Busulfan + Fludarabine, An Effective And Low Toxic Regimen In Children With Malignant And Non-Malignant Diseases

Abstract

Busulfan as myeloablative agent is used in conditioning prior to pediatric HSCT: mainly in combination with cyclophosphomide. We recently found a clear association between busulfan exposure and outcomes (survival/event free survival). However, toxicity leading to morbidity and associated mortality remains a limiting factor. Comparison studies in adults showed a favorable toxicity profile for fludarabine + busulfan (FludBu) compared to the conventional BuCy regimen. In paediatrics, limited data is available regarding this regimen. FludBu was recently introduced to replace the BuCy regimen in our center for myeloid malignancies and all non-malignant indications. We compared the outcomes with our BuCy historic controls. Fludarabine was given in 1 hour prior to a 3 hour infusion of once daily busulfan. The target area under the curve (AUC) for Bu was>74 mg∗h/L (in total) in both groups. Busulfan dose targeting, based on therapeutic drug monitoring was performed before the second dose. Primary endpoints were event free survival (EFS) and survival. Secondary endpoints were acute graft-versus-host disease (aGvHD), neutropenic period and the number of erythrocytes and thrombocytes transfusions. A risk factor analysis was performed using univariable and multivariable COX regression. 13 patients were included in the FludBu group (median follow up median 119 days; range 42-1593) and 44 in the BuCy group (710 days; range 6-1686). The groups were comparable regarding donor source, age, gender, indication for SCT and match-grade. EFS and Survival in FludBu and BuCy was 85% vs 71% (NS) and 92% vs. 73% (NS), respectively. No difference in aGvHD (≥grade 2) was found between the 2 groups. The period of neutropenia was median 12 in the FludBu group compared to 20.5 in the BuCy group (HR 0.38, p=0.05, CI95% 0.20-0.75). The median number of erythrocytes transfusion was 1 (range 1-13) in the FludBu group and 5 (0-22) in the BuCy group (p=0.20) and thrombocyte infusions 5 (range 0-33) vs 10 (range 2-44)(p=0,15). Busulfan with a total target AUC of >74 mg∗h/l in combination fludarabine showed to be an effective and low toxic regimen. Interesting is the significantly shorter neutropenic period and lower number of transfusions (erythrocytes and thrombocytes) needed in the FludBu group in comparison to BuCy. Although a small series, FludBu showed promising results. Further follow up and extension of the series is needed.