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Imatinib Mesylate May Improve Fasting Blood Glucose in Diabetic Ph+ Chronic Myelogenous Leukemia Patients Responsive to Treatment

University "La Sapienza," Rome, Italy

To the Editor:

Imatinib mesylate therapy has shown significant activity against Philadelphia-chromosome positive chronic myelogenous leukemia (Ph + CML). This drug is a selective competitive inhibitor of the Bcr-Abl tyrosine kinase, but at therapeutic concentrations, it also inhibits the activity of other tyrosine kinases such as platelet-derived growth factor receptor beta (PDGF-ß) and c-kit.¹ Imatinib can be safely administered in CML patients with type 2 diabetes.

Here we report on our experience on the treatment of seven diabetic CML patients with imatinib. In six of these patients, we observed an improvement of fasting blood glucose levels (FG), which allowed a consequent reduction of oral antidiabetic drugs or insulin dosage. Of the seven patients, three were men, and four were women; median age was 66 years (range, 57 to 70 years). Four patients were in chronic phase, and all were given imatinib at 400 mg/d; of these four patients, three were resistant to prior interferon alfa (IFN-) given for a median of 25 months, while in one patient, imatinib was the first-line therapy. Three patients were in accelerated phase and were given imatinib at 600 mg/d; all of them had been pretreated with IFN- and hydroxyurea for a median time of 20 months.

All patients had been diagnosed as diabetic at least 10 years before CML onset. Three patients were using insulin, and four patients were taking oral antidiabetic drugs for glycemic control. Before starting with imatinib the median glucose level was 220 mg/dL (range, 162 to 305 mg/dL). After 3 months of therapy, six of seven patients had obtained a complete cytogenetic response. At the same time, concomitant improvement of FG with consequent reduction of antidiabetic drugs dosage was observed, although patients had apparently maintained the same lifestyle and alimentary habits. In particular, median FG was 110 mg/dL (range, 96 to 127 mg/dL), as compared with an FG of 160 mg/dL (range, 96 to 220 mg/dL; P = .0004) as evaluated after 3 months of precedent IFN- therapy. At the time of this writing, all patients have completed 12 months of therapy, six have maintained cytogenetic response and concomitant good glycemic control (median glucose level, 108 mg/dL; range, 89 to 124 mg/dL; as compared with 208 mg/dL; range, 171 to 245 mg/dL after 12 months of precedent therapy; P = .004) still on reduced antidiabetic drugs dosage. Only the accelerated-phase patient (patient 1), who was resistant to imatinib after 1 year of therapy, did not obtain a good control of blood glucose level despite increasing insulin dosages. Differences between fasting glucose concentrations before and after imatinib therapy are shown in Figure 1.

View larger version (45K): [in this window] [in a new window]   Fig 1. Patient 1 was unresponsive to imatinib. Patient 3 was treated with imatinib as first-line therapy. IFN, interferon; FG, fasting blood glucose; pt., patient.

In our experience, only patients responding to imatinib concomitantly obtained an improvement of FG; this suggests that the drug, at therapeutic concentrations, may act not only on Bcr-Abl tyrosine kinase, but also on intracellular pathways involved in peripheral insulin action in the host's normal cells, through metabolic changes capable of influencing the normal enzyme activities in these cells as well.

In type 2 diabetes, the normal insulin signaling pathways are disrupted, and abnormal signaling in muscle, adipose tissue, liver, and pancreas leads to insulin resistance.⁵ Insulin resistance is brought about by a reduction of key signaling proteins such as insulin receptor substrate (IRS) -1 and IRS-2, and recently, a role for elevated free fatty acid concentrations and/or accumulation of intracellular lipids has been evoked in reduced-insulin sensitivity. It is possible that, as for K562 cells in vitro, imatinib also exerts its effect on normal cells in vivo by reducing fatty acid concentrations through a low rate of glucose carbon flow. However, it cannot be excluded that imatinib could interfere with any of the potentiallly disrupted molecular mechanisms downstream the IRS in the "diabetic cell," thus contributing to restore almost normal glucose tolerance.

Another rather simplistic interpretation of our findings could be that glucose tolerance was improved in CML patients as a positive side effect of leukemic response, which could, by itself, imply reduced insulin resistance. However, this hypothesis is weakened by the clinical observation that four of the seven patients studied achieved disease remission with no improvement of FG during prior IFN- therapy.

In conclusion, we suggest that the role of imatinib on glucose metabolism warrants further investigation both in diabetic and nondiabetic CML patients. In fact, gaining insight into the yet partially unknown mechanisms of action of imatinib might, on one hand, contribute to overcoming imatinib resistance in hematologic malignancies and, conversely, help to better understand molecular abnormalities underlying insulin resistance in diabetes and other pathological conditions.

Authors' Disclosures of Potential Conflicts of Interest

The authors indicated no potential conflicts of interest.

REFERENCES

1. Kantarjian H, Sawyers C, Hochhaus A, et al: Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. N Engl J Med 346:645–652, 2002[Abstract/Free Full Text]

2. Boren J, Cascante M, Marin S, et al: Gleevec (STI571) influences metabolic enzyme activities and glucose carbon flow toward nucleic acid and fatty acid synthesis in myeloid tumor cells. J Biol Chem 276:37747–37753, 2001[Abstract/Free Full Text]

3. Bentley J, Walker I, McIntosh E, et al: Glucose transport regulation by p210 Bcr-Abl in a chronic myeloid leukaemia model. Br J Haematol 112:212–215, 2001[CrossRef][Medline]

4. Van den Abbeele AD, Badawi RD: Use of positron emission tomography in oncology and its potential role to assess response to imatinib mesylate therapy in gastrointestinal stromal tumors (GISTs). Eur J Cancer 38:S60–S65, 2002

5. Rhodes CJ, White MF: Molecular insight into insulin action and secretion. Eur J Clin Investig 32:3–13, 2002

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