Ponatinib coronary microangiopathy: novel bedside diagnostic approach and management with N-acetylcysteine

Wu, Mingfu; Hodovan, James; Kumar, Kris; Moulton, Bart; Olson, Sven R.; Gilbert, Aubre; Wood, Matthew D.; Lindner, Jonathan R.

doi:10.1182/bloodadvances.2020002644

Cited by 7 publications

(3 citation statements)

References 13 publications

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“…The patient was started on high doses of intravenous corticotherapy (methylprednisolone 80 mg daily) as well as on daily plasmapheresis, which was discontinued when ADAMTS13 deficiency was excluded (ADAMTS13 activity was 77%) and no improvement was seen after two days. Based on some supporting evidence showing a reduction of the concentration of ultra-large von Willebrand factor (VWF) multimers in vitro and in an animal model in thrombotic thrombocytopenic purpura (TTP), as well as a resolution of abnormal electrocardiogram (ECG) findings in a patient with ponatinib-associated drug-induced TMA affecting the coronary microvasculature, a trial with N-acetylcysteine (NAC; 8,000 mg daily after a loading dose of 12,000 mg) was done (16)(17)(18). Unfortunately, again without result and NAC was discontinued after two days.…”

Section: Case Presentationmentioning

confidence: 99%

Gemcitabine-induced thrombotic microangiopathy treated with eculizumab: a case report

Eeckhaut¹,

Hannon²,

Schurgers³

et al. 2022

J Gastrointest Oncol

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Background: Gemcitabine is a broadly used chemotherapeutic agent that can cause a rare but lifethreatening complication called thrombotic microangiopathy (TMA). Early recognition is crucial as therapy options are limited.Case Description: We report the case of a 46-year-old patient with pancreatic adenocarcinoma who presented with severe anemia and thrombocytopenia as well as acute kidney injury. A diagnosis of gemcitabine-induced TMA was made. He became rapidly transfusion and dialysis dependent. Despite discontinuation of gemcitabine and treatment with high-dose corticotherapy as well as plasmapheresis, no improvement in both renal and hematological parameters was seen. Treatment with eculizumab was initiated. One week after the first administration, the patient no longer required packed cells nor platelet transfusions and one month later, dialysis could be discontinued. After five doses, treatment with eculizumab was stopped. Four months later, his serum creatinine was 1 mg/dL. Conclusions: This case report illustrates the promising beneficial effects of eculizumab in gemcitabineinduced TMA, both regarding transfusion dependence as well as improvement in renal function, thereby allowing further therapy options in patients with an active malignancy.

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Section: Case Presentationmentioning

confidence: 99%

Gemcitabine-induced thrombotic microangiopathy treated with eculizumab: a case report

Eeckhaut¹,

Hannon²,

Schurgers³

et al. 2022

J Gastrointest Oncol

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“…Ponatinib has been shown to cause microvascular coronary angiopathy by inducing von Willebrand factor-mediated platelet-endothelial adhesion [ 120 ]. Myocardial contrast echocardiography was used as a rapid bedside diagnosis of coronary microvascular disease in cases of suspected ponatinib-induced acute MI with elevated troponin [ 121 ].…”

Section: Etiology and Mechanisms Of Myocardial Infarction In Cancer P...mentioning

confidence: 99%

Mechanisms of Myocardial Ischemia in Cancer Patients: A State-of-the-Art Review of Obstructive Versus Non-Obstructive Causes

Balanescu¹,

Bloomingdale²,

Donisan³

et al. 2022

Rev. Cardiovasc. Med.

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In patients with cancer, myocardial infarction (MI) has distinct features and mechanisms compared to the non-oncology population. Triggers of myocardial ischemia specific to the oncology population have been increasingly identified. Coronary plaque disruption, coronary vasospasm, coronary microvascular dysfunction, spontaneous coronary artery dissection, and coronary oxygen supply-demand mismatch are all causes of MI that have been shown to have specific triggers related to either the treatments or complications of cancer. MI can occur in the presence or absence of atherosclerotic coronary artery disease (CAD). MI with nonobstructive CAD (MINOCA) is a heterogeneous syndrome that has distinct pathophysiology and different epidemiology from MI with significant CAD (MI-CAD). Recognition and differentiation of MI-CAD and MINOCA is essential in the oncology population, due to unique etiology and impact on diagnosis, management, and overall outcomes. There are currently no reports in the literature concerning MINOCA as a unified syndrome in oncology patients. The purpose of this review is to analyze the literature for studies related to known triggers of myocardial ischemia in cancer patients, with a focus on MINOCA. We propose that certain cancer treatments can induce MINOCA-like states, and further research is warranted to investigate mechanisms that may be unique to certain cancer states and types of treatment.

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“…5–7 Ponatinib is a third-generation tyrosine kinase inhibitor (TKI) currently approved for treating patients with CML with the gatekeeper mutation breakpoint cluster region-Abelson T315I, for which no alternative therapy exists since earlier TKIs are ineffective against this mutation. 8–10 Unfortunately, serious cardiac adverse events were reported in patients given ponatinib, leading to its temporary suspension from the market. 11 Ponatinib has been linked to cardiomyopathy, heart failure, and vascular occlusion in up to 9% of patients.…”

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confidence: 99%

Integrated Stress Response Potentiates Ponatinib-Induced Cardiotoxicity

Yan,

Han,

Kwon

et al. 2024

Circulation Research

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Background: Mitochondrial dysfunction is a primary driver of cardiac contractile failure; yet, the cross talk between mitochondrial energetics and signaling regulation remains obscure. Ponatinib, a tyrosine kinase inhibitor used to treat chronic myeloid leukemia, is among the most cardiotoxic tyrosine kinase inhibitors and causes mitochondrial dysfunction. Whether ponatinib-induced mitochondrial dysfunction triggers the integrated stress response (ISR) to induce ponatinib-induced cardiotoxicity remains to be determined. Methods: Using human-induced pluripotent stem cells–derived cardiomyocytes (hiPSC-CMs) and a recently developed mouse model of ponatinib-induced cardiotoxicity, we performed proteomic analysis, molecular and biochemical assays to investigate the relationship between ponatinib-induced mitochondrial stress and ISR and their role in promoting ponatinib-induced cardiotoxicity. Results: Proteomic analysis revealed that ponatinib activated the ISR in cardiac cells. We identified GCN2 (general control nonderepressible 2) as the eIF2α (eukaryotic translation initiation factor) kinase responsible for relaying mitochondrial stress signals to trigger the primary ISR effector—ATF4 (activating transcription factor 4), upon ponatinib exposure. Mechanistically, ponatinib treatment exerted inhibitory effects on ATP synthase activity and reduced its expression levels resulting in ATP deficits. Perturbed mitochondrial function resulting in ATP deficits then acts as a trigger of GCN2-mediated ISR activation, effects that were negated by nicotinamide mononucleotide, an NAD + precursor, supplementation. Genetic inhibition of ATP synthase also activated GCN2. Interestingly, we showed that the decreased abundance of ATP also facilitated direct binding of ponatinib to GCN2, unexpectedly causing its activation most likely because of a conformational change in its structure. Importantly, administering an ISR inhibition, ISRIB, protected human-induced pluripotent stem cell–derived cardiomyocytes against ponatinib. Ponatinib-treated mice also exhibited reduced cardiac function, effects that were attenuated upon systemic ISRIB administration. Importantly, ISRIB does not affect the antitumor effects of ponatinib in vitro. Conclusions: Neutralizing ISR hyperactivation could prevent or reverse ponatinib-induced cardiotoxicity. The findings that compromised ATP production potentiates GCN2-mediated ISR activation have broad implications across various cardiac diseases. Our results also highlight an unanticipated role of ponatinib in causing direct activation of a kinase target despite its role as an ATP-competitive kinase inhibitor.

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Ponatinib coronary microangiopathy: novel bedside diagnostic approach and management with N-acetylcysteine

Abstract: Key Points Ponatinib produces a coronary microangiopathy that mimics myocardial infarction and can be detected rapidly by contrast echocardiography. N-acetylcysteine therapy can potentially resolve ischemic complications caused by ponatinib-related microangiopathy.

Cited by 7 publications

References 13 publications

Gemcitabine-induced thrombotic microangiopathy treated with eculizumab: a case report

Gemcitabine-induced thrombotic microangiopathy treated with eculizumab: a case report

Mechanisms of Myocardial Ischemia in Cancer Patients: A State-of-the-Art Review of Obstructive Versus Non-Obstructive Causes

Integrated Stress Response Potentiates Ponatinib-Induced Cardiotoxicity

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