Ibrutinib Performance in CLL Patients Hailed

The novel targeted agent ibrutinib has demonstrated dramatic activity in hard-to-treat patients with CLL when used alone and in combination with rituximab.

John C. Byrd, MD

The novel targeted agent ibrutinib has demonstrated dramatic activity in hard-to-treat patients with chronic lymphocytic leukemia (CLL) when used alone and in combination with rituximab (Rituxan), raising the prospect of a promising new therapy for elderly and frail patients who currently have few viable options.

The findings of two studies into the drug were discussed at a press briefing Saturday during the 54th Annual Meeting of the American Society of Hematology at the Georgia World Congress Center in Atlanta.

Ibrutinib, a Bruton’s tyrosine kinase (BTK) inhibitor, is the most advanced in a new class of anticancer agents, and researchers were clearly excited about its potential.

The drug is an oral, well-tolerated medication that produces “excellent responses,” without the need for the more intensive chemotherapy regimens that serve as first-line treatments for younger and fitter patients, said Claire E. Dearden, MD, consultant hematologist and head of the CLL Unit at The Royal Marsden NHS Foundation Trust in London, who served as moderator for the briefing.

“There’s a lot of excitement about the possibility of the landscape changing and leaning toward having chemotherapy-free treatments for patients with CLL that are as effective as giving them chemotherapy agents,” said Dearden. “It’s hugely exciting for us as clinicians but also for the patient community.”

The median age for diagnosis of CLL is 72 years, but such patients often are not able to tolerate the primary treatment regimen that includes the chemotherapy agents fludarabine and cyclophosphamide along with the humanized monoclonal antibody rituximab, researchers noted.

Ibrutinib is an irreversible inhibitor of BTK, an enzyme that plays an essential role in B-cell receptor signaling and several other pathways, said John C. Byrd, MD, lead author of one of the studies and director of the Division of Hematology at The Ohio State University Comprehensive Cancer Center—James Cancer Hospital and Solove Research Institute in Columbus.

So far, he said, there is no indication that inhibiting BTK activates other cancer-causing pathways.

Responses High in Elderly Patients

Ibrutinib, formerly known as PCI-32765, was evaluated in a phase IB/II study in patients with CLL or small lymphocytic leukemia. The primary goal of the study was to determine the safety of the low and high doses; while secondary objectives included response rates and progression-free survival (PFS).

Results were reported for 116 patients who were stratified into three cohorts: treatment-naïve ≥65 years (n = 31), relapsed/refractory (RR) (n = 61), and high-risk RR (n = 24). Participants in the first two groups received dosages of either 420 mg/d or 840 mg/d, while those in the third group received the dosage of 420 md/d. High risk was defined as progression of disease within 24 months of initiation of prior treatment or failure to respond to previous therapy.

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Dr. John Byrd Discusses Ibrutinib in CLL

The overall response rates, which included partial and complete responses, were 68% in the treatment-naïve group at 20.3 months’ follow-up and 71% in the combined results for the two RR groups at follow-up ranging from 14.7 months for the high-risk RR patients and 22.1 months for the RR group.

Among previously untreated patients, there was a 96% estimated rate of both PFS and overall survival (OS) at 22 months’ follow-up. For patients in the RR groups, there was a 76% PFS rate and an 85% OS rate at 22 months.

The majority of adverse events were grade ≤2, with diarrhea (54%), fatigue (29%), and upper respiratory tract infection (29%) the most frequently reported, according to the abstract. The incidence of hematologic toxicity ≥grade 3 was “relatively infrequent,” and there was no evidence of long-term safety concerns, the abstract indicates.

“There’s rarely something that comes along that you see helping patients so much,” said Byrd. “The quicker we get this across the finish line to patients, the better it’s going to be. This is a special therapy that all of us have seen really help patients.” The drug is being developed under the FDA’s Fast Track program for patients with CLL/SLL who have relapsed or refractory disease after at least one prior therapy, according to Pharmacyclics, Inc, which is developing ibrutinib in collaboration with Janssen Biotech, Inc.

Jan A. Burger, MD, PhD

Rituximab Combination Helps High-Risk Group

In a second study, researchers sought to accelerate response to ibrutinib by pairing the drug with rituximab in 40 patients with CLL/SLL considered high risk, including those harboring the del17p/TP53 mutation or del11q deletion, or those with <3 years remission after first-line chemo-immunotherapy. The median age was 65 (ages 35—82), and nearly 28% had early-stage disease while the remainder were stage III or IV.

Participants received continuous daily ibrutinib at 420 mg/d in combination with weekly rituximab (375 mg/m2) for the first four weeks and then monthly rituximab until cycle 6. Daily single-agent ibrutinib continued until progression. In all, 38 of 40 patients continued on therapy without disease progression. The overall response rate was 83%, with one patient exhibiting a complete response and the others achieving partial responses. In addition, three patients had a partial response with lymphocytosis, two participants did not exhibit any response, and results were too early to evaluate in two other patients.

The most common adverse event was diarrhea, followed by bone pain/myalgias, and fatigue.

Jan A. Burger, MD, PhD, lead author and associate professor of Medicine in the Department of Leukemia at The University of Texas MD Anderson Cancer Center in Houston, said larger-scale studies of the ibrutinib-rituximab combination are needed. He also said the rate of complete remissions might increase with more effective combination therapies.


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 (TN) and relapsed or refractory (RR) chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) patients including patients with high-risk (HR) disease: new and updated results of 116 patients in phase Ib/II study. Presented at: 54th ASH Annual Meeting; December 8-11, 2012; Atlanta, GA. Abstract 189.

Burger JA, Keating MJ, 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. Presented at: 54th ASH Annual Meeting; December 8-11, 2012; Atlanta, GA. Abstract 187.


View coverage from the 2012 ASH Meeting

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