The combination of ibrutinib with bendamustin plus rituximab (BR) demonstrated a significant improvement in progression-free survival compared with BR alone in patients with pretreated chronic lymphocytic leukemia or small lymphocytic lymphoma.
Simon Rule, MD
The combination of ibrutinib (Imbruvica) with bendamustine and rituximab (BR) demonstrated a significant improvement in progression-free survival (PFS) compared with BR alone in patients with pretreated chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), according to results from the phase III HELIOS study presented at the 2015 ASCO Annual Meeting.
At a median follow-up of 17.2 months, PFS with ibrutinib was not yet reached, as compared with 13.3 months for patients receiving BR alone (HR = 0.203; 95% CI, 0.150-0.276;P<.0001). The PFS benefit held up across subgroups of high-risk patients. The significant PFS benefit was determined during an interim analysis in March 2015, at which point the study was unblinded and patients receiving placebo were allowed to cross over to the ibrutinib arm. Findings from the study will be submitted to the FDA, according to the drug's developer, Pharmacyclics.
“The HELIOS data are particularly exciting, as they demonstrate that ibrutinib combination therapy improved PFS rates three-fold in previously treated patients with CLL or SLL, versus chemo-immunotherapy alone,” study investigator Simon Rule, MD, Consultant Hematologist, Department of Hematology, and Head of the Lymphoma Service, Derriford Hospital, Plymouth, UK, said in a statement. “As clinicians, we have continued to search for safe and effective options for people who have relapsed or become refractory to treatment. These results suggest the combination of ibrutinib, bendamustine and rituximab may be a favorable option for many patients who have received previous therapy.”
The double-blind phase III HELIOS trial randomized 578 previously treated patients with measurable relapsed/refractory CLL/SLL to BR for a maximum of six cycles plus either placebo (n = 289) or 420 mg/day of ibrutinib (n = 289). The full six cycles of BR were completed by 83% and 78% of patients in the ibrutinib and placebo arms, respectively.
The median patient age was 64 years and patients had received an average of two prior therapies. Patients with 17p deletions (>20% of cells) were not included in the study.
The study was powered to detect a hazard ratio of 0.70 with a P value of .025 for significance. PFS was the primary outcome measure, with secondary endpoints focused on overall survival (OS) and objective response rate (ORR).
The interim analysis was conducted following 50% of events. At the time of the review, 31% (n = 90) of patients had progressed on placebo and crossed over to the ibrutinib arm, as allowed by the study design.
ORR was 82.7% in the ibrutinib arm versus 67.8% in the control group (P<.0001). Complete response (CR) rates (including CR with incomplete blood count recovery) were 10.4% versus 2.8% with ibrutinib versus placebo, respectively.
The OS analysis showed a nonsignificant 37% reduction in the risk of death (P = .0598). The crossover to the ibrutinib arm that was allowed when the trial was unblinded confounded the OS data, the researchers noted.
The toxicity profile was similar between the two study arms, and the adverse events (AEs) in the triplet arm were consistent with previously reported safety outcomes for ibrutinib and BR.
The most frequently reported all-grade AEs in the ibrutinib versus the placebo arm were neutropenia (58.2% vs 54.7%), nausea (36.9% vs 35.2%), diarrhea (35.5% vs 23.7%), thrombocytopenia (30.7% vs. 24.4%), pyrexia (24.7% vs. 22%), anemia (22.6% vs 28.9%), and fatigue (21.6% vs 22.6%). Neutropenia (53.7% vs 50.5%) and thrombocytopenia (15.0% in each arm) were the most commonly reported grade 3/4 AEs.
Rates of grade 1/2 bleeding were higher in the triplet versus the BR-alone arm, including hematoma (8% vs 1%), contusion (7.7% vs 3.1%), epistaxis (5.9% vs 3.1%), ecchymosis (3.1% vs 0.7%), and petechiae (2.8% vs 0.3%). Grade ≥3 hemorrhage occurred in 3.8% of patients receiving the triplet, compared with 1.7% for those receiving BR alone. Grade 3/4 major hemorrhage and atrial fibrillation rates were 2.1% versus 1.7% and 2.8% versus 0.7% in the ibrutinib versus placebo arms, respectively. AEs led to treatment discontinuation in 14.2% and 11.8% of patients in the triplet and control arms, respectively.
“This becomes one of the most important changing points in the history of CLL, where the treatment of CLL patients will no longer be BR, but BR with ibrutinib,” lead study author Asher Chanan-Khan, MD, a professor of Medicine at Mayo Clinic, said when presenting the HELIOS data during a press briefing at the 2015 ASCO Annual Meeting. “The side effect profile was very tolerable and expected for each of the individual drugs that was in this regimen.”
Ibrutinib is an irreversible small-molecule inhibitor of BTK and works by blocking B-cell activation and signaling, preventing the growth of malignant B cells that overexpress BTK.
The FDA initially approved Ibrutinib in November 2013 for patients with MCL following at least one prior therapy. In February 2014, the FDA approved ibrutinib for patients with previously treated CLL, which was then followed by a full FDA approval and a new indication for high-risk patients with 17p deletions in July 2014. Ibrutinib was also granted an indication for ibrutinib Waldenström’s macroglobulinemia in January 2015.
Chanan-Khan AAA, Cramer P, Demirkan F, et al. Ibrutinib combined with bendamustine and rituximab (BR) in previously treated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL): first results from a randomized, double-blind, placebo-controlled, phase III study.J Clin Oncol. 2015;33 (suppl; abstr LBA7005).