Comparison of allogeneic transplant outcomes using conditioning with different dose of busulfan for children with acute myeloid leukemia
Olesya V. Paina, Zhemal Z. Rahmanova, Liubov A. Tsvetkova, Polina V. Kozhokar, Anastasia S. Frolova, Kirill A. Ekushov, Inna V. Markova, Sergey N. Bondarenko, Elena V. Babenko, Alexander L. Alyanskiy, Ildar M. Barkhatov, Elena V. Semenova, Ludmila S. Zubarovskaya, Boris V. Afanasyev
Raisa Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov First Saint Petersburg State Medical University, St. Petersburg, Russia
Contact: Dr. Olesya V. Paina
Allogeneic hematopoietic cell transplantation (HCT) is a potentially curative therapy for pediatric patients with acute myeloid leukemia (AML). The conditioning regimen administered to this group of patients is usually based on busulfan combined with cyclophosphamide (BuCy), fludarabine (BuFlu) or other agents. Comparisons of myeloablative conditioning (MAC) versus reduced intensity conditioning (RIC) in a few studies have demonstrated the contradictory results in relapse and toxicity rates. We evaluated whether 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.
Materials 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 I.V.) conditioning in R. Gorbacheva Memorial Institute from 2002 to 2018. The patients were divided into 3 groups: Bu1 – patients, who received busulfan at the dose 8-10 mg/kg, n=34 (31%); busulfan dose in Bu2 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 was assessed by Mann-Whitney U-test.
Engraftment was achieved in 95 (86%) of patients. Graft failure occurred in 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 progressive 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 in CR. Grade 3-4 regimen-related toxicity was observed 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) was observed in 8 pts from all groups: 4 in Bu2 (11%), 3 in Bu3 (7%) and only 1 pts in Bu1 (3%) who was previously treated of gemtuzumab ozogamicin, p=0.4. Majority of 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) was not different. Acute GVHD grade 3-4 was observed 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.
The transplantation results of children with comparable AML disease status were not associated with significant differences in outcomes according to the dose of busulfan. Higher dose of busulfan may increase incidence of grade 3-4 toxicity (p=0.04), acute grade 3-4 GVHD (p=0.09) and increased early TRM (p=0.05).
Busulfan, allo-HSCT, acute myeloid leukemia, children.