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
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
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