Hypophosphatemia Observed in Chronic Myeloid Leukemia Patients Treated with Imatinib Mesylate (Gleevec®) Is Related to Digestive Side-Effects.

The therapeutic strategy in chronic myeloid leukemia (CML) has been totally modified with the development of Imatinib Mesylate (Gleevec®), a specific inhibitor of Bcr/Abl tyrosine kinase activity. However, many side-effects are reported with Gleevec, generally low grade. We report a new side-effect in patients treated with Glevec® for CML: hypophosphatemia. Between September 2001 and February 2005, 38 patients with CML were treated with Gleevec®. Thirty-four patients (18 males, 16 females) had a complete clinical and biological follow-up including into bone metabolism. Fifteen patients presenting a low level of serum phosphorus. Hyphosphatemia appeared within a median of 15 months (range: 1–47). Comparison of normal and hypophosphatemic patients did not show any statistically significant difference regarding age, treatment duration and dose of Gleevec®. Moreover, in 17 patients, we investigated the plasma level of Gleevec® as described by Mahon FX et coll. And did not find a correlation between the phosphorus level and concentration of Gleevec® (1). We next investigated phosphorus metabolism starting with digestive excretion because Gleevec® is known to induce gastro-intestinal side-effects. A multivariate analysis showed a correlation between hypophosphatemia and diarrhea (p<0.05). It suggests that the hypophosphatemia is related to digestive dysfunction. Moreover, we gave oral phosphorus supplementation for 3 months to 3 patients and failed to rescue normal phosphorus levels but exacerbated in all patients the digestive side-effects. This finding does not support interest in phosphorus supplementation.

Interestingly, we observed a low cross-laps serum level in all patients, independently of their phosphatemia status. A similar observation was recently reported by Berman E and coll in 16 patients treated for gastrointestinal stromal tumors and CML (2). They suggested inhibition of the platelet-derived growth factor (PDGF) receptor b. Parathyroid hormone levels were similar in both groups and the low levels in the phosphorus group tended to correlate with an increased level of serum 1,25-dihydroxyvitamin D, but did not reach significance. This is could be in favour of an inhibition of bone remodelling by Gleevec® independently of hypophosphatemia. This suggests a possible implication of FGF23, a major regulator of phosphorus metabolism, that need to be further investigated.