Curing Acute Lymphoblastic Leukemia in Children Without New Agents
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Curing Acute Lymphoblastic Leukemia in Children Without New Agents Applying Lessons Learned in Biology, Pharmacology and Molecular Biology A Paradigm for Disease Treatment. Joseph M. Wiley, MD Division of Pediatric Hematology-Oncology Chairman, Department of Pediatrics

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Curing Acute Lymphoblastic Leukemia in Children Without New AgentsApplying 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 Children’s Hospital at Sinai, Baltimore, MD


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

Goals and Objectives


Conflicts of interest

Speaker’s Bureau Biology of ALL

Enzon Pharmaceuticals (Oncospar)

Grant Funding

Children’s Oncology Group- Chairman’s Grant

NHLBI- Sickle Cell Network

Children’s 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

Conflicts of Interest


Acute leukemia

Clonal Disorder of Lymphohematopoietic System Biology of ALL

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

Acute Leukemia


Acute leukemia in childhood

Incidence is ~ 1/2000- 1/2500 by age 18 Biology of ALL

Peak incidence age 4

More common in whites and boys

Associated with RT exposure

Increased incidence in Down’s, FA, AT, Bloom’s, etc.

Acute Leukemia in Childhood


Acute leukemia in childhood1

Acute Lymphoblastic Leukemia (ALL) Biology of ALL

80% of Acute Leukemia

85% B- cell Lineage

15% T- cell Lineage

Acute Nonlymphoblastic Leukemia (ANLL)

20 % of Childhood Leukemia

Acute Leukemia in Childhood


Acute lymphoblastic leukemia is the most common childhood cancer
Acute Lymphoblastic Leukemia Is Biology of ALLthe Most Common Childhood Cancer

Yearly Incidence of Childhood Cancers


Acute lymphoblastic leukemia

The most common group of pediatric malignancies Biology of ALL

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

Acute Lymphoblastic Leukemia


Acute lymphoblastic leukemia clinical features

Few, if any distinguishing features Biology of ALL

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

Acute Lymphoblastic LeukemiaClinical Features


Acute lymphoblastic leukemia clinical features1

Fever, bone pain, limp Biology of ALL

Peripheral blood cytopenias

Hepatosplenomegaly, lymphadenopathy

Infections, fatigue, bleeding

CNS symptoms, airway compression

Acute Lymphoblastic LeukemiaClinical Features


Acute lymphocytic leukemia peripheral smears
Acute Lymphocytic Leukemia Biology of ALLPeripheral Smears


Acute lymphocytic leukemia bone marrow aspirates
Acute Lymphocytic Leukemia Biology of ALLBone Marrow Aspirates


Acute lymphoblastic leukemia prognostic features

Risk Factors for Relapse in ALL Biology of ALL

Standard Risk High Risk

____________________________________________

Age 1-9 years of age <1 yr., > 10 yrs.

WBC at

Diagnosis < 50,000/mm3 >50,000/mm3

Cytogenetics Many abnormal. t(9:22), t(4:11)

Acute Lymphoblastic LeukemiaPrognostic Features


All treatment

Induction Biology of ALL

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

ALL- Treatment


Years of Biology of ALL

Diagnosis

Number of

Children

100

1995-97

1299

1993-95

1585*

1989-93

3402

80

1983-89

3711

1978-83

2984

60

1975-78

1313

1972-75

936

% Survival

40

1970-72

499

20

C C G

Bleyer

1968-70

402

0

2

6

8

10

4

Total Number of

Patients Treated:

16,131

Years After Study Entry

*Excluding infants.

Survival of Patients With Acute Lymphoblastic Leukemia, 1968-1997

CNS Prophylaxis introduced


Seer 5 year survival rates age 15 years
SEER 5-Year Survival Rates Biology of ALLAge < 15 years

Jemal A et al. CA Cancer J Clin. 2004;54:8-29.


C C G Biology of ALL

Bleyer

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


Key components of successful therapy

Empiric multi-agent chemotherapy Biology of ALL

Pre-symptomatic CNS therapy

Post-induction intensification

Anti-metabolite therapy

Re-induction/re-consolidation

Risk adapted therapy

Key Components of Successful Therapy


Acute leukemia in childhood biologic features

Morphologic Features Biology of ALL

Immunophenotype

Karyotype

DNA features

Response to therapy

Acute Leukemia in ChildhoodBiologic Features


Genetic heterogeneity in childhood all children s oncology group
Genetic Heterogeneity in Childhood ALL Children’s Oncology Group

14q11

Ph

t(1;19)

11q23

3%

2%

4%

“Normal”

4%

26%

TEL-AML1

18%

< 45 Chrom

1%

45 Chrom

3%

> 50 Chrom

Pseudodiploid

47-50 Chrom

26%

10%

6%


Genotype Correlates with Outcome GroupChildren’s Oncology Group

100

Trisomies 4,10,17 (n = 746)

TEL (n =176)

80

t(1;19) (n = 139)

60

t(4;11) (n = 44)

Probability

40

t(9;22) (n=132)

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

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


Rate of initial response is strong predictor of event free survival
Rate of Initial Response is Strong Predictor of Event-Free-Survival

<5 % 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


Cog all risk groups b precursor all
COG ALL Risk Groups Event-Free-SurvivalB-Precursor ALL

  • NCI Risk Groups

  • Trisomies 4, 10, & 17

  • TEL/AML 1

  • Rapidity of Response

  • CNS Disease

  • MRD - End of Induction

  • MLL (t(4:11))

  • BCR-ABL (t(9:22))

  • Chromosomes <45

Low Risk

Standard Risk

High Risk

Very High Risk


Outcome by New Risk Group Definitions Event-Free-Survival

B-precursor ALL

Low Risk (n=544)

100

Standard Risk (n=1471)

80

High Risk (n=880)

Probability

60

Very High Risk (n=78)

40

Risk Group4 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



Acute lymphoblastic leukemia b precursor standard risk cog aall0331
Acute Lymphoblastic Leukemia Event-Free-SurvivalB-Precursor Standard Risk (COG AALL0331)


Prognostic significance of mrd pog 9906 higher risk

Event-Free Survival Event-Free-Survival

100

n=156

80

60

p-value = 0.00304

Probability (%)

40

n=79

MRD Negative

MRD > .01%

20

0

0

1

2

3

4

5

Years

Prognostic Significance of MRD POG 9906 (Higher Risk)

Michael Borowitz


Day 29 mrd 01 is prognostic in all studies

POG 9900 Event-Free-Survival

DAY 29 MRD (>.01%) IS PROGNOSTIC IN ALL STUDIES

9905

SR

9904

LR

9905

IR

9906

HR


Prognostic Significance of Day 8 Blood MRD Event-Free-Survival

Courtesy of Michael Borowitz, MD


Mrd and outcome approaches to define a favorable subset
MRD and Outcome Event-Free-SurvivalApproaches to Define a Favorable Subset

Courtesy of Michael Borowitz, MD

Define Unfavorable

Subset

Define Favorable

Subset


Prognostic significance of tel and trisomy depends on mrd status
Prognostic significance of TEL and Trisomy Event-Free-Survivaldepends on MRD status

NCI HR

Day 29 MRD <.01%

NCI HR

Day 29 MRD >.01%


98 Event-Free-Survival1%

923%

756%

4 y EFS

% S.E.


Proposed 2009 classification
Proposed 2009 Classification Event-Free-Survival

EFS(%) Patients (%)

Low Risk – NCI SR Triple Trisomy, TEL-AML 1; Day 8 PB, Day 29 BM MRD Negative

95 13

>85 50

Standard Risk – NCI SR w/o TT, Tel; NCI HR TT, Tel; day 29 BM Negative (< 0.01%)

70–85 17

High Risk – NCI HR; SR EM; day 29 BM MRD Negative (< 0.01%)

50 20

Very High Risk – NCI SR or HR; day 29 BM MRD > 0.01%


Recent improvements in all results

Large, Randomized Clinical Trials Event-Free-Survival

Combination of Biology stratification with refined use of “old” formulary

Intensification of early treatment

Recent improvements In ALL Results


Changes in chemotherapy strategies in all

1970’s Therapy Event-Free-Survival

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

Changes in Chemotherapy Strategies in ALL

No new drugs- Just smarter ways to give them!!


Dexamethasone versus prednisone and daily oral versus weekly intravenous mercaptopurine for patients with standard-risk acute lymphoblastic leukemia: a report from the Children’s Cancer Group

Bostrom BC, et Blood. 2003;101:3809-3817


Day 7 slow response hr subset chosen to test of augmented bfm

C C G intravenous mercaptopurine for patients with standard-risk acute lymphoblastic leukemia: a report from the Children’s Cancer Group

Bleyer

Day 7 Slow Response HR Subset Chosen to Test of Augmented BFM

<5% Blasts (Leukemia Cells) in Bone Marrow by

Steinherz PG, JCO

P < 0.001


Augmented bfm longer and stronger postinduction intensification

Stronger intensification intravenous mercaptopurine for patients with standard-risk acute lymphoblastic leukemia: a report from the Children’s Cancer Group

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

Augmented ‘BFM’Longer and stronger postinduction intensification


Success of longer and stronger postinduction intensification ser

C C G intravenous mercaptopurine for patients with standard-risk acute lymphoblastic leukemia: a report from the Children’s Cancer Group

Bleyer

Success of Longer and Stronger Postinduction Intensification (SER)

Nachman JB et al. N Engl J Med. 1998;338:1663-1671.

CCG-1882

P < .001


CCG-1961 DFS From RER Randomization: intravenous mercaptopurine for patients with standard-risk acute lymphoblastic leukemia: a report from the Children’s Cancer GroupComparison 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


Why study asparaginase
Why Study Asparaginase? intravenous mercaptopurine for patients with standard-risk acute lymphoblastic leukemia: a report from the Children’s Cancer Group


Asparaginase intolerance inferior outcome
Asparaginase Intolerance: intravenous mercaptopurine for patients with standard-risk acute lymphoblastic leukemia: a report from the Children’s Cancer GroupInferior Outcome


Dfci all consortium protocols objectives
DFCI ALL Consortium Protocols: intravenous mercaptopurine for patients with standard-risk acute lymphoblastic leukemia: a report from the Children’s Cancer GroupObjectives

DFCI Prot # ASN post Ind EFS

81-01 None 74% +/- 3%

85-01 20 wks 78% +/- 3%

91-01 30 wks 83% +/- 2%


Improved outcome for children with acute lymphoblastic leukemia: results of Dana-Farber Consortium Protocol 91-01Silverman LB, et al, Blood. 2001;97:1211-1218)


Recent advances in pediatric all

CCG 1922 (Std Risk) leukemia: results of Dana-Farber Consortium Protocol 91-01 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

Recent Advances in Pediatric ALL


Recent advances in pediatric all1

With Increased intensity comes (often) increased toxicity leukemia: results of Dana-Farber Consortium Protocol 91-01

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

Recent Advances in Pediatric ALL


Osteoporosis osteopenia osteonecrosis in pediatric cancer survivors

Corticosteroids leukemia: results of Dana-Farber Consortium Protocol 91-01

Methotrexate

Radiation to weight-bearing bones

Hormonal influences from gonadal, thyroid, and growth hormones

Chronic graft-versus-host disease requiring prolonged therapy with corticosteroids

Osteoporosis/Osteopenia/ Osteonecrosis in Pediatric Cancer Survivors


Osteonecrosis During the Treatment of Childhood Acute Lymphoblastic Leukemia: A Prospective MRI StudyOjala AE, et al Medical and Pediatric Oncology 32:11–17 (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.


Dexamethasone versus prednisone and daily oral versus weekly intravenous mercaptopurine for patients with standard-risk acute lymphoblastic leukemia: a report from the Children’s Cancer Group

Bostrom BC, et Blood. 2003;101:3809-3817


Osteonecrosis as a Complication of Treating Acute intravenous mercaptopurine for patients with standard-risk acute lymphoblastic leukemia: a report from the Children’s Cancer GroupLymphoblastic Leukemia in Children: A Report From the Children’s Cancer Group (CCG 1882)

Mattano LA, et al,. J Clin Oncol 18:3262, 2000


Osteonecrosis as a Complication of Treating Acute intravenous mercaptopurine for patients with standard-risk acute lymphoblastic leukemia: a report from the Children’s Cancer GroupLymphoblastic Leukemia in Children: A Report From the Children’s Cancer Group (CCG 1882)

Mattano LA, et al,. J Clin Oncol 18:3262, 2000


Acute leukemia outcome measures
Acute Leukemia intravenous mercaptopurine for patients with standard-risk acute lymphoblastic leukemia: a report from the Children’s Cancer GroupOutcome 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


Relapsed all remains a common problem
Relapsed ALL Remains a intravenous mercaptopurine for patients with standard-risk acute lymphoblastic leukemia: a report from the Children’s Cancer GroupCommon Problem


Most patients who relapse once die despite high remission induction rates and bmt

Most Patients Who Relapse Once Die! intravenous mercaptopurine for patients with standard-risk acute lymphoblastic leukemia: a report from the Children’s Cancer GroupDespite high remission-induction rates and BMT

CCG-1900 series trials

Survival After 1st Relapse


Acute leukemia1

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

Acute Leukemia


Summary

Summary childhood has been dramatic in 40 years

Your head is round so that your thinking can change direction…


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