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Diagnosis and Management Of Acute Leukemia in Children and Adolescents

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. Pediatric Cancer Incidence USA.

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Diagnosis and Management Of Acute Leukemia in Children and Adolescents

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  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 IncidenceUSA

  3. Childhood Cancer

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

  5. myeloblast promyelocyte myelocyte metamyelocyte band neutrophil Myeloid Maturation MATURATION 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

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

  8. Acute Leukemia • Accumulation of blasts in the marrow

  9. 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

  10. 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

  11. 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

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

  13. 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

  14. Ataxia-Telangactasia

  15. 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

  16. 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)

  17. Clinical Presentation Very heterogenous • Pallor • Petechiae • Hepatosplenomegaly • Adenopathy • Fever • Bony pain

  18. Clinical Presentation

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

  20. Gum Hypertrophy

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

  22. Leukostasis • Accumulation of blasts in microcirculation with impaired perfusion • lungs: hypoxemia, pulmonary infiltrates • CNS: stroke • Mostly seen with WBC >> 50 x 109/L in AML and > 100 X109/L in ALL

  23. 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

  24. 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

  25. WBC < 10.000 53% 10,000-49,000 30% > 50,000 17%

  26. Newly Diagnosed Patients withLeukemia- 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

  27. 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)

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

  29. ALL

  30. AML

  31. Auer rods in AML

  32. Cytochemistry

  33. Morphology/ Cytochemistry

  34. 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

  35. Blood Cells Immunophenotype

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

  37. Classification - ALL

  38. Classification - AML

  39. 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

  40. AML-associated chromosomalabnormalities 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%

  41. PROGNOSTIC FACTORS survival Tx DISEASE Heterogeneity Intensity Specificity

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

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

  44. 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

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