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Original Article

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Blood Res 2022; 57(4):

Published online December 31, 2022

https://doi.org/10.5045/br.2022.2022174

© The Korean Society of Hematology

Prognostic impact of total body irradiation dose in pediatric acute lymphoblastic leukemia patients treated with allogeneic hematopoietic stem cell transplantation in second complete remission

Wonjin Jang, Suejung Jo, Jae Won Yoo, Seongkoo Kim, Jae Wook Lee, Pil-Sang Jang, Nack-Gyun Chung, Bin Cho

Author Info. +

Division of Hematology and Oncology, Department of Pediatrics, College of Medicine, The Catholic University of Korea, Seoul, Korea

Correspondence to : Jae Wook Lee, M.D., Ph.D.
Department of Pediatrics, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seocho-gu, Banpo-daero 222, Seoul 06591, Korea
E-mail: dashwood@catholic.ac.kr

Received: August 31, 2022; Revised: October 17, 2022; Accepted: November 3, 2022

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

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Background
Allogeneic HSCT may improve survival in pediatric ALL patients who relapse. In this study, we analyzed the outcome and prognostic factors of 62 ALL patients (35 male, 56.5%) who received allogeneic HSCT in second complete remission (CR) at our institution between April 1st 2009 and December 31st 2019.
Methods
The median time from diagnosis to relapse was 35.1 months (range, 6.0‒113.6 mo). Fifty-three patients (85.5%) experienced bone marrow relapse only. The number of patients who received transplant according to each donor type was as follows: HLA matched family donor 17 (27.4%), matched unrelated donor (UD) 22 (35.5%), mismatched donor 23 (37.1%). All patients received HSCT with a myeloablative conditioning, 58 patients (93.5%) with the incorporation of TBI [31 patients 12 Gray (Gy), 24 patients 13.2 Gy, 3 patients 8 Gy].
Results
The 5-year event-free survival (EFS), and overall survival of the study group was 41.3±6.3% (26/62), and 42.3±6.6% (27/62), respectively. The cumulative incidence of relapse and transplant-related mortality was 57.1±6.4% and 1.6±1.6%, respectively. Infant ALL, shorter time from diagnosis to relapse, and TBI dose of 12 Gy, rather than 13.2 Gy, resulted in significantly worse EFS. In multivariate analysis, infant ALL and TBI dose of 12 Gy during conditioning predicted significantly lower EFS.
Conclusion
In our study group, treatment with a higher dose of TBI during conditioning resulted in better EFS for ALL patients who underwent HSCT in second CR. Further study is needed to determine potential long-term complications associated with a higher TBI dose.

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Keywords: Acute lymphoblastic leukemia, Children, Hematopoietic stem cell transplantation, Total body irradiation, Second complete remission

Article

Original Article

Blood Res 2022; 57(4): 256-263

Published online December 31, 2022 https://doi.org/10.5045/br.2022.2022174

Copyright © The Korean Society of Hematology.

Prognostic impact of total body irradiation dose in pediatric acute lymphoblastic leukemia patients treated with allogeneic hematopoietic stem cell transplantation in second complete remission

Wonjin Jang, Suejung Jo, Jae Won Yoo, Seongkoo Kim, Jae Wook Lee, Pil-Sang Jang, Nack-Gyun Chung, Bin Cho

Division of Hematology and Oncology, Department of Pediatrics, College of Medicine, The Catholic University of Korea, Seoul, Korea

Correspondence to:Jae Wook Lee, M.D., Ph.D.
Department of Pediatrics, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seocho-gu, Banpo-daero 222, Seoul 06591, Korea
E-mail: dashwood@catholic.ac.kr

Received: August 31, 2022; Revised: October 17, 2022; Accepted: November 3, 2022

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Background
Allogeneic HSCT may improve survival in pediatric ALL patients who relapse. In this study, we analyzed the outcome and prognostic factors of 62 ALL patients (35 male, 56.5%) who received allogeneic HSCT in second complete remission (CR) at our institution between April 1st 2009 and December 31st 2019.
Methods
The median time from diagnosis to relapse was 35.1 months (range, 6.0‒113.6 mo). Fifty-three patients (85.5%) experienced bone marrow relapse only. The number of patients who received transplant according to each donor type was as follows: HLA matched family donor 17 (27.4%), matched unrelated donor (UD) 22 (35.5%), mismatched donor 23 (37.1%). All patients received HSCT with a myeloablative conditioning, 58 patients (93.5%) with the incorporation of TBI [31 patients 12 Gray (Gy), 24 patients 13.2 Gy, 3 patients 8 Gy].
Results
The 5-year event-free survival (EFS), and overall survival of the study group was 41.3±6.3% (26/62), and 42.3±6.6% (27/62), respectively. The cumulative incidence of relapse and transplant-related mortality was 57.1±6.4% and 1.6±1.6%, respectively. Infant ALL, shorter time from diagnosis to relapse, and TBI dose of 12 Gy, rather than 13.2 Gy, resulted in significantly worse EFS. In multivariate analysis, infant ALL and TBI dose of 12 Gy during conditioning predicted significantly lower EFS.
Conclusion
In our study group, treatment with a higher dose of TBI during conditioning resulted in better EFS for ALL patients who underwent HSCT in second CR. Further study is needed to determine potential long-term complications associated with a higher TBI dose.

Keywords: Acute lymphoblastic leukemia, Children, Hematopoietic stem cell transplantation, Total body irradiation, Second complete remission

Fig 1.

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Figure 1.5-year OS of the patient group.
Blood Research 2022; 57: 256-263https://doi.org/10.5045/br.2022.2022174

Fig 2.

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Figure 2.5-year EFS according to (A) age at diagnosis (B) time from diagnosis to relapse and (C) TBI dose during HSCT conditioning.
Blood Research 2022; 57: 256-263https://doi.org/10.5045/br.2022.2022174

Fig 3.

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Figure 3.5-year (A) EFS and (B) OS according to donor type (matched family donor vs. matched UD).
Blood Research 2022; 57: 256-263https://doi.org/10.5045/br.2022.2022174

Table 1 . Patient characteristics at diagnosis and relapse..

N=62 (%)
Median age at diagnosis, years (range)6.1 (0.2–16.4)
Gender
Male35 (56.5)
Female27 (43.5)
Immunophenotype
Pre-B58 (93.5)
T cell3 (4.8)
Mixed phenotype (Pre-B/T)1 (1.6)
Genetics at diagnosisa)
ETV6-RUNX113 (21)
High hyperdiploidy6 (9.7)
E2A-PBX14 (6.5)
MLL (+)4 (6.5)
Hypodiploidy1 (1.6)
Others18 (29)
Normal karyotype5 (8.1)
Overall risk group at diagnosisa)
Low6 (9.7)
Standard6 (9.7)
High21 (33.9)
Very high17 (27.4)
Median age at relapse, years (range)9.8 (1.1–19.8)
Time from diagnosis to relapse (mo)
Early (<18)16 (25.8)
Intermediate (18–36)16 (25.8)
Late (>36)30 (48.4)
Type of relapse
BM only53 (85.5)
Isolated EM5 (8.1)
BM+EM4 (6.5)

a)Initial diagnosis and treatment at a different institution and subsequent transfer after relapse resulted in missing data for 11 and 12 patients for ‘Genetics’ and ‘Overall risk group at diagnosis’ respectively..

Abbreviations: BM, bone marrow; EM, extramedullary; MLL (+), MLL rearrangement (+); Pre-B, precursor B cell..

Table 2 . Hematopoietic stem cell transplantation characteristics..

N=62 (%)
Donor typea)
Matched familial17 (27.4)
Matched unrelated22 (35.5)
Mismatched familial6 (9.7)
Mismatched unrelated17 (27.4)
Cell source
BM7 (11.3)
PBSC49 (79.0)
CB6 (9.7)
Donor to recipient gender
Female to male24 (38.7)
Others38 (61.3)
ABO compatibility
Match23 (37.1)
Mismatch39 (62.9)
Conditioning regimen
TBI-Cy±ATG28 (45.2)
TBI-Ara-Cy±ATG22 (35.5)
TBI-Flu-Ara5 (8.1)
TBI-Bu-Flu±ATG3 (4.8)
Bu-Flu-ATG3 (4.8)
Bu-Cy1 (1.6)
Fractionated TBI doseb)
13.2 Gy24 (41.4)
12 Gy31 (53.4)
8 Gy3 (5.2)
ATG dose, 2.5 mg/kg/dayc)
Cumulative 7.5 mg/kg20 (51.3)
Cumulative 10 mg/kg3 (7.7)
ATG dose, 1.25 mg/kg/dayc)
Cumulative 3.75 mg/kg15 (38.5)
Cumulative 5 mg/kg1 (2.6)
GVHD prophylaxis
CS-MTX55 (88.7)
Tac-MMF4 (6.5)
CS-PTCy3 (4.8)

a)HLA compatibility based on matching for HLA-A, B, C, DRB1 alleles. b)Based on 58 patients who received TBI as part of conditioning. c)Based on 39 patients who received rabbit ATG as part of conditioning..

Abbreviations: Ara, cytarabine; ATG, rabbit anti-thymocyte globulin; BM, bone marrow; Bu, busulfan; CB, cord blood; CS, cyclosporine; Cy, cyclophosphamide; Flu, fludarabine; GVHD, graft-versus-host disease; Gy, Gray; MTX, methotrexate; MMF, mycophenolate mofetil; PBSC, peripheral blood stem cells; PTCy, post-transplantation cyclophosphamide; Tac, tacrolimus; TBI, total body irradiation..

Table 3 . Analysis of risk factors for EFS (N=62)..

Patients (events)5-year EFS (±SE, %)P
Gender0.538
Male35 (22)37.1±8.2
Female27 (14)46.9±9.8
Age at diagnosis (yr)<0.001
<14 (4)0
1–9.940 (21)46.5±8.0
≥1018 (11)38.9±11.5
Genetics0.212
ETV6-RUNX113 (9)30.8±12.8
High hyperdiploidy6 (1)83.3±15.2
E2A-PBX14 (3)25.0±21.7
MLL (+)4 (3)25.0±21.7
Hypodiploidy1(0)100
Others18 (13)27.8±10.6
Normal karyotype5 (3)40.0±21.9
Time from diagnosis to relapse0.005
<18 months16 (13)18.8±9.8
18–36 months16 (10)34.4±12.3
>36 months30 (13)56.7±9.0
Donor typea)0.332
Matched familial17 (13)23.5±10.3
Matched unrelated22 (10)54.5±10.6
Mismatched familial6 (4)33.3±19.2
Mismatched unrelated17 (9)44.6±12.4
Cell source0.158
Bone marrow7 (6)14.3±13.2
PBSC49 (27)44.9±7.1
Cord blood6 (3)41.7±22.2
Donor-recipient gender0.548
Female to male24 (15)37.5±9.9
Others38 (21)43.7±8.2
ABO compatibility0.941
Match23 (13)43.5±10.3
Mismatch39 (23)39.9±7.9
TBI doseb)<0.001
12 Gy31 (25)17.0±6.9
13.2 Gy24 (7)70.8±9.3

a)HLA compatibility based on matching for HLA-A, B, C, DRB1 alleles. b)Based on 55 patients who received either 12 Gy or 13.2 Gy TBI as part of conditioning..

Abbreviations: Gy, Gray; PBSC, peripheral blood stem cells; TBI, total body irradiation..

Table 4 . Multivariate study of risk factors for EFS..

Hazard ratio95% CIP
Age at diagnosis (yr)
1–9.91
≥101.300.57–3.000.535
<120.462.59–161.560.004
Time from diagnosis to relapse
>36 months1
18–36 months1.410.56–3.550.463
<18 months2.070.83–5.190.120
TBI dose
13.2 Gy1
12 Gy4.381.84–10.430.001

Abbreviations: Gy, Gray; TBI, total body irradiation..
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