients experienced disease progression; 2 of these patients transformed from classic to blastoid MCL and 1 patient transformed from classic to pleomorphic MCL.
Baseline PET scans were performed in 40 patients, and 35 were positive. Within that group, 26 patients were found to have achieved complete metabolic response (CMR) at best response (74%), 8 did not have a PET scan at best response, and 1 patient had residual disease. Of the 26 patients who experienced CMR, 81% (n = 21) were bone marrow negative for MCL and 1 patient had residual disease; 4 patients did not undergo bone marrow evaluation. The median number of ibrutinib and rituximab cycles to reach CR was 7 (range, 2-51).
Additionally, the median PFS and OS were not reached with the doublet. The 3-year PFS rate was 87% (95% CI, 0.73-0.94) and the 3-year OS rate was 94% (95% CI, 0.82-0.98).
Notably, those with a high Ki-67 were noted to have a trend of higher risk of disease progression and/or death vs those with a low Ki-67 (P = not significant). Moreover, those who experienced a CR as their best response to treatment were noted to have significantly longer PFS and OS vs those who did not. Those with high-risk simplified and modified MIPI score had a significantly higher risk of disease progression. OS was noted to be inferior in high-risk patients.
As of January 2021, 56% of the 50 patients discontinued ibrutinib/rituximab and left the study because of progressive disease (8%), toxicities (42%), or miscellaneous reasons (6%). Of the 21 patients who discontinued because of toxicity, 10 did so because of grade 3 atrial fibrillation. At the time of discontinuation, 16 of the 28 patients who discontinued were in CR. Of the 10 patients who experienced atrial fibrillation, 6 had new onset and 4 had a history.
Most adverse effects (AEs) reported with the combination were either grade 1 or 2 in severity. The most common grade 3 or 4 AEs included atrial fibrillation (22%), fatigue (18%), diarrhea (14%), and myalgias (14%). Grade 3 or 4 hematologic toxicities included anemia (4%), neutropenia (8%), and thrombocytopenia (4%).
A total of 4 patients experienced grade 3 or 4 bleeding while receiving ibrutinib; 3 of these patients were receiving aspirin and/or enoxaparin and 1 patient who had retinal bleeding had recently undergone glaucoma surgery and had a history of vitreous surgery. One patient experienced grade 3 hematuria and gram-negative urinary tract infection, although this resolved with the administration of antibiotics.
Thirty-four percent of the 50 patients developed atrial fibrillation, and 10 needed to discontinue ibrutinib because of a grade 3 effect. Nine of the 17 patients who developed this toxicity had no history, and 6 had baseline ECG abnormalities, including 1 with first-degree atrioventricular block, 1 with right bundle branch block, 3 with sinus bradycardia, and 1 with miscellaneous abnormalities.
“We recommend that pretreatment assessment of cardiovascular risk factors is beneficial before IR therapy,” study authors concluded. “Long-term follow-up and randomized studies with standard treatments are needed to further evaluate the efficacy, safety, and pattern of relapse with [ibrutinib and rituximab] combination.”