title: 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.
authors.affiliation: Department of Medicine/Division of Blood and Marrow Transplant, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: George L
authors.initials: GL
authors.lastname: Chen
authors.forename: Sally
authors.initials: S
authors.lastname: Arai
authors.forename: Mary E D
authors.initials: ME
authors.lastname: Flowers
authors.forename: Joanne M
authors.initials: JM
authors.lastname: Otani
authors.forename: Jingxin
authors.initials: J
authors.lastname: Qiu
authors.forename: Ethan C
authors.initials: EC
authors.lastname: Cheng
authors.forename: Alex
authors.initials: A
authors.lastname: McMillan
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Johnston
authors.forename: Judith A
authors.initials: JA
authors.lastname: Shizuru
authors.forename: David B
authors.initials: DB
authors.lastname: Miklos
mesh_terms: D000305:Adrenal Cortex Hormones; D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects; D001549:Benzamides; D002908:Chronic Disease; D018572:Disease-Free Survival; D004351:Drug Resistance / Q000187:drug effects*; D005260:Female; D005500:Follow-Up Studies; D006086:Graft vs Host Disease / Q000188:drug therapy* / Q000401:mortality; D006801:Humans; D000068877:Imatinib Mesylate; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000008:administration & dosage* / Q000009:adverse effects; D011743:Pyrimidines / Q000008:administration & dosage* / Q000009:adverse effects; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000037:antagonists & inhibitors*
chemical_list: D000305:Adrenal Cortex Hormones; D000911:Antibodies, Monoclonal; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D020796:Receptor, Platelet-Derived Growth Factor alpha