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Pediatric acute lymphoblastic leukemia
incidence of malignancy in general. Familial predisposition specific to leukemia is uncommon but has resulted in the identification of predisposing non-silent variants that are also observed in sporadic ALL cases, including TP53 germline mutations and low hypodiploid B-ALL, ETV6 variants and hyperdiploid ALL, and PAX5 mutations and B-ALL with dicentric/isochromosome 9.10-13 These suscep-
tibility genes are targets of somatic mutation in ALL: ETV6 and PAX5 are rearranged, amplified/deleted, and mutated in B-ALL,14,15 as is TP53 in hypodiploid ALL.10 Germline variants of IKZF1 are observed in familial B-ALL and immunodeficiency,16,17 and somatic IKZF1 alterations are enriched in Philadelphia chromosome (Ph)-positive, Ph- like, and DUX4-rearranged B-ALL.18-20 RUNX1 germline
Table 1A. Treatment results for acute lymphoblastic leukemia in major pediatric clinical trials.
Study Years Subtype of study
Age Patients (y) (n)
1-17 3720 (randomized
pts)
1-30 2979
1-9 5377
1-30 1562
1-18 551
1-18 778
1-24 3126
1-45 1509
0-18 598
Steroid during induction (mg/m2/day)
Pred 60 (1867 pts) /Dex 10 (1853 pts) [R]
Pred 60 (427 pts)/ Dex 10 (424 pts)
MTX (g/m2 /dose)
5
HD-MTX 5 (1282 pts)/ C-MTX (1291 pts)
Cranial Complete irradiation remission
Cumulative incidence of relapse (5y, %) (SE or 95% CI)
Pred: 15.6 (0.8) Dex: 10.8 (0.7) (P<0.001)
HD-MTX: 136 pts C-MTX: 183 pts
124 of 3992 pts who continued post- induction
HD-MTX: 59 pts C-MTX: 32 pts
51 of 551 total 41 of 463 pts randomized PEG: 20 of 232 Native: 21 of 231
8.3 (1.0)
8.8
(7.8-9.8) (2.1-3.3)
AIEOP/BFM ALL 2000
COG AALL0232
COG AALL0331
COG AALL0434
DFCI ALL Consortium Protocol 05-001
DCOG ALL10
MRC UK ALL 2003
NOPHO ALL2008
SJCRH
Total XVI
2000-2006
2004-2011
2005-2010
2007-2014
2005-2010
2004-2012
2003-2011
2008-2014
2007-2017
BandT
B, HR
B, SR
T
BandT
BandT
BandT
BandT
BandT
[R] [R]
HR/T /CNS3
SER/ CNS3
CNS3
IR/HR
CNS3/T/B
with WBC ≥100k/VHR
>3y and HR who do not receive HCT
(%)
Pred: 97.8 Dex: 97.8 (P=1.00)
NA
98.0
NA
95.5
98.0
98.9
91.2
98.7
Death in remission (5y, %) (SE or 95% CI)
Pred: 1.7 Dex: 2.3 (P=0.24)
HD-MTX: 24 pts C-MTX: 25 pts (P=0.90)
25 of 3992 pts who continued post-
induction
HD-MTX: 11 pts C-MTX: 8 pts
2 of 551 total
2.6
Event-free survival (5y, %) (SE or 95% CI)
Pred: 80.8 (0.9) Dex: 83.9 (0.9) (P=0.024)
75.3 (1.1) HD-MTX: 79.6 (1.6) C-MTX: 75.2 (1.7) (P=0.008)
88.96 (0.46) (6y)
83.8 (81.2-86.4) (5y DFS) HD-MTX: 85.3 (81.0-89.5) C-MTX: 91.5 (88.1-94.8) (P=0.005)
85 (82-88) (5y DFS) PEG: 90 (86-94) Native: 89 (85-93) (P=0.58)
87.0 (1.2)
87.3 (86.1-88.5)
85 (1)
88.2
Overall survival (5y, %) (SE or 95% CI)
Pred: 90.5 (0.7) Dex: 90.3 (0.7) (P=0.61)
85.0 (0.9) HD-MTX: 88.9 (1.2) C-MTX: 86.1 (1.4) (P=0.025)
95.54 (0.31) (6y)
89.5 (87.4-91.7) HD-MTX: 89.4 (85.7-93.2) C-MTX: 93.7 (90.8-96.6) (P=0.036)
91 (88-93) PEG: 96 (93-98) Native: 94 (89-96) (P=0.30)
91.9 (1.0)
91.6 (90.6-92.6)
91 (1)
94.1
(aged 1-9 y) Dex 6
Pred 60
Pred 40
Pred 60
Dex 6
Pred 60
or Dex 10 (T/WBC≥100k)
Pred 40
0.1 (and escalating) with or without asparaginase
HD-MTX 5 (512 pts)/ C-MTX (519 pts) [R]
5
5
0.02 (SR/IR), C-MTX (HR)
CNS3 (until 2009)
None
None
2.7
5
2.5 (LR), 5
10 (1)
6.6
3 (0)
2.7
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(SR/HR)
(4.4-8.7)
(1.4-4.0)
(84.9-91.5)
(91.7-96.5)
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