Ibrutinib as Initial Therapy for Patients with Chronic Lymphocytic Leukemia

Abstract

Background: Chronic lymphocytic leukemia (CLL) primarily affects older persons who often have coexisting conditions in addition to disease-related immunosuppression and myelosuppression. We conducted an international, open-label, randomized phase 3 trial to compare two oral agents, ibrutinib and chlorambucil, in previously untreated older patients with CLL or small lymphocytic lymphoma.

Methods: We randomly assigned 269 previously untreated patients who were 65 years of age or older and had CLL or small lymphocytic lymphoma to receive ibrutinib or chlorambucil. The primary end point was progression-free survival as assessed by an independent review committee.

Results: The median age of the patients was 73 years. During a median follow-up period of 18.4 months, ibrutinib resulted in significantly longer progression-free survival than did chlorambucil (median, not reached vs. 18.9 months), with a risk of progression or death that was 84% lower with ibrutinib than that with chlorambucil (hazard ratio, 0.16; P<0.001). Ibrutinib significantly prolonged overall survival; the estimated survival rate at 24 months was 98% with ibrutinib versus 85% with chlorambucil, with a relative risk of death that was 84% lower in the ibrutinib group than in the chlorambucil group (hazard ratio, 0.16; P=0.001). The overall response rate was higher with ibrutinib than with chlorambucil (86% vs. 35%, P<0.001). The rates of sustained increases from baseline values in the hemoglobin and platelet levels were higher with ibrutinib. Adverse events of any grade that occurred in at least 20% of the patients receiving ibrutinib included diarrhea, fatigue, cough, and nausea; adverse events occurring in at least 20% of those receiving chlorambucil included nausea, fatigue, neutropenia, anemia, and vomiting. In the ibrutinib group, four patients had a grade 3 hemorrhage and one had a grade 4 hemorrhage. A total of 87% of the patients in the ibrutinib group are continuing to take ibrutinib.

Conclusions: 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. (Funded by Pharmacyclics and others; RESONATE-2 ClinicalTrials.gov number, NCT01722487.).

Figure 1. Progression-free Survival with Ibrutinib versus Chlorambucil

Shown is progression-free survival as assessed by the independent review committee (Panel A) and by the investigators (Panel B). The tick marks indicate patients with censored data. The median progression-free survival in the ibrutinib group was not reached (NR). Panel C shows subgroup analyses of progression-free survival as forest plots of hazard ratios for disease progression or death. The sizes of the circles are proportional to the sizes of the subgroups; error bars indicate 95% confidence intervals. The dashed vertical line represents the overall treatment effect for all patients. The upper limit of the normal range (ULN) for the lactate dehydrogenase level was 250 U per liter. Eastern Cooperative Oncology Group (ECOG) performance-status scores range from 0 to 5, with 0 indicating no symptoms and higher scores indicating increasing disability.

Figure 2. Overall Survival and Response Rates with Ibrutinib versus Chlorambucil

Shown are overall survival with ibrutinib versus chlorambucil (Panel A) and the best response to treatment as assessed by the independent review committee (Panel B). The tick marks indicate patients with censored data. Categories for response assessments included complete response (CR) or complete response with incomplete blood-count recovery (CRi), nodular partial response (nPR; according to the International Workshop on Chronic Lymphocytic Leukemia criteria for response, nPR was defined as a complete response with lymphoid nodules in the bone marrow), partial response (PR), partial response with lymphocytosis (PR-L), stable disease, and progressive disease. In the ibrutinib group, five patients (4%) had a complete response and one (1%) had a complete response with incomplete blood-count recovery. In the chlorambucil group, two patients (2%) had a complete response. Data were unknown, missing, or could not be evaluated for six patients in the ibrutinib group and for eight in the chlorambucil group. The rate ratios and P values are based on the Cochran–Mantel–Haenszel chi-square test, stratified according to ECOG performance-status score (0 or 1 vs. 2) and disease stage (Rai stage ≤II vs. III or IV). Percents may not sum as expected owing to rounding.

Figure 3. Hematologic Variables over Time in the Safety Population

Shown are the mean hemoglobin values (Panel A) and mean platelet counts (Panel B) over time in the safety population in each treatment group. The safety population included all patients who received at least one dose of the study drug. Each tick mark represents day 1 of the cycle (C). The baseline measurement was the last measurement on or before day 1 of the first cycle. I bars represent standard errors.