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Pediatric Leukemias. Resident Education Lecture Series. Leukemia incidence: 4.1 cases/100,000 children < 15 years ALL most common; 2000 cases/year (we see 30-40 cases/year) AML @ 500 cases/year (we see ~ 6) CML < 100 cases/year, and CLL not seen JMML even less common.

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Pediatric leukemias

Pediatric Leukemias

Resident Education Lecture Series


Cancer of the bone marrow

Leukemia incidence:4.1 cases/100,000 children < 15 years

ALL most common; 2000 cases/year (we see 30-40 cases/year)

AML @ 500 cases/year (we see ~6)

CML < 100 cases/year, and CLL not seen

JMML even less common

Typically presents with s/s of anemia, fever, bone pain, bleeding/bruising, HSM/LAD (less in AML; large spleen in CML)

Probable genetic component based on twin studies;

linked to trisomy 21, Fanconi, p53 mutations, Bloom, AT, ionizing radiation, and benzene

Cancer of the bone marrow

Major types

Factoids


Definitions

Marrow

M1: < 5% blasts in normocellular marrow

(remission marrow)

M2: 5-25% blasts

M3: > 25% blasts

(definition of leukemia)

CNS* (varies by protocol & disease)

CNS 1: cytospin (-), independent of cell count

CNS 2: cytospin (+), <5 WBC on count

CNS 3: cytospin (+), >5 WBC; or CNS sxs

Traumatic: this is worse than CNS 2!

Definitions


All treatment eras
ALL: TREATMENT ERAS

% cured

  • 1945-55 single agents < 1

  • 1955-65 combination therapy 5

  • 1965-75 CNS “prophylaxis” 45

  • 1975-85 tumor biology 50

  • 1985-95 intensification therapy 75

  • 1995-2005 molecular biology 80

    pharmacology

    genome polymorphisms


Improved Survival in Childhood ALL

by Study Era

Estimated Survival Percentage

Years From Study Entry


All subtypes
ALL subtypes

  • Formerly L1, L2, L3 (morphology); no longer used (L3 morphology = mature B, aka Burkitt)

  • Now surface markers

    • B-lineage: 85%

      • Early pre-B 57%; pre-B 25%

    • T-ALL: 13%

    • B (mature): 1-2% (surface Ig)

    • True biphenotypic is bad; a few T or AML marks in o/w classic ALL is fine

  • And molecular subsets


All early chemotherapy
ALL: EARLY CHEMOTHERAPY

  • Variable ability of drugs to induce remission:

    • Prednisone

    • Vincristine 60 %

    • Asparaginase

    • Methotrexate

    • Mercatopurine 20 %

    • Cyclophosphamide

  • Drugs good for inducing remission were less effective for sustaining remission


Early combination chemotherapy
Early Combination Chemotherapy

  • Induction

    • Prednisone + vincristine 84 %

    • PV + asparaginase 94-98 %

    • PVA + daunorubicin 98-99 %

  • Post-induction

    • Methotrexate 5 mos

    • Methotrexate + mercaptopurine 12 mos

    • MM + prednisone + vincristine 12-18 mos

  • 95 % of patients still relapsed, frequently only in the csf


Chemotherapy for all

1967

ASPARAGINASE

CYCLOPHOSPHAMIDE

MERCAPTOPURINE

METHOTREXATE

PREDNISONE

VINCRISTINE

2004

ASPARAGINASE

CYCLOPHOSPHAMIDE

CYTOSINE ARABINOSIDE

DEXAMETHASONE

DOXORUBICIN

ETOPOSIDE

METHOTREXATE

MERCAPTOPURINE

PREDNISONE

THIOGUANINE

VINCRISTINE

CHEMOTHERAPY for ALL


Cns prophylaxis
CNS “PROPHYLAXIS”

STUDY # PTS # CNSRL # CCR

  • ST J I-III 41 15 7

  • ST J V: + CSXRT 35 3 18

  • ST J 6: + CXRT/it MTX 45 2 23

    - CXRT 49 33 7

    C = cranial; CS = craniospinal; XRT = radiation; it = intrathecal

    CNSRL = CNS relapse; CCR = continuous complete remission

    Subsequent studies have shown similar results with intrathecal treatment alone.

    XRT now reserved for patients with CNS leukemia and patients with higher risk T-ALL.


Intensive chemotherapy
Intensive Chemotherapy

  • Postulate: early intensive chemotherapy with a combination of drugs will improve cure by

    • more rapid elimination of sensitive cells

    • prevention of the development of resistance

    • treatment of resistant cells


Treatment strategies for all
TREATMENT STRATEGIES FOR ALL

STANDARD

I

CNS

MODERN

INTENSIVE

I

CNS


Successful intensification for all what s inside the box
SUCCESSFUL INTENSIFICATION FOR ALL:WHAT’S INSIDE THE BOX?

  • Weekly asparaginase (DFCC)

  • Intermediate-high dose methotrexate

    (MCCC; POG/CCG)

  • Delayed reinduction-intensification

    (BFM/CCG)

  • Multiple rotating pairs of drugs (MCCC; POG)

    All of these improved cure rates to 70-80%


Favorable prognostic factors in all
Favorable Prognostic Factors in ALL

  • AGE 1-9

  • WBC lower

  • Gender female

  • Chromosomes t(12;21), hyperdiploid

  • Treatment response rapid

  • Residual disease (MRD) less


Genetic heterogeneity in childhood all st jude children s hospital
Genetic Heterogeneity inChildhood ALL:St. Jude Children’s Hospital


B-Precursor ALL: Genotype and Outcome:

Children’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

0

0

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

Years Followed

10/2001


Residual disease monitoring at end induction flow cytometry
Residual Disease Monitoring at End Induction: Flow Cytometry

Dx

POG ALinC17 to Date:

1016 samples received

95% compliance

MRD Sensitivity

1/1000 - 1/10,000

24 hr turn around

28.6% positivemedian .069%

d29

Tumor

Tumor


Prognostic value of mrd in childhood all
PROGNOSTIC VALUE OF MRDIN CHILDHOOD ALL

%

RFS

MONTHS

van DONGEN

L 352:1731, 1998


Minimal residual disease and relapse risk
MINIMAL RESIDUAL DISEASE and RELAPSE RISK

END INDUCTION

WEEK 14

WEEK 32

n=123

RR 10%

MRD-

RR 7%

RR 2/8

14

8

n=42

RR 43%

18

4

MRD +

RR 4/4

RR 68%

COUSTAN-SMITH

BLOOD 96:2691, 2000


Genetic context of mrd may be important
GENETIC CONTEXT OF MRD MAY BE IMPORTANT

MRD+ End Induction

Overall

1972

13.0%

21.8%


Cog all risk groups 2004 b precursor all
COG ALL Risk Groups 2004:B-Precursor ALL

  • NCI Risk Groups

  • Trisomies 4, 10, & 17

  • TEL/AML 1

  • CNS Disease

  • MLL

  • Slow Early Response

  • End of Induction MRD

  • BCR-ABL

  • Chromosomes <45

  • Induction Failure

Low Risk

Standard Risk

High Risk

Very High Risk


Principles of cure
Principles of Cure

  • Cure depends upon a complex interaction of patient, disease and treatment-related factors

  • Treatment of all patients with similar regimens risks both overtreatment and undertreatment of individuals

  • Understanding differences in tumor and host genetics (polymorphisms) will be crucial to individualization of therapy


AML

Still an evil disease


Aml subtypes
AML subtypes

M6

M1

M4 and M4eo

M3

M7


Acute myelocytic leukemia aml
ACUTE MYELOCYTIC LEUKEMIA: AML

M0 undifferentiated

M1 AML without differentiation

M2 AML with differentiation

M3 promyelocytic leukemia

M4 myelomonocytic leukemia

M5 monocytic leukemia

M6 erythroleukemia

M7 megakaryocytic leukemia


Prognostic factors

WBC > 100,000

Secondary

Monosomy 7 (7q-)

? Very young

? Splenomegaly

? M4 and M5

? M1 w/o Auer rods

M4eo (inv16)

M6

M# = t(15;17)

Matched sibling transplant up-front

Down Syndrome

? t(8;21)

(latest paper says no)

? Rapid CR

Prognostic factors

Bad

Good

Ugly

EFS ranges 45-80%


Aml induction therapy
AML: INDUCTION THERAPY

  • Two cycles of cytosine arabinoside + daunorubicin +/-thioguanine and other agents gives remissions in 70-90%

  • Timed sequential therapy (giving the second cycle at a specified time) does not the increase remission rate but does increase long-term cures when compared to waiting for marrow recovery (or failure) before giving the second cycle (Blood 87:4979, 1996)


Aml post induction therapy
AML: Post-induction Therapy

  • Chemotherapy alone has given 30-50 % cure rates.

  • Cure is higher after timed-sequential induction therapy (42% vs. 27%).

  • Short (4-12 months) of post-induction therapy is adequate

  • CNS leukemia is less common than in ALL; ‘prophylaxis’ may be accomplished with high dose Ara-C +/- intrathecal Ara-C


Aml bone marrow transplantation
AML: Bone Marrow Transplantation

  • Bone marrow transplantation from a matched sibling donor during first remission gives better cure rates than chemotherapy (50-60 % vs. 30-50 %)

  • Autologous BMT during first remission gives results similar to chemotherapy

  • BMT from a matched sibling in second remission gives 30-40 % cure rate but is limited by the difficulty in achieving second remission.


Aml treatment issues
AML Treatment Issues

  • 50% incidence of serious bacterial infection: therefore use of G-CSF accepted

  • New protocol is European-based and returns to the old high-dose Ara-C, with the addition of myelotarg (anti-CD33, aka gemtuzumab)


Special circumstances
Special circumstances

  • Granulocytic sarcoma

  • Down syndrome

    • Increased incidence of all leukemias; ALL still > AML total, but RELATIVE increase of AML

    • Do not use intensive timing (increased toxicity with therapy), but OK to use anthracyclines even with CHD

    • M7 AML most often

    • Transient Myeloproliferative Disease occurs in newborn period

  • M3 (the 15;17 translocation)


Promyelocytic leukemia m 3
Promyelocytic Leukemia: M3

  • Characterized by a translocation [t(15;17)] that fuses the retinoic acid receptor and PML genes

  • The t(15;17) transcript blocks differentiation that depends upon the normal receptor

  • High dose all-trans retinoic acid overcomes this blockade

  • Arsenic trioxide may cause apoptosis or may induce differentiation in PML cells


Promyelocytic leukemia m 31
Promyelocytic Leukemia: M3

  • Induction: all-trans retinoic acid +/- an anthracycline

  • Intensification: anthracycline +/- Ara-C

  • Continuation: intermittent all-trans retinoic acid +/- chemotherapy

RESULTS: 90-95 % remission

: 70-85 % event-free survival

: high salvage rate of relapses with

retinoic acid, arsenic or BMT

Blood 105:3019, 2005

JClinOncol 22:1404, 2004


CML

On which we are going to spend very little time


Cml overview
CML overview

  • BCR-ABL fusion protein is generally P210, whereas Ph+ALL is usually P190.

  • 3 phases

    • Chronic

      • Some systemic sxs; peripheral and marrow blasts < 10% (NCI says 5%), thrombo- and leukocytosis

    • Accelerated

      • Progressive sxs including splenomegaly; blasts 10 (5?) -30%, baso’s+eo’s > 20%

    • Blast

      • Extramedullary disease symptoms; blasts > 30%, blasts that look like ALL or AML


Cml treatment
CML treatment

  • Gleevac: aka STI571, aka imatinib mesylate

    tyrosine kinase inhibitor that blocks the function of the BCR-ABL fusion protein

    • Morphologic vs cytogenetic vs molecular remission

  • Additional chemo required if disease has progressed

    • IFN, Ara-C, hydroxyurea

  • Transplant still the Rx of choice for Peds


JMML

  • Juvenile myelomonocytic leukemia

  • Sometimes called JCML

  • Think of it as stem cell leukemia, but it acts like an MDS more than a leukemia

  • Associated with NF1 (10+%)

  • Young kids (nearly all < 4; most < 2)

  • Lab findings include high HgbF, hypersensitivity to GM-CSF (in vitro), monosomy 7, NO BCR-ABL, < 20% blasts + pro’s (marrow or peripheral), and monocytosis (can have a very high total WBC)

  • Usually treated with SCT, although very often fatal


From abp certifying exam content outline
From ABP Certifying Exam Content Outline

  • Pancytopenia 1. General aspects

  • Recognize that a bone marrow aspirate is necessary in the evaluation of a child with multiple pancytopenias


From abp certifying exam content outline continued
From ABP Certifying Exam Content Outline, continued

  • WBC disorders b. Acquired (leukemia)

  • Understand that aplastic anemia and childhood leukemia may both present with purpura, pallor, and fever

  • Know that the absence of blasts in the peripheral blood of a patient with pancytopenia does not rule out the diagnosis of leukemia

  • Recognize bone pain as a symptom of leukemia

  • Understand that most patients with acute lymphoblastic leukemia will be cured of their disease using current treatment strategies

  • Identify the central nervous system and testicles as important sites of relapse of acute lymphoblastic leukemia

  • Identify Down syndrome as a disease with an increased risk of leukemia


Credits
Credits

  • Meghen Browning MDBruce Camitta MDAnne Warwick MD MPH


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