Paper Details

Background   Tyrosine kinase inhibitors (TKIs) have transformed chronic myeloid leukemia (CML) into a long-term manageable disease, making treatment-related late toxicities increasingly important.  Olverembatinib is an effective third-generation TKI for patients with TKI-resistant and/or intolerant CML, including those with heavily-treated disease; however, these patients often have prolonged prior TKI exposure and baseline cardiometabolic vulnerability.  The long-term burden, clinical consequences, and risk determinants of major cardio- and cerebrovascular adverse events (MACCEs) during olverembatinib therapy remain insufficiently characterized.

Aim   To evaluate the incidence, clinical spectrum, management, outcomes, and risk factors of major cardio- and cerebrovascular adverse events (MACCEs) during long-term olverembatinib therapy in patients with TKI-resistant and/or intolerant CML.

Methods   We retrospectively analyzed 232 patients with TKI-resistant and/or intolerant chronic- or accelerated-phase CML treated with olverembatinib.  141 (61%) patients were enrolled in clinical trials (ChiCTR1900027568, NCT03883087, NCT03883100 and NCT04126681), whereas the remaining 91 (39%) were from post-marketing clinical practice.  Initial olverembatinib doses were ≤ 20 mg every other day (QOD) in 10 patients (4%), 30 mg QOD in 84 (36%), 40 mg QOD in 118 (51%), and ≥ 45 mg QOD in 20 (8%).  In this study, MACCEs was defined as a composite outcome, occurring throughout the follow-up period, including the new-onset or worsening hypertension, symptomatic arrhythmia, and arterial or venous occlusive events occurring during olverembatinib therapy.  Cumulative incidences of MACCEs were estimated using competing-risk methods, and clinical risk factors were evaluated using multi-variable Fine–Gray sub-distribution hazard models.  Baseline targeted DNA sequencing was performed in 190 patients with available blood samples before olverembatinib initiation to explore associations between clonal hematopoiesis of indeterminate potential (CHIP)-related mutations and MACCEs.  CHIP-related mutations were defined as somatic variants in predefined genes recurrently implicated in clonal hematopoiesis, without implying definitive CHIP in the setting of CML.

Results   232 TKI-resistant and/or intolerant patients with chronic- or accelerated-phase CML receiving olverembatinib therapy were included.  164 (71%) patients were male.  Median age was 43 years (IQR, 32 - 54 years).  190 (82%) patients received at least 2 TKIs therapy previously.  Median duration of prior TKI-therapy was 49 months (IQR, 19 - 89 months).  With a median follow-up of 57 months (IQR, 16 - 85 months), 85 patients (37%) experienced at least one MACCE, with a 7-year cumulative incidence of 52% (95% CI, 44 - 60%).  New-onset or worsening hypertension was the most frequent event, occurring in 56 patients (24%), whereas vascular occlusive events occurred in 34 patients (15%) and represented the most serious complications.  MACCEs were managed according to event type and severity, mainly through olverembatinib dose reduction, treatment interruption, switching or discontinuation, and concomitant cardiovascular treatment.  After dose reduction, vascular adverse events were generally stabilized or improved in most patients, and therapy responses were largely maintained or further deepened, although recurrent cerebrovascular events occurred in a small subset.  In multi-variable Fine-Gray models, older age, diabetes, alcohol use, prior nilotinib exposure, and higher total cholesterol were significantly associated with MACCEs.  Exploratory clinical weighted scores stratified patients into distinct vascular risk groups (all p-values < 0.001), with good time-dependent discrimination for MACCEs and related endpoints (AUROC: 0.70 - 0.85).  CHIP-related mutations, involving TET2, DNMT3A and CREBBP were significantly associated with MACCEs or specific MACCE components.

Conclusions   MACCEs are frequent and clinically relevant during long-term olverembatinib therapy in patients with TKI-resistant and/or intolerant CML.  Dose reduction may help stabilize or improve vascular adverse events while preserving treatment responses in most patients.  These findings support earlier identification of patients at increased vascular risk, close longitudinal monitoring, individualized cardiovascular management, and timely response-adapted dose optimization.