Long-Term Cardiac, Vascular and Hypertensive Safety of Bosutinib in Patients with Philadelphia Chromosome-Positive (Ph+) Leukemia Resistant or Intolerant to Prior Therapy

Introduction: TKI therapy has been linked with cardiac (CA) and vascular (VA) events. Bosutinib is a dual Src/Abl tyrosine kinase inhibitor (TKI) approved for treating adults with chronic (CP), accelerated (AP), or blast phase (BP) Ph+ chronic myeloid leukemia (CML) with resistance or intolerance to prior therapy. An open-label, phase 1/2 study of bosutinib (NCT00261846) demonstrated efficacy and safety in this population (Cortes, Blood, 2011). In this study, 22% of patients (pts) had a medical history of CA disorders (MedDRA SOC Cardiac Disorders) and 33% had a medical history of VA and hypertensive disorders (MedDRA SOC Vascular Disorders) at baseline. Here we present the long-term CA, VA and hypertension (HTN) safety data for pts enrolled in this study and its ongoing extension study (NCT01903733) after a minimum of 7 years from last patient enrolled.

Methods: Pts with chronic Ph+ CML in 2nd line after imatinib (CP2L), 3rd line after imatinib and dasatinib and/or nilotinib (CP3L), and AP/BP CML or Ph+ acute lymphocytic leukemia after at least imatinib (ADV) were included. Patients received bosutinib starting at 500 mg/d. Terms included in CA, VA, and HTN clusters are specified in Table footnotes. Treatment-emergent adverse events (TEAEs) were defined as any event increasing in severity from baseline, or any new event starting during bosutinib therapy or within 30 days of last bosutinib dose.

Results: 570 pts (284 CP2L, 119 CP3L, 167 ADV) were included in this safety update. Time from last enrolled patient to data cutoff date was approximately 8 years for CP2L and 7 years for CP3L and ADV, with 26.1% of CP2L, 10.9% of CP3L, and 6.0% of ADV still receiving treatment. The median (range) treatment durations (mo) in the CP2L, CP3L, and ADV groups were 25.6 (0.2-133.1), 8.6 (0.2-127.9), 4.0 (0.03-126.8), respectively. Rates of TEAEs, serious adverse events (SAEs), treatment withdrawals, and drug-related events (as determined by investigator) in the CA, VA, and HTN clusters were generally similar across patient groups (Table). There were 4 (3 CP2L, 1 ADV), 10 (1 C2PL, 2 CP3L, 7 ADV), and 0 TEAEs leading to death in the CA, VA, and HTN clusters, respectively. Overall incidence of grades (Gr) 3-5 TEAEs in the CA cluster was 6.1% (6.7, 7.6, and 4.2% for the CP2L, CP3L, and ADV groups, respectively), with pericardial effusion (3.9%), atrial fibrillation (3.0%), and congestive cardiac failure (2.6%) being the most frequent preferred terms (PTs). Overall incidence of Gr 3-5 TEAEs in the VA cluster was 6.0% (5.6, 5.9, and 6.6% for the CP2L, CP3L, and ADV groups, respectively); the most frequent PTs were angina pectoris (1.8%), coronary artery disease (1.4%), and acute MI (0.9%). Overall incidence of Gr 3 TEAEs (no Gr 4-5 events) in the HTN cluster was 3.2% (3.5%, 2.5%, and 3.0% for the CP2L, CP3L, and ADV groups, respectively), with the most frequent PTs being HTN (8.4%) and BP increased (0.5%).

Rates of temporary treatment interruption were 31.3% in the CA cluster (37.5%, 27.8%, and 22.7% for the CP2L, CP3L, and ADV affected pts, respectively), 15.7% in the VA cluster (22.2%, 0.0%, and 13.3% for the CP2L, CP3L, and ADV affected pts, respectively), and 7.5% in the HTN cluster (13.8%, 0.0%, and 0.0% for the CP2L, CP3L, and ADV affected pts, respectively). Successful treatment rechallenge was achieved in 81.0%, 100%, and 100% of pts with temporary treatment interruption who were rechallenged in the CA, VA, and HTN clusters, respectively. Dose was reduced in 8.8% of affected CA cluster pts (12.5%, 11.1%, and 0.0% for the CP2L, CP3L, and ADV groups, respectively), 5.9% of VA cluster pts (7.4%, 11.1%, and 0.0% for the CP2L, CP3L, and ADV groups, respectively), and no HTN pts. The proportion of affected pts in the CP2L, CP3L, and ADV groups treated with concomitant medication ranged from 45.5-50.0% in the CA cluster, 20.0-48.1% in the VA cluster, and 72.4-92.3% in the HTN cluster.

Conclusion: In this analysis, which is the longest follow-up safety report of its kind for any TKI to date, the incidence of CA, VA, and HTN events in pts with Ph+ leukemia resistant or intolerant to prior therapy who were treated with bosutinib was relatively low irrespective of treatment line and disease stage. The majority of CA, VA, and HTN events were not SAEs and only infrequently led to treatment withdrawal. Treatment rechallenge was successful for the majority of pts with temporary treatment discontinuations due to CA, VA, and HTN cluster events.

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