Matched Pair Analysis of Intravenous vs Oral Busulphan as Part of Fludarabine-Busulphan-Campath (Alemtuzumab) Reduced Intensity Conditioning (RIC) Haematopoietic Stem Cell Transplantation (HSCT).

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 > CR1, CML > 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 (>0.5x10^9/kg) and platelet (>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 (>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.