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Curing Acute Lymphoblastic Leukemia in Children Without New Agents

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Applying Lessons Learned in Biology, Pharmacology and Molecular Biology A Paradigm for Disease Treatment Joseph M. Wiley, MD Division of Pediatric Hematology-Oncology – PowerPoint PPT presentation

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Title: Curing Acute Lymphoblastic Leukemia in Children Without New Agents


1
Curing Acute Lymphoblastic Leukemia in Children
Without New Agents  Applying Lessons Learned in
Biology, Pharmacology and Molecular BiologyA
Paradigm for Disease Treatment
  • Joseph M. Wiley, MD
  • Division of Pediatric Hematology-Oncology
  • Chairman, Department of Pediatrics
  • The Herman and Walter Samuelson Childrens
    Hospital at Sinai, Baltimore, MD

2
Goals and Objectives
  • The attendees will gain an understanding of the
    basic Biology of ALL
  • The attendees will learn the biologic features
    that predict for prognosis with therapy of ALL
  • The attendees will learn the importance of
    response to therapy as a prognostic factor in ALL
  • The attendees will gain an understanding of the
    importance of the role of clinical trials in
    childhood cancer

3
Conflicts of Interest
  • Speakers Bureau
  • Enzon Pharmaceuticals (Oncospar)
  • Grant Funding
  • Childrens Oncology Group- Chairmans Grant
  • NHLBI- Sickle Cell Network
  • Childrens Cancer Foundation Scientific Grant
  • Off Label Usage
  • Almost all Pediatric chemotherapy drugs are off
    label
  • Alternative funding
  • Get a check from my mom on my birthday

4
Acute Leukemia
  • Clonal Disorder of Lymphohematopoietic System
  • Malignant event - probably as a result of a
    sequence of events
  • Clonal expansion leads to marrow replacement
  • Complex interaction of genetic, immunologic,
    pathologic and clinical features

5
Acute Leukemia in Childhood
  • Incidence is 1/2000- 1/2500 by age 18
  • Peak incidence age 4
  • More common in whites and boys
  • Associated with RT exposure
  • Increased incidence in Downs, FA, AT, Blooms,
    etc.

6
Acute Leukemia in Childhood
  • Acute Lymphoblastic Leukemia (ALL)
  • 80 of Acute Leukemia
  • 85 B- cell Lineage
  • 15 T- cell Lineage
  • Acute Nonlymphoblastic Leukemia (ANLL)
  • 20 of Childhood Leukemia

7
Acute Lymphoblastic Leukemia Is the Most Common
Childhood Cancer
Yearly Incidence of Childhood Cancers
8
Acute Lymphoblastic Leukemia
  • The most common group of pediatric malignancies
  • A paradigm for success in cancer treatment
  • Recent discoveries lend insight to the great
    heterogeneity of the disease
  • Goal is to decrease toxicity while tailoring
    therapy to risk

9
Acute Lymphoblastic LeukemiaClinical Features
  • Few, if any distinguishing features
  • Anemia is more severe out of proportion to other
    abnormalities
  • Suspicion raised when 2 or more hematopoietic
    lineages involved
  • Systemic Illness that persists when other
    diagnostic candidates should fade

10
Acute Lymphoblastic LeukemiaClinical Features
  • Fever, bone pain, limp
  • Peripheral blood cytopenias
  • Hepatosplenomegaly, lymphadenopathy
  • Infections, fatigue, bleeding
  • CNS symptoms, airway compression

11
Acute Lymphocytic Leukemia Peripheral Smears
12
Acute Lymphocytic Leukemia Bone Marrow Aspirates
13
Acute Lymphoblastic LeukemiaPrognostic Features
  • Risk Factors for Relapse in ALL
  • Standard Risk High Risk
  • ____________________________________________
  • Age 1-9 years of age lt1 yr., gt 10 yrs.
  • WBC at
  • Diagnosis lt 50,000/mm3 gt50,000/mm3
  • Cytogenetics Many abnormal. t(922), t(411)

14
ALL- Treatment
  • Induction
  • 4-6 week therapy with non myelosuppressive drugs
    (ex anthracyclines- high risk)
  • Consolidation
  • 4-10 months therapy with cyclical rounds of
    various drugs based in anti metabolite backbone
    (methotrexate, thiopurines)
  • Maintenance
  • 2-3 years of less intensive treatment

15
Survival of Patients With Acute Lymphoblastic
Leukemia, 1968-1997

CNS Prophylaxis introduced
16
SEER 5-Year Survival RatesAge lt 15 years
Survival 1974-1976 Survival 1992-1999 Increase Survival Decrease Death
Bone 55 72 31 38
Brain 55 70 27 33
Hodgkins 78 94 21 23
ALL 53 85 60 68
AML 14 47 236 38
Jemal A et al. CA Cancer J Clin. 2004548-29.
17
EFS of Young Adults Aged 16 to 21 on CCG and
CALGB Trials for ALL (1988-1995)
1.0
EFS of Young Adults with ALL
0.8
CCG
0.6
Proportion
0.4
CALGB (median 2.5 y)
CALGB (median 2.5)
0.2
0.0
0
2
4
6
8
10
Years
18
Key Components of Successful Therapy
  • Empiric multi-agent chemotherapy
  • Pre-symptomatic CNS therapy
  • Post-induction intensification
  • Anti-metabolite therapy
  • Re-induction/re-consolidation
  • Risk adapted therapy

19
Acute Leukemia in ChildhoodBiologic Features
  • Morphologic Features
  • Immunophenotype
  • Karyotype
  • DNA features
  • Response to therapy

20
Genetic Heterogeneity in Childhood ALL Childrens
Oncology Group
Ph
t(119)
14q11
11q23
2
4
3
Normal
4
26
TEL-AML1
18
lt 45 Chrom
1
45 Chrom
3
gt 50 Chrom
Pseudodiploid
47-50 Chrom
26
10
6
21
Genotype Correlates with OutcomeChildrens
Oncology Group
100
Trisomies 4,10,17 (n 746)
TEL (n 176)
80
t(119) (n 139)
60
t(411) (n 44)
Probability
40
t(922) (n132)
4 Yr EFS () SE () Tris 4,10,17
92.1 1.1 TEL 89.0
3.1 t(119) 68.9 4.1 t(411)
49.9 11.2 t(922) 27.5
4.4
20
B-precursor ALL
0
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Years Followed
10/2001
22
Rate of Initial Response is Strong Predictor of
Event-Free-Survival
lt5 Blasts in Bone Marrow
Day 7 Rapid Early Response
Event-Free Survival ()
Day 14 Intermediate Early Response
p.0005
Day 28 Slow Early Response
Years
Steinherz, et al JCO 14 389-398, 1996
23
COG ALL Risk GroupsB-Precursor ALL
  • NCI Risk Groups
  • Trisomies 4, 10, 17
  • TEL/AML 1
  • Rapidity of Response
  • CNS Disease
  • MRD - End of Induction
  • MLL (t(411))
  • BCR-ABL (t(922))
  • Chromosomes lt45

Low Risk
Standard Risk
High Risk
Very High Risk
24
Outcome by New Risk Group Definitions
B-precursor ALL
100
Low Risk (n544)
Standard Risk (n1471)
80
High Risk (n880)
Probability
60
Very High Risk (n78)
40
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
20
0
0
1
2
3
4
5
6
7
8
9
10/2001
Years Followed
25
Flow Cytometry for ALL Identification
26
Acute Lymphoblastic LeukemiaB-Precursor Standard
Risk (COG AALL0331)
MRD of Patients
gt 1.0 42 2.7
0.1-0.99 89 5.7
lt0.1 1435 91.6
Total 1566 100
27
Prognostic Significance of MRD POG 9906 (Higher
Risk)

Michael Borowitz
28
DAY 29 MRD (gt.01) IS PROGNOSTIC IN ALL STUDIES
POG 9900
9905 SR
9904 LR
9905 IR
9906 HR
29
Prognostic Significance of Day 8 Blood MRD
Courtesy of Michael Borowitz, MD
30
MRD and Outcome Approaches to Define a Favorable
Subset
Overall Day 8 Blood MRD negative Day 29 Marrow MRD positive
3 Yr Event-Free Survival 743 875 vs 714 586 vs 795
Courtesy of Michael Borowitz, MD
Define Unfavorable Subset
Define Favorable Subset
31
Prognostic significance of TEL and Trisomy
depends on MRD status
NCI HR Day 29 MRD lt.01
NCI HR Day 29 MRD gt.01
32
98?1
92?3
75?6
4 y EFS ?S.E.
33
Proposed 2009 Classification
EFS() Patients ()
Low Risk NCI SR Triple Trisomy, TEL-AML 1 Day
8 PB, Day 29 BM MRD Negative
95 13
gt85 50
Standard Risk NCI SR w/o TT, Tel NCI HR TT,
Tel day 29 BM Negative (lt 0.01)
7085 17
High Risk NCI HR SR EM day 29 BM MRD Negative
(lt 0.01)
50 20
Very High Risk NCI SR or HR day 29 BM MRD gt
0.01
34
Recent improvements In ALL Results
  • Large, Randomized Clinical Trials
  • Combination of Biology stratification with
    refined use of old formulary
  • Intensification of early treatment

35
Changes in Chemotherapy Strategies in ALL
  • 1970s Therapy
  • Induction
  • Vcr/Steroids/Dauno/Asn
  • Continuation
  • Cyclo/6-TG/ARA-C
  • 6-MP/Mtx
  • IT Mtx/- HC/ARA-C
  • Asn
  • Maintenance
  • VCR/Pred Pulses
  • Daily 6MP/Wkly MTX
  • Year 2005
  • Induction
  • Vcr/Steroids/Dauno/PEG-Asn
  • Continuation
  • Cyclo/6-TG/ARA-C
  • 6-MP/Mtx
  • IT Mtx/- HC/ARA-C
  • PEG-Asn
  • Maintenance
  • VCR/Pred Pulses
  • Daily 6MP/Wkly MTX

No new drugs- Just smarter ways to give them!!
36
Dexamethasone versus prednisone and daily oral
versus weekly intravenous mercaptopurine for
patients with standard-risk acute lymphoblastic
leukemia a report from the Childrens Cancer
Group

Bostrom BC, et Blood. 20031013809-3817
37
Day 7 Slow Response HR Subset Chosen to Test of
Augmented BFM
lt5 Blasts (Leukemia Cells) in Bone Marrow by
Steinherz PG, JCO
P lt 0.001
38
Augmented BFMLonger and stronger postinduction
intensification
  • Stronger intensification
  • More therapy in less time
  • Vcr Capizzi I - Mtx/asparaginase for oral
    6-MP/Mtx in interim maintenance (no leukovorin)
  • Vcr/asparaginase during 2 weeks of count
    suppression following Cpm/araC/thiopurine pulses
  • Longer Intensification
  • DI phase x 2
  • 10 versus 4 months of postinduction
    intensification

39
Success of Longer and Stronger Postinduction
Intensification (SER)
Nachman JB et al. N Engl J Med.
19983381663-1671.
CCG-1882
P lt .001
40
CCG-1961 DFS From RER RandomizationComparison
of Stronger Versus Standard Strength
Intensification for Rapid Early Responders
Stronger 81
Intensified MTX/Asn
Standard 70
N 1299 RHR 0.65 P 0.0004
Seibel, NL et al Blood 2008 111 2548-2555
41
Why Study Asparaginase?
42
Asparaginase Intolerance Inferior Outcome
43
DFCI ALL Consortium ProtocolsObjectives
  • DFCI Prot ASN post Ind EFS
  • 81-01 None 74 /- 3
  • 85-01 20 wks 78 /- 3
  • 91-01 30 wks 83 /- 2

44
Improved outcome for children with acute
lymphoblastic leukemia results of Dana-Farber
Consortium Protocol 91-01Silverman LB, et al,
Blood. 2001971211-1218)
45
Recent Advances in Pediatric ALL
  • CCG 1922 (Std Risk) Dexamethasone for Prednisone
  • CCG 1961 (High Risk) Intensified MTX/ASP
  • BFM-90, 95 antimetabolitie (MTX, 6TG, ARA-C)
  • dexamethasone, asparaginase
  • DFCI 91-01 Intensified Asparaginase, HDMTX,
  • Increased Dexamethasone

46
Postinduction intensification Postinduction intensification Postinduction intensification
Study Intervention EFS
CCG-105 Average risk DI 60 vs 74 _at_ 10 years
CCG-1881 Lower risk DI 77 vs 83 _at_ 7 years
CCG-1891 Average risk DDI 76 vs 83 _at_ 6 years
CCG-1882 Higher risk/SER Longer stronger intensification 55 vs 75 _at_ 5 years
CCG-1961 Higher risk/RER Stronger intensification 70 vs 81 _at_ 5 years
47
Recent Advances in Pediatric ALL
  • With Increased intensity comes (often) increased
    toxicity
  • Toxicities can be supported through improved
    understanding of the biology and pharmacogenetics
    of individual patient tolerance to agents
  • Unique genetic and pharmacodynamic features of
    individual agents have a major impact on the
    outcome, toxicity and late sequalae of cancer
    chemotherapy

48
Osteoporosis/Osteopenia/ Osteonecrosis in
Pediatric Cancer Survivors
  • Corticosteroids
  • Methotrexate
  • Radiation to weight-bearing bones
  • Hormonal influences from gonadal, thyroid, and
    growth hormones
  • Chronic graft-versus-host disease requiring
    prolonged therapy with corticosteroids

49
Osteonecrosis During the Treatment of Childhood
Acute Lymphoblastic Leukemia A Prospective MRI
StudyOjala AE, et al Medical and Pediatric
Oncology 321117 (1999)
The T1-weighted coronal planes (1.0 T, SE 500/15)
of the right shoulder in a 3-year-old boy with
IR ALL. A The scan after the delayed
intensification phase reveals osteonecrosis in
the proximal humerus. B At the cessation of the
therapy, 2.5 years later, the lesion of
osteonecrosis has disappeared.
50
Dexamethasone versus prednisone and daily oral
versus weekly intravenous mercaptopurine for
patients with standard-risk acute lymphoblastic
leukemia a report from the Childrens Cancer
Group

Bostrom BC, et Blood. 20031013809-3817
51
Osteonecrosis as a Complication of Treating
AcuteLymphoblastic Leukemia in Children A
Report From the Childrens Cancer Group (CCG
1882)
Mattano LA, et al,. J Clin Oncol 183262, 2000
52
Osteonecrosis as a Complication of Treating
AcuteLymphoblastic Leukemia in Children A
Report From the Childrens Cancer Group (CCG
1882)
Mattano LA, et al,. J Clin Oncol 183262, 2000
53
Acute LeukemiaOutcome Measures
  • Hypothesis Increased emphasis on outcomes of
    therapy including measures of psychological,
    emotional and physical well-being will optimize
    treatment
  • Approach Parallel studies to address
  • Burdens of care (financial, emotional)
    Neurotoxicity (methotrexate, dexamethasone)
  • Effects of intensified therapy on stem cells
  • Bone mineral content and avascular necrosis

54
Relapsed ALL Remains a Common Problem
55
Most Patients Who Relapse Once Die! Despite
high remission-induction rates and BMT
CCG-1900 series trials Survival After 1st Relapse
Site of relapse (n) 3-year Survival Rate
Any site (809) 40
Bone marrow (505) 28
Isolated CNS (185) 60
Isolated testes (52) 60
56
Acute Leukemia
  • Progress in treatment and cure rates for leukemia
    in childhood has been dramatic in 40 years
  • Progress has been achieved through subsequent
    clinical research
  • Incorporation of biology has led to tailoring
    therapy and improving outcomes
  • There is room for new agents but biology and
    genetics are stronger factors in controlling
    outcomes
  • Better understanding of the right way to give
    currently available agents still shows benefits
    in current trial strategies

57
Summary
  • Your head is round so that your thinking can
    change direction
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