Relapse following discontinuation of imatinib mesylate therapy for FIP1L1/PDGFRA-positive chronic eosinophilic leukemia: implications for optimal dosing

Abstract

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. This trial was registered at http://www.clinicaltrials.gov as no. NCT00044304.

Figure 1

Molecular relapse in the setting of imatinib dose de-escalation in FIP1L1/PDGFRA-positive CEL. Results of molecular testing for FIP1L1/PDGFRA by nested RT-PCR (rectangular bar beneath graph) are shown for 7 subjects as a function of time. The subject number is indicated by the white numeral. Each rectangle represents a 1-month period. Black rectangles indicate the presence of the fusion gene, and gray rectangles indicate the absence of the fusion gene. White rectangles represent months during which testing was not performed. Imatinib dose (y-axis) as a function of time (x-axis) is indicated by the gray shaded area. The dashed line in graph 1 represents the eosinophil count over time for this subject. All 5 subjects who underwent dose de-escalation (A), and neither subject who was maintained on stable high-dose imatinib (B), experienced molecular relapse.

Figure 2

Bone marrow biopsy findings in a FIP1L1/PDGFRA-positive subject (subject 3). Before imatinib treatment (A), at 1 month following initiation of treatment (B), and at the time of molecular relapse (C). Posttreatment resolution of eosinophilia and hypercellularity was maintained despite molecular relapse. Sections were stained with hematoxylin and eosin (H&E), magnification 400×, and images were obtained by digital microscopy using an Olympus BH-Z microscope (Olympus America, Melville, NY) equipped with a DPlan 40 × 10.65 numeric aperture objective. Images were captured using an Olympus DP12 digital camera system and recorded on a 3.3V Smart Media (SSFDC) card. Imaging software was Adobe Photoshop version 6.0 (Adobe Systems, San Jose, CA).