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Introduction to leukemia
- 1. INTRODUCTION TO LEUKEMIA DR. R. RAJKUMAR M.D., D.M. CONSULTANT MEDICAL ONCOLOGIST
- 2. Leukemia: Definition ⢠a progressive, malignant disease of the blood-forming organs, marked by distorted proliferation and development of leukocytes and their precursors in the blood and bone marrow http://medical-dictionary.thefreedictionary.com/leukemia
- 3. Pathogenesis (Of Cancer and also of Leukemia)
- 4. DNA changes â˘Toxins/Carcinogens â˘Radiation â˘Errors of metabolism â˘Chronic inflammation â˘Transforming viruses â˘Point mutations â˘Deletions â˘Translocations â˘Amplification â˘Numeric changes GAIN OR LOSS OF FUNCTION OF GENES Malignant Transformation
- 5. âgain or loss of function of genesâ ONCOGENES TUMOR SUPPRESSOR GENES
- 6. Malignant Transformation 2 DNA changes DNA repair Cellular regulatory& monitoring mechanisms Apoptosis Immune system proliferation Mutagenic Insults or germ line mutations 1ST HIT More insults 2nd HIT Transformation Loss of contact inhibition, growth factor dependence/regulation, apoptosis Additional hits Invasion, Angiogenesis, Metastasis⌠Clonal selection
- 7. Two-Hit Hypothesis of Leukmogenesis Class I Mutations Class II Mutations FLT3-ITD FLT3-TKD KIT RAS PTPN11 JAK2 PML-RARA RUNX1-RUNX1T1 CBFB-MYH11 MLL fusions CEBPA NPM1? AML Proliferation and/or survival advantage Impaired differentiation, apoptosis Gilliland et al. Curr Opin Hematol (2001) 8:189-191. WHO Book 2008
- 8. Acute vs. Chronic Acute Chronic Myeloid Lymphoid Acute myeloid leukemia Chronic myeloid leukemia Other CMPNs Acute lymphoblastic leukemia (B or T) Adult T lymphocytic leukemia T-cell LGL Leukemia T-Prolymphocytic leukemia Aggressive NK/T leukemia Chronic lymphocytic leukemia Hairy cell leukemia Other circulating B cell lymphomas Sezary Syndrome Adult T lymphocytic leukemia T-cell LGL Leukemia T-Prolymphocytic leukemia
- 9. ACUTE CHRONIC Onset Rapid Insidious Time to death or complications Minutes to weeks Weeks to Years Treatment Aggressive, urgent Long term, milder Predominant Cell Immature Mature Curability Potential ?
- 10. Acute Leukemias â Initial Findings ⢠CBC abnormalities â Leukocytosis or leukopenia â Other cytopenias â Blasts ⢠Related Issues â Bleeding (thrombocytopenia, DIC) â Infection â Organ/Tissue infiltration
- 15. Incidence of Acute Leukemias Wintrobeâs Clinical Hematology
- 16. AML vs ALL: Morphology ⢠CAUTION: With the exception of Auer rods, there is morphologic overlap between the two diagnoses. Non-Lymphoblasts Lymphoblasts Size 3-4 x size of RBC 1.5-2 x size of RBC Auer rods May be present Absent Granules Often present Rare N:C ratio Moderate High Chromatin Open or finely dispersed Moderately condensed Nucleoli More, prominent Inconspicuous
- 17. Acute Leukemia - Management Principles ⢠Stabilize ⢠Pre-treatment eval/prep ⢠Risk Stratify ⢠Remission Induction ⢠Consolidation â based on risk ⢠Maintenance/surveillance
- 18. Emergent Issues ⢠Leukostasis ⢠Tumor Lysis ⢠Infection ⢠Bleeding ⢠DIC
- 19. AML â Cytogenetic stratification
- 20. AML Prognosis ⢠Good â t(8;21) (M2) â t(15;17) (M3) â inv(16) (M4eo) ⢠Intermediate â Normal ⢠Poor â Complex â 11q23 (M5) â t(6;9) (M2) â inv(3) (M1/5) â t(1;22) (M7) â MDS ⢠5q- ⢠7q- ⢠+8 ⢠Good â NPM1 mut. â CEBPA mut. ⢠Poor â FLT3-ITD â High ERG â High BAALC â MLL-PTD
- 21. AML Molecular Risk Stratification Hematology 2008
- 22. ALL survival by genetic subtype NEJM 2004
- 23. Acute Leukemia â Treatment Concept Specific management strategies are based on risk profile
- 24. AML - Risk Adapted Therapy
- 25. ALL â Risk Adapted Therapy
- 26. Acute Promyelocytic Leukemia â the case for targeted therapy NEJM 2009, 360:928-930
- 27. More Examples for Targeted Therapy in Acute Leukemias ⢠Imatinib in philadlephia positive ALL ⢠Rituximab in CD20 positive mature B ALL ⢠FLT3 inhibitors ⢠HIDAC inhibitors
- 28. Acute Leukemia â Future ⢠Extensive genetic analysis of disease ⢠Personalized therapy ⢠MRD based surveillance ⢠Modified stem cell transplant
- 30. Copyright Š2003 American Society of Hematology. Copyright restrictions may apply. Hematology 2003;2003:597-618 CLL â Proposed Model
- 31. Presentation/Clinical Features ⢠Lymphocytosis ⢠Lymphadenopathy ⢠Splenomegaly and related symptoms ⢠Constitutional symptoms â rare initially ⢠Immune deficiency ⢠Anemia/Thrombocytopenia
- 32. Diagnosis â Peripheral smear Small, mature looking Lymphocytes
- 33. Diagnosis â Flow Cytometry Co-expression of CD5 and CD19,23
- 34. Staging â Rai Stage Feature Median Survival 0 Lymphocytosis only >150 mos 1 Lymphadenopathy 101 2 Spleno/Hepato megaly 71 3 Anemia 19 4 Thrombocytopenia 19
- 35. Dohner H et al. N Engl J Med 2000;343:1910-1916 Prognostic Variables: Cytogenetics 13q deletion 12q trisomy, Normal 11q deletion 17q deletion
- 36. CLL â When to Treat? ⢠Non-immune Anemia/ Thrombocytopenia ⢠Symptomatic splenomegaly ⢠Symptomatic Lymphadenompathy Treat based on risk Classic Paradigm Proposed Paradigm
- 37. Copyright Š2003 American Society of Hematology. Copyright restrictions may apply. Keating, M. J. et al. Hematology 2003;2003:153-175 Figure 4. Time-to-treatment failure and survival of 202 chronic lymphocytic leukemia (CLL) patients treated with fludarabine, cyclophosphamide, and rituximab (FCR) as initial therapy Is CLL Curable?
- 38. CML â Course Chronic Phase Accelerated Phase Blast Crisis â˘Increased blasts â˘Increased basophilia â˘Worsening symptoms â˘New soft tissue masses â˘New cytogenetic abnormalities â˘Acute Leukemia â˘Poor prognosis â˘Myeloid or Lymphoid Median 5-7 years Weeks - Months
- 39. CML â Clinical Presentation ⢠Non-specific constitutional symptoms ⢠Symptoms related to elevated abnormal WBC â Leukostasis, tissue infiltration, Sweetâs syndrome, Urticaria ⢠Symptoms related to splenomegaly or other sites of extramedullary hematopoiesis ⢠Symptoms related to high metabolic rate â fever, weight loss, hyperuricemia ⢠Incidental finding
- 40. Goldman J and Melo J. N Engl J Med 2003;349:1451-1464 The t(9;22) Translocation and Its Products: the BCR-ABL Oncogene on the Ph Chromosome and the Reciprocal ABL-BCR on the Derivative 9q+ Chromosome
- 41. Goldman J and Melo J. N Engl J Med 2003;349:1451-1464 Physiologic Regulation by the Normal ABL Protein and Deregulation by BCR-ABL of Key Cellular Processes Such as Proliferation, Adherence, and Apoptosis
- 42. Diagnosis - Molecular ⢠Cytogenetic analysis (Karyotype) will be positive for t(9:22) in ~90% ⢠PCR or FISH for the BCR-ABL transcript are positive in >95% ⢠The remainder are atypical cases, and may be positive for variant translocations or other abnormalities
- 43. CML â Management ⢠An allogeneic stem cell transplant is still the only proven curative modality, but involves high upfront mortality and morbidity ⢠Tyrosine Kinase inhibitors are the mainstay of treatment, likely do not cure the disease completely, but can afford long term survival
- 44. Savage D and Antman K. N Engl J Med 2002;346:683-693 Mechanism of Action of BCR-ABL and of Its Inhibition by Imatinib
- 45. Copyright Š2005 American Society of Hematology. Copyright restrictions may apply. Deininger, M. W.N. Hematology 2005;2005:174-182 Figure 1. Progression-free survival of newly diagnosed chronic myeloid leukemia patients treated with 400 mg imatinib daily according to molecular responses at 12 months
- 46. Chronic Leukemias â changing principles ⢠Treat for symptoms ď treat by risk ⢠Nonspecific cytoreduction ď targeted therapies ⢠MRD based surveillance ⢠Palliative intent ď curative?
Editor's Notes
- Figure 1. Probability of Survival from the Date of Diagnosis among the Patients in the Five Genetic Categories. The median survival times for the groups with 17p deletion, 11q deletion, 12q trisomy, normal karyotype, and 13q deletion as the sole abnormality were 32, 79, 114, 111, and 133 months, respectively. Twenty-five patients with various other chromosomal abnormalities are not included in the analysis.
- Figure 1. The t(9;22) Translocation and Its Products: the BCR-ABL Oncogene on the Ph Chromosome and the Reciprocal ABL-BCR on the Derivative 9q+ Chromosome. In classic CML, BCR-ABL is transcribed into messenger RNA (mRNA) molecules with e13a2 or e14a2 junctions, which are then translated into the p210BCR-ABL oncoprotein. This oncoprotein is a hybrid containing functional domains from the N-terminal end of BCR (dimerization [DD], SRC-homology 2 [SH2]-binding, and the Rho GTP-GDP exchange-factor [GEF] domains) and the C-terminal end of ABL. (Only SRC-homology regions 2, 3, and 1 [SH2, SH3, and SH1, respectively], and the DNA- and actin-binding domains are shown.) Tyrosine 177 (Y177) in the BCR portion of the fusion gene and tyrosine 412 (Y412) in the ABL portion are important for the docking of adapter proteins and for BCR-ABL autophosphorylation, respectively. P-S/T denotes phosphoserine and phosphothreonine.
- Figure 2. Physiologic Regulation by the Normal ABL Protein and Deregulation by BCR-ABL of Key Cellular Processes Such as Proliferation, Adherence, and Apoptosis. The enzymatic (tyrosine kinase) activity of the normal ABL protein (p145ABL), encoded by its SRC-homology 1 (SH1) domain, is kept under tight control, probably by the intramolecular binding of an N-terminal cap region encompassed by the first exon (1b or 1a) and the first part of exon a2.53 In the BCR-ABL fusion protein (p210BCR-ABL), lack of the ABL cap region and a dimerization domain encoded by the first exon of BCR are responsible for constitutive activation of the ABL SH1 domain, resulting in uncontrolled signal transduction and an abnormal cellular phenotype. The various functional domains of the ABL protein include the SRC-homology 3 and 2 regulatory domains (SH3 and SH2, respectively), the SH1 domain with its ATP-binding site, the nuclear-localization signal motif, the nuclear-export signal motif, the DNA-binding domain, and the G-actin and F-actin DNA-binding domains. The last two are important for the control of cytoskeletal organization, cell adherence, cell motility, and integrin receptor-mediated signal transduction.54,55
- Figure 2. Mechanism of Action of BCR-ABL and of Its Inhibition by Imatinib. Panel A shows the BCR-ABL oncoprotein with a molecule of adenosine triphosphate (ATP) in the kinase pocket. The substrate is activated by the phosphorylation of one of its tyrosine residues. It can then activate other downstream effector molecules. When imatinib occupies the kinase pocket (Panel B), the action of BCR-ABL is inhibited, preventing phosphorylation of its substrate. ADP denotes adenosine diphosphate. Adapted from Goldman and Melo1 with the permission of the publisher.