Combination of ATG and Post-Transplant Cyclophosphamide for Gvhd Prophylaxis in Matched and Mismatched Donor Peripheral Blood Stem Cell Transplants for Myeloid Malignancies

Abstract

Introduction ATG and post-transplant cyclophosphamide (PTCy) have been individually shown to be efficacious in reducing rates of GVHD in HLA matched and mismatched transplants. We adopted a combination regimen of ATG and PTCy for GVHD prophylaxis in HLA matched and mismatched transplants for myeloid malignancies in our centre, to decrease the rates of acute and chronic GVHD. Objectives We assessed the overall and progression free survival, incidence of acute and chronic GVHD, relapse rates and non-relapse mortality with this protocol. Patients and Methods Reduced intensity conditioning protocol consisted of iv Fludarabine, iv Busulphan, and low dose TBI. GVHD prophylaxis was with Thymoglobulin total dose 4.5mg/kg, PTCy total dose 100 mg/kg and cyclosporine. The stem cell source was G-CSF stimulated PBSCs. Results 169 patients (median age 58 y, range 19-74y) with high-risk myeloid malignancies (AML-64.5%, MDS-19%, MPN-12%) were treated with this protocol after obtaining institutional approval. The donor types were as follows-10/10 matched unrelated donor (MUD) in 67, 9/10 mismatched unrelated (MMUD) in 24, 10/10 matched related donor(MRD) in 35 and haplo-identical (HI) donors in 43 patients. The median follow-up in the entire cohort was 12 months. The 1year OS in the MUD, MMUD, MRD and HI groups were 73%, 54%, 74% and 56% respectively and the corresponding 1 year PFS were 66%, 38%, 49% and 51% respectively. The percentage of graft failure (primary and/or secondary) in the 4 groups were 1.5%, 12.5%, 0% and 16.3% respectively. The relapse rates were 21% in MUD, 42% in MMUD, 29% in MRD and 14% in HI groups. The MMUD patients had significantly inferior OS (p=0.03), and PFS (p=0.003), and significantly higher risk of relapse(p=0.009), compared to MUD patients. The overall incidence of grade 3-4 acute GVHD in our patients was 10 % and of moderate/severe NIH stage chronic GVHD was 11.6% which is low compared to conventional GVHD prophylaxis regimes. The percentages for grade 3-4 acute GVHD according to donor type were 16.4% in MUD, 4.2% in MMUD, 5.8% in MRD and 9.3% in HI groups and that of moderate/severe NIH stage chronic GVHD were 7.5%, 8.4%, 11.4% and 16.3% respectively. There were high rates of viral reactivation observed with this dual T lymphocyte suppression strategy. The overall incidences of CMV, and EBV reactivation and BK cystitis were 48%, 33% and 17% respectively. In addition, there were 12 pathologically confirmed cases of post-transplant lympho-proliferative disorder. Conclusion Our experience shows that PT-Cy and ATG can be combined for GVHD prophylaxis in PBSCTs for high risk myeloid malignancies and results in low rates of Gr3-4 acute GVHD and moderate/severe chronic GVHD across different donor types with acceptable relapse rates. High rates of viral re-activation are a concern and need close monitoring.