Cardiovascular Events Among Patients with Chronic Myeloid Leukemia (CML) Treated with Tyrosine Kinase Inhibitors (TKIs)
Authors: Sam Princy Yohannan , Ahaneku Hycienth , Nogueras-Gonzalez Graciela M. , Jabbour Elias , Garcia-Manero Guillermo , Borthakur Gautam , Wierda William G. , Daver Naval , Kadia Tapan , Burger Jan , Pierce Sherry , DiNardo Courtney D , Ravandi Farhad , Kantarjian Hagop M. , Cortes Jorge E. 
Published: October 2019

Abstract

Background
TKIs are the mainstay of treatment for CML. Cardiovascular events may occur during the course of therapy with TKI. We present a single institution experience of cardiovascular events among CML patients receiving initial therapy with various TKIs.
Methods
We retrospectively assessed 584 CML patients enrolled on consecutive or parallel prospective frontline TKI clinical trials (imatinib, n=281; dasatinib, n=120; nilotinib, n=132, ponatinib n=51). Treatment-emergent adverse events (TEAE) under the MedRA heading "Cardiovascular" were analyzed. Over 1,080 unique terms are included under this MedRA heading. Poisson regression models assessed factors associated with occurrence of cardiovascular and arterio-thrombotic events.
Results
The median age (range) at start of treatment was 49 yrs (15 - 87); 41% were female and 79% were white. The overall median time of follow-up was 66 mos, with the longest follow-up for the imatinib (117 mos) cohort and the shortest for the ponatinib (13 mos) cohort. Co-morbid predisposing conditions were present at baseline in the majority of patients, with significant imbalance among treatment arms. Cardiovascular events occurred in 53% of all patients. Hypertension (new or worsening, 42%) was the most prevalent cardiovascular TEAE, followed by rhythm/rate disorders (11%). Arterio-thrombotic event occurred in 7% of all patients (coronary artery disease in 4%, cerebrovascular in 2%, peripheral arterial in 2%). Overall, the incidence rate (IR) of cardiovascular and arterio-thrombotic TEAEs were 13.9 and 1.1 per 100-person years respectively. Ponatinib showed the highest IR of TEAEs (85.5 and 5.1 per 100-person years respectively).
In a multivariate analysis, the incidence risk ratio (IRR) of cardiovascular and arterio-thrombotic events were higher for all 2nd-3rd generation TKIs compared to imatinib. The IRR with ponatinib for cardiovascular events was 7.1 (95% CI: 4.7-10.7; p≤0.001) and for arterio-thrombotic events 6.6 (95% CI: 1.8-23.8 p=0.004); dasatinib and nilotinib showed similar IRR among them, both higher than imatinib. In addition, older age was associated with higher IRR of cardiovascular (IRR=1.01, 95% CI: 1.0-1.02; p=0.003) and arterio-thrombotic (IRR=1.04, 95% CI: 1.00-1.07; p=0.023) events adjusted for other variables.
Conclusion
Cardiovascular TEAE are common during the course of therapy with TKI for patients with CML, predominantly for older patients and those on 2nd and 3rd generation TKI (particularly ponatinib). These patients require close monitoring during treatment. Investigation on the mechanism for cardiovascular TEAE with TKIs is required.

Disclosures
Jabbour: BMS: Consultancy; Pfizer: Research Funding; ARIAD: Research Funding; ARIAD: Consultancy; Pfizer: Consultancy; Novartis: Research Funding. Wierda:Novartis: Research Funding; Abbvie: Research Funding; Acerta: Research Funding; Gilead: Research Funding; Genentech: Research Funding. Daver:Otsuka: Consultancy, Honoraria; Sunesis: Consultancy, Research Funding; Ariad: Research Funding; Kiromic: Research Funding; Pfizer: Consultancy, Research Funding; Karyopharm: Honoraria, Research Funding; BMS: Research Funding. Kadia:BMS: Research Funding; Novartis: Honoraria. Burger:Portola: Consultancy; Gilead: Research Funding; Roche: Other: Travel, Accommodations, Expenses; Janssen: Consultancy, Other: Travel, Accommodations, Expenses; Pharmacyclics, LLC, an AbbVie Company: Research Funding. DiNardo:Daiichi Sankyo: Other: advisory board, Research Funding; Novartis: Other: advisory board, Research Funding; Agios: Other: advisory board, Research Funding; Abbvie: Research Funding; Celgene: Research Funding. Ravandi:Seattle Genetics: Consultancy, Honoraria, Research Funding; BMS: Research Funding. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding.