Ibrutinib plus chemoimmunotherapy confers durable responses in younger patients with CLL
Most patients with chronic lymphocytic leukemia who received ibrutinib plus fludarabine, cyclophosphamide and rituximab continued to maintain deep responses after longer-term follow-up, results of a single arm, phase 2 trial showed.
Patients with the more aggressive unmutated immunoglobulin heavy-chain variable region (IGHV) also had deep responses, according to the updated results, presented at ASH Annual Meeting and Exposition. The safety profile of the treatment remained consistent with the individual toxicities of ibrutinib (Imbruvica; Pharmacyclics, Janssen) and fludarabine, cyclophosphamide and rituximab (FCR).
“Ibrutinib is known to release CLL cells from the protective niches of the lymph node and bone marrow microenvironments,” Matthew S. Davids, MD, MMSc, director of clinical research in the division of lymphoma at Dana-Farber Cancer Institute and associate professor of medicine at Harvard Medical School, told Healio. “We hypothesized that combining ibrutinib with the most potent chemoimmunotherapy regimen in CLL, FCR, could eradicate the resistant cells that often lead to relapse in patients treated with FCR alone, particularly in those patients with unmutated IGHV.
Davids and senior author Jennifer R. Brown, MD, PhD, director of the CLL Center at Dana-Farber and professor of medicine at Harvard Medical School, designed the study of front-line ibrutinib plus FCR (iFCR) to investigate whether it could induce durable remission for patients with CLL regardless of IGHV status. They noted that ibrutinib has demonstrated excellent efficacy and tolerability among young, fit patients with CLL, but required indefinite therapy when given as a single agent, which was less appealing for some younger patients compared with a time-limited therapy.
The analysis included 85 patients (median age, 55 years; range, 38-65) at nine U.S. sites between October 2014 and April 2018. Patients eligible for the trial had to be aged 65 years or younger without restriction by IGHV mutation status and had to meet International Workshop on Chronic Lymphocytic Leukemia treatment criteria.
Researchers administered ibrutinib dosed at 420 mg daily for 7 days, followed by a combination of ibrutinib with FCR for up to six cycles. Patients who responded continued on ibrutinib maintenance (median maintenance cycles, 24; range, 0-81); patients with bone marrow-undetectable minimal residual disease (MRD) after 2 years of maintenance discontinued therapy.
The primary objective was to determine the rate of complete remission/complete remission with incomplete hematologic recovery (CR/CRi) with bone marrow-undetectable MRD 2 months after combination therapy. Assessment of response rates, PFS, OS, and rates of bone marrow-undetectable MRD after 2 years of ibrutinib maintenance, as well as safety/tolerability, served as secondary objectives.
Median follow-up in this updated analysis was 40.3 months (range, 3.1-76).
Results showed a 55% complete response rate with bone marrow-undetectable MRD at any point on study, which compares favorably to the 20% rate expected with FCR alone in historical studies. The best rate of bone marrow-undetectable MRD was 84%, among the highest rates ever achieved for a regimen in CLL.
After 2 years of ibrutinib maintenance, researchers reported a CR/CRi rate of 77%, (n = 44 of 57); bone marrow-undetectable MRD rate of 81% (n = 50 of 62); and peripheral blood-undetectable MRD rate of 81% (n = 55 of 68). Researchers observed no differences in MRD or response rates based on IGHV status. The overall PFS rate at median follow-up was 97% and the OS rate was 99%.
Thirteen of 61 patients (21.3%) who completed ibrutinib plus FCR and initiated ibrutinib maintenance in a bone marrow-undetectable MRD state have demonstrated recurrent bone marrow MRD. All seven patients who underwent retreatment with ibrutinib monotherapy (five due to clinical progression and two due to recurrent bone marrow-MRD without clinical progression) achieved partial response, and none has progressed to date on retreatment.
In the safety analysis, the most common treatment-emergent grade 3 or grade 4 adverse events were hematologic and included neutropenia (40%), thrombocytopenia (32%) and anemia (11%). Additionally, 10 patients (12%) experienced grade 3 or higher febrile neutropenia and 20 patients (24%) had a grade 3 or higher infection. Researchers observed any-grade atrial fibrillation among 8% of patients and ventricular arrhythmia in one patient. The only death on study to date has been one patient with presumed sudden cardiac death 17 months into ibrutinib maintenance.
Two patients developed myelodysplastic syndrome; both are in complete response for CLL and myelodysplastic syndrome after undergoing allogeneic stem cell transplantation. No major bleeding events occurred, and no patients developed Richter’s syndrome, according to researchers.
“Based on the deep remissions observed irrespective of IGHV status, the promising durability of response and the generally manageable safety profile, iFCR is worthy of exploring in comparative studies among younger, fit patients with CLL who desire the possibility of functional cure with time-limited therapy,” Davids said.
For more information:
Matthew S. Davids, MD, MMSc, can be reached at matthew_davids@dfci.harvard.edu.
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Davids MS, et al. Abstract 221. Presented at: ASH Annual Meeting and Exposition. Dec. 11-14, 2021; Atlanta.