Long-Term Outcome of Methotrexate-Free GVHD Prophylaxis Using Sirolimus and Tacrolimus in Matched Related (MRD) and Unrelated Donor (URD) Peripheral Blood Stem Cell Transplantation (PBSCT).
Authors: Cutler Corey , Li Shuli , Ho Vincent , Koreth John , Alyea Edwin , Soiffer Robert J. , Antin Joseph H. 
Published: April 2020

Methotrexate (Mtx) is an antiproliferative agent associated with toxicity and delayed engraftment after transplantation. Sirolimus is an immunosuppressive mTOR inhibitor that acts synergistically when administered with tacrolimus. We assessed the combination of sirolimus and tacrolimus without Mtx after MRD and URD PBSCT in concurrent trials. Methods Eligible subjects had HLA-A, B, C and DRβ1 matched MRD and URD donors. Conditioning consisted of cytoxan (1800 mg/m2 x 2 days) and TBI (14 Gy, 7 fractions with lung shielding). Tacrolimus (serum conc. 5–10 ng/mL) and sirolimus (serum conc. 3–12 ng/mL) were given as GVHD prophylaxis. No Mtx was given. G-CSF (5 μg/kg/day) was administered from day+12 until neutrophil engraftment as needed. PCP, VZV, and HSV prophylaxis was used, and CMV was treated pre-emptively. No routine anti-fungal prophylaxis was given. Results 53 MRD and 30 URD recipients were enrolled between 7/2002 and 8/2005. The median number of stem cells infused was lower in MRD recipients (7.6 x106 CD34+ cells/kg vs. 10.2 x106 CD34+ cells/kg, p&lt;0.001). Neutrophil engraftment was similar in MRD and URD patients (14 vs. 13.5 days, p=0.2). Platelet engraftment to 20 x106/ml (12 vs. 12 days, p=0.13) and to 100 x106/ml (17.5 vs. 17 days, p=0.32) were similar in the two cohorts. The median time to hospital discharge was 19 days in both groups (p=0.95), with only 2 deaths prior to discharge. Acute lung injury (IPS/DAH) occurred in only 1 subject and was not fatal. 7 (8.4%) subjects developed hepatic veno-occlusive disease (VOD) and was the cause of death in 4. Thrombotic microangiopathy (TMA) was noted in 6 subjects (MRD 5, URD 1; combined incidence 7.3%) and resolved with the elimination of tacrolimus. Renal function recovered in all individuals and TMA did not contribute to the cause of death in any subject. The cumulative incidence of grade II–IV acute GVHD was 20.5%, and was not different between cohorts (18.9 vs. 23.3%, p=0.78). There were only 3 cases of grade III–IV acute GVHD (2 MRD, 1 URD). In a competing risk model (relapse/death as competing risk) the cumulative incidence of chronic GVHD was 52.4% and was not different between groups (50.9 vs. 53.3%, p=0.67). The median follow-up of all surviving patients is 29.5 months from transplantation. Non-relapse and relapse-related mortality at 30 days was 0%. At 100 days they were 4.8% and 1.2% respectively (overall 100 day mortality 6%), without differences in cohorts. Relapse-free survival for the entire group was 72.3% and 68.1% at 1 and 2 years (MRD 71.7% and 66.0%; URD 73.3% at both times points, log rank p=0.6). Overall survival at 1 and 2 years is 77.1% and 71.7% (MRD 77.4% and 69.8%; URD 76.7% at both time points, log-rank p=0.67). The causes of death (n=24) include relapse(13), VOD(4), late pulmonary disease(3), GVHD(2), infection and organ failure(2). Conclusions Sirolimus in lieu of Mtx in a tacrolimus-based GVHD prophylactic regimen is associated with lower transplant-related toxicity, lower rates of acute GVHD and excellent outcomes than would be expected with a Mtx-based regimen. Moreover, MRD and URD outcomes appear to be equivalent, suggesting that the historical disparity in outcomes between MRD and URD transplantation can be abrogated with effective GVHD prophylaxis. This regimen is worthy of further study and broader use in MRD and URD PBSCT.