CALGB 100801 (Alliance): A Phase II Multi-Center NCI Cooperative Group Study of the Addition of Azacitidine (AZA) to Reduced-Intensity Conditioning (RIC) Allogeneic Transplantation for High Risk Myelodysplasia (MDS) and Older Patients with Acute Myeloid Leukemia (AML): Results of a “test dose” Strategy to Target Busulfan Exposure

Relapse remains the major cause of death in older patients transplanted for AML in first complete remission (CR1) or for patients with advanced MDS at any age. Conventional myeloablative conditioning followed by allogeneic blood or marrow transplantation is associated with significantly less relapse compared with RIC when performed in younger patients with AML or MDS, but the toxicity of this approach in older patients is prohibitive. We hypothesized that pharmacokinetic targeting to optimize busulfan (Bu) exposure, combined with the administration of AZA post transplantation would mitigate the risk of relapse while avoiding non-relapse mortality (NRM) and ultimately improve progression free survival (PFS). Here we report the results of a Bu test dose strategy targeting daily Bu exposure as determined by the area under the plasma concentration versus time curve (AUC). The primary endpoint of the study was two year progression free survival (PFS). An important secondary objective was to determine whether administration of a test dose of Bu with post test sampling would enable achievement of a daily target Bu AUC level of 4000 uM*min in at least 80% of the recipients. We used this strategy as part of a RIC regimen on a prospective multi-center phase II trial conducted by the Alliance (formerly Cancer and Leukemia Group B (CALGB)). Eligibility included patients with AML in CR1 aged 60-74 years inclusive, MDS with IPSS risk > Int-2 with less than 10% marrow blasts and age <75, availability of a well matched sibling or volunteer unrelated donor (VUD), and absence of significant end-organ damage prior to transplantation. The study completed accrual in 10/2013. 67 patients were registered, and 63 transplanted with 39 receiving grafts from VUDs and 23 from matched siblings. The donor type was not documented at the time of this abstract for one patient. The median age was 63 (44-74), 18 had AML and 45 had MDS. Ten centers enrolled at least one patient. All patients were conditioned with a uniform regimen consisting of fludarabine IV (days -7 to -3), busulfan IV (Bu) targeted to a daily AUC of 4000uM*min (Days -6 to -3) following administration of a 25mg/m2 test dose on one day between Days -14 to -9, and antithymocyte globulin (days -6, -5 and-4 (two doses for matched sibs and three for VUDs only). Body surface area was calculated using a corrected weight formula in overweight individuals (ideal weight + 25% of the difference between ideal and actual weight). Beginning day +42, all patients were planned to receive up to six monthly cycles of AZA at 32mg/m2 subcutaneously x 5days. The proportion of patients who actually received AZA and the median number of cycles received will be reported at the time of abstract presentation. 58 patients received a test dose of Bu and had target validation samples drawn on day -6, following the first dose. Test dose was infused over 45 minutes and blood samples were drawn at end of infusion and 1, 2, 4, and 6 hours after test dose completion. Bu target level validation samples were then obtained at the same time points following the Day-6 dose of Bu. The validation results are depicted in the table:

90% of patients were within 20% of the target AUC (95% CI=0.79-0.96) based on the validation sample. Maximum non-hematologic CTCAE v4.0 toxicity was grade 3 in 28 (50%), grade 4 in 6 (11%), and grade 5 in 5 (9%) of the 56 patients with available adverse event data. There were ten deaths within the first 100 days after transplant; six of these were due to NRM. With a median follow up of 564 days, the estimated overall survival at 2 years was 39 %. In conclusion, the preliminary results of this prospective multi-center trial suggest a strategy of targeting busulfan exposure to an AUC of 4000uM*min based on a prior “test dose” is successful in the majority of patients without causing excessive non-hematologic toxicity even in older patients. Further follow up is necessary to determine whether this results in less relapse and improved PFS.