Assessment of Rabbit Antithymocyte Globulin (rATG) Dose-Intensity in Patients with Hematological Malignancies Undergoing Allogeneic Stem Cell Transplantation (ASCT) Following Reduced Intensity Conditioning (RIC) with Fludarabine, Busulfan and rATG (FBA)
Authors: Hamadani Mehdi , Blum William , Benson Don , Blum Kristie A , Porcu Pierluigi , Elder Patrick , Krugh David , Bechtel Thomas , Andritsos Leslie , Garzon Ramiro , Penza Sam , Lin Thomas S. , Devine Steven 
Published: April 2020

Abstract
Incorporation of rATG in RIC regimens not only reduces rates of graft-versus-host disease (GVHD), but it also promotes effective engraftment of donor cells. However rATG at doses ≥7.5mg/kg, is associated with significant infectious complications (Hamadani M. ASH 2007). We hence embarked on a strategy designed to evaluate lower dose (6mg/kg) rATG in patients (pts) undergoing RIC with FBA. All pts (n=47) were conditioned with F (30 mg/m2/day, days-7 to -3), B (0.8 mg/kg/dose IV × 8 doses) and either 7.5mg/kg of rATG (7.5rA) (n=39) or 6mg/kg of rATG (6rA) (n=8), followed by micro-dose methotrexate and tacrolimus. Criteria for selection included advanced age (&gt;55yrs), prior autograft, and/or high co-morbidity index (median 1, range 0–4). There were 31 male and 16 female pts with a median age of 57 years (range 24–70 yrs). Diagnoses included AML (N=17), NHL (N=10), Hodgkin’s lymphoma (N=4), CML (N=5), advanced CLL (N=8), and others (N=3). 74% (N=35) had high-risk disease. Six pts had previously undergone autologous SCT. 36% had a Karnofsky performance status of 70 or 80% at the time of transplant. 9 pts (19%) had one or more antigen or allele level mismatches with their donors. Stem cell source included peripheral blood (N=43) or bone marrow (N=4). 42 pts (89%) received grafts from unrelated donors. All pts engrafted neutrophils and platelets promptly (median 15 and 17 days, respectively). One patient had secondary graft failure, and another AML patient previously only treated with decitabine experienced secondary graft rejection. Both of these patients received 7.5rA. Overall rates of grade II–IV and III–IV acute GVHD were 27% (N=13) and 17% (N=8) respectively. 17 pts (41%) developed chronic GVHD but extensive chronic GVHD was seen in only 21% (N=9). Day 100 and overall non-relapse mortality (NRM) was 6% (N=3) and 23% (N=11). Causes of death included disease progression=6, post-transplant lymphoproliferative disorder (PTLD)=2, GVHD=3, infection=4, and others=2. CMV, EBV, and BK-virus reactivation occurred in 55% (N=26), 25% (N=12) and 21% (n=10) respectively. Compared to pts receiving 7.5rA, ones receiving 6rA had fewer CMV (61% vs. 25%; p-value=0.05) and BK-viral (25% vs. 0%; p-value=0.03) reactivations and lower rate of relapse (33% vs. 12.5%; p-value=0.20), NRM (28% vs. 0%; p-value=0.01), and acute GVHD (33% vs. 0%; p-value=0.01). None of the 6rA pts developed PTLD. Overall lineage-specific chimerism analysis showed 100% donor CD33+ chimerism at all time points (days 30, 60, 90, and 180) and median donor CD3+ chimerism of 94%, 97%, 99% and 100% at days +30, +60, +90 and +180. No difference was seen in the two rATG doses. 36 pts (76%) were in CR after ASCT. The median follow-up of surviving patients is 12 months (range 3–26 months). Rates of overall survival (OS) and progression free survival (PFS) at 1year are 66% and 52% respectively. Using the Log-Rank test, OS and PFS was not statistically significant between recipients of matched and mismatched grafts, and between pts with high-risk or standard-risk disease. In conclusion, our preliminary data suggests that 6rA promotes effective donor cell engraftment, without compromising GVHD control, and may be associated with lower rates of infectious complications and disease relapse. Systematic evaluation of rATG dose de-escalation is continuing at our institution.