Long Term Infectious Complications Following Reduced Intensity Conditioning (RIC)Allogeneic HLA-Identical Sibling Transplantation (allo-SCT).
Authors: Etienne A. , Mohty M. , Faucher C. , Ferrando M. , Benramdane R. , Zandotti C. , Collet L. , Vey N. , Stoppa A.M. , Coso D. , Viens P. , Gastaut J.A. , Blaise D. 
Published: April 2020

Abstract
In the setting of RIC for allo-SCT, promising results have been reported in regards to decreased early transplant-related complications. However, long term outcomes are still poorly defined. Of note, the epidemiology of long term transplant-related infections is still sparse. Our current knowledge of long term infectious complications after RIC allo-SCT is still primarily based on results of analyses performed in the standard myeloablative allo-SCT setting. This prospective report describes infectious complications occurring beyond six months after allo-SCT, in 81 consecutive patients who received a RIC regimen prior to allo-SCT from HLA-identical siblings. Patients’ characteristics are as follow: median age: 49 (range, 18–63) y. 33 patients (41%) had a myeloid malignancy, 34 (42%) had a lymphoid malignancy, and 14 patients (17%) were treated for metastatic non-hematological malignancies. 21 patients (26%) from this series received donor bone marrow (BM), while the remaining 60 patients (74%) received peripheral blood stem cells (PBSC). In addition to fludarabine and busulfan, the RIC regimen included high dose ATG in 20 patients (25%) and low dose ATG in 50 patients (62%). The remaining 11 patients (13%) received a low dose irradiation-based RIC. With a median follow-up of 26 (range, 9–68) months, 67 patients (83%) experienced at least one infectious episode (microbiologically documented, n=33; or non-documented infections, n=34) beyond the first six months after allo-SCT developing at a median of 8 (range, 6–34) months. A total number of 221 infectious episodes was observed, of which 123 (56%) required hospitalization and systemic anti-microbial therapy. 94 episodes (43%) could be documented (bacterial, n=28; viral, n=56; fungal, n=10). Microbiologically documented infections were distributed as follow: gram negative bacteria (16%), other bacteria (14%), CMV positive antigenemia (17%), HSV (25%), VZV (15%), other viruses (3%), aspergillus (4%), candida species (6%). 81% of patients (n=54) with an infection were under systemic immunosuppressive therapy for chronic GVHD. In a univariate analysis performed in the 33 patients with a documented infection, age &lt;50 (P=0.06), the use of PBSCs as stem cell source (P=0.03) and a history of DLI administration (P=0.002), exerted a protective effect against infection occurrence. Interestingly, in a multivariate analysis, DLI administration (for progressive disease or mixed chimerism) was the strongest factor significantly associated with a decreased risk of long term infections (P=0.002; RR=0.23; 95%CI, 0.1–0.6), indirectly highlighting the protective effect of donor origin immunity after allo-SCT. In this series of patients surviving at least 6 months after RIC allo-SCT, the overall long term transplant-related mortality was 14% (n=11), of whom 6 deaths were attributed to infections (3 bacterial septicemia, 2 aspergillosis, 1 pneumocystosis), giving a cumulative incidence of long term-infectious related mortality of 7% (95%CI, 1.4–12.6%). Obviously, prospective efforts to develop optimal antimicrobial preventive strategies after RIC allo-SCT are still needed. However, the results from this analysis compare favorably with data from the standard myeloablative allo-SCT setting, further underlining the overall benefits of RIC preparative regimens before allo-SCT.