High Rates of Early Donor Chimerism in Intermediate and Poor Risk Patients Undergoing Stem Cell Transplantation Using Reduced Toxicity Ablative Conditioning Regimen Incorporating Busulfan Pharmacokinetics

The impact of early donor cell chimerism on outcomes of reduced-intensity conditioning SCT in myeloid disorders is ill defined. To explore the impact of measuring busulfan pharmacokinetics (Bu PK) in conditioning regimens on early donor chimerism, we undertook a retrospective analysis of patients with myeloid disorders who received four days of fludarabine and busulfan with or without measuring Bu PK at our center in the last 10 years.

Methods: Chimerism assay was performed using a quantitative fluorescence-based short tandem repeat– polymerase chain reaction (STR-PCR) with capillary electrophoresis for PCR product resolution.

Results: Thirty patients were identified and included in the study. All patients received fludarabine (40 mg/m2/day x 4 doses), busulfan (3.2mg/kg/dose IV x 4 doses). Of these thirty patients, 7 had Bu PK measured. There were 21 male and 9 female patients with a median age of 62 years (range 48–72yrs). Median time to follow up was 13.3 months. Disease risk was considered advanced in 17 patients, intermediate in 3 and early in 10. All patients in the Bu PK group had advanced disease except one had early disease. Regarding cytogenetics, all patients in the Bu PK group had high or intermediate risk cytogenetics. Median blast number at time of SCT was 5%. Stem cell source included peripheral blood in all patients.

There were no primary graft failures. Total Donor cell Chimerism analysis in the Bu PK group showed 100% donor at both time points (days 30, 100) in all patients except in one who relapsed at day 30 (85.7%). While in the non-PK group only 7 out of 23 (30%) patients had complete chimerism at day 30 and day 100. Complete donor chimerism at day 100 in the non-PK group was 47.8% compared to 85.7% in the PK (p=0.18). Ten out of 23 patients (43.5%) in the non-PK group had decreasing donor chimerism by day 100, while in the PK group only one patient (14%) who relapsed had decreasing donor chimerism by day 100 with an odds ratio of  0.241 (95% Confidence Interval =0.025-2.357; p-value=0.22). None developed sinusoidal obstructive syndrome.

Conclusion: In this small cohort from a single center, we found that patients with myeloid disorders who received fludarabine busulfan for 4 days incorporating Bu PK had a trend for higher rates of early complete donor chimerism and less decreasing donor chimerism by day100 despite having intermediate or high risk disease at time of SCT. Longer follow up is needed for our patients to see if there is effect on relapse or survival but previous studies have showed that  low or decreasing donor chimerism early after SCT is an independent risk factor for relapse and impaired survival. This is especially important in myeloid disorders. Bu PK may help target better level for inducing early total donor chimerism and donor chimerism may identify high-risk patient cohorts who may benefit from additional therapeutic interventions.