Myeloablative Timed Sequential Busulfan Is Safe in Older Patients

Background: 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. BMT CTN is conducting a prospective study to compare these two approaches. To further improve survival for older patients, a MA regimen with low NRM is needed. Timed sequential therapy (TST), giving two courses of chemotherapy 1 week apart, has higher antileukemic effect in in-vitro and in-vivo in studies of patients with AML, including phase 3 studies. We hypothesized that MA dose of busulfan delivered per principles of TST enhances antileukemic effect without increasing toxicity. We therefore designed a study to test safety of two MA schedules of busulfan targeting busulfan exposure (AUC) of 16000 μmol.min and 20000 μmol.min. AUC of 20000 μmol.minis close to total average drug exposure achieved with IV busulfan fixed dose of 12.8mg/kg.

Methods: Patients were randomized to receive total busulfan exposure of 16,000 μmol.min(16K) or 20,000 μmol.min( 20K). Patients received IV busulfan 80 mg/m² per day on day -13 and -12 in outpatient clinic, fludarabine 40 mg/m² day x 4 (day -6 to -3) and IV busulfanx 4 (day -6 to -3). Busulfan was dosed to achieve target AUC of 16K or 20K 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 day 1, 3, 6, and 11. Stem cells were infused on day 0. Primary endpoint of the study was to compare 100 day non-relapse mortality in two arms with stopping rules built in for safety. Patients with hematological malignancies were eligible for the study if they had adequate organ function and 8/8 matched related or unrelated donor. We enrolled patients on this study who were 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 as safety was established. Fisher’s exact test was used to compare toxicity and NRM rates between arms. Cox proportional hazards regression was used to estimate the effects of clinical variables on overall survival.

Results: 97 patients were enrolled on the study until the DSMB stopped the randomization and permitted continued accrual onto the higher dose arm with busulfan AUC of 20,000 μmol.min. 49 were randomized to busulfan AUC of 16K and 48 to 20K. For all patients, median age was 60 (18-75) years. 3 (2%) patients were less than 40 years of age, 12 (12%) 40-49, 33 (34%) 50-59, 39 (40%) 60-69, and 10 (10%) 70-79 years. 53 patients had AML/MDS, 24 CML/MPD, 16 myeloma, and 4 lymphoid malignancies. Based on revised disease risk index, 3 had low risk, 53 intermediate risk, 35 high risk, and 6 very high risk disease. Donor was related for 43 and unrelated for 54. Comorbidity scores were 0 in 23, 1-2 in 24, and ≥ 3 in 50.

With a median follow up of 9.2 months (range 1.8-24) in surviving patients, 100 day NRM was similar in two groups, 4% in 16K and 6% in 20K (p=0.68). Maximum toxicity per patient was not significantly different between arms (Table 1, p=0.37). The 1-year unadjusted survival rates (95% CI) in combined disease risk indexes low and intermediate vs high and very high were 67 (50-79)% and 38 (19-57)%, respectively for all 97 patients. Multivariable Cox regression analysis for overall survival showed increased risk of death for older age (HR 1.05; p=0.03), comorbidity 3 and higher (HR 1.89 p=0.08), and high or very high risk index (HR 2.04; p= 0.05). After also accounting for donor relation and cell type, Bu AUC of 20k showed improved overall survival and a 50% reduction in the risk of death (HR 0.50, P= 0.058).

Conclusion: Myeloablative timed sequential busulfan regimen is safe in older patients and patients with comorbidities. The regimen with busulfan AUC of 20,000 μmol.min appears promising and needs to be studied further.