Treatment of steroid‐refractory chronic graft‐versus‐host disease with imatinib: Real‐life experience of the Spanish group of hematopoietic transplantation (GETH)

Abstract

Treatment of steroid‐refractory chronic graft‐versus‐host disease (cGVHD) is a challenge. Here, we describe a retrospective analysis of 66 patients with steroid‐refractory cGVHD treated with imatinib (starting dose of 100 mg in 70% of patients; maximum dose of 100‐200 mg in 74%). Most patients had multi‐organ involvement (≥2 organs, 83%), with the most affected being skin (85%), oral mucosa (55%), eyes (42%), and lungs (33%). The overall response rate was 41% (21 partial and three complete responses). The organ with the best response rate was the skin (46%), followed by gastrointestinal tract (43%), liver (41%), the oral mucosa (36%), eyes (29%), and lungs (18%). Imatinib led to steroid tapering in 17/38 patients. Twenty‐five (38%) patients experienced imatinib‐related adverse events, comprising extra‐hematologic toxicity (n = 24, 36%) and hematologic toxicity (n = 6, 9%). No cases of grade 4‐5 toxicity were reported. The main causes of imatinib discontinuation were treatment failure (52%) and toxicity (9%). After a median follow‐up of 41 months, the 3‐year overall survival was 81%, with no difference between imatinib responders and non‐responders. These real‐life results show that imatinib is safe and has moderate efficacy in patients with heavily pre‐treated cutaneous sclerotic cGVHD; however, activity against lung cGVHD is very limited.

Results of Multicenter Phase II Study With Imatinib Mesylate in Allogeneic Recipients With Steroid-Refractory Chronic GVHD

“…Increasing the imatinib dose was difficult in many patients because of nausea, vomiting, and edema. However, the mean imatinib dose did not differ between the imatinib responders and nonresponders, in agreement with previous studies 2 , 5 , 22 , 30 , 43 . Therefore, careful selection of patients who might obtain clinical benefit from imatinib therapy should be considered.…”

“…However, Olivieri et al 5 were the first to report that imatinib was effective against all types of GVHD, including that with visceral involvement, based on the analysis of long-term outcomes of 39 patients with steroid-refractory cGVHD receiving imatinib. In a recent study including the hematopoietic transplantation data of 66 patients with steroid-refractory cGVHD from Spain, skin, gastrointestinal tract, and liver were more responsive to imatinib treatment compared with the lungs and eyes 30 . Similarly, the current study evaluating imatinib treatment for severe cGVHD involving the liver and gastrointestinal tract shows promising results.…”

“…The rate of imatinib response varies from 17% to 79% in patients with refractory cGVHD, whereas a statistically significant association between daily imatinib dose and therapeutic effect has not yet been established 5 , 22 – 26 , 30 . A study with low-dose daily imatinib (50–100 mg) showed some effect for refractory cGVHD with fibrotic features 22 .…”

Tyrosine kinase inhibitors: relapse prophylaxis after allogeneic hematopoietic stem cell transplantation in adults with Philadelphia chromosome-positive acute lymphoblastic leukemia

“…We understand that a larger group of patients is needed to assess the effect of chronic GvHD upon RFS in the time-dependent manner. It is worth to mention, that TKIs, especially imatinib, being a multikinase inhibitor of several signaling pathways implicated in skin fibrosis, is known as potential option to treat sclerotic steroid refractory GvHD, in view of fibroblast growth inhibition, and decreased collagen production in dermal fibroblasts [60,61]. However, the incidence of chronic GVHD in our group was even higher in the TKIs prophylaxis group.…”

Lymphocyte Depleting and Modulating Therapies for Chronic Lung Allograft Dysfunction

“…Imatinib (100-400 mg daily) seemed to stabilise FEV 1 in some BOS patients after allogeneic haematopoietic stem cell transplantation, and in subgroup analyses of some patients treated with imatinib for chronic GvHD. (Magro et al, 2009;Olivieri et al, 2013;Olivieri et al, 2009;Parra Salinas et al, 2021;Stadler et al, 2009;Sánchez-Ortega et al, 2016;Watanabe et al, 2015) There is minimal data from preclinical animal studies regarding the use of imatinib in CLAD, showing that imatinib improved luminal airway obstruction in experimental bronchiolitis obliterans (Pandolfi et al, 2020;von Suesskind-Schwendi et al, 2013;Watanabe et al, 2017), possibly through reduction of migration and differentiation of fibrocytes in the allograft (Watanabe et al, 2017).…”