Differential Impact of Dose Escalated Busulfan on Allogeneic Transplant for High, Intermediate and Low Risk Disease

Disease relapse, graft vs host disease and infection remain the major barriers to successful allogeneic stem cell transplantation. We previously presented data on the use of escalated AUC based dosing of a continuous infusion (CI) of IV busulfan over four days (Walko, BBMT, S218,2012). In that report, we described use of a test dose and day 1 and 4 PK values to determine the dose delivered, and identified dose limiting toxicities as rash and mucositis at an AUC of 8300 um-min/day and identified an AUC MTD of approximately 6912 uM-min/day x 4 days; a 40% increase over a standard AUC dose of 4800uM-min/day. Here we report additional analyses to identify patients (pts) likely to benefit from this higher dose of continuous infusion busulfan.

METHODS. Patients with advanced hematologic malignancies and adequate organ function who were appropriate for a MUD or MRD allogeneic transplant were enrolled on an IRB approved trial of a test dose of busulfan (.8 mg/kg x 1) followed by escalated dose busulfan (4800-8300 uM-min/d) given as a 90 hour continuous infusion along with fludarabine at 30 mg/m2/d x 5.  Pts received tacrolimus and either alemtuzamab (30), ATG + MTX (19) or MTX alone (6) as GVH prophylaxis with standard anti-infective and supportive care. RESULTS: 55 pts (median age 41, range 20-55) with myeloid (38), lymphoid (8), or biphenotypic (1) leukemias, MDS or MF (1) or lymphomas (7) were enrolled.  All 55 subjects were analyzed according to their being in the AUC low (group 1, 19 pts), middle (group 2, 19 pts), or high dose (group 3, 17 pts). 17 subjects had low, 20 had intermediate, and 18 had high-risk disease by CIBMTR criteria. For the entire group, univariate analysis identified age, recipient CMV status, and disease risk as significant factors for overall (OS) and relapse free survival (RFS). Co-morbidity scores, GVH occurrence or prophylaxis, donor/recipient sex and donor type (MUD or MRD) were not significant, nor was the non-relapse mortality rate different between the three AUC groups. Multivariable analysis identified CMV status as borderline significant (p=.07), and high vs low AUC dose (p=.053) and disease risk (p=.01) as significant for both OS and RFS. Outcomes were similar between AUC groups 2 and 3. Differences in OS and RFS were limited to the good and intermediate risk patients as outcomes for high-risk patients were poor for all AUC groups (0/17 RFS and 1/17 OS). When analyzing the 38 good and intermediate risk patients, the OS and RFS were 66% and 62.5% for combined AUC groups 2 and 3 compared to 31% (p=.02) for both OS and RFS in AUC group 1.

CONCLUSIONS: Targeted, PK based, CI busulfan that is approximately 40% higher than standard doses can result in apparent benefit for patients with CIBMTR low or intermediate risk disease. These doses were unable to demonstrate benefit in high-risk patients for whom other approaches such as immunotherapy, hypomethylating agents, or small molecule inhibitors may be needed.