Myeloablative Fractionated Busulfan with Fludarabine in Older Patients: Long Term Disease-Specific Outcomes of a Prospective Phase II Clinical Trial.

Abstract

BACKGROUND\nCompared to reduced-intensity conditioning regimen, myeloablative conditioning (MAC) for hematopoietic stem cell transplantation (HCT) reduces relapse but is avoided in older patients due to higher non-relapse mortality (NRM). To meet the need for a myeloablative regimen for older patients, we developed a novel fludarabine and busulfan MAC regimen. We fractionated the dose of busulfan and gave it for six days over a two-week period and demonstrated the feasibility and safety of this approach. However, the disease-specific efficacy of this regimen is not known.\n\n\nOBJECTIVES\nThe purpose of this study was to estimate the efficacy of fractionated busulfan regimen by estimating diseases specific survival outcomes.\n\n\nSTUDY DESIGN\nThe conditioning regimen consisted of busulfan and fludarabine. On days -13 and -12 before HCT, patients received 80mg/m2 busulfan intravenously (IV) daily in an outpatient clinic. Additional chemotherapy was administered during inpatient treatment from day -6 through day -3, including fludarabine 40mg/m2 and busulfan IV once daily. The dosing of busulfan was determined from PK analyses to achieve for the course a target AUC of 20,000±12% μmol.min, which is close to the average exposure of myeloablative dose of busulfan. 150 patients with high-risk hematological malignancies up to 75 years were enrolled on this prospective phase II study. The objective was to evaluate NRM, relapse, survival, the rates of graft-versus-host disease (GVHD), and long-term complications.\n\n\nRESULTS\nThe median age of the patient population was 61 years (interquartile range, 55-67). The most common diagnoses were acute myeloid leukemia (AML; N=59, 39.3%), myelodysplastic syndrome (MDS; n=29, 19.3%), and myelofibrosis (MF; N=22, 14.7%). Most had an unrelated donor (n=93, 62%) and received peripheral blood graft (n=110, 73.3%). Over half had an HCT-Specific Comorbidity Index of ≥3 (n=79, 52.7%). The median follow-up among survivors was 43.4 months (IQR, 38.9-50.4). In patients with AML in complete remission, MDS, and myelofibrosis, 3 year OS was 66.7% (95% CI, 50.2-88.5%), 43.6% (95% CI, 28.6-66.4%), and 59.1% (95% CI, 41.7-83.7%) respectively. The cumulative incidence of NRM was 22% (15.3%-28.7%), extensive chronic GVHD was 27% (95% CI, 20-34%), bronchiolitis obliterans was 4.7% (95% CI, 1.3-8.1%), and secondary malignancies was 8.7% (95% CI, 4.1-13.2%) at 3 years.\n\n\nCONCLUSION\nLengthening the duration of busulfan (fractionation) permits safe delivery of myeloablative conditioning in older patients, leading to prolonged survival.