Breakthrough Therapy Ibrutinib Effective in CLL and MCL Lymphomas

Two studies recently published in the New England Journal of Medicine provide additional evidence that the targeted therapy ibrutinib is an effective treatment for multiple types of non-Hodgkin lymphoma (NHL). Several members of the Lymphoma Research Foundation's (LRF) Scientific Advisory Board (SAB) and its Mantle Cell Lymphoma Consortium (MCLC) contributed to the studies, which evaluated the anti-cancer drug's safety and effectiveness in mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL).

Ibrutinib is the first drug designed to target a protein called Bruton's tyrosine kinase (BTK). BTK is critical to the growth and survival of B-cells, the type of immune system cells affected in 85 percent of NHL. By preventing BTK from functioning, ibrutinib kills the malignant B-cells but, unlike many current NHL therapies, leaves the healthy T-cells in the immune system largely unaffected. This enables a patient to remain healthier during treatment, increasing their chances for long-term survival. Ibrutinib's success in early trials has prompted the US Food and Drug Administration (FDA) to designate it a "breakthrough therapy," giving it an accelerated approval process. (A previous study of ibrutinib's effect on DLBCL was covered last summer.)

The MCL study, on which MCLC member Michael Wang, MD of the University of Texas MD Anderson Cancer Center, served as lead author, focused on patients who had relapsed or refractory MCL after previous treatment. With an average follow-up period of 15 months, 68 percent of the 111 patients in the study responded to treatment, with 21 percent of the total achieving a complete remission. The average progression-free survival period was 14 months, and most side effects were minor. The trial, which is still ongoing, suggests ibrutinib is not only highly effective, but safer for use than other current treatments for MCL. "These are unprecedented response rates for monotherapy in the relapsed setting," Dr. Wang said, "Based on these results it is apparent that ibrutinib therapy provides a well tolerated, effective, and convenient (orally administered) therapy for relapsed patients with MCL."

A number of SAB and MCLC members contributed to the study including Andre Goy, MD (John Theurer Cancer Center), Brad Kahl, MD (University of Wisconsin), Ranjana Advani, MD (Stanford University), Michael E. Williams, MD (University of Virginia), and Kristie Blum, MD (Ohio State University) who are members of both groups, along with MCLC members Simon Rule, MD (Derriford Hospital, UK) and Martin Dreyling, MD (University of Munich-Grosshadern). Preliminary data from this study was also presented by Dr. Wang at LRF's annual MCL Workshop in April. (More information on the workshop and the MCL Consortium can be found in the Summer 2013 Research Report.)

The CLL study followed 85 patients with relapsed CLL, with an average of three previous treatments for each patient. The overall response rate to treatment was 71 percent, and two patients achieved a complete response. Reponse to treatment also proved to be long-lasting; an estimated 75 percent of patients reached 26 months of progression-free survival. Even more encouraging, many of the patients in the study had forms of CLL that often indicate poor prognosis, but responded to treatment at rates comparable to the overall group. In contrast to the MCL study, the CLL study also tested two dosage levels of ibrutinib but found similar response levels – supporting the use of a lower dose and lowering the risk of side effects.

Contributors to the CLL study included SAB members Kristie Blum, MD (Ohio State University) and Morton Coleman, MD (Weill-Cornell) as well as former SAB member Susan O'Brien, MD (MD Anderson).

Taken together, these trials demonstrate ibrutinib's effectiveness as a single agent therapy in relapsed and refractory B-cell lymphomas. Dr. Kristie Blum, who contributed to both studies, said the effectiveness, ease of administration, and limited toxicity of ibrutinib has demonstrated will positively impact the standard of care for these lymphomas. "I anticipate ibrutinib is going to change the paradigm for treatment of MCL and CLL where traditionally intensive combination chemotherapy regimens and sometimes stem cell transplantation are utilized to a model where oral drugs with limited side effects allowing long term dosing are favored." It is another encouraging sign for a drug which has established an impressive early track record in treating a variety of B-cell lymphoma patients.

The full text of the studies is available on the New England Journal of Medicine website:

August 2013