To the editor:

Imatinib has had an impressive impact on the management of chronic myeloid leukemia (CML) patients, with the majority achieving durable complete cytogenetic responses, and, at present, tyrosine kinase inhibitor therapy is expected to be life-long. As a result of this dramatic change in the prognosis of CML, new clinical and scientific challenges are to be met and the clinical focus now includes the management of long-term side effects.

It is anticipated that most patients with newly diagnosed hematologic malignancies will experience weight loss before and during the initial course of treatment because of a multifactorial process. The impact of imatinib therapy on body habitus in newly diagnosed patients with CML has not been previously reported. We conducted a retrospective analysis on weight change in newly diagnosed patients with CML in chronic phase (CP) subsequently treated with imatinib. Fifty adult patients with CML (median age 47.6 years [25-78]; male [n = 29], female [n = 21]) in CP were consecutively treated with 400 mg daily of imatinib and their weight analyzed at 6 monthly intervals for a period of 24 months. Patients were excluded if additional co-morbidities that could influence weight loss or gain were present, such as thyroid disorders, diabetes, and clinical fluid retention. The median weight at the start of imatinib therapy was 76.8 kg (range 49.7-123). There was a statistically significant gain in weight in evaluable patients even at 6 months (P < .0001), with more than 75% of patients gaining weight (Tables 1 and 2). The median BMI at the start of imatinib therapy was 26.3 kg (18.3-47.5) Our data show that even with a high starting percentage of by definition, obese (BMI > 30) patients (20%), the percentage of obese patients more than doubles by 18 months after the start of imatinib treatment, and is statistically significant.

Obesity is associated with increased cancer incidence and mortality. Complex molecular links exist between obesity and metabolic dysfunction. Imatinib principally targets the tyrosine kinase activity of BCR-ABL1, in addition to inhibitory effects on KIT, ARG, and platelet-derived growth factor receptor (PDGFR) kinases. Obesity is recognized to be associated with macrophage accumulation and inflammation in adipose tissue and macrophage-secreted factors have been reported to inhibit the differentiation of preadipocytes into adipocytes.1  Macrophage-conditioned medium has been found to stimulate PDGFR tyrosine phosphorylation, which can be inhibited by the addition of imatinib. Inhibition of PDGFR by imatinib has been found to disrupt the prosurvival effect on preadipocyte survival. PDGF is also strongly implicated in atherosclerosis and stimulates proteoglycan synthesis, however imatinib reduces low-density lipoprotein binding in vitro and aortic deposition in vivo.2  Imatinib has also been variably reported to have a favorable effect on glucose metabolism in diabetic patients, possibly by affecting insulin signaling pathways,3  protection against pancreatic cell death, and improved insulin sensitivity. Furthermore, imatinib has been reported to induce normalization of the levels of serum cholesterol, triglycerides as well as low- and high-density lipoproteins. Mast cell disorders can be responsive to imatinib and it is notable that mast cells have been recognized to contribute to diet-induced obesity and diabetes.4 

Therefore, it is apparent that the observed increase in weight of several patients treated with imatinib may be secondary to a complex etiology. Further prospective investigations aimed at investigating the molecular mechanisms of this metabolic effect and its clinical impact is warranted.

Acknowledgments: The authors are grateful for support from the National Institute of Health Research Biomedical Research Centre Funding Scheme (United Kingdom).

Conflict-of-interest disclosure: The authors declare no competing financial interests.

Correspondence: Dr Dragana Milojkovic, Department of Haematology, Imperial College London, Du Cane Road, London W12 0NN, United Kingdom; e-mail: d.milojkovic@imperial.ac.uk.

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