Two novel agents have shown promising activity in chronic lymphocytic leukemia (CLL), including poor-risk patients: the Bcl-2 inhibitor ABT-199 and the small-molecule PI3K inhibitor IPI-145. Both drugs achieved excellent response rates in heavily pretreated relapsed/refractory patients including those with poor-risk cytogenetics.
If preliminary results are validated in phase III studies, ABT-199 and IPI-145 will be poised to join an explosion of new therapies—obinutuzumab (Gazyva), ibrutinib (Imbruvica), and idelalisib among them—that promise to improve outcomes for all CLL patients.
ABT-199
ABT-199 is targeted to the B-cell lymphoma (Bcl)-2 protein associated with tumor cell proliferation and survival. The goal of therapy with the agent is to inhibit Bcl-2 and induce apoptosis in tumors.
The phase I trial of ABT-199 included 57 evaluable patients with relapsed or treatment-resistant CLL or small lymphocytic leukemia.1 Patients were allocated to dose cohorts ranging from 150 to 1,200 mg. Patients in the first cohort began at 200 mg, with all three showing laboratory features of tumor lysis syndrome, prompting a modification to begin at 50 mg in subsequent cohorts with a stepwise dose escalation. With this graduated dosing scheme, tumor lysis syndrome occurred in three of 43 patients, leading to a reduction in initial dose to 20 mg for the first week and a slower increase in dose escalation up to 400 mg over the first few weeks of treatment in the safety expansion cohort.
In addition, prophylaxis and monitoring have been instituted. This strategy appears to prevent or reduce the likelihood of tumor lysis syndrome, said lead author John Seymour, MBBS, PhD, Peter McCallum Cancer Center, Melbourne, Australia, at the 2013 Annual Meeting of the American Society of Hematology (ASH).
Patients had received a median of four prior therapies (range, 1–11). Nineteen (37%) had 17p deletion, and 75% had unmutated immunoglobulin heavy chain variable region (IgHV).
Of 57 patients, 50 (88%) had at least a partial nodal response, and median time to 50% reduction in nodal masses was 6 weeks. The investigators observed at least a 50% reduction in the bone marrow infiltrate at 24 weeks in 89% of patients, and median time to 50% reduction in peripheral blood lymphocyte count was 15 days.
Overall response rate was 84% (47 of 56 patients), with complete response in 13 (23%) and partial response in 34 (61%). Among patients with 17p deletion, the overall response rate was 82% (14 of 17 patients), with complete response in 12% (2 patients) and partial response in 71% (12 patients).
Ongoing Studies
“We are very encouraged by these early results and, in particular, by the high rate of complete response among patients with treatment-resistant or relapsed CLL. Our ongoing studies will seek to improve the efficacy while carefully monitoring toxicities to deliver the maximum benefit to high-risk patients where conventional chemotherapy has proven inadequate,” Dr. Seymour stated.
ABT-199 monotherapy and combination trials in CLL have begun enrolling patients. These include a phase II monotherapy study in patients with del(17p) and relapsed CLL, as well as combination studies of ABT-199 plus rituximab (Rituxan) or obinutuzumab in the relapsed setting.
IPI-145
IPI-145, a potent, oral small-molecule inhibitor of PI3K-gamma and -delta, is being studied in a range of hematologic malignancies.
A phase I dose-escalation study of 193 patients included a total of 67 CLL patients, 52 with treatment-resistant or relapsed CLL and 15 with untreated CLL.2 Median age was 67. Twice-daily treatment with IPI-145 at doses of 8 to 75 mg in 28-day cycles showed clinical activity in relapsed or treatment-resistant CLL at all doses studied. Importantly, the drug was active in patients with poor-risk cytogenetics (17p deletion or TP53 mutation).
Nodal response was defined as a 50% or greater reduction in lymphadenopathy. Among 43 evaluable relapsed/refractory patients, 42 (98%) had a nodal response on computed tomography assessment, and 24 of 27 patients (89%) dosed at ≤ 25 mg twice daily had a nodal response. Nodal responses were seen in three of six evaluable treatment-naive patients, including two with a TP53 mutation.
Overall response rate in 47 evaluable patients with relapsed refractory CLL was 47%, with one complete response defined by International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria. Overall response rate was 50% in 12 patients with relapsed/refractory disease and poor-risk cytogenetics treated at < 25 mg twice daily and 29% in 7 patients with poor-risk cytogenetics treated at 75 mg twice daily.
The drug was generally well tolerated without the degree of myelosuppression seen with traditional chemotherapy. The investigators selected the 25-mg twice-daily dose for phase III study.
Development Supported
“These data support phase III development as monotherapy in CLL. Our study suggests that IPI-145 may lend itself well to long-term therapy of patients with CLL. While it has a tolerability profile similar to other drugs in its class, it may actually be more potent, which could contribute to its value for patients with relapsed or refractory disease in particular,” said lead author Ian W. Flinn, MD, PhD, Director of the Hematologic Malignancies Research Program at the Sarah Cannon Research Institute, Nashville.
“Emerging data also support development of this compound in other hematologic malignancies, including indolent non-Hodgkin lymphoma and T-cell malignancies,” Dr. Flinn added.
Another PI3K-delta inhibitor, idelalisib, showed promise in a phase III study of previously treated CLL patients reported at the ASH meeting.3 ■
Disclosure: Dr. Seymour is a consultant and advisor for Genentech, Roche, and AbbVie. Dr. Flinn is a consultant for and has received research funding from Infinity Pharmaceuticals.
References
1. Seymour JF, Davids MS, Pagel JM, et al: Bcl-2 inhibitor ABT-199 monotherapy shows anti-tumor activity including complete remissions in high-risk relapsed/refractory chronic lymphocyctic leukemia and small lymphocytic leukemia. ASH Annual Meeting. Abstract 872. Presented December 10, 2013.
2. Flinn I, Patel M, Kahl BS, et al: Preliminary safety and efficacy of IPI-145, a potent inhibitor of phosphoinositide-3-kinase-delta, gamma, in patients with chronic lymphocytic leukemia. ASH Annual Meeting. Abstract 677. Presented December 9, 2013.
3. Furman RR, Sharman JP, Coutre SE, et al: A phase 3, randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of idelalisib and rituximab for previously treated patients with chronic lymphocytic leukemia. ASH Annual Meeting. Abstract LBA-6. Presented December 10, 2013.
