Time- and Dose-Response Relationships of Imatinib Mesylate (Glivec) Therapy for Chronic Hypereosinophilic Syndromes.

HES (hypereosinophilic syndrome with organ damage), CEL (chronic eosinophilic leukemia with chromosome marker and/or myeloproliferation/dysplasia) and CIH (chronic idiopathic hypereosinophilia) are diseases that pose a therapeutic challenge and are potentially Glivec-sensitive. This drug inhibits BCR-ABL type tyrosine kinase (TK) as well as Platelet-Derived-Growth-Factor Alpha and Beta (FIP1L1-PDGFRA and ETV6-PDGFRB, detectable in HES and allied conditions) and c-kit related TKs.

A study was planned to assess 1) the response to escalating doses of Glivec (starting dose 100 mg/d, maximum 400 mg/d, weekly increment 100 mg/d as necessary) and 2) the diagnostic profile of Glivec-responsive cases. Eligible patients had BCR-ABL- HES, CEL, or CIH with eosinophilia >5x10e9/l. Diagnostic work-up included marrow morphology and cytogenetics, PDGFRA/B rearrangement study, and immunophenotype for the detection of expanded (Vbeta) T-cell clones (TCC). Glivec was kindly provided by Novartis Oncology, Italy, to be administered for 12 consecutive weeks. A complete remission (CR) was defined by an eosinophil count <0.35x10e9/l with disappearance of clinical signs/symptoms.

Starting 11/’04, 18 patients were identified (14 M), aged 26–80 years (median 54), with a disease history of 0.2–12 years (median 3.4). Blood eosinophilia was 0.67–17.5x10e9/l (median 2.1), with diagnosis of HES (n= 8), CEL (n= 6) or CIH (n= 4). Cytogenetics was abnormal in 5/14 (36%): 1 t(4;8), 1 der(5) t(1;5)(q25;q34) del(5)(q?), 1 del(5)(q32) i(17), and 2 -Y as possible constitutional anomaly; a TCC was detected in 3/9 (33%); FIP1L1-PDFGRA and ETV6-PDGFRA rearrangements were found in 4/17 (24%) and 0/9 (0%), respectively. As of 07/’05, 16 cases are evaluable (2/4 PDGFRA+), 8 having completed the study. Four patients were withdrawn very early because nonresponders at increased dosage (n=3) or noncompliant (n=1), and 4 are still on study. A CR was documented in 6/8 who completed the trial, 3 with CEL and t(4;8) or an involved chromosome 5, 2 with PDGFRA+ HES, and 1 with PDGFRA-/B- HES. No patient with TCC responded. As concerns dose-/time-response relationships, 4 cases were fully responsive to 100 mg/d through the 12 weeks of the study, and 2 required 200 mg/d from the 6th and 11th week, respectively (cases with longer HES history: 12 and 11 years; one with prior blastic transformation), whereas eosinophil blood counts (x10e9/l) varied as follows from baseline to 1st and 4th weeks: 1.95 (0.88–17.5) to 0.20 (0.02–2.09) to 0.15 (0.00–0.4). However, both PDGFRA+ cases remained molecularly positive, while the single evaluable patient achieved only a transient cytogenetic remission. Time to progression (>0.35) was short following drug withdrawal (5 patients: 1, 1, 3, 3, 3 months). Glivec is highly active in hypereosinophilic syndromes with PDGFR rearrangements and other gene lesions that need to be properly identified. These cases respond very early even at the lower dosage. However, an early stopping of therapy can be followed by rapid progression as indicated also by the persistence of cytogenetic/molecular lesions in some cases. This dictates a continuing molecular/cytogenetic monitoring for dose titration like in chronic myelogenous leukemia.