Pediatric Pediatric LeukemiasLeukemias

Resident Resident Education Education

Lecture SeriesLecture Series

Cancer of the bone marrowCancer of the bone marrow

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

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

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

CML < 100 cases/year, CML < 100 cases/year, and CLL not seenand CLL not seen

JMML even less JMML even less commoncommon

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

Probable genetic Probable genetic component based on component based on twin studies; twin studies; linked to trisomy 21, linked to trisomy 21,

Fanconi, p53 Fanconi, p53 mutations, Bloom, AT, mutations, Bloom, AT, ionizing radiation, and ionizing radiation, and benzenebenzene

Major types Factoids

DefinitionsDefinitions

MarrowMarrow M1: < 5% blasts in M1: < 5% blasts in

normocellular normocellular marrowmarrow

(remission marrow)(remission marrow) M2: 5-25% blastsM2: 5-25% blasts M3: > 25% blastsM3: > 25% blasts

(definition of (definition of leukemia)leukemia)

CNS* CNS* (varies by protocol & (varies by protocol & disease)disease) CNS 1: cytospin (-), CNS 1: cytospin (-),

independent of cell independent of cell countcount

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

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

Traumatic: this is Traumatic: this is worse than CNS 2!worse than CNS 2!

ALL: TREATMENT ERASALL: TREATMENT ERAS

1945-551945-55 single agents single agents < 1< 1 1955-651955-65 combination therapy combination therapy 55 1965-751965-75 CNS “prophylaxis” CNS “prophylaxis” 4545 1975-851975-85 tumor biology tumor biology 5050 1985-951985-95 intensification therapy intensification therapy 7575 1995-20051995-2005 molecular biology molecular biology

8080

pharmacologypharmacology

genome polymorphismsgenome polymorphisms

% cured

Years From Study Entry

Est

imat

ed S

urv

ival

Per

cen

tag

eImproved Survival in Childhood ALL

by Study Era

0

20

40

60

80

100

0 2 4 6 8 10 12

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)

ALL subtypesALL subtypes Formerly L1, L2, L3 (morphology); no Formerly L1, L2, L3 (morphology); no

longer used (L3 morphology = mature B, longer used (L3 morphology = mature B, aka Burkitt)aka Burkitt)

Now surface markersNow surface markers B-lineage:B-lineage: 85%85%

Early pre-B 57%; pre-B 25%Early pre-B 57%; pre-B 25% T-ALL: T-ALL: 13%13% B (mature): B (mature): 1-2%1-2% (surface Ig)(surface Ig) True biphenotypic is bad; a few T or AML True biphenotypic is bad; a few T or AML

marks in o/w classic ALL is finemarks in o/w classic ALL is fine And molecular subsetsAnd molecular subsets

ALL: EARLY CHEMOTHERAPYALL: EARLY CHEMOTHERAPY

Variable ability of drugs to induce Variable ability of drugs to induce remission:remission: PrednisonePrednisone VincristineVincristine 60 %60 % AsparaginaseAsparaginase MethotrexateMethotrexate MercatopurineMercatopurine 20 %20 % CyclophosphamideCyclophosphamide

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

Early Combination Early Combination ChemotherapyChemotherapy

InductionInduction Prednisone + vincristinePrednisone + vincristine 84 % 84 % PV + asparaginase PV + asparaginase 94-98 %94-98 % PVA + daunorubicinPVA + daunorubicin 98-99 %98-99 %

Post-inductionPost-induction MethotrexateMethotrexate 5 mos 5 mos Methotrexate + mercaptopurineMethotrexate + mercaptopurine 12 12

mosmos MM + prednisone + vincristineMM + prednisone + vincristine 12-18 mos 12-18 mos

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

CHEMOTHERAPY for ALLCHEMOTHERAPY for ALL

19671967 ASPARAGINASEASPARAGINASE CYCLOPHOSPHAMICYCLOPHOSPHAMI

DEDE MERCAPTOPURINEMERCAPTOPURINE METHOTREXATEMETHOTREXATE PREDNISONEPREDNISONE VINCRISTINEVINCRISTINE

20042004 ASPARAGINASEASPARAGINASE CYCLOPHOSPHAMIDECYCLOPHOSPHAMIDE CYTOSINE ARABINOSIDECYTOSINE ARABINOSIDE DEXAMETHASONEDEXAMETHASONE DOXORUBICINDOXORUBICIN ETOPOSIDEETOPOSIDE METHOTREXATEMETHOTREXATE MERCAPTOPURINEMERCAPTOPURINE PREDNISONEPREDNISONE THIOGUANINETHIOGUANINE VINCRISTINEVINCRISTINE

CNS “PROPHYLAXIS”CNS “PROPHYLAXIS”

STUDYSTUDY # PTS # CNSRL # CCR # PTS # CNSRL # CCR ST J I-IIIST J I-III 41 15 7 41 15 7 ST J V: + CSXRTST J V: + CSXRT 35 3 18 35 3 18 ST J 6: + CXRT/it MTXST J 6: + CXRT/it MTX 45 45 2 23 2 23

- CXRT- CXRT 49 49 33 33 7 7 C = cranial; CS = craniospinal; XRT = radiation; it = intrathecalC = cranial; CS = craniospinal; XRT = radiation; it = intrathecal CNSRL = CNS relapse; CCR = continuous complete remissionCNSRL = CNS relapse; CCR = continuous complete remission

Subsequent studies have shown similar Subsequent studies have shown similar results with intrathecal treatment alone.results with intrathecal treatment alone.

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

Intensive ChemotherapyIntensive Chemotherapy

Postulate: Postulate: early intensive early intensive chemotherapy with a combination of chemotherapy with a combination of drugs will improve cure bydrugs will improve cure by more rapid elimination of sensitive cellsmore rapid elimination of sensitive cells prevention of the development of prevention of the development of

resistanceresistance treatment of resistant cellstreatment of resistant cells

TREATMENT STRATEGIES FOR ALLTREATMENT STRATEGIES FOR ALL

I

I INTENSIVE

CNS

CNS

STANDARD

MODERN

SUCCESSFUL INTENSIFICATION FOR SUCCESSFUL INTENSIFICATION FOR ALL:WHAT’S INSIDE THE BOX?ALL:WHAT’S INSIDE THE BOX?

Weekly Weekly asparaginaseasparaginase (DFCC) (DFCC) Intermediate-high dose Intermediate-high dose methotrexatemethotrexate

(MCCC; POG/CCG)(MCCC; POG/CCG) Delayed Delayed reinduction-intensificationreinduction-intensification

(BFM/CCG)(BFM/CCG) Multiple Multiple rotating pairsrotating pairs of drugs (MCCC; of drugs (MCCC;

POG)POG)

All of these improved cure rates to 70-80%All of these improved cure rates to 70-80%

Favorable Prognostic Factors in ALLFavorable Prognostic Factors in ALL

AGEAGE 1-9 1-9 WBCWBC lower lower GenderGender female female ChromosomesChromosomes t(12;21), t(12;21),

hyperdiploidhyperdiploid Treatment response rapidTreatment response rapid Residual disease (MRD)Residual disease (MRD) less less

Genetic Heterogeneity inGenetic Heterogeneity in Childhood ALL:Childhood ALL:

St. Jude Children’s HospitalSt. Jude Children’s Hospital> 50

TEL:AML t (12;21)

RANDOM

BCR-ABL t(9;22)

t 11q23

< 45

TCR B 7q35

TCR AD 14q11

MYC

E2A-PBX t(1;19)

B-Precursor ALL: Genotype and Outcome:

Children’s Oncology Group

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 160

20

40

60

80

100

Pro

babi

lity

10/2001

TEL (n =176)

4 Yr EFS (%)4 Yr EFS (%) SE (%)SE (%)Tris 4,10,17 92.1Tris 4,10,17 92.1 1.1 1.1TELTEL 89.0 89.0 3.1 3.1t(1;19)t(1;19) 68.9 68.9 4.1 4.1t(4;11)t(4;11) 49.9 49.9 11.2 11.2t(9;22)t(9;22) 27.5 27.5 4.4 4.4

4 Yr EFS (%)4 Yr EFS (%) SE (%)SE (%)Tris 4,10,17 92.1Tris 4,10,17 92.1 1.1 1.1TELTEL 89.0 89.0 3.1 3.1t(1;19)t(1;19) 68.9 68.9 4.1 4.1t(4;11)t(4;11) 49.9 49.9 11.2 11.2t(9;22)t(9;22) 27.5 27.5 4.4 4.4

Years Followed

t(4;11) (n = 44)

t(9;22) (n=132)

t(1;19) (n = 139)

Trisomies 4,10,17 (n = 746)

TumorTumor

Dx

d29

POG ALinC17 to Date:1016 samples received

95% compliance

MRD Sensitivity 1/1000 - 1/10,00024 hr turn around

28.6% positivemedian .069%

Residual Disease MonitoringResidual Disease Monitoring at End Induction: Flow Cytometry at End Induction: Flow Cytometry

PROGNOSTIC VALUE OF MRDPROGNOSTIC VALUE OF MRDIN CHILDHOOD ALLIN CHILDHOOD ALL

0

20

40

60

80

100

3 15 27 39 51 63

LOWINTERMEDHIGH

%RFS

MONTHSvan DONGENL 352:1731, 1998

MINIMAL RESIDUAL DISEASEMINIMAL RESIDUAL DISEASE and RELAPSE RISK and RELAPSE RISK

n=123

RR 10%

n=42

RR 43%

14

18 4

8

RR 7%

RR 68%

RR 2/8

RR 4/4

COUSTAN-SMITHBLOOD 96:2691, 2000

END INDUCTION WEEK 14 WEEK 32

MRD-

MRD +

GENETIC CONTEXT OF MRD GENETIC CONTEXT OF MRD MAY BE IMPORTANTMAY BE IMPORTANT

Abnormality n >.1% >.01%

BCR-ABL 41 63% 73%

E2A-PBX1 87 6.9% 12.6%

TEL-AML1 431 2.6% 7.9 %

Trisomy 4&10 431 9.3% 19.3%

MRD+ End Induction

Overall 13.0% 21.8%1972

COG ALL Risk Groups 2004:COG ALL Risk Groups 2004:B-Precursor ALLB-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 CurePrinciples of Cure

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

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

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

AMLAML

Still an evil Still an evil diseasedisease

AML AML subtypessubtypes

M1

M3

M7

M4 and M4eo

M6

ACUTE MYELOCYTIC LEUKEMIA: AMLACUTE MYELOCYTIC LEUKEMIA: AML

MM00 undifferentiatedundifferentiated

MM11 AML without differentiationAML without differentiation

MM22 AML with differentiationAML with differentiation

MM33 promyelocytic leukemiapromyelocytic leukemia

MM44 myelomonocytic leukemiamyelomonocytic leukemia

MM55 monocytic leukemiamonocytic leukemia

MM66 erythroleukemiaerythroleukemia

MM77 megakaryocytic leukemiamegakaryocytic leukemia

Prognostic factorsPrognostic factors

WBC > 100,000WBC > 100,000 SecondarySecondary Monosomy 7 (7q-)Monosomy 7 (7q-) ? Very young? Very young ? Splenomegaly? Splenomegaly ? M4 and M5? M4 and M5 ? M1 w/o Auer rods? M1 w/o Auer rods

M4eo (inv16)M4eo (inv16) M6M6 M# = t(15;17)M# = t(15;17) Matched sibling Matched sibling

transplant up-fronttransplant up-front Down SyndromeDown Syndrome ? t(8;21)? t(8;21)

(latest paper says (latest paper says no)no)

? Rapid CR? Rapid CREFS ranges 45-80%

Good Bad

Ugly

AML: INDUCTION THERAPYAML: INDUCTION THERAPY

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

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

AML: Post-induction TherapyAML: Post-induction Therapy

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

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

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

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

AML: Bone Marrow TransplantationAML: Bone Marrow Transplantation

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

Autologous BMT during first remission Autologous BMT during first remission gives results similar to chemotherapygives results similar to chemotherapy

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

AML Treatment AML Treatment IssuesIssues

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

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

Special circumstancesSpecial circumstances Granulocytic sarcomaGranulocytic sarcoma Down syndromeDown syndrome

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

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

M7 AML most oftenM7 AML most often Transient Myeloproliferative Disease occurs in Transient Myeloproliferative Disease occurs in

newborn periodnewborn period

M3 (the 15;17 translocation)M3 (the 15;17 translocation)

Promyelocytic Leukemia: MPromyelocytic Leukemia: M33

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

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

High dose all-trans retinoic acid overcomes High dose all-trans retinoic acid overcomes this blockadethis blockade

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

Promyelocytic Leukemia: MPromyelocytic Leukemia: M33

Induction: all-trans retinoic acid +/- an Induction: all-trans retinoic acid +/- an anthracyclineanthracycline

Intensification: anthracycline +/- Ara-CIntensification: anthracycline +/- Ara-C Continuation: Continuation: intermittentintermittent all-trans all-trans

retinoic acid +/- chemotherapyretinoic 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

CMLCML

On which we are going to On which we are going to spend very little timespend very little time

CML overviewCML overview

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

3 phases3 phases ChronicChronic

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

AcceleratedAccelerated Progressive sxs including splenomegaly; Progressive sxs including splenomegaly;

blasts 10 (5?) -30%, baso’s+eo’s > 20%blasts 10 (5?) -30%, baso’s+eo’s > 20% BlastBlast

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

CML treatmentCML treatment Gleevac: aka STI571, aka imatinib Gleevac: aka STI571, aka imatinib

mesylatemesylate

tyrosine kinase inhibitor that blocks the tyrosine kinase inhibitor that blocks the function of the BCR-ABL fusion proteinfunction of the BCR-ABL fusion protein Morphologic vs cytogenetic vs molecular Morphologic vs cytogenetic vs molecular

remissionremission Additional chemo required if disease has Additional chemo required if disease has

progressedprogressed IFN, Ara-C, hydroxyureaIFN, Ara-C, hydroxyurea

Transplant still the Rx of choice for PedsTransplant still the Rx of choice for Peds

JMMLJMML Juvenile myelomonocytic leukemiaJuvenile myelomonocytic leukemia Sometimes called JCMLSometimes called JCML Think of it as stem cell leukemia, but it acts like Think of it as stem cell leukemia, but it acts like

an MDS more than a leukemiaan MDS more than a leukemia Associated with NF1 (10+%)Associated with NF1 (10+%) Young kids (nearly all < 4; most < 2)Young kids (nearly all < 4; most < 2) Lab findings include high HgbF, hypersensitivity Lab findings include high HgbF, hypersensitivity

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

Usually treated with SCT, although very often Usually treated with SCT, although very often fatalfatal

From ABP From ABP Certifying Exam Content OutlineCertifying Exam Content Outline

Pancytopenia Pancytopenia 1. General aspects1. General aspects Recognize that a bone marrow aspirate is Recognize that a bone marrow aspirate is

necessary in the evaluation of a child with necessary in the evaluation of a child with multiple pancytopeniasmultiple pancytopenias

From ABP From ABP Certifying Exam Content Outline, Certifying Exam Content Outline, continuedcontinued WBC disorders WBC disorders b. Acquired (leukemia)b. Acquired (leukemia)

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

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

Recognize bone pain as a symptom of leukemiaRecognize bone pain as a symptom of leukemia

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

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

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

CreditsCredits

Meghen Browning MDMeghen Browning MDBruce Camitta MDBruce Camitta MDAnne Warwick MD MPHAnne Warwick MD MPH