acıbadem university pediatric hematology- oncology prof. cengiz canpolat m.d. pediatric...

Acıbadem UniversityPediatric Hematology-

Oncology

Prof. Cengiz Canpolat M.D.Pediatric Hematology-Oncology

Leukemias Clonal expansion and arrest at a specific

stage of normal myeloid or lymphoid hematopoiesis

Acute leukemia consitutes %97 of childhood leukemias

ALL(%75) AML (%20) Acute undifferentiated leukemia (<%0.5) Acute mixed lineage leukemia (AMLL) Chronic myeloid leukemias consitute %3

1-Ph-pozitive2-Juvenile myelomonositic leukemia(JMML)

Leukemias (incidence)

ALL: 3-4/100.000 cases white children per year

AML: appr. 1/5-1/6 of ALL cases Peak incidence between 2-5 y %25-30 of all childhood cancers

Acute Leukemia

Etiology Environmental factors-ionizing radiation,

chemicals (benzene in AML) Viral infections (EBV and Mature B cell

leukemia) Drugs: alkylating agents+ XRT

increases the risk of AML

Acute LeukemiaEtiology

Genetic considerations:a-identical twins-if one twin develops leukemia during the first 5 y of life the risk in the second is %20b-incidence of leukemia in a sibling of a leukemia patient is X 4 general populationc-chromosomal abnormalities (trisomy 21, bloom synd., fanconi anemia)

Acute LeukemiaEtiology

Increased incidence with the following genetically determined conditions:a-congenital agamaglobulinemiab-Shwachman-Diamond syndromec-Ataxia telengiectasiad-Li-Fraumeni syndromee-NFf-DB anemiag-Kostmann disease

Acute Lymphoblastic Leukemia

Epidemiology Peak incidence at 4 years More common in whites than blacks Outcome white=black Incidence higher among boys than girls ALL rare in north Africa and middle east,

NHL more common ALL more common in India and China but

less common than in western countries Higher incidence of ALL in industrialized

countries


Clonal pathogenesis; ALL occurs as a consequence of malignant transformation of a single abnormal progenitor cell with a capacitiy to expand by indefinite self-renewal

During normal development progenitor cells are at higher risk for spontaneous mutation

There are two distinct genetic events in leukemogenesis, one initiational, one promotional


Molecular pathogenesis; single mutation or multiple mutagenic events cause the induction of malignancy

Normal protooncogenes by changing their patterns of expression or by direct mutation become oncogenes which in turn cause malignancy

Tumor supressor genes by getting lost or by mutation can lead to malignancy

Chromosomal translocations are the main cytogenetic event, there are also deletions and mutations in DNA


Molecular pathogenesis; p53, p16, p15, WT11, TEL(12p12), KIP (12p13) are all tm supressor genes

P53 is most frequenly found altered gene in human cancers

Pediatric ALL can be associated with p53 mutations

Apoptosis (programmed cell death) is also abnormal in pediatric ALL because of mutations in the responsible gene


Evaluation of the patient; Detailed Hx and PE CBC, blood chemistries, coagulopathy

secreen, hepatitis screen, viral serologies, Tb skin test

BMA for light and EM, cytochemistry, cytogenetics, flow cytometry, molecular genetics

Gene rearrangement studies by PCR CXR ECHO


Evaluation of the patient; LP Cultures Dental examination Ophtalmic evaluation


Clinical manifestations; Fever, malaise, anorexia, weakness, bleeding,

intractable infection. Onset may be insidious PE shows pallor, petechiae, ecchymoses,

infection, HM, SM, LAP Can imitate almost any disease: ARF,

nephritis, IMN, ITP, pertussis, aplastic anemia, etc

May present with consumptive coagulopathy (esp. APL)

Renal involvement may cause hematuria, hypertension, renal failure


Clinical manifestations; Meningeal involvement may cause

headache, emesis, papilledema Recurrent fever, frequent infections,

extremity pains may be confused with other diseases


Laboratory findings; Anemia, leukocytosis, leukopenia,

neutropenia, thrombocytopenia, blasts on PBS

Increased serum uric acid levels, hyperpotasemia, hypercalcemia, hyperphosphatemia

Increased LDH Low serum Igs in 30% aPT, aPTT may be prolonged Serum chemistries may be abnormal


Prognostic factors; Initial WBC count <50.000/mm3 good

prognosis Age (>1 y and <10y good prognosis, infants

<1 y worst prognosis) Immunophenotype (early pre B cell best

prognosis, mature T cell worse, mature B cell used to be bad)

DNA index>1.16, hyperdiploidy with >50 chr. good pr. (incr. apoptosis, incr. sensitivity to chemo.)


Prognostic factors; Certain type of translocations in leukemic

blasts Early response to chemotherapy (day 8 and

15 blast % in BM) Day 8 blast count in PB Residual leukemia during treatment (day 8

in PB and day 29 in BM)(MRD) CNS disease at diagnosis adverse

prognostic factor


Proposed risk classification system of pre B cell ALLRisk group Features Low (treated same as standard) age 1-9

WBC<50.000 tel-AML or

trisomy 4,10Standard Age1-9, WBC<50.000

not tel-AML or trisomy 4,10

High age>10, WBC>50.000 CNS 3 or testic. dis

Very high Ph+ leukemia, < 45 chr., induction

failure

Day 29 BM Flow MRD P9904/5/6 Day 29 BM Flow MRD P9904/5/6 MRD >.01% is an optimal cutoff MRD >.01% is an optimal cutoff (n=1960)(n=1960)

0 2 3 4 5 6

0.0

0.2

0.4

0.6

0.8

1.0

Ye

Eve

nt-

free

su

rviv

al p

rob

abi

lity

Day 29 Negative (n=1579)Day 29 0.01-0.1% (n=173)Day 29 >0.1% (n=208)

P< 0.0001

881% 50% of events

685%

515%

4 y EFS

1

Day 8 Blood Flow MRD P9904/5/6 Day 8 Blood Flow MRD P9904/5/6 (n=1933)(n=1933)

0 2 3 4 5 6

0.0

0.2

0.4

0.6

0.8

1.0

Years

Eve

nt-

free

su

rviv

al p

rob

abi

lity

1: MRD Negative (sensitivity = 0.01%) (n=603)2: 0.01% < MRD ≤ 0.1% (n=341)3: 0.1% < MRD ≤ 1.0% (n=501)4: 1.0% < MRD ≤ 10.0% (n=373)5: MRD > 10% (n=116)

P< 0.0001

922%, 16% of events

4 y EFS

1

Significant Prognostic Factors Significant Prognostic Factors Based onBased onCOG Studies Multivariate AnalysisCOG Studies Multivariate Analysis

Day 29 MRD (0.01% cutoff): HR=3.86

NCI risk group: HR=2.1

Trisomy 4/10 status: HR=0.485

Day 8 PB MRD: HR=1.63

TEL/AML1 status: HR=0.699

2009 B-Precursor Classification 2009 B-Precursor Classification (n=1687/yr)(n=1687/yr)

Low– NCI Std Risk Trisomy 4/10 or TEL; D8 blood & D29 BM MRD < 0.01%

Standard– Std Risk w/o or High Risk with Trisomy 4/10,TEL; D29 MRD < 0.01%

High– High Risk or Std Risk w/ CNS/testes; D29 < 0.01% or D29 positive if SR T4/10, TEL

Very High– Std or High Risk; D29 MRD > 0.01%

EFS Patients

95+% 16%

85-94% 41%

70-85% 28%

<70% 15%


Most common cytogenetic abnormalities: 11q23 poor prognosis, 80% of infant ALL, 85% of 20

leukemia) t(4;11), 2%, MLL-AF4 fusion, CD10- B phenotype, infancy,

hyperleukocytosis, dismal outcome with CT t(11;19) 5-6%, E2A-PBX1 fusion, pre B phenotype, poor

prognosis, intensive therapy is necessary t(12;21), 25% of pre B cases excellent prognosis t(9;22), 3-5%, BCR-ABL fusion, B lineage, older age,

hyperleukocytosis, dismal outcome with CT t(8;14), 1-2%, MYC-IGH fusion, B phenotype, boys>girls,

L3 morphology, bulky extramed. disease, favorable prognosis


Immunophenotype distribution

1-pre B cell 80%2-mature B cell 1-2%3-T cell 15-20%

-older age-high initial WBC-extramedullary disease-improved prognosis on intensified protocols


Prognostic significance of chr. abnormalities in ALL

Chromosomal abn. 5-y EFSHyperdiploidy

>50 chr. 80%(65-90%)47-50 chr. 90%(50-98%)

Near triploid, 66-73 chr. Not known, good?Near tetraploid, 82-94 chr. Not konown,<60%Normal diploid, 46 chr. 80%(65-90)Hypodiploidy,<46 chr. 71% (55-85%)Pseudodiploid 73% (55-85%)t(1;19) 53%t(4;11) 45%t(9;22) 14%


Leukemia or lymphoma? Sometimes pts. present with massive

HSM, LAP and mediastinal mass (esp. T cell leukemia)

How do we decide whether it is leukemia or lymphoma?

Look at the blast % in BM, if greater than %25 it is leukemia, otherwise lymphoma


CNS leukemia: (occurs<5% in ALL) Signs and sypmtoms of raised IC pressure

(morning headaches, vomiting, pailledema, sixth nerve palsy)

Signs and sypmtoms of parenchymal involvement (hemiparesis, cranial nerve palsies, convulsions, ataxia, dysmetria etc.)

Hypothalamic syndrome (polyphagia with excessive weight gain, hirsutism,

Diabetes insipidus (posterior pituitary inv.) Chloromas of the spinal cord (back and leg pain,

numbness, weakness) CNS hemorrhage (AML>ALL; leukocytosis,

thrombocytopenia)


Testicular leukemia: Painless swelling in one or both testicles Incidence of testicular relaps is 10-23% during

treatment; median time 13 months Diagnose established by testicular Bx on both

sides 10% of false negativity on Bx High initial wbc (>20.000), T cell origin,

mediastinal mass, significant LAP and HSM; high chance of testicular leukemia

Initial screening unnecessary at the time of diagnosis unless suspected in PE


Treatment: phases Remission induction CNS preventive therapy Consolidation Interim maintenance I and II Intensification I / II Maintenance


Aims of therapy1-to induce a clinical and hematologic remission2-to maintain remission by systemic chemotherapy and prophylactic CNS therapy3-to treat the complications of therapy and disease


Complete remission No symptoms attributable to the disease (eg.

fever, bone pain) No hepatosplenomegaly, lymphadenopathy,

or other clinical evidence of residual leukemic tissue infiltration)

Normal PB findings Less than 5% blasts in a normocellular BM No CNS or extramedullary disease Blasts fall from 1012 to 109


CNS preventive therapy: High increased WBC count, T cell disease, very

young age, thrombocytopenia, LAP, HSM, black race increase the risk of CNS leukemia

CNS, because of the blood-brain barrier, acts as a sanctuary for blasts

Cranial XRT unnecessary for standard-risk pts Cranial XRT indicated only for those who have

CNS leukemia and for those who are poor responders to chemo


CNS preventive therapy: XRT has long term adverse CNS sequela Prophylaxis and treatment usually done

with IT MTX or TIT (MTX, ARA-C, Hydrocortisone)

IT MTX can cause arachnoiditis (Headaches, N/V, meningitis) but self-limited

Encephalopathy, myelopathy, seizures


Duration of treatment: 2.5 to 3.5 years of Rx required for ALL in

most modern protocols Duration of Rx longer for boys than for

girls Prognosis better if relaps occurs after Rx is

finished Prognosis poor if relaps occurs during Rx In mature B cell ALL, treatment is shorter

because there is rapid growth rate


Bone marrow transplantation: Currently allogeneic BMT is routinely

advocated for pts in 2nd remission Pts who suffer late relapses (longer than 30

mo after remission or after completing Rx) is to be treated with chemo. BMT is reserved for subsequent relapse

5-Year Survival Rates for Children (< 15 5-Year Survival Rates for Children (< 15 yrs) yrs) Acute Lymphoblastic Leukemia: 1960 - Acute Lymphoblastic Leukemia: 1960 - 20042004

3%

34%

71%

83%88%

0%

20%

40%

60%

80%

100%

1960-63 1970-73 1981-83 1990-92 1996-2004


Supportive care: R-thrombopoietin (not available everywhere) RBC and platelet transfusions Empiric use of broad spectrum of ab in F/N

pts PCP prophylaxis with TMP/SMZ VZIG within 72-96 hrs of exposure to VZV Infusion of blood products Better management of tm lysis syndrome

Acute Myeloid Leukemia 15-20% of all childhood leukemia Only 40-50% of newly diagnosed cases can be

expected to be cured AML/ALL ratio is 1:4, except congenital leukemia

cases (in the first 4 weeks of life) which is mainly AML

Incidence stable from birth to age 10 exept for a peak in the neonatal period and a slight increase during adolescence

Equally distributed among all ethnic groups (significantly more in hispanics)

AML associated with orbital granulocytic sarcoma (OGS) in Turkish children

Males=females

Acute Myeloid Leukemia

Predisposing factors: Acquired factors; XRT, benzene EMF contraversial Smoking and marijuana use during

pregnancy, increased AML in fetus Rx with alkylating agents (Nitrogen

Mustard, Cyclophosphamide, Melphalan) increased AML risk 4-5 years after Rx, deletion of chr. 5 and 7 common

Long exposure to VP-16, VM-26; AML shortly after Rx, subtype M4-M5

Acute Myeloid LeukemiaPredisposing factors: Genetic factors;

Identical twins-100% concordance Fanconi’s anemia->50% by 40 yrs of age Bloom syndrome DB anemia Kostmann syndrome-risk increases with

age Down syndrome; most common prognostic

factor -14 fold increase NF-1-activation of RAS


Secondary AML can evolve from1-MDS and MPS2-ionizing radiation+chemotherapy

-nitrogen mustard-CTX-IFX-chlorambucil-melphalan-VP-16

Acute Myeloid LeukemiaClassification:

M1: AML without maturation (less than 10% PMN) M2: AML with maturation (more than 10% PMN) M3: Acute promyelocytic leukemia M4: Acute myelomonocytic leukemia M5a: Acute monoblastic leukemia M5b: Acute monocytic leukemia M6: Erythroleukemia M7: Megakaryoblastic leukemia M0: Acute undifferantiated leukemia%20 or more blasts are required for the Dx of AMLFAB classification is being replaced by WHO

classification

WHO Classification of AML

1-With recurrent genetic abnormalities t(8;21)(q22;q22), (AML1/ETO) Abnormal bone marrow eosinophilis

and inv(16)(p13q22) or t(16;16)(p13;q22), (CBFβMYH11)

Acute promyelocytic leukemia 11q23 (MLL) abnormalities

Vardinman JW, et al. Blood 2002; 100:2292-2302

WHO Classification of AML

2-With multilineage dysplasia Following MDS Without MDS, but with dysplasia in at

least 50% cells in >2 myeloid lineages

3-Therapy-related Alkylating agent / radiation-related

type Topoisomerase II inhibitor-related type Others

4-Not otherwise categorized

Potential Risk FactorsPrognostic Factor High Risk Favorable Risk

CytogeneticsDeletion 5q

Monsomy 5 or 7

t(15;17)

inv (16)

t(8;21)

Meschinchi, Arceci. Oncologist. 2007;21:341-355

Mutations of Signal Transduction Pathways

FLT3-ITD, high ITD-AR

Response to Therapy Poor response to therapy

Rapid response to therapy

Molecular AlterationsFLT3 Internal Tandem Duplication (ITD)

Activating mutations in the gene result in autonomous, cytokine-independent cell proliferation

Age-dependent increase in prevalence 12% of pediatric AML patients have FLT3-

ITD

Strongly correlated with older age, higher initial WBC counts, and poorer overall outcome

Ratio of ITD to wild-type allele (ITD-AR) greater than 0.4 associated with high risk for relapse and a survival rate <20%Meshinchi S, et al. Blood. 2006;108(12):3654-3661; Golub TR, Arceci RJ. Acute Myelogenous Leukemia. In: Pizzo

PA, Poplack DG, eds. Principles and Practice of Pediatric Oncology. 5th edition. Philadelphia, PA: Lippincott Williams & Wilkins. 2006;591-644

Outcomes: Impact of Treatment Response

• BM blasts day 28 ≥ 20% (RR 2.8, 95% CI 1.7-4.7, P <0.001)

*Day 28 bone marrows obtained between days 28 and 42 from start of the first course. pEFS = probability of event free survival; pOS = probability of overall survival

Kaspers GJ, et al. Blood. 2007;110. Abstract 1843.

BM Day “28”

At 2 years Overall <20% >20%

pEFS (%)

(95% CI)

28

(23-34)

38

(31-45)

2

(0-5)

pOS (%)

(95% CI)

39

(34-45)

49

(42-56)

14

(6-23)

Outcomes: Impact of MRD

Sievers EL, et al. Blood. 2003;101(9):3398-3406

Acute Myeloid LeukemiaMixed lineage leukemia:

6% of ALL cases demonstrate expression of 2 or more myeloid antigen expression

17% of AML cases demonstrate 2 or more lymphoid antigen expression

Rare cases have distinct populations of lymhoblast and myeloblasts; biphenotypic leukemia

Mixed-lineage expression does not affect prognosis if treated with aggressive multiagent Rx

Rx should be initially based on the predominat cell population then followed by Rx for the second lineage


Most common cytogenetic abnormalities: -5 or del5q 11-q35 -7 or del 7q22-q36 (myeloproliferative

disorders, JCML) Trisomy 8 (20 AML) t(8;21) t(9;22) t(15;17) presence establishes dx regardles of

BM blast count inv (16) t(16;16)

Acute Myeloid LeukemiaClinical and LAB features: Same as ALL Leukemia cutis is often the 1st sign in infant

leukemia DIC especially in M3 ¼ have wbc greater than 100.000 HM or SM in more than 50% Massive LAP less than 25% esp. in M4, M5 Chloromas in bones and soft tissues or around the

orbis; more common in M4 or M5 Testicular involvement relatively uncommon CNS leukemia in 5-15%

Acute Myeloid LeukemiaPrognostic factors: 1-well accepted adverse factors

Wbc greater than 100.000 Secondary AML or prior MDS Monosomy 7 FLIT3 ITD MRD present after induction

2-possible adverse factors: Splenomegaly FAB M4 or M5 More than 1 course of CT for complete response Age M1 with auer rods


Possible favorable factors: t(8;21) t(15;17) survival 72% t(9;11/M3 subtype) Inv 16/M4eo Intermediate karyotype-survival 43% Unfavorable karyotype: monosomy 5,

monosomy 7, del(5q), and del(3q), other complex karyotypes-survival 17%


Treatment: Bleeding: keep plt level above 20.000 Empirical abs for F/N Manage tumor lysis syndrome with hydration,

alkalinization, allopurinol Manage leukostasis with leukophoresis or

exchange transfusion CT: RI with DNM, ARA-C, Mitoxantrone, DXM,

6-TG Most recent protocols use double RI Rx


Treatment: 15-20% fail to enter remission Less than 10% die early from induction,

hemorrhage Those who fail may be treated with other

active combination of drugs After RI those who have suitable donors may

go to BMT, agressive postremission Rx is also justified with ARA-C, L-Asp and sometimes with IL-2

Acute Myeloid LeukemiaTreatment of refractory or recurrent disease

Treatment is difficult Induction may be attempted with HD Ara-C

and L-asp regimen or ID Ara-C, mitoxantrone and etoposide

regimen The second one achieves a remission rate of

76% AHSCT should be carried out once the

remission has been attained (30-50% long term survival)

Prognosis of those who fail to enter remission is very poor (10% 1 y DFS)

Thank you for your attention

acıbadem university pediatric hematology- oncology prof. cengiz canpolat m.d. pediatric...

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