Sirolimus and Thrombotic Microangiopathy after Allogeneic Hematopoietic Stem Cell Transplantation

Abstract

Thrombotic microangiopathy (TMA) may occur after allogeneic hematopoietic stem cell transplantation (HSCT) and is related in part to calcineurin inhibitor toxicity. We observed a higher-than-expected rate of TMA when calcineurin inhibitors were combined with sirolimus. To determine the incidence of and risk factors for TMA after HSCT, we performed a retrospective cohort analysis of myeloablative allogeneic HSCT recipients between 1997 and 2003. TMA diagnosis required the simultaneous occurrence of (1) creatinine increase >2 mg/dL or >50% above baseline, (2) schistocytosis, (3) increased lactate dehydrogenase, and (4) no evidence of disseminated intravascular coagulopathy. A total of 111 sirolimus-exposed subjects were compared with 216 nonexposed subjects after HSCT. TMA occurred in 10.8% of the sirolimus group and 4.2% in the nonsirolimus group (odds ratio, 2.79; P=.03). Sirolimus exposure was associated with TMA earlier than in nonsirolimus patients (25 versus 58 days; P=.04). Only the use of sirolimus (exact odds ratio, 3.49; P=.02) and grade II to IV acute graft-versus-host disease (exact odds ratio, 6.60; P=.0002) were associated with TMA in regression analyses. Treatment of TMA varied among affected individuals. Renal recovery was complete in 92% of sirolimus-treated patients. Overall survival after TMA diagnosis was better for sirolimus subjects than for nonsirolimus subjects (58.3% versus 11.1%; P=.02). Sirolimus seems to potentiate the effects of calcineurin inhibitors on TMA after HSCT. TMA associated with sirolimus seems reversible and has a favorable prognosis when compared with TMA associated with calcineurin inhibitors alone. A careful monitoring strategy for TMA should be used with a sirolimus-containing graft-versus-host disease prophylaxis regimen.

Clinicopathological manifestations and treatment of intestinal transplant-associated microangiopathy

“…15 Several reports have documented an increased incidence of systemic TAM with sirolimus in combination with other calcineurin inhibitors. 23,24 Systemic TAM resolved with discontinuation of calcineurin inhibitors in most cases. In addition, we recently established a rat model of intestinal microangiopathy induced by tacrolimus alone.…”

Calcineurin inhibitor-free GVHD prophylaxis with sirolimus, mycophenolate mofetil and ATG in Allo-SCT for leukemia patients with high relapse risk: an observational cohort study

“…However, in combination with CNI, an increased incidence of transplantation-associated thrombotic microangiopathy and possibly sinusoidal obstruction syndrome has been observed. 8,29 On the other hand, sirolimus exerts protection against viral infections, especially CMV reactivation. 30 On the basis of the observations mentioned, we changed the GVHD prophylaxis within the FLAMSA-RIC protocol from CYA and MMF to sirolimus, and MMF for leukemia patients with high relapse risk.…”

Eculizumab therapy in adults with allogeneic hematopoietic cell transplant-associated thrombotic microangiopathy

“…5,6 Known risk factors of HCT-TMA include radiation, chemotherapy, ABO incompatibility, calcineurin inhibitors, sirolimus, viral infections and GvHD. 7,8 Common treatment approaches to HCT-TMA are largely ineffective and include withdrawal of calcineurin inhibitors, plasma exchange and intravenous immune globulin (IVIG), resulting in high mortality and morbidity rates. 3,9 We report a retrospective study of five patients who developed HCT-TMA and were treated with complement inhibition using eculizumab.…”