IBRUTINIB (IMBRUVICA) as a front-line agent proved superior to standard-of-care chemoimmunotherapy for chronic lymphocytic leukemia (CLL) in older patients in A041202, an Alliance-led National Clinical Trials Network study.¹

Jennifer A. Woyach, MD

At a follow-up of 38 months, the median progression-free survival was not reached with ibrutinib versus 43 months with bendamustine plus rituximab (Rituxan). The addition of rituximab to ibrutinib did not increase this benefit, reported Jennifer A. Woyach, MD, of The Ohio State University Comprehensive Cancer Center, Columbus, during the plenary session at the 2018 American Society of Hematology (ASH) Annual Meeting & Exposition.

“Ibrutinib alone and ibrutinib plus rituximab results in superior progression-free survival compared with [bendamustine plus rituximab] in the front-line setting for older patients with CLL,” Dr. Woyach said. “With these results, ibrutinib is justified as a standard of care for patients aged 65 and older.”

David Steensma, MD

ASH press briefing moderator, David Steensma, MD, Associate Professor of Medicine and Attending Physician at Dana-Farber Cancer Institute/Harvard Cancer Center, indicated that many physicians have already begun to use ibrutinib in the front-line setting, and the study confirms it is “a very reasonable option.”

Treatment of CLL

THE MOST effective initial therapy for older adults with CLL has not been established, since chemoimmunotherapy has never been compared with targeted therapy with the Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib. Chemoimmunotherapy became the gold standard after studies showed the addition of an anti-CD20 antibody to chemotherapy prolongs survival.

“Bendamustine plus rituximab has become the standard aggressive treatment for patients aged 65 or older. Although ibrutinib has been approved by the U.S. Food and Drug Administration for untreated CLL since 2016, it has been compared only to chlorambucil, which is relatively ineffective, and never before to aggressive chemoimmunotherapy,” Dr. Woyach said.

The prospective A041202 trial evaluated ibrutinib in older patients, who are typically underrepresented in clinical trials, although they constitute the bulk of the CLL population. The trial also explored the important clinical question of whether rituximab adds benefit to ibrutinib in the first-line setting.

“With these results, ibrutinib is justified as a standard of care for patients aged 65 and older [with CLL].”

— Jennifer A. Woyach, MD

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Study Design

ALLIANCE A041202 was a multicenter National Cancer Institute National Clinical Trials Network phase III trial comparing bendamustine plus rituximab (arm 1) with ibrutinib (arm 2) and with the combination of ibrutinib plus rituximab (arm 3) to determine whether ibrutinib-containing regimens improve progression-free survival over chemoimmunotherapy and whether the addition of rituximab to ibrutinib yields better outcomes than ibrutinib alone.

Dosing was bendamustine at 90 mg/m2 on days 1 and 2 of each 28-day cycle, plus rituximab at 375 mg/m2 on day 0 of cycle 1, then rituximab at 500 mg/m2 on day 1 for cycles 2 to 6; ibrutinib at 420 mg daily until disease progression, alone and with rituximab at 375 mg/m2 weekly for 4 weeks starting at cycle 2, day 1, then day 1 of cycles 3 to 6.

The study randomly assigned 547 patients aged ≥ 65 years (median age, 71 years) with previously untreated, symptomatic CLL to treatment. Patients had a creatinine clearance ≥ 40 mL/min, bilirubin ≤ 1.5 times the upper limit of normal, and no significant life-limiting intercurrent illness or need for warfarin treatment.

High-risk Rai stage (stage III/IV) was seen in 54% of patients; unmethylated Zap-70 (zeta chain–associated protein kinase 70), in 53%; and del(17p) or del(11q), in 28%. The primary analysis included 525 patients (96%). 

Better Outcomes With Ibrutinib

WITH A median follow-up of 38 months, the median progression-free survival was 43 months with bendamustine plus rituximab and was not reached for patients receiving ibrutinib alone or with rituximab (hazard ratio = 0.37; one-sided P < .0001). There were no differences in outcomes or reduction in risk for ibrutinib plus rituximab vs single-agent ibrutinib. The 2-year progression-free survival estimates were 74% for bendamustine plus rituximab, 87% for ibrutinib, and 88% for ibrutinib/rituximab, respectively, he reported.

Ibrutinib was superior to bendamustine plus rituximab in all subgroups except those with methylated Zap-70 (which equates to mutated IgVH), where there was a nonsignificant trend. Since the addition of rituximab was not beneficial, Dr. Woyach would consider using this combination only in those with autoimmune hemolytic anemia or immune thrombocytopenia purpura or very high white blood cell counts.

At this time, with short follow-up and crossover allowed, there are no significant differences in overall survival among the arms, and the median overall survival has not been reached in any cohort.

Adverse Events

GRADES 3 to 5 treatment-emergent adverse events were seen in 428 of 537 evaluable patients. Grade ≥ 3 hematologic toxicity, especially neutropenia and thrombocytopenia, was seen in 61% of the bendamustine plus rituximab cohort, 41% of the ibrutinib monotherapy cohort, and 38% of patients receiving ibrutinib/rituximab (P < .001). High-grade no-hematologic toxicities were observed in 63%, 74%, and 74%, respectively (P = .04). Up to 17% of patients receiving ibrutinib developed atrial fibrillation.

“BTK inhibition with ibrutinib is not without significant toxicity in older patients, so close monitoring is warranted, and strategies to discontinue therapy are of interest,” Dr. Woyach added. ■

DISCLOSURE: Dr. Woyach has consulted for Janssen and received research funding from MorphoSys, KaroPharma, Janssen, Acerta, and AbbVie. Dr. Steensma disclosed financial relationships with H3 Biosciences, Janssen, Novartis, Otsuka, and Takeda.

REFERENCE

1. Woyach JA, Ruppert AS, Heerema NA, et al: Ibrutinib alone or in combination with rituximab produces superior progression-free survival compared with bendamustine plus rituximab in untreated older patients with chronic lymphocytic leukemia: Results of Alliance North American Intergroup Study A041202. 2018 ASH Annual Meeting & Exposition. Abstract 6. Presented December 2, 2018.