Preliminary Evidence Suggests Ibrutinib Is a Home-Run for CLL

Ibrutinib, an investigational Bruton’s tyrosine kinase inhibitor, achieved excellent results in clinical trials of patients with chronic lymphocytic leukemia (CLL) presented at the 54th Annual Meeting of the American Society of Hematology.

“We are encouraged that these results with ibrutinib continue to support the possibility that we can address some of the critical unmet needs in CLL/SLL. ….Rarely does a drug come along that helps patients this much. This drug is highly effective and very well tolerated. We are looking forward to pharmacyclics bringing this drug forward. The quicker we get this drug across the finish line, the better,” stated John R. Byrd, MD, D. Warren Brown Chair of Leukemia Research, Director, Division of Hematology, Ohio State University Comprehensive Cancer Center, Columbus, OH.

Dr Byrd was lead author of a phase II trial that included 116 patients with CLL/small lymphocytic leukemia (SLL)—elderly naïve patients, relapsed/refractory patients, and high-risk relapsed/refractory patients. Treatment with single-agent ibrutinib achieved excellent progression-free survival (PFS) at 26 months for both elderly, treatment naïve patients (estimated PFS 96%) and relapsed refractory high-risk CLL/SLL patients (estimated PFS 75%).

A second phase II study in 40 patients with high-risk CLL who received ibrutinib combined with rituximab showed an overall response rate of 83%, and no disease progression in 38 or 40 patients who are continuing on therapy. These patients typically have inferior outcomes compared with low- and intermediate-risk patients.

“This study shows profound activity for this combination in high-risk patients with CLL. The overall response rate is favorable compared with standard treatment and the toxicity compares favorably to other treatment options,” stated Jan Burger, MD, lead author of this phase II trial, associate professor, University of Texas MD Anderson Cancer Center, Houston, TX.

The first phase II study enrolled 116 patients from May 10 through July 11, 2012. Treatment-naïve elderly patients and relapsed/refractory patients received oral ibrutinib 420 mg/day or 840 mg/day; the high-risk relapsed/refractory group received 420 mg/day. Patients with relapsed/refractory disease had been treated with at least 2 prior therapies; those patients in the high-risk group experienced a relapse within 2 years of chemo-immunotherapy.

Although the phase II study included 3 groups of patients, Dr Byrd gave separate results for 2 groups—elderly treatment-naïve patients (n = 31) and pooled results for relapsed/refractory and high-risk relapsed refractory patients (n = 85).

Overall response rates were 68% in the treatment-naïve patients at a median follow-up time of 20.3 months and 71% in the relapsed/refractory and high-risk relapsed refractory group at a median follow-up time of 15.7 months. At 26 months, estimated overall survival is 96% and 83%, respectively.

Most adverse events were grade 1 or 2. The most common treatment-related adverse events were diarrhea, fatigue, nausea, and rash. Myelosuppresion was rare.

The second phase II study included 40 patients who received ibrutinib 420 mg/day combined with rituximab “to accelerate response,” Dr Burger said. High risk was defined as having 1 of the following characteristics—deletion of 17, TP53 mutation, deletion of 11q, or less than 3 years of remission after first-line chemo-immunotherapy.

No disease progression was observed in 95% of the entire group and in 90% of those patients with 1p deletions. Ibrutinib achieved rapid reduction in the size of lymph nodes and spleen; 84% experienced more than 50% decrease in lymph node size. As in the previous trial, treatment was well tolerated, with transient and infrequent grade-3 and -4 toxicities that included febrile neutropenia, anemia, mucositis, and pneumonia.