Ibrutinib: a force with a dark side?

In this issue of Blood, Martin et al report poor outcomes for ibrutinib-refractory patients with mantle cell lymphoma (MCL). MCL, an uncommon B-cell lymphoma driven by dysregulated cyclin D1, responds well to initial therapy but is destined to relapse. Subsequent single-agent treatments had modest response rates and duration until the advent of ibrutinib. These data are important, given that ibrutinib is not curative, so clinicians will increasingly encounter patients with MCL who require therapy after ibrutinib.¹ 

Dr Ogden Bruton described X-linked recessive agammaglobulinemia in 1952, well before B cells were known. The mutated enzyme, identified in 1993 and termed “Bruton tyrosine kinase” (BTK), results in absent mature B cells. The covalent BTK inhibitor ibrutinib was synthesized in 2005, underwent first-in-human testing in 2009, and was approved by the US Food and Drug Administration for chronic lymphocytic leukemia (CLL) only 4 years later in 2013 under breakthrough designation and accelerated approval processes.

The multicenter retrospective analysis of Martin et al¹  identified 114 patients whose MCL progressed on ibrutinib and noted that the median survival from the last ibrutinib dose was only 3 months. For the 27% of patients who did not receive additional lymphoma therapy, presumably because of poor clinical status and/or rapid disease growth, median survival was <1 month. These poor outcomes may simply reflect a heavily pretreated population that was refractory to ibrutinib given, on average, as fourth-line therapy. Despite the number of prior regimens, however, many patients had not been exposed to the most commonly used agents because less than two-thirds had prior anthracycline, approximately one-half had prior bendamustine, one-third had prior cytarabine, and one-fifth had prior stem cell transplant. This raises the alternative (not mutually exclusive) possibility that ibrutinib selects more aggressive clones. Similarly poor outcomes occurred after ibrutinib treatment of CLL, with concerns about clonal selection leading to Richter’s transformation.² 

Ibrutinib is remarkably effective in MCL, as well as CLL and Waldenström macroglobulinemia. In MCL, highly concordant results were reported from the initial phase 1B/2 study on which its approval was based³  and the recently published phase 3 randomized trial of ibrutinib compared with temsirolimus,⁴  the two agents having been approved in Europe to treat relapsed MCL. In each trial, response rates for ibrutinib were ∼70% with median progression-free survival of about 14 to 15 months. This means, however, that 30% of patients do not respond and that half will progress in a little more than 1 year, so the Martin et al¹  results are sobering. One ray of hope is that in the phase 3 trial,⁴  patients who discontinued ibrutinib did not have such a bleak outcome. These patients were less heavily pretreated (median, 2 prior regimens), but the trial also included patients who were intolerant of ibrutinib as well as those with progressive disease. If patients who cannot tolerate ibrutinib do better than those whose MCL is resistant, that would indicate that ibrutinib resistance, not merely exposure, is a marker for aggressive subclones. High proliferative rate, assessed by gene signatures or by Ki-67 immunohistochemistry, is a powerful prognostic marker in MCL. The limited data in Martin et al¹  suggest that Ki-67 is higher after ibrutinib treatment, whereas data from Dreyling et al⁴  suggest that highly proliferative blastoid MCL is ibrutinib resistant, although these conclusions are based on inadequate data because repeat biopsies are not often available. Proliferation is not the only factor. Mechanisms of ibrutinib resistance identified to date include BTK mutations that block ibrutinib binding,⁵  activating mutations downstream of BTK including phospholipase Cγ2,^5,6  and upregulation of pathways that bypass BTK.⁶  Knowledge of resistance mechanisms as well as empiric preclinical data suggest rational agents to follow or combine with ibrutinib, including proteasome inhibitors (NCT02269085),⁷  CDK4/6 inhibitors (NCT02159755),⁸  and BCL-2-targeted agents (NCT02471391),⁹  as well as PI3K/AKT/mTOR inhibitors (NCT02268851).⁴  Mathematical modeling may also be able to simplify the preclinical development of combination therapies, given the array of agents, doses, and schedules that need to be tested.¹⁰  Also of interest will be whether ibrutinib overcomes the poor prognostic import of aberrant p53 in MCL as it does in CLL. Ibrutinib is a wonderful addition but not a panacea. Much work needs to be done to optimize its use.

Ibrutinib treatment currently continues until progression or toxicity, but monitoring sensitive molecular or flow cytometric assessments of minimal residual disease will permit investigation of whether earlier discontinuation can reduce toxicity and cost without compromising outcomes. Ibrutinib-based combinations are attractive but need to be administered in the context of clinical trials because unexpected toxicities can occur. Use in the first-line setting is also tempting, and a randomized trial of bendamustine-rituximab with or without continuous ibrutinib as initial MCL therapy has completed enrollment. However, the data from Martin et al¹  indicate the need for cautious interpretation of early data because progression-free survival, virtually certain to be prolonged by the addition of continuous ibrutinib, is not an adequate end point; we need to ensure that early benefit does not mask later deleterious effects. It will be critical going forward that sequential biopsies be obtained and interrogated for molecular genetic alterations so that prognostic factors and resistance pathways for specific targeted therapeutics can be delineated. This will inform sequential or concomitant use of the increasing number of treatment options, prolonging the lives of our patients and raising the possibility of cure.