Ibrutinib Effective and Safe Treatment Option in CLL

Roxanne Nelson

December 09, 2012

ATLANTA, Georgia — A novel investigational therapeutic agent appears to be an effective and safe treatment option for patients with chronic lymphocytic leukemia (CLL). According to 2 new studies presented here at the American Society of Hematology (ASH) 54th Annual Meeting, the novel Bruton's tyrosine kinase (BTK) inhibitor ibrutinib (Pharmacyclics, Inc) is both highly active and well tolerated and can induce durable remissions in patients who are treatment-naive or relapsed/refractory.

As previously reported by Medscape Medical News, preliminary results with ibrutinib already generated excitement among researchers when they were reported earlier this year.

Dr. John Byrd

"Ibrutinib offers great potential to significantly change the treatment landscape in CLL," 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, Columbus, told journalists here.

BTK is expressed across non-T cell hematopoietic lineages with predominately the B-cell phenoptype and is essential for B-cell receptor signaling, chemokine mediated migration and adhesion, and TLR signaling, he explained.

The majority of B-cell tumors are dependent upon BTK for proliferation and survival, and ibrutinib is the first in class irreversible inhibitor of BTK to enter clinical development.

Although chemoimmunotherapy approaches such as fludarabine, cyclophosphamide, and rituximab have markedly improved outcomes, primarily of younger, fit patients, fludarabine-based therapy is less well tolerated in older adults. It also carries significant risk for cellular immune suppression and myelosuppression that has limited protracted use, noted Dr. Byrd during a press briefing.

In addition, almost all patients will eventually relapse after fludarabine-based chemoimmunotherapy, and thus far, there are not any really effective salvage regimens that can induce a durable remission.

Used as Monotherapy

In the first study, Dr. Byrd and colleagues evaluated the use of ibrutinib as monotherapy in patients with CLL or small lymphocytic lymphoma (SLL). The large, multicohort phase Ib/II trial included both treatment-naive and or relapsed/refractory patients (n = 116). The patients who were treatment naive were all aged 65 years or older; relapsed/refractory patients had undergone 2 or more prior therapies, including a purine analogue. Those who were high risk were defined as having relapsed within 2 years following combination treatment or genetic mutation del17p. The cohort was enrolled into 5 groups that assessed ibrutinib at fixed doses of 420 mg or 840 mg daily until disease progression.

The primary objective was to determine the safety of both dosing regimens; secondary objectives included evaluating efficacy, pharmacokinetics/pharmacodynamics, and safety over the long term.

The median follow-up for treatment-naive patients was 20.3 months, 22.1 month for relapsed/refractory patients, and 14.1 month for high-risk patients.

For treatment-naive patients, there was a 68% response rate; 10% had a complete response and 58% a partial response.

In previously untreated patients, 96% had progression-free survival at 22 months; overall survival was 96%. Dr. Byrd noted that no long-term safety issues were identified.

In the relapsed/refractory group, 71% experienced a response, with 2% a complete response. Among those in the relapsed/refractory group, progression-free survival was 76% at 22 months, and slightly shorter but more than 50% in the del17p subset of patients, said Dr. Byrd. Overall survival was 85% in this cohort, and as with the other group, no long-term safety issues were identified.

The majority of adverse events were grade 2 or less; the most common were diarrhea (54%), fatigue (29%), upper respiratory tract infection (29%), rash (28%), nausea (26%), and arthralgias (25%). Hematologic toxicities of grade 3 or higher were relatively uncommon.

"Most side effects were modest and went away after the first cycle," said Dr. Byrd. "The cytopenias were low — we saw less than 25% in refractory group and less than 10% in the treatment-naive group. With other drugs, we tend to see much higher rates," he added.

In Combination With Rituximab

In the second study, researchers from the University of Texas MD Anderson Cancer Center in Houston evaluated the combined use of ibrutinib and rituximab (Rituxan) in high-risk CLL/SLL (del17p/TP53 mutation or del11q deletion or fewer than 3 years' remission after first-line chemoimmunotherapy).

Dr. Jan Burger

"The combination of ibrutinib and rituximab has profound activity in high-risk CLL," said lead author Jan Burger, MD, PhD, adding that "some of the responses were so dramatic."

"The addition of rituximab accelerates response compared to single-agent ibrutinib," said Dr. Burger, an associate professor of medicine in the Department of Leukemia at MD Anderson. "Ibrutinib alone or in combination with rituximab should be rapidly developed for high-risk patients."

In this phase II study, Dr. Burger and colleagues evaluated combination therapy in 40 high-risk patients. The treatment regimen consisted of 420 mg of ibrutinib daily in combination with weekly rituximab for 4 weeks, followed by ibrutinib daily plus monthly rituximab for 6 months, and then followed by single-agent ibrutinib.

At a median follow-up of 4 months, 38 of 40 patients continued on therapy without disease progression. Of the 20 patients who were evaluable for an early response assessment at 3 months, 17 achieved a partial remission, for an overall response rate of 85%. An additional 3 patients achieved a partial response with persistent lymphocytosis.

As in the previous study, noted Dr. Burger during the press briefing, the treatment was well tolerated, with only 13 cases of grade 3 or grade 4 toxicities. Mild diarrhea was the most frequent, along with bone pain and fatigue. In addition, 21 patients reported on questionnaires that their overall health was improved, as was their quality of life after 3 cycles of treatment.

Fills an Unmet Need

Ibrutinib appears to be highly selective for transformed B cells, and "so the results are really quite gratifying," and also the drug appears to have low toxicity, commented ASH president Armand Keating, MD, professor of medicine and director of hematology at the University of Toronto, Canada, during a premeeting telephone press briefing.

Although the current treatments have improved outcomes, this is reasonably toxic therapy for older patients, and it is mainly older patients who develop CLL, and "so there is a pretty large cohort of patients for whom it is really a challenge to provide effective treatment," Dr. Keating said.

"We now have on our hands an easily administered drug, which may be an effective and safe treatment for these groups of patients who are not well served by the treatments available at the moment," said Claire E. Dearden, MD, moderator of the press conference, consultant hematologist and head of the CLL Unit at the Royal Marsden National Health Service Foundation Trust in London, United Kingdom.

"There is a lot of excitement with the landscape changing, and having the possibility of chemotherapy free treatments," she added.

Several of the authors in both studies have relationships with industry.

American Society of Hematology (ASH) 54th Annual Meeting. Abstracts 187, 189. Presented December 9, 2012.

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