1124 - Efficacy and toxicity of ibrutinib in CLL - Croatian experience. A non-interventional, real world study of KroHem

Ibrutinib has revolutionized the treatment of CLL. Despite being a targeted agent it does cause off-target toxicities, most notably cardiac and hemorrhagic. Factors affecting the risk of adverse outcomes are incompletely understood and the type and extent of pretreatment evaluation needed to identify patients at an increased risk of serious cardiovascular side-effects unknown.
In order to evaluate the efficacy and toxicity of ibrutinib treatment and risk factors for adverse outcomes KroHem collected data on Croatian patients starting treatment between the time the drug became reimbursable in 2015 until December 31, 2021.
We identified 436 patients fulfilling entry criteria (Table); 404 (92.7%) responded to treatment. 312 patients (71.6%) are alive, 263 of these (60.3%) progression-free and 233 (53.4%) still on therapy. 34 patients (7.8%) died after progression, 18 (4.1%) suddenly or of cardiovascular causes, 4 (0.9%) of bleeding, 13 (3.0%) of other tumors, 16 (3.7%) of COVID19, 20 (4.6%) of other infections, 2 frail elderly (0.5%) after general deterioration, and in 17 (3.9%) the cause of death is unknown. 60 (13.8%) patients stopped treatment for insufficient response or progression, of whom 19 with Richter’s syndrome; 75 (17.2%) due to intercurrent death; 55 (12.6%) for toxicity: cardiovascular 26, bleeding 8, gastrointestinal 5, cutaneous 5, neurologic 3, hematologic 3, infections 3 and pneumonitis and ocular 1 each; 7 (1.6%) for patient decision; and 6 (1.4%) for treatment of another disease. Cardiovascular side effects occurred in 25.0% of patients and hemorrhagic in 15.6%. The dose of ibrutinib was permanently reduced in 22.2% of patients.
Median follow-up of the cohort was 29 mo, range 1-95 mo; estimated median overall survival (OS) 75 mo, progression-free survival (PFS) 54 mo and time on treatment (TT) 44 mo (Fig). Factors significantly related to OS in multivariate analysis were stage (Binet A median OS not reached, B 75 mo, C 55 mo, p=0.009); treatment line (1st line median not reached, 2nd 75 mo, ≥3rd 54 mo, p=0.036) and age (≤68 y median not reached, 68-75 y 55 mo, >75 y 42 mo, p < 0.0001). Factors significantly related to PFS in multivariate analysis were treatment line (1st line median 67mo, 2nd 54 mo, ≥3rd 40 mo, p=0.023 ), age (≤68 y median 64 mo, 68-75 y 43 mo, >75 y 37 mo, p < 0.0001), and pretreatment history or ECG finding of cardiac arrhythmia (no 54 mo, yes 39 mo, p=0.001). Factors significantly related to TT in multivariate analysis were age (≤68 y median 56 mo, 68-75 y 41 mo, >75 y 25 mo, p < 0.0001), pretreatment cardiac arrhythmia (no 51 mo, yes 24 mo, p < 0.0001) and need for permanent ibrutinib dose reduction (no median 51 mo, yes 27 mo, p < 0.0001). Sex, FISH and presence of arterial hypertension were not independently significantly related to any of these outcomes.
Pretreatment cardiologic consultation did not improve TT, PFS, OS, risk of stopping treatment due to cardiovascular side effects or risk of cardiovascular or sudden death neither in the whole cohort nor in the subgroup of patients without pretreatment cardiac arrhythmia.
Our analysis confirms the efficacy of ibrutinib in treatment of CLL. Outcome, especially of front-line patients, seems inferior to that reported in clinical trials. A possible explanation is that the drug was first approved only for patients with del 17p and in early relapse, which therefore comprise an extraordinarily high proportion of our cohort. Another possible explanation is the adverse effect of the COVID19 pandemics. Age was the most important prognostic factor, those older than 75 did significantly less well. Patients with cardiac arrhythmias are at an increased risk of having to stop treatment early. Del 17p did not appear to be a significant negative prognostic factor, possibly due to the number of high-risk patients in our cohort and a relatively short follow-up. Around 4% of patients die of cardiovascular side effects and additional 6% have to stop ibrutinib for same reasons. Routine pretreatment cardiologic consultation is insufficient to reduce this risk. Additional studies are needed to improve early identification of these patients for whom alternative treatments might be more suitable.