Is Functional Cure Achievable in Young CLL Patients with Ibrutinib?

Take-aways:

• In a multicenter, single-arm, phase II trial, researchers evaluated whether time-limited ibrutinib plus chemoimmunotherapy could provide durable remission for CLL patients.
• Study participants received ibrutinib 420 mg daily for 7 days, followed by ibrutinib plus FCR for up to 6 cycles. Responders received ibrutinib maintenance, and those with undetectable MRD after 2 years discontinued therapy.
• After 2 years of ibrutinib maintenance, the rates of CR/CRi and undetectable MRD were 77% and 81%, respectively, regardless of IGHV status.

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According to findings presented at the 2021 American Society of Hematology Annual Meeting, at more than 3 years of follow-up, most patients with chronic lymphocytic leukemia (CLL) who were treated with a combination of ibrutinib plus standard chemoimmunotherapy experienced sustained, durable responses. The benefits of this time-limited therapy approach were seen regardless of IGHV status, noted lead author Matthew S. Davids, MD, MMSc, from Dana-Farber Cancer Institute.

The authors explained that, given the excellent efficacy and tolerability of ibrutinib in a broad population of young, fit patients with CLL patients, they wanted to evaluate whether time-limited ibrutinib plus chemoimmunotherapy could provide durable remission for CLL patients, irrespective of IGHV status. “We hypothesized that combining ibrutinib with FCR as initial therapy would lead to a high rate of CR with undetectable [measurable residual disease in the bone marrow] in a broad population of younger, fit patients,” Dr. Davids said during his presentation.

In this multicenter, single-arm, phase II trial, investigators enrolled CLL patients age ≤65 years without restriction by IGHV mutation status, who met International Workshop on Chronic Lymphocytic Leukemia (iwCLL) treatment criteria. Patients received ibrutinib 420 mg daily for 7 days, followed by the addition of fludarabine, cyclophosphamide, and rituximab (FCR) for up to 6 cycles. Responders continued on ibrutinib maintenance following the combination treatment, and patients with undetectable measurable residual disease (MRD) after 2 years of maintenance discontinued therapy.

The study’s primary objective was to determine the rate of complete response (CR)/CR with incomplete hematologic recovery (CRi) with undetectable MRD 2 months after ibrutinib plus FCR. Secondary objectives were to assess response rates, progression-free survival (PFS) and overall survival (OS), as well as MRD negativity after 2 years of ibrutinib maintenance.

A total of 85 patients were enrolled at 9 US cites. Participants’ median age was 55 years (range, 38-65), and IGHV was unmutated in 46 of 79 evaluable patients (58.2%). del17p and TP53 mutation were present in 4 of 83 (4.8%) and 3 of 81 (3.7%) patients, respectively. The median number of FCR cycles completed was 6 (range, 1-6).

Dr. Davids presented data from a median follow-up of 40.3 months (range, 3.1-76), at which point the median number of ibrutinib maintenance cycles was 24 (range, 0-81). The rate of CR with undetectable MRD at any point on study is 55%, and the rate of undetectable MRD in any response was 84%. Following 2 years of ibrutinib maintenance, the rates of CR/CRi and undetectable MRD in patients with available data were 77% and 81%, respectively, with no differences based on IGHV status.

PFS and OS for all patients were 97% and 99%, respectively. The researchers noted that 13 of 61 patients (21.3%) who completed ibrutinib FCR and started ibrutinib maintenance while in MRD negativity have had recurrent MRD. Seven of these patients underwent retreatment with ibrutinib monotherapy (5 due to clinical progression and 2 due to recurrent MRD without clinical progression), and all 7 achieved PR with retreatment.
The most common treatment-emergent grade 3/4 adverse events were hematologic, and included neutropenia (40%), thrombocytopenia (32%), and anemia (11%).

Regarding these findings, Dr. Davids and coauthors concluded that, “among the few patients with recurrence after this time-limited therapy, all have responded to retreatment with ibrutinib monotherapy.” The data suggest that “iFCR is worthy of exploring in comparative studies in younger, fit CLL patients who desire the possibility of functional cure with time-limited therapy.”

Disclosures: This research was supported in part by Pharmacyclics LLC. Study authors report financial relationships with Pharmacyclics LLC, the manufacturers of ibrutinib.

Reference

Davids MS, Brander DM, Tyekucheva S, et al. Longer term follow-up of a multicenter, phase 2 study of ibrutinib plus fludarabine, cyclophosphamide, rituximab (iFCR) as initial therapy for younger patients with chronic lymphocytic leukemia. Abstract #640. Presented at the 2021 American Society of Hematology Annual Meeting, December 13, 2021.