Thrombotic Microangiopathy Associated with Sirolimus Level after Allogeneic Hematopoietic Cell Transplantation with Tacrolimus/Sirolimus-Based Graft-versus-Host Disease Prophylaxis

Abstract

Post-transplant thrombotic microangiopathy (TMA) is a multi-factorial complication of allogeneic hematopoietic cell transplantation (allo-HCT) whose incidence is increased when using a sirolimus plus tacrolimus regimen for acute graft-versus-host disease (aGVHD) prophylaxis. We evaluated the incidence and possible risk factors for TMA in a case series of 177 patients who received allo-HCT using SIR/TAC-based GVHD prophylaxis. Donors were either sibling (n=82) or matched unrelated (n=95). Within the first 100 days post-HCT, 30 (17%) patients were diagnosed with TMA, and an additional nine patients (5%) were classified as probable TMA cases. The median time to TMA onset was 4.6 weeks (range: 1.6-10.6). Thirty-four patients developed both TMA and aGVHD, with the majority of patients (81%) developing aGVHD first. By multivariable analysis, the following factors were found to be associated with increased risk of TMA: day 14 serum sirolimus: ≥9.9 ng/ml (HR: 2.19, 95% CI: 1.13-4.27, p=0.02), presence of prior aGVHD grades II-IV (HR: 3.04, 95% CI: 1.38-6.71, p<0.01), and fully myeloablative conditioning (HR: 3.47, 95% CI: 1.60-7.53, p<0.01). The risk factors for TMA suggest that when using sirolimus/tacrolimus for GVHD prophylaxis, careful monitoring and adjustment of sirolimus dosages is critical, particularly in patients with active aGVHD.

Risk factors for thrombotic microangiopathy in allogeneic hematopoietic stem cell recipients receiving GVHD prophylaxis with tacrolimus plus MTX or sirolimus

“…17,20,34 Our results show that, although levels above the upper normal limit of TAC (410 ng/mL in the TAC/SIR group or 415 ng/mL in the TAC/MTX group) are not associated with TA-TMA, very high levels (425 ng/mL) are an independent risk factor for TA-TMA development. Accordingly, correct drug management is crucial to prevent this complication, 17,20,34,35 especially among patients who suffer from compromised organ function, either due to acute GVHD or from transplantation-related morbidity. This close monitoring is especially critical in the first 4 months after transplantation, as 75% of patients with TA-TMA were diagnosed before day þ 110 post HSCT, mainly when patients have developed severe grade III-IV acute GVHD.…”

“…16 The combination of TAC and SIR (TAC/SIR) in both solid organ transplantation and HSCT is associated with an increased risk of TA-TMA in some studies. [17][18][19][20][21][22] Moreover, few comparisons of TAC/ SIR with other TAC-based regimens have been reported. In fact, two recent studies suggest that TA-TMA incidence does not differ significantly between patients who received TAC/SIR and those who received TAC/MTX for GVHD prophylaxis.…”

Pre-transplant sirolimus might improve the outcome of haploidentical peripheral blood stem cell transplantation with post-transplant cyclophosphamide for patients with severe aplastic anemia

“…At the same time, we were concerned about the high incidence of thrombotic microangiopathy reported with the combination of CSA and sirolimus, and hence aimed for a lower CSA level. 11 Incidentally, a preclinical study by Fitzhugh et al 12 published in 2013 (9 months after initiation of our clinical study) reported on synergism of sirolimus and PTCY in a mismatched murine model. In their experiments, the authors had reported on sustained mixed chimerism with PTCY and sirolimus.…”

Post-bone marrow transplant thrombotic microangiopathy

“…In a more recent study, Shayani et al 20 published a case series of 177 patients who underwent allogeneic hematopoietic stem cell transplantation at City of Hope. Out of the 177 patients studied, 30 (17%) were diagnosed with definite TMA, and an additional nine patients (5%) were classified as probable TMA based on the institutional diagnostic criteria.…”