Pediatric Leukemias - PowerPoint PPT Presentation

Loading...

PPT – Pediatric Leukemias PowerPoint presentation | free to download - id: 279f5-NDIyM



Loading


The Adobe Flash plugin is needed to view this content

Get the plugin now

View by Category
About This Presentation
Title:

Pediatric Leukemias

Description:

Resident Education Lecture Series. Cancer of the bone marrow. Leukemia incidence: ... 1955-65 combination therapy 5. 1965-75 CNS 'prophylaxis' 45. 1975-85 ... – PowerPoint PPT presentation

Number of Views:2280
Avg rating:3.0/5.0
Slides: 43
Provided by: ABWar
Learn more at: http://www.mcw.edu
Category:

less

Write a Comment
User Comments (0)
Transcript and Presenter's Notes

Title: Pediatric Leukemias


1
Pediatric Leukemias
  • Resident Education Lecture Series

2
Cancer of the bone marrow
Major types
Factoids
  • Leukemia incidence 4.1 cases/100,000 children 15 years
  • ALL most common 2000 cases/year (we see 30-40
    cases/year)
  • AML _at_ 500 cases/year (we see 6)
  • CML
  • 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

3
Definitions
  • CNS (varies by protocol disease)
  • CNS 1 cytospin (-), independent of cell count
  • CNS 2 cytospin (),
  • CNS 3 cytospin (), 5 WBC or CNS sxs
  • Traumatic this is worse than CNS 2!
  • Marrow
  • M1
  • (remission marrow)
  • M2 5-25 blasts
  • M3 25 blasts
  • (definition of leukemia)

4
(No Transcript)
5
ALL TREATMENT ERAS
cured
  • 1945-55 single agents
  • 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

6
Improved Survival in Childhood ALL by Study Era

Estimated Survival Percentage
Years From Study Entry
7
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

8
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

9
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

10
CHEMOTHERAPY for ALL
  • 2004
  • ASPARAGINASE
  • CYCLOPHOSPHAMIDE
  • CYTOSINE ARABINOSIDE
  • DEXAMETHASONE
  • DOXORUBICIN
  • ETOPOSIDE
  • METHOTREXATE
  • MERCAPTOPURINE
  • PREDNISONE
  • THIOGUANINE
  • VINCRISTINE
  • 1967
  • ASPARAGINASE
  • CYCLOPHOSPHAMIDE
  • MERCAPTOPURINE
  • METHOTREXATE
  • PREDNISONE
  • VINCRISTINE

11
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.

12
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

13
TREATMENT STRATEGIES FOR ALL
STANDARD
I
CNS
MODERN
INTENSIVE
I
CNS
14
SUCCESSFUL INTENSIFICATION FOR ALLWHATS 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

15
Favorable Prognostic Factors in ALL
  • AGE 1-9
  • WBC lower
  • Gender female
  • Chromosomes t(1221), hyperdiploid
  • Treatment response rapid
  • Residual disease (MRD) less

16
Genetic Heterogeneity in Childhood ALL St. Jude
Childrens Hospital
17
B-Precursor ALL Genotype and Outcome Childrens
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
0
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Years Followed
10/2001
18
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 positive median .069
d29
Tumor
Tumor
19
PROGNOSTIC VALUE OF MRD IN CHILDHOOD ALL
RFS
MONTHS
van DONGEN L 3521731, 1998
20
MINIMAL RESIDUAL DISEASE and RELAPSE RISK
END INDUCTION
WEEK 14
WEEK 32
n123 RR 10
MRD-
RR 7
RR 2/8
14
8
n42 RR 43
18
4
RR 4/4
MRD
RR 68
COUSTAN-SMITH BLOOD 962691, 2000
21
GENETIC CONTEXT OF MRD MAY BE IMPORTANT
MRD End Induction
Overall
13.0
21.8
1972
22
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
  • Induction Failure

Low Risk
Standard Risk
High Risk
Very High Risk
23
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

24
AML
  • Still an evil disease

25
AML subtypes
M6
M1
M4 and M4eo
M3
M7
26
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

27
Prognostic factors
Good
Bad
  • M4eo (inv16)
  • M6
  • M t(1517)
  • Matched sibling transplant up-front
  • Down Syndrome
  • ? t(821)
  • (latest paper says no)
  • ? Rapid CR
  • WBC 100,000
  • Secondary
  • Monosomy 7 (7q-)
  • ? Very young
  • ? Splenomegaly
  • ? M4 and M5
  • ? M1 w/o Auer rods

Ugly
EFS ranges 45-80
28
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
    874979, 1996)

29
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

30
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.

31
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)

32
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 1517 translocation)

33
Promyelocytic Leukemia M3
  • Characterized by a translocation t(1517) that
    fuses the retinoic acid receptor and PML genes
  • The t(1517) 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

34
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 1053019, 2005
JClinOncol 221404, 2004
35
CML
  • On which we are going to spend very little time

36
CML overview
  • BCR-ABL fusion protein is generally P210, whereas
    PhALL is usually P190.
  • 3 phases
  • Chronic
  • Some systemic sxs peripheral and marrow blasts
  • Accelerated
  • Progressive sxs including splenomegaly blasts
    10 (5?) -30, basoseos 20
  • Blast
  • Extramedullary disease symptoms blasts 30,
    blasts that look like ALL or AML

37
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

38
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
  • Lab findings include high HgbF, hypersensitivity
    to GM-CSF (in vitro), monosomy 7, NO BCR-ABL, 20 blasts pros (marrow or peripheral), and
    monocytosis (can have a very high total WBC)
  • Usually treated with SCT, although very often
    fatal

39
(No Transcript)
40
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

41
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

42
Credits
  • Meghen Browning MD Bruce Camitta MD Anne Warwick
    MD MPH
About PowerShow.com