A Dose Escalation Trial of Imatinib for Steroid Dependent Chronic Graft-Versus-Host Disease with Anti-PDGFRA Antibody Analysis.

Anti-PDGFRA antibodies (APA) are associated with cGVHD and are hypothesized to stimulate PDGFRA signal transduction resulting in collagen deposition (Svegliati et al. Blood 2007). Imatinib inhibits PDGFRA activation and may reduce clinical manifestations in patients with cGVHD. We conducted a phase 1 dose escalation trial of imatinib in steroid dependent cGVHD and correlated response with measurements of APA.

All 15 subjects had extensive steroid dependent NIH defined cGVHD previously treated with ≥ 2 agents. Median age was 46 years (20-68). Mean time to study enrollment from transplant was 5.1 years and from cGVHD diagnosis was 4.1 years. Steroid dependence was defined as progressive cGVHD refractory to prednisone ≥ 0.5 mg/kg/d for ≥ 1 month or cGVHD requiring prednisone ≥ 0.25 mg/kg/d for ≥ 3 months. Subjects were treated with imatinib for 6 months starting at 200 mg daily with dose escalation to 400 mg after 4 weeks as tolerated and if a complete response did not occur. Steroids and one other immunosuppressant were allowed. Steroids were tapered as tolerated while other immunosuppressant dosing remained constant during the trial. The primary endpoint was safety and tolerability measured by CTCAE v. 3.0 criteria. Secondary endpoints were clinical response, change in daily prednisone requirement, and rate of treatment failure. Clinical assessment by medical providers, change in musculoskeletal function measured by grip strength and joint range of motion, and patient reported symptom burden measured by the Lee cGVHD scale were recorded. Treatment failure (TF) was defined as discontinuation of imatinib due to intolerance or cGVHD progression requiring new therapy.

Imatinib was considered safe if no deaths or life threatening adverse events (CTCAE ≥ Grade 4) could be attributed to it. A ≥ 25% response rate was considered promising and worthy of phase 2 investigation.

APA were detected by ELISA and immunoblotting against the extracellular PDGFRA domain.

The study began on 9/24/08 and completed accrual on 8/4/09. Among the 14 subjects evaluable for safety and tolerability, 9 were dose escalated to 400 mg. 3/9 did not tolerate the increased dose and were dose reduced. All but 1 subject tolerated 200 mg. Possibly related grade 1-2 adverse events included edema (10), nausea (7), fatigue (6), LFT elevation (6), diarrhea (4), muscle cramping (4), confusion (3), flatulence (3), fever (2) and LDH elevation, vomiting, weight loss, erythema, heartburn, tachycardia, hypertension, and headache (1 each). Grade 3-4 adverse events were muscle cramping and pulmonary infiltrates (1 each at 400 mg) and vascular insufficiency (1 at 200 mg). One subject on prednisone, cyclosporine, and imatinib 200 mg experienced respiratory failure due to H1N1 infection and died at 16 weeks.

8/15 subjects have completed ≥ 6 months of therapy and are evaluable for clinical response. Seven of these subjects were dose escalated after an average of 87 days (28-160) of treatment at 200 mg. Responses by Hopkins criteria (HC, Jacobsohn et al. JCO 2007) were first observed at the 200 mg dose level in 6 subjects at an average of 47 days (27-110). Response was observed at 400 mg but not 200 mg in 1 subject. One subject failed to respond to both 200 and 400 mg. Some early responses were not durable. Evaluation by HC at 6 months demonstrated 1 major response, 4 minor responses, and 3 progressive disease. Evaluation by NIH criteria (Filipovich et al. BBMT 2005) at 6 months demonstrated 2 partial responses, 3 non-responses, and 3 treatment failures. Musculoskeletal function was improved in 3, unchanged in 3, and worse in 2 subjects. Patient reported Lee cGVHD symptom burden (Lee et al. BBMT 2002) was rated as improved in 2, unchanged in 3, and worse in 3. On average, the daily weight adjusted steroid dose decreased by 20%.

APA were detected pre-treatment in 3/8 fully evaluable subjects. Two achieved minor responses, but the 3^rd experienced early progression and was censored. Of the 5 cases without detected APA, 1 had a major response, 2 had minor responses, and 2 had disease progression.

Imatinib at 200 and 400 mg is safe and appears to be effective in some cGVHD patients. Tolerability is decreased at 400 mg. APA are present in some but not all imatinib responders, suggesting that imatinib exerts its effects through mechanisms in addition to abrogation of PDGFRA signal transduction. Further phase 2 investigation is warranted.

Chen:Novartis: Research Funding. Off Label Use: Imatinib for chronic graft versus host disease. Otani:Novartis: Research Funding. Miklos:Novartis: Research Funding.