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Trent and colleagues, in their original study of heart failure in patients receiving imatinib, discuss the retrospective nature of similar studies and the difficulty of attributing symptoms of heart failure to the drug.1 The symptoms of heart failure, including edema and pleural effusion, can also result from T-cell abnormalities with the tyrosine kinase inhibitors. Peripheral edema can arise from a T-helper-1 (Th1) cell-mediated hypersensitive reaction, whereas pleural effusions and pulmonary involvement are known to be T-cell-mediated.2 In support of the latter, a series of 40 patients on dasatinib yielded 6 individuals who developed pleural effusions and lung involvement with lymphocytic infiltration, rather than cardiac impairment.3 If edema and pulmonary involvement develop secondary to T-cell abnormalities, withholding the drug until symptoms resolve, followed by gradual reintroduction at lower doses, is preferable to attributing these adverse effects to “drug-induced cardiac toxicity”.3

The importance of imatinib to T-cell responses has been studied. However, its effects on the balance between the Th1 and Th2 clones are likely as important.4 Although the cytokines elaborated by either of these clones can serve as autocrine growth factors, they also regulate the development and differentiation of each other.5 For this reason, edema or pleural effusion in certain individuals may be explained by the balance of Th1 to Th2 suppression by imatinib. Relative excess of the former causes adverse effects, whereas the latter can be beneficial in autoimmune disorders. Individuals with autoimmune disorders with a higher Th2:Th1 ratio are suitable candidates for imatinib for similar reasons.

Thus, it is important to dissect the adverse effects of imatinib into those related to T-cell and heart abnormalities, so that an effective drug is not withheld.

REFERENCES

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  • 1
    Trent JC, Patel SS, Zhang J, et al. Rare incidence of congestive heart failure in gastrointestinal stromal tumor and other sarcoma patients receiving imatinib mesylate. Cancer. 2010; 116: 184-192.
  • 2
    Li L, Elliott JF, Mosmann TR. IL-10 inhibits cytokine production, vascular leakage, and swelling during T-helper-1 cell-induced delayed-type hypersensitivity. J Immunol. 1994; 153: 3967-3978.
  • 3
    Bergeron A, Réa D, Levy V, et al. Lung abnormalities after dasatinib treatment for chronic myeloid leukemia. Am J Respir CritCareMed. 2007; 176: 814-818.
  • 4
    Seggewiss R, Price DA, Purbhoo MA. Immunomodulatory effects of imatinib and second generation tyrosine kinase inhibitors on T cells and dendritic cells. Cytotherapy. 2008; 10: 633-641.
  • 5
    Abbas AK, Murphy KM, Sher A. Functional diversity of helper T lymphocytes. Nature. 1996; 383: 787-793.

Jecko Thachil MRCP, FRCPath*, * University of Liverpool, Liverpool, United Kingdom.