Use of Intravenous Busulphan for Reduced Intensity Conditioning (RIC) Haematopoietic Stem Cell Transplantation (HSCT) Is Associated with Delayed T-Cell Full Donor Chimerism and Lower Incidence of Acute Graft Versus Host Disease.
Authors: Lim ZiYi , Thanigaikumar Murugaiyan , Gandhi Shreyans , Pearce Laurence , Kenyon Michelle , Ho Aloysius Y.L. , Devereux Stephen , Pagliuca Antonio , Mufti Ghulam J. 
Published: April 2020

Abstract
The use of IV busulphan (Bu) has reported improved bioavailability with lower variability of busulphan plasma levels, and may reduce the effects of transplant related toxicity particularly in the context of myeloablative regimens. In contrast, there is limited data avaliable on the use of IV Bu in the setting of reduced conditioning (RIC) regimens. We retrospectively analysed data from 163 consecutive patients treated at our centre for myeloid malignancies (AML n=78, MDS/MPD n=73, CML n= 12) using RIC HSCT, and evaluated the engraftment and chimerism kinetics as well as the early transplant outcomes between patients receiving either IV or oral Bu. Patients received fludarabine (30mg/m2 × 5 days), alemtuzumab (20mg × 5 days) and either oral Bu (4mg/kg × 2 days) or IV Bu (3.2mg/kg × 2 days). 84 consecutive patients received oral Bu up to Jan 2004. Thereafter, 79 consecutive patients received IV Bu. The median age of the cohort was 53 years(range: 19–72). 50 patients received stem cells from HLA-matched sibling donor, and 113 from a volunteer unrelated donor. 128 patients received PBSC and 35 received BM stem cells. 64 patients had early disease vs 99 advanced disease (advance disease defined as AML &gt; CR1, CML &gt; CP1, MDS with RAEB or AML with multilineage dysplasia). Median follow-up was 1531 days (range: 853–1987) for the oral Bu group and 551 days (range: 228–1072) for the IV Bu group. There was no difference between groups in terms of recipient age, stem cell dose/source, donor type, prior therapies or disease type. However, patients receiving IV Bu had more advanced disease compared with oral Bu (70% vs 52%, p=0.03). There was no significant difference in the median time to neutrophil and platelet regeneration between groups. In contrast lymphoid(CD3) engraftment was significantly delayed in the IV Bu group, with 35% vs 53%(p=0.04) recipients achieving full donor chimerism(FDC) at day 30, and 32% vs 51%(p=0.03) at day 100. The cumulative incidence of acute GvHD was lower in the IV Bu group 18% vs 29%(p=0.04), with no difference in the cummulative incidence of chronic GvHD between groups. Early(1-year) transplant-related mortality (TRM) was higher in the oral Bu group(TRM:: 25%vs13%, p=0.07) with a significantly lower overall survival(60%vs79%, p=0.02) primarily as a result of death from GvHD and related infection complications. There was no significant difference in relapse incidence at 1 year between cohorts(IV Bu 27% vs oral Bu 23%, p=0.84). On multivariate analysis, the type of conditioning regimen had no effect on the overall transplant outcomes. Attainment of CD3 FDC at day 30(HR: 2.14, 95%CI: 1.26–3.63, p&lt;0.01) and advanced disease stage(HR:2.62, 95%CI: 1.41–4.89, p&lt;0.01) were the only significant variables associated with a poorer OS. In contrast, the presence of CD3 mixed donor chimerism at day 30(HR:2.70, 95%CI: 1.24–5.90, p=0.01) was the only independent variable associated with improved TRM. Advanced disease stage was the only independent predictor of disease relapse(HR:2.34, 95%CI: 1.17–4.66, p=0.02). In summary, RIC HSCT with IV busulphan is a safe and well tolerated regimen. When compared with oral Bu, use of IV Bu as part of an FBC regimen is associated with delayed attainment of CD3 FDC, and is associated with a corresponding lower incidence of acute GvHD and early complications.