Application for Ibrutinib Regimen in CLL Submitted to FDA

A supplemental new drug application has been submitted to the FDA for ibrutinib in conjunction with bendamustine and rituximab. The combination would treat patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma.

Simon Rule, MD

A supplemental new drug application has been submitted to the FDA for ibrutinib (Imbruvica) in conjunction with bendamustine and rituximab (BR). The combination would treat patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), according to AbbVie, which codevelops the BTK inhibitor along with Janssen Biotech.

The FDA application is rooted in findings from the phase III HELIOS study, where adding ibrutinib to standard BR reduced the risk of disease progression by 80%. This was compared with BR plus placebo in patients with pretreated CLL or SLL. The double-blind trial randomized 578 previously treated patients with measurable relapsed/refractory CLL/SLL to BR for a maximum of 6 cycles plus either placebo (n = 289) or 420 mg/day of ibrutinib (n = 289). The full 6 cycles of BR were completed by 83% and 78% of patients in the ibrutinib and placebo arms, respectively.

"The [HELIOS] data confirm the therapy's ability to enhance the effectiveness of a commonly used treatment option in these patients when it is added to the bendamustine and rituximab combination,” HELIOS investigator Simon Rule, MD, consultant haematologist, Department of Haematology, and head of the Lymphoma Service, Derriford Hospital, United Kingdom, said in a statement.

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.

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.

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 may have confounded the OS data.

The toxicity profile was similar between the 2 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.

The FDA initially approved ibrutinib in November 2013 for patients with mantle cell lymphoma following at least 1 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.

Additionally, a supplemental new drug application has been submitted for ibrutinib as a therapy for treatment-naive patients with CLL who are over the age of 65.

"We are dedicated to fully understanding the utility of Imbruvica and have several studies underway designed to evaluate the impact of the therapy as a single agent and in combination in a number of blood cancers. Ultimately, our goal for Imbruvica is to be a treatment option that extends the lives of patients across a variety of types of cancers," Erik von Borcke, president of Pharmacyclics, an AbbVie Company, said in a statement.


  1. 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).