Once daily intravenous busulfan as part of a busulfan/cyclophosphamide conditioning regimen for allogeneic hematopoietic stem cell transplantation

Abstract

Objective: Busulfan (Bu) is frequently used as part of myeloablative conditioning regimens prior to stem cell transplantation (SCT), especially to avoid total body irradiation. Hepatic venoocclusive disease (HVOD) is a well-recognized dose-limiting toxicity for oral Bu-preparative regimens. The purpose of this review was to evaluate the toxicity, efficacy, 100-day mortality, overall and disease free survival in patients treated with single daily dose intravenous (iv) Bu as part of a Bu/Cyclophosphamide (Cy) conditioning regimen for allogeneic SCT. Patients and Methods: 29 consecutive patients undergoing allogeneic SCT received iv Bu as part of their conditioning between March 2002 and August 2003. Conditioning consisted of iv Bu (3.2mg/kg once daily x 4 doses) followed by high dose Cy and allogeneic SCT. The donors were HLA-matched siblings (n = 23), 1 antigen mismatched related donors (n = 1) and matched unrelated donors (n = 5). All patients received graft versus host disease (GVHD) prophylaxis consisting of Cyclosporine A and Methotrexate. Results: 28 patients engrafted with a median time for neutrophil recovery of 21 days (12,29) and median time for platelets recovery of 18 days (10,49). 14 patients (48.3%) developed HVOD, 10 mild (34.5%), 2 moderate (6.9%) and 2 severe HVOD (6.9%). Acute GVHD grade II-IV occurred in 18 patients (64.3%). 3 patients (10.3%) died in the first 100 days after the transplant, with 1 death due to severe HVOD (3.4%), 1 due to graft failure (3.4%) and 1 to other transplant related toxicity (3.4%). After a median follow up of 8 months (1,16) chronic GVHD occurred in 12 out of 24 evaluable patients (50%), 2 patients relapsed (6.9%), 1 patient is still in a partial remission (3.4%) and a total of 7 patients died (24.1%). 22 patients (75.9%) were alive at their last follow up. Overall survival at 6 months was 84.5%, and at 1 year 69.4%. 6-month disease-free survival was 80.7% and at 1 year 67.3%. Conclusions: Conditioning regimens with single daily dose iv Bu allowed consistent engraftment from related and unrelated donors. Only one graft failure occurred in a patient undergoing a second allogeneic SCT from a second matched related donor. 14 patients met criteria for HVOD, but the majority of them were mild. Treatment related mortality was limited. Overall survival and disease-free survival rates are encouraging thus meriting further studies for defining the role of iv Bu as a preferred substitute for oral Bu. Objective: Busulfan (Bu) is frequently used as part of myeloablative conditioning regimens prior to stem cell transplantation (SCT), especially to avoid total body irradiation. Hepatic venoocclusive disease (HVOD) is a well-recognized dose-limiting toxicity for oral Bu-preparative regimens. The purpose of this review was to evaluate the toxicity, efficacy, 100-day mortality, overall and disease free survival in patients treated with single daily dose intravenous (iv) Bu as part of a Bu/Cyclophosphamide (Cy) conditioning regimen for allogeneic SCT. Patients and Methods: 29 consecutive patients undergoing allogeneic SCT received iv Bu as part of their conditioning between March 2002 and August 2003. Conditioning consisted of iv Bu (3.2mg/kg once daily x 4 doses) followed by high dose Cy and allogeneic SCT. The donors were HLA-matched siblings (n = 23), 1 antigen mismatched related donors (n = 1) and matched unrelated donors (n = 5). All patients received graft versus host disease (GVHD) prophylaxis consisting of Cyclosporine A and Methotrexate. Results: 28 patients engrafted with a median time for neutrophil recovery of 21 days (12,29) and median time for platelets recovery of 18 days (10,49). 14 patients (48.3%) developed HVOD, 10 mild (34.5%), 2 moderate (6.9%) and 2 severe HVOD (6.9%). Acute GVHD grade II-IV occurred in 18 patients (64.3%). 3 patients (10.3%) died in the first 100 days after the transplant, with 1 death due to severe HVOD (3.4%), 1 due to graft failure (3.4%) and 1 to other transplant related toxicity (3.4%). After a median follow up of 8 months (1,16) chronic GVHD occurred in 12 out of 24 evaluable patients (50%), 2 patients relapsed (6.9%), 1 patient is still in a partial remission (3.4%) and a total of 7 patients died (24.1%). 22 patients (75.9%) were alive at their last follow up. Overall survival at 6 months was 84.5%, and at 1 year 69.4%. 6-month disease-free survival was 80.7% and at 1 year 67.3%. Conclusions: Conditioning regimens with single daily dose iv Bu allowed consistent engraftment from related and unrelated donors. Only one graft failure occurred in a patient undergoing a second allogeneic SCT from a second matched related donor. 14 patients met criteria for HVOD, but the majority of them were mild. Treatment related mortality was limited. Overall survival and disease-free survival rates are encouraging thus meriting further studies for defining the role of iv Bu as a preferred substitute for oral Bu.