Long-term outcome and prospective validation of NIH response criteria in 39 patients receiving imatinib for steroid-refractory chronic GVHD

Abstract

Key Points• Efficacy of imatinib in steroidrefractory chronic GVHD was prospectively compared across 3 different response systems, with high agreement.• Validity of quantitative-based assessment of response with NIH criteria was confirmed by its prognostic impact on longterm survival.Forty adults aged 28 to 73 years were entered into a prospective trial of imatinib for the treatment of steroid-refractory chronic graft-versus-host disease (SR-cGVHD). After 6 months, intention-to-treat (ITT) analysis of 39 patients who received the drug, regardless of the duration of treatment, revealed 14 partial responses (PR), 4 minor responses (MR) with relevant steroid sparing (46%) according to Couriel criteria, and 20 ‡ PR (51.3%), as per the National Institutes of Health (NIH) criteria and NIH severity score changes. The best responses were seen in the lungs, gut, and skin (35%, 50%, and 32%, respectively). After a median follow-up of 40 months, 28 patients were alive, with a 3-year overall survival (OS) and event-free survival of 72% and 46%, respectively. The 3-year OS was 94% for patients responding at 6 months and 58% for nonresponders according to NIH response, suggesting that these criteria represent a reliable tool for predicting OS after second-line treatment. Monitoring of anti-platelet-derived growth factor receptor (PDGF-R) antibodies showed a significant decrease in PDGF-R stimulatory activity in 7 responders, whereas it remained high in 4 nonresponders. This study confirms the efficacy of imatinib against SR-cGVHD and suggests that the response at 6 months significantly predicts long-term survival. This study is registered at https://eudract.ema.europa.eu/ (EUDRACT

NIH response criteria measures are associated with important parameters of disease severity in patients with chronic GVHD

“…The only therapeutic intervention study published thus far, which strictly applied NIH criteria, was in a cohort of 39 steroid-refractory patients. 7 The results of that study suggested the NIH overall response calculation change was predictive for survival, and a significant correlation between the NIH overall response calculation and the 4-point Courriel clinicianassessed response scale was found. Baird et al 8 have shown that NIH organ and global severity scores are valid measures of cGVHD disease burden, and that the NIH lung score is the strongest predictor of survival outcomes.…”

Imatinib for bronchiolitis obliterans after allogeneic hematopoietic stem cell transplantation

“…Furthermore, the previous studies determined response rates at 3 and 6 months after initiation of imatinib treatment. 6,7 Our second patient (case 2) has achieved long-time survival with ultimate stabilization of FEV 1 , even though he did not appear to show improvement 6 months after initiation of imatinib. To the best of our knowledge, there have not been any published cases of cGVHD where the patient received continuous TKI therapy over a 10-year period and achieved long-term survival.…”

“…4 Several studies have shown that imatinib can ameliorate chronic GVHD (cGVHD). [5][6][7] However, there are few published reports of studies that have focused on the efficacy of TKIs used to treat BO associated with cGVHD. Here, we describe two patients who had undergone allogeneic hematopoietic stem cell transplantation (allo-SCT) and developed biopsy-proven BO that was successfully treated with TKIs.…”

“…To the best of our knowledge, there have not been any published cases of cGVHD where the patient received continuous TKI therapy over a 10-year period and achieved long-term survival. Although 1-4 months of imatinib treatment for patients with moderate-to-severe pulmonary cGVHD has shown limited efficacy, 10 the response rate was improved when imatinib treatment was planned for at least 6 months, 7 suggesting that a longer duration of therapy may be more effective. In the absence of toxicity or intolerance, prolonged imatinib treatment may be beneficial for the treatment of BO.…”

Imatinib ameliorates bronchiolitis obliterans via inhibition of fibrocyte migration and differentiation

“…In the two cases, imatinib treatment stabilized the patients' pulmonary function and prolonged their survival time. Several studies have also described the efficacy of imatinib in the treatment of BO in patients with chronic graft-versus-host disease (10)(11)(12). In the rat BO model of heterotopic tracheal transplantation (HTT), imatinib inhibited the tracheal luminal occlusion 30 days after transplantation compared with vehicle-treated allografts (13,14).…”