Ibrutinib/Rituximab vs Standard Chemoimmunotherapy in Previously Untreated CLL
In an interim analysis of the phase III E1912 trial reported in The New England Journal of Medicine, Shanafelt et al found that ibrutinib/rituximab improved progression-free and overall survival vs standard chemoimmunotherapy in patients 70 years old or younger with previously untreated chronic lymphocytic leukemia (CLL) without chromosome 17p13 deletion.
Study Details
In the multicenter trial, 529 patients were randomly assigned 2:1 between March 2014 and June 2016 to receive ibrutinib and rituximab for six cycles (after a single cycle of ibrutinib alone) followed by ibrutinib until disease progression (n = 354) or standard chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab (n = 175). The primary endpoint was progression-free survival in the intent-to-treat population.
Patients in the ibrutinib/rituximab group received ibrutinib 420 mg per day until disease progression or unacceptable toxicity, and rituximab 50 mg/m2 on day 1 of cycle 2, 325 mg/m2 on day 2 of cycle 2, and 500 mg/m2 on day 1 of cycles 3 through 7 in 28-day cycles.
Standard chemoimmunotherapy consisted of six cycles of fludarabine 25 mg/m2 and cyclophosphamide 250 mg/m2 on days 1 through 3, with rituximab 50 mg/m2 on day 1 of cycle 1, 325 mg/m2 on day 2 of cycle 1, and 500 mg/m2 on day 1 of cycles 2 through 6 in 28-day cycles.
Progression-Free and Overall Survival
First interim analysis was performed in September 2018. Median follow-up was 33.6 months. Progression-free survival at 3 years was 89.4% in the ibrutinib/rituximab group vs 72.9% in the chemoimmunotherapy group (hazard ratio [HR] = 0.35, P < .001), with the results meeting protocol-defined efficacy threshold for the interim analysis. Overall survival at 3 years was 98.8% vs 91.5% (HR = 0.17, P < .001).
Subgroup analyses of progression-free survival showed superiority of ibrutinib/rituximab independent of age, sex, and Rai stage, and among patients with chromosome11q22.3 deletion. Progression-free survival was significantly better with ibrutinib/rituximab among 281 patients without immunoglobulin heavy-chain variable region (IGHV) mutation (3-year rate = 90.7% vs 62.5%, HR = 0.26, 95% confidence interval [CI] = 0.14–0.50) but not among 114 patients with an IGHV mutation (87.7% vs 88.0%, HR = 0.44, 95% CI = 0.14–1.36).
Assessment of minimal residual disease (MRD) in peripheral blood at 12-month response assessment in 276 (78.0%) of the ibrutinib/rituximab group and 103 (58.9%) of the standard chemoimmunotherapy group showed a lower MRD-negativity rate at cycle 12 in the ibrutinib/rituximab group (8.3% vs 59.2%).
Adverse Events
Grade ≥ 3 adverse events occurred in 80.1% of the ibrutinib/rituximab group vs 79.7% of the chemoimmunotherapy group, with the most common in the ibrutinib/rituximab group including neutropenia (26% vs 45% in control group), increased lymphocytes (22% vs 8%), hypertension (19% vs 8%), and leukocytosis (18% vs 8%). Infectious complications of grade ≥ 3 occurred in 10.5% vs 20.3% of patients. Other grade ≥ 3 adverse events included hemorrhagic events in 1.1% vs 0% of patients and cardiac toxicity in 6.5% vs 1.8%. Atrial fibrillation of any grade was observed in 7.4% vs 3.2%.
The investigators concluded, “The ibrutinib/rituximab regimen resulted in progression-free survival and overall survival that were superior to those with a standard chemoimmunotherapy regimen among patients 70 years of age or younger with previously untreated CLL.”
Disclosure: The study was funded by the National Cancer Institute and Pharmacyclics. For full disclosures of the study authors, visit nejm.org.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
