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

1. Acıbadem University Pediatric Hematology-Oncology Prof. Cengiz Canpolat M.D.Pediatric Hematology-Oncology

2. 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-pozitive 2-Juvenile myelomonositic leukemia(JMML)

3. 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

4. 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

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

6. Acute Leukemia Etiology Increased incidence with the following genetically determined conditions: a-congenital agamaglobulinemia b-Shwachman-Diamond syndrome c-Ataxia telengiectasia d-Li-Fraumeni syndrome e-NF f-DB anemia g-Kostmann disease

7. 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

8. Acute Lymphoblastic Leukemia 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

9. Acute Lymphoblastic Leukemia 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

10. Acute Lymphoblastic Leukemia 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

11. Acute Lymphoblastic Leukemia 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

12. Acute Lymphoblastic Leukemia Evaluation of the patient; LP Cultures Dental examination Ophtalmic evaluation

13. Acute Lymphoblastic Leukemia 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

14. Acute Lymphoblastic Leukemia Clinical manifestations; Meningeal involvement may cause headache, emesis, papilledema Recurrent fever, frequent infections, extremity pains may be confused with other diseases

15. Acute Lymphoblastic Leukemia 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

16. Acute Lymphoblastic Leukemia 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.)

17. Acute Lymphoblastic Leukemia 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

18. Acute Lymphoblastic Leukemia Proposed risk classification system of pre B cell ALL Risk group Features Low (treated same as standard) age 1-9 WBC<50.000 tel-AML or trisomy 4,10 Standard 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

19. Day 29 BM Flow MRD P9904/5/6 MRD >.01% is an optimal cutoff (n=1960) 881% 50% of events 1.0 4 y EFS 0.8 685% 0.6 515% Event-free survival probability 0.4 0.0001 < P 0.2 Day 29Negative (n=1579) Day 290.01-0.1%(n=173) Day 29>0.1%(n=208) 0.0 1 0 2 3 4 5 6 Ye

20. Day 8 Blood Flow MRD P9904/5/6 (n=1933) 1.0 922%, 16% of events 0.8 4 y EFS 0.6 Event-free survival probability 0.4 < P 0.0001 1: MRD Negative (sensitivity = 0.01%) (n=603) 0.2 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) 0.0 1 0 2 3 4 5 6 Years

21. SignificantPrognosticFactorsBased onCOG StudiesMultivariateAnalysis • 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

22. 2009 B-Precursor Classification (n=1687/yr) EFS Patients 95+% 16% 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% 85-94% 41% 70-85% 28% 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% <70% 15%

23. Acute Lymphoblastic Leukemia Mostcommoncytogeneticabnormalities: 11q23 poorprognosis, 80% of infant ALL, 85% of 20leukemia) t(4;11), 2%, MLL-AF4 fusion, CD10- B phenotype, infancy, hyperleukocytosis, dismaloutcomewith CT t(11;19) 5-6%, E2A-PBX1 fusion, pre B phenotype, poorprognosis,intensivetherapy is necessary t(12;21), 25% of pre B casesexcellentprognosis t(9;22), 3-5%, BCR-ABL fusion, B lineage, olderage, hyperleukocytosis, dismaloutcomewith CT t(8;14), 1-2%, MYC-IGH fusion, B phenotype, boys>girls, L3 morphology, bulkyextramed. disease, favorableprognosis

24. Acute Lymphoblastic Leukemia Immunophenotypedistribution 1-pre B cell 80% 2-mature B cell 1-2% 3-T cell 15-20% -olderage -highinitial WBC -extramedullarydisease -improvedprognosis on intensifiedprotocols

25. Acute Lymphoblastic Leukemia Prognostic significance of chr. abnormalities in ALL Chromosomal abn. 5-y EFS Hyperdiploidy >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%

26. Acute Lymphoblastic Leukemia Leukemiaorlymphoma? Sometimespts. presentwithmassive HSM, LAP andmediastinalmass (esp. T cellleukemia) How do wedecidewhether it is leukemiaorlymphoma? Look at theblast % in BM, ifgreaterthan %25 it is leukemia, otherwiselymphoma

27. Acute Lymphoblastic Leukemia 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)

28. Acute Lymphoblastic Leukemia 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

29. Acute Lymphoblastic Leukemia Treatment: phases Remission induction CNS preventive therapy Consolidation Interim maintenance I and II Intensification I / II Maintenance

30. Acute Lymphoblastic Leukemia Aims of therapy 1-to induce a clinical and hematologic remission 2-to maintain remission by systemic chemotherapy and prophylactic CNS therapy 3-to treat the complications of therapy and disease

31. Acute Lymphoblastic Leukemia Completeremission 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 1012to 109

32. Acute Lymphoblastic Leukemia 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

33. Acute Lymphoblastic Leukemia 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

34. Acute Lymphoblastic Leukemia 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

35. Acute Lymphoblastic Leukemia 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

36. 5-Year Survival Rates for Children (< 15 yrs) Acute Lymphoblastic Leukemia: 1960 - 2004

37. Acute Lymphoblastic Leukemia 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

43. 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

44. 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

45. Acute Myeloid Leukemia Predisposing 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

46. Acute Myeloid Leukemia Secondary AML can evolve from 1-MDS and MPS 2-ionizing radiation+chemotherapy -nitrogen mustard -CTX -IFX -chlorambucil -melphalan -VP-16

47. Acute Myeloid Leukemia Classification: 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 AML FAB classification is being replaced by WHO classification

48. 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

49. 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

50. Potential Risk Factors Response to Therapy Poor response to therapy Rapid response to therapy Meschinchi, Arceci. Oncologist. 2007;21:341-355