acute lymphoblastic leukemia in children

8/19/2019 Acute Lymphoblastic Leukemia in Children.

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T he n e w e n g l a n d j o u r n a l o f medicine

n engl j med 373;16 nejm.org October 15, 2015 1541

Review Article

Approximately 6000 cases of acute lymphoblastic leukemia (ALL)

are diagnosed in the United States annually; half the cases occur in chil-dren and teenagers. In the United States, ALL is the most common cancer

among children and the most frequent cause of death from cancer before 20 yearsof age.1,2 Presenting symptoms of ALL include bruising or bleeding due to thrombo-cytopenia, pallor and fatigue from anemia, and infection caused by neutropenia.Leukemic infiltration of the liver, spleen, lymph nodes, and mediastinum is com-mon at diagnosis. Extramedullary leukemia in the central nervous system (CNS)

or testicles may require specific modifications in therapy.Since the first description in 1948 of temporary remission of leukemia inducedby chemotherapy,3 pediatric ALL has provided a model for improvement of survivalamong patients with cancer by progressive improvements in the efficacy of multi-agent chemotherapy regimens and by stratif ication of treatment intensity accordingto the clinical features of the patient, the biologic features of the leukemia cells,and the early response to treatment, all of which are predictive of the risk of re-lapse. Collectively, these advances have increased the survival rate from less than10% in the 1960s to 90% today (Fig. 1). New discoveries are revealing the promiseand challenges of precision-medicine strategies that integrate leukemia genomicsinto contemporary therapy.

Epidemiology and R isk Factors

In the United States, the incidence of ALL is about 30 cases per million persons younger than 20 years of age, with the peak incidence occurring at 3 to 5 years of age.4 The incidence varies significantly according to race and ethnic group: 14.8 cases permillion blacks, 35.6 cases per million whites, and 40.9 cases per million Hispan-ics.5 Childhood ALL develops more frequently in boys than in girls (male:femaleratio, 55% to 45%).

Several genetic factors (most prominently Down’s syndrome6) are associated with an increased risk of ALL, but most patients have no recognized inheritedfactors. Genomewide association studies have identified polymorphic variants inseveral genes (including ARID5B, CEBPE , GATA3, and IKZF1) that are associated with

an increased risk of ALL or specific ALL subtypes.7-9 Rare germline mutations inPAX5 and ETV6 are linked to familial ALL.10,11 Few environmental risk factors areassociated with ALL in children. Increased rates of the disease have been linkedto exposure to radiation and certain chemicals, but these associations explain onlya very small minority of cases.

Genetic Basis of ALL

ALL comprises multiple entities with distinct constellations of somatic geneticalterations (Fig. 2).12 These genetic alterations include aneuploidy (changes in chro-

From the Division of Oncology and Cen-ter for Childhood Cancer Research, Chil-dren’s Hospital of Philadelphia, Perel-man School of Medicine at the Universityof Pennsylvania, Philadelphia (S.P.H.);and the Department of Pathology andHematological Malignancies Program,St. Jude Children’s Research Hospital,Memphis, TN (C.G.M.). Address reprintrequests to Dr. Hunger at the Children’sHospital of Philadelphia, 3060 Colket

Translational Research Bldg., 3501 CivicCenter Blvd., Philadelphia, PA 19104, orat [email protected]; or to Dr.Mullighan at St. Jude Children’s ResearchHospital, 262 Danny Thomas Pl., MailStop 342, Memphis, TN 38105, or [email protected].

N Engl J Med 2015;373:1541-52.

DOI: 10.1056/NEJMra1400972

Copyright © 2015 Massachusetts Medical Society.

Dan L. Longo, M.D., Editor

Acute Lymphoblastic Leukemia in Children

Stephen P. Hunger, M.D., and Charles G. Mullighan, M.D.

The New England Journal of Medicine

Downloaded from nejm.org at UFPE on December 6, 2015. For personal use only. No other uses without permission.

Copyright © 2015 Massachusetts Medical Society. All rights reserved.


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n engl j med 373;16 nejm.org October 15, 20151542

T h e n e w e n g l a n d j o u r n a l o f medicine

mosome number), chromosomal rearrangementsthat deregulate gene expression or result in ex-pression of chimeric fusion proteins, deletions andgains of DNA, and DNA sequence mutations.13 Onaverage, childhood ALL genomes contain only10 to 20 nonsilent coding mutations at the time

of diagnosis and about twice as many at the timeof relapse.14 Many mutations perturb key cellularprocesses, including the transcriptional regulationof lymphoid development and differentiation;cell-cycle regulation; the TP53–retinoblastomaprotein tumor-suppressor pathway; growth factorreceptor, Ras, phosphatidylinositol 3-kinase, and JAK–STAT signaling; nucleoside metabolism;and epigenetic modification. Perturbation of thelatter two processes is common at relapse.14,15

ALL may be of B-cell precursor or T-cell lin-eage. In 25 to 30% of children with B-cell ALL,

leukemic cells have high hyperdiploidy (>50chromosomes) due to nonrandom chromosomegains. This subtype is associated with an excel-lent prognosis. Hypodiploidy (


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(q34;q11.2) translocation that results in forma-tion of the Philadelphia (Ph) chromosome, andchromosomal rearrangements involving the chro-mosome 11q23 mixed-lineage leukemia (MLL)gene. The Ph chromosome encodes BCR-ABL1,

an activated tyrosine kinase. MLL (KMT2A ) en-codes a histone methyltransferase that is involvedin epigenetic regulation of blood-cell develop-ment. More than 70 different translocations tar-get MLL, creating fusion proteins that mediateaberrant self-renewal of hematopoietic progeni-tors.23 MLL translocations are particularly com-mon in ALL that develops before 1 year of age(75% of cases). MLL-rearranged leukemias have very few additional somatic mutations, particu-larly in infants.24

Genomic profiling and sequencing studies haveidentified additional subtypes of ALL. These in-clude cases with deregulation of the transcriptionfactor gene ERG25,26 and cases with complex intra-chromosomal amplification of chromosome 21.27

In several subtypes of ALL, there is no singledefining chromosomal alteration, but these sub-types are defined by other pathological or ge-nomic features. For example, early T-cell precur-sor ALL is an aggressive stem-cell and progenitorleukemia that has a distinct immunophenotypeand genetic alterations targeting transcriptionfactors, signaling pathways, and epigenetic reg-ulation.28,29 Patients with Ph-like ALL have aleukemic-cell gene-expression profile that issimilar to that in patients with Ph-positive ALL,

Figure 2. Proposed Sequential Acquisition of Genetic Alterations Contributing to the Pathogenesis and Relapse of ALL.

As shown in Panel A, either common inherited variants or, rarely, deleterious germline mutations confer a predispo-sition to ALL. Initiating lesions, commonly translocations, are acquired in a lymphoid progenitor. Secondary se-

quence mutations and structural genetic alterations contribute to an arrest in lymphoid development and perturba-

tion of multiple cellular pathways, resulting in clinically manifest leukemia. PI3K denotes phosphatidylinositol3-kinase. As shown in Panel B, ALL is commonly genetically polyclonal at diagnosis. Initial therapy suppresses oreliminates more proliferative predominant clones, leaving subclones that harbor or acquire mutations that confer

resistance to specific chemotherapeutic agents. Less commonly, relapse clones share no genetic alterations with

diagnosis clones and probably are a second leukemia in persons with a genetic predisposition.

Hematopoieticstem cells

Lymphoidprogenitor

Pro-B or pre-Bcell

Lymphoblast

A

Predisposition

Initiating translocations

Secondary mutations

Diagnosis

B

Diagnosis

Remission

Relapse Second leukemia

Selectionor acquisitionof mutations

CREBBP

NT5C2 and PRPS1TP53

RasMismatch repair

Epigenetic

Tumor suppressorsKinase–Ras–PI3K signaling

Lymphoid signalingTranscriptional signaling

Transcriptional coactivatorsChromatin remodeling

Self-renewalDevelopmental arrest

Epigenetic reprogrammingProliferation

Remission-inductiontherapy

Common variants

IKZF1, CEBPE, ARID5B

Rare mutations

PAX5, ETV6, TP53





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but they do not have BCR-ABL1 and harbor adiverse range of genetic alterations that activatetyrosine kinase signaling.30 The most commonof these alterations are fusions that involve“ABL-class” kinases (ABL1, ABL2, CSF1R, andPDGFRB), which can be targeted with ABL1 in-hibitors such as imatinib and dasatinib, and

fusions, mutations, or deletions that activate JAK–STAT signaling (including rearrangementsof JAK2, CRLF2, EPOR , and mutations of JAK1, JAK2, and JAK3 and the interleukin-7 receptor).

With the exception of MLL-rearranged leuke-mia in infants, each of these subtypes typicallyhas multiple additional genetic alterations. Thesealterations commonly target genes encoding pro-teins involved in cell signaling, tumor-suppressorfunctions, and lymphoid differentiation. The twomost common target genes governing B-lymphoiddevelopment are PAX5 (mutated in 35% of cases ofALL in children) and IKZF1 (mutated in 15%).25,31

Prognostic Fact ors

Factors that are predictive of an increased or a de-creased chance of cure are considered when deci-sions are made about the intensity of chemothera-py and the selection of patients in first remissionfor allogeneic hematopoietic-cell transplantation(Table 1). Major prognostic factors include theclinical features that are present at diagnosis, bio-

logic and genetic features of leukemia cells, andearly response to treatment.

Clinical Features

The patient’s age and initial white-cell count arepredictive of outcome, with older age or a higher white-cell count portending a worse prognosis.A consensus conference defined “standard risk”(age 1 to 9.99 years and initial white-cell countof


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T a b l e 1 .

I m p o r t a n t P r o g n o s t i c F a c t o r s i n A c u t e L y m p h o b l a s t i c L e u k e m i a ( A L L ) i n C h i l d r e n . *

V a r i a b l e

F a v o r a b l e F a c t o r

A d v e r s e F a c t o r

U s e i n R i s k

S t r a t i f i c a t i o n

D e m o g r a p h i c a n d c l i n i c a l f e a t u r e s

A g e

1 t o < 1 0 y r

< 1 y r o r ≥ 1 0 y r

T h i s f e a t u r e i s a p a r t o f N

C I r i s k g r o u p d e f i n i t i o n

S e x

F e m a l e

M a l e

N

o

R a c e o r e t h n i c g r o u p

W h i t e , A s i a n

B l a c k ,

N a t i v e A m e r i c a n , H

i s p a n i c

N

o

I n i t i a l w h i t e - c e l l c o u n t

L o w e r ( < 5 0 , 0

0 0 / m m

3 )

H i g h e r ( ≥ 5 0 , 0

0 0 / m m

3 )

P a r t o f N C I r i s k

g r o u p d e f i n i t i o n

B i o l o g i c o r g e n e t i c f e a t u r e s

o f l e u k e m i a c e l l s

I m m u n o p h e n o t y p e

B - c e l l l i n e a g e

T - c e l l l i n e a g e

O f t e n u s e d t o s e l e c t t h e r a p y b a c k b o n e

C y t o g e n e t i c f e a t u r e s

E T V 6 - R U N X 1 ,

h y p e r d i p l o i d y , f a v o r a b l e

c h r o m o s o m e t r i s o m i e s

B C R - A B L 1 , M L L r e a r r a n g e m e n t s , h

y p o d i p l o i d y

O f t e n u s e d t o s e l e c t t r e a t m e n t i n t e n s i t y , a s s i g n

t h e p a t i e n t t o H S C T , o r b o t h ; s o m e f e a t u r e s

( e . g . , B C R - A B L 1 ) c a n

b e u s e d t o s e l e c t t a r -

g e t e d t h e r a p y

G e n o m i c f e a t u r e s

E R G d e l e t i o n s

I K Z F 1 d e l e t i o n s o r m u t a t i o n s ; P h i l a d e l p h i a c h r o m o -

s o m e – l i k e A L L w i t h k i n a s e g e n e a l t e r a t i o n s

S o m e r e s e a r c h g r o u p s u

s e I K Z F 1 d e l e t i o n s t o

a s s i g n p a t i e n t s t o m

o r e i n t e n s i v e t h e r a p y ;

k i n a s e g e n e m u t a t i o n s m a y b e u s e d t o

a s s i g n p a t i e n t s t o t a r g e t e d t h e r a p y , b u t t h i s

i s n o t y e t p a r t o f r o u t i n e c a r e

E a r l y r e s p o n s e t o t r e a t m e n t

R e s p o n s e t o 1 w k o f g l u c o c o r t i c o

i d

t h e r a p y

G o o d r e s p o n s e t o p r e d n i s o n e

( < 1 0 0 0 b l a s t s / m m

3 )

P o o r r e s p o n s e t o p r e d n i s o n e ( ≥ 1 0 0 0 b l a s t s / m m

3 )

E a s y t o m e a s u r e a n d u s e

d b y m a n y g r o u p s ; m a y

b e s u p p l a n t e d b y M R D

M a r r o w b l a s t s a f t e r 1 – 2 w k o f m u l -

t i a g e n t t h e r a p y

M 1 m a r r o w ( < 5 % b l a s t s ) b y d a y 8 o r 1 5

N o M 1 m a r r o w ( ≥ 5 % b l a s t s ) b y d a

y 8 o r 1 5

E a s y t o m e a s u r e a n d u s e d p r e v i o u s l y b y m a n y

g r o u p s ; n o w b e i n g s u p p l a n t e d b y M R D

M R D q u a n t i t a t i o n d u r i n g o r a t e n d

o f i n d u c t i o n

R e a c h i n g l o w ( < 0 . 0

1 % ) o r u n d e t e c t a b l e

M R D b y s p e c i f i c t i m e p o i n t s

P e r s i s t e n c e o f M R D ≥ 0 . 0

1 % a t s p e

c i f i c t i m e p o i n t s ;

t h e h i g h e r i t i s , t

h e w o r s e t h e p r o g n o s i s

M o s t i m p o r t a n t s i n g l e p

r o g n o s t i c f a c t o r f o r

c o n t e m p o r a r y t h e r a p y ; c r i t i c a l f o r m o d e r n

r i s k s t r a t i f i c a t i o n

M R D a t 3 – 4 m o

L o w ( < 0 . 0

1 % ) , p r e f e r a b l y u n d e t e c t a b l e

P e r s i s t e n c e o f M R D ≥ 0

. 0 1 %

M a y h e l p s e l e c t p a t i e n t s

f o r H S C T o r n e w t h e r -

a p i e s i n f i r s t r e m i s s i o n

* H S C T d e n o t e s h e m a t o p o i e t i c s t e m - c e l l t r a n s p l a n t a t i o n ,

M R D m i n i m a l r e s i d u a l d i s e a s e , a n d N C I N a t i o n a l C a n c e r I n s

t i t u t e .





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means of flow cytometric detection of aberrantcombinations of cell-surface antigens.47,48

The risk of treatment failure and death is 3 to

5 times as high among children with levels ofminimal residual disease that are 0.01% or higherat the end of induction therapy and at later timepoints than among those with levels that arelower than 0.01%.45,46,49,50 Intensification of thera-py for patients with higher levels of minimal re-sidual disease improves their outcome.48,51 Emerg-ing next-generation-sequencing techniques fordetection of minimal residual disease may beuseful by providing sensitive detection of leuke-mia cells below the level detected reliably byother techniques.52

Treatment

Improvements in Survival over Time

Almost 50 years ago, combination chemotherapyinduced remission (disappearance of clinical evi-dence of leukemia and restoration of normalhematopoiesis) in 80 to 90% of children withALL. However, the disease relapsed in almost allthese children, usually in the CNS, with survival

rates of 10 to 20%.53 Survival increased consider-ably with the addition of craniospinal or cranialirradiation and intrathecal chemotherapy.54

A major milestone in therapy for children with ALL was the development of an intensiveeight-drug, 8-week induction and consolidationregimen as introduced by Riehm et al.55 This regi-

men, which is now called protocol I, became thebasis for the Berlin–Frankfurt–Münster regimen, which is the core of most contemporary therapiesfor ALL.

Since this regimen was introduced, large co-operative research groups and individual institu-tions have enrolled 75 to 95% of children whohave a diagnosis of ALL in North America andWestern Europe into clinical trials. These trialshave led to remarkable improvements in survival, with 5-year event-free survival rates of up to 85%and overall survival rates of up to 90%, accordingto the most recently reported data (Table 3).37

Contemporary Therapy

The basic components of various therapies forchildren with ALL are similar and include sev-eral discrete phases. Induction therapy lasts 4 to6 weeks and includes a glucocorticoid (prednisoneor dexamethasone), vincristine, an asparaginasepreparation, optional use of an anthracycline, andintrathecal chemotherapy. Almost all patients at-tain remission, but this is not a cure, since relapse

will occur universally without additional therapy.After remission, treatment includes 6 to 8months of intensive combination chemotherapythat is designed to consolidate remission andprevent development of overt CNS leukemia.Treatment in an 8-week delayed-intensification(protocol II) phase, based on the 8-week Berlin–Frankfurt–Münster protocol I, is then administered.Repeated courses of methotrexate, administeredeither through short intravenous infusion or at highdoses over 24 hours followed by administration offolinic acid to “rescue” normal tissues from toxic

effects, are a critical component of contempo-rary ALL regimens.

Patients then receive low-intensity “anti-metabolite”-based maintenance therapy for 18 to30 months. This therapy consists of daily oralmercaptopurine or thioguanine and weekly oralmethotrexate. Some regimens also include peri-odic 5-to-7-day “pulses” of glucocorticoids and vincristine. The exact reasons why maintenancetherapy is required and the most effective composi-

CharacteristicPrecursor B-Cell ALL

(N=8393)T-Cell ALL(N=1671)

number (percent)

Race†

White 6375 (76.0) 1219 (73.0)

Black 542 (6.5) 230 (13.8)

Asian 374 (4.5) 85 (5.1)

Other 254 (3.0) 32 (1.9)

Unknown 848 (10.1) 105 (6.3)

Ethnic group†

Hispanic 1809 (21.6) 238 (14.2)

Not Hispanic 6243 (74.4) 1373 (82.2)

Unknown 341 (4.1) 60 (3.6)

Sex

Female 3831 (45.6) 450 (26.9)

Male 4562 (54.4) 1221 (73.1)

* Data are from unpublished results of COG ALL trials AALL0232 (ClinicalTrials.gov number, NCT00075725), AALL0331 (NCT00103285), and AALL0434(NCT00408005). Percentages may not sum to 100 owing to rounding.

† Race or ethnic group was reported by parents or guardians.

Table 2. Demographic Characteristics of Patients in Children’s OncologyGroup (COG) ALL Trials.*





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T a b l e 3 .

O u t c o m e s o f C o n t e m p o

r a r y T r i a l s I n v o l v i n g C h i l d r e n a n d A d o l e s c e

n t s w i t h A L L i n N o r t h A m e r i c a a n d W e s t e r n E u r o p e . *

R e s e a r c h G r o u p

T r i a l

R e f e r e n c e

R e g i o n

Y e a r s

S u b g r o u p

N o . o f

P a t i e n t s

E v e n t

- f r e e

S u r v i

v a l †

O v e r a l l

S u r v i v a l †

p e r c e n t

C O G

M a n y t r i a l s

H u n g e r e t a l . 3 7

U n i t e d S t a t e s ,

C a n a d a ,

A u s t r a l i a ,

N e w Z e a l a n d

2 0 0 0 – 2 0 0 5

A l l p a t i e n t s

B - c e l l A L L

T - c e l l A L L

6 9 9 4

5 8 4 5

4 5 7

N / A

N / A

N / A

9 1 . 3

9 2 . 0

8 1 . 5

S J C R H

T o t a l T h e r a p y S t u d y X V

P u i e t a l . 5

6

U n i t e d S t a t e s

2 0 0 0 – 2 0 0 7


B - c e l l A L L

T - c e l l A L L

4 9 8

4 2 2

7 6

8 5 . 6

8 6 . 9

7 8 . 4

9 3 . 5

9 4 . 6

8 7 . 6

D F C I

D F C I A L L C o n s o r t i u m

P r o t o c o l 0 0

– 0 1

V r o o m a n e t a l . 5

7

U n i t e d S t a t e s , C a n a d a

2 0 0 0 – 2 0 0 4


B - c e l l A L L

T - c e l l A L L

4 9 2

4 4 3

4 9

8 0 . 0

8 2 . 0

6 9 . 0

9 1 . 0

N / A

N / A

A I E O P - B F M

A I E O P - B F M

A L L 2 0 0 0

C o n t e r e t a l . ,

4 9

S c h r a p p e

e t a l . 5

0

W e

s t e r n E u r o p e

2 0 0 0 – 2 0 0 6


B - c e l l A L L

T - c e l l A L L

4 4 8 0

4 0 1 6

4 6 4

8 0 . 3

8 0 . 4

7 5 . 9

9 1 . 1

9 1 . 8

8 0 . 7

M R C - N C R I

U K A L L 2 0 0 3

V o r a e t a l . 5

8

U n i t e d K i n g d o m

2 0 0 3 – 2 0 1 1


B - c e l l A L L

T - c e l l A L L

3 1 2 6

2 7 3 1

3 8 8

8 7 . 2

N / A

N / A

9 1 . 5

N / A

N / A

D C O G

D C O G P r o t o c o

l A L L - 9

V e e r m a n e t a l . 5

9

T h e N e t h e r l a n d s

1 9 9 7 – 2 0 0 4


B - c e l l A L L

T - c e l l A L L

8 5 9

7 0 1

9 0

8 1 8 2 7 2

8 6

N / A

N / A

E O R T C C L G

E O R T C C L G 5 8 5 9 1

D o m e n e c h e t a l . 6 0

B e l g i u m ,

F r a n c e

1 9 9 8 – 2 0 0 8


1 9 4 0

8 2 . 6

8 9 . 7

N O P H O

A L L - 2 0 0 0

S c h m i e g e l o w e t a l . 6

1

D e n m a r k , F i n l a n d ,

I c e l a n d ,

N o r w a y ,

S w e d e n

2 0 0 0 – 2 0 0 7


B - c e l l A L L

T - c e l l A L L

1 0 2 3

9 0 6

1 1 5

7 9 8 1 6 4

8 9

9 1

7 2

* I n f a n t s y o u n g e r t h a n 1 y e a r o f a g e w e r e e x c l u d e d f r o m t h e s e s t u d i e s w h e n

p o s s i b l e .

A I E O P d e n o t e s I t a l i a n A s s o c i a t i o

n o f P e d i a t r i c H e m a t o l o g y a n d O n c o l o g y , B F M

B e r l i n – F r a n k f u r t –

M ü n s t e r ,

D C O G D u t c h C h i l d h o o

d O n c o l o g y G r o u p ,

D F C I D a n a – F a r b e r C a n c e r I n s t i t u t e ,

E O R T C C L G E u r o p e a n O r g a

n i z a t i o n f o r R e s e a r c h a n d T r e a t m e n t o f C a

n c e r – C h i l d r e n ’ s

L e u k e m i a G r o u p ,

M R C - N C R I M e d i c a l R e s e a r c h C o u n c i l – N a t i o n a l C a n c e r R

e s e a r c h I n s t i t u t e ,

N / A n o t a v a i l a b l e ,

N O P H

O N o r d i c S o c i e t y o f P a e d i a t r i c H a e m a t o l o g y a n d O n c o l o g y ,

S J C R H S t . J u d e C h i l d r e n ’ s R e s e a

r c h H o s p i t a l , a n d U K A L L M e d i c a l R e s e a r c h C o u n c i l W o r k i n g P a r t y o n L e u k a e m i a i n C

h i l d r e n U K N a t i o n a l A c u t e L y m p h o b l a s t i c

L e u k a e m i a T r i a l .

† S u r v i v a l p e r c e n t a g e s s h o w n a r e t h e r a t e s a t 5 y e a r s e x c e p t f o r t h e r a t e s f o r

t h e A I E O P - B F M

t r i a l , w h i c h w e r e r e p o r t e d

a t 7 y e a r s .





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tion and duration of chemotherapy are unknown.Because maintenance therapy is prolonged andrequires daily oral drug administration, adherencecan be problematic; 20% of patients are less than90% adherent, and decreased adherence is associ-ated with a risk of relapse that is 4 times as highas the risk among patients whose rate of adher-

ence is 90% or more.62 Host polymorphisms mayinfluence both the efficacy and toxicity of mer-captopurine, which is the backbone of mainte-nance therapy.63

CNS-Directed Therapy

Cranial irradiation dramatically improved curerates among patients with ALL in the 1960s and1970s, but it was associated with an increasedrisk of secondary CNS tumors, delayed growth,endocrinopathies, and neurocognitive effects.64 Consequently, CNS irradiation has been limited toprogressively smaller patient subgroups over time.

Several research groups have eliminated CNSirradiation for most or all children with newlydiagnosed ALL, and their results are quite simi-lar to those obtained by groups that continue toinclude irradiation in therapy for children withALL.56,59 The current role of CNS irradiation iscontroversial, but all groups now treat at least80% of children who have newly diagnosed ALL without the use of cranial irradiation.

Treatment of Relapsed ALL, Including

Hematopoietic-Cell Transplantation

Relapse occurs in 15 to 20% of children with ALL,and cure rates are much lower after relapse.65 Prog-nostic factors at relapse include the time to re-lapse (a shorter time is associated with a worseprognosis), immunophenotype (T-cell immuno-phenotype is associated with a worse prognosis),and the site of relapse (bone marrow disease isassociated with a worse prognosis than extra-medullary disease).66 Leukemia cells obtained frompatients with early relapse frequently harbor mu-

tations that decrease sensitivity to common che-motherapy drugs.67,68 If relapse occurs after thecompletion of primary treatment, most children will enter a second remission, and the chance forcure is about 50%. If relapse occurs during ther-apy, the chance of attaining a second remission isonly 50 to 70%, and only 20 to 30% of patientsare cured.

Allogeneic hematopoietic-cell transplantationis used much more commonly after relapse (in≥50% of patients) than during primary therapy

(in 5 to 10% of patients). Assessment of the mini-mal residual disease response may be helpful indetermining which patients should undergo trans-plantation during a second remission and whichpatients should not.69

ALL is frequently a polyclonal disease, andmutations in subclones may be selected by chemo-

therapy and promote resistance. These includeCREBBP mutations that are linked to resistance toglucocorticoids67 and NT5C2 and PRPS1 mutationsthat are associated with resistance to thiopu-rines.68,70,71 In future studies, it will be importantto identify emerging mutations that are associ-ated with resistance and explore the potentialfor modifying therapy to circumvent relapse.

Targeted Therapy and Precision Medicine

The dramatic improvements in survival amongchildren with ALL over the past 50 years are duealmost exclusively to identification of the mosteffective doses and schedules of chemotherapeu-tic agents that have been widely available for de-cades rather than to the development of newtherapies. Recent discoveries regarding the geneticbasis of ALL and the development of therapiesthat target molecular lesions that drive survivalof ALL cells have paved the way for the expandinguse of precision-medicine approaches to cancer.72 One notable example is the use of tyrosine kinaseinhibitors in patients with chronic myeloid leu-

kemia, a cancer that is driven by the BCR-ABL1fusion oncoprotein.73 Treatment with tyrosine ki-nase inhibitors (imatinib and related agents) hasconverted chronic myeloid leukemia from a dis-ease requiring intensive therapy that often includedhematopoietic stem-cell transplantation to a chronicdisease that can in most cases be managed success-fully for decades with oral tyrosine kinase in-hibitors, with the potential for discontinuationof treatment in some patients.74

The BCR-ABL1 fusion protein also occurs in25% of adults and in 3 to 5% of children with

ALL (Ph-positive ALL), and in ALL, as compared with chronic myeloid leukemia, it is associated with secondary genetic alterations, part icularlyalterations of IKZF1.75 Before the use of tyrosinekinase inhibitors, less than half the children with Ph-positive ALL survived.41 Combining ima-tinib with cytotoxic chemotherapy has proved tobe highly effective in children with Ph-positiveALL and has minimized the need for hematopoi-etic-cell transplantation in the first remission.76-78

Ph-like ALL is associated with a poor progno-





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sis, and it is a logical candidate for individuallytailored tyrosine kinase inhibitor therapy.30,43,79 Adiverse range of genetic alterations activate kinasesignaling in Ph-like ALL; these include a highfrequency of rearrangements that converge on alimited number of signaling pathways, includingABL-class and JAK–STAT signaling. Extensive pre-

clinical studies show that the activation of sig-naling pathways induced by these alterations issensitive to tyrosine kinase inhibitors; this sug-gests that precision-medicine approaches shouldbe successful in this ALL subgroup. These findingsare supported by anecdotal reports of dramaticresponses of chemotherapy-refractory Ph-like ALLto tyrosine kinase inhibitor therapy.30,80 This isparticularly important in older children andadults, in whom Ph-like ALL is more common.30

An important challenge in the design of futureclinical trials will be to ensure adequate enroll-ment of patients harboring each class of geneticalteration. To meet this challenge, internationalclinical trials that involve multiple cooperativegroups will have to be developed, as has beendone successfully in studies of Ph-positive ALL.

Immunotherapy

CD19 is a cell-surface antigen that is present athigh density on most B-cell ALL cells. Severalgroups have developed strategies to transduce au-tologous T-cells with an anti-CD19 antibody frag-

ment coupled to intracellular signaling domains ofthe T-cell receptor, thereby redirecting cytotoxicT lymphocytes to recognize and kill B-cell ALLcells. These chimeric antigen receptor–modifiedT cells provide a major new treatment option.

In one study, 30 children with heavily pre-treated ALL that had relapsed multiple times weretreated with chimeric antigen receptor–modifiedT cells; 90% of the children attained remission, with sustained remission in about two thirds.Approximately three quarters of the children were alive 6 months after the infusion.81 Remis-

sions were durable with 1 to 3 years of follow-up.Many patients had a severe cytokine-releasesyndrome after activation of the cytotoxic T cellsin vivo. This syndrome was accompanied byhigh levels of serum interleukin-6 that could betreated successfully with the anti–interleukin-6monoclonal antibody tocilizumab. Studies of thedurability of chimeric antigen receptor T-celltherapy (ClinicalTrials.gov number, NCT02445222)and its role in patients with ALL who have less-advanced disease (NCT02435849) are ongoing.

A different strategy to harness the T-cell im-mune response against ALL cells is provided byblinatumomab, a genetically modified antibodythat contains fragments that recognize both CD19and CD3 (which is present on all T cells) and there-fore brings T cells into direct contact with B-cellALL cells, allowing the cytotoxic T cells to kill

them.82 Blinatumomab is now being tested inchildren with a first relapse of B-cell ALL(NCT02101853).

Short-Term and Long-Term Toxic Effects

of Treatment

About 1 to 2% of children with ALL die beforeattaining remission, and an additional 1 to 2%die from toxic effects during remission.83 Patients with Down’s syndrome, infants, older teenagers,and those receiving more intensive therapy havean increased risk of death from toxic effects,mostly due to infection. Risks can be mitigatedby modifications to therapy and supportive care.As cure rates for childhood ALL improve, treat-ment-related death accounts for a higher percent-age of all deaths.

One of the most vexing problems associated with contemporary therapy for ALL is osteone-crosis, which occurs in 5 to 10% of patients.84 The risk is much higher among teenagers (15 to20%) than among young children, and girls areaffected more commonly than boys. Osteonecro-

sis most commonly affects major joints, particu-larly the hips, knees, shoulders, and ankles, andoften requires surgical management, including joint replacement. Modifications to glucocorti-coid administration schedules can decrease therisk of osteonecrosis.85

Additional treatment-related effects includethe metabolic syndrome and obesity, cardiovas-cular impairment, and CNS and peripheral nervoussystem toxic effects. Each is caused by highly effec-tive antileukemic agents, and a person’s risk oftoxic effects is inf luenced by host genetic factors

that influence drug metabolism and activity.Thus, an important goal is the tailoring of drugexposure according to the predicted risk of bothrelapse and specific toxic effects.

A child who is cured of ALL is expected tohave 60 to 80 years of remaining life. Criticalquestions are whether that expected life span isshortened by the leukemia, its treatment, or both, whether chronic health conditions that affect dailylife develop at a higher frequency or increased se- verity in survivors than in persons who were never





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treated for childhood ALL, and whether thereare lasting emotional or neurocognitive effectsthat limit full realization of a survivor’s poten-tial. Unfortunately, many ALL survivors do havechronic toxic effects,86 and the neurocognitiveeffects appear to increase as they approach mid-dle age.64 Continued long-term follow-up of per-

sons who had ALL in childhood is essential todefine the risks and to develop strategies to de-crease risks, ameliorate toxic effects, or both.

Implications of the Successof Treatment

Survival rates among teenagers with ALL are in-ferior to those among young children, and survival is even worse among young adults.87,88 Thereasons for these differences are multifactorialand include treatment factors, a higher preva-lence of unfavorable genetic subtypes among theolder patients, the reduced ability of teenagersand young adults to receive intensive therapy with-out untoward side effects, and social factors suchas insurance coverage and lack of parental super- vision of therapy. Institutions and cooperativegroups treating young adults with ALL have suc-cessfully adopted treatment modeled on pediatricregimens. This strategy is feasible for patients upto about 50 years of age, with early results sug-gesting major improvements in survival.89

Since the population of children is higher inlow-income and middle-income countries than inhigh-income countries, the total number of chil-dren with a diagnosis of ALL is also higher inthese countries; these children have inferior survival as compared with children treated in high-income countries.90 Because ALL can be diagnosed with simple techniques and treated successfully with relatively inexpensive chemotherapeutic agents,

it is feasible to rapidly improve the outcome inchildren with ALL in low-income and middle-income countries. Partnerships and “twinning”relationships between centers in high-income cen-ters in North America and Western Europe andpediatric cancer centers in Asia, Central and SouthAmerica, and Eastern Europe have substantially

improved survival among children with ALL.90-92

Conclusions

In the past few years, we have witnessed tremen-dous advances in our understanding of the biol-ogy of ALL and the remarkable efficacy of targetedchemical and biologic therapeutic approaches inotherwise refractory disease. It is anticipated thatin the next several years, the genomic landscapeof ALL will be completely described, the biologiccauses for treatment failure fully elucidated, andthe roles of a range of new chemical and bio-logic agents defined. As the cure rate for child-hood ALL approaches 100%, major challenges will be to identify persons who require less inten-sive therapy to achieve cure and to refine com-plex, toxic regimens to incorporate simpler, saferapproaches that will result in a high quality oflife coupled with long-term survival.

Dr. Hunger reports receiving consulting fees from Jazz Phar-maceuticals, Sigma-Tau Pharmaceuticals, and Spectrum Phar-maceuticals and owning stock in Amgen; Dr. Mullighan, receiv-ing consulting fees from Incyte Pharmaceuticals and speakingfees from Amgen Pharmaceuticals; and Drs. Hunger and Mul-

lighan, being named as inventors on a pending patent applica-tion related to gene-expression signatures for detection of un-derlying Philadelphia chromosome–like events and therapeutictarget ing in leukemia (PCT/US2012/069228). No other potentialconflict of interest relevant to this article was reported.

Disclosure forms provided by the authors are available withthe full text of this article at NEJM.org.

We thank the many colleagues who provided helpful com-ments on this article, including Drs. William Carroll, MignonLoh, Shannon Maude, Camille Pane, Elizabeth Raetz, SusanRheingold, Sarah Tasian, David Teachey, and Naomi Winick.

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