IBRUTINIB COMBINED WITH BENDAMUSTINE/RITUXIMAB IN PREVIOUSLY TREATED CHRONIC LYMPHOCYTIC LEUKEMIA/SMALL LYMPHOCYTIC LYMPHOMA (CLL/SLL): FIRST RESULTS FROM A RANDOMIZED, DOUBLE-BLIND, PHASE 3 STUDY

Background
Despite considerable therapeutic advances, virtually all patients with CLL/SLL will relapse and bendamustine/rituximab (BR) is often used in this case. Ibrutinib is a first-in-class, once-daily, oral covalent inhibitor of Bruton’s tyrosine kinase, an essential enzyme in the B-cell receptor signaling pathway and a key mechanism promoting disease progression in B-cell malignancies. Clinical trials of ibrutinib have demonstrated a favourable benefit/risk profile in several B-cell malignancies, including previously-treated CLL, leading to the approval of ibrutinib single agent therapy in multiple countries. 

Aims
The international, multicentre, double-blind, placebo-controlled phase 3 HELIOS study evaluated  the efficacy and safety of ibrutinib in combination with BR (ibrutinib+BR) compared with placebo plus BR (placebo+BR) in patients  with previously treated CLL/SLL. The preplanned interim analysis reported here showed that the primary end point was met, upon which the Independent Data Monitoring Committee recommended unblinding the study. 

Methods
Patients were randomized 1:1 to receive BR (≤6 cycles) with either  ibrutinib (420 mg daily) or placebo. Stratification factors included whether the patient was refractory to purine analogs and the number of prior therapies. Patients with del17p (>20% of cells) were excluded. The primary end point was independent review committee (IRC)-assessed progression-free survival (PFS). Secondary end points included IRC-assessed overall response rate (ORR) and overall survival (OS).

Results
In total, 578 patients were randomized (289 per arm); median age was 64 yrs; 38% had Rai Stage III/IV disease; median of 2 prior therapies. Six cycles of BR were completed in 81.9% and 77.4% of patients in the ibrutinib and placebo arms, respectively. At a median follow-up of 17.2 months, IRC-assessed PFS was significantly longer with ibrutinib+BR vs placebo+BR (median not reached vs 13.3 months; HR: 0.203, 95% CI: 0.150-0.276, P<0.0001); PFS results were consistent across all subgroups. IRC-assessed ORR was 82.7% vs 67.8% (P<0.0001) and the rate of complete response/complete response with incomplete marrow recovery (CR/CRi)   was 10.4% vs 2.8% with ibrutinib+BR vs placebo+BR, respectively. Investigators reported  ORRs of 86.2% vs 68.9%, P<0.0001, and rates of CR/CRi of 21.4% vs 5.9%, respectively. Median OS was not reached (HR 0.628: 95% CI 0.385, 1.024; P=0.06). Ninety patients (31%) in the placebo+BR arm with confirmed progressive disease crossed over to receive ibrutinib, as permitted per the protocol. The incidence of most adverse events (AEs) was similar between arms. The most common all-grade AEs with ibrutinib+BR and placebo+BR respectively were neutropenia (58.2% vs 54.7%) and nausea (36.9% vs 35.2%); the most common grade 3/4 AEs were neutropenia (53.7% vs 50.5%) and thrombocytopenia (15.0% each arm). Rates of grade 3/4 atrial fibrillation were 2.8% and 0.7%, and major hemorrhage were 2.1% and 1.7%.

Summary
The addition of ibrutinib to BR significantly reduced the risk of progression or death by 80% compared with placebo+BR. The ORR was also significantly improved with ibrutinib+BR vs placebo+BR. Safety of ibrutinib+BR was consistent with the known profiles for ibrutinib and for BR. The data further support ibrutinib as an important treatment option for patients with previously treated CLL/SLL.

Keyword(s): B cell chronic lymphocytic leukemia, Bendamustine, Non-Hodgkin's lymphoma, Phase III

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