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Ibrutinib plus rituximab (IR) appears to have superior efficacy relative to the combination of fludarabine, cyclophosphamide, and rituximab (FCR) in previously untreated chronic lymphocytic leukemia (CLL). The findings, from the phase 3 FLAIR trial (ISRCTN Registry Identifier: ISRCTN01844152), were presented by Peter Hillmen, MBChB, PhD, of St James’s University Hospital in the United Kingdom, at the 2021 American Society of Hematology (ASH) Annual Meeting.

FLAIR is an ongoing, randomized, controlled, open, parallel-group, phase 3 trial in previously untreated CLL requiring therapy. The study excluded patients older than age 75 years or with more than 20% 17p-deleted cells. Patients, enrolled at 113 centers in the United Kingdom, were randomly assigned (1:1) to receive either 6 cycles of FCR (fludarabine 24 mg/m2/day for 5 days, cyclophosphamide 150 mg/m2/day for 5 days, and rituximab 375 mg/m2 on day 1/2 of cycle 1; 500 mg/m2 on day 1 of cycles 2-6) every 28 days or IR (ibrutinib 420 mg/day and rituximab 6 doses, as for FCR) for up to 6 years.

The primary endpoint was investigator-assessed progression-free survival (PFS). Key secondary endpoints included overall survival [OS], safety, and toxicity. Dr  Hillmen presented results from a planned interim analysis (data cutoff date, May 24, 2021).

Between 2014 and 2018, a total of 771 patients (FCR, 385 patients; IR, 386 patients) were randomly assigned in the study and analyzed in the intention-to-treat population. Overall, most patients (73.3%) were male, and the median age was 62 years, with 33.6% of patients older than 65 years. IGHV mutation status was available for 94.3% patients (50.3% IGHV unmutated and 38.1% mutated IGHV, and 5.9% Subset 2). The arms were well-balanced for disease characteristics.

At a median follow-up duration of 52.7 months, IR demonstrated superior PFS compared with FCR (median PFS, not reached vs 67 months; hazard ratio [HR], 0.44; 95% CI, 0.32-0.60; P <.001). In subgroup analyses, PFS was significantly better with IR compared with FCR in patients with IGHV unmutated CLL (not estimable vs 62 months; HR, 0.40; 95% CI, 0.27-0.59; P <.001) but not in patients with IGHV mutated CLL (HR, 0.68; 95% CI, 0.38-1.22; P =.197).

No difference in OS was observed between the 2 arms (HR, 1.01; 95% CI, 0.61-1.68; P =.956). A total of 29 deaths occurred in the FCR arm, including 4 CLL, 3 Richter’s transformation [RT], 3 secondary malignancies, 3 COVID-19, and 2 cardiac/sudden deaths, and 30 deaths occurred in the IR arm, including 3 CLL, 1 RT, 3 COVID-19, and 9 cardiac/sudden deaths (7 had a history of hypertension or cardiac disease).

After CLL progression, 90% of patients on FCR and 35% of those on IR received second-line targeted therapies.

Serious adverse events (SAEs) were reported in 53.7% and 53.4% of patients in the FCR and IR arms, respectively. Dr Hillmen highlighted notable differences for SAEs by organ class between FCR and IR, including infections (33.6% vs 27.1%), blood and lymphatic system disorders (19.8% vs 10.7%), and cardiac disorders (1.1% vs 8.3%).

“In conclusion, ibrutinib plus rituximab has a superior survival with a hazard ratio of 0.4, compared with FCR, and there was no difference in overall survival, [most likely due to] the crossover to targeted therapy after FCR in this trial,” concluded Dr Hillmen.

Disclosure: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures. 

Reference

Hillmen P, Pitchford A, Bloor A, et al. Ibrutinib plus rituximab is superior to FCR in previously untreated CLL: results of the phase III NCRI FLAIR trial. Presented at ASH 2021; December 11 to 14, 2021. Abstract 642.

This article originally appeared on Hematology Advisor