Fludarabine, Low Dose Busulfan and Antithymocyte Globulin for Reduced-Intensity Conditioning (RIC) Prior to Allogeneic Stem Cell Transplantation (allo-SCT).
Authors: Malard F. , Brissot Eolia , Chevallier Patrice , Guillaume Thierry , Delaunay Jacques , Ayari Sameh , Dubruille Viviane , Gouill Steven Le , Mahe Beatrice , Gastinne Thomas , Blin Nicolas , Saulquin Beatrice , Harousseau Jean-Luc , Moreau Philippe , Milpied Noel-Jean , Mohty Mohamad 
Published: October 2019

Abstract
Abstract 3341
Poster Board III-229
Allo-SCT procedures are currently undergoing a profound evolution. The spectra of patients and diseases for which this approach is now considered have increased considerably over the past years. This is mainly due to the introduction in routine practice of the so-called nonmyeloablative or RIC regimens. While it is well established that fludarabine is the backbone drug to secure engraftment, there is a wide variability in the degree of myeloablation between the different RIC protocols, and the toxicity profile might vary significantly from one protocol to another. The combination of fludarabine and Busulfan (usually 8 mg/Kg total dose) with or without ATG, is among the most widely used RIC protocols worldwide.
In an attempt to further decrease the toxicity of the transplant procedure, we hypothesized that further reduction (50%) of the Busulfan dose can allow improving transplant outcome. With this background, this pilot study tested the combination of Fludarabine (120 mg/m2), Busulfan (4 mg/Kg total dose administered orally over a single day) and ATG (Thymoglobuline®, 2.5 mg/Kg/d for 2 days) as a RIC regimen prior to allo-SCT in a single centre series of 46 patients. The cohort included 27 males (59%) and 19 females (41%) with a median age at time of allo-SCT of 57 (range, 12-64) y. Diagnoses included 21 cases of AML (46%), 12 NHL (26%), 6 Hodgkin diseases (13%), 3 ALL (6.5%), 2 myeloproliferative syndromes (4%), 1 MDS (2%) and 1 CLL (2%). Before allo-SCT, 23 patients (50%) underwent and failed previous stem cell transplantation (auto or allo). PBSCs were used as stem cell source in 42 patients (91%), while 4 patients (9%) received classical bone marrow. A matched-related donor was used in 18 cases (39%) and an unrelated donor in 28 cases (61%).
With a median follow-up of 30.4 (range, 23.7-50.8) months, the median peripheral blood chimerism of donor origin at day 30 after allo-SCT was 99%. 20 patients (43.5%) experienced grade 2-4 acute GVHD, including 13 cases (28.3%) of grade 3-4 acute GVHD. Nine patients (19.6%) experienced some form of chronic GVHD (5 extensive and 4 limited). At time of last follow-up, 26 patients (56.5%) were still alive. Relapse or disease progression occurred in 13 patients at a median of 3.5 (range, 0.6-18) months after allo-SCT. Disease progression accounted for 7 deaths, while transplant-related causes (acute GVHD, n=5; MOF, n=3; infections, n=2; other causes, n=3) were observed in 13 cases, for a TRM rate of 28.3%. The KM estimates of disease-free survival (DFS) and overall survival (OS) at 3 years after allo-SCT were 46.9% and 56.5% respectively. Interestingly, OS was lower in the AML subgroup (n=21) as compared to the remaining 25 patients with other diagnoses (42.9% vs. 68%, p=0.09).
We conclude that low dose Busulfan (4 mg/kg total dose) combined with fludarabine and ATG is a feasible RIC regimen that can allow engraftment after allo-SCT in heavily pre-treated patients. The toxicity profile of this regimen is acceptable. However, in the setting of AML, disease control may be a matter of concern, especially in the early period after allo-SCT, suggesting that this type of RIC should be reserved for patients with lymphoid or indolent malignancies.

Disclosures
No relevant conflicts of interest to declare.