Allogeneic haematopoietic stem cell transplantation with myeloablative conditioning regimen based on different dosage of busulfan in children and adolescents with acute lymphoblastic leukemia
Elena V. Semenova, Olesya V. Paina, Liubov A. Tsvetkova, Polina V. Kozhokar, Anastasia S. Frolova, Zhemal Z. Rahmanova, Kirill A. Ekushov, Inna V. Markova, Sergey N. Bondarenko, Elena V. Babenko, Ildar M. Barkhatov, Alexander L. Alyanskiy, 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 haemopoietic stem cell transplantation (allo-HSCT) is an effective option in the treatment of high risk children with acute lymphoblastic leukemia (ALL). Myeloablative busulfan-containing regimens are one of the standards for pre-transplant conditioning in these patients. However, the question of optimal toxicity and effectiveness dose of busulfan is still not resolved. The goal of this study was to evaluate the impact of intensity busulfan (Bu) dose in myeloablative conditioning regimen on overall survival (OS), relapse-free survival (RFS), early transplant-related mortality (TRM), incidence of toxicity, acute graft-versus-host desease (GVHD) and primary graft failure in transplantation in children and adolescents with ALL.
Materials and methods
This study included 144 patients (pts) who were divided into 3 groups: the Bu1 group included children who received Bu in conditioning regimen at a dose of 8 to 10 mg/kg (n=37, 26%), Bu2 group was administered Bu at 12 mg/kg (n=57, 39%); and Bu3 (>14 mg/kg in 50 cases, 35%). The median age at the time of HSCT in Bu1 patients was 15 years (4-18); Bu2, 11 years (2-18); Bu3, 11 (3-18) years old; the respective p levels were: for cohorts 1 vs 2=0.028; 1 vs 3=0.005; 2 vs 3=0.6.
Allo-HSCT in complete remission (CR) of the disease was performed in 29 (78%) Bu1 pts, 32 (56%) Bu2 pts, 36 (72%) Bu3 pts (respective p values were: for cohorts 1 vs 2=0.028; for 1 vs 3=0.5; for 2 vs 3=0.09. In the 1st СR, we observed 10 (27%) Bu1 pts, 11 (19%) Bu2 pts, 7 (14%) Bu3 pts, with respective p values for cohorts 1 vs 2=0.4; for 1 vs 3=0.3; for 2 vs 3=0.9. The main conditioning regimen was a combination of Bu with fludarabine (BuFlu) (n=28, 76%) in Bu1 group, BuFlu (n=28, 49%) and GIAC (n=21, 37%) in Bu2, Bu with cyclophosphamide (n=39, 78%) in Bu3, at p values between groups 1 vs 2=0.05; group 1 vs 3 <0.001, and for groups 2 vs 3=0.4. Cyclophosphamide as GVHD prophylaxis was used in 19 (51%) children in Bu1, 41 (72%) in Bu2, 14 (28%) in Bu3. The p values for the groups were as follows: 1 vs 2=0.04; 1 vs 3=0.027; for groups 2 vs 3 <0.001.
Probabilities of OS, RFS, TRM were estimated by means of Kaplan-Meier method. Incidence of toxicity, acute GVHD and primary graft failure was evaluated by Mann-Whitney U-test.
Effective transplant engraftment was documented in 31 (84%) Bu1 patients, 50 (88%) Bu2, and in 46 (92%) Bu3 patients. The incidence of primary graft failure was similare: 14% in Bu1, 9% in Bu2; 8% in Bu3, respectively, p values for 1 vs 2=0.5; for p 1 vs 3=0.4; p 2 vs 3=0.8. At a median follow-up of 2 years the OS of pts with CR at the time of HSCT was 55% in the Bu1 group, 71% in the Bu2 group and 58% in Bu3, p values were as follows: 1 vs 2=0.4, 1 vs 3=1, 2 vs 3=0.4. At the 1st + 2nd CR, the OS was 52%, 78%, 66%, respectively; p 1 vs 2=0.2, p 1 vs 3=0.4, p 2 vs 3=0.4. The OS of children without CR at the time of HSCT comprised: 25%, 20%, 21%, with p values for 1 vs 2=0.8, p 1 vs 3=0.6, p 2 vs 3=0.2. RFS in pts with CR before HSCT was 62% in Bu1 patients, 70% in Bu2 and 66% in Bu3, with p levels for 1 vs 2=0.9; for 1 vs 3=0.6; for 2 vs 3=0.6. At the 1st + 2nd CR RFS was 57%, 74%, 59%, with p values for 1 vs 2=0.5; for 1 vs 3=0.7; for 2 vs 3=0.6. RFS of children with progression at the time of HSCT was, respectively, 25%, 36%, 21%, with p levels for 1 vs 2=0.9; for 1 vs 3=0.8; for 2 vs 3=0.8. Among children at CR of the disease at the time of HSCT, toxicity of grade 3-4 occurred more often in Bu1 group (n=7, 24% ), than in Bu2 (n=18, 56%) and Bu3 (n=17, 47%), p levels for 1 vs 2=0.008; for 1 vs 3=0.057; for p 2 vs 3=0.4 Severe mucositis was the most frequent complication in these children. Toxicity grade of 3-4 was not different and developed in 4 (50%) children Bu1 with progression of disease: 19 (76%) in Bu2, 10 (71%) in Bu3, with p values for 1 vs 2=0.17; for 1 vs 3=0.4; for 2 vs 3=0.8. Acute GVHD grade 3-4 was observed in 7 children (23%) with Bu1, 10 (20%) in Bu2, 8 (17%) in Bu3, with appropriate p levels for 1 vs 2=0.7; for 1 vs 3=0.6; for 2 vs 3=0.8. TRM up to D+100 was significantly lower in Bu1 (0%), than in Bu2 (13%), and Bu3 (11%) among the pts with CR, with p values for 1 vs 2=0.047; for 1 vs 3=0.067; for 2 vs 3=0.8. Upon the disease progression at allo-HSCT, this index was similar: 25%, 12%, 7%, with p levels for 1 vs 2=0.4; for 1 vs 3=0.2; for 2 vs 3=0.5.
These data demonstrated, that decrease dose of Bu in the myeloablative conditioning regimens is not associated with decline of OS and RFS in children with same status of ALL. However, decrease doses of Bu reduced toxicity and early transplant mortality in pts with ALL in CR before allo-HSCT.
Acute lymphoblastic leukemia, busulfan, allo-HSCT, children.