Adult Matched Sibling Blood Cell Transplants (BCT) after Myeloablative Conditioning Incorporating Daily Intravenous (IV) Busulfan (BU) and Low-Dose Antithymocyte Globulin (ATG): Outcomes with Particular Respect to Transplant-Related Mortality (TRM) in 140 Patients.
Authors: Russell James A. , Chaudhy Ahsan M. , Jeje Oluyeme , Quinlan Diana , Stewart Douglas , Morris Donald , Bahlis Nizhar J. , Savoie Lynne , Brown Christopher B. , Larratt Loree , Geddes Michelle , Turner A. Robert 
Published: April 2020

Abstract
Intravenous BU allows more predictable exposure and is more convenient to administer once daily than the conventional four times daily regimen. Low-dose pretransplant ATG may reduce morbidity and mortality from graft-versus-host disease (GVHD). We have investigated a myeloablative regimen incorporating these agents in 140 adults aged 18–65 (median 47) receiving a first MRD SCT between 05/99 and 01/04. Conditioning comprised fludarabine (FLU) 50mg/m2on days −6 to −2 and IV BU (Busulfex, ESP Pharma) 3.2 mg/kg daily days −5 to −2 inclusive (FLUBUP) in 116 patients (pts) with additional TBI 200cGy x 2 in 24 (14 ALL, 8AML, 2 biphenotypic). Forty-three pts had standard-risk (SR) acute leukemia in CR1 (35 AML, 8 ALL), and 23 had active acute leukemia (HA) (18 AML±MDS, 3 ALL, 2 biphenotypic). A third group of 74 other (OTH) pts comprised 2 AML CR2, 2 ALL CR2, 2 CML (1 AP, 1CP2), 13 MDS, 11 MM, 24 NHL, 6 HD (2 with CLL), 8 CLL, 5 other. All pts were given cyclosporine A, “short course” methotrexate with folinic acid and Thymoglobulin (Genzyme) (ATG) 4.5 mg/kg in divided doses over 3 consecutive days pretransplant finishing D0. Followup of survivors is 6–61 months, median 26. Incidence of acute GVHD (aGVHD) grade II–IV was 19±4%, grade III–IV 6±2% and chronic GVHD (cGVHD) 66±5% (at 2 years). Projected TRM is 4±2% at 100 days, 10±3% at 1 year and 14±4% at 5 years. For acute leukemia pts projected TRM at one year is 5±5% vs 12±5% with (n = 24) and without (n = 47) TBI respectively (p = ns). Four non-relapse deaths occurred before day 100 one each from myocardial infarct (MI), acute GVHD, candidiasis and VOD. Ten deaths between days 102–569 were related to aGVHD in one and complications in pts with cGVHD in 9 (occurring in 1 pt after 2nd BCT for graft failure) including 1 VZV, 3 other infection, 1 PE, 1 MI. Of 11 follicular NHL pts 3 died of cGVHD and its complications after 1st BCT compared with 5 of 129 others (p = 0.02). Twelve of the transplant-related deaths were in 76 pts ≥ 46 years old compared with 2 in 64 younger pts (TRM = 23±6%, vs 4±3%, p = 0.01). Of 55 relapsed pts 17 are alive, 8 of these are in remission after more treatment and/or onset of GVHD. Projected 5-year disease-free survival and survival respectively is 46±5% and 57±5% for all pts, 62±8% and 76±7% for SR, 51±7% and 59±9% for OTH, and 9±6% and 16±8% for HA. This study indicates that: 1) regimen related mortality is low in MRD BCT recipients given this regimen 2) cGVHD is the main cause of TRM 3) pts with follicular NHL seem to be comparatively susceptible to death related to cGVHD 4) addition of 400cGy TBI does not increase risk of TRM and 5) older age remains a risk factor for TRM.