Leukemia in Pediatrics - Dr. Julius King Kwedhi
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Definition A group of malignant diseases in which genetic abnormalities in a hematopoietic cell give rise to an unregulated clonal proliferation of cells The progeny of these cells have a growth advantage over normal cellular elements, with an increased rate of proliferation & a decreased rate of spontaneous apoptosis Disruption of normal marrow function, leading to marrow failure
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Leukemia in Pediatrics - Dr. Julius King Kwedhi
- 1. LEUKAEMI PEDIATRICS DR. JULIUS KWEDHI GROUP 100 5TH YEAR SECHENOV UNIVERSITY
- 2. LEUKEMIA DEFINITION ▸A group of malignant diseases in which genetic abnormalities in a hematopoietic cell give rise to an unregulated clonal proliferation of cells ▸The progeny of these cells have a growth advantage over normal cellular elements, with an increased rate of proliferation & a decreased rate of spontaneous apoptosis ▸Disruption of normal marrow function, leading to marrow failure
- 4. LEUKEMIA GENETIC CONDITIONS ▸Down syndrome ▸Falcon anemia ▸Bloom syndrome ▸Diamond-Blackfan anemia ▸Shwachman-Diamond syndrome ▸Kostmann syndrome ▸Neurofibromatosis type 1 ▸Ataxia-telangiectasia ▸Severe combined immune deficiency ▸Paroxysmal nocturnal hemoglobinuria ▸Li-Fraumeni syndrome
- 5. LEUKEMIA ENVIRONMENTAL FACTORS ▸Ionizing radiation ▸Drugs ▸Alkylating agents ▸Epipodophyllotoxin ▸Benzene exposure
- 6. LEUKEMIA TYPES OF LEUKEMIAS ▸Acute Llymphoblastic Leukaemia (ALL) ▸Acute Myelogenous Leukaemia (AML) ▸Chronic Myelogenous Leukemia (CML) ▸Juvenile Myelomonocytic Leukemia (JMML) ▸Infant Leukemia ▸Other acute and chronic leukemias not fitting in the above categories.
- 7. ACUTE LYMPHOBLASTIC LEUKEMIA ACUTE LYMPHOBLASTIC LEUKEMIA ▸Diagnosed in approximately 2,400 Children <15 yr of age in USA, each year. ▸Peak incidence at 2-3 years ▸Boys>gils ▸More common in children with certain chromosomal abnormalities: Down syndrome, Bloom syndrome, ataxia- telangectasia, Falcon anaemia.
- 8. ACUTE LYMPHOBLASTIC LEUKEMIA ETIOLOGY ▸Unknown ethology ▸Associated with several genetic and environmental factors: radiation, Epstein-Barr viral infection ▸Purported to be caused by post conception somatic mutations in lymphoid cells ▸Identified leukemics-specific fusion-gene sequence in archived neonatal blood spots
- 9. ACUTE LYMPHOBLASTIC LEUKEMIA CLINICAL MANIFESTATIONS ▸Nonspecific and relatively brief ▸Anorexia ▸Fatigue ▸Malaise ▸Irritability ▸Intermittent, low-grade fever ▸Bone or joint pain ▸Signs and symptoms of marrow failure ▸Fatique, exercise intolerance, bruising or epistaxis
- 10. ACUTE LYMPHOBLASTIC LEUKEMIA CLINICAL EXAMINATION ▸Pallor ▸Listlessness ▸Purpuric ▸Petechial skin lesions ▸Mucous membrane haemorrhage (reflect marrow failure) ▸Lymphadenopathy ▸Splenomegaly ▸Hepatomegaly ▸Joint swelling ▸Signs of increased intracranial pressure indicating CNS involvement (e.g. papilledema, retinal haemorrhages, cranial nerve palsies) ▸Respiratory distress
- 11. ACUTE LYMPHOBLASTIC LEUKEMIA LABORATORY ▸Bone marrow aspiration and biopsy ▸Flow cytometry ▸Cytogenetic studies ▸Molecular studies ▸Leukocyte counts <10,000/uL ▸Thrombocytopenia ▸Blasts in CSF
- 12. ACUTE LYMPHOBLASTIC LEUKEMIA TREATMENT ▸Risk-directed therapy ▸Initial therapy: Remission induction ▸Second phase therapy: Consolidation ▸Maintenance phase of therapy ▸Period of treatment = intensification
- 13. ACUTE MYELOGENOUS LEUKEMIA ACUTE MYELOGENOUS LEUKEMIA ▸Accounts for 11% of cases of childhood leukaemia in USA ▸370 children diagnosed annually ▸Acute promyelocytic leukaemia (APL) is a subtype more common. ▸Associated with several chromosomal abnormalities
- 14. ACUTE MYELOGENOUS LEUKEMIA RISK FACTORS ▸Ironizing radiation ▸Chemotherapeutic agents (e.g. alkylating agents, epipodophyllotoxin) ▸Organic solvents ▸Paroxysmal nocturnal hemoglobinuria ▸Down syndrome ▸Falcon anemia ▸Bloom syndrome ▸Kostmann syndrome ▸Shwachman-Diamond syndrome ▸Diamond-bLACKFAN SYNDROME ▸Li-Fraumeni syndrome ▸Neurofibromatosis type 1
- 15. ACUTE MYELOGENOUS LEUKEMIA CELLULAR CLASSIFICATION ▸The characteristic feature of AML is that >20% of bone marrow cells on bone marrow aspiration or biopsy touch preparations constitute a fairly homogenous population of blast cells, with features similar to those that characterise early differentiation states of the myeloid monocyte- megakaryocyte series of blood cells. ▸WHO Classification of Acute myeloid Neoplas s
- 16. ACUTE MYELOGENOUS LEUKEMIA CLINICAL MANIFESTATIONS ▸Replacement of bone marrow by malignant cells that leads to secondary bone marrow failure causes the signs and symptoms: ▸All findings associated with marrow failure ▸Subcutaneous nodules (blueberry muffin lessons) ▸Infiltration of the gingiva ▸Disseminated intravascular coagulation (esp. indicative of APL) ▸Discrete masses called chloromas or granulocytic sarcomas
- 17. ACUTE MYELOGENOUS LEUKEMIA DIAGNOSIS ▸Bone marrow aspiration and biopsy: Reveals a hyper cellular marrow with monotonous patterns of cells ▸Flow cytometry ▸Special stains that identify myeloperoxidase-containing cells
- 18. ACUTE MYELOGENOUS LEUKEMIA TREATMENT ▸Aggressive multiagent chemotherapy (85-90% success) ▸Therapy targeted to genetic markers ▸Matched-sibling bone marrow or stem cell transplantation after remission ▸All-transretinoic acid (ATRA, tretinoin) combined with anthracyclines and cytarabine ▸Arsenic trioxide ▸5% of patients die of either infection or bleeding before remission can be achieved
- 19. CHRONIC MYELOGENOUS LEUKEMIA CHRONIC MYELOGENOUS LEUKEMIA ▸A clonal disorder of the hematopoietic tissue ▸2-3% of childhood leukaemia ▸99% caused by Philadelphia chromosome translocation (t(9;22)(q34;q11)) resulting in a BCR-ABL fusion protein.
- 20. CHRONIC MYELOGENOUS LEUKEMIA SIGNS AND SYMPTOMS ▸Nonspecific ▸Fever ▸Fatigue ▸Weight loss ▸Anorexia ▸Splenomegaly (causing pain in the left upper quadrant of abdomen) ▸Neurologic symptoms
- 21. CHRONIC MYELOGENOUS LEUKEMIA DIAGNOSIS ▸High white cell count with myeloid cells at all stages of differentiation in the peripheral blood and bone ▸Cytogenetic and molleluclar studies ▸Initial chronic phase: malignant clone produces an elevated leukocyte count with predominance of mature forms but with increased numbers of immature granulocytes ▸Mild anemia ▸Thrombocytosis ▸Accelarated or “blast crisis” phase: blood counts rise dramatically (Clinical picture indistinguishable from acute leukaemia)
- 22. CHRONIC MYELOGENOUS LEUKEMIA TREATMENT ▸Imatinib (Gleevec) - inhibits the BCR-ABL tyrosine kinase ▸Second-generation tyrosine kinase inhibitors (e.g. dasatinib) ▸Hydroxyurea
- 23. JUVENILE MYELOMONOCYTIC LEUKEMIA JUVENILE MYELOMONOCYTIC LEUKEMIA ▸A clonal proliferation of hematopoietic stem cells that typically affects children younger than 2 yr of age. ▸Rare ▸<1% of childhood leukaemia ▸There is not Philadelphia chromosome ▸Mutations that lead to activation of RAS oncogene pathway including NFI and PTPN11
- 24. JUVENILE MYELOMONOCYTIC LEUKEMIA CLINICAL PRESENTATION ▸Rashes ▸Lymphadenopathy ▸Splenomegaly ▸Hemorrhagic manifestations
- 25. JUVENILE MYELOMONOCYTIC LEUKEMIA LABORATORY ▸Peripheral blood reveals: ▸Elevated leukocyte count ▸Increased monocytes ▸Thrombocytopenia ▸Anemia ▸Erythroblasts ▸Bone marrow shows a myelodysplastic pattern, with blasts making up <20% of cells
- 26. JUVENILE MYELOMONOCYTIC LEUKEMIA TREATMENT ▸Stem cell transplantation
- 27. INFANT LEUKEMIA INFANT LEUKEMIA ▸About 2% of all childhood leukaemia ▸Before 1 year of age ▸Ratio of ALL to AML is 2:1 ▸Leukemic clones noted ▸Chromosome translocations in utero during fatal hematopoiesis —-> malignant clone formation ▸Poor prognosis ▸<80% show rearrangements of MLL gene at 11q23 band translocation, the majority of which are the t(4;11)
- 28. INFANT LEUKEMIA CLINICAL PRESENTATION ▸Organomegaly due to hyperleukocytosis and extensive tissue infiltration ▸CNS disease ▸Subcutaneous nodules (a.k.a. leukaemia cutis) ▸Tachypnea due to diffuse pulmonary infiltration by leukaemia cells ▸Leukaemia cell morphology is usually that of large irregular lymphoblats, with a phenotype negative for the CD10 marker.
- 29. INFANT LEUKEMIA TREATMENT ▸Very intensive chemotherapy programs (very aggressive) ▸Stem cell transplantation ▸Infants with AML often present with CNS or skin involvement and have a subtype known as acute myelomonocytic leukemia. Treatment same as AML in older children and has similar outcome. ▸Meticulous supportive therapy needed.