Matched Pair Analysis of Intravenous vs Oral Busulphan as Part of Fludarabine-Busulphan-Campath (Alemtuzumab) Reduced Intensity Conditioning (RIC) Haematopoietic Stem Cell Transplantation (HSCT).
Authors: Lim ZiYi , Milojkovic Dragana , Pearce Laurence , Kenyon Michelle , Ho Aloysius , Devereux Stephen , Pagliuca Antonio , Mufti Ghulam 
Published: April 2020

Abstract
The use of IV busulphan (Bu) has reported improved bioavailability with lower variability of plasma levels, and may reduce the incidence of hepatic veno-occlusive disease (HVOD) and lower the transplant related toxicity. We performed a retrospective matched 2:1 case analysis to evaluate the impact of the use of oral vs IV busulphan as part of RIC HSCT on toxicity as well as engraftment.
75 patients received fludarabine (30mg/m2 x 5 days), alemtuzumab (20mg x 5 days) and either oral Bu (4mg/kg x 2 days) (25 patients) or IV Bu (3.2mg/kg x 2 days) (50 patients). 25 patients received IV Bu between Jan 2004 and Jan 2005. Each of these patients was matched for sex, diagnosis, disease stage, donor status and cell source with 2 comparable historical patients receiving oral Bu. There were 42 male and 33 female patients. Median age was 55 years (range:22–72). Median follow-up was 850 days (range: 39–1820) for the oral Bu group and 228 days (range: 38–453) for the IV Bu group.
All patients were being treated for myeloid malignancies: AML n=21, MDS/MPD n=45, CML n= 9. There were 33 sibling matched HSCT, 27 matched VUD HSCT and 15 HLA-mismatched VUD HSCT. 63 patients received PBSC and 12 received BM, the median CD34 cell dose was 5.17 x 106/kg (range:1.2–18.5) and 2.49 x 106/kg (range:0.7–4.9) respectively. 28 patients had early disease vs 48 advanced disease (advance disease defined as AML &gt; CR1, CML &gt; CP1, MDS with RAEB or AML with multilineage dysplasia). 5 patients in the oral group and 3 patients in the IV group had a previous allogenic HSCT. No patients had a previous history of hepatic impairment.
Median time to neutrophil (&gt;0.5x10^9/kg) and platelet (&gt;20x10^9/kg) regeneration was 12 days and 14 days respectively, with no significant difference between both arms. There was 1 case of primary graft failure and 1 case of HVOD in both arms. Both patients with HVOD had a previous allogeneic HSCT. Myeloid (CD15) engraftment occurred rapidly in both groups with full donor chimerism (&gt;95% donor chimerism) achieved at day+28/day+100/day+180 in 92%/90%/86% IV and 90%/85%/89% oral Bu patients. Lymphoid (CD3) engraftment was delayed in both groups, with full donor chimerism in 28%/26%/37% of IV Bu and 56%/57%/49% of oral Bu patients at day+28/day+100/day+180. 14 patients in the oral Bu group had grade I–III acute graft versus host disease (aGvHD), of which 3 had Gd III aGvHD. In contrast, 4 patients in the IV Bu group developed Gd I–III aGvHD, with 1 patient having Gd III aGvHD. The day +100 treatment related mortality (TRM100) was 8% in both groups. The overall survival (OS), disease free survival (DFS) and relapse incidence at day +200 for the IV vs oral groups was (86% vs 70%, p=0.30), (75% vs 60%, p=0.21), and (18% vs 24%, p=0.36) respectively.
In summary, RIC HSCT with both oral and IV busulphan appears to be safe and well tolerated regimen with a low incidence of HVOD and low TRM100. Persisting CD3 mixed donor chimerism is seen in both arms, with a trend to lower incidence of aGvHD with IV Bu (p=0.09) with no significant difference in early relapse, DFS, OS.