Comparison of Allogeneic Transplant Outcomes Using Conditioning with Different Dose of Busulfan for Children with Acute Myeloid Leukemia
Authors: Paina Olesia V , Rakhmanova Zhemal Zarifovna , Kozhokar Polina Valerievna , Frolova Anastasia S , Ekushov Kirill Alexandrovich , Tsvetkova Luibov , Bykova Tatiana A , Markova Inna V , Bondarenko Sergey N. , Barkhatov Ildar M , Alyanski Aleksandr , Babenko Elena , Moiseev Ivan S , Popova Marina O , Semenova Elena Vladimirovna , Zubarovskaya Ludmila S , Zander Axel , Afanasyev Boris 
Published: November 2019

Background. Allogeneic hematopoietic cell transplantation (HCT) is a potentially curative therapy for patients with acute myeloid leukemia (AML). The conditioning regimen administered for this patient based on busulfan combined with cyclophosphamide (BuCy), fludarabine (BuFlu) or some other agents. Comparisons of myeloablative conditioning (MAC) versus reduced intensity conditioning (RIC) have demonstrated a various results between relapse and toxicity in a few reports. We supposed, that dose intensity of busulfan across regimens may affect treatment outcomes.
The goal of this retrospective study was to evaluate the impact dose of busulfan to overall survival (OS), transplant-related mortality (TRM), relapse-free survival (RFS), toxicity, the incidence of primary graft failure and acute graft-versus-host disease (GVHD) in transplantation in children and adolescents with AML.
Material and methods. We analyzed 110 AML pediatric patients with the median age 9 y.o. (range 1-19), who underwent first allo-HSCT with busulfan based (per os and IV) conditioning in R.M. Gorbacheva Memorial Institute from 2002 to 2018. Patients were divided into 3 groups: Bu1 - patients, who received busulfan at the dose 8-10 mg/kg, n=34 (31%), in Bu2 - dose of busulfan was 12 mg/kg, n= 35 (32%), in Bu3 - dose of busulfan was >12 mg/kg, n= 41 (37%). In Bu1 busulfan was combined with Flu in 31 pts (91%) and Cy in 3 (9%); in Bu2 - with Flu in 12 (34%) , Cy in 7 (20%) and other agents in 16 (46%); in Bu3 - with Cy in 32 (78%), with Flu in 7 (17%) and other agents in 2 pts (5%) (p < 0.001). Patients in Bu2 received more Cy based GVHD prophylaxis regimens (69% vs 44% in Bu1, vs 29% in Bu3, p = 0.003) and more HAPLO grafts (51% vs 29% in Bu1, vs 15% in Bu3, p = 0.003). The complete remission at the HSCT was observed in 79 % in Bu1, 49% in Bu2, 61% in Bu3 p=0,02. Probabilities of OS, RFS, TRM were estimated by using the Kaplan-Meier method. Incidence of toxicity, acute GVHD and primary graft failure - by using Mann - Whitney U-test.
Results. Transplant engraftment was achieved in 95 (86%) of patients. Graft failure occurs in the 5 patients of Bu1 group (15%), in the 6 pts of Bu2 (17%) and in the 4 pts of Bu3 (10%), p=0,7. Median follow-up was 2 years for Bu1 and Bu3, 1 year for Bu2. OS was similar (Bu1=59% vs Bu2=60% vs Bu3=51%), p=0,7. OS of pts with CR before HSCT was 70% in Bu1, 82% in Bu2, 60% in Bu3, p=0,3 and 14%, 39%, 38% for pts with progression disease (PD), respectively, p=0,5. RFS was 74% in Bu1, 82% in Bu2, 64% in Bu3 at CR, p=0,4; 43%, 39% and 38% in pts with progression, respectively, p=0,9. Median of RFS were also similar for the pts in PD, (4 months in Bu1, 5 months in Bu2 and Bu3), p=0,9 and not achieved for pts at CR. Drug related toxicity grade 3-4 experienced in 35% pts in Bu1, 29% in Bu2, in 54% in Bu3, p=0,04. Mucositis and toxic hepatitis were the most common adverse events. Sinusoidal obstruction syndrome (SOS) experienced in 8 pts from different group: 4 from Bu2 (11%), 3 from Bu3 (7%) and only 1pts from Bu1 (3%) with previously treated of gemtuzumab ozogamicin, p=0,4. The most pts with SOS (3/5) had PD at the HSCT. Cumulative incidence of acute GVHD grade 2 (15% vs 14% vs 10%, p=0,8) were not different. Acute GVHD grade 3-4 was observed a bit more often in Bu3 (34%), than in Bu1 (18%) and Bu2 (17%), p=0,09. TRM up to +100 days was also higher in Bu3 (15%), than in Bu2 (6%) and Bu1 (0%), p=0,05.
Conclusions. The transplant results of children with similar disease status of AML, received conditioning with various dose of busulfan, were not associated with significant differences in overall outcomes. The higher dose busulfan may increase incidence of toxicity grade 3-4 (p=0,04) and acute GVHD grade 3-4 (p=0,09) with increasing of early TRM (p=0,05).

Disclosures
Moiseev: Celgene: Consultancy, Other: Travel grants; Novartis: Consultancy, Honoraria, Other: Travel grants, Speakers Bureau; Pfizer: Other: Travel grants; MSD: Other: Travel grants; BMS: Other: Travel grants; Takeda: Other: Travel grants.