SUMMARY: The American Cancer Society estimates that approximately 18,960 new cases of Chronic Lymphocytic Leukemia (CLL) will be diagnosed in 2016 and approximately 4660 patients will die from the disease. CLL is a disease of the elderly and the average age at the time of diagnosis is 72 years. There are two main types of lymphocytes, B and T lymphocytes/cells. B-cell CLL is the most common type of leukemia in adults. Normal B-cell activation and proliferation is dependent on B-cell receptor (BCR) signaling. This signaling is also important for initiation and progression of B-cell lymphoproliferative disorders. Bruton's Tyrosine Kinase (BTK) is a member of the Tec family of kinases, downstream of the B-cell receptor and is predominantly expressed in B-cells. It is a mediator of B-cell receptor signaling in normal and transformed B-cells. Following binding of antigen to the B-Cell Receptor, kinases such as Syk (Spleen Tyrosine Kinase), Lyn (member of the Src family of protein tyrosine kinases) and BTK (Bruton's Tyrosine Kinase) are activated, with subsequent propagation through PI3K/Akt, MAPK, and NF-κB pathways. This results in B-cell activation and proliferation. IMBRUVICA® (Ibrutinib) is an oral, irreversible inhibitor of BTK and inhibits cell proliferation and promotes programmed cell death (Apoptosis) by blocking B-cell activation and signaling. The FDA initially granted accelerated approval to IMBRUVICA® in February 2014 for previously treated patients with CLL and this was followed by full FDA approval and a new treatment indication for high-risk CLL patients with 17p deletions, in July 2014. Previously published studies had shown significant Response Rates and and Event-Free Survival with BR (Bendamustine-TREANDA® and Rituximab-RITUXAN®) in FLUDARA® (Fludarabine) refractory patients, with Chronic Lymphocytic Leukemia.
The HELIOS study is a double-blind, randomized, phase III trial which evaluated the benefit of combining IMBRUVICA® with BR compared to placebo plus BR, in patients with previously treated, relapsed/refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma. In this study, of the 578 randomized patients, 289 patients received a maximum of six cycles of BR with IMBRUVICA® 420 mg PO daily and 289 patients received BR with placebo. The median patient age was 64 years, patients had received a median of two prior therapies and 38% of the patients had Rai Stage III/IV disease. Patients with 17p deletions in more than >20% of cells, were excluded. The planned six cycles of BR were completed by 83% in the IMBRUVICA® group and 78% in the placebo group. The primary endpoint was Progression Free Survival (PFS). Secondary endpoints included Overall Survival (OS) and Overall Response Rate (ORR).
Following an interim analysis, this study was unblinded as there was a significant PFS benefit with IMBRUVICA® and patients receiving placebo, were allowed to cross over to the IMBRUVICA® group, per study protocol,. Thirty one percent (31%) of the patients in the BR plus placebo group with confirmed progressive disease crossed over to receive BR plus IMBRUVICA®. At a median follow up of 17.2 months, the PFS in the IMBRUVICA® plus BR group was not yet reached whereas the PFS was 13.3 months for patients receiving placebo plus BR (HR=0.203; P<0.0001). This PFS benefit was seen across subgroups of high-risk patients as well. The ORR was 82.7% in the IMBRUVICA® plus BR group compared to 67.8% in the placebo plus BR group (P <0.0001). Complete Response (CR) rates which included CR with incomplete blood count recovery were 10.4% versus 2.8% with IMBRUVICA® and placebo, respectively. The median OS was not reached. The incidence of most adverse events were comparable between the two treatment groups and the most frequent side effects were neutropenia affecting about 55% of the patients and nausea experienced by about 35% of the patients.
The authors concluded that IMBRUVICA® plus BR resulted in an 80% reduction in the risk of disease progression, as well as improved Overall Response Rates, compared to placebo plus BR. This triplet combination of IMBRUVICA®, TREANDA® and RITUXAN® should therefore be considered an important treatment option for patients with previously treated Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma. Ibrutinib combined with bendamustine and rituximab compared with placebo, bendamustine, and rituximab for previously treated chronic lymphocytic leukaemia or small lymphocytic lymphoma (HELIOS): a randomised, double-blind, phase 3 study. Chanan-Khan A, Cramer P, Demirkan F, et al. The Lancet Oncology 2016;17:200-211