Prospective Phase II Study of HSCT Using Targeted Busulfan, Fludarabine, Etoposide Conditioning for Pediatric ALL

Background: Hematopoietic stem cell transplantation (HSCT) is one of the important treatment options for very high-risk pediatric acute lymphoblastic leukemia (ALL). Conditioning including total body irradiation is commonly used, but irradiation-free chemo-conditioning has also been tried in consideration of long-term toxicity. Here, we report the results of phase II, prospective study of HSCT using targeted busulfan, fludarabine, and etoposide conditioning regimen.

Methods: Patients were enrolled from 2014 Feb to 2021 Aug. Patients eligible for this study had ALL aged < 21 years old who needs HSCT and had matched siblings or unrelated donors. The primary endpoint was 1-year event-free survival (EFS). Engraftment rate was the second endpoint. We estimated the sample size on a 20% increase in 1-year EFS rate (to 80%) than historical data, with a type I error of 5% and power of 80%. The conditioning regimen included targeted busulfan (age > 1 year, 120 mg/m2; age < 1 year, 80 mg/m²) which was administered once daily as the first dose on day 8, and a targeted dose of busulfan was used according to the therapeutic drug monitoring results on days 7 to 5, fludarabine (40mg/m² once daily i.v. on days 8 to 3), and etoposide (20 mg/kg once daily i.v. on days 4 to 2).

Results: A total of 36 patients met the eligible criteria. The median age at HSCT was 8.1 years old (range, 1.0-18.9) and 20 were male (61.1%). The median follow-up time was 4.3 years (range 0.8-8.0). All patients received mobilized peripheral blood stem cells, and 14 patients (38.9%) from matched sibling donors, and the others from matched unrelated donors (10/10 17 patients; 9/10, 5 patients). The indications for HSCT were recurrence (11/36, 30.6%), induction failure (5/36, 13.9%), and very-high risk features (20/36, 55.6%) including Philadelphia chromosome, MLL rearrangement, hyperleukocytosis, and hypodiploidy. The infused total nuclear cell counts and CD34 positive cell counts were 13.5 x 10⁸/recipient body weight (range, 4.8-39.0) and 7.5 x 10⁶/recipient body weight (range, 1.1-18.1), respectively. All patients achieved neutrophil (median 10 days) and platelet engraftment (median 13 days). The cumulative incidences of acute graft-versus-host disease (GVHD) grade II to IV, grade III to IV, moderate to severe chronic GVHD, relapse, and non-relapse mortality were 36.1%, 2.8%, 8.4%, 33.6%, and 3.1%, respectively. The 1-year EFS and overall survival (OS) rate were 80.5% (95% confidence interval [CI] 67.9-93.4) and 94.3% (95% CI 86.7-100). The 3-year EFS and OS rates were 63.3% (95% CI 46.4-80.2) and 84.8% (95% CI 92.5-97.1), respectively. The donor type, age, and complete remission status were not significantly associated with the EFS or OS rates. Among 10 patients who relapsed after HSCT, 7 patients are alive following a second HSCT (5 patients) and salvage chemotherapy with another tyrosine kinase inhibitor (2 patients).

Conclusions: Our study shows a favorable outcome of irradiation-free, chemo-conditioning regimen using targeted busulfan, fludarabine, and etoposide in very-high risk childhood and adolescent ALL. Our study met 80% of the 1-year EFS rate, which was the primary endpoint. The 3-year OS rates, which are more than 20% higher than the EFS rates, show that many patients can be successfully treated even after recurrence. However, efforts are needed to improve long-term EFS using various modern innovative treatments.