Recent clinical trials have shown that the addition of immunotherapy has substantially improved cure rates for children and adolescents newly diagnosed with B-acute lymphoblastic leukemia. Most of these patients now have outcomes similar to those previously seen in only the most favorable subgroups. As such, efforts are underway to study whether the incorporation of immunotherapy can allow for elements of traditional toxic chemotherapy to be removed while maintaining excellent outcomes. In this article, we discuss important considerations for such studies, including those related to which patients are appropriate targets of deintensification efforts and which elements of therapy are or are not appropriate candidates for omission.

1.
Mullighan
CG.
Genomic characterization of childhood acute lymphoblastic leukemia
.
Semin Hematol
.
2013
;
50
(
4
):
314
-
324
.
Google Scholar
 
2.
Hunger
SP
,
Mullighan
CG.
Acute lymphoblastic leukemia in children
.
N Engl J Med
.
2015
;
373
(
16
):
1541
-
1552
.
Google Scholar
 
3.
Borowitz
MJ
,
Devidas
M
,
Hunger
SP
, et al;
Children's Oncology Group
.
Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia and its relationship to other prognostic factors: a Children's Oncology Group study
.
Blood
.
2008
;
111
(
12
):
5477
-
5485
.
Google Scholar
 
4.
Mattano
LA
,
Devidas
M
,
Friedmann
AM
, et al.
Outstanding outcome for children with standard risk-low (SR-Low) acute lymphoblastic leukemia (ALL) and no benefit to intensified peg-asparaginase (PEG-ASNase) therapy: results of Children's Oncology Group (COG) Study AALL0331
.
Blood
.
2014
;
124
(
21
):
793
.
Google Scholar
 
5.
Angiolillo
A
,
Schore
RJ
,
Devidas
M
, et al.
Intensification of oral methotrexate is not superior to standard methotrexate dosing during maintenance in children with National Cancer Institute (NCI) standard-risk B actue lymphoblastic leukemia (SR B-ALL): a report from the Children's Oncology Group (COG) study AALL0932
.
Blood
.
2017
;
130
(suppl
1
):
140
.
Google Scholar
 
6.
Conter
V
,
Valsecchi
MG
,
Cario
G
, et al.
Four additional doses of PEG-L- asparaginase during the consolidation phase in the AIEOP-BFM ALL 2009 protocol do not improve outcome and increase toxicity in high-risk ALL: results of a randomized study
.
J Clin Oncol
.
2024
;
42
(
8
):
915
-
926
.
Google Scholar
 
7.
Kirkwood
AA
,
Goulden
N
,
Moppett
J
, et al.
High dose methotrexate does not reduce the risk of CNS relapse in children and young adults with acute lymphoblastic leukaemia and lymphoblastic lymphoma. Results of the randomised phase III study UKALL 2011
.
Blood
.
2022
;
140
(
suppl 1
):
516
-
518
.
Google Scholar
 
8.
Kantarjian
H
,
Stein
A
,
Gökbuget
N
, et al.
Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia
.
N Engl J Med
.
2017
;
376
(
9
):
836
-
847
.
Google Scholar
 
9.
von Stackelberg
A
,
Locatelli
F
,
Zugmaier
G
, et al.
A phase 1/phase 2 study of blinatumomab in pediatric patients with relapsed/refractory acute lymphoblastic leukemia
.
J Clin Oncol
.
2016
;
34
(
36
):
4381
-
4389
.
Google Scholar
 
10.
Brown
PA
,
Ji
L
,
Xu
X
, et al.
Effect of postreinduction therapy consolidation with blinatumomab vs chemotherapy on disease-free survival in children, adolescents and young adults with first relapse of B-cell acute lymphoblastic leukemia: a randomized clinical trial
.
JAMA
.
2021
;
325
(
9
):
833
-
842
.
Google Scholar
 
11.
Locatelli
F
,
Zugmaier
G
,
Rizzari
C
, et al.
Effect of blinatumomab vs chemotherapy on event-free survival among children with high-risk first-relapse B-cell acute lymphoblastic leukemia: a randomized clinical trial
.
JAMA
.
2021
;
325
(
9
):
843
-
854
.
Google Scholar
 
12.
Kantarjian
HM
,
DeAngelo
DJ
,
Stelljes
M
, et al.
Inotuzumab ozogamicin versus standard therapy for acute lymphoblastic leukemia
.
N Engl J Med
.
2016
;
375
(
8
):
740
-
753
.
Google Scholar
 
13.
O'Brien
MM
,
Ji
L
,
Shah
NN
, et al.
Phase II trial of intotuzumab ozogamicin in children and adolescents with relapsed or refractory B-cell acute lymphoblastic leukemia: Children's Oncology Group Protocol AALL1621
.
J Clin Oncol
.
2022
;
40
:
956
-
967
.
Google Scholar
 
14.
Litzow
MR
,
Sun
Z
,
Mattison
RJ
, et al.
Blinatumomab for MRD-negative acute lymphoblastic leukemia in adults
.
N Engl J Med
.
2024
;
391
(
4
):
320
-
333
.
Google Scholar
 
15.
Gupta
S
,
Rau
RE
,
Kairalla
JA
, et al.
Blinatumomab in standard-risk B-cell acute lymphoblastic leukemia in children
.
N Engl J Med
.
2025
;
392
(
9
):
875
-
891
.
Google Scholar
 
16.
McNeer
JL
,
Rau
RE
,
Gupta
S
,
Maude
SL
,
O'Brien
MM.
Cutting to the front of the line: immunotherapy for childhood acute lymphoblastic leukemia
.
Am Soc Clin Oncol Educ Book
.
2020
;
40
:
1
-
12
.
Google Scholar
 
17.
Hogan
LE
,
Brown
PA
,
Ji
L
, et al.
Children's Oncology Group AALL1331: phase III trial of blinatumomab in children, adolescents, and young adults with low-risk B-cell ALL in first relapse
.
J Clin Oncol
.
2023
;
41
(
25
):
4118
-
4129
.
Google Scholar
 
18.
Queudeville
M
,
Stein
AS
,
Locatelli
F
, et al.
Low leukemia burden improves blinatumomab efficacy in patients with relapsed/refractory B-cell acute lymphoblastic leukemia
.
Cancer
.
2023
;
129
(
9
):
1384
-
1393
.
Google Scholar
 
19.
van der
Sluis IM
,
De Lorenzo
P
,
Kotecha
RS
, et al.
Blinatumomab added to chemotherapy in infant lymphoblastic leukemia
.
N Engl J Med
.
2023
;
388
(
17
):
1572
-
1581
.
Google Scholar
 
20.
Bassan
R
,
Chiaretti
S
,
Della Starza
I
, et al.
Up-front blinatumomab improves MRD clearance and outcome in adult Ph- B-lineage ALL: the GIMEMA LAL2317 phase 2 study
.
Blood
.
2025
;
145
(
21
):
2447
-
2459
.
Google Scholar
 
21.
Pennesi
E
,
Michels
N
,
Brivio
E
, et al.
Inotuzumab ozogamicin as single agent in pediatric patients with relapsed and refractory acute lymphoblastic leukemia: results from a phase II trial
.
Leukemia
.
2022
;
36
(
6
):
1516
-
1524
.
Google Scholar
 
22.
DeAngelo
DJ
,
Yin
J
,
Advani
AS
, et al.
Addition of inotuzumab to a pediatric inspired chemotherapy regimen in young adult patients with B-cell acute lymphoblastic leukemia: findings from the Alliance A041501 phase 3 randomized trial
.
Blood
.
2024
;
144
:
308
.
Google Scholar
 
23.
Stelljes
M
,
Raffel
S
,
Alakel
N
, et al.
Inotuzumab ozogamicin as induction therapy for patients older than 55 years with Philadelphia chromosome-negative B-precursor ALL
.
J Clin Oncol
.
2024
;
42
(
3
):
273
-
282
.
Google Scholar
 
24.
Chevallier
P
,
Leguay
T
,
Delord
M
, et al;
Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL) and the European Working Group for Adult Acute Lymphoblastic Leukemia (EWALL); European Working Group for Adult Acute Lymphoblastic Leukemia (EWALL)
.
Inotuzumab ozogamicin and low-intensity chemotherapy in older patients with newly diagnosed CD22+ Philadelphia chromosome-negative B-cell precursor acute lymphoblastic leukemia
.
J Clin Oncol
.
2024
;
42
(
36
):
4327
-
4341
.
Google Scholar
 
25.
Jabbour
E
,
Short
NJ
,
Senapati
J
, et al.
Mini-hyper-CVD plus inotuzumab ozogamicin, with or without blinatumomab, in the subgroup of older patients with newly diagnosed Philadelphia chromosome-negative B-cell acute lymphocytic leukemia: long-term results of an open-label phase 2 trial
.
Lancet Haematol
.
2023
;
10
:
e433
-
e444
.
Google Scholar
 
26.
Wieduwilt
MJ
,
Yin
J
,
Kour
O
, et al.
Chemotherapy-free treatment with inotuzumab ozogamicin and blinatumomab for older adults with newly diagnosed, Ph-negative, CD22-positive, B-cell acute lymphoblastic leukemia: Alliance A041703
.
J Clin Oncol
.
2023
;
41
(
16
, suppl):
7006
.
Google Scholar
 
27.
Kantarjian
H
,
Short
NJ
,
Haddad
FG
, et al.
Results of the simultaneous combination of ponatinib and blinatumomab in Philadelphia chromosome- positive ALL
.
J Clin Oncol
.
2024
;
42
:
4246
-
4251
.
Google Scholar
 
28.
Hodder
A
,
Mishra
AK
,
Enshaei
A
, et al.
Blinatumomab for first-line treatment of children and young persons with B-ALL
.
J Clin Oncol
.
2024
;
42
(
8
):
907
-
914
.
Google Scholar
 
29.
Bassal
M
,
Silva
M
,
Patel
S
, et al.
Phase-specific risks of outpatient visits, emergency visits, and hospitalizations during Children's Oncology Group-based treatment for childhood acute lymphoblastic leukemia: a population-based study
.
Pediatr Blood Cancer
.
2021
;
68
(
10
):
e29141
.
Google Scholar
 
30.
Dixon
SB
,
Chen
Y
,
Yasui
Y
, et al.
Reduced morbidity and mortality in survivors of childhood acute lymphoblastic leukemia: a report from the Childhood Cancer Survivor Study
.
J Clin Oncol
.
2020
;
38
(
29
):
3418
-
3429
.
Google Scholar
 
31.
Bansal
M
,
Sharma
KK
,
Vatsa
M
,
Bakhshi
S.
Comparison of health-related quality of life of children during maintenance therapy with acute lymphoblastic leukemia versus siblings and healthy children in India
.
Leuk Lymphoma
.
2013
;
54
(
5
):
1036
-
1041
.
Google Scholar
 
32.
Rensen
N
,
Steur
LMH
,
Grootenhuis
MA
, et al.
Parental functioning during maintenance treatment for childhood acute lymphoblastic leukemia: effects of treatment intensity and dexamethasone pulses
.
Pediatr Blood Cancer
.
2020
;
67
(
11
):
e28697
.
Google Scholar
 
33.
Parker
K
,
Cottrell E, Stork L, Lindemulder S
. Parental decision making regarding consent to randomization on Children's Oncology Group AALL0932.
Pediatr Blood Cancer
.
2021
;
68
(
4
):
e28907
.
Google Scholar
 
34.
O'Brien
MM
,
McNeer
JL
,
Rheingold
SR
, et al.
A phase 3 trial of inotuzumab ozogamicin for high-risk B-ALL: second safety phase results from Children's Oncology Group AALL1732
.
J Clin Oncol
.
2023
;
41
(
16
, suppl):
10016
.
Google Scholar
 
35.
Schore
RJ
,
Angiolillo
AL
,
Kairalla
JA
, et al.
Outstanding outcomes with two low intensity regimens in children with low-risk B-ALL: a report from COG AALL0932
.
Leukemia
.
2023
;
37
(
6
):
1375
-
1378
.
Google Scholar
 
36.
Brady
SW
,
Roberts
KG
,
Gu
Z
, et al.
The genomic landscape of pediatric acute lymphoblastic leukemia
.
Nat Genet
.
2022
;
54
(
9
):
1376
-
1389
.
Google Scholar
 
37.
Leahy
AB
,
Devine
KJ
,
Li
Y
, et al.
Impact of high-risk cytogenetics on outcomes for children and young adults receiving CD19-directed CAR T-cell therapy
.
Blood
.
2022
;
139
(
14
):
2173
-
2185
.
Google Scholar
 
38.
Jabbour
E
,
O'Brien
S
,
Huang
X
, et al.
Prognostic factors for outcome in patients with refractory and relapsed acute lymphocytic leukemia treated with inotuzumab ozogamicin, a CD22 monoclonal antibody
.
Am J Hematol
.
2015
;
90
(
3
):
193
-
196
.
Google Scholar
 
39.
Kantarjian
HM
,
DeAngelo
DJ
,
Stelljes
M
, et al.
Inotuzumab ozogamicin versus standard of care in relapsed or refractory acute lymphoblastic leukemia: final report and long-term survival follow-up from the randomized, phase 3 INO-VATE study
.
Cancer
.
2019
;
125
(
14
):
2474
-
2487
.
Google Scholar
 
40.
Zhao
Y
,
Laird
AD
,
Roberts
KG
, et al.
Association of leukemic molecular profile with efficacy of inotuzumab ozogamicin in adults with relapsed/refractory ALL
.
Blood Adv
.
2024
;
8
(
12
):
3226
-
3236
.
Google Scholar
 
41.
Pui
C-H
,
Howard
S-C
.
Current management and challenges of malignant disease in the CNS in paediatric leukaemia
.
Lancet Oncol
.
2008
;
9
(
3
):
257
-
268
.
Google Scholar
 
42.
Jeha
S
,
Pei
D
,
Choi
J
, et al.
Improved CNS control of childhood acute lymphoblastic leukemia without cranial irradiation: St Jude Total Therapy Study 16
.
J Clin Oncol
.
2019
;
37
(
35
):
3377
-
3391
.
Google Scholar
 
43.
Thastrup
M
,
Duguid
A
,
Mirian
C
,
Schmiegelow
K
,
Halsey
C.
Central nervous system involvement in childhood acute lymphoblastic leukemia: challenges and solutions
.
Leukemia
.
2022
;
36
(
12
):
2751
-
2768
.
Google Scholar
 
44.
Hasle
H
,
Clemmensen
IH
,
Mikkelsen
M.
Risks of leukaemia and solid tumours in individuals with Down's syndrome
.
Lancet
.
2000
;
355
(
9199
):
165
-
169
.
Google Scholar
 
45.
Rabin
KR
,
Devidas
M
,
Chen
Z
, et al.
Outcomes in children, adolescents, and young adults with Down Syndrome and ALL: a report from the Children's Oncology Group
.
J Clin Oncol
.
2024
;
42
(
2
):
218
-
227
.
Google Scholar
 
46.
Li
AM
,
Rabin
KR
,
Kairalla
J
, et al.
Blinatumomab associated seizure risk in patients with Down syndrome and B-lymphoblastic leukemia: an interim report from Children's Oncology Group (COG) Study AALL1731
.
Blood
.
2021
;
138
:
2304
.
Google Scholar
 
47.
Karol
SE
,
Yang
W
,
Van Driest
SL
, et al.
Genetics of glucocorticoid- associated osteonecrosis in children with acute lymphoblastic leukemia
.
Blood
.
2015
;
126
(
15
):
1770
-
1776
.
Google Scholar
 
48.
Diouf
B
,
Crews
KR
,
Lew
G
, et al.
Association of an inherited genetic variant with vincristine-related peripheral neuropathy in children with acute lymphoblastic leukemia
.
JAMA
.
2015
;
313
(
8
):
815
-
823
.
Google Scholar
 
49.
Yang
W
,
Karol
SE
,
Hoshitsuki
K
, et al.
Association of inherited genetic factors with drug-induced hepatic damage among children with acute lymphoblastic leukemia
.
JAMA Netw Open
.
2022
;
5
(
12
):
e2248803
.
Google Scholar
 
50.
Alexander
S
,
Aupérin
A
,
Bomken
S
, et al;
Children's Oncology Group; European Intergroup for Childhood Non-Hodgkin's Lymphoma
.
Effect of rituximab on immune status in children with mature B-cell non-Hodgkin lymphoma: a prespecified secondary analysis of the Inter-B-NHL Ritux 2010 trial
.
Lancet Haematol
.
2023
;
10
(
6
):
e445
-
e457
.
Google Scholar
 
51.
Szczawinska-Poplonyk
A
,
Schwartzmann
E
,
Bukowska-Olech
W
, et al.
The pediatric common variable immunodeficiency—from genetics to therapy: a review
.
Eur J Pediatr
.
2022
;
181
(
4
):
1371
-
1383
.
Google Scholar
 
52.
Ward
ZJ
,
Yeh
JM
,
Bhakta
N
,
Frazier
AL
,
Girardi
F
,
Atun
R.
Global childhood cancer survival estimates and priority-setting: a simulation-based analysis
.
Lancet Oncol
.
2019
;
20
(
7
):
972
-
983
.
Google Scholar
 
Copyright © 2025 by The American Society of Hematology
2025
You do not currently have access to this content.