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Original Article

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Blood Res 2021; 56(3):

Published online September 30, 2021

https://doi.org/10.5045/br.2021.2021045

© The Korean Society of Hematology

Impact of timely BCR-ABL1 monitoring before allogeneic stem cell transplantation among patients with BCR-ABL1-positive B-acute lymphoblastic leukemia

Siew Lian Chong1,2, Asral Wirda Ahmad Asnawi1,2, Tze Shin Leong3, Jenq Tzong Tan4, Kian Boon Law5, Siong Leng Hon6, Rui Jeat Fann1,7, Sen Mui Tan1

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1Department of Haematology, Hospital Ampang, Selangor, 2Faculty of Medicine and Health Sciences, Universiti Sains Islam Malaysia, Nilai, 3Department of Haematology, Hospital Umum Sarawak, Kuching, 4Department of Medicine, Hospital Taiping, Taiping, 5Institute for Clinical Research, National Institutes of Health (NIH), Shah Alam, 6Department of Medicine, Hospital Melaka, Melaka, 7Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, Kajang, Malaysia

Correspondence to : Asral Wirda Ahmad Asnawi, M.D., Ph.D. Faculty of Medicine and Health Sciences, Universiti Sains Islam Malaysia, Persiaran Ilmu, Putra Nilai, Nilai, Negeri Sembilan 71800, Malaysia E-mail: wirda@usim.edu.my

Received: March 2, 2021; Revised: May 27, 2021; Accepted: July 30, 2021

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
With the emergence of tyrosine kinase inhibitors and the incorporation of stringent measurable residual disease (MRD) monitoring, risk stratification for BCR-ABL1-positive acute lymphoblastic leukemia (ALL) patients has changed significantly. However, whether this monitoring can replace conventional risk factors in determining whether patients need allogeneic stem cell transplantation is still unclear. This study aimed to determine the impact of BCR-ABL1 monitoring on the outcome of patients with BCR-ABL1-positive ALL after allogeneic stem cell transplantation.
Methods
We retrospectively analyzed the survival outcome of patients with BCR-ABL1-positive ALL based on the quantification of BCR-ABL1 at 3 timepoints: the end of induction (timepoint 1), post-consolidation week 16 (timepoint 2), and the end of treatment for patients who were either transplant-eligible or non-transplant eligible (timepoint 3).
Results
From 2006 to 2018, a total of 96 patients newly diagnosed with BCR-ABL1-positive ALL were treated with chemotherapy and tyrosine kinase inhibitors. Thirty-eight (41.3%) patients achieved complete remission, and 33 patients underwent allogeneic stem cell transplantation. Our data showed that pre-transplant MRD monitoring by real-time quantitative polymerase chain reaction had the highest correlation with survival in patients with BCR-ABL1-positive ALL, especially for those who underwent allogeneic stem cell transplantation.
Conclusion
Patients without MRD pre-transplantation had superior survival compared with those who had MRD, and they had excellent long-term outcomes after allogeneic stem cell transplantation.

Keywords ALL, BCR-ABL1, Philadelphia, Survival, TKI

Article

Original Article

Blood Res 2021; 56(3): 175-183

Published online September 30, 2021 https://doi.org/10.5045/br.2021.2021045

Copyright © The Korean Society of Hematology.

Impact of timely BCR-ABL1 monitoring before allogeneic stem cell transplantation among patients with BCR-ABL1-positive B-acute lymphoblastic leukemia

Siew Lian Chong1,2, Asral Wirda Ahmad Asnawi1,2, Tze Shin Leong3, Jenq Tzong Tan4, Kian Boon Law5, Siong Leng Hon6, Rui Jeat Fann1,7, Sen Mui Tan1

1Department of Haematology, Hospital Ampang, Selangor, 2Faculty of Medicine and Health Sciences, Universiti Sains Islam Malaysia, Nilai, 3Department of Haematology, Hospital Umum Sarawak, Kuching, 4Department of Medicine, Hospital Taiping, Taiping, 5Institute for Clinical Research, National Institutes of Health (NIH), Shah Alam, 6Department of Medicine, Hospital Melaka, Melaka, 7Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, Kajang, Malaysia

Correspondence to:Asral Wirda Ahmad Asnawi, M.D., Ph.D. Faculty of Medicine and Health Sciences, Universiti Sains Islam Malaysia, Persiaran Ilmu, Putra Nilai, Nilai, Negeri Sembilan 71800, Malaysia E-mail: wirda@usim.edu.my

Received: March 2, 2021; Revised: May 27, 2021; Accepted: July 30, 2021

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
With the emergence of tyrosine kinase inhibitors and the incorporation of stringent measurable residual disease (MRD) monitoring, risk stratification for BCR-ABL1-positive acute lymphoblastic leukemia (ALL) patients has changed significantly. However, whether this monitoring can replace conventional risk factors in determining whether patients need allogeneic stem cell transplantation is still unclear. This study aimed to determine the impact of BCR-ABL1 monitoring on the outcome of patients with BCR-ABL1-positive ALL after allogeneic stem cell transplantation.
Methods
We retrospectively analyzed the survival outcome of patients with BCR-ABL1-positive ALL based on the quantification of BCR-ABL1 at 3 timepoints: the end of induction (timepoint 1), post-consolidation week 16 (timepoint 2), and the end of treatment for patients who were either transplant-eligible or non-transplant eligible (timepoint 3).
Results
From 2006 to 2018, a total of 96 patients newly diagnosed with BCR-ABL1-positive ALL were treated with chemotherapy and tyrosine kinase inhibitors. Thirty-eight (41.3%) patients achieved complete remission, and 33 patients underwent allogeneic stem cell transplantation. Our data showed that pre-transplant MRD monitoring by real-time quantitative polymerase chain reaction had the highest correlation with survival in patients with BCR-ABL1-positive ALL, especially for those who underwent allogeneic stem cell transplantation.
Conclusion
Patients without MRD pre-transplantation had superior survival compared with those who had MRD, and they had excellent long-term outcomes after allogeneic stem cell transplantation.

Keywords: ALL, BCR-ABL1, Philadelphia, Survival, TKI

Fig 1.

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Figure 1.OS and DFS after stem cell transplantation according to BCR-ABL1 transcript level at certain timepoints. Post-induction MRD (A). Post-consolidation week 16 (B). End of treatment (C). The overall cohort (D).Abbreviations: DFS, disease-free survival; MRD, measurable residual disease; OS, overall survival.
Blood Research 2021; 56: 175-183https://doi.org/10.5045/br.2021.2021045

Table 1 . Baseline clinical characteristics of all patients with BCR-ABL1-positive ALL..

Total (N=96)Parameter
Age, years 15–39 (AYA)40–59 (adult)≥60 (elderly)
N (%)53 (55.2)38 (39.6)5 (5.2)
Median (range)37.5 (14–59)
SexMaleFemale
N (%)42 (43.8)54 (56.3)
EthnicityMalayChineseIndianOthers
N (%)48 (50.0)37 (38.5)9 (9.4)2 (2.1)
WCC, at diagnosis>30×109/L<30×109/L
N (%)51 (53.1)45 (46.9)
Median (range), ×109/L36 (2–500)
MRD statusTP1TP2TP3
≥0.1%<0.1%≥0.1%<0.1%≥0.1%<0.1%
N312525401336
Missing403147
Treatment modalitiesGMALL/BFMHyper-CVADTKIs
Yes (2012–2018)No (2006–2011)
N (%)49 (51)47 (49)62 (64.6)34 (35.4)
Treatment responseRemission post-inductionOverall remissionRelapseRefractoryInduction death
N (%)80 (83.3)38 (41.3)34 (37.0)10 (10.9)4 (4.3)
TransplantYesNo
N (%)38 (39.6)
(33-Allogeneic; 5-Autologous)		58 (60.4)

Values are presented as mean, median (range), or number (%)..

Abbreviations: ALL, acute lymphoblastic leukemia; AYA, adolescent and young adult; MRD, measurable residual disease; TKI, tyrosine kinase inhibitor; TP1, timepoint 1; TP2, timepoint 2; TP3, timepoint 3; WCC, white cell count..

Table 2 . Allogeneic stem cell transplant recipient details..

Total (N=33)Parameter
Age, years 15–39 (AYA)40–59 (adult)≥60 (elderly)
N (%)20 (60.6)13 (39.4)0 (0)
Median (range)37 (15–59)
SexMaleFemale
N (%)16 (48.5)17 (51.5)
EthnicityMalayChineseIndianOthers
N (%)15 (45.5)15 (45.5)3 (9.0)0 (0)
Disease status at transplantCR1CR>1
N (%)28 (84.8)5 (15.2)
Pre-transplant BCR-ABL1 level<0.1%≥0.1%
N (%)25 (75.8)8 (24.2)
WCC at diagnosis>30×109/L<30×109/L
N (%)21 (63.6)12 (36.4)
Median (range), ×109/L48 (2–500)
Blood type mismatchNoneMinorMajorBidirectional
N (%)25 (75.8)4 (12.1)3 (9.1)1 (3.0)
Gender mismatch (donor-recipient)Female to maleMale to femaleMale to maleFemale to femaleMissing
N (%)4 (12.1)8 (24.2)10 (30.3)10 (30.3)1 (3.0)
CMV statusRecipient negativeRecipient positiveMissing
N (%)
Donor negative3 (9.1)2 (6.1)5 (15.1)
Donor positive1 (3.0)22 (66.7)
Type of allogeneic transplantMatched- siblingMatched- unrelatedHaplo-matchedCord blood
N (%)27 (81.8)3 (9.1)2 (6.1)1 (3.0)
Stem cell sourcePeripheral bloodBone marrowUmbilical cord
N (%)32 (97.0)01 (3.0)
Median stem cell dose (×106/kg)5.0 (3.0-11)
Conditioning regimenMyeloablativeRICTBI-basedNon-TBI
N (%)29 (87.9)4 (12.1)22 (66.7)11 (33.3)
Post-transplant responseRemissionRelapse/death
N (%)23 (69.7)10 (30.3)
GVHDAcuteChronic
N (%)13 (44.8)14 (50.0)
Grade I 4Limited 7
Grade II 6Extensive 7
Grade III 3
Grade IV0
Missing45
No GVHD
N (%)16 (55.2)14 (50.0)
Mortality rateAliveDead
N (%)20 (60.6)13 (39.4)
Relapse/disease progression6
Infection/transplant-related mortality7

Values are presented as mean, median (range), or number (%)..

Abbreviations: AYA, adolescent and young adult; CR, complete remission; GVHD, graft-versus-host disease; RIC, reduced intensity conditioning; TBI, total body irradiation; GVHD, graft-versus-host disease; WCC, white cell count..

Table 3 . Univariable analysis of factors predictive for OS..

CharacteristicAll BCR-ABL1-positive ALL patientsTransplanted BCR-ABL1-positive ALL patients
3-year OS (%)P3-year OS (%)P
Age group
AYA39.00.06452.90.690
Adult and elderly19.655.0
Sex
Male33.60.87654.20.906
Female26.852.9
WCC at diagnosis
>30×109/L25.50.58552.30.684
<30×109/L35.963.6
MRD status (%)≥0.1<0.1≥0.1<0.1
TP136.736.10.974
TP223.553.10.077
TP311.565.40.00525.073.90.003
Chemotherapy
GMALL/BFM25.70.081
Hyper-CVAD33.7
TKI
Yes (2012–2018)33.70.390
No (2006–2011)23.5
Transplant
Yes58.9<0.001
No10.6
Disease status at transplant
CR165.90.003
CR>116.7

Significant P-value <0.05..

Abbreviations: ALL, acute lymphoblastic leukemia; AYA, adolescent and young adult; CR, complete remission; MRD, measurable residual disease; OS, overall survival; TKI, tyrosine kinase inhibitor; TP1, timepoint 1; TP2, timepoint 2; TP3, timepoint 3; WCC, white cell count..

Table 4 . Multivariable analysis of factors predictive of OS and DFS in transplant recipients..

CharacteristicRisk of relapse or deathRisk of death
HR95% CIPHR95% CIP
Pre-transplant BCR-ABL1 level ≥0.1%4.1061.226–13.7520.0224.3581.301–14.5970.017
Transplant in CR>13.7871.113–11.5200.0334.5821.352–15.5280.016

P-value <0.05..

Abbreviations: CI, confidence interval; CR, complete remission; DFS, disease-free survival; HR, hazard ratio; OS, overall survival..
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