Late-chronic cardiotoxicity and heart failure caused by ibrutinib:a case report and literature review

JianZHU, Su-YanBIAN?

Department of Cardiology, the Second Medical Center, National Clinical Research Center of Geriatric Disease, Beijing Key Laboratory of Chronic Heart Failure Precision Medicine, Chinese PLA General Hospital, Beijing, China

Richter syndrome (RS) is a rare transformation of relatively low-grade malignant chronic lymphocytic leukemia (CLL) to more aggressive lymphoma. The most common form of RS is transformation to diffuse large B-cell lymphoma (＞ 95%) and much less frequently (＜ 1%)to Hodgkin lymphoma (HL), plasma blast lymphoma, or other rare lymphomas.[1]Once transformed,the prognosis is extremely poor with a median survival of five to fourteen months.[2]There are presently no standard salvage approaches for RS.[3]

Ibrutinib, oral irreversible Bruton’s tyrosine kinase (BTK) covalent inhibitor, has been proved efficient and well-tolerated in the treatment of CLL/small lymphocytic lymphoma (SLL) and other hematologic malignancies.[4-6]Due to its remarkable efficacy for relapsed and refractory CLL/SLL, a few studies investigated ibrutinib’s efficacy in patients with RS, which have achieved some activity for both ibrutinib monotherapy[7,8]and in combination with nivolumab.[8-10]With the increasing use of ibrutinib, more and more cardiovascular adverse drug reactions (CV-ADR) have emerged.[11]Hypertension and arrhythmia are reported as the most common CV-ADRs of ibrutinib. Recently, a small case series of heart failure (HF)[12]and cardiovascular toxicity[13]associated with ibrutinib have been addressed. However, to be best of our knowledge,ischemic myocardial injury with HF has not been reported. Herein, we will present a case of new-onset myocardial ischemia with non-obstructive coronary arteries and heart failure with preserved ejection fraction developed seventeen months after treatment with ibrutinib for relapsed RS.

An 83-year-old Chinese man presented with an enlarged right cervical lymph node (LN) occasionally detected by an annual physical examination in June 2008. Six months later, he was initially diagnosed as Binet B, Rai stage I (Binet and Rai are commonly used staging criteria for chronic lymphocytic leukemia) CLL/SLL on the LN biopsy. The patient was managed with wait and see until December 2014, when he developed constitutional symptoms and progressive LN enlargement. Core needle biopsy of the newly enlarged submandibular LN confirmed his diagnosis as the RS transformation to non-Hodgkin’s lymphoma (T and B cells mixed type). Therefore, he was treated with interferon for three weeks (30 μg per day), resulting in a partial response. However, three months later, repeated LN biopsy revealed Richter’s transformation to classical HL, mixed cell type. Thus, R-ABVD (rituximabadriamycin + bleomycin + vincaleukoblastinum +dacarbazine) chemotherapeutic regimen was applied to reach a complete remission (CR) though with a IV degree of myelosuppression. Stringent follow-up was adopted until March 2019, when his disease relapsed with progressive lymphadenopathy, among which the largest LN in the abdominal cavity was measured 7 cm × 5 cm on magnetic resonance scan with a specific uptake value of 9.4 on fludeoxyglucose positron emission tomography.Ibrutinib was initiated at a dose of 280 mg, then added to 420 mg daily from April 2019, with which our patient achieved CR after six months. However,the patient presented to outpatient clinics with occasional epigastric pain on April 21, 2020. Electrocardiography (ECG) was detected with newly emerged inverted T waves in leads V3 to V5 (Figure 1). Further coronary computed tomography angiography examination showed multiple calcified plaques in the three main coronary arteries (calcification Agatston score: 343.3) with only minor or mild lumen stenosis (Figure 2). He was not receiving any other prescribed medication except ibrutinib and rosuvastatin. On September 1, 2020, the patient was hospitalized with persistent dull pain in the left upper abdomen accompanied by progressive fatigue.Further examination ruled out the most common acute abdominal diseases. Repeated ECG on September 6 showed the T wave inversion in the pre cordial leads deeper than ever. At the same time, he was noted to have an elevated troponin I of 0.236 μg/L(Reference: 0.00-0.07 μg/L) and N-terminal probrain natriuretic peptide (NT-proBNP) of 2,798 pg/mL (Reference: ＞ 75 years old, ＜ 450 pg/mL),which peaked at 0.576 μg/L and 3,485 pg/mL respectively during his hospitalization. Transthoracic echocardiography (TTE) showed a normal left ventricular ejection fraction (LVEF) of 57%, mildly enlarged left ventricle [left ventricular end-diastolic diameter (LVEDD) 55 mm], and slightly diffused hypokinesis in the apex, lateral and anterior wall of the left ventricle, but no evidence of structure and valvular heart disease. Then, he was diagnosed as non-ST-segment elevation myocardial infarction(NSTEMI). Aspirin, clopidogrel, metoprolol, isosorbide mononitrate, and rosuvastatin were given according to cardiologic risk stratification and adherence to NSTEMI guidelines. Moreover, he was managed for HF with loop diuretics and natriuretic peptide. Then, cardiac catheterization was performed to rule out ischemic heart disease, revealing three-vessel nonobstructive coronary artery disease (Figure 3). A myocardial perfusion magnetic resonance imaging was also performed, which showed a LVEF of 44%with no signs of myocardial scarring (Figure 4).Considering the probability of late-chronic cardiotoxicities related to the use of ibrutinib, the frequent bleeding side effects of ibrutinib, especially when combined with the dual antiplatelet therapy,and the sustained remission of RS, ibrutinib was discontinued from October 30, 2020. Then his symptoms gradually disappeared, serum troponin I and NT-proBNP turned back to normal after ten days. A repeat TTE in November 2020 showed a LVEF of 61%, LVEDD 49 mm, and no regional wall motion abnormalities. However, the T wave inversion in the precordial leads persistently detected in ECG until February 2021, when the T wave changes significantly improved.

Figure 1 The 12-lead electrocardiogram study. A serial electrocardiograms has been taken before and after the initiation of ibrutinib,which showed the gradually deepened T waves in precordial leads V1 through V6. However, after ibrutinib discontinued, these T waves inversions slowly restored. NT-proBNP: N-terminal pro-brain natriuretic peptide.

Figure 2 Coronaries and LV morphology visualized by 64-slice multidetector computed tomography. (A): Curved CT image shows calcium plagues in proximal LAD coronary artery with slight stenosis; (B): curved CT image shows relatively normal RCA; (C): curved CT image shows normal LCX coronary artery; and (D): normal LV morphology. CT: computed tomography; LAD: left anterior descending artery; LCX: left circumflex artery; LV: left ventricle; RCA: right coronary artery.

Though our patient had a history of hypertension for twenty years, his blood pressure had been well controlled with essentially normal cardiac function. Neither heart disease nor other cardiovascular risk factors was reported before initiation of ibrutinib. He suffered from atypical epigastric pain with abnormal ECG T wave findings at 12thmonth of ibrutinib treatment, then progressed to symptomatic HF with solid evidence of myocardial injuries, including ischemic T wave inversion, positive cardiac biomarkers, and left ventricular global hypokinesis at 17thmonth of ibrutinib use. Surprisingly though, a negative workup for ischemic or valvular etiologies of cardiac injury, leading to the presumptive conclusion that ibrutinib was the cause of his cardiac injury. The prompt improvement in cardiac function after cessation of ibrutinib also suggested a causative role of ibrutinib in our patient’s presentations. To the best of our knowledge, this is the first reported case of ibrutinib-induced ischemic myocardial injury with non-obstructive coronaries and HF.

Figure 3 Coronary angiographic studies. Neither (A) nor (B) shows significant stenosis in the left and right coronary arteries with coronary angiography.

Figure 4 Cardiac magnetic resonance imaging results. (A): Left ventricular diastolic image from the apical five-chamber view; (B):left ventricular systolic image from the apical five-chamber view; (C): left ventricular diastolic image from the apical two-chamber view; (D): left ventricular systolic image from the apical two-chamber view; (E): myocardial perfusion image of the apical five-chamber view; and (F): myocardial perfusion image of the short axis of the heart. LA: left anterior; LP: left posterior; RA: right anterior; RP: right posterior.

Tyrosine kinases (TKs) are enzymes that play a major role in growth factor signaling, both in normal and malignant cells. As a member of the nonreceptor TKs kinase family, BTK is expressed in nearly all cells of the hematopoietic system and involved in many other signal transduction pathways in B cells. Therefore, it is regarded as a star target for the treatment of B-cell malignant tumors.Ibrutinib selectively and irreversibly inhibits BTK within B lymphocytes to block constitutively activated intracellular signaling pathways which are essential for cell migration and survival. Due to ibrutinib’s high specificity for the BTK receptor, relatively little off-target toxicity would be expected.Currently, the exact mechanism of chronic cardiotoxicity caused by ibrutinib has not yet been fully clarified. It has been hypothesized that inhibition of inositol phosphoinositide 3-kinase (PI3K)-Akt pathway with ibrutinib via BTK is suggested to be the most probable explanation of the development of cardiac injury and HF.[14]The PI3K-Akt pathways have been confirmed to be important for cardiac myocyte homeostasis and play a critical role in cardioprotection under stress.[15-17]Inhibition of BTK with ibrutinib might down-regulate the cardio-protective signaling mediated by PI3K/Akt, which might be involved in ibrutinib’s cardiotoxicities.[15]

In summary, though ibrutinib showed active and well-tolerated in this elderly patient with Richter transformation, chronic cardiotoxicity and HF might be related to this medication. Extended follow-up,closer monitoring and CV-ADR investigation after ibrutinib initiation are essential even for asymptomatic patients to check for possible side effects including serious cardiac events.

ACKNOWLEDGMENTS

This study was supported by the National Nature Science Foundation of China (No.81670217). All authors had no conflicts of interest to disclose.