Ibrutinib is a first-in-class, once-daily inhibitor of Bruton tyrosine kinase that is approved for various B-cell malignancies. However, the drug is associated with increased rates of low-grade hemorrhage and sometimes serious hemorrhage, which is listed as a warning in the  prescribing information. Patients with chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), and mantle cell lymphoma (MCL) are at an increased risk for major hemorrhage (MH) compared to the general population.

Researchers conducted a study in patients with CLL/SLL or MCL to characterize the risks of MH with ibrutinib and evaluate the potential association of MH with concomitant use of antiplatelet or anticoagulant agents. Jennifer R. Brown, MD, PhD, at the Dana-Farber Cancer Institute in Boston, MA, discussed the findings at the ASH Annual Meeting.

The researchers collected data from four randomized, controlled trials (RCTs), including:

  • RESONATE, which investigated ibrutinib versus ofatumumab in patients with relapsed/refractory CLL/SLL
  • RESONATE-2, which investigated ibrutinib versus chlorambucil in older patients with treatment-naïve CLL/SLL
  • HELIOS, which investigated bendamustine and rituximab with or without ibrutinib in patients with relapsed/refractory CLL/SLL
  • RAY, which investigated ibrutinib versus temsirolimus in patients with relapsed/refractory MCL

The cohort included 756 ibrutinib-treated patients and 749 comparator-treated patients (RCT ibrutinib and comparator pools, respectively). An additional analysis included 1,768 ibrutinib-treated patients with B-cell malignancies (CLL/SLL, MCL, diffuse large B-cell lymphoma, marginal zone lymphoma, follicular lymphoma, or Waldenström’s macroglobulinemia) from completed clinical studies of single-agent or combination regimens with ibrutinib (total ibrutinib pool).

Median treatment duration was longer with ibrutinib-treated patients compared to comparators (13.1 versus 7.8 months). Nearly twice the proportion of patients in the total ibrutinib pool had a history of bleeding disorders. Among the RCTs, the proportion of MH was higher with ibrutinib (4.4%) compared to the comparator (2.8%); however, given the longer exposure to ibrutinib, the exposure-adjusted incidence rate was similar between RCT ibrutinib and comparator pools (3.3 per 1,000 person-months).

The median time to onset of first events was 155 days (range = 2–596) in the RCT ibrutinib pool, 27 days (range = 1–455) in the RCT pool of comparators, and 128 days (range = 1–678) in the total ibrutinib pool.

In the total ibrutinib pool, the proportion of MH was 4.1% and exposure-adjusted incidence rate was 3.8 per 1,000 person-months. In the RCT pool, most patients with MH experienced one event, with longer median time to onset with ibrutinib versus comparators.

Grade 3 or 4 MH and serious adverse events (AEs) of MH occurred in 3.2% and 3.7% in the RCT ibrutinib pool, respectively, versus 2.3% and 1.7% in the RCT comparator pool. Fatal MH occurred in three patients in the RCT ibrutinib pool, including subdural hematoma (n = 1), postprocedural hemorrhage (n = 1), and aortic aneurysm (n = 1), whereas none occurred in the comparator arms.

According to univariate analysis, use of anticoagulants or antiplatelets was similarly associated with increased risk of MH in both the ibrutinib and comparator arms in the RCT pool. Anticoagulant or antiplatelet exposure-adjusted relative risk was 1.2 (95% CI = 0.6–2.5) in the RCT ibrutinib pool, 2.4 (95% CI = 1.0–5.6) in the RCT comparator pool, and 1.9 (95% CI = 1.2–3.0) in total ibrutinib pool.

Among the 311 ibrutinib-treated patients exposed to any anticoagulant (mean = 94 days, median = 16 days, range = 1–667) in the total ibrutinib pool, MH occurred in 20 patients (6.4%). Among the 677 ibrutinib-treated patients exposed to any antiplatelet (mean = 230 days, median = 174 days, range = 1–982) in the total ibrutinib pool, MH occurred in 30 patients (4.4%). “The duration of anticoagulant use in our clinical trials may not be reflective of [its] use in the real-world practice setting,” the researchers noted.

In the total ibrutinib pool, MH led to a dose reduction in one patient (<1%) and discontinuation in 21 patients (1%). Among 20 cases of central nervous system MH, 13 patients discontinued, and among 53 cases of noncentral nervous system MH, 8 patients discontinued.

“Use of anticoagulants or antiplatelet was associated with MH in both ibrutinib and comparators with a similar degree of association, suggesting that ibrutinib therapy does not alter the effect of [these agents] on MH risk,” the researchers concluded.

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