1. By : SHASHIDHARA and SHASHIKUMAR

2. HEMATOPIESIS 3. LEUKEMIA 4. INTRODUCTION Malignant disorders of the haematopoietic stem cell compartment, characteristically associated with increased numbers of white blood cells in the bone marrow and/or peripheral blood Incidence is 10/100000 per annum. Males are affected more frequently than females (acute leukemia 3:2, chronic lymphocytic leukemia 2:1, chronic myeloid leukemia 1.3:1) Acute leukemia occurs at all ages, chronic leukemia occur mainly in middle and old age 5. HISTORY The discovery of leukemia is largely contributed to German physician Rudolf Ludwig Karl Virchow (1821-1902) and English physician, pathologist and physiologist John Hughes Bennett (1812-1875) as they were the first to observe the disease In 1845 Edinburgh pathologist Bennett reported a case of hypertrophy of the spleen and liver in which death took place from suppuration of the blood in the Edinburgh medical journal. Few weeks later Virchow in berlin published a very similar case. Bennett thought that the patient had an infection, Virchow suspected a neoplastic disorder that he soon called white blood disease or leukemia 6. CLASSIFICATION 7. Myeloid neoplasms Lymphoid neoplasms Histiocytic neoplasms 8. MYELOID NEOPLASMS Includes neoplasms of myeloid cell lineage There are 5 categories Myeloproliferative disorders Myeloproliferative/myelodysplastic diseases Myelodysplastic syndromes (MDS) Acute myeloid leukemia Acute biphenotypic leukemia 9. LYMPHOID NEOPLASMS Leukemias of lymphoid lineage and lymphomas of B, T or NK cell origin Includes B cell neoplasms ( including plasma cell disorders), T cell neoplasms, NK cell neoplasms and Hodgkins diseaseHISTIOCYTIC NEOPLASMS Neoplastic proliferations of histiocytes in Langerhans cell histiocytisis 10. CONTD. In acute leukemia there is proliferation of primitive stem cells leading to an accumulation of blasts, predominantly in the bone marrow, which causes bone marrow failure In chronic leukemia the malignant clone is able to differentiate, resulting in an accumulation of more mature cells Lymphocytic and lymphoblastic cells are derived from the lymphoid stem cell (B cells and T cells) Myeloid refers to the other lineage, i.e. precursors of red cells, granulocytes, monocytes and platelets 11. MYELOPROLIFERATIVE DISORDERS 12. DEFINITION They are a group of clonal myeloid neoplasms in which a genetic alteration occurs in a hematopoietic progenitor cell leading to its proliferation resulting in an increase in the peripheral blood white blood cells (WBCs), red blood cells (RBCs), platelets, or a combination of these cells. 13. GENETIC MUTATIONGenetic MutationNational Cancer Institute 14. CLASSIFICATION Chronic myeloid leukemia Polycythemia vera Essential thrombocythaemia Primary myelofibrosis Systemic mastocytosis Chronic eosinophilic leukemia Stem cell leukemia 15. COMMON FEATURES Common pathologic feature of the myeloproliferative disorder is the presence of mutated, constitutively activated tyrosine kinases Hematopoietic growth factors act on normal progenitors by binding to surface receptors and activating tyrosine kinases, which turn on pathways that promote growth and survival Then mutated tyrosine kinase circumvent normal controls and lead to the growth factor-independent proliferation and survival of marrow progenitors Most myeloproliferative disorders originate from multipotent myeloid progenitors 16. CONTD Increased proliferative drive in the bone marrow Homing of the neoplastic stem cells to secondary hematopoietic organs, producing extramedullary hematopoiesis Variable transformation to a spent phase characterized by marrow fibrosis and peripheral blood cytopenias Variable transformation to acute leukemia 17. CONTD The diagnosis of leukemia is usually suspected from an abnormal blood count, often a raised white count, and is confirmed by examination of the bone marrow This includes the morphology of the abnormal cells, analysis of cell surface markers (immunophenotyping), clone specific chromosome abnormalities and molecular changes The features in the bone marrow not only provide an accurate diagnosis but also give valuable prognostic information 18. CHRONIC MYELOID LEUKEMIA 19. DEFINITION A clonal expansion of a hematopoietic stem cell possessing a reciprocal translocation between chromosome 9 and 22 resulting in head to tail fusion of the breakpoint cluster region (BCR) gene on chromosome 22q11 with ABL1 (named after Abelson murine virus) gene located on chromosome 9q34 20. INTRODUCTION Chronic myeloid leukemia (CML) accounts for about 14% of all leukemia It is one of the family of myeloproliferative neoplasms (MPNs) Almost exclusively a disease of adults with the peak of presentation between 40-60 Philadelphia chromosome demonstrated cytogenetically(95%) or molecularly(5%) Slowly progressive 21. HISTORY The Philadelphia cytogenecists Peter Nowel and David Hungerford discovered an abnormally small G-group chromosome that we now call the Philadelphia chromosome (Ph) 13yrs later Janet Rowley recognized that Ph was the product of a reciprocal translocation between chromosome 9 and 22 In 1980s the translocation partners were identified as BCR and ABL, followed by the discovery that unregulated tyrosine kinase activity is critical to BCR-ABLs ability to transform cells 22. EPIDEMIOLOGY Incidence 0.2 to 2.0 per 100000 people per year Gender Higher in men than in women (1.3:1) Age Incidence increases slowly with age until the middle forties there after rises rapidly Median age is 66yr 23. CONTD Geographic and/or ethnic variations might contribute to the variability of incidences Most of the patients who get admitted medical therapy studies are 50 to 60yr (median approximately 53yr) Patients in bone marrow transplantation studies are even younger (median age approximately 40yr) 24. RISK FACTORS 25. IONISING RADIATION Radiotherapy Atomic bombing X-ray CYTOTOXIC DRUGS Alkylating agents Exposure to benzene GENETIC identical twin of patientsdowns syndrome IMMUNOLOGICAL immune deficiency states 26. ETIOLOGY 27. CML was the first malignancy to be linked to a clear genetic abnormality Approximately 95% of the patients with CML have a chromosome abnormality known as the Philadelphia (Ph) chromosome This is a shortened chromosome 22 resulting from a reciprocal translocation of material with chromosome 9 The break on chromosome 22 occurs at breakpoint cluster region (BCR) The fragment from chromosome 9 carries the abl oncogene which forms a chimeric gene with the remains of the BCR 28. CONTD This BCR ABL chimeric gene codes for a 210kDa protein with tyrosine kinase activity The chimeric gene is transcribed into a hybrid BCR-ABL1 mRNA in which exon 1 of ABL1 is replaced by variable numbers of 5 BCR exons Bcr-Abl fusion proteins p210BCR-ABL1 are produced that contain NH2terminal domains of Bcr and COOH-terminal domains of Abl A rare breakpoint occurring within 3 region of the BCR gene yields a fusion protein of 230 kDa, p230BCR-ABL1 Bcr-abl fusion protiens can transform hematopoietic progenitor cells in vitro 29. CONTD Attachment of the BCR sequences to ABL1 results in 3 critical functional changes Abl protein becomes constitutively active as a tyrosine kinase (TK) enzyme, activating downstream kinases that prevent apoptosis The DNA-protein-binding activity of Abl is attenuated; and The binding of Abl to cytoskeletal actin microfilaments is enhanced 30. CONTD.. Chromosomal instability of the malignant clone is a basic feature of CML Heterogeneous structural alterations of the TP53 gene, as well as structural alterations and lack of protein production of the retinoblastoma 1 (RB1) gene and the catalytic component of telomerase, is associated with disease progression Rare patients show alterations in the rat sarcoma viral oncogene homologue (RAS) 31. CONTD Sporadic reports also document presence of an altered v-mync myelocytomatosis viral oncogene homologue (MYC) gene Progressive de novo DNA methylation at BCR-ABL1 locus and hypomethylation of the LINE-1 retrotransposon promoter promotes blastic transformation Interleukin 1 may be involved in the progression of CML to the blastic phase Functional inactivation of the tumour suppressor protein phosphatase A2 32. CLINICAL FEATURES 33. SYMPTOMS Insidious in onset, some are asymptomatic others may present with fatigue, malaise and weight loss or have symptoms resulting from splenic enlargement, such as early satiety and left upper quadrant pain or mass Less common features related to granulocyte or platelet dysfunction are infection, thrombosis or bleeding Occasionally leukostatic manifestations due to severe leukocytosis or thrombosis such as vasoocclusive disease, CVA, MI, venous thrombosis, priapism, visual disturbances, pulmonary insufficiency 34. SYMPTOMS AT PRESENTATION SymptomPresent (%)Tiredness Weight loss Breathlessness Abdominal pain and discomfort Lethargy Anorexia Sweating Abdominal fullness Bruising Vague ill health37 26 21 21 13 12 11 10 7 7 35. PROGRESSION OF CML Characterised by worsening of symptoms Unexplained fever Significant weight loss Increasing dose requirements Bone and joint pain Bleeding, thrombosis and infection Less than 10-15% of newly diagnosed patients present with accelerated disease or with de novo blastic phase CML 36. SIGNS Minimal to moderate spenomegaly Mild hepatomegaly Persistent splenomegaly despite continued medication is a sign of disease acceleration Lymphadenopathy and myeloid sarcomas are unusual 37. CHRONIC PHASE Approximately 85% of the patients with CML are in this phase at the time of diagnosis It is sometimes called the stable phase Patients are usually asymptomatic (25 to 60%) In symptomatic patients, the most common presenting signs and symptoms are Fatigue Left upper quadrant pain or mass Weight loss Palpable spleen in 30 to 70% of patients Liver is enlarged in 10 to 20% 38. CONTD Patients with very high WBC counts may have manifestations of hyperviscosity, including priapism, tinnitus, stupor, visual changes and CVA If untreated or treated with drugs that do not significantly affect the Philadelphia- chromosome cells in the marrow, chronic phase is associated with a median survival of 4 to 5 yrs In the absence of treatment chronic phase progresses to this phase 39. ACCELERATED PHASE This is an ill-defined transitional phase The criteria used in all the studies with interferon and tyrosine kinase inhibitors include the presence of any one of the following factors 40. CONTD Cytogenetic evolution with new abnormalities in addition to Philadelphia chromosome The classification used may affect the expected outcome of a group of patients More frequently symptomatic, including fever, night sweats, weight, progressive splenomegaly Accelerated phase indicates that the disease is progressing and transformation to blast crisis is imminent With imatinib therapy 4 yr survival rate exceeds 50% 41. BLAST CRISIS This is the final phase in the evolution of CML, behaves like an acute leukemia with rapid progression and short survival It is diagnosed if any of the following is present > 20% blasts in the marrow or peripheral blood Large clusters of blasts in the bone marrow on biopsy Development of chloroma (solid focus of leukemia outside the bone marrow- CNS, lymph nodes, skin etc) 42. CONTD Recent evidence suggests patients with 20 to 29% blasts have a significantly better prognosis than those having at least 30% blasts Approximately 70% of these patients have a myeloid phenotype, 25% have a lymphoid phenotype and 5% have an undifferentiated phenotype Symptoms include weight loss, fever, night sweats, bone pain Anemia, infectious complications and bleeding are common 43. CONTD Subcutaneous nodules or hemorrhagic tender skin lesions, lymphadenopathy and signs of CNS leukemia may be present Patients in blastic phase usually die within 3 to 6 months Prognosis is slightly better in lymphoid blastic phase 44. HEMATOLOGICAL FINDINGS 45. Elevated white blood cell count with increase in both immature and mature granulocytes