Excellent Preliminary Results for Ibrutinib in Chronic Lymphocytic Leukemia

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Although still in preliminary testing with no phase III data, ibrutinib is poised to become an important new agent for patients with chronic lymphocytic leukemia (CLL). Two phase II trials reported at the 54th Annual Meeting of the American Society of Hematology (ASH) found that ibrutinib achieved excellent response rates and progression-free survival in previously untreated elderly patients, patients with relapsed/refractory disease, and high-risk relapsed/refractory patients.1,2 Moreover, the drug appears to be extremely safe thus far, with little or no myelosuppression as a single agent over about 3 years of experience in clinical trials.

Highly Effective, Well Tolerated Drug

CLL expert John Byrd, MD, lead author of the larger of the phase II studies reported at the ASH meeting, stated, “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.” Dr. Byrd is D. Warren Brown Chair of Leukemia Research and Director of the Division of Hematology at Ohio State University Comprehensive Cancer Center in Columbus.

Ibrutinib is an investigational inhibitor of Bruton’s tyrosine kinase, a key mediator of B-cell survival mechanisms. In preclinical studies, ibrutinib blocked these mechanisms, driving cells into apoptosis. The novel agent is being studied alone or in combination with other drugs for the treatment of several B-cell malignancies, including CLL and small lymphocytic leukemia (SLL), a similar disease with slightly different manifestations.

Multicenter Trial

The phase Ib/II, multicenter trial reported by Dr. Byrd enrolled three groups of 116 patients with CLL or SLL: elderly treatment-naive patients, relapsed/refractory patients, and high-risk relapsed/refractory patients.1 At the ASH Annual Meeting, he presented results for elderly treatment-naive patients (n = 31) and pooled results for relapsed/refractory and high-risk relapsed/refractory patients (n = 85).

At 26 months, single-agent ibrutinib produced an estimated progression-free survival rate of 96% in elderly treatment-naive patients and estimated progression-free survival rate of 75% in relapsed refractory high-risk CLL/SLL patients. Overall response rates were 68% in the treatment-naive patients at a median follow-up of 20.3 months and 71% in the relapsed/refractory and high-risk relapsed refractory group at a median follow-up of 15.7 months. At 26 months, estimated overall survival rates were 96% and 83%, respectively.

Treatment-naive elderly patients and relapsed/refractory patients received oral ibrutinib at 420 mg/d or 840 mg/d; the high-risk relapsed/refractory group received 420 mg/d. Patients with relapsed/refractory disease had been treated with at least two prior therapies; those in the high-risk group experienced a relapse within 2 years of chemoimmunotherapy.

Ibrutinib was very well tolerated. Most adverse events were grade 1 or 2. The most common treatment-related adverse events were diarrhea, fatigue, nausea, and rash. Myelosuppression was rare.

Single-center Trial

A second phase II, single-center study was based on 40 patients with high-risk CLL treated with the combination of ibrutinib plus rituximab (Rituxan), a standard agent in this setting.2 Overall response rate was 83% in these high-risk pretreated patients. Of 40 patients, 38 have no evidence of disease progression and are continuing therapy.

This group of patients is known to have worse outcomes than low- and intermediate-risk patient, explained lead author Jan Burger MD, Associate Professor at The University of Texas MD Anderson Cancer Center in Houston.

“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 Dr. Burger.

Patients were treated with ibrutinib at 420 mg/d combined with rituximab. High-risk criteria for entry included one of the following characteristics: deletion of 17p; TP53 mutation, deletion of 11q, or short (< 3 years) remission after first-line chemoimmunotherapy.

No disease progression was observed in 95% of the entire group and in 90% of those with 17p deletions ibrutinib achieved rapid reduction in the size of lymph nodes and spleen; 84% experienced > 50% decrease in lymph node size. As in the trial by Dr. Byrd and colleagues, treatment was well tolerated, with transient and infrequent grade 3/4 toxicities that included febrile neutropenia, anemia, mucositis, and pneumonia. ■

Disclosure: Dr. Byrd reported no potential conflicts of interest. Dr. Burger has received research funding from Pharmacyclics, Gilead, Genzyme, and Noxxon.


1. Byrd JC, Furman RR, Coutre S, et al: The Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib (PCI-32765) promotes high response rate, durable remissions, and is tolerable in treatment naïve and relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic leukemia (SLL) patients including patients with high-risk disease: New and updated results of 116 patients in a phase Ib/II study. 2012 ASH Annual Meeting. Abstract 189. Presented December 9, 2012.

2. Burger JA, Keating M, Wierda WG, et al: The Btk inhibitor ibrutinib (PCI-32765) in combination with rituximab is well tolerated and displays profound activity in high-risk chronic lymphocytic leukemia (CLL) patients. 2012 ASH Annual Meeting. Abstract 187. Presented December 9, 2012.

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