Reduced intensity conditioning regimen (RIC) extends allogeneic hematopoietic cell transplantation (HCT) to older patients and patients with comorbidities. Compared to myeloablative (MA) conditioning, RIC has higher rate of relapse but lower rate of non-relapse mortality (NRM), resulting in similar survival. To further improve survival for older patients, a MA regimen with low NRM is needed. We hypothesized that a myeloablative busulfan dose could be safely administered over a longer period of time. We previously reported safety of two MA schedules of busulfan targeting busulfan exposure (AUC) of 16,000 and 20,000 μmol-min. Because the regimen with AUC of 20,000 was well tolerated, we further expanded this study and hereby report results in patients with AML/MDS treated with busulfan AUC of 20000 μmol-min. All patients received a fixed dose of IV busulfan 80 mg/m2 per day on day -13 and -12 in the outpatient clinic. Subsequently they were hospitalized (on day -7) and received fludarabine 40 mg/m2 day followed by IV busulfan daily for 4 days (day -6 to -3). The dose of busulfan on day -6 to -3 was adjusted to achieve a total AUC of 20,000 μmol-min based on pharmacokinetic studies done on day -13 and day -6. GVHD prophylaxis was Tacrolimus (day -2 onwards) and mini dose methotrexate 5mg/m2 on days 1, 3, 6 and 11. Patients with AML or MDS were eligible for the study if they had adequate organ function and an HLA 8/8 matched related or unrelated donor. On this study, we enrolled patients who were otherwise suitable for RIC. When the study began, upper age limit for eligibility was 70 years, but this was increased to 75 years during the course of the study once safety of this regimen was established. Sixty six patients, 21 with MDS and 45 with AML, were enrolled on the study. Median age was 65 years (range 29-75 years) years. Stem cell donor was HLA identical sibling for 21 (32%) patients and HLA- matched (8/8) unrelated for 45 (68%) patients. 23 (35%) of the patients had poor-risk disease based on cytogenetic studies. Of the 45 AML patients, 14 (31%) patients were in remission and 31 (69%) had active disease at the time of transplant. With a median follow up of 7.8 months (range 1.3-35) for surviving patients, 1 year overall survival (OS), progression free survival (PFS), relapse rate and non-relapse mortality were 65% (CI 50%-80%), 56% (CI 41%-71%), 21% (CI 10%-33%) and 19% (CI 9%-32%), respectively. At day 100, cumulative incidence of acute grade 2-4 GVHD was 36% (24%-47%) and grade 3-4 GVHD was 9% (4%-18%). OS data in different subgroups are summarized in the figure below. Myeloablative timed sequential busulfan regimen is safe and appears promising in older patients with AML/MDS.

Major ABO mismatching is not considered a contraindication to allogeneic haematopoietic stem cell transplantation (HSCT). Modern reduced-intensity conditioning and reduced-toxicity regimens cause much less myeloablation than conventional myeloablative regimens, such as cyclophosphamide with busulfan or total body irradiation, which may affect the incidence of pure red cell aplasia (PRCA). We estimated the incidence and described the natural history of PRCA in patients with major ABO-mismatched donor stem cells. Between 2007 and 2008, 161 (27% of all patients undergoing HSCT) underwent allogeneic HSCT with major ABO-mismatched stem cells and 12 (7·5%) of these patients developed PRCA. Thirty and ninety day T-cell and myeloid cell chimerism and neutrophil and platelet engraftment did not differ between patients who developed PRCA and those who did not. The only risk factor associated with PRCA was the use of a fludarabine/busulfan conditioning regimen. All patients with PRCA needed red cell transfusion for several months after HSCT resulting in significant iron overload. Pure red cell aplasia resolved spontaneously in the majority (seven patients) but only resolved after stopping tacrolimus in three patients. Hence, after major ABO-mismatched HSCT, the incidence of PRCA was 7·5% and it resolved spontaneously or after withdrawal of immunosuppression in the majority of patients.