Correspondence

Another Look at Imatinib Mesylate

N Engl J Med 2007; 356:1183March 15, 2007

Article

To the Editor:

Strebhardt and Ullrich (Dec. 7 issue)1 discuss the study by Kerkelä et al., which suggested that imatinib is cardiotoxic.2 However, there are controversial data on the role of imatinib on cardiac function that are not discussed. We published data showing that a reduced dose of imatinib (30 mg per kilogram of body weight per day) was cardioprotective in hypertensive rats.3 Kerkelä et al. examined various doses of imatinib but showed a loss of cardiac function only at higher doses than those used in other studies.3-5 Furthermore, clinical evidence of the cardiotoxicity of imatinib is circumstantial. Only 3 of 10 selected patients who received imatinib and subsequently had cardiac dysfunction were free of underlying cardiac disease or risk factors. No detailed cardiac data are available for subjects receiving imatinib who did not have heart failure.

For the time being, the evidence of the clinical significance of the cardiotoxicity of imatinib remains thin. There is a need for studies to evaluate how frequently cardiotoxicity develops in patients receiving imatinib, taking into account dose levels of the drug, preexisting cardiac conditions, and the use of additional cardiotoxic drugs.

Mark W. Schellings, M.Sc.
Maastricht University, 6229 ER Maastricht, the Netherlands

Bob Löwenberg, M.D., Ph.D.
Erasmus Medical Center, 3000 CA Rotterdam, the Netherlands

Yigal M. Pinto, M.D., Ph.D.
University Hospital Maastricht, 6202 AZ Maastricht, the Netherlands
y.pinto@cardio.azm.nl

Dr. Pinto reports receiving consulting fees from Novartis.

5 References

1. 1

   Strebhardt K, Ullrich A. Another look at imatinib mesylate. N Engl J Med 2006;355:2481-2482
   Full Text | Web of Science | Medline

2. 2

   Kerkela R, Grazette L, Yacobi R, et al. Cardiotoxicity of the cancer therapeutic agent imatinib mesylate. Nat Med 2006;12:908-916
   CrossRef | Web of Science | Medline

3. 3

   Schellings MW, Baumann M, van Leeuwen RE, et al. Imatinib attenuates end-organ damage in hypertensive homozygous TGR(mRen2)27 rats. Hypertension 2006;47:467-474
   CrossRef | Web of Science | Medline

4. 4

   Lassila M, Allen TJ, Cao Z, et al. Imatinib attenuates diabetes-associated atherosclerosis. Arterioscler Thromb Vasc Biol 2004;24:935-942
   CrossRef | Web of Science | Medline

5. 5

   Schermuly RT, Dony E, Ghofrani HA, et al. Reversal of experimental pulmonary hypertension by PDGF inhibition. J Clin Invest 2005;115:2811-2821
   CrossRef | Web of Science | Medline

Author/Editor Response

There is no doubt that the kinase inhibitor imatinib has revolutionized the treatment of patients with chronic myeloid leukemia (CML). In a recent randomized study of 553 patients, the 5-year estimated survival rate was 89% for patients receiving initial imatinib therapy at a daily dose of 400 mg.1 Congestive heart failure was an extremely rare event in this study. Other trials involving patients with CML have also shown that imatinib greatly improves the risk–benefit ratio.1,2 The 10 patients described by Kerkelä et al.3 had preexisting conditions, including hypertension in 7 patients, diabetes in 4, and coronary artery disease in 3. Seven patients received elevated daily doses of imatinib (600 to 800 mg); all 10 patients had normal left ventricular function before treatment, and cardiac dysfunction developed after 1 to 14 months of therapy.3 Recent recommendations call for a 400-mg dose of imatinib as standard treatment for CML; the dose may be increased to 600 to 800 mg if patients have a suboptimal response or if treatment fails.4 Careful, long-term monitoring of individual patients is required to answer the question of whether elevated doses of imatinib substantially increase the risk of cardiotoxicity, as Kerkelä et al. observed in humans and mice.

Klaus Strebhardt, Ph.D.
J.W. Goethe University, 60590 Frankfurt, Germany

4 References

1. 1

   Druker BJ, Guilhot F, O'Brien SG, et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med 2006;355:2408-2417
   Full Text | Web of Science | Medline

2. 2

   Kantarjian H, Sawyers C, Hochhaus A, et al. Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. N Engl J Med 2002;346:645-652[Erratum, N Engl J Med 2002;346:1923.]
   Full Text | Web of Science | Medline

3. 3

   Kerkela R, Grazette L, Yacobi R, et al. Cardiotoxicity of the cancer therapeutic agent imatinib mesylate. Nat Med 2006;12:908-916
   CrossRef | Web of Science | Medline

4. 4

   Baccarani M, Saglio G, Goldman J, et al. Evolving concepts in the management of chronic myeloid leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood 2006;108:1809-1820
   CrossRef | Web of Science | Medline

Citing Articles (1)

Citing Articles

1. 1

   Antonio Luiz Ribeiro, Milena Soriano Marcolino, Henrique N.S. Bittencourt, Márcia M. Barbosa, Maria do Carmo P. Nunes, Vitor Fonseca Xavier, Nelma C.D. Clementino. (2008) An evaluation of the cardiotoxicity of imatinib mesylate. Leukemia Research 32:12, 1809-1814
   CrossRef