Acute Lymphoblastic Leukemia (ALL): Advances? YES!

Acute Lymphoblastic Leukemia
(ALL): Advances?
YES!
Stephen P. Hunger, M.D
STOP! Children’s Cancer Chair
Chief, Pediatric Hematology/Oncology
Vice Chair, COG ALL Committee
University of Florida College of Medicine

Outline
• Overview
– Childhood cancer incidence and epidemiology
– Acute leukemia: epidemiology and pathobiology
• Childhood ALL
– Classification and treatment
• ALL in adolescents and young adults (AYA)
• Relapsed childhood ALL
• The role of SCT in children and AYA with ALL

Causes of Mortality Before Age
20 in the United States
#1 Unintentional Injury
#2 Homicide
#3 Suicide
#4 Cancer

Epidemiology of Cancer in
Children and Young Adults
• 30% of U.S. population is

Cancer Mortality: Causes Among
U.S Children 0-19 Years of Age
7% 6% Leukemia
3%
35% CNS tumors
7%
Endocrine
Other
8%
Soft Tissue
Kidney
Bone tumors
9%
NHL
25%

Acute Leukemias
ALL
• 3% of all cancers
– 30-35% for children
• #1 cause of cancer death at ¡ 35 yrs
• ~3250 cases/yr in US 0-19 yr olds
– 4000-5000 ALLs/yr in US
• Median age 10 years (children=adults)
– 2500 ALLs/yr in US 0-19 yrs
– 9000 AMLs/yr in US
• Median age 65 years (adults>>children)
– 650 AML/yr in US 0-19 yrs
AML

Leukemia Subtypes by Age
14%
2%3%
9% 4%
ALL
AML
CML
Other
36%
51%
81%
0-5 years 15-19 years

ALL: Molecular Pathogenesis
• While ALLs are morphologically similar, they are
clinically and biologically heterogeneous
• ALL is not caused by a single mutation but
requires 2-6 mutations
– Mutations almost always somatic
• Initiating mutations often result from chromosome
translocations
– Initiating events can occur in utero

ALL: Cytogenetics
• Careful analysis shows that 90% + of ALLs contain
cytogenetic abnormalities
– Abnormalities are acquired (somatic; not present in
germline) and disappear when remission is achieved
• Some cytogenetic abnormalities have important
prognostic and therapeutic implications
• Types of abnormalities
– Numerical: Gain or loss or one or more chromosomes
– Structural: Exchanges of information between
(translocations) or within (inversions) chromosomes

ALL: Role of Chromosome
Translocations
• ALL is biologically heterogeneous
• Role of chromosome translocations
– Critical role in leukemogenesis
– Specific recurrent abnormalities are powerful predictors of
outcome and can be used for treatment stratification in riskadapted
therapy
– Oncogenes involved in leukemogenesis play a critical role
in normal hematopoiesis
– Identify targets and pathways for rationally-designed
therapeutic interventions

Common Targets of
Translocations in Leukemia
Gene Location #Partners
E2A 19p13.3 3 cloned
MLL (HRX) 11q23 30+, 18 cloned
CBFα or β 21q22/16p13 5 cloned
TEL (ETV6) 12p13 9+ cloned
RARα 17q21 4 cloned

Molecularly-Targeted Therapy: Imatinib
in Chronic Myelogenous Leukemia
N Engl J Med 348: 994, 2003

Outline
• Overview
– Childhood cancer incidence and epidemiology
– Acute leukemia: epidemiology and pathobiology
• Childhood ALL
– Classification and treatment
• ALL in adolescents and young adults (AYA)
• Relapsed childhood ALL
• The role of SCT in children and AYA with ALL

Therapy of Childhood ALL:
Milestones
• 1948: Aminopterin induces temporary remissions in
children with leukemia (Farber)
– First demonstration that chemotherapy was effective for
cancer
• Early 1960s: First cures of childhood ALL
• Early 1970s: Adoption of prophylactic CNS Rx
– Radiation initially; most now receive intrathecal chemotherapy
• 1960s-present: Empiric optimization of chemo regimens
• 1980s-present: Improved understanding of biology
paves way for new era of targeted biological therapies

Estimated Survival Percentage
Improved Survival in Childhood
ALL
100
80
60
40
20
0
0 2 4 6 8 10 12
Years From Study Entry
1996-2000
(n=3421)
1989-1995
(n=5121)
1983-1988
(n=3711)
1978-1983
(n=2984)
1975-1977
(n=1313)
1972-1975
(n=936)
1970-1972
(n=499)
1968-1970
(n=402)

Treatment of Childhood ALL:
Progress Continues
1
0.9
CCG EFS COMPARISON BY STUDY ERAS
0.8
PROBABILITY
0.7
0.6
0.5
0.4
0.3
0.2
0.1
3 YEAR EFS (p=.0001):
1983-89 74.5%
1989-95 81.4%
1996-01 84.5%
1983-89
(N=3711)
1989-95
(N=5121)
1996-01
(N=3806)
0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19
YEARS OF FOLLOW-UP

Improvements in Outcome of
Children with ALL: Reasons
• Critical improvements in supportive care
– Transfusion support + treatment of infections
• Introduction of new chemotherapy agents has played a
relatively minor role
• Major improvements have come through a series of
empirically-designed clinical trials
– Essential role of US and European cooperative groups
– Importance of treatment stratification and risk-adjusted
therapy

Chemotherapy Agents Used in
Childhood ALL: FDA Approval
• 6-Mercaptopurine 1953
• Methotrexate 1953
• Prednisone 1955
• Dexamethasone 1958
• Cyclophosphamide 1959
• Vincristine 1964
• Cytosine Arabinoside 1969
• L’Asparaginase 1978
• Daunorubicin 1979

Key Components of Successful ALL
Therapy
• Empiric multi-agent
chemotherapy
• Pre-symptomatic CNS
therapy
• Risk adapted therapy
• Post-induction
intensification

Prevention of CNS Leukemia
Dramatically Improves ALL Outcome
• 1960s: induced remissions in most
patients but very high rate of early
CNS relapses
– 50-75% had CNS relapse within 6-12
months
• Most chemo agents have poor CNS
penetration and prophylactic CNS
treatment is essential
– Dramatic increase in cure rates in early
70s with universal use of craniospinal
irradiation
– Most patients now receive intensive
intrathecal chemo rather than
irradiation
CSF cytospin
Lymphoblast in CSF

Risk Group Stratification and
Risk-Adjusted Therapy
• Patients are grouped to select proper treatment strategy
– High risk patients fare poorly when treated with less intensive
regimens appropriate for standard risk patients but do much
better with more intensive therapy
– Data based on groups, but therapy is applied to individuals
• Risk group definitions
– NCI/Rome criteria based on age and initial WBC
– New COG criteria include genetic features and early
treatment response

Clinical Risk Groups in Childhood B-
Precursor ALL: NCI/Rome Criteria
• Standard risk (~65% patients with EFS ~80%)
– Age 1.00-9.99 years
– Initial white blood count

Biological Features Refine
• Immunophenotype
Clinical Risk Groups
– T-ALL patients fare relatively poorly when treated with low
intensity therapy but do well when treated more intensively
– Mature B-ALL (Burkitt’s) treated very differently
• Ploidy
– Hyperdiploid DNA index (DI >1.16) = favorable
• Best group defined by “triple trisomies” (+4, +10, +17)
– Hypodiploid (

Genetic Heterogeneity in
Childhood ALL
11q23
4%
TEL-AML1
18%
14q11
3%
Ph
2%
t(1;19)
4%
“Normal”
26%
< 45 Chrom
1%
45 Chrom
3%
Pseudodiploid
10%
47-50 Chrom
6%
> 50 Chrom
26%

Genotype and Outcome in
Childhood ALL
100
Probability
80
60
40
TEL (n =176)
Trisomies 4,10,17 (n = 746)
t(4;11) (n = 44)
t(1;19) (n = 139)
20
0
4 Yr EFS (%) SE (%)
Tris 4,10,17 92.1 1.1
TEL 89.0 3.1
t(1;19) 68.9 4.1
t(4;11) 49.9 11.2
t(9;22) 27.5 4.4
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
Years Followed
t(9;22) (n=132)
B-precursor ALL
10/2001

Day 7 Marrow Response Predicts
Outcome for Children with HR-ALL
1.00
Event-Free Survival
0.75
0.50
0.25
RER
IER
SER
d7 d14 d28
M1 M1 M1
M2/M3 M1 M1
M2//M3 M2/M3 M1
0 12 24 36 48 60 72 84
Time (months)
Steinherz et al: JCO 1996: 14:389-398

COG ALL Risk Groups
Age, WBC
Immunophenotype
Trisomies
Ploidy
Translocations
Marrow response
MRD
Low Risk
Standard Risk
High Risk
Very High Risk

Outcome by New COG Risk
Group Definitions
Probability
100
80
60
Low Risk (n=544)
High Risk (n=880)
Standard Risk (n=1471)
40
20
0
Risk Group 4 Yr EFS (%) SE (%)
Low 91.5% 1.6
Standard 82.1% 1.4
High 72.9% 2.1
Very High 33.6% 6.0
Very High Risk (n=78)
0 1 2 3 4 5 6 7 8 9
Years Followed
POG ALinC 16
B-precursor ALL
10/2001

Contemporary Therapy of Childhood
ALL: General Overview
• Remission induction
– Remission = normal blood counts, normocellular marrow
with

Risk-Adapted Therapy: Different
Questions for Different Groups
• Low risk (~90% cure)
– Intensify modestly or reduce therapy?
• Standard risk (~82% cure)
– Test treatments effective in HR patients
• High risk (~73% cure)
– Add additional agents
• Very high risk (~35% cure)
– New strategies needed
• Novel intensive chemo backbone
• Gleevec for Ph+ ALL
• SCT for some patients

Day 7 Marrow Response Predicts
Outcome for Children with HR-ALL
1.00
Event-Free Survival
0.75
0.50
0.25
RER
IER
SER
d7 d14 d28
M1 M1 M1
M2/M3 M1 M1
M2//M3 M2/M3 M1
0 12 24 36 48 60 72 84
Time (months)
Steinherz et al: JCO 1996: 14:389-398

Slow Early Response – Rationale
for “Augmented” BFM
• German efforts to improve outcome for
prednisone poor responders included addition of
high dose Ara-C, high dose methotrexate,
ifosfamide and vindesine
– No improvement in outcome in 2 consecutive trials
• Since addition of new myelotoxic drugs did not
improve outcome, CCG chose to intensify
Vincristine and L-Asparaginase and to use IV
Methotrexate without rescue

“Standard” vs. “Augmented” Therapy:
Dose Intensity in First Year
Standard BFM
Augmented BFM
VCR 15 30
L-ASP 15 53
CTX 3 4
Ara-C Courses 6 8
IV MTX 0 10

CCG 1882: Augmented BFM
Therapy
Induction
Interim
Re-induction
Interim
Re-induction
Maint
Consolidation
Maint
Consolidation
Maint
Re-consolidation
I
I
II
II
Differences Between Standard and Augmented Therapy
Extend consolidation from 4 to 8 weeks and add a 2 week course of
VCR/L-ASP to neutropenic phase of each 4 week block
Capizzi pulses replace oral 6MP/MTX for interim maintenance
VCR-IV MTX without Lcv rescue-ASP
Addition of a second interim maintenance and re-induction reconsolidation
course

CCG-1882: Augmented Therapy Improves EFS for
Patients with an SER (M3 Marrow at day 7)
Probability
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
DATA UPDATED DEC 2004
Augmented BFM (n=155)
BFM (n=156)
Log Rank p=.0006
8-Year EFS RHR
BFM 52.3%(s.d. 6.5%) 1.9
Augmented BFM 70.2%(s.d. 6.7%) Baseline
0 1 2 3 4 5 6 7 8 9 10 11 12
Nachman et al., NEJM 338: 1663-1671, 1998
Years Followed (from Randomization)

CCG-1882: Augmented Therapy Improves Survival
for Patients with an SER (M3 Marrow at day 7)
Probability
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
DATA UPDATED DEC 2004
Augmented BFM (n=155)
BFM (n=156)
Log Rank p=.01
8-Year Survival RHR
BFM 63.7%(s.d. 6.1%) 1.7
Augmented BFM 75.2%(s.d. 6.4%) Baseline
0 1 2 3 4 5 6 7 8 9 10 11 12
Years Followed (from Randomization)
Nachman et al., NEJM 338: 1663-1671, 1998

CCG 1961: A Pivotal Trial for the
Design of New COG ALL Studies
• 2078 children with NCI HR ALL from 9/16/96-5/1/02
• Tested components of augmented BFM
– Randomized 1303 RER (day 7 M1/M2 marrow) patients to receive 1 of 4
arms in a 2 x 2 manner
• A: Standard therapy with 1 IM and 1 DI phase
• B: Standard with 2 IM and 2 DI phases
• C: Standard + augmented consolidation, IM and DI
• D: Augmented BFM with 2 IM and DI phases
• Differences between augmented BFM in 1882 and 1961
– No XRT for RER patients in 1961
– 1882 used native L’Asp throughout; 1961 had native in induction and PEG
thereafter

CCG 1961: Results
• Augmented BFM is superior to standard BFM
• Augmented BFM has increased morbidity but no
difference in mortality
– Major morbidity is avascular necrosis of bone in
patients 13+ years old
• Risk can be decreased significantly by interrupted Dex
• There is no benefit to longer duration of intensive
therapy
• Regimen C (augmented BFM with 1 IM + 1 DI) is
the standard regimen for future HR-ALL trials

CCG-1961 EFS Outcome by RER Groups:
Augmented Therapy Improves EFS
1
0.9
Augmented BFM (N=647)
Standard BFM (N=646)
Probability
0.8
0.7
Log rank p = .001
0.6
0.5
5 Yr EFS RHR
Augmented BFM 81.0% Baseline
Standard BFM 70.2% 1.54
0 1 2 3 4 5 6 7 8
Years Followed
Seibel NL et al Blood 102: #787, 2003

CCG-1961 EFS Outcome by RER Groups:
No Benefit to Prolonged Intensification
1
0.9
Standard Duration (N=645)
Increased Duration (N=648)
Probability
0.8
0.7
0.6
0.5
Log rank p = .45
5 Yr EFS RHR
Standard Duration 76.3% Baseline
Increased Duration 74.8% 1.11
0 1 2 3 4 5 6 7 8
Seibel NL et al Blood 102: #787, 2003
Years Followed

CCG-1961 EFS Outcome by RER Groups
Probability
1
0.9
0.8
0.7
0.6
0.5
Log rank p = .01
5 Yr EFS RHR
SBFM/SD 71.1% Baseline
ABFM/SD 81.5% .68
ABFM/ID 80.7% .71
SBFM/ID 69.3% 1.13
SBFM/SD (N=321)
ABFM/SD (N=324)
ABFM/ID (N=323)
SBFM/ID (N=325)
0 1 2 3 4 5 6 7 8
Years Followed
Seibel NL et al Blood 102: #787, 2003

Outline
• Overview
– Childhood cancer incidence and epidemiology
– Acute leukemia: epidemiology and pathobiology
• Childhood ALL
– Classification and treatment
• ALL in adolescents and young adults (AYA)
• Relapsed childhood ALL
• The role of SCT in children and AYA with ALL

Incidence of ALL by Age:
SEER 1986-1995
60
50
40
30
20
Cases per million
10
0
0-4
yr
5-9
yr
10-
14 yr
15-
19 yr
20-
24 yr
25-
29 yr
30-
34 yr

ALL 5-Year Survival Rates:
SEER 1986-1995
90
80
70
60
50
40
30
20
10
0
0-4
yr
5-9
yr
10-14
yr
15-19
yr
20-24
yr
25-29
yr
30-34
yr
5 yr Survival

AYA ALL: Reasons for
Differences in Outcome
• Age is a powerful predictor of outcome
– UKALL studies
• Selective entry onto trials results in children receiving
more “state of the art” therapy
• Treatment on pediatric trials is better: CCG vs.
CALGB and FRALLE-94 vs. LALA-94 comparisons
– Better therapy vs. more comprehensive and aggressive
treatment approach
• Parallel pediatric and adult trials will help to address this question

The Impact of Age on Outcome in
ALL with Identical Therapy:
UKALL X and XA
Age (n) DFS S
1-9 yr (1349) 62% 81%
10-14 yr (238) 49% 72%
15-19 yr (200) 35% 60%
20-39 yr (228) 29% 43%
Proportional hazard
analysis
Age RR
10 yr old 1
20 yr old 2
40 yr old 4
Chessels et al: Leukemia 12: 463-473, 1998

Accrual to NCI Cooperative Group
Clinical Trials: 10/97-9/98
2500
2000
1500
1855
1263
Patients < 20 years old:
~1% of patients with CA
22% of total cooperative group accrual
1000
997
761
819
500
413
126 162
0
00-04 5-9 10-14 15-19 20-24 25-29 30-34 35-39
Age (Years)

Enrollment in NCI Cooperative
Group Protocols: 15-19 years of age
Adult Groups
2.8%
Pediatric
Groups
97.2%

AYA ALL Patients: Outcome on
CCG vs. CALGB Trials
• CALGB 1988-98: 103 patients 16-20 years
– 93% CR rate, 38% 6 yr EFS
– Outcome similar to patients 21-29 yrs on same trials
• CCG 1989-1995: 196 patients 16-21 years
– 96% CR rate, 64% 6 yr EFS
• No significant differences in characteristics
between CALGB and CCG patients
Stock et al: Blood 96: 467a, 2000 (abstr.)

Acute Lymphoblastic Leukemia:
Disease Free Survival is Better on Pediatric Trials
Stock W Sather H, Dodge RK, Bloomfield CD, Larson A, Nachman J.
Blood 96: 467a, 2000.
CCG-1800 Series 16-21 Year-Olds (N = 175)
68+2%
DFS
16-20 Years (N = 103)
CALGB
20-29 Years (N = 123)

AYA ALL: Comparison of
FRALLE-93 and LALA-94
• Adolescents 15-20 yrs. enrolled 6/93-9/94
– Pediatric FRALLE-93: 77 pts (median 15.9 yrs)
– Adult LALA-94: 100 pts (median 17.9 yrs)
• No other significant differences in characteristics
between FRALLE-94 and LALA-94 patients
• Outcome significantly better on pediatric trial
– FRALLE-93: CR 94%, 5-year EFS 67%
– LALA-94: CR 83%, 5-year EFS 41%
Boissel et al, JCO 21: 774, 2003

AYA with ALL: CCG 1961
• 262 AYA ALL patients entered onto CCG 1961
trial for high risk ALL from 11/96 to 5/02
• Overall 5 yr. EFS 68%, 5 yr. Survival 77%
– Rapid responders randomized to 4 regimens
• Augmented therapy: 83% 5 yr EFS
• Standard therapy: 61% 5 yr EFS
– Slow responders had 76% 5 yr. EFS (all received
augmented therapy)
– Initial WBC
• Less than 50,000: 73% 5 yr. EFS
• More than 50,000: 54% 5 yr. EFS
Nachman et al, Blood 104: 196a, 2004 (abstr.)

CCG-1961 Augmented vs. Standard BFM
EFS outcome (Age 16+ subset)
Probability
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
AUG BFM (N=87)
STD BFM (N=76)
p=.11
5-Yr EFS
AUG BFM 83.3% (s.d.9.8%)
STD BFM 60.8% (s.d.11.0%)
0 1 2 3 4 5 6 7 8
Years Followed

CCG 1961: Effective Therapy
Negates the Impact of Older Age
Age Group
1 yr
2-5 yr
6-9 yr
10-15 yr
16+ yr
O/E
1.40
0.67
1.20
1.06
1.04
4yr EFS
64.2%
79.3%
66.9%
69.5%
73.6%

ALL in Adolescents and Young
Adults: Conclusions
• Outcome is superior for similar patients treated on
pediatric trials
– Difference is substantial: cure rates are 20-30% higher in
absolute numbers
– Therapy vs. the context in which it is delivered?
• Adolescents with ALL should be treated in pediatric
centers on pediatric protocols
– Where would you want your teenager treated if s/he had
ALL?
• Therapies effective in adolescents should be tested in
young adults
– Dissect the benefits of the therapy vs. the system

COG AALL0232: HR B-Precursor
ALL
• 2 x 2 randomized trial
– Induction
• 14 days Dex vs. 28 days Pred (rest of trial is Dex)
– Interim Maintenance
• Capizzi escalating IV MTX without rescue + Asp vs. 4 courses HD
MTX
• Efforts to improve AYA ALL outcome
– Eligibility for COG AALL0232 increased from

Outline
• Overview
– Childhood cancer incidence and epidemiology
– Acute leukemia: epidemiology and pathobiology
• Childhood ALL
– Classification and treatment
• ALL in adolescents and young adults (AYA)
• Relapsed childhood ALL
• The role of SCT in children and AYA with ALL

Relapsed Leukemia
• Reasons for relapse are uncertain
– The patient was not treated intensively enough
the first time
– The patient’s leukemia cells developed
resistance to particular chemotherapy agents
• In general, treatment must be changed or
intensified after relapse

Childhood ALL: Prognostic Factors
at Relapse
• Site of relapse
– Bone marrow worse than extramedullary
• CNS, testicular, etc
• Time to relapse
– Earlier much worse than later
• Genetic features
– Relapsed T-ALL very poor outcome in some studies
• No cures with chemo alone in recent matched cohort study
– Relapsed Ph+ ALL has a dismal prognosis and less
then 50% of patient will achieve a 2nd remission
– Relapsed TEL-AML1+ ALL does relatively well
• 80% vs 33% 2 year EFS in BFM REZ 90-06

ALL: Outcome Following Relapse by
Site and Time in CCG 100 Series
Site
BM only
0-17 mo.
18-35 mo.
36+ mo.
CNS only
0-17 mo.
18-35 mo.
36+ mos.
Number
642
233
194
215
220
102
84
34
6 yr EFS
16%
5%
10%
33%
37%
24%
44%
59%
6 yr OS
20%
6%
11%
43%
48%
33%
59%
72%
Gaynon PS et al, Cancer 82: 1387-95, 1998

CCG 1941: Marrow Relapse within
12 Months of Completing Therapy
• Only about 70% of
patients achieved
remission
• Overall EFS from
study entry is 15-20%
• No difference based
on post-induction
therapies
Figure 1. Probability of event-free survival after marrow
relapse according to treatment received. Data from
CCG-1941. Alt BMT=alternative BMT. Chemo =
chemotherapy. CBMT = family donor BMT.

ALL With BM Relapse:
AALL01P2 and AALL0433
Remission Induction
+/- new agent
for early
relapse
0-35 months CR1 36+ months CR1
Alternative Donor BMT
Matched Sib BMT
Chemotherapy

ALL with Extramedullary Relapse
0-17 mos. CR1:
AALL0433
18+ mos. CR1:
AALL02P2
Matched Sib BMT
Chemotherapy

Early Relapse ALL: Integrate New
Agents with Intensive Chemotherapy
• Limited benefit from treatment intensification alone
• Stem cell transplant is only part of the answer
– Many patients never get to transplant
– Very high risk of relapse post transplant
• Hypothesize that integration of newer molecularly targeted
therapies into chemotherapy backbones will increase # of CR
and depth of CR pre SCT
• COG ALL plan
– Develop an effective therapeutic backbone
– Integrate promising agents into backbone and test efficacy
• 4 month EFS and MRD assessment of leukemia kill

Integration of New Agents with Intensive
Chemotherapy in Relapsed ALL
Reduction
Phase
Reinduction
Block 1
Reinduction
Block 2
Reinduction
Block 3
AALL01P2
VCR, PRED,
PEG, DOX
CTX, VP-16, MTX
ARA-C, ASP
MRD
Future new agent pilot studies
MRD
VCR, PRED,
PEG, DOX
CTX, VP-16, MTX
ARA-C, ASP
Time
MRD
ADVL0423 (Epratuzumab) in 2005
Correlate with 4
month EFS

Outline
• Overview
– Childhood cancer incidence and epidemiology
– Acute leukemia: epidemiology and pathobiology
• Childhood ALL
– Classification and treatment
• ALL in adolescents and young adults (AYA)
• Relapsed childhood ALL
• The role of SCT in children and AYA with ALL

The Role of SCT in ALL in CR1
• Little role for routine use of SCT in patients with
ALL

SCT for Children and
Adolescents with ALL in CR1
• Matched sibling SCT is generally considered the
therapy of choice for:
– Ph+, Hypodiploidy with n

SCT for Children and Adolescents
with ALL Following Relapse
• Matched sib SCT indicated for ALL with 1 st
marrow relapse at any time or early CNS relapse
(