Study Explores Causes of Bleeding in Patients with CLL, MCL Taking Ibrutinib

A new study of patients with chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) offers new information about why a significant proportion of these patients suffer from bleeding when prescribed the Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib (Imbruvica).

About 4 in 10 patients will have bleeding as a complication of ibrutinib therapy, and 3% to 4% of patients taking the drug will develop major bleeding, wrote corresponding author Mikhail A. Panteleev, DSc, of Lomonosov Moscow State University, in Russia, and colleagues.

The group wanted to see if they could ascertain predictive markers of bleeding complications, and get a better understanding of why it happens. Their findings were published in The Journal of Thrombosis and Haemostasis.

The investigators recruited 50 patients with CLL and 16 patients with MCL who received ibrutinib therapy. They then assessed the platelet activity in these patients, using flow cytometry and light transmission aggregometry.

Before the initiation of treatment, patients had decreased platelet counts, impaired aggregation with adenosine diphosphate (ADP), and decreased binding of CD62P, PAC1, and annexin V upon stimulation, the authors said. Those observations held true in both the CLL and MCL groups.

The patients in the study had higher-than-average rates of bleeding after ibrutinib, with 28 (56%) CLL patients and 10 (62%) MCL patients experiencing the side effect.

As time went on, the investigators noticed patterns among the patients who experienced bleeding, though they were different in the CLL and MCL groups. In the CLL cohort, those who experienced bleeding had decreased aggregation with ADP and decreased platelet counts prior to therapy. In the MCL cohort, bleeding was reported in patients with decreased dense granule release before therapy.

Once therapy was initiated, ADP- and ristocetin-induced platelet aggregation increased in the MCL patients, as did collagen-induced aggregation in patients with CLL, Panteleev and colleagues wrote.

Based on their findings, the investigators proposed hypotheses for why bleeding seems to increase and then decrease in patients on ibrutinib.

“For CLL, we can hypothesize that this pattern results from a combination of three major mechanisms: an originally decreased platelet count in CLL; impaired reactivity of the CLL platelets independently of platelet count; and an inhibitory effect of ibrutinib on platelets.”

Panteleev and colleagues said these patients start therapy with a decreased platelet counts and decreased responses to ADP. CLL and ibrutinib similarly affect platelet function in these patients, but platelet count appears to be the factor that determines whether or not a patient experiences bleeding.

“Later, the ADP aggregation is improved, suggesting that, once again, we have two factors which are not sufficient to cause bleeding,” they wrote.

The MCL conclusions are based on a smaller number of patients, but the authors said the causes of bleeding in these patients appear to be different from the CLL group. Chiefly, platelet counts were less impaired in these patients, and neither platelet count nor ADP correlated with bleeding in this group, the authors said.

“Interestingly, platelet dense granule release was the main parameter that was different between patients who would or would not develop bleeding on therapy,” they wrote. “While the dynamics of all parameters during therapy were similar to that in the patients with CLL... we did not find significant differences between bleeding and nonbleeding patients.”

More research will be needed to confirm the findings, the authors wrote, particularly in the case of MCL, which had the smaller study population. However, the investigators said their data appear to show that, in some patients with CLL, ibrutinib “shifts the balance” in terms of platelet function leading to bleeding, but over time, improved response to ADP resolves the problem.

Reference

Dmitrieva EA, Nikitin EA, Ignatova AA, et al. Platelet function and bleeding in chronic lymphocytic leukemia and mantle cell lymphoma patients on ibrutinib. J Thromb Haemost. Published online June 8, 2020. doi:10.1111/jth.14943