Clinical features predict responsiveness to imatinib in platelet-derived growth factor receptor-alpha-negative hypereosinophilic syndrome

Abstract

Background: With the exception of the presence of the FIP1L1-PDGFRA fusion gene, little is known about predictors of imatinib response in clinically-defined hypereosinophilic syndrome (HES).

Methods: Subjects with FIP1L1-PDGFRA-myeloid neoplasm (FP; n =12), PDGFRA-negative HES with ≥4 criteria suggestive of a myeloid neoplasm (MHES; n =10), or steroid-refractory PDGFRA-negative HES with <4 myeloid criteria (SR; n = 5) were enrolled in a prospective study of imatinib therapy (NCT00044304: registered at clinicaltrials.gov). The primary outcome was an eosinophil count <1.5 × 109/L at one month and improvement of clinical symptoms. Clinical, molecular, and bone marrow responses to imatinib were assessed. A retrospective cohort of 18 subjects with clinically-defined HES who received imatinib (300-400 mg daily ≥ 1 month) were classified according to the criteria used in the prospective study.

Results: Overall, imatinib response rates were 100% in the FP group (n = 16), 54% in the MHES group (n = 13) and 0% in the SR group (n = 16). The presence of ≥ 4 myeloid features was the sole predictor of response. After ≥ 18 months in complete remission, imatinib was tapered and discontinued in 8 FP and 1 MHES subjects. Seven subjects (6 FP, 1 MHES) remain in remission off therapy for a median of 29 months (range 14-36).

Conclusions: Clinical features of MHES predict imatinib response in PDGFRA-negative HES.

Trial registration: ClinicalTrials.gov NCT00044304 NCT00001406.

Keywords: PDGFRA-negative; eosinophilia; hypereosinophilic syndrome; imatinib; myeloid neoplasm.

Conflict of interest statement

Conflicts of interest

No conflicts of interest are reported for any of the authors.

Published 2016. This article is a U.S. Government work and is in the public domain in the USA.

Figures

Figure 1

Imatinib response rates differ between corticosteroid nonresponder (SR), PDGFRA-associated (FP), and myeloid (MHES) groups. Response rates are shown separately for the prospective (A) and retrospective (B) cohorts. Peripheral eosinophil counts pre- and 1 month post-imatinib are shown for the prospective and retrospective cohorts combined (C-E). FP—FIP1L1-PDGFRA-associated myeloid neoplasm, MO—month, MHES—PDGFRA-negative, myeloid HES, SR —PDGFRA-negative, nonmyeloid, corticosteroid nonresponder.

Figure 2

Bone marrow cellularity, eosinophilia, and fibrosis were significantly improved in FP subjects but not in MHES or SR subjects in the prospective cohort. Bone marrow percent cellularity, percent eosinophilia, and fibrosis grade before and one month after initiation of imatinib therapy are shown for subjects with PDGFRA-associated disease (FP) (n = 11), PDGFRA-negative MHES who were imatinib-responsive (MHES-R) (n = 5) or imatinib-unresponsive (MHES-NR) (n = 3), and PDGFRA-negative, corticosteroid-resistant HES without myeloid features (SR) (n = 4). *P < 0.05 or **P < 0.01 as compared to pre, Wilcoxon matched pairs signed rank test.

Figure 3

Clinical features suggestive of a myeloid neoplasm are associated with imatinib responsiveness in PDGFRA-negative patients. The response to imatinib (responders—black bars, nonresponder—gray bars) is shown as a function of the number of features suggestive of a myeloid neoplasm in the PDGFRA-negative subjects in the combined prospective and retrospective cohorts.