As reported in The New England Journal of Medicine and at the 2015 American Society of Hematology Annual Meeting, Jan A. Burger, MD, PhD, and colleagues found that first-line treatment with the oral Bruton’s tyrosine kinase inhibitor ibrutinib (Imbruvica) improved progression-free and overall survival vs oral chlorambucil (Leukeran) in the phase III RESONATE-2 trial in older patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma.¹ Dr. Burger is Associate Professor, Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston. Earlier this month, the U.S. Food and Drug Administration approved ibrutinib for the first-line treatment of patients with chronic lymphocytic leukemia (CLL), based on data from the phase III RESONATE-2 trial.

Study Details

In this open-label trial conducted in the United States, Europe, and elsewhere, 269 patients aged ≥ 65 years with CLL (n = 249, 93% of total) or small lymphocytic lymphoma were randomized starting in March 2013 to receive oral ibrutinib at 420 mg once daily until disease progression or unacceptable toxicity (n = 136) or up to 12 cycles of chlorambucil at a starting dose of 0.5 mg/kg and up to 0.8 mg/kg on days 1 and 15 of 28-day cycles (n = 133). The primary endpoint was progression-free survival assessed by an independent review committee.

For the ibrutinib and chlorambucil groups, median age was 73 and 72 years, 65% and 61% were male, and the Eastern Cooperative Oncology Group (ECOG) performance status was 0 or 1 for 92% and 91%. In addition, 90% and 95% had CLL, 21% and 19% had chromosome 11q22.3 deletion, 43% and 45% had unmutated IGHV, and 44% and 47% had Rai stage III or IV disease.

Improved Outcomes

Median follow-up was 18.4 months. On independent review committee assessment, median progression-free survival was not reached in the ibrutinib group vs 18.9 months in the chlorambucil group (hazard ratio [HR] = 0.16, P < .001). On investigator assessment, median progression-free survival was not reached vs 15.0 months (HR = 0.09, P < .001). Progression-free survival at 18 months was 90% vs 52%, including rates of 89% vs 47% among patients with unmutated IGHV and 89% vs 51% among those with mutated IGHV.

Results were similar across higher-risk subgroups, including patients with Rai stage III or IV disease (HR = 0.15, 95% confidence interval [CI] = 0.07–0.34), ECOG performance status of 2 (HR = 0.19, 95% CI = 0.04–0.98), chromosome 11q22.3 deletion (HR = 0.03, 95% CI = 0.00–0.23), and unmutated IGHV (HR = 0.13, 95% CI = 0.06–0.31).

Median overall survival was not reached in either group. Estimated overall survival at 24 months was 98% with ibrutinib vs 85% with chlorambucil (HR = 0.16, P = .001). Overall response rate was 86% vs 35% (P < .001), with 4% of patients in the ibrutinib group having a partial response with lymphocytosis; complete response was observed in 4% vs 2%. Sustained increases in hemoglobin (84% vs 45%, P < .001) and platelet count (77% vs 43%, P = .005) were more common with ibrutinib. At the time of reporting, 87% of patients in the ibrutinib group continued to take ibrutinib.

Adverse Events

The most common adverse events of any grade in the ibrutinib vs chlorambucil group were diarrhea (42% vs 17%), fatigue (30% vs 38%), cough (22% vs 15%), and nausea (22% vs 39%), with hypertension occurring in 14%. The most common adverse events in the chlorambucil group were nausea, fatigue, neutropenia (23% vs 19%), and vomiting (20% vs 13%). The most common grade 3 or 4 adverse events in the ibrutinib vs chlorambucil group were neutropenia (10% vs 18%), anemia (6% vs 8%), hypertension (4% vs 0%), pneumonia (4% vs 2%), and diarrhea (4% vs 0%). The most common grade 3 or 4 adverse events in the chlorambucil group were neutropenia, anemia, thrombocytopenia (6% vs 2%), and fatigue (5% vs 1%). Four ibrutinib patients had grade 3 hemorrhage, and one patient had grade 4 hemorrhage. Adverse events led to discontinuation of treatment in 9% vs 23% of patients.

The investigators concluded: “Ibrutinib was superior to chlorambucil in previously untreated patients with CLL or small lymphocytic lymphoma, as assessed by progression-free survival, overall survival, response rate, and improvement in hematologic variables.” ■

Disclosure: The study was funded by Pharmacyclics and others. For full disclosures of the study authors, visit www.nejm.org.

Reference

1. Burger JA, Tedeschi A, Barr PM, et al: Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N Engl J Med 373:2425-2437, 2015.