Fludarabine and Busulfan-Based Reduced Intensity Conditioning (RIC) Allogeneic HLA-Identical Transplantation (allo-SCT) with or without Anti-Thymocyte Globulin (ATG): Comparison between Two Prospective Studies in Patients with Myeloid Malignancies.
Authors: Mohty Mohamad , Martino R. , Faucher C. , Perez-Simon J.A. , Vey N. , Caballero M.D. , Gastaut J.A. , Miguel J. San , Blaise D. , Sierra J. 
Published: April 2020

In an attempt to reduce toxicity in patients not eligible for standard myeloablative allo-SCT, different RIC regimens aiming to induce an allogeneic graft-vs-tumor (GVT) effect, have been investigated and could result in durable donor cell engraftment. All of these protocols have been shown to be highly immunosuppressive, but because of the variability in degree of myeloablation or inclusion or not of T cell depleting agents such as Campath or ATG, transplant-related events might vary from one protocol to another. We report here a comparison between two prospective RIC strategies for allo-SCT from an HLA-identical sibling in patients with myeloid malignancies (60 AML, 27 MDS and 21 CML). The first RIC regimen (group I, n=56) was based on fludarabine (Flu), busulfan (Bu) and a combined GVHD prophylaxis with CSA and short course methotrexate (MTX; days 1, 3, 6). The second RIC regimen (group II, n=52) included ATG as part of the preparative regimen in addition to Flu and Bu, but used a single GVHD prophylaxis with CSA alone. The kinetic of engraftment was strictly comparable between the two groups: median of 16 days for ANC&gt;500/μL; 12 (group I) vs. 13 (group II) days for platelet &gt;20000/μL. 13 patients (23%) experienced grade 2–4 acute GVHD in group I, as compared to 20 patients (38%) in group II (P=NS). The incidence of extensive chronic GVHD was also comparable between both groups (40% in group I vs. 48% in group II; P=NS). Moreover, 10 patients (18%) in group I died from transplant-related mortality as compared to 11 (21%) in group II (P=NS) with disease progression being the major cause of death in both groups. Both protocols could exert a potent GVT effect, and the incidence of relapse or disease progression was comparable (21%, group I vs. 35% group II; P=NS). In multivariate analysis including protocol type (I vs. II), demographic and disease characteristics and transplant-related events, chronic GVHD was the most powerful protective factor against relapse or disease progression (RR=0.11; P&lt;10e-5). Overall, these data establish that regardless of the type of the RIC regimen, RIC-allo-SCT is a valid and beneficial approach for patients with myeloid malignancies. The Flu-Bu-ATG-CSA-RIC approach seems to be comparable to the Flu-Bu-CSA+MTX approach as for major outcomes (engraftment, GVHD, TRM). However, it is unlikely that different RIC strategies are simply interchangeable. A detailed analysis of other outcomes such as chimerism kinetic, immune recovery profile and toxicity (infections, mucositis, liver toxicity...) is still warranted. A patient-tailored approach considering the potential GVT effect benefit and procedure-related toxicities, adjusted for quality of life may be crucial determinants for the ultimate outcome.