Sirolimus and Tacrolimus without Methotrexate as Graft-vs.-Host Disease Prophylaxis after Matched, Unrelated Peripheral Blood Stem Cell Transplantation: Excellent GVHD Control with Low Transplant-Related Morbidity and Mortality.
Authors: Cutler Corey , Li Shuli , Kim Haesook T. , Macdonell Rebecca , Ho Vincent , Alyea Edwin , Lee Stephanie J. , Soiffer Robert J. , Antin Joseph H. 
Published: October 2019

Sirolimus (Rapamycin, Rap) is an immunosuppressant structurally similar to tacrolimus (Tac), however, Rap inhibits T cell function via FKBP12/mTOR and may also inhibit dendritic cell function. Rap is synergistic with Tac and has no overlapping toxicity, allowing their use in combination. We have shown that Rap, Tac and low-dose methotrexate (Mtx) is effective GVHD prophylaxis after unrelated donor (URD) transplantation and the combination of Rap and Tac alone is effective in matched, related donor (MRD) transplantation. Since Mtx is associated with transplant-related toxicity and delayed engraftment, we hypothesized that Rap and Tac, without Mtx, would provide effective GVHD prophylaxis in URD transplantation while minimizing transplant-related morbidity and mortality.

Methods: 28 subjects underwent peripheral blood stem cell transplantation (PBSCT) from 6/6 HLA-matched unrelated donors after Cy/TBI conditioning. GVHD prophylaxis consisted of Rap (target serum level 3–12 ng/ml) and Tac (target serum level 5–10 ng/ml). Filgrastim (5 μ g/kg) was administered from day+12 until engraftment, if needed.

Results: The median age of subjects was 43.5 years (range 22–54). Diagnoses were AML(11), CML(6), NHL(4), MDS(3), ALL(2), MPD(1) and HD(1). The median times to neutrophil engraftment (>500/μ L) and platelet engraftment (>20,000/μ L and >100,000/μ L) were 13.5 (range 11–14), 12 (range 9–25), and 17 (range 12–101) days, respectively. All 28 patients survived to first hospital discharge, at a median of 19 days from day 0 (range 14–55). Gr. II acute GVHD occurred in 4 patients (14.3%) and Gr. IV acute GVHD occurred in 1 patient (3.5%), for an overall rate of Gr. II–IV acute GVHD of 17.9%. GVHD resolved with corticosteroids in all but 1 case. Transplant-related morbidity was low, without any cases of idiopathic pneumonia syndrome/diffuse alveolar hemorrhage. Two subjects developed VOD and one subject developed thrombotic microangiopathy. Reactivation of HHV-6 with limbic encephalitis was noted in 2 patients. Nine of 24 evaluable patients developed chronic GVHD (7 extensive, 2 limited). Five patients relapsed, one of whom achieved a complete remission after immunosuppression withdrawal and DLI. Causes of death include relapse(2), VOD(1), and relapse with VOD and hepatic GVHD(1). The median follow-up is 197 days (range 80–557). Treatment-related mortality at 100 days is 3.5%. Relapse-free and overall survival at day 100 are both 92.7%, and at 1 year are 75.4 and 83.6%, respectively.

Conclusions: Rap and Tac without Mtx is effective for GVHD prophylaxis after matched URD PBSCT, leading to acute GVHD in 17.9% of treated patients, which is similar to our experience using Rap and Tac in MRD transplantation. Furthermore, the omission of Mtx is associated with minimal transplant-related morbidity and mortality. This combination is worthy of broader study in unrelated donor transplantation.