Severe Gut Acute Graft Versus host Disease (GVHD) Influence Thrombotic Microangiopathy in 86 Allogeneic Hematopoietic Stem Cell Recipients Who Received Tacrolimus-Based Regimen for GVHD Prophylaxis
Authors: Labrador Jorge , López-Godino Oriana , López-Corral Lucía , Pérez-López Estefanía , Cabrero-Calvo Mónica , Pérez-López Roberto , Bastida José María , López-Parra Miriam , Alberca Ignacio , González-Porras José Ramón , Caballero Dolores 
Published: October 2019

Abstract
Abstract 1955

Background and aims:
Transplantation-associated thrombotic microangiopathy (TA-TMA) is a significant complication of allogeneic stem cell transplantation (HSCT). Although endothelial injury represents the final common pathway of disease, the exact pathophysiology of TA-TMA remains unclear. A variety of potential risk factors have been proposed such as different conditioning regimens, the development of acute graft versus host disease (GVHD), concomitant infection, or the use of calcineurin inhibitor (cyclosporine, tacrolimus) and sirolimus. The recent use of both tacrolimus and sirolimus for GVHD prophylaxis suggest increasing the risk of TA-TMA, especially in patients receiving busulfan and cyclophosphamide. However, there are little studies in which tacrolimus/sirolimus GVHD prophylaxis was compared with other tacrolimus-based regimens in order to determine the really increased incidence of TA-TMA.
The purpose of this study was to determine the incidence and risk factors of TA-TMA in 86 allogeneic-HSCT recipients who received tacrolimus-based regimens (with sirolimus or with methotrexate) for GVHD prophylaxis.

Patients and Methods:
We conducted a retrospective cohort study of 86 consecutive allogeneic-HSCT recipients (aged over 18 years) transplanted in our unit between September 2007 and July 2012; GVHD prophylaxis consisted on tacrolimus and methotrexate (N = 19) or tacrolimus and sirolimus (N= 64); 3 patients received tacrolimus and sirolimus for acute GVHD treatment. Median age was 51 years (range 20–68) and 59.3% male. 40.7% of patients were diagnosed of acute leukemia, 23.3% myelodisplastic syndrome, 23.2% lymphoproliferative disorders, 7% multiple myeloma, 5.9% other hematological malignancies. The EBMT status at the moment of HSCT was intermediate/advanced in 63% of patients. The source of stem cells was peripheral blood in 87.2% and bone marrow in 12.8%. 57% of patients receiving an unrelated donor transplant. Nineteen patients (22.1%) received a HLA-mismatch graft. Reduced intensity conditioning was administered in 74.4%. 67.4% developed acute GVHD, 58.1% grade II-IV acute GVHD. Median follow-up was 248 days (range 16–1357).
The diagnosis of TA-TMA was considered according to probable TMA criteria as defined by validation study by Cho et al.

Results:
TA-TMA occurred in 9/86 patients (10,5%): 2/19 patients in the tacrolimus-methotrexate regimen group (10.5%) and 7/67 in the tacrolimus/sirolimus regimen group (10.4%). Median time until diagnosis of TA-TMA was 67 days (range, 37 – 405 days), and 8/9 patients were diagnosed before the day +110 post-HSCT; none of them developed chronic GVHD previously to the diagnosed of TA-TMA. Several variables have been analyzed but only acute GVHD (p=0.026) and acute gut GVHD (p=0.007) were significantly associated with TA-TMA in the univariate analysis. Of note, in the tacrolimus/sirolimus group, only acute gut GVHD (p=0.04) but not acute GVHD, was associated with TA-TMA. In the multivariate analysis, only grade ≥2 acute gut GVHD retained their association with TA-TMA development (OR = 13.33, 95% CI = 1.51 – 117.38).

Conclusions:
In contrast to previously published evidence, these data support that the use of tacrolimus/sirolimus GVHD prophylaxis does not increase the risk of TA-TMA compared to tacrolimus/methotrexate regimen. However, none of the patients included in our study have received busulfan-cyclophosphamide conditioning.
On the other hand, the most important risk factor for TA-TMA in allogeneic-HSCT recipients who received tacrolimus-based GVHD prophylaxis regimens was grade ≥2 acute gut GVHD. Consequently we propose especially close monitoring for TA-TMA in these patients.

Disclosures:
No relevant conflicts of interest to declare.