leukemia.pptx

How to manage it

1. The Leukemias By Dr CK Mwandama Department of Internal medicine, University Teaching Hospital, Lusaka 29/06/17

2. Introduction Definition The word leukemia literally means “white blood” referring to neoplastic proliferation of white blood cells or leukocytes. Leukemias are haematologic neoplasms characterized by clonal malignant proliferation of either mature white blood cells or their precursors .

3. Lymphopoesis

4. Classification of leukemia Leukemia Morphologic Lineage Disease Progression Myeloid Lymphoid Acute Chronic

5. Classification of Leukemia Leukemias are classified as lymphoid or myeloid, depending on the affected progenitor stem cell type. Leukemias are also classified as acute or chronic depending on the duration of evolution of the disease

6. Classification of leukemia Leukaemias are classified in 4 major types Acute Lymphocytic Leukemia (ALL) Acute Myelogenous Leukemia (AML) Chronic Lymphocytic Leukemia (CLL) Chronic Myelogenous Leukemia (CML)

7. Incidence Leukaemia CLL - Chronic Lymphocytic ALL - Acute Lymphocytic CML - Chronic Myelogenous AML - Acute Myelogenous

8. Classification of leukemias Acute Leukaemias In acute leukemias onset of disease is often abrupt, within weeks, and death may occur within weeks to months without treatment. Typically, leukocyte development halts at the blast phase with most leukocytes undifferentiated or blasts. In acute leukemia, the WBC may remain low because the cells are halted at the blast stage

9. Classification of Leukemias Chronic Leukaemias Onset is much slower, often over months or years. The majority of leukocytes are mature Typically manifest with very high WBC counts

10. Pathophysiology of Leukemia Leukemias appears to result from a combination of factors genetic predisposition chromosomal changes chemical agents(benzene) chemotherapeutic agents. radiation immunocompromise viruses

11. Leukemogenesis & Lymphomagenesis

12. Pathophysiology of Leukemias Leukemogenesis is characterized by ; blockage of cell differentiation self-sustainable proliferation abnormal cell cycle progression impaired apoptosis

13. Pathophysiology of Leukemia Genetic abnormalities identified in the propagation of leukemogenesis include chromosomal translocations gene deletions Amplifications point mutations

14. Pathophysiology of Leukemia Proto-oncogenes associated with leukemogenesis include ABL-Chronic myeloid leukemia N- Ras-Haematologic Malignancies FMS-Leukemia c-MYC- Burkitts Leukemia

15. Acute Lymphoblastic Leukemia Characterized by presence of lymphoblasts in the bone marrow, peripheral blood ,liver, spleen, lymph nodes and soft tissues Philadelphia chromosome positive(t9:22 translocation) Classified into 3 stages L1: Small homogeneous blasts; mostly in children L2: Large heterogeneous blasts; mostly in adults L3: “Burkitt” large basophilic B-cell blasts with vacuoles

16. Acute Myeloid Leukemia Characterized by uncontrolled proliferation of myeloblasts, hyperplasia of bone marrow and spleen FAB Classification M0 -- Undifferentiated AML M1 -- AML without maturation M2 -- AML with maturation M3 -- Acute Promyelocytic Leukemia M4 -- Acute Myelomonocytic Leukemia M5 -- Acute Monocytic Leukemia M6 -- Erythroleukemia (DiGuglielmo’s) M7 -- Megakaryoblastic Leukemia

17. Acute Myeloid Leukemia WHO classification AML with recurrent cytogenic translocations AML with multi-lineage dysplasia AML and myelodysplasia, therapy related AML, not otherwise categorized

18. Chronic Myeloid leukemia Disease Progression Estimated Survival Chronic Phase (CP) Accelerated Phase (AP) Blast Crisis (BC) 3 - 5 year s 6 - 12 months 3 - 6 months

19. Chronic myeloid Leukemia Characterized by excessive development of mature neoplastic granulocytes in the bone marrow and peripheral blood Ultimately infiltration into the liver and spleen Philadelphia chromosome(Ph) is present in up to 95% of patients Characterized by reciprocal translocation of long arm of chromosomes 22 and chromosome 9 Ph chromosome is almost specific to CML

20. Chronic myeloid Leukemia Abelson proto-oncogene (c-ABL) come into juxtaposition with the “break point cluster region”(BCR) producing the BCR-ABL fusion oncogene Resultant oncoprotein is a hyperactive tyrosine kinase Ph chromosome is also seen in ALL and chronic neutrophilic leukemia

21. Chronic Lymphocytic Leukemia Exclusive in elderly Hyper-mature lymphocytes with highly condensed nuclei Massive splenomegaly and Lymph node enlargement is noticeable throughout the body

22. Chronic Lymphocytic Leukemia CLL is staged as follows Stage 0-Absolute lymphocyte count >15 000 Stage 1-Absolute lymphocytosis with lymphadenopathy Stage 2-Absolute lymphocytosis with lymphadenopathy with hepatomegaly and or splenomegaly Stage 3-Absolute lymphocytosis with lymphadenopathy with hepatomegaly and or splenomegaly plus anaemia(Hb <11) Stage 4-Absolute lymphocytosis with lymphadenopathy with hepatomegaly and or splenomegaly plus thrombocytopenia(platelet count < 100 000)

23. Overall clinical features Bone Marrow Failure Anemia Neutropenia Thrombocytopenia Infiltration Leukemia meningitis Hepatosplenomegaly Central nerve palsy Granulocytic sarcoma Leukemic orchitis Lymphadenopathy Hyperleukocytosis Central nervous system l eukostasis/stroke Respiratory distress syndrome Metabolic Hypercalcemia Hyperphosphatemia Hyperkalemia Hypercoagulation Hyperuricemia Weight loss

24. Overall Clinical features ALL AML CLL CML Signs/Symptoms Fatigue, weight loss, night sweats, bruising, bleeding Fatigue, weight loss, night sweats White blood cell High/low High/low High High Hemoglobin Normal/low Normal/low Normal/low Normal Platelets Low Low Normal/high Normal/high BM Blasts > 20% > 20% None 0-10% Chronic Phase Spleen/Liver May be enlarged Normal May be enlarged May be enlarged

25. Approach to Diagnosis Medical history and physical CBC with differential Bone marrow biopsy and aspiration Chemistry panel Cytogenetics Immunophenotyping

26. Treatment of Acute Leukemia Goals of treatment are as follows Induction therapy Rapidly achieve complete response (CR) Consolidation therapy Maintain CR Eliminate clinically undetectable leukemia Prevent/delay relapse Maintenance therapy Eliminate residual leukemia Prolong remission CNS therapy Prevent relapse

27. Chemotherapy for Acute Leukemias ALL AML Class Agents Class Agents Vinca Alkaloids Vincristine Anthracyclines Daunorubicin Idarubicin Corticosteroids Dexamethasone Prednisone Pyrimidine Analog Cytarabine Anthracyclines Doxorubicin Daunorubicin Antimetabolite Hydroxyurea Antimetabolite Methotrexate Alkylator Cyclophosphamide Enzyme L- Asparaginase

28. Chemotherapy for Chronic Leukemia CLL CML Class Agents Class Agents Purine analog Fludarabine Tyrosine kinase inhibitors Imatinib, Dasatinib Nilotinib Steroids Methylprednisolone Alkylators Cyclophosphamide, Chlorambucil, Bendamustine Monoclonal antibodies Rituximab, Alemtuzumab, Ofatumumab

29. Bone Marrow /Stem cell transplant Goals of this therapy are as follows Total myelosuppression of patient’s neoplastic BM Transplant an HLA-matched BM from any of the following Patient’s own stem cells removed before Identical twin Sibling Volunteer

30. Supportive care Isolation with total barrier nursing Blood and platelets transfusion Antibiotic cover G-CSF Anti-emetics Prevention of tumor lysis syndrome

31. References Oxford Handbook of Clinical Haematology, 2nd Edition Oxford Handbook of Clinical Medicine, 9th Edition

32. END!!! Questions??