• Maximum tolerated dose [ Time Frame: Day 42 ] [ Designated as safety issue: Yes ]
  
• Dose-limiting toxicity [ Time Frame: Day 42 ] [ Designated as safety issue: Yes ]
  

• Accuracy of targeted busulfan dosing [ Time Frame: Day -7 to Day -4 ] [ Designated as safety issue: No ]
  
• Overall and disease-free survival [ Time Frame: 5 years ] [ Designated as safety issue: No ]
  

Drug: Busulfan
Dose adjusted treatment with a maximally intensive busulfex based regimen

Allogeneic hematopoietic cell transplantation (allo-HCT) from a matched related (MRD) or matched unrelated (MUD) donor can effect a cure or prolongation of overall and disease-free survival in a significant proportion of patients with hematologic malignancies. Unlike autologous stem cell transplantation, this approach ensures a graft that is free of tumor-cell contamination, and enables the provision of adoptive immunotherapy mediated by donor-derived T-lymphocytes and possibly natural killer cells (graft-versus-malignancy effect, GVM).

The majority of allogeneic transplants over the years have utilized either oral busulfan or total body irradiation (TBI) as the ablative component of the conditioning regimen in conjunction usually with cyclophosphamide or etoposide for immunosuppression or additional anti-tumor efficacy. While these approaches have been curative in anywhere from 20% to 70% of patients, depending on the disease status and diagnosis, such approaches have also been associated with treatment related mortality rates (TRM) of 20% to 50%, again varying with patient age, quality of donor match, cytomegalovirus (CMV) infection risk, etc. In trials where regimens using TBI have been compared to busulfan based regimens, the overall outcomes have generally been similar, although there is a suggestion that TBI may be slightly more effective in reducing relapse risk for acute leukemia patients but has greater cumulative toxicities. Toxicities between the two approaches are different, with busulfan resulting in more hepatic toxicity and TBI generating more acute pulmonary, GI, lung, ocular toxicity, and second malignancies as well as inducing growth retardation in children.

In this study we will escalate the dose of continuous infusion busulfan based on AUC data obtained from pharmacokinetics following a single dose of this drug prior to initiating the ablative regimen. It is hypothesized that this approach will allow for identification of a new maximum tolerated dose (MTD) with different dose-limiting toxicities than observed with intermittent infusion schedules. These higher doses may allow for greater efficacy and less toxicity than conventional administration schedules.