Association of Treatment with Sirolimus (SIR) and Calcineurin Inhibitor (CNI) for Prevention or Treatment of Graft-Vs-Host Disease (GVHD) with Transplant Associated Microangiopathy (TAM).
Authors: Rosenthal Joseph , Bolotin Ellen , Pawlowska Anna , Oliver Cheryl , Maroongroge Sean , Forman Stephen 
Published: April 2020

Abstract
Sirolimus (SIR), an inhibitor of mammalian target of rapamycin (mTOR), is an immunosuppressive agent that is synergistic with CNI to prevent or treat GVHD in patients (pts) undergoing allo-HST (Cutler, Biol Blood Marrow Transplant. 2004;10:328). Transplant associated microangiopathy (TAM) is a multi-factorial complication of allo- HST, associated with CNI. Recently, the addition of SIR to CNIs was reported to result in a higher than expected (10.8%) incidence of TAM (Cutler et al. Biol Blood Marrow Transplant. 2005; 11:551). We analyzed the incidence and clinical characteristics of TAM in 2 groups of pediatric patients (pts): the prevention group (GP): pts who received SIR and tacrolimus (TAC) for prevention; and the treatment group (TG): pts treated with SIR and a CNI (TAC or cyclosporine) for exacerbation of GVHD.
Methods: A retrospective chart review of pts with allo-HST who received SIR/TAC for either prevention or treatment of GVHD. Demographic data, clinical course, occurrence of GVHD and TAC and SIR levels were recorded. TAM was defined as serum creatinine (SCr) of ≥ 50% above baseline, elevated LDH levels (&gt;X2 upper limit of normal), presence of schistocytes or persistence of nucleated red blood cells, and prolonged or progressive thrombocytopenia. For PG the risk period was defined between days −1 to +60 of HSC. The risk period for the TG was defined from the first day of SIR/TAC until day +30 after the last dose was given.
Results: Records of 45 pts who were treated with SIR/TAC were reviewed. The median age of 21 patients in PG was 9.1 yr (2.9–22); male gender, n=13. The median age in 24 TG pts was14.7 yr (3.3–20.6); male gender, n= 11. Conditioning regimens consisted of TBI based regimens (64%), or chemotherapy only (36%). Diagnoses included ALL (40%), AML (27 %), NHL (9%), Fanconi’s (4 %), and other (9%). The median follow up for the surviving patients is 28.6 months. TAM criteria were met in 15 ( 30%) patients who received SIR/TAC, 5 PG pts (23.8%) and 10 TG pts ( 41.6%). Two PG patients died from multi-organ failure (MOF) related to other reasons (VOD, n=1 and multi-organism infection, n=1). Both pts had hemolytic uremic syndrome (HUS), possibly contributing to MOF. One patient developed seizures secondary to thrombotic thrombocytopenic purpura (TTP) as a complication of TAM. TAC and SIR levels were within the desired range (WDR, (≤10 ng/ml, for each) in this patient and signs and symptoms of TAM and TTP resolved after discontinuation of both TAC and SIR. In 2 patients TAM findings were asymptomatic, without progression to HUS or TTP. SIR/TAC levels in these patients were all WDR. Among 10 TG pts that met TAM criteria, 2 pts progressed to HUS and one developed severe TTP. All 3 patients with complicated TAM died (HUS, n=1, MOF, n=1, and idiopathic pneumonitis, n=1). Two of the pts with laboratory, but not clinically apparent TAM died (invasive fungal infection, n=1, IP n=1). In all TG pts with TAM either TAC (n=7) or SIR (n=6) levels exceeded WDR. To identify possible risk factors for TAM, the following parameters were analyzed: age, conditioning regimen, disease type, degree of HLA match. In the PG, only organ failure or high-grade GVHD could be identified as risk factors. In the TG, TAC or SIR levels exceeding WDR, in addition to ac GVHD or chronic GVHD present in all patients, were associated with an increased risk for clinical significant TAM.
Conclusion: Organ damage, either by acute GVHD or from other reasons may contribute to development of clinically significant TAM in pts undergoing allo-HST treated with SIR plus CNI. Monitoring TAC or SIR levels and early diagnosis of TAM may prove to be critical in patients with progressive organ damage of GVHD.