Midostaurin-associated perimyocarditis: a case report of severe cardiotoxicity of novel targeted treatments for acute myeloid leukaemia and review of the literature

Abstract

Background

Midostaurin is a multikinase inhibitor for the treatment of Fms-like tyrosine 3 (FLT3)-mutated acute myeloid leukaemia (AML). Cardiac adverse events like QTc-prolongation, pericardial effusion, and congestive heart failure have been described. Inflammatory diseases associated with midostaurin are rarely reported.

Case summary

A 24-year-old man with newly diagnosed AML and FLT3-ITD mutation was treated with intensive remission-induction chemotherapy and midostaurin. After 5 days of midostaurin, the patient reported severe focal chest pain. Due to laboratory evidence of acute myocardial cell damage, coronary macroangiopathy and pulmonary artery embolism were ruled out via computed tomography. Cardiovascular magnetic resonance showed evidence for active perimyocarditis with myocardial oedema and late gadolinium of the basal, midventricular, and apical lateral wall of the left ventricle. Therapeutic drug monitoring did not reveal excessive midostaurin plasma levels, and hence, initially suspected drug interaction with posaconazole administered for antifungal prophylaxis was considered less likely to be causative. After discontinuing midostaurin, clinical signs of perimyocarditis improved. During continued high-dose cytarabine therapy, no further cardiac events occurred. It was concluded that perimyocarditis was an adverse effect of midostaurin since the inhibition of FTL3 may have led to a loss of cardiomyocyte protective capacity against oxidative stress-induced apoptosis, as previously described in vitro.

Discussion

In addition to the most frequently reported non-cardiac adverse effects of midostaurin, serious cardiotoxic complications appear to occur and may require discontinuation of therapy. This case highlights the importance of interdisciplinary work-up of a cardio-oncology pathway even in presumably low-risk patients and particularly in the context of rare cases of cardiotoxicity in novel cancer treatments.

Learning point.

• To raise awareness of the importance of the interdisciplinary evaluation of cardio-oncological pathways even in patients with supposedly low risk and especially in connection with rare cases of cardiotoxicity in novel cancer treatments.

Introduction

Midostaurin is a multikinase inhibitor to treat Fms-like tyrosine 3 (FLT3)-mutated acute myeloid leukaemia (AML). It was licensed in the European Union in 2019 after the randomized controlled RATIFY-trial showed a superior overall survival in patients receiving midostaurin from Day 8 to 21 after intensive remission-induction chemotherapy (RIC) vs. patients receiving the latter alone.¹ Midostaurin is also licensed for maintenance treatment after allogeneic stem cell transplantation and systemic mastocytosis.

The most frequently reported adverse effects (AEs) are anaemia, nausea, and rash or desquamation.¹ Treatment with midostaurin was also associated with QT-prolongation, pericardial disease, atrial fibrillation, and heart failure.² The concomitant use of anthracyclines may further increase cardiovascular effects. Furthermore, there is a risk of drug–drug interactions (DDIs) with standard-of-care antifungal prophylaxis with triazoles as midostaurin is metabolized via the cytochrome p450 system (CYP) 3A4 enzyme which is inhibited by triazoles.³ Antifungal prophylaxis during RIC is strongly recommended by international guidelines; however, concerns of DDI has led to omission of triazoles in this setting.^3,4 Of note, incidence of invasive fungal diseases seems to be higher in midostaurin-treated patients.⁵

We report a case of a young man with AML who received 3 + 7 chemotherapy plus midostaurin and developed perimyocarditis.

Summary figure

September 2021	Initial diagnosis of AML (NPM1 mutated AML according to World Health Organization (WHO), AML M4 according to the FAB classification)
From 17 September	RIC with ‘3 + 7’ (cytarabine (200 mg/m2 on Days 1 to 7 and daunorubicin 60 mg/m2 on Days 1 to 3) and midostaurin 50 mg twice daily was initiated on Day 8
29 September 2021	Occurrence of cardiac symptoms: chest pain without radiation, sinus tachycardia with troponinaemia, and emergency transthoracic echocardiography
30 September 2021	Cardiac magnetic resonance imaging examination with evidence of myocarditis, discontinued therapy with midostaurin
December 2021	Transthoracic echocardiography with normal left ventricular (LV) function without global wall movement disorders or a pericardial effusion
February 2022	Matched unrelated donor (MUD) haematopoietic stem cell transplantation without further cardiac adverse events

Case presentation

A 24-year-old previously healthy man presented to the emergency department with severe fatigue and dyspnoea. There was no relevant past medical history, medication intake, or allergies. Initial haematology at admission showed leucocytosis of 15.7 × 10³/µL, haemoglobin of 10.1 g/dL, and a decreased count of thrombocytes of 120 × 10⁹/L. Microscopy of a peripheral blood smear showed 15% myeloid blasts, and diagnosis was confirmed by bone marrow examination with myeloid blasts of 50%. The final diagnosis was of AML (NPM1 mutated AML according to WHO, AML M4 according to the FAB classification). Molecular genetic analysis was positive for FLT3-internal tandem duplication (ITD). According to the European Leukemia Net (ELN) 2022 classification, the patient’s risk was favourable; he was ECOG 0. Treatment was initiated by RIC with ‘3 + 7’ (cytarabine (200 mg/m² on Days 1 to 7 and daunorubicin 60 mg/m² on Days 1 to 3), and midostaurin 50 mg twice daily was initiated on Day 8. The initial treatment phase was tolerated well, but the patient developed febrile neutropenia and was treated with empiric broad-spectrum antibiotics.

On Day 12, the patient reported severe focal chest pain without radiation. The 12-lead electrocardiogram showed a sinus tachycardia at a heart rate of 105 b.p.m. with normal QTC 445 ms without ST elevation or PR depression (Figure 1). Chemistry results showed troponinaemia (high-sensitivity troponin T of 1.26 µg/L [upper limit of normal value (ULN) < 0.014 ug/L]), while creatine kinase and myocardial creatine kinase were within normal range. C-reactive protein was moderately increased at 52.1 mg/L and increased up to 151.8 mg/L in the following days (while still on antibiotic treatment for febrile neutropenia). A preliminary assessment by transthoracic echocardiography revealed a preserved ejection fraction of 54% and normal right ventricular function, without relevant valve abnormalities and absence of a pericardial effusion (Figure 2). The patient was transferred to the intermediate care ward, and a computed tomography scan of the chest was ordered and excluded pulmonary embolism and aortic dissection (Figure 3). For further evaluation of coronary macroangiopathy, cardiovascular magnetic resonance (CMR) was performed which showed active perimyocarditis with myocardial oedema and late gadolinium enhancement. This was associated with basal and midventricular septal/inferoseptal hypokinesia with preserved ejection function (EF 60%). In addition, there was a basal pericardial effusion with a maximum border width of 11 mm (Figure 4). Endomyocardial biopsy was not performed due to thrombocytopenia and associated procedural risk. Plasma analysis provided no evidence for a systemic viral infection (negative for adenovirus-DNA, EBV-VCA IgG/M, EBV-EBNA1 IgG, enterovirus RNA, Mumps IgM, parvovirus B19 IgM/DNA, Rubella IgM) as aetiology.

Figure 1.

The 12-lead electrocardiogram shows a tachycardic sinus rhythm with normal times (PQ-time 118 ms, QRS 90 ms, QTcB 445 ms).

Figure 2.

Transthoracic echocardiography showing a four-chamber subxiphoidal view. The echocardiography revealed a preserved normal left and right ventricular function without relevant valve abnormalities and pericardial effusion.

Figure 3.

4Ch (A) and 3Ch (B) late gadolinium enhancement depicting patchy subepicardial lesions of the basal, midventricular, and apical lateral wall of the left ventricle (arrows).

Figure 4.

Short-axis late gadolinium enhancement (A) showing corresponding patchy subepicardial lesions of the basal lateral wall of the left ventricle (arrows) with concomitant oedema in short-axis T2-weighted black blood fat-saturated sequence (B, arrows). These findings are consistent with the 2018 Lake Louise Criteria for the diagnosis of acute endocarditis.

Midostaurin plasma level measured on Day 11 was 5.5 mg/dL (no ULN available). The patient had received antifungal prophylaxis with posaconazole from the beginning of RIC, and twice weekly therapeutic drug monitoring (TDM) from plasma revealed concentrations between 662 and 967 µg/L, interpreted as within the target for prophylactic use and not elevated.

Due to the temporal relation of onset of symptoms and midostaurin initiation, the latter was discontinued as potential trigger of perimyocarditis and oral treatment with a beta-blocker was started due to concomitant symptomatic supraventricular extrasystole. Colchicine, non-steroidal agents, or steroids were not administered.

The patient’s symptoms resolved 3 days after the above event. Troponinaemia peaked at 1.56 µg/L on Day 3 after onset of symptoms (see Supplementary material online, Figure S1). Bone marrow aspirate on Day 20 after RIC showed complete remission, and he continued treatment for AML with a consolidation treatment consisting of four cycles of high-dose cytosine arabinoside (HiDAC) and regular cardiology examination. As no relevant LV dysfunction was evident, a re-challenge with midostaurin or an alternative FLT3-inhibitor was discussed among the treating team; however, it was decided against resuming due to a questionable risk-benefit ratio as well as morphologic and molecular remission after RIC. Interval transthoracic echocardiography after 3 months revealed a normal LV function without global wall movement disorders or a pericardial effusion.

Due to an increase in the measurable residual disease marker after the 4th cycle of HiDAC, a MUD haematopoietic stem cell transplantation was performed. Midostaurin was not resumed as per treating physicians’ decision.

Discussion

We report a case of a 24-year-old man without pre-existing cardiovascular disease who developed perimyocarditis, possibly due the multikinase inhibitor midostaurin to treat FLT3-mutated AML. With chest pain and laboratory evidence of acute myocardial cell damage, active perimyocarditis with myocardial oedema and late gadolinium enhancement was detected in the CMR. We assumed that midostaurin could have contributed to increase the oxidative stress of the concomitant anthracycline.

FLT3 is a surface receptor with intracellular tyrosine kinase activity and an essential factor for proliferation and differentiation of myeloid progenitor cells.⁶ The pathogenesis of cardiac injury associated with FLT3-inhibitors has not yet been fully understood. FTL3 was identified as a cardioprotective system against oxidative stress–induced apoptosis. Activation with the FLT3 ligand protects cardiomyocytes from apoptosis via an Akt-dependent mechanism involving Bcl-2 family protein regulation and inhibition of the mitochondrial death pathway. The protective effect of FLT3 on cardiomyocytes may explain the possible cardiotoxic effects of FLT3-targeted anti-cancer therapy, especially in patients with pre-existing ischaemic heart disease.⁷

In a WHO Pharmacovigilance Database analysis, midostaurin as a cause of severe or fatal cardiotoxicity was identified and associated with heart failure, atrial fibrillation, pericardial disease, and QT prolongation.² Diabetes mellitus, arterial hypertension, chronic renal failure, and ischaemic heart disease were described as independent comorbidities associated with an increased risk of heart failure during therapy with tyrosine kinase-targeting drugs, in particular trastuzumab, cetuximab, panitumumab, and sunitinib.⁸ All of these factors were not present in our patient.

There are two case reports of FLT-inhibitor-induced toxicity in the literature describing lung injury during therapy (Table 1).⁹ One case of acute systolic heart failure associated with the second generation FLT3-inhibitor gilteritinib in a 56-year-old woman with relapsed AML without pre-existing cardiovascular disease has been reported. In this patient, after four doses of gilteritinib, transthoracic echocardiography revealed a new reduced ejection fraction without pericardial effusion. The CMR captured a picture of ‘patchy midwall’ suggestive of myocardial oedema or inflammation consistent with inflammatory cardiomyopathy. After discontinuation of gilteritinib and initiation of a heart failure therapy, the systolic function normalized after 5 months.¹⁰ Our patient had a different manifestation with pericardial and myocardial involvement; however, the onset of potential cardiotoxicity was within 5 days after treatment initiation, similarly early to the previously discussed patient.¹⁰ A systematic review reported that the majority of AEs occurred within 50 days of midostaurin initiation.² No further cardiac complications were observed after discontinuation of the tyrosine kinase inhibitor and initiation of a heart failure therapy while even an improvement in cardiac function was noted, despite resumption of chemotherapy.

Table 1.

Cases of midostaurin-related toxicity from the literature

Authors, journal	Title
Lee B et al., Drug Induc. Case Reports. 2018	The culprit midostaurin in a case of drug-induced pneumonitis
Poorva Vaidya et al., World J Oncol. 2019 Dec9	Midostaurin-related interstitial lung injury in FLT 3+ acute myeloid leukemia post-allogenic transplant

In a systematic review of drug-associated myocarditis reported in the WHO Pharmacovigilance Database, 188 patients received therapy with cytotoxic drugs, including daunorubicin and doxorubicin.¹¹ The risk of non-reversible cardiotoxicity of anthracyclines increases as the cumulative dose administered increases, whereas there is a different risk level for each patient.¹² In addition to dose-dependent late cardiotoxicity, there are case reports of acute anthracycline-induced cardiotoxicity which manifests as LV dysfunction, pericarditis, or arrhythmias which can be reversible.¹² In our case, the patient received RIC with daunorubicin and cytarabine, thus presenting a conceivable but less likely explanation for perimyocarditis. In addition, a toxic summing effect of both anthracycline and midostaurin was discussed among the treating team.

In the future, emerging triplet therapies consisting of the bcl-2 inhibitor venetoclax, hypomethylating agents, and FLT3-inhibitors or other targeted drugs may be implemented more frequently in the treatment of AML, while their effect on cardiac AEs remains to be determined.

To assess potential toxicity of midostaurin resulting from DDI, plasma level monitoring was performed.¹³ It revealed a level of 5.5 mg/dL, which was not considered excessively high compared to data from the RATIFY study and to real-life observations.^14,15 Therapeutic drug monitoring may be of use to identify clinically relevant DDI, especially in the presence of strong CYP3A4 inhibitors such as posaconazole which was administered as antifungal prophylaxis in our patient.¹⁶ However, routine TDM for midostaurin is not broadly available yet and reference ranges are pending to be established.

The 2022 ESC guidelines for the management of patients receiving midostaurin recommend minimizing DDIs, QTc time control, and close electrolyte surveillance.¹⁷

The early detection of cardiovascular complications and the immediate and correct treatment continues to be a challenge during anti-cancer treatment. Therefore, awareness as well as targeted preventive measures during potential cardiotoxic therapy must be warranted. It can be speculated, if there was a benefit from implementing echocardiographic monitoring or regular sampling for troponin into treatment protocols for high-risk patients and treatments, while excessive screening may also lead to potentially harmful procedures in a fraction of patients. This case highlights the necessary interdisciplinary diagnostic and therapeutic work-up to suspect, identify, and finally diagnose and treat cardiotoxicity of novel cancer treatments. To improve the management of cardiovascular diseases during cancer therapy, an interdisciplinary approach with cardiologists and oncologists is necessary, for example, by introducing a specialized cardio-oncology service.

Lead author biography

Dr Alev Kalkan is a cardiologist at Leverkusen General Hospital. She finished medical school at the University of Cologne Medical School in 2017 and absolved her residency at the Department of Cardiology of the University Hospital of Cologne. Her clinical and scientific interest lies in cardiac intensive care and emergency medicine.

Supplementary material

Supplementary material is available at European Heart Journal – Case Reports online.

 

Consent: The authors confirm that written consent for submission and publication of this case report including the images and associated text has been obtained from the patient in line with the COPE guidelines.

Funding: The compilation of this report was part of our routine duties and did not receive any additional funding.

Data availability

Non-identifiable data underlying this article will be shared on reasonable request to the corresponding author.