Abstract

Observational findings demonstrating improved survival for younger adults following pediatric, as opposed to adult, acute lymphoblastic leukemia (ALL) regimens have been translated into international, prospective multicenter clinical trials testing the pediatric regimen in young adult ALL. The results of these studies confirm the feasibility of delivering the pediatric regimen in the adult oncology setting and establish the superiority of this approach relative to historical adult cooperative group regimen results. Specific toxicities, including thrombosis, hepatotoxicity, and osteonecrosis, are more prevalent in adults receiving the pediatric regimen relative to young children. Persistent minimal residual disease (MRD) is a strong prognostic indicator in adults receiving the pediatric regimen; sensitive, high-quality MRD evaluation should be performed in all patients receiving these therapies. Incorporation of targeted agents, particularly in the frontline and MRD+ setting, will usher in the next era of the pediatric regimen in adult ALL.

References

References
1.
Coustan-Smith
E
,
Mullighan
CG
,
Onciu
M
, et al
.
Early T-cell precursor leukaemia: a subtype of very high-risk acute lymphoblastic leukaemia
.
Lancet Oncol
.
2009
;
10
(
2
):
147
-
156
.
2.
Jain
N
,
Lamb
AV
,
O’Brien
S
, et al
.
Early T-cell precursor acute lymphoblastic leukemia/lymphoma (ETP-ALL/LBL) in adolescents and adults: a high-risk subtype
.
Blood
.
2016
;
127
(
15
):
1863
-
1869
.
3.
Bond
J
,
Graux
C
,
Lhermitte
L
, et al
.
Early response-based therapy stratification improves survival in adult early thymic precursor acute lymphoblastic leukemia: a Group for Research on Adult Acute Lymphoblastic Leukemia study
.
J Clin Oncol
.
2017
;
35
(
23
):
2683
-
2691
.
4.
Liu
Y
,
Easton
J
,
Shao
Y
, et al
.
The genomic landscape of pediatric and young adult T-lineage acute lymphoblastic leukemia
.
Nat Genet
.
2017
;
49
(
8
):
1211
-
1218
.
5.
Steinherz
PG
,
Seibel
NL
,
Sather
H
, et al
.
Treatment of higher risk acute lymphoblastic leukemia in young people (CCG-1961), long-term follow-up: a report from the Children’s Oncology Group [published online ahead of print 28 February 2019]
.
Leukemia
.
doi:10.1038/s41375-019-0422-z
.
6.
Stock
W
,
Luger
SM
,
Advani
AS
, et al
.
A pediatric regimen for older adolescents and young adults with acute lymphoblastic leukemia: results of CALGB 10403
.
Blood
.
2019
;
133
(
14
):
1548
-
1559
.
7.
Gaynon
PS
,
Angiolillo
AL
,
Carroll
WL
, et al
;
Children’s Oncology Group
.
Long-term results of the Children’s Cancer Group studies for childhood acute lymphoblastic leukemia 1983-2002: a Children’s Oncology Group report
.
Leukemia
.
2010
;
24
(
2
):
285
-
297
.
8.
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
.
9.
Silverman
LB
,
Stevenson
KE
,
O’Brien
JE
, et al
.
Long-term results of Dana-Farber Cancer Institute ALL Consortium protocols for children with newly diagnosed acute lymphoblastic leukemia (1985-2000)
.
Leukemia
.
2010
;
24
(
2
):
320
-
334
.
10.
Pui
CH
,
Pei
D
,
Sandlund
JT
, et al
.
Long-term results of St Jude Total Therapy Studies 11, 12, 13A, 13B, and 14 for childhood acute lymphoblastic leukemia
.
Leukemia
.
2010
;
24
(
2
):
371
-
382
.
11.
Conter
V
,
Aricò
M
,
Basso
G
, et al
;
Associazione Italiana di Ematologia ed Oncologia Pediatrica
.
Long-term results of the Italian Association of Pediatric Hematology and Oncology (AIEOP) Studies 82, 87, 88, 91 and 95 for childhood acute lymphoblastic leukemia
.
Leukemia
.
2010
;
24
(
2
):
255
-
264
.
12.
Stock
W
,
Johnson
JL
,
Stone
RM
, et al
.
Dose intensification of daunorubicin and cytarabine during treatment of adult acute lymphoblastic leukemia: results of Cancer and Leukemia Group B Study 19802 [published correction appears in Cancer. 2014;120(14):2222]
.
Cancer
.
2013
;
119
(
1
):
90
-
98
.
13.
Goldstone
AH
,
Richards
SM
,
Lazarus
HM
, et al
.
In adults with standard-risk acute lymphoblastic leukemia, the greatest benefit is achieved from a matched sibling allogeneic transplantation in first complete remission, and an autologous transplantation is less effective than conventional consolidation/maintenance chemotherapy in all patients: final results of the International ALL Trial (MRC UKALL XII/ECOG E2993)
.
Blood
.
2008
;
111
(
4
):
1827
-
1833
.
14.
Rytting
ME
,
Thomas
DA
,
O’Brien
SM
, et al
.
Augmented Berlin-Frankfurt-Münster therapy in adolescents and young adults (AYAs) with acute lymphoblastic leukemia (ALL)
.
Cancer
.
2014
;
120
(
23
):
3660
-
3668
.
15.
Stock
W
,
La
M
,
Sanford
B
, et al
;
Cancer and Leukemia Group B studies
.
What determines the outcomes for adolescents and young adults with acute lymphoblastic leukemia treated on cooperative group protocols? A comparison of Children’s Cancer Group and Cancer and Leukemia Group B studies
.
Blood
.
2008
;
112
(
5
):
1646
-
1654
.
16.
Boissel
N
,
Auclerc
MF
,
Lhéritier
V
, et al
.
Should adolescents with acute lymphoblastic leukemia be treated as old children or young adults? Comparison of the French FRALLE-93 and LALA-94 trials
.
J Clin Oncol
.
2003
;
21
(
5
):
774
-
780
.
17.
Larsen
EC
,
Devidas
M
,
Chen
S
, et al
.
Dexamethasone and high-dose methotrexate improve outcome for children and young adults with high-risk B-acute lymphoblastic leukemia: a report from Children’s Oncology Group study AALL0232
.
J Clin Oncol
.
2016
;
34
(
20
):
2380
-
2388
.
18.
Huguet
F
,
Chevret
S
,
Leguay
T
, et al
;
Group of Research on Adult ALL (GRAALL)
.
Intensified therapy of acute lymphoblastic leukemia in adults: report of the randomized GRAALL-2005 clinical trial
.
J Clin Oncol
.
2018
;
36
(
24
):
2514
-
2523
.
19.
Huguet
F
,
Leguay
T
,
Raffoux
E
, et al
.
Pediatric-inspired therapy in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia: the GRAALL-2003 study [published correction appears in J Clin Oncol. 2009;27(15):2574]
.
J Clin Oncol
.
2009
;
27
(
6
):
911
-
918
.
20.
DeAngelo
DJ
,
Stevenson
KE
,
Dahlberg
SE
, et al
.
Long-term outcome of a pediatric-inspired regimen used for adults aged 18-50 years with newly diagnosed acute lymphoblastic leukemia
.
Leukemia
.
2015
;
29
(
3
):
526
-
534
.
21.
Toft
N
,
Birgens
H
,
Abrahamsson
J
, et al
.
Results of NOPHO ALL2008 treatment for patients aged 1-45 years with acute lymphoblastic leukemia
.
Leukemia
.
2018
;
32
(
3
):
606
-
615
.
22.
Siegel
SE
,
Stock
W
,
Johnson
RH
, et al
.
Pediatric-inspired treatment regimens for adolescents and young adults with Philadelphia chromosome-negative acute lymphoblastic leukemia: a review
.
JAMA Oncol
.
2018
;
4
(
5
):
725
-
734
.
23.
Siegel
SE
,
Advani
A
,
Seibel
N
, et al
.
Treatment of young adults with Philadelphia-negative acute lymphoblastic leukemia and lymphoblastic lymphoma: hyper-CVAD vs. pediatric-inspired regimens
.
Am J Hematol
.
2018
;
93
(
10
):
1254
-
1266
.
24.
Rytting
ME
,
Jabbour
EJ
,
Jorgensen
JL
, et al
.
Final results of a single institution experience with a pediatric-based regimen, the augmented Berlin-Frankfurt-Münster, in adolescents and young adults with acute lymphoblastic leukemia, and comparison to the hyper-CVAD regimen
.
Am J Hematol
.
2016
;
91
(
8
):
819
-
823
.
25.
Alabdulwahab
AS
,
Elsayed
HG
,
Sherisher
MA
,
Zeeneldin
A
,
Alghamdi
K
,
Elbjeirami
WM
.
The Dana Farber consortium protocol (DFCP) vs. classic hyper-CVAD for treatment of acute lymphoblastic leukemia in patients <50 Y. Single institution experience
.
Leuk Res
.
2017
;
60
:
58
-
62
.
26.
Kozlowski
P
,
Åström
M
,
Ahlberg
L
, et al
;
Swedish Adult ALL Group
.
High relapse rate of T cell acute lymphoblastic leukemia in adults treated with hyper-CVAD chemotherapy in Sweden
.
Eur J Haematol
.
2014
;
92
(
5
):
377
-
381
.
27.
Douer
D
,
Aldoss
I
,
Lunning
MA
, et al
.
Pharmacokinetics-based integration of multiple doses of intravenous pegaspargase in a pediatric regimen for adults with newly diagnosed acute lymphoblastic leukemia
.
J Clin Oncol
.
2014
;
32
(
9
):
905
-
911
.
28.
Stock
W
,
Douer
D
,
DeAngelo
DJ
, et al
.
Prevention and management of asparaginase/pegasparaginase-associated toxicities in adults and older adolescents: recommendations of an expert panel
.
Leuk Lymphoma
.
2011
;
52
(
12
):
2237
-
2253
.
29.
Grose
K
,
Sen
JM
,
Morris
AL
, et al
.
Decrease of asparaginase induced thrombotic events with antithrombin III monitoring and repletion [abstract]
.
Blood
.
2018
;
132
(
suppl 1
):
1381
.
30.
Farrell
K
,
Fyfe
A
,
Allan
J
,
Tait
RC
,
Leach
M
.
An antithrombin replacement strategy during asparaginase therapy for acute lymphoblastic leukemia is associated with a reduction in thrombotic events
.
Leuk Lymphoma
.
2016
;
57
(
11
):
2568
-
2574
.
31.
Rausch
CR
,
Paul
S
,
Marx
KR
, et al
.
L-carnitine and vitamin B complex for the treatment of pegasparaginase-induced hyperbilirubinemia
.
Clin Lymphoma Myeloma Leuk
.
2018
;
18
(
5
):
e191
-
e195
.
32.
Berry
DA
,
Zhou
S
,
Higley
H
, et al
.
Association of minimal residual disease with clinical outcome in pediatric and adult acute lymphoblastic leukemia: a meta-analysis
.
JAMA Oncol
.
2017
;
3
(
7
):
e170580
.
33.
Short
NJ
,
Jabbour
E
,
Albitar
M
, et al
.
Recommendations for the assessment and management of measurable residual disease in adults with acute lymphoblastic leukemia: a consensus of North American experts
.
Am J Hematol
.
2019
;
94
(
2
):
257
-
265
.
34.
Wood
B
,
Wu
D
,
Crossley
B
, et al
.
Measurable residual disease detection by high-throughput sequencing improves risk stratification for pediatric B-ALL
.
Blood
.
2018
;
131
(
12
):
1350
-
1359
.
35.
Curran
E
,
Stock
W
.
Taking a “BiTE out of ALL”: blinatumomab approval for MRD-positive ALL
.
Blood
.
2019
;
133
(
16
):
1715
-
1719
.
36.
Gökbuget
N
,
Dombret
H
,
Bonifacio
M
, et al
.
Blinatumomab for minimal residual disease in adults with B-cell precursor acute lymphoblastic leukemia
.
Blood
.
2018
;
131
(
14
):
1522
-
1531
.
37.
Dhédin
N
,
Huynh
A
,
Maury
S
, et al
;
GRAALL group
.
Role of allogeneic stem cell transplantation in adult patients with Ph-negative acute lymphoblastic leukemia
.
Blood
.
2015
;
125
(
16
):
2486
-
2496
.
38.
Sutton
R
,
Shaw
PJ
,
Venn
NC
, et al
.
Persistent MRD before and after allogeneic BMT predicts relapse in children with acute lymphoblastic leukaemia
.
Br J Haematol
.
2015
;
168
(
3
):
395
-
404
.
39.
Leung
W
,
Pui
CH
,
Coustan-Smith
E
, et al
.
Detectable minimal residual disease before hematopoietic cell transplantation is prognostic but does not preclude cure for children with very-high-risk leukemia
.
Blood
.
2012
;
120
(
2
):
468
-
472
.
40.
Logan
AC
,
Vashi
N
,
Faham
M
, et al
.
Immunoglobulin and T cell receptor gene high-throughput sequencing quantifies minimal residual disease in acute lymphoblastic leukemia and predicts post-transplantation relapse and survival
.
Biol Blood Marrow Transplant
.
2014
;
20
(
9
):
1307
-
1313
.
41.
Pui
CH
,
Campana
D
,
Pei
D
, et al
.
Treating childhood acute lymphoblastic leukemia without cranial irradiation
.
N Engl J Med
.
2009
;
360
(
26
):
2730
-
2741
.
42.
Winter
SS
,
Dunsmore
KP
,
Devidas
M
, et al
.
Improved survival for children and young adults with T-lineage acute lymphoblastic leukemia: results from the Children’s Oncology Group AALL0434 methotrexate randomization
.
J Clin Oncol
.
2018
;
36
(
29
):
2926
-
2934
.
43.
Kelly
MJ
,
Pauker
SG
,
Parsons
SK
.
Using nonrandomized studies to inform complex clinical decisions: the thorny issue of cranial radiation therapy for T-cell acute lymphoblastic leukemia
.
Pediatr Blood Cancer
.
2015
;
62
(
5
):
790
-
797
.
44.
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
.
45.
Schmiegelow
K
,
Heyman
M
,
Gustafsson
G
, et al
;
Nordic Society of Paediatric Haematology and Oncology (NOPHO)
.
The degree of myelosuppression during maintenance therapy of adolescents with B-lineage intermediate risk acute lymphoblastic leukemia predicts risk of relapse
.
Leukemia
.
2010
;
24
(
4
):
715
-
720
.
46.
Baker
KS
,
Syrjala
KL
.
Long-term complications in adolescent and young adult leukemia survivors
.
Hematology Am Soc Hematol Educ Program
.
2018
;
2018
:
146
-
153
.
47.
Muffly
L
,
Alvarez
E
,
Lichtensztajn
D
,
Abrahão
R
,
Gomez
SL
,
Keegan
T
.
Patterns of care and outcomes in adolescent and young adult acute lymphoblastic leukemia: a population-based study
.
Blood Adv
.
2018
;
2
(
8
):
895
-
903
.
48.
Muffly
L
,
Li
Q
,
Alvarez
E
, et al
.
Hematopoietic cell transplantation in young adult acute lymphoblastic leukemia: a United States population-level analysis
.
J Adolesc Young Adult Oncol
.
2019
;
8
(
3
):
254
-
261
.
49.
Wolfson
J
,
Sun
CL
,
Wyatt
L
,
Stock
W
,
Bhatia
S
.
Adolescents and young adults with acute lymphoblastic leukemia and acute myeloid leukemia: impact of care at specialized cancer centers on survival outcome
.
Cancer Epidemiol Biomarkers Prev
.
2017
;
26
(
3
):
312
-
320
.
50.
Advani
AS
,
Copelan
EA
.
Navigating the nexus of MRD and novel agents in ALL
.
Hematology Am Soc Hematol Educ Program
.
2019
;
2019
:
9
-
16
.
51.
Winter
SS
,
Dunsmore
KP
,
Devidas
M
, et al
.
Safe integration of nelarabine into intensive chemotherapy in newly diagnosed T-cell acute lymphoblastic leukemia: Children’s Oncology Group study AALL0434
.
Pediatr Blood Cancer
.
2015
;
62
(
7
):
1176
-
1183
.
52.
Dunsmore
KP
,
Winter
S
,
Devidas
M
, et al
.
COG AALL0434: a randomized trial testing nelarabine in newly diagnosed T-cell malignancy [abstract]
.
J Clin Oncol
.
2018
;
36
(
suppl 15
):
10500
.
53.
DeAngelo
DJ
,
Yu
D
,
Johnson
JL
, et al
.
Nelarabine induces complete remissions in adults with relapsed or refractory T-lineage acute lymphoblastic leukemia or lymphoblastic lymphoma: Cancer and Leukemia Group B study 19801
.
Blood
.
2007
;
109
(
12
):
5136
-
5142
.
54.
Abaza
Y
,
M Kantarjian
H
,
Faderl
S
, et al
.
Hyper-CVAD plus nelarabine in newly diagnosed adult T-cell acute lymphoblastic leukemia and T-lymphoblastic lymphoma
.
Am J Hematol
.
2018
;
93
(
1
):
91
-
99
.
55.
Ribera
JM
,
Oriol
A
,
Sanz
MA
, et al
.
Comparison of the results of the treatment of adolescents and young adults with standard-risk acute lymphoblastic leukemia with the Programa Español de Tratamiento en Hematología pediatric-based protocol ALL-96
.
J Clin Oncol
.
2008
;
26
(
11
):
1843
-
1849
.
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