1. Diagnosis and Management Of Acute Leukemia in Children and Adolescents Grand Rounds September 20, 2010 St. Elizabeth Hospital, Lafayette, Indiana Bassem. I. Razzouk, MD, FAAP Medical Director, St. Vincent Children’s Center For Cancer & Blood Diseases

2. Pediatric Cancer Incidence USA YearPopulation < 20 yrs Incidence per 10 5 New cases per year 199872,935,00016.712,183 199973,120,00016.812,321 200073,306,00017.012,448

3. Childhood Cancer

4. Hematopoiesis PLURIPOTENT STEM CELL COMMITTED PROGENITOR CELL RECOGNIZABLE BONE MARROW PRECURSOR CELL MATURE BLOOD CELL myeloblast monoblast pronormoblastred cell neutrophil monocyte basophil platelet CFU-Baso CFU-Eos CFU-GM BFU-E/CFU-E eosinophil pre-T pre-B myeloid progenitor cell lymphoid progenitor cell lymphoblast T-cell B-cell & plasma cell MIXED PROGENITOR CELL CFU-Megmegakaryocyte pluripotent stem cell

5. Myeloid Maturation myeloblastpromyelocytemyelocytemetamyelocytebandneutrophilMATURATION Adapted and modified from U Va website

6. Principles of leukemogenesis A multistep process Neoplastic cell is a hematopoietic pleuripotent cell or early myeloid cell Dysregulation of cell growth and differentiation (associated with mutations) Proliferation of the leukemic clone with differentiation blocked at an early stage

8. Classification of Leukemias AcuteChronic Myeloid origin Lymphoid origin Acute Myeloid Leukemia (AML) Acute Lymphoblastic Leukemia (ALL) Chronic Myeloid Leukemia (CML) Chronic Lymphocytic Leukemia (CLL)

9. Acute Leukemia Accumulation of blasts in the marrow

10. Epidemiology Childhood leukemia represents 12% of all leukemias; 60% of all acute lymphoblastic leukemias Leukemia is the most common cancer diagnosed in children at 4.3/100.000

11. Epidemiology ALL/AML = 5 Peak incidence –ALL: 2 to 5 years –AML: 1 year, increases with age Boys > girls –T-cell 4 times greater incidence –Infant leukemia > in girls

12. Significance of Acute Leukemia A hematologic urgency/emergency Usually fatal within weeks to months without chemotherapy With treatment, moderate to high morbidity ( acute and long term) due to disease or treatment-related complications Notify Peds H/O promptly if acute leukemia is suspected

13. Causes of Acute Leukemias Idiopathic (most) underlying hematologic disorders chemicals, drugs ionizing radiation viruses (HTLV I) hereditary/genetic conditions

14. Predisposing Factors Genetic Syndromes –Down syndrome: 10-20 times increased incidence (600 times in megakaryoblastic type) –Bloom syndrome –Neurofibromatosis –Schwachman syndrome –Ataxia Telangiectasia –Klinefelter syndrome

15. Ataxia-Telangactasia

17. Predisposing Factors Familial aggregation –Concordance in Twins High birth weight Ionizing radiation Non-ionizing radiation (?EMF) Alcohol consumption/cigarette smoking Breast feeding has protective effect

18. Clinical Manifestations Symptoms due to: –marrow failure –tissue infiltration –leukostasis –constitutional symptoms: Fever, weight loss, night sweats, anorexia –other (DIC) Usually short duration ( 4-8 weeks)

19. Clinical Presentation Very heterogenous –Pallor –Petechiae –Hepatosplenomegaly –Adenopathy –Fever –Bony pain

20. Clinical Presentation

21. Infiltration of tissues/organs Enlargement of liver, spleen, lymph nodes Gum hypertrophy bone pain other organs: CNS, skin, testis, any organ

22. Gum Hypertrophy

23. Chloromas Granulocytic Sarcoma (myeloblastoma) –Localized mass of primitive myeloid cells that infiltrate extramedullary sites –Involvement of every organ system has been reported

27. Leukostasis Accumulation of blasts in microcirculation with impaired perfusion lungs: hypoxemia, pulmonary infiltrates CNS: stroke Mostly seen with WBC >> 50 x 10 9 /L in AML and > 100 X10 9 /L in ALL

28. Differential Diagnosis Juvenile Rheumatoid Arthritis- caution to use steroids / oral methotrexate before completely ruling out leukemia Mycobacterial infections ( TB & non-TB) Infectious mononucleosis Aplastic anemia Neuroblastoma Rhabdomyosarcoma Hypereosinophilic syndrome

29. Laboratory Data White blood cell count: variable Hemoglobin levels: low Platelet count: low Serum chemical values –Uric Acid and LDH: elevated –Calcium: elevated Chest X-ray: Mediastinal Mass; Preferable to do CXR with initial diagnosis of asthma, especially if you plan to use steroids Coagulation screening: abnormal

30. WBC < 10.00053% 10,000-49,00030% > 50,00017%

31. Newly Diagnosed Patients with Leukemia- Work-up Establish a diagnosis Peripheral blood and bone marrow studies Morphology Immunopathology (cell markers) Cytogenetics Molecular Genetics Risk assessment Protocol enrollment- patients enrolled on clinical trials have better outcome Consent Process

32. Bone Marrow Aspirate/Biopsy Necessary for diagnosis: Aspirate for ALL; Aspirate/biopsy for AML Useful for determining type Useful for prognosis Acute leukemias are defined by the presence of > 20% blasts (AML) or 25 % blasts (ALL) in bone marrow (% of nucleated marrow cells)

33. Diagnosis Morphology, cytochemistry and immunophenotype Leukemia Acute vs. Chronic Lymphoid vs. Myeloid

34. ALL

35. AML

36. Auer rods in AML

37. Cytochemistry

38. Morphology/ Cytochemistry

39. Key Points In ALL And AML The childhood acute leukemias are a very heterogeneous group of diseases Accurate diagnosis is important Selection of optimal therapy is pivotal

40. Blood Cells Immunophenotype

41. Immunologic Classification CD3, CD7, CD10, CD19, CD79 Lymphoid Myeloid M6/M7 CD41a, CD61, and CD42b FVIIIHemoglobin Lymphoid Vs. M0-M7

42. Classification - ALL

43. Classification - AML

44. Genetics of Childhood ALL B-lineage ALL Translocation Fusion Incidence Cure rates t(12;21) TEL-AML1 25% 90% t(1;19) E2A-PBX1 5-6% 75% t(4;11) MLL-AF4 2-5% 35% t(9;22) BCR-ABL 3-5% <30% (70 % ) with TKI’s

45. AML-associated chromosomal abnormalities Abnormality Fusion FAB Incidence t(8;21) AML1-ETO M2 15% inv (16) CBFβ-MYH11 M4Eo 8-12% t(15;17) PML-RAR  M3 8- 10% t(9;11) MLL-AF9 M4,M5 7% t(11;19) MLL-ELL M4, M5 1% t(1;22) Unknown M7 1%

47. PROGNOSTIC FACTORS DISEASE Tx HeterogeneityIntensity Specificity

48. Prognostic Factors - ALL Initial white blood cell count Age at diagnosis Immunophenotype Genetic Features Extramedullary involvement ( CNS, testis) Response to therapy

49. ALL- Risk Groups St. Jude Estimated COG Low 40% Standard Standard 50% High High 10% Very High

50. Prognostic Factors- AML Favorable –Age < 1 year of age –Genetics: t(15;17), inv16, t(8;21) and t(1;22) –Down syndrome Intermediate –Genetics: normal karyotype, other 11q23 –Residual disease after induction High-risk –Cytogenetics: -7, -5, t(6;9), complex karyotype –AML arising from MDS –Persistent disease after induction

51. Risk Assignment Provisional risk assignment at diagnosis Definitive assignment at end of induction therapy after evaluation of response to early therapy is available The objective of rigorous risk assignment is to avoid over- or under- treatment

52. Principles of Treatment combination chemotherapy –first goal is complete remission –further Rx to prevent relapse supportive medical care –transfusions, antibiotics, nutrition, metabolic /electrolyte abnormalities psychosocial support –patient and family

53. Therapeutic Concepts in ALL Induce a complete remission and restore normal hematopoiesis avoiding excessive toxicity Reduce inapparent leukemia with short-term, high-dosage cytocidal therapy early in remission when the child is well and drug sensitivity is greatest Prevent CNS leukemia (concept of sanctuary) Use prolonged combination chemotherapy to eradicate residual disease when there is no evidence of leukemia

54. Basic Therapy in Childhood ALL Induction Treatment 4-8 wk Consolidation treatment (intensification) 2-10 wk Continuation treatment (maintenance) 2-3 y Reinduction therapy (delayed intensification) 2-7 wk CNS-directed therapy 1-2 y Cessation of therapy 2.5 y for girls, 3.5 y for boys

55. Facts about Childhood ALL Long-term Event Free Survival ( EFS) greater than 80% Accomplished by –Multiagent Chemotherapy –CNS-Directed Therapy –Improved Supportive Care –Trageted therapy with tyrosine kinase inhibitors ( Gleevec and others) for Philadelphia positive ALL –Treatment of adolescents and young adults ( up to 30 years) on “Pediatric Inspired protocols”

56. Survival of ALL According to Treatment Era at St. Jude

57. Pediatric AML Treatment Standard Induction Therapy 80%-90% achieve hematologic CR Differentiation therapy : All trans retinoic acid ( ATRA) for specific variant ; acute promyelocytic leukemia ( APL); which needs emergency treatment since patients present with bleeding Post-remission Therapy Historical controls suggest High dose Ara-C consolidation improves outcome Recent data suggest 60-70% of children with matched family donors achieved cure with Allo transplant, but data is conflicting Maintenance Therapy No data demonstrates efficacy

58. Results of St. Jude AML Trials

59. Supportive Care Patient stabilization –Metabolic : hydration, alkalinization, allopurinol, and occasionally Rasbruicase ( recombinant urate oxidase) for tumor lysis syndrome –Hemorrhage (DIC)- FFP, platelets –Infection- Braod spectrum antibiotics (Cefipeme) –Leukostasis- leukapheresis in AML /early therapy Central Venous Catheter Blood Products ( irradiated, leukoreduced, CMV negative until CMV status is known)

60. Hematopoietic Stem Cell transplantation Permits “rescue” from otherwise excessively toxic treatment especially in relapsed/refractory cases Additional advantage of graft-vs-leukemia effect in allogeneic transplants Less used for Philadelphia positive ALL, CML, and AML with tyrosine kinase inhibitors and better outcome with chemotherapy Trade-off for allogeneic transplantation: greater anti-leukemic effect but more toxicity

61. Side Effects of Therapy-Acute Nausea/vomiting/mucositis/hair loss Neutropenia/Anemia/Thrombocutopenia Infections/fever Extravsation of vesicants ( Vincristine, Anthracyclines)- Central line Weight loss/anorexia- Nutritional Support SIADH- VCR/Cyclophosphamide Hemorraghic cystistis- Cyclophosphamide; Hydration/MESNA

62. Long term Side effects Neuro-Cognitive abnormalities: High-dose and intrathechal Methotrexate, Cranial irradiation Second cancers : Cyclo/Etoposide, radiation Cardiomyopathy: Anthracyclines ( dose dependent) Sterility: cyclophosphamise, Stem cell transplantation, Radiation Endocrine abnormalities: radiation Employment problems/Insurance Psycho-social support: parents /siblings Obesity: ? Females, ? Cranial radiation