Congestive heart failure is a rare event in patients receiving imatinib therapy

Imatinib is a selective inhibitor of the Abl, platelet-derived growth factor receptor (PDGFR), and stem cell receptor (c-Kit) tyrosine kinases.¹  Imatinib has revolutionized the treatment of chronic myeloid leukemia (CML) and other diseases such as Philadelphia chromosome (Ph)–positive acute lymphoblastic leukemia (ALL), hypereosinophilic syndrome (HES), and gastrointestinal stromal tumors (GISTs).^2–6  In CML, more than 80% of patients achieve a complete cytogenetic remission with imatinib. After 60 months, a projected 89% of patients are alive and 83% are alive and event-free.⁷  In Ph⁺ ALL, the addition of imatinib to standard chemotherapy has led to a significant improvement in remission duration and overall survival in both newly diagnosed and refractory patients.^5,6 Other potential therapeutic benefits of imatinib have been suggested, such as decreased pulmonary pressure in patients with pulmonary hypertension⁸  and lower cholesterol.⁹ 

Overall, imatinib is well tolerated. The commonly reported adverse events are nausea, diarrhea, muscle cramps, skin rash, and fluid retention.¹⁰  Recently, a preclinical study by Kerkelä and colleagues¹¹  suggested that imatinib may be cardiotoxic in animal models. Cardiac muscle biopsies of mice treated with 200 mg/kg of imatinib revealed stress-induced mitochondrial changes such as mitochondrial biogenesis, increased numbers of mitochondria, and pleomorphic mitochondria. The investigators studied the mechanisms of these events and suggested it might be related to inhibition of Abl. Cardiomyocytes transduced with the imatinib-resistant c-abl with a T315I mutation were protected from the imatinib-induced cell death.¹¹  In addition, 10 patients who had developed congestive heart failure (CHF) and had been exposed to imatinib at some point were summarized. The report, however, did not assess the frequency of this adverse event or the potential risk factors associated with it. To evaluate the incidence and significance of CHF in patients treated with imatinib, we analyzed our experience in patients treated with imatinib.

The medical records of all patients with hematologic malignancy (including ALL, acute myeloid leukemia, CML in any phase of the disease, or myeloproliferative disorders such as polycythemia vera, hypereosinophilic syndrome, systemic mastocytosis, and chronic myelomonocytic leukemia) who received imatinib on clinical trials at the M. D. Anderson Cancer Center from July 28, 1998, to July 27, 2006, were reviewed. Institutional review board (IRB) approval was granted by the M. D. Anderson Cancer Center, and informed consent was obtained in accordance with the Declaration of Helsinki. In addition, all recorded and reported serious adverse events in these patients were reviewed, with particular attention to those considered to have some potential cardiac origin. These included shortness of breath, dyspnea, chest pain, arrhythmia, cardiac events, myocardial infarction, angina, pleural effusion, and peripheral edema. In these trials, patients received imatinib alone or in combination with chemotherapy or other investigational agents (ie, tipifarnib, lonafarnib, decitabine, or homoharringtonine). In these trials, patients were seen at our institution every 1 to 3 months for the first year and every 3 to 6 months after that. Patients were asked to keep a diary documenting intake of their medication as well as any adverse events they may have encountered. Between visits to our institution, patients followed up with their local physicians, and the research personnel followed the patients by telephone for compliance and adverse events. All adverse events that were unexpected (ie, not listed in the investigator's brochure) or serious (ie, resulting in death, life-threatening adverse experiences, hospitalization, persistent disability, or congenital abnormality or birth defect) were required to be reported to the IRB. All other adverse events were not reported to the IRB, but had to be submitted as part of the annual review and final report of each protocol. The prior history of patients was reviewed with particular attention to conditions considered to constitute a cardiac risk factor. Similarly, the patients' medications before the start of imatinib or at the time treatment was started were recorded. All clinical notes, consultation notes, concomitant medications, laboratory tests, radiologic and other imaging tests, and any cardiac work-up performed on these patients around the time of the adverse event were reviewed. The Framingham criteria were applied to patients with symptoms or signs of systolic heart failure.¹²  Patients with a documented low cardiac ejection fraction were also considered to have CHF, even in the absence of symptoms.

A total of 1276 patients were enrolled on imatinib clinical trials and included in this analysis. The median follow up from the time imatinib was started was 47 months (range, 1 to 86 months). The median age for all patients was 52 years (range, 15 to 84 years); 536 were women. The imatinib dose at time of enrollment was less than 400 mg in 18 patients, 400 mg in 519 patients, 500 mg in 7 patients, 600 mg in 460 patients, 800 mg in 265 patients, and 1000 mg in 6 patients. A total of 22 patients were identified as having CHF during the course of imatinib therapy. The median age for the 22 patients was 70 years (range, 49 to 83 years), and 10 were women (Table 1). Their diagnosis at the time of imatinib initiation was: CML in chronic phase (CP) in 11 patients (out of 561 patients treated in CP; 1.96%), accelerated phase (AP) in 4 patients (out of 384 patients treated in AP; 1.04%), blastic phase (BP) in 2 patients (of 123 patients; 1.62%); myeloproliferative disorder in 4 patients (of 124 patients treated; 3.2%); and Ph⁺ ALL in 1 patient (of 74 patients treated; 1.35%). Also reviewed were 10 patients with c-kit⁺ AML who received imatinib, but none developed CHF.

The incidence of new onset CHF increased with increasing age. None of the patients who were younger than 45 years developed symptoms of CHF. The incidence was 0.3% (1 in 322 patients) among patients aged 45 to 55 years, 1.7% (5 in 291 patients) among those aged 56 to 65 years, 2.8% (6 in 211 patients) for patients aged 66 to 75 years, and 9.3% (4 of 43 patients) for those aged 76 to 85 years. There was no correlation between dose and incidence of CHF. There were 5 (2%) instances of CHF of the 271 patients treated with a starting dose of 800 mg or higher, compared with 8 (2%) of 467 treated at a dose of 500 to 600 mg daily, 8 (2%) of 519 receiving 400 mg daily, and 1 (6%) of 18 treated with 300 mg daily.

Of the 22 patients with CHF, 12 (55%) patients had received prior interferon-α (IFN-α) therapy for a median of 14 months (range, 2-79 months), and 3 patients had received anthracyclines (Table 2). Of the 3 patients who received anthracyclines, 2 developed CHF while on anthracycline therapy (1 patient after third cycle of HyperCVAD [total doxorubicin dose of 100 mg/m²]; the second shortly after receiving the first cycle of idarubicin [12 mg/m²], cytarabine, and imatinib). The third patient had received doxorubicin 15 years before developing CHF. A total of 18 (82%) of the 22 patients had previous cardiac conditions or other medical conditions that could be considered as risk factors for cardiac disease: prior history of CHF (6 [27%]patients), diabetes mellitus (DM; 6 [27%] patients), hypertension (10 [45%] patients), coronary artery disease (CAD; 8 [36%] patients), arrhythmia (3 [14%] patients), and cardiomyopathy (1 [5%] patient). The median time from start of imatinib therapy to a cardiac adverse event was 162 days (range, 2-2045 days), and the daily dose of imatinib at the time of CHF was 300 mg in 1 patient, 400 mg in 8 patients, 600 mg in 8 patients, and 800 mg in 5 patients. Thus, 9 (1.6%) of 537 patients who received therapy with 400 mg/day imatinib or less developed CHF, compared with 13 (1.7%) of 738 treated at higher doses (P = .99).

At the time CHF was identified, 8 of the cases were considered possibly or probably related to imatinib. A total of 15 patients had an echocardiogram or multiple gated acquisition (MUGA) scan at the time of the event, and 9 of the 15 had documented low left ventricular ejection fractions (LVEFs; < 50%). In only 2 of these 9 patients was there an echocardiogram done prior to imatinib (LVEF 45-50% and 50-59%, respectively). Of the 9 patients with low ejection fractions at the time of the event, 7 had one or more prior cardiac conditions (4 had CAD, 2 had CHF, and 1 had cardiomyopathy) or hypertension (3 patients). Of the other 2 patients, 1 was on anagrelide prior to the event, and the other had progressive disease with blast crisis and ultimately died 13 months later (no further cardiac follow-up). Half (11) of the 22 patients continued imatinib therapy with dose adjustments and management of CHF symptoms without further complications. Of the 11 patients who continued therapy, 5 had imatinib dose reductions, and 6 continued at the same imatinib dose. In addition to dose modifications, diuretics, beta blockers, and angiotensin-converting enzyme inhibitors were added to the treatment regimen. Of the 11 patients who discontinued therapy, 3 had disease progression, 6 patients discontinued therapy because of CHF, and 2 died while on therapy (1 from neutropenic sepsis; and 1 with progressive disease with ascites, lower limb edema, and dyspnea prior to imatinib initiation; this patient received imatinib for 2 days but continued with deterioration of his general condition and died on the third day). No postmortem analysis was done on these 2 patients.

We also reviewed all deaths on the study. A total of 18 patients died while receiving imatinib (including the 2 patients previously mentioned). Of those, the cause of death was disease progression in 10 patients, sepsis in 3 patients, unknown causes in 3 patients, central nervous system hemorrhage in 1 patient, and CHF in 1 patient (previously mentioned).

Conflicting animal and in vitro data regarding the cardiac effects of imatinib have been published.^11,13,14  In 1 study, imatinib was found to be cardioprotective in hypertensive rats. In this model, homozygous TGR (mRen2) 27 rats were used. These animals develop hypertension and left ventricular (LV) dysfunction secondary to persistently increased angiotensin levels. Angiotensin also activates PDGFR, leading to activation of extracellular signal–related kinase (ERK) 1/2 signaling, which in turn leads to LV dysfunction and cardiac collagen accumulation. The investigators demonstrated a cardioprotective effect of imatinib possibly mediated through inhibition of PDGFR both in animals and in cell cultures.¹⁴ 

The second study suggested a cardiotoxic effect of imatinib through inhibition of c-abl, leading to activation of the endoplasmic reticulum stress response. This ultimately activates jun amino terminal kinases (JNKs). JNK has several targets, 1 of which is BCL2-associated X protein (Bax). Activated Bax causes collapse of the mitochondrial potential, release of cytochrome c, and cell death.¹¹  This study suggested that imatinib is cardiotoxic, and that its use can lead to severe left ventricular dysfunction and heart failure. The conclusion was based on the cell culture and animal studies, as well as a collection of 10 patients identified as having CHF while receiving imatinib. Of those 10 patients, 5 are included in this analysis (3 with CML, 1 with essential thrombocytosis, and 1 with ALL). The other 5 were either not enrolled on clinical trials, did not have leukemia, or were not treated at our institution.

In this analysis, we evaluated the incidence of CHF among patients receiving imatinib on clinical trials. After a median follow-up time of 47 months, we identified 22 (1.7%) patients who met the Framingham criteria for CHF. Patients who developed CHF were older than those who did not have this complication (median age, 70 years vs 52 years; P = .001). The incidence of CHF increased with increasing age: none of the youngest patients developed CHF; 9% of patients aged 75 years had CHF. This is similar to the reported incidence of CHF in the general population, where the 5-year risk of developing CHF increases with age. In the Framingham study, the 5-year risk of CHF for men was 0.8%, 1.3%, 4%, and 8.3% for patients at the index ages of 40, 50, 60, 70, and 80 years, respectively. For women, the 5-year risk of CHF was 0.1%, 0.1%, 0.7%, 2.2%, and 7.8%, respectively (Table 3).¹⁵ 

DM, hypertension, coronary artery disease, arrhythmia, and history of CHF (all well known heart failure risk factors)^16–18  were present in 18 of the 22 patients. In addition, 13 (59%) patients had previously received 1 or more known cardiotoxic drugs^19–21  (IFN-α in 12 patients, anthracyclines in 3 patients, and anagrelide in 1 patient). CHF could have been precipitated or exacerbated by imatinib-associated fluid retention in these patients with a possibly already compromised heart function. Fluid retention is a known side effect of imatinib reported in previous studies, with grades 3 and 4 incidence ranging from 1.4% to 8% (Table 4). This complication decreased with longer follow-up with fluid retention (all grades) occurring in 20.2% and 5.6% of patients at 2 and 4 years, respectively, in the IRIS study.²⁸ 

In response to the original observation by Kerkelä et al, several letters were published, including a preliminary analysis of our own experience, all of them suggesting a very low incidence of reported CHF.^29–32  In the Novartis clinical database, which includes 2327 patients with an average exposure of 2.5 years, 12 cases of CHF were considered to be possibly or probably related to imatinib. With 5595 years of exposure, the calculated incidence was 0.2% per year.²⁹  The Italian cooperative study group on CML reviewed their experience with imatinib in 4 consecutive studies and found 3 confirmed cardiac deaths in 833 patients. All 3 patients died of myocardial infarction with no history of left ventricular dysfunction.³⁰ 

It is possible that this analysis underestimates the incidence of cardiotoxicity, considering the retrospective nature of the analysis, and that it included only patients on clinical trials with documented reported adverse events, usually grade 3 or 4 toxicities. However, patients in these studies were rigorously monitored and followed prospectively, and all adverse events were reviewed and reported, with multiple layers of quality control. It is also possible that subclinical cardiotoxicity might have been overlooked, as patients were not routinely followed with cardiac evaluation (eg, by echocardiogram or brain natriuretic peptide). However, we believe that such clinically insignificant variations in cardiac function, and even the more clinically relevant ones, are outweighed by the extraordinary benefit derived with imatinib in these patients with leukemia. One important issue to consider is the potential interaction with other medications, whether prescription, over the counter, or chemotherapy/biological agents that patients may be using while on imatinib. Because of the nature of this analysis, we can only address the concomitant chemotherapeutic or biologic agents administered to those patients. A total of 16 patients received single-agent imatinib, while 6 received imatinib in combination with other chemotherapeutic or biologic agents (3 with interferon and cytarabine, 1 with decitabine, 1 with idarubicin and cytarabine, and 1 with the HyperCVAD regimen).

We conclude that CHF is very uncommon in patients receiving imatinib. It appears to occur at rates similar to those expected in the general population. Fluid retention should be managed adequately, and symptoms suggestive of systolic heart failure should be properly investigated and managed when they occur. At the present time, there is no indication for routine cardiac monitoring of all patients treated with imatinib. Certainly, patients with significant cardiac history should be followed closely, and those with symptoms suggestive of a possible cardiac condition be properly and opportunely evaluated.

Contribution: E.A. designed and research, analyzed data, and wrote the paper; J.B. analyzed data and reviewed the paper; H.K. designed research and reviewed the paper; and J.C. designed research, analyzed data, and wrote the paper.

Conflict-of-interest disclosure: H.K. and J.C. receive research funds from Novartis Pharmaceuticals, whose product was studied in the present work. The other authors declare no competing financial interests.

Correspondence: Jorge Cortes, Department of Leukemia, The University of Texas, M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Unit 428, Houston, TX 77030; e-mail: jcortes@mdanderson.org.