Long Term Infectious Complications Following Reduced Intensity Conditioning (RIC) Allogeneic HLA-Identical Sibling Transplantation (allo-SCT).
Authors: Etienne Anne , Mohty Mohamad , Faucher Catherine , Furst Sabine , El-Cheikh Jean , Zandotti Christine , Berger Pierre , Vey Norbert , Stoppa Anne-Marie , Bouabdallah Reda , Viens Patrice , Gastaut Jean-Albert , Blaise Didier 
Published: October 2019

Abstract
In the setting of RIC for allo-SCT, long term outcomes are still poorly defined. Of note, the epidemiology of long term transplant-related infections is still sparse. This prospective report describes infectious complications occurring beyond 6 months after allo-SCT, in 159 consecutive patients who received a RIC allo-SCT from an HLA-identical sibling. Patients characteristics are as follow: median age was 50 (range, 18–68) years. 68 patients (43%) had a myeloid malignancy, whereas 66 patients (41%) had a lymphoid malignancy. The remaining 25 patients (16%) were treated for metastatic non-hematological malignancies. The majority of patients (n=126, 79%) had an advanced disease with high risk features precluding the use of myeloablative allo-SCT. 24 patients (15%) received donor bone marrow (BM), while the remaining 135 patients (85%) received PBSCs. In addition to fludarabine and busulfan, the RIC regimen included high dose ATG in 20 patients (13%) and low dose ATG in 95 (60%). 24 patients (15%) received fludarabine, busulfan and TLI, while the remaining 24 patients (15%) received fludarabine and low dose TBI. With a median follow-up of 19 (range, 6–90) months, 120 patients (75%) experienced at least one infectious episode (total number of episodes, 366) beyond the first six months after allo-SCT developing at a median of 8 (range, 6–34) months. In all, 212 infectious episodes (58%) required hospitalization (7% in the intensive care unit) for a median duration of 10 (1–91) days. 144 episodes (39%) could be documented (bacterial, n=48; viral, n=78; fungal, n=18). Microbiologically documented infections were distributed as follow: gram negative bacteria (18%), other bacteria (15%), CMV positive antigenemia (17%), HSV (19%), VZV (15%), other viruses (3%), aspergillus (6%), candida species (6%), other (1%). 76% of patients with an infection were under systemic immunosuppressive therapy for chronic GVHD at time of infection. Moreover, 85 patients (71%) experienced more than one infectious episode (median, 2; range, 1–12). In multivariate analysis, active or prior history of extensive chronic GVHD and the use of a BM graft were the strongest factors significantly associated with an increased risk of long term infections (P=0.0003; RR=2.04; 95%CI, 1.4–3.0; and P=0.005; RR=2; 95%CI, 1.2–3.2 respectively), highlighting the raising concern about the deleterious impact of severe chronic GVHD occurring after RIC allo-SCT, but also the protective effect of donor origin immunity based on graft origin and content. In this series of patients surviving at least 6 months after RIC allo-SCT, the overall long term transplant-related mortality was 11% (n=18), of whom 12 deaths were attributed to chronic GVHD and its complications including infections, and 5 deaths solely attributed to infections. In all, these results suggest that, despite reduction in early toxicity associated with the use of RIC regimens, long term debilitating chronic GVHD and its corollary of continuous immunosuppression and subsequent infections are still a matter of concern. Prospective efforts to develop optimal antimicrobial preventive strategies are needed to further improve the safety of the procedure and the overall benefits of RIC preparative regimens before allo-SCT.