https://orcid.org/0000-0002-2199-6869
Key Points
Contemporary trials no longer demonstrate the previous benefits conferred by vincristine-steroid pulses during maintenance for B-cell ALL.
Decreasing or removing pulses likely does not affect survival or risk of relapse but is associated with reduced toxicity.
Abstract
The benefit associated with the incorporation of vincristine-corticosteroid pulses in maintenance therapy for pediatric acute lymphoblastic leukemia (ALL) is unclear, particularly in the context of modern intensive therapy. This systematic review and meta-analysis examined the impact of reducing the frequency of vincristine-steroid pulses during maintenance for pediatric patients newly diagnosed with B-cell ALL. Two authors reviewed all eligible studies identified through a comprehensive search, extracted data from 25 publications (12 513 patients), and assessed the risk of bias. We created historical and contemporary subgroups; the latter included trials providing both a version of Protocol III from the early Berlin-Frankfurt-Munster trials and eliminating routine prophylactic cranial radiation. Meta-analysis of event-free survival data suggested no benefit between more frequent or less frequent pulses in contemporary trials (hazard ratio [HR], 0.96; 95% confidence interval [CI], 0.85-1.09), which differed significantly from historical trials (HR, 0.79; 95% CI, 0.68-0.91; P = .04). We found no significant impact of reduced pulse frequency on overall survival or relapse risk. There was however increased odds of grade 3+ nonhepatic toxicity in the high-pulse frequency group (odds ratio, 1.31; 95% CI, 1.12-1.52). This systematic review suggests that the previous benefit conferred by frequent pulses of vincristine-steroids in maintenance therapy for pediatric B-cell ALL in historical trials no longer applies in contemporary trials but is associated with toxicity. These results will help guide the development of the next phase of clinical trials in the field of pediatric ALL and question the continued use of pulses in maintenance among patients not in clinical trials, particularly those experiencing toxicity.
References
1.
Howlader
N
, Noone
A
, Krapcho
M
, et al. SEER Cancer Statistics Review (CSR) 1975-2016
. Accessed 31 October 2022. https://seer.cancer.gov/csr/1975_2016/.2.
Hunger
SP
. Development and refinement of augmented treatment regimens for pediatric high-risk acute lymphoblastic leukemia
. Am Soc Clin Oncol Educ Book
. 2012
:611
-615
.3.
Hunger
SP
, Mullighan
CG
. Acute lymphoblastic leukemia in children
. N Engl J Med
. 2015
;373
(16
):1541
-1552
.4.
Pui
CH
, Robison
LL
, Look
AT
. Acute lymphoblastic leukaemia
. Lancet
. 2008
;371
(9617
):1030
-1043
.5.
Rivera
GK
. Advances in therapy for childhood non-B-lymphoblastic leukaemia
. Baillieres Clin Haematol
. 1994
;7
(2
):273
-298
.6.
Bhatia
S
, Landier
W
, Hageman
L
, et al. 6MP adherence in a multiracial cohort of children with acute lymphoblastic leukemia: a Children’s Oncology Group study
. Blood
. 2014
;124
(15
):2345
-2353
.7.
Bhatia
S
, Landier
W
, Hageman
L
, et al. Systemic exposure to thiopurines and risk of relapse in children with acute lymphoblastic leukemia: a children’s oncology group study
. JAMA Oncol
. 2015
;1
(3
):287
-295
.8.
Bhatia
S
. Understanding causes of inferior survival in adolescent and young adults with acute lymphoblastic leukemia [abstract]
. Cancer Epidemiol Biomarkers Prev
. 2020
;29
(suppl_12
). Abstract IA22.9.
Childhood ALL Collaborative Group
. Duration and intensity of maintenance chemotherapy in acute lymphoblastic leukaemia: overview of 42 trials involving 12,000 randomised children
. Lancet
. 1996
;347
(9018
):1783
-1788
.10.
Eden
TOB
, Pieters
R
, Richards
S
; Childhood acute lymphoblastic leukaemia collaborative group CALLCG
. systematic review of the addition of vincristine plus steroid pulses in maintenance treatment for childhood acute lymphoblastic leukaemia - an individual patient data meta-analysis involving 5659 children
. Br J Haematol
. 2010
;149
(5
):722
-733
.11.
Conter
V
, Valsecchi
MG
, Silvestri
D
, et al. Pulses of vincristine and dexamethasone in addition to intensive chemotherapy for children with intermediate-risk acute lymphoblastic leukaemia: a multicentre randomised trial
. Lancet
. 2007
;369
(9556
):123
-131
.12.
Angiolillo
AL
, Schore
RJ
, Kairalla
JA
, et al. Excellent outcomes with reduced frequency of vincristine and dexamethasone pulses in standard-risk b-lymphoblastic leukemia: results from children’s oncology group AALL0932
. J Clin Oncol
. 2021
;39
(13
):1437
-1447
.13.
Yang
W
, Cai
J
, Shen
S
, et al. Pulse therapy with vincristine and dexamethasone for childhood acute lymphoblastic leukaemia (CCCG-ALL-2015): an open-label, multicentre, randomised, phase 3, non-inferiority trial
. Lancet Oncol
. 2021
;22
(9
):1322
-1332
.14.
Lange
BJ
, Blatt
J
, Sather
HN
, Meadows
AT
. Randomized comparison of moderate-dose methotrexate infusions to oral methotrexate in children with intermediate risk acute lymphoblastic leukemia: a childrens cancer group study
. Med Pediatr Oncol
. 1996
;27
(1
):15
-20
.15.
Janka-Schaub
GE
, Winkler
K
, Jurgens
H
, Goebel
U
, Gutjahr
P
, Spaar
HJ
. Intermediate-dose methotrexate in the treatment of childhood acute lymphocytic leukaemia: lack of benefit during maintenance therapy following intensive induction therapy
. Eur J Pediatr
. 1986
;145
(1-2
):14
-17
.16.
Nagatoshi
Y
, Matsuzaki
A
, Suminoe
A
, et al. Randomized trial to compare LSA2L2-type maintenance therapy to daily 6-mercaptopurine and weekly methotrexate with vincristine and dexamethasone pulse for children with acute lymphoblastic leukemia
. Pediatr Blood Cancer
. 2010
;55
(2
):239
-247
.17.
Felice
MS
, Rossi
JG
, Gallego
MS
, et al. No advantage of a rotational continuation phase in acute lymphoblastic leukemia in childhood treated with a BFM back-bone therapy
. Pediatr Blood Cancer
. 2011
;57
(1
):47
-55
.18.
Sackmann Muriel
F
, Svarch
E
, Pavlovsky
S
, et al. Alternating pulses of vincristine-prednisone with cytarabine-cyclophosphamide vs vincristine-prednisone in the maintenance therapy of acute lymphoblastic leukemia
. Cancer Treat Rep
. 1984
;68
(4
):581
-586
.19.
Bancillon
A
. Traitement des leucemies aigues lymphoblastiques de l’enfant. Resultats du protocole FRALLE 83
. Arch Fr Pediatr
. 1991
;48
(8
):593
-594
.20.
Tierney
JF
, Stewart
LA
, Ghersi
D
, Burdett
S
, Sydes
MR
. Practical methods for incorporating summary time-to-event data into meta-analysis
. Trials
. 2007
;8
:16
.21.
Sterne
JAC
, Savović
J
, Page
MJ
, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials
. BMJ
. 2019
;366
:l4898
.22.
McGuinness
LA
, Higgins
JPT
. Risk-of-bias VISualization (robvis): an R package and Shiny web app for visualizing risk-of-bias assessments
. Res Syn Meth
. 2021
;12
(1
):55
-61
.23.
Higgins
JPT
, Thompson
SG
, Deeks
JJ
, Altman
DG
. Measuring inconsistency in meta-analyses
. BMJ
. 2003
;327
(7414
):557
-560
.24.
Richardson
M
, Garner
P
, Donegan
S
. Interpretation of subgroup analyses in systematic reviews: A tutorial
. Clin Epidemiol Glob Health
. 2019
;7
(2
):192
-198
.25.
In:
Schunemann
H
, Brozek
J
, Guyatt
G
, Oxman
A
, eds. GRADE handbook: handbook for grading the quality of the evidence and the strength of recommendations using the GRADE approach
. GRADE Working Group
; 2013
https://gdt.gradepro.org/app/handbook/handbook.html#h.hnedbo8gqjqk.26.
Riehm
H
, Gadner
H
, Henze
G
, et al. Results and significance of six randomized trials in four consecutive ALL-BFM studies. In: Büchner
T
, Schellong
G
, Hiddemann
W
, Ritter
J
, eds. Acute Leukemias II. Haematology and Blood Transfusion/Hämatologie und Bluttransfusion
. Springer
; 1990
:439
-450
.27.
Möricke
A
, Zimmermann
M
, Reiter
A
, et al. Long-term results of five consecutive trials in childhood acute lymphoblastic leukemia performed by the ALL-BFM study group from 1981 to 2000
. Leukemia
. 2010
;24
(2
):265
-284
.28.
Karachunskiy
A
, Herold
R
, von Stackelberg
A
, et al. Results of the first randomized multicentre trial on childhood acute lymphoblastic leukaemia in Russia
. Leukemia
. 2008
;22
(6
):1144
-1153
.29.
Page
MJ
, McKenzie
JE
, Bossuyt
PM
, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews
. BMJ
. 2021
;372
:n71
.30.
Schmiegelow
K
, Forestier
E
, Hellebostad
M
, et al. Long-term results of NOPHO ALL-92 and ALL-2000 studies of childhood acute lymphoblastic leukemia
. Leukemia
. 2010
;24
(2
):345
-354
.31.
Koh
K
, Kato
M
, Saito
AM
, et al. Phase II/III study in children and adolescents with newly diagnosed B-cell precursor acute lymphoblastic leukemia: protocol for a nationwide multicenter trial in Japan
. Jpn J Clin Oncol
. 2018
;48
(7
):684
-691
.32.
JPRN-UMIN000009339.
Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) ALL-B12: a multi-center phase II/III study in children with newly diagnosed B-cell precursor acute lymphoblastic leukemia. 2012
. Updated 24 November 2022. Accessed 9 March 2023. https://trialsearch.who.int/Trial2.aspx?TrialID=JPRN-UMIN000009339.33.
ISRCTN64515327.
United Kingdom trial for children and young adults with acute lymphoblastic leukaemia and lymphoma 2011
. 2011. Updated 16 March 2023. https://trialsearch.who.int/Trial2.aspx?TrialID=ISRCTN64515327.34.
Fernbach
DJ
, George
SL
, Sutow
WW
, et al. Long-term results of reinforcement therapy in children with acute leukemia
. Cancer
. 1975
;36
(5
):1552
-1559
.35.
Aur
RJA
, Hustu
HO
, Verzosa
MS
, Wood
A
, Simone
JV
. Comparison of two methods of preventing central nervous system leukemia
. Blood
. 1973
;42
(3
):349
-357
.36.
Ortega
JJ
, Javier
G
, Montagut
JM
, Toran
N
. Leucemia aguda linfoblastica en ninos. Largas supervivencias obtenidas con los protocolos C2-72 y D-74 (1972-1977)
. An Esp Pediatr
. 1986
;24
(2
):87
-97
.37.
van der Does-van den Berg
A
, De Koning
J
, Reerink
H
, de Vries
JA
, van Zanen
GE
. Acute lymphocytic leukaemia in childhood in the Netherlands; study ALL I, 1972-1973 [in Dutch]
. Ned Tijdschr Geneeskd
. 1975
;119
(38
):1445
-1451
.38.
Bleyer
WA
, Coccia
PF
, Sather
HN
, et al. Reduction in central nervous system leukemia with a pharmacokinetically derived intrathecal methotrexate dosage regimen
. J Clin Oncol
. 1983
;1
(5
):317
-325
.39.
Bleyer
WA
, Sather
HN
, Nickerson
HJ
, et al. Monthly pulses of vincristine and prednisone prevent bone marrow and testicular relapse in low-risk childhood acute lymphoblastic leukemia: a report of the CCG-161 study by the Childrens Cancer Study Group
. J Clin Oncol
. 1991
;9
(6
):1012
-1021
.40.
Henze
G
, Langermann
HJ
, Brämswig
J
, et al. Ergebnisse der Studie BFM 76/79 zur Behandlung der Akuten Lymphoblastischen Leukämie bei Kindern und Jugendlichen
. Klin Pädiatr
. 1981
;193
(3
):145
-154
.41.
Lange
BJ
, Bostrom
BC
, Cherlow
JM
, et al. Double-delayed intensification improves event-free survival for children with intermediate-risk acute lymphoblastic leukemia: a report from the Children’s Cancer Group
. Blood
. 2002
;99
(3
):825
-833
.42.
Burger
B
, Beier
R
, Zimmermann
M
, Beck
JD
, Reiter
A
, Schrappe
M
. Osteonecrosis: a treatment related toxicity in childhood acute lymphoblastic leukemia (ALL) - experiences from trial ALL-BFM 95
. Pediatr Blood Cancer
. 2005
;44
(3
):220
-225
.43.
Aricò
M
, Boccalatte
MFP
, Silvestri
D
, et al. Osteonecrosis: an emerging complication of intensive chemotherapy for childhood acute lymphoblastic leukemia
. Haematologica
. 2003
;88
(7
):747
-753
.44.
De Moerloose
B
, Suciu
S
, Bertrand
Y
, et al. Improved outcome with pulses of vincristine and corticosteroids in continuation therapy of children with average risk acute lymphoblastic leukemia (ALL) and lymphoblastic non-Hodgkin lymphoma (NHL): report of the EORTC randomized phase 3 trial 58951
. Blood
. 2010
;116
(1
):36
-44
.45.
Schore
RJ
, Angiolillo
AJ
, Kairalla
JA
, et al. Outcomes with reduced intensity therapy in a low-risk subset of children with National Cancer Institute (NCI) standard-risk (SR) B-lymphoblastic leukemia (B-ALL): A report from Children’s Oncology Group (COG) AALL0932
. J Clin Oncol
. 2020
;38
(suppl 15
):10509
.46.
Van der Does-Van den Berg
A
, Veerman
AJP
, Van Wering
ER
, et al. Childhood acute lymphoblastic leukemia in the Netherlands
. Int J Pediatr Hematol
. 1998
;5
(2-4
):125
-139
.47.
Zheng
DJ
, Lu
X
, Schore
RJ
, et al. Longitudinal analysis of quality of life outcomes in children during treatment for acute lymphoblastic leukemia: a report from the Children’s Oncology Group (COG) AAL0932
. Cancer
. 2018
;124
(3
):571
-579
.48.
Aricò
M
, Valsecchi
MG
, Rizzari
C
, et al. Long-term results of the AIEOP-ALL-95 trial for childhood acute lymphoblastic leukemia: insight on the prognostic value of DNA index in the framework of Berlin-Frankfurt-Muenster based chemotherapy
. J Clin Oncol
. 2008
;26
(2
):283
-289
.49.
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
.50.
Bhatia
S
. Late effects among survivors of leukemia during childhood and adolescence
. Blood Cells Mol Dis
. 2003
;31
(1
):84
-92
.51.
Mody
R
, Li
S
, Dover
DC
, et al. Twenty-five-year follow-up among survivors of childhood acute lymphoblastic leukemia: a report from the Childhood Cancer Survivor study
. Blood
. 2008
;111
(12
):5515
-5523
.52.
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
.53.
Al-Saadi
LS
, Chan
MF
, Al-Azri
M
. Prevalence of anxiety, depression, and post-traumatic stress disorder among children and adolescents with cancer: a systematic review and meta-analysis
. J Pediatr Hematol Oncol Nurs
. 2022
;39
(2
):114
-131
.54.
Mitchell
HR
, Lu
X
, Myers
RM
, et al. Prospective, longitudinal assessment of quality of life in children from diagnosis to 3 months off treatment for standard risk acute lymphoblastic leukemia: results of Children’s Oncology Group study AALL0331
. Int J Cancer
. 2016
;138
(2
):332
-339
.55.
Myers
RM
, Balsamo
L
, Lu
X
, et al. A prospective study of anxiety, depression, and behavioral changes in the first year after a diagnosis of childhood acute lymphoblastic leukemia: a report from the Children’s Oncology Group
. Cancer
. 2014
;120
(9
):1417
-1425
.56.
Teachey
DT
, Hunger
SP
, Loh
ML
. Optimizing therapy in the modern age: differences in length of maintenance therapy in acute lymphoblastic leukemia
. Blood
. 2021
;137
(2
):168
-177
.57.
Kato
M
, Ishimaru
S
, Seki
M
, et al. Long-term outcome of 6-month maintenance chemotherapy for acute lymphoblastic leukemia in children
. Leukemia
. 2017
;31
(3
):580
-584
.58.
Al-Mahayri
ZN
, AlAhmad
MM
, Ali
BR
. Long-term effects of pediatric acute lymphoblastic leukemia chemotherapy: can recent findings inform old strategies?
. Front Oncol
. 2021
;11
:710163
.59.
Hinze
L
, Möricke
A
, Zimmermann
M
, et al. Prognostic impact of IKZF1 deletions in association with vincristine-dexamethasone pulses during maintenance treatment of childhood acute lymphoblastic leukemia on trial ALL-BFM 95
. Leukemia
. 2017
;31
(8
):1840
-1842
.60.
Clappier
E
, Grardel
N
, Bakkus
M
, et al. IKZF1 deletion is an independent prognostic marker in childhood B-cell precursor acute lymphoblastic leukemia, and distinguishes patients benefiting from pulses during maintenance therapy: results of the EORTC Children’s Leukemia Group study 58951
. Leukemia
. 2015
;29
(11
):2154
-2161
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