Pharmacokinetically Targeted Intravenous Busulfan Combined with Fludarabine (BuFlu) as Conditioning Prior to Allogeneic Peripheral Blood Hematopoietic Cell Transplant: Pretransplant Predictors of Outcomes.

Abstract 3347

Poster Board III-235

We report here our experience with 145 consecutive patients (pts) treated with IV busulfan and fludarabine (BuFlu) as conditioning prior to allogeneic hematopoietic cell transplant (HCT). Bu was dosed at 130mg/m²/day on days 1 and 2 with pharmacokinetic (PK) targeting for days 3 and 4; the dose of Flu was 40mg/m²/day for 4 days. The median age was 48 (range 22-68) years. Median HCT Comorbidity Index (HCT-CI) was 3 (range 0-9) and median Karnofsky performance status (KPS) was 100% (60-100%). Sixty-two pts received grafts from HLA matched siblings, 61 from matched unrelated donors (MUD), and 22 from 1 antigen/allele mismatched MUD (mMUD). Disease status was categorized in 50 pts as standard risk (acute leukemia in CR1 or CML in CP1) and in 91 pts as high risk (including acute leukemias > CR1, CML.>.CP1, MDS, MPD, lymphoma, myeloma, and CLL). 4 pts had aplastic anemia. Bu doses were targeted to a daily area under the concentration time curve (AUC) value of 5300 uM*min. Median actual AUC after the first dose was 5002 uM*min (range 3609-8190 uM*min) and doses 3 and 4 were adjusted in 92 pts (63%) to achieve the overall target AUC. Median total Bu dose to achieve AUC target was 520 mg/m² (range 332-1040 mg/m²). Median Bu clearance (Cl) was 2.7 ml/min/kg (range 1.5-5.2 ml/min/kg). Maximum Bu concentrations (Cmax) after the first dose was 3315 ng/ml (range 1135-4848 ng/ml). First dose Bu AUC, Cmax, and Cl were not correlated with age, race, ethnicity, KPS, or HCT-CI. Women had significantly higher Cl than men (median 2.9 vs 2.6 ml/min/kg; p=0.001). Grade 3 or 4 elevations in hepatic transaminases occurred in 15 pts (10%), hepatic VOD/SOS in 6 pts (4%), and interstitial pneumonitis in 4 pts (3%). None of these toxicities were associated with any of the PK parameters measured. 100 day and 1 year non-relapse mortality (NRM) were 7% and 23% respectively. In multivariable analyses, neither first dose Bu AUC nor Bu Cl were associated with NRM. Having an unrelated donor (MUD: HR 2.68; p=0.025 and mMUD: HR 3.64; p=0.009) and a diagnosis of CML (HR 3.82; p<0.001) or lymphoma (HR 5.15; p=0.005) were associated with increased NRM. In multivariable analyses of relapse, only first dose AUC was significantly associated, with >6000 uM*min predictive of an increased risk of relapse (HR 2.66; p=0.007). The only significant predictor of overall and progression-free survival in multivariable analysis was disease risk. Overall and progression -free survivals at 2 years for the standard risk vs high risk groups were 61% and 57% vs 39% and 32% (p=0.04 and p=0.03, respectively). The increased risk of relapse in the high first dose AUC group may be related to an association between Bu Cl and uptake into malignant cells or the presence of a larger proportion of patients in this group with high risk features other than the predefined disease risk. We conclude that PK targeting of Bu provides a safe method of delivering high doses given that increased toxicity and NRM were not seen in pts with high first dose AUC due to dose adjustment.