Imatinib as Salvage Therapy for Patients with Refractory cGVHD: the Interim Analysis of the Prospective GITMO* Multicenter Study*Gruppo Italiano Trapianto Di Midollo Osseo.

of this study was to assess the response rate, evaluated according to the stringent criteria suggested by the NIH Consensus Conference for cGVHD and to confirm the safety of low dose Imatinib in this setting.

were both clinical and biological: 1-to evaluate the clinical outcome (OS at 1 and 2 years) and quality of life; 2-to test a reliable technique for screening these patients for the presence of stimulating anti-PDGFR antibodies before and after the end of Imatinib treatment. The study was planned as phase 2 trial (optimal two stages Simon design), and enrolled 24 patients with cGVHD, refractory to two or more lines of therapy, including steroids. Nine Italian Centres enrolled 24 adults patients, starting from February 2008 to August 2009; 18 patients are now evaluable for toxicity and for the response at 3 and 6 months; 13 were male and 5 female; the median age was 47 years (range 31-62). The median duration of cGVH was 36 (range 3-148) months and all patients received 2 or more lines of therapy; the main cGVH target was represented by lung in 9 patients (5 patients had severe abnormalities of the functional tests with compromised Lung Functional Score), skin in 8 patients and bowel in 8 patients. Most patients had multi-organ involvement. The treatment with Imatinib was planned for a minimum of 6 months, starting at the initial dose of 100 mg/day, then increasing the dose to 200 mg/day until 3rd month; if no response and in absence of severe toxicity, patients were allowed to receive 400 mg/day until 6th month. The response has been defined as CR or PR, and was evaluated after 3 and 6 months of therapy; the kind of response (CR or PR) was defined according to the Curiel criteria, integrated by the criteria suggested by the NIH Consensus Conference for cGVHD.

the treatment was well tolerated (all patients were able to complete the treatment for at least 6 months) and we did not observe toxic deaths; the toxicity was mild (no grade 3-4 toxicities have been reported) and 3 Severe Adverse Events have been reported (3 cases of pneumonia), probably related to the immunesuppression due to cGVHD instead to the Imatinib treatment. The ORR at 3 months was 72% and 56% at 6 months (9 PR and 1CR); 3 patients were able to stop or significantly decrease steroids. With a median follow-up of 6 months 15 out of the 18 evaluable patients are alive while 3 died of progressive cGVHD. The preliminary results of this multicenter study confirm that low-dose Imatinib is safe and effective in patients affected by refractory cGVHD; the slightly lower response rate observed at 6 months, compared to the previous study probably reflects the different population enrolled: older patients in the present study (the median age was 47, compared to 27 in the previous study; absence of pediatric patients who showed the best responses), most of them with lung involvement (9) and 5 with severe impairment of Lung Functional Score. These data encourage the use of Thyrosin Kinase Inhibitors in patients with refractory cGVHD and the evaluation of these drugs in phase 3 trials; furthermore the extensive evaluation of biological activity of these drugs could be able to select those patients who could benefit of this approach. This study was supported by the Italian medicines Agency (AIFA) within the independent drug research program contract no. FARM7ZWZ7Y.

Off Label Use: yes we report the results obtained with Imatinib off-label in patients with refractory cGVHD.