Risk stratification and impact of donor type on breakthrough invasive fungal infections in haematopoietic cell transplant with post-transplant cyclophosphamide and mould-active prophylaxis

Abstract

Incidence of breakthrough proven-probable invasive fungal infections (b-PP-IFIs) in allogeneic haematopoietic cell transplant recipients (allo-HCT-r) receiving mould-active prophylaxis (MAP) and post-transplant cyclophosphamide (PT-Cy) is largely unknown. Retrospective study on allo-HCT-r, classified at high-risk for IFIs whether ≥1 of the following conditions was met: 1] active disease; 2] cord-blood; 3] previous transplant; 4] acute graft-versus-host-disease (a-GVHD) grade≥3; 5] mismatched-related or unrelated donor with neutropenia before transplant or grade-2 a-GVHD or Cytomegalovirus infection. Objectives were to estimate cumulative incidence function (CIF) of b-PP-IFIs, evaluate infection-related mortality (IRM) and predictive factors of b-PP-IFIs. Overall, 473 allo-HCT-r (n = 286 posaconazole, n = 187 voriconazole) were analysed: 64.7% were at high-risk, 81.6% received PT-Cy. Fifteen b-PP-IFIs occurred: 14/306 in high-risk, 1/167 in non-high-risk group. CIF of b-PP-IFIs in high-risk group was 2.0% (95%CI = 0.8-4.1%) at 30-day and 5.1% (95%CI = 2.9-8.2%) at 1-year post-transplant. The 1-year CIF of IRM was higher in allo-HCT-r with b-PP-IFIs compared to those without [46.7% (95%CI = 19.6-70%) vs. 8.2% (95%CI = 5.3-9.2%), Gray's test: p < 0.001]. In allo-HCT-r receiving PT-Cy, neutropenia before transplant [sHR 7.54 (95%CI = 1.81-31.43)] and chronic myeloproliferative disorders versus AML/MDS [sHR 7.72 (95%CI = 1.68-35.42)] increased risk of b-PP-IFIs, while donor type did not. MAP effectively prevented IFIs. PT-Cy conferred a comparable risk of b-PP-IFIs in matched compared to mismatched-transplants.