Plateletcrit and the Risk of Bleeding in Patients with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma Treated with Bruton's Tyrosine Kinase Inhibitors

BACKGROUND: Bleeding occurs in a significant proportion of patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) treated with Bruton's tyrosine kinase inhibitors (BTKi) which cause platelet dysfunction with their off-target kinase activity. Considering the controversial association of low platelet count with the risk of bleeding during BTKi treatment, this study evaluated whether plateletcrit (PCT), a measure of total circulating platelet mass, may be used to identify CLL/SLL patients under higher bleeding risk during this particular treatment.

OBJECTIVE&METHODS: This retrospective multicenter study was conducted in two hematology centers in Croatia in the period between 06/2015 and 06/24 and included CLL/SLL patients treated with BTKi. PCT was calculated as platelet count x mean platelet volume (MPV) / 10 000. Comorbidities were assessed with the Cumulative Illness Rating Scale (CIRS). Time to bleeding (TTB; death being a censoring event) was the primary outcome of interest. Survival analyses were performed with the Kaplan-Meier method, log-rank test and the Cox-regression analysis. Statistics were performed with MedCalc Statistical Software (Ostend, Belgium, v.22.023).

RESULTS: A total of 72 BTKi-treated (ibrutinib=48, acalabrutinib=22, zanubrutinib=1, ibrutinib/acalabrutinib sequentially=1) CLL/SLL patients were included; median age at the time of BTKi treatment was 70 years (range 41-87), 31 (43.1%) were females, and the median CIRS was 8 (4-25). Thirty-three patients (45.8%) had 17p(p53) abnormality, and 1 (1.4%), 7 (9.7%), 17 (23.6%), 13 (18.1%), and 34 (47.2%) had Rai stages 0, I, II, III, and IV, respectively. Twelve (16.7%) and 7 (10.1%) patients concomitantly recieved antiplatelets or anticoagulants, respectively.

Median platelet count, MPV, and PCT were 151x10⁹L (range 21-411), 9fL (range 7.1-13.6) and 0.13% (range 0.02-0.45). PCT was lower in patients with higher Rai stages (p<0.001), those using antiplatelets (p=0.001), patients with higher lymphocytes (p=0.024) and lower hemoglobin levels (p=0.001) with no differences with respect to other analyzed variables.

Median follow-up was 22.5 months (range 1-108) with 8 (11.1%) bleeding events (nosebleeeds=2, haemorrhagic pleural effusion=2, macrohematuria=1, rectorrhagia=1, severe sideropenic anemia=1, skin hematomas=1) ocurring during this period of time. Median TTB was not reached for the entire cohort. There were no differences in platelet count, MPV and PCT between patients who experienced bleeding during the follow-up and those who did not (p>0.050 for all analyses).

Receiver operating curve defined the optimal cut-off of PCT for prognostication of bleeding at >0.18%. Univariately, patients with low (<0.18%) PCT (n=15) had superior TTB (HR 0.13, p=0.043) when compared to patients with higher PCT. Platelet count and MPV were not prognostic (p<0.050 for both analyses). High (>8) CIRS (p=0.003) was also univariately associated with an inferior TTB, whereas the use of antiplatelets/anticoagulants was of borderline significance (p=0.070). In the multivariate Cox regression analysis, high PCT (HR 6.02; p=0.014) and high CIRS (HR 5.23; p=0.022) remained independently of each other associated with an inferior TBB when additionally adjusted for sex, antiplatelets/anticoagulants and disease stage.

DISCUSSION: Interestingly, low PCT was independently associated with less bleeding events, despite the fact that patients having low PCT had more advanced disease and more often used antiplatelets. Further validation and clarification of the pathophysiological rationale underlying this intriguiging observation is needed. Although this effect may potentially be explained with patient-related specifics and physician-related bias (i.e, more liberal administration of aspirin in patients with higher platelet count) it could also resemble an essential thrombocythemia-like phenomenon (i.e, acquired Willebrand's disease in patients with extreme thrombocytosis) where higher circulating platelet mass during BTKi treatment may be associated with more bleedings.

Krecak:janssen: Honoraria; astra zeneca: Honoraria. Grubesic:astra zeneca: Honoraria; janssen: Honoraria. Franjic:janssen: Honoraria. Jaksic:janssen: Honoraria; astra zeneca: Honoraria; abbvie: Honoraria; ElyLilly: Honoraria. Peric:astra zeneca: Honoraria; abbvie: Honoraria.