A subset of patients presenting with hypereosinophilic syndrome (HES) have clinical features consistent with a myeloproliferative disorder. These patients have aggressive disease characterized by tissue fibrosis, including endomyocardial fibrosis and myelofibrosis and a poor prognosis with 5 year mortality rates as high as 50%, if left untreated. The peripheral blood mononuclear cells of the overwhelming majority of these patients have an interstitial deletion in chromosome 4, leading to the formation of the imatinib-sensitive FIP1L1/PDGFRA fusion gene, thus fulfilling the WHO criteria for a diagnosis of chronic eosinophilic leukemia (CEL). We have established a novel RT-PCR assay to test for FIP1L1/PDGFRA fusion gene in peripheral blood samples of patents with eosinophilia. Positive patients are followed over time and treatment responses to imatinib are monitored using this novel RT-PCR assay. ? Although imatinib is clearly the treatment of choice for FIP1L1/PDGFRA-positive chronic eosinophilic leukemia (CEL), little is known about optimal dosing, duration of treatment, and the possibility of cure in this disorder. To address these questions, 5 patients with FIP1L1/PDGFRA-positive CEL with documented clinical, hematologic, and molecular remission on imatinib (400 mg daily) and without evidence of cardiac involvement were enrolled in a dose de-escalation trial. The imatinib dose was tapered slowly with close follow-up for evidence of clinical, hematologic, and molecular relapse. Two patients with endomyocardial fibrosis were maintained on imatinib 300 to 400 mg daily and served as controls. All 5 patients who underwent dose de-escalation, but neither of the control patients, experienced molecular relapse (P < .05). None developed recurrent symptoms, and eosinophil counts, serum B12, and tryptase levels remained suppressed. Reinitiation of therapy at the prior effective dose led to molecular remission in all 5 patients, although 2 patients subsequently required increased dosing to maintain remission. These data are consistent with suppression rather than elimination of the clonal population in FIP1L1/PDGFRA-positive CEL and suggest that molecular monitoring may be the most useful method in determining optimal dosing without the risk of disease exacerbation.
| Klion, Amy D; Robyn, Jamie; Maric, Irina et al. (2007) Relapse following discontinuation of imatinib mesylate therapy for FIP1L1/PDGFRA-positive chronic eosinophilic leukemia: implications for optimal dosing. Blood 110:3552-6 |
| Maric, Irina; Robyn, Jamie; Metcalfe, Dean D et al. (2007) KIT D816V-associated systemic mastocytosis with eosinophilia and FIP1L1/PDGFRA-associated chronic eosinophilic leukemia are distinct entities. J Allergy Clin Immunol 120:680-7 |
