Life and Death

Researchers from eight different medical institutions have reported that Gleevec (imatinib mesylate) can cause significant cardiac toxicity in patients with chronic myeloid leukemia (CML) and can cause similar cardiac damage in mice. The details of this study appeared in the August 2006, issue of Nature Medicine .[1] An earlier publication from Korea reported two cases of heart failure with elevated levels of brain natriuretic peptide (BNP) following Gleevec therapy.[2]

Gleevec is the treatment of choice for patients with CML and gastrointestinal stromal tumors (GIST). Gleevec targets the kinase activity of a fusion protein Bcr-Abl and is considered to be a well tolerated drug. However, side effects do occur, including a variety of skin reactions in approximately 10% of patients, joint effusions, hypopigmentation, renal dysfunction, hepatic dysfunction, myelosuppression and anemia. Reports of mild peripheral edema have been previously reported but no episodes of congestive heart failure attributed to Gleevec have been reported. Recently, researchers from the Memorial Sloan-Kettering Cancer Center have reported that some patients taking Gleevec develop hypophosphatemia with associated changes in bone and mineral metabolism (see related news).

In the Nature Medicine report, ten CML patients treated with Gleevec at the M.D. Anderson Cancer Center in Houston developed congestive heart failure between one and 14 months after starting the drug. All had normal heart function when they began taking Gleevec with an average left ventricular ejection fraction of 56%. On repeat testing the average left ventricular ejection fraction was 25%. Biopsies of two patients showed abnormalities characteristic of toxin-induced myopathy. This report did not include the incidence of cardiotoxicity.

These authors also reported that mice treated with Gleevec developed cardiotoxicity, which resulted in dysfunction in left ventricular function leading to left ventricular dilation. In mouse heart cells, Gleevec treatment caused a loss of mitochondrial function and consequent cell death. These researchers speculated that the cardiac effect was directly due to inhibition of the Abl kinase.

These researchers recommended that patients taking Gleevec should be followed closely for signs of heart failure.

The Korean report described two patients with congestive heart failure associated with Gleevec therapy. They attributed heart failure to elevated levels of BNP.

Comments: These two studies point out that patients receiving Gleevec can develop significant congestive heart failure. Further studies will be needed to know the true incidence and whether or not there is a dose relationship. This side effect should not prevent patients with CML from taking Gleevec, but more attention should be paid to this potential side effect.

References

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[1] Kerkela R, Grazette L, Yacobi R, et al. Cardiotoxicity of the cancer therapeutic agent imatinib mesylate. Nature Medicine. 2006;12:908-916.