Post-Transplant Cyclophosphamide (PTCY) Results in Remarkably Low Incidence of Chronic Graft-Versus-Host Disease in Unrelated or Matched Sibling Donor Stem Cell Transplantation without Compromising Immune Reconstitution and Graft-Versus-Leukemia Effect

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PTCY was first applied in the haploidentical stem cell transplantation (SCT) setting and is gradually being used in mismatched unrelated or fully matched donor transplants. We prospectively tested this approach in SCT from matched or mismatched unrelated (MUD/MMUD) and matched sibling donors (MSD) to reduce the incidence of acute and especially chronic graft-vs-host disease (GVHD). From 01/2021 to 05/2023, 51 consecutive patients, aged 18-69 (median 52) years, received allogeneic SCT with PTCY for AML/MDS (n=36), NHL/CLL (n=2), primary myelofibrosis (n=2), CML (n=2), or ALL (n=9). Disease risk index (DRI) was intermediate in most patients (34/51), and high in 10. The conditioning regimen was myeloablative in 37 patients and reduced-intensity in 14. 36 patients received grafts from 8/8 MUD, 12 from MMUD (7/8), and 3 from MSD. Graft source was peripheral blood in all cases, with a median CD34+ cell dose of 6.97x10e6/kg (range, 3.27-15.82). PTCΥ was administered on days +3 and +4 at a dose of 50 mg/kg/day. Additional GvHD prophylaxis included tacrolimus and mycophenolate mofetil starting on day 0. In patients with no evidence of GvHD immunosuppression was gradually withdrawn by day +90. We evaluated the safety and efficacy of the procedure in terms of engraftment, non-relapse mortality (NRM), acute or chronic GvHD (aGVHD/cGVHD), relapse, survival, and immune reconstitution. Cumulative incidence (CI) of neutrophil engraftment (>500/ul) was 95.8%, and was achieved at a median of 16 (range 13-27) days. CI of grade ΙΙ-IV aGVHD was 46.7% (95%CI, 34.1-63.8), however grade ΙΙΙ-IV aGVHD occurred only in 3.9% (95%CI, 1.0-15.5). CI of cGVHD at 18 months was 13.4% (95%CI, 5.8-31.0), with only 1 case of extensive cGVHD. At a median follow-up of 14.5 (range 1-28) months, disease-free (DFS) and overall survival (OS) at 18 months was 76.8% (95%CI, 65.5-90.0) and 76.3% (95%CI, 64.9-89.8), respectively, and did not differ significantly between MUD and MMUD SCT (Figure 1A). GvHD-free, relapse-free survival (GRFS) was 63.5% (95%CI, 50.3-80.1)(Figure 1B). CI of relapse and NRM was 4.3% and 15.5%, respectively. Infections accounted for NRM in the majority of cases. Median absolute CD8+ and CD4+ T cell counts were420/ul (range, 20-2225) and 179/ul (range, 13-594) respectively at 6 months versus 552/ul (range, 55-3002) and 364/ul (range, 60-787) respectively at 12 months. Viral infections occurred in 28 patients (respiratory:13, BKV cystitis:11, CMV infection/disease:7). In addition, 2 fungal and 1 atypical mycobacterial infection were documented. In conclusion PTCY resulted in a remarkably low incidence of cGVHD in MUD and MMUD SCT. Relapse rate was low, immune reconstitution was robust for CD8+ but somewhat delayed for CD4+ T cells. However, opportunistic infections were not increased. Thus, PTCY may revert the negative impact of HLA mismatch in unrelated SCT and is also a beneficial option for MUD and MSD transplants.

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