March-April 2018, Volume 15, Issue 2
Beyond Ibrutinib for Mantle Cell Lymphoma
Published on: February 21, 2018
Wang M, Rule S, Zinzani PL, et al. Acalabrutinib in relapsed or refractory mantle cell lymphoma (ACE-LY-004): a single-arm, multicentre, phase 2 trial. Lancet. 2017; 10.1016/S0140-6736(17)33108-2. [Epub ahead of print].
Despite advances in the treatment of mantle cell lymphoma (MCL) in the past few decades, and the development of new agents with activity in this disease, it remains an incurable malignancy with a relatively short survival compared with other treatable but incurable B cell non-Hodgkin lymphomas (B-NHLs). With cure remaining elusive, the discovery of well-tolerated and effective therapies is an important goal in the management of patients.
The Bruton’s tyrosine kinase (BTK) ibrutinib was approved by the U.S. Food and Drug Administration (FDA) for the treatment of relapsed MCL in 2013, based on a response rate of 68 percent and a duration of response of 17.5 months in a phase II study.1 Only about one-fifth of patients, however, had a complete response, bleeding complications and atrial fibrillation were present in 5 to 10 percent of patients, and infection occurred in up to one-third of patients, including invasive central nervous system aspergillus infections. These toxicities are thought to be due to the fact that ibrutinib is a relatively promiscuous tyrosine kinase inhibitor and also inhibits both Tec and IL-2–inducible T cell kinase.
Acalabrutinib, however, is a more specific BTK inhibitor and therefore may have a more favorable adverse effect and toxicity profile. Additionally, it is dosed twice daily, which investigators postulate may result in improved BTK inactivation given that, like ibrutinib, it is a covalent inhibitor, and BTK synthesis in the malignant lymphocyte may be faster than the 24-hour dosing interval of ibrutinib. Given this, it was investigated in a phase II study of relapsed/refractory MCL by Dr. Michael Wang and colleagues. One hundred twenty-four patients who had relapsed or were refractory to one to five prior lines of therapy, but who had not received a prior BTK inhibitor, were treated. The response rate was 82 percent, with 40 percent of patients having achieved a complete response. At a median follow-up of 15.2 months, the median duration of response had not been reached. At 12 months, 72 percent of patients remained in response, and 87 percent of patients were alive. The drug was very well tolerated, with no cases of atrial fibrillation and only one case of grade 3 bleeding. Only 6 percent of patients discontinued therapy due to adverse events, the most common of which included neutropenia (10%), anemia (9%), and pneumonia (5%). Based on these results, acalabrutinib was FDA approved for the treatment of relapsed/refractory MCL in October 2017.
There remain unanswered questions with respect to this new drug for MCL. Longer follow-up is needed to determine the durability of response, and more patients will need to be treated to get an accurate assessment of the risks for bleeding and atrial fibrillation with this more specific, but still not completely specific, tyrosine kinase inhibitor. The activity of acalabrutinib in certain high-risk subsets, including the blastoid and pleomorphic variants of MCL, is also unknown at present. Finally, although these results do seem to compare favorably to those seen with ibrutinib, the median number of prior therapies on this trial was two, compared with three on the pivotal phase II study of ibrutinib, and so these patients were treated relatively early in their disease course. It has been shown recently that the efficacy of ibrutinib is greatest when used in the second-line setting, so this difference may account for some of the improvement in efficacy seen on this study. Unanswered questions aside, acalabrutinib is an important new tool with a beneficial adverse effect profile for use in this largely incurable disease.
Wang ML, Rule S, Martin P, et al. Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. N Engl J Med. 2013;369:507-516.
Conflict of Interests
Dr. Jacobson indicated no relevant conflicts of interest.
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