A phase 1 study of imatinib for corticosteroid-dependent/refractory chronic graft-versus-host disease: response does not correlate with anti-PDGFRA antibodies

Abstract

Stimulatory antiplatelet derived growth factor receptor α (PDGFRA) antibodies have been associated with extensive chronic graft-versus-host disease (cGVHD). We performed a phase 1 dose escalation trial of imatinib in corticosteroid-dependent/refractory cGVHD to assess the safety of imatinib and test the hypothesis that abrogation of PDGFRA signaling can ameliorate the manifestations of cGVHD. Fifteen patients were enrolled. Mean follow-up time was 56.6 weeks (range, 18-82.4 weeks). Imatinib 400 mg daily was associated with more frequent moderate to life-threatening adverse events than 200 mg daily. The main adverse events were nausea, edema, confusion, diarrhea, liver function test elevation, fatigue, and myalgia. The overall response rate was 40% (6 of 15). The treatment failure rate was 40% (6 of 15). Twenty percent (3 of 15) of subjects had stable disease. Of 4 subjects with phospho-PDGFRA and phospho-PDGFRB immunohistochemistry studies before and after treatment, inhibition of phosphorylation was observed in 3 but correlated with response in one. Anti-PDGFRA antibodies were observed in 7 of 11 evaluable subjects but correlated with clinical activity in 4. We conclude that cGVHD responds to imatinib through multiple pathways that may include PDGFRA signal transduction. This study is registered at www.clinicaltrials.gov as #NCT00760981.

Figures

Figure 1

Disposition of trial participants. Dose of imatinib received, duration of treatment with imatinib, and reason for discontinuation of imatinib are shown.

Figure 2

Adverse event severity in relation to imatinib dose and duration of imatinib treatment. Grade 2, 3, and 5 adverse events occurred more frequently on imatinib 400 mg than 200 mg daily. No grade 4 adverse events occurred. Only those adverse events possibly, probably, or definitely attributed to imatinib are shown. Gray represents 200 mg imatinib daily; and black, 400 mg imatinib daily.

Figure 3

Pharmacodynamic effects of imatinib. *Antiphosphorylated PDGFRA staining (original magnification × 400) before (A) and after (B) imatinib treatment (patient 1) and *antiphosphorylated PDGFRB staining (original magnification × 400) before (C) and after (D) imatinib treatment (patient 11). Microscope: Olympus BX45; camera: Olympus DP25; acquisition software: CellSens Standard (Olympus).

Figure 4

Anti-PDGFRA antibody status and clinical responses. Immunoblot detection of anti-PDGFRA antibodies and ELISA confirmation are shown with corresponding clinical outcomes for each subject. MI indicates minor response; MA, major response; PD, progressive disease; and SD, stable disease.