Conversion from calcineurin inhibitor to ruxolitinib as GVHD prophylaxis during patients with transplant-associated thrombotic microangiopathy.

BACKGROUND: Transplant-associated thrombotic microangiopathy (TA-TMA) is a fatal complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT) with multifactorial etiology. Existing clinical guidelines recommend discontinuation or tapering of calcineurin inhibitors (CNIs) as the primary intervention after the initial TMA diagnosis; however, data on the options for immunosuppression manipulation (ISM) are limited. Ruxolitinib is an effective option in treatment of steroid refractory graft-versus-host disease (SR-GVHD), which seems promising to replace CNIs as a prophylactic agent with better GVHD control in patients with TA-TMA. METHODS: We retrospectively analyzed the outcomes of 48 TA-TMA patients who received ISM with steroids (steroid group) or ruxolitinib (ruxolitinib group) as CNI substitutes. RESULTS: The primary endpoint was not met: the ORR at 4 weeks did not differ significantly between the ruxolitinib and steroid groups (65.2% vs. 80.0%, P = 0.250). However, in exploratory secondary analyses, more patients in the ruxolitinib group achieved complete response (CR) than in the steroid group (40% vs. 13%, P=0.036), and first remission was achieved more rapidly (13.5 vs. 25 days, P=0.046). Additionally, the ruxolitinib group demonstrated faster normalization of lactate dehydrogenase (LDH) levels and significantly better overall survival (HR 0.32, 95% CI 0.12-0.84, p=0.025) and relapse-free survival (HR 0.41, 95% CI 0.17-0.99, p=0.048) than the steroid group. Although hematologic recovery was slower in the ruxolitinib group than in the steroid group, we attribute this to ruxolitinib-induced myelosuppression. Infection was a significant risk factor in the ruxolitinib group (P=0.0426). However, there were no significant differences in the incidence of infection following treatment with steroid or ruxolitinib: pneumonia (26.1% vs. 16%, P=0.487), sepsis (17.4% vs. 12%, P=0.696), Epstein-Barr virus (EBV) reactivation (47.8% vs. 36%, P=0.406), or Cytomegalovirus (CMV) reactivation (56.5% vs. 52%, P=0.753). CONCLUSION: In this pilot study, the primary endpoint (ORR) was not met. Exploratory secondary analyses suggest that replacing CNIs with ruxolitinib during TA-TMA is feasible and may be associated with more rapid LDH normalization and CR, at the cost of slower peripheral count recovery; these observations are hypothesis-generating and require confirmation in adequately powered, prospective, multicenter studies.