Case Presentation: A 36-year-old male with a past medical history of chronic phase chronic myelogenous leukemia with multiple relapses, never achieving remission, and recently diagnosed with the T315I resistant mutation treated with single agent ponatinib presented to the ED with complaints of pleuritic chest pain and shortness of breath. Exam was notable for mid neck jugular venous distention and mild crackles in bilateral lung bases. Pertinent labs included a WBC 78 K/mcL with neutrophilia, EKG showing nonischemic pattern with normal troponins, and a B-type natriuretic peptide of 600. Chest x-ray showed pulmonary vascular congestion. His echo showed a severely depressed left ventricular systolic function of 10% with global longitudinal strain severely depressed at -5% and severe global hypokinesis. Last echo from 2021 showed an ejection fraction of 40-45%. Oncology was consulted and given the association of ponatinib with vascular, as well as cardiovascular toxicity, ponatinib was held while excluding other etiologies for heart disease. However, left heart catheterization at an outside hospital earlier in the year was consistent with nonischemic cardiomyopathy. Cardiology was consulted and he was started on guideline-directed medical therapy with recovery in ejection fraction to 25% within two months of discontinuing ponatinib. Given his T315I mutation and limited treatment options, he was instead started on asciminib.
Discussion: While 90% to 95% of chronic myeloid leukemia (CML) patients possess a reciprocal translocation of t(9;22) which constitutively activates tyrosine kinase, some carry mutations that confer resistance to tyrosine kinase inhibitors (TKIs)2. For those with the T315I mutation, which is resistant to the first and second generation TKIs, third-generation TKIs are preferred with ponatinib considered first given its effectiveness in T315I-mutated CML3. Ponatinib however, is associated with substantial cardiovascular toxicity, higher than that reported with other tyrosine kinase inhibitors1. Asciminib is also a third-generation TKI with a possibly better toxicity profile, but lesser activity in T315I-mutated CML3. In this study, we describe a case of ponatinib-induced heart failure leading to ventricular fibrillation arrest in the setting of severe cardiomyopathy.
Conclusions: While the mechanism of cardiac toxicity from ponatinib is unclear, data reveals that ponatinib is the most cardiotoxic agent among all TKIs4. In our patient with no prior history of heart disease, hyperlipidemia, diabetes, hypertension, or family history of coronary artery disease, the decision to start ponatinib was made given this T315I mutation, for which ponatinib is the only inhibitor with activity against. Although he did fine initially, he endorsed progressively severe fatigue and dyspnea with minimal exertion raising the concern for cardiac dysfunction. While his heart failure symptoms were initially managed with GDMT, recurrent hospital admissions since diagnosis for heart failure exacerbations necessitated the discontinuation of this drug. This case underscores the importance of further investigation in minimizing the adverse effects associated with CML-TKIs, as well as developing interventions for managing ponatinib-induced cardiotoxicity in the hospital setting. As opposed to our patient, early recognition of TKI-induced cardiac dysfunction and prompt drug cessation could’ve helped prevent his recurring symptoms and exacerbations requiring hospitalization.