Chronic lymphocytic leukemia (CLL) is the most prevalent hematologic cancer among adults in the United States, with more than 15,000 new diagnoses expected this year.1,2 Approximately 70% of patients are diagnosed after age 65, including 40% after age 75, making tolerability of therapy an important consideration.2 Although initial treatment with cytotoxic chemotherapy and/or immunomodulating therapies can provide durable responses for many patients, they are associated with significant toxicity and most patients eventually will relapse. The prognosis for patients with relapsed CLL varies depending on several factors, including the initial therapy, the duration of remission, and the presence of cytogenetic abnormalities (ie, poorer in the presence of 17p and 11q deletions, better in the presence of immunoglobulin heavy-chain variable-region [IGHV] mutation).2,3 Acquired resistance to initial therapy or inability to tolerate treatment-related toxicity further limit treatment options for those with relapsed CLL.
Phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) is an important mediator of B-cell–receptor signaling, a key factor in the development of CLL. The delta isoform of PI3K (PI3K-delta) is highly expressed in lymphoid tissue and has been identified as crucial to development of malignant CLL: its inhibition induces apoptosis in CLL cells. Idelalisib, an oral, small-molecule inhibitor of PI3K-delta has demonstrated acceptable toxicity and clinical efficacy in patients with relapsed or refractory CLL in phase 1 and 2 trials.2,4,5 Rituximab, although not approved by the US Food and Drug Administration as monotherapy, is generally well tolerated and is a recommended treatment option for relapsed CLL in patients over age 70 years who are resistant to or cannot tolerate other medications. However, response rates are variable and progression-free survival (PFS) with rituximab monotherapy is relatively short.2,4
A study led by Richard Furman, MD, from Weill Cornell Medical College in New York, NY, assessed the potential of combining idelalisib with rituximab for refractory CLL. In this phase 3 study, 220 patients with CLL who had progressed within 24 months of previous treatment and could not receive cytotoxic agents were randomly assigned to treatment with intravenous rituximab plus oral idelalisib or placebo. In results published in the New England Journal of Medicine, Dr. Furman and colleagues reported that it quickly became obvious that combined therapy was superior to rituximab alone, and the study was terminated at the first interim analysis due to “overwhelming efficacy” in the idelalisib arm. The primary endpoint, PFS at 24 weeks, was twice as long with idelalisib versus placebo (93% vs 46%) and overall survival at 1 year was 92% compared with 80% (Table 1). Significant PFS benefits also were seen in all subgroups, including patients without IGHV mutation, patients with 17p deletion, and those patients older than age 65 years.4
Table 1. Adjusted Hazard Ratio for Idelalisib Versus Placebo4
|Hazard Ratio (95% CI)||P Value|
|Progression-free survival at 24 weeks||0.15 (0.08-0.28)||<0.001|
|Death at 12 months||0.28 (0.09-0.86)||0.02|
Grade 3 or higher adverse events reported with idelalisib but not placebo were diarrhea (n=4) and rash (n=2). Anemia, neutropenia, and thrombocytopenia were common in both groups. Consistent with findings from a phase 1 trial, elevated hepatic aminotransferase occurred more frequently with idelalisib than with placebo, including six patients (5%) with grade 3 or higher, and resolved with treatment interruption. Most patients were able to continue treatment without further incident.3,4
The addition of idelalisib to rituximab was well tolerated and prolonged PFS and survival in a population of frail older patients who had relapsed after prior therapy, representing an advance in treatment of relapsed or refractory CLL. Additional research with idelalisib is underway and promises to offer another option for treatment of CLL.
- American Cancer Society. Cancer Facts & Figures 2014. Atlanta, GA: American Cancer Society; 2014. http://www.cancer.org/acs/groups/content/@research/documents/webcontent/acspc-042151.pdf. Accessed April 21, 2014.
- 2. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Non-Hodgkin’s Lymphomas. Version 2.2014. www.NCCN.org. Accessed April 17, 2014.
- Brown JR. The treatment of relapsed refractory chronic lymphocytic leukemia. Hematology Am Soc Hematol Educ Program. 2011;2011:110-118.
- Furman RR, Sharman JP, Coutre SE, et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med. 2014;370(11):997-1007.
- Brown JR, Byrd JC, Coutre SE, et al. Idelalisib, an inhibitor of phosphatidylinositol 3 kinase p110∂, for relapsed/refractory chronic lymphocytic leukemia. Blood. 2014 March 10. [Epub ahead of print].