Efficiency and Toxicity of Imatinib Mesylate Combined with Atorvastatin Calcium for Steroid-Refractory Chronic Graft-Versus-Host Disease

Background: Chronic graft-versus-host disease (cGVHD) represents the most common long-term complication associated with allogeneic hematopoietic stem cell transplantation. Moreover, steroid-refractory cGVHD (SR-cGVHD) presents new challenges for treatment. Currently, while imatinib and statins drugs have been recognized to regulate T cell function, their effects and mechanism in combined treatment for cGVHD remain unknown.

Methods: A total of 60 SR-cGVHD patients were entered into a clinical single-arm trial investigating the combination of imatinib mesylate and atorvastatin calcium for the treatment of SR-cGVHD. The efficacy, safety, and immune effects were evaluated after treatment using the 2014 NIH scoring system and changes in T cell subclones. The primary end points consisted of the overall response rate (ORR) after 6 months of treatment with imatinib mesylate and atorvastatin calcium, which were evaluated according to the NIH criteria. The secondary end point consisted of an evaluation of survival, the changes of T cell subsets and adverse events.

Results: At baseline, 45% (27/60) of the patients had moderate cGVHD and 55.0% (33/60) patients had severe cGVHD. There were 32 (53.3%) patients with skin involvement, 31 (51.7%) patients with liver involvement, and 21 (35.0%) with clinical lung involvement, with compromised forced expiratory volume and/or diffusion capacity of the lung for carbon monoxide. There were 23 (38.3%) patients who exhibited oral mucosal involvement, 12 (20.0%) with joint and fascia involvement and 11 (18.3%) who exhibited gastrointestinal tract involvement, eyes 13 (21.7%), genitalia 2 (3.3%). The median follow up was 17 (4-25) months. At the 6 months follow-up, 70.0% of the patients achieved a clinical response, Complete response (CR) was achieved in 26.7% of the patients. After 6 months of treatment, the ORR rate of the liver, skin, eyes and oral cavity was 80.6%, 78.1%, 61.5%, and 60.9%, respectively, the liver was also the organ that achieved the highest CR of 58.1%. The cumulative overall survival rate, relapse and NRM for all treated patients was 78.9%, 15.5% and 11.7% (Fig A-C). Patients who achieved CR and PR showed a better survival outcomes (P= 0.0106) (Fig D). There was a decreased proportion of Th17 cells (P = 0.0171), whereas there was an increase in Treg cells (P = 0.0147) after 3 months in the clinical response patients. No toxic deaths were observed in this study, The main adverse was edema (13.3%) and nausea (10%).

Conclusion: Imatinib mesylate and atorvastatin calcium combination treatment was effective for treating SR-cGVHD and significantly induced improvement in target organ injury, especially in the liver. T cell regulation may play an important role in this process.

No relevant conflicts of interest to declare.