Predictors of overall survival among patients treated with sirolimus/tacrolimus vs methotrexate/tacrolimus for GvHD prevention

Abstract

Sirolimus (SIR)/tacrolimus (TAC) is an alternative to methotrexate (MTX)/TAC. However, rational selection among these GvHD prophylaxis approaches to optimize survival of individual patients is not possible based on current evidence. We compared SIR/TAC (n=293) to MTX/TAC (n=414). The primary objective was to identify unique predictors of overall survival (OS). Secondary objective was to compare acute and chronic GvHD, relapse, non-relapse mortality, thrombotic microangiopathy (TMA), hepatic veno-occlusive disease (VOD/SOS), and acute kidney injury. Day 100 grades II-IV acute GvHD was significantly reduced in SIR/TAC vs MTX/TAC group (63 vs 73%, P=0.02). An interaction between GvHD prophylaxis groups and comorbidity index (hematopoietic cell transplantation (HCT)-CI) significantly impacted OS. Patients with HCT-CI⩾4 had significantly worse OS with MTX/TAC (HR 1.86, 95% CI 1.14-3.04, P=0.01) while no such effect was seen for SIR/TAC (HR 0.78, 95% CI 0.48-1.26, P=0.31). Other end points did not significantly differ between groups except TMA and VOD/SOS were increased in the SIR/TAC group, but excess death from these complications was not observed. We conclude, GvHD prophylaxis approach of SIR/TAC is associated with reduced grades II-IV acute GvHD, comparable toxicity profile to MTX/TAC, and improved OS among patients with HCT-CI⩾4.

Pacritinib Combined with Sirolimus and Low-Dose Tacrolimus for GVHD Prevention after Allogeneic Hematopoietic Cell Transplantation: Preclinical and Phase I Trial Results

“…The decision to combine pacritinib with SIR/TAC is supported by extensive translational investigations (1,6-10). We have refined the use of SIR/TAC in GVHD prevention and developed a strategy to achieve a low incidence of VOD or TMA (7)(8)(9). Of the two patients that developed TMA with PAC/SIR/TAC, the severity was mild with no major adverse consequences.…”

“…In both cases of TMA, the patients improved with either no intervention or discontinuation of tacrolimus. Further, SIR/TAC enhances the immune reconstitution of Tregs and limits severe mucositis compared to tacrolimus plus (7)(8)(9)26). This is important as our published data in mice show that JAK2-deficient T cells favor a Treg phenotype over pathogenic Th17 cells (6).…”

“…To enhance the immune suppressive potency afforded by pacritinib, and leverage its beneficial effects toward Tregs, we combined pacritinib with our sirolimus (target range 5-14ng/ml) and low dose tacrolimus (3-7ng/ml) (SIR/TAC) GVHD prophylaxis regimen (7,8). Exposure to SIR and specifically limiting the dose of TAC (3-7ng/ml) assists in the reconstitution and function of Tregs across conditioning regimens and donor sources (7,9). The addition of JAK2 inhibition to mTOR blockade also parallels our prior study in mice where we demonstrated that concurrent suppression of T cell costimulation and cytokine activation prevents GVHD while maintaining GVL (10).…”

Hepatic veno-occlusive disease following sirolimus-based immune suppression

“…The consecutive series of HCT procedures has been previously published [8]. Ursodeoxycholic acid was routinely administered as VOD/SOS prophylaxis in all patients.…”

“…Comprehensive patient, disease, and HCT characteristics were collected (as previously described) including variables previously shown to be associated with VOD/SOS [8]. Liver injury variables included total serum Bilirubin, AST, ALT, weight gain, ascites, abdominal pain, tacrolimus and sirolimus levels (ng/ml), new thrombocytopenia during liver injury, serum ammonia, doppler ultrasound and MRI liver findings, liver biopsy findings, diuretic use, sirolimus and/or tacrolimus dose reduction and discontinuation, resolution of VOD and cause of death.…”