LEUKEMIA- CHRONIC MYELOID LEUKEMIA

1. LEUKEMIA- CHRONIC MYELOID LEUKEMIA Dr. Kiran H S Assistant Professor Pathology, YMC

3. OVERVIEW • Epidemiology • Etiology & molecular pathogenesis • Clinical features • Diagnosis • Course of disease • Treatment

4. Epidemiology • Commonest leukemia constituting about 25- 30% of all Leukemias in India. • 5th to 6th decade. • 50-70% of leukemias in India • Male predominance (1.4:1) • About 50%- asymptomatic

5. Chronic Lymphoid Leukemias & Myeloproliferative Disorders

6. Chronic Myeloproliferative Disorders • are malignant clonal proliferations of multipotent stem cells. While all three cell lines (myeloid, erythroid and megakaryocytic) are involved in each disorder, each has specific genetic abnormalities. • As a result the dominant cell differs in each allowing for the subclassification of the chronic myeloproliferative disorders. • Chronic myeloid leukemia (CML), • Polycythemiavera (PV), • Primary myelofibrosis (MF) and • Essential thrombocythemia (ET)

7. Chronic myeloproliferative disorders are • acquired, malignant clonal disorders • characterized by expansion of pluripotent stem cells showing deranged production of one or more myeloid lines and having a variable predisposition to transform to leukemia.

8. Chronic Myeloid Leukemia (CML) • 15% of all leukemia • is an acquired clonal MPN of the abnormal pluripotent hematopoietic stem cell. • Malignant disorder of multipotent stem cells with predominance of mature granulocytes and their precursors accumulating in excess in the marrow and blood.

9. It is distinguished by the presence of chimeric fusion BCR-ABL gene & characteristic chromosomal abnormality i.e Philadelphia(Ph) chromosome in more than 90% of cases.

10. Etiology and Pathogenesis • Not known. • Exposure to ionising radiation may increase the risk and is dose dependent.

11. MOLECULAR PATHOGENESIS:CML & Philadelphia chromosome (Ph') • Its an acquired chromosomal abnormality present in all proliferating hematopoietic stem cells. • Balanced reciprocal translocation between chromosome 9 and 22… t(9,22)(q34;q11.2) • Translocation results in increase in length of chromosome 9 and shortened long arm of one of the chromosome 22. • Shortened chromosome 22 – Ph chromosome.

12. MOLECULAR PATHOGENESIS:CML & Philadelphia chromosome (Ph') • t(9;22)(q34;q11) in which the c-abl gene from 9 is juxtaposed with the bcr sequence on 22. • This leads to a chimeric gene (bcr-abl) the product of which is an aberrant 210kD tyrosine kinase (thought to be involved in cell regulation). • Mature myeloid cells appear to live longer and thus accumulate. bcr-abl gene product

13. BCR-ABL (Tyrosine Kinase) Etiopathogenesis

15. Clinical features A. Symptoms • At diagnosis – 70% symptomatic • Easy fatigability • Loss of sense of well-being • Decreased tolerance to exertion • Anorexia • Abdominal discomfort • Early satiety * • Weight loss • Excessive sweating

16. A. Symptoms • Uncommon symptoms • Bleeding • Night sweats • Heat intolerance • Gouty arthitis • Left upper-quadrant and left shoulder pain* • Urticaria • Hyperleukocytic Syndrome —dyspnea, tachypnea, hypoxia, lethargy, slurred speech Clinical features

17. A. Symptoms • Acute febrile neutrophilicdermatosis (Sweet syndrome) Clinical features

18. B. Signs • Pallor • Splenomegaly • Sternal tenderness • Rarely hepatomegaly, lymphadenopathy – Poor prognostic indicators Clinical features

19. Diagnosis • Laboratory studies Blood counts and blood smear • Hemoglobin concentration is decreased • Nucleated red cells in blood film • The leukocyte count above 25,000/μl (even > 1,00,000/μl), • Hypersegmentedneutrophils • The basophil and eosinophil counts are increased (Absolute) • The platelet count is normal or increased • Blast cells ~ 3 % (<10% in the chronic phase)

20. Laboratory studies Peripheral smear Diagnosis

21. Laboratory studies Hypercellular Replacement of fat Granulopoiesis Megakaryocytopoiesis Erythropoiesis Bone marrow

22. Laboratory studies Bone Marrow studies • Mitotic figures are increased • Macrophages that mimic Gaucher cells * • Macrophages - engorged with lipids- yield ceroidpigment - imparting a granular and bluish cast - sea-blue histiocytes. • Dwarf megakaryocytes • Increased reticulin fibrosis (Collagen type III) * • Angiogenesis Diagnosis

23. Laboratory studies Other lab features : • Neutrophil Alkaline Phosphatase reduced • Serum B12 and transcobalaminincreased (>10 ULN) • Serum uric acid increased • Lactate dehydrogenase increased • Mean histamine levels increased

24. Cytogenetics • Study of the number and structure of chromosomes • Samples from bone marrow myeloid cells • The presence of the Philadelphia chromosome – shortened chromosome 22* • Cytogenetics cannot identify complex translocations Diagnosis

25. Cytogenetics Diagnosis

26. Molecular Probes • FISH (Fluorescence In Situ Hybridization) • Detect the BCR-ABL fusion gene on chromosome 22 • Qualitative Diagnosis

27. Molecular Probes • PCR (Polymerase Chain Reaction) • Most sensitive test to identify and measure the BCR-ABL gene(Quantitative) • Can be performed on blood/marrow cells • Amplifies the BCR-ABL derived abnormal mRNA • One abnormal cell in one million cells can be detected Diagnosis

28. Course of the disease • CML has 3 phases I. Chronic Phase • Most patients are asymptomatic • Incidental leukocytosis/splenomegaly • Bleeding and infectious complications are uncommon in the chronic phase

29. I. Chronic Phase • Most patients are asymptomatic • Incidental leukocytosis/splenomegaly • Bleeding and infectious complications are uncommon in the chronic phase • Usually lasts for 2 to 6 years. • P.smear- NCNC anaemia, Leukocytosis, Blasts <10%, Thrombocytosis. • Decreased LAP score.

31. II. Accelerated phase defined by • 10%–19% blasts in blood or bone marrow • >20% basophils in blood or bone marrow • Thrombocytosis, thrombocytopenia unrelated to therapy (<1 lakh>). • Associated with BM fibrosis. • New clonal chromosome abnormalities • Anemia progresses and cause fatigue, loss of sense of well-being • Splenomegaly • Ranges from 4-5 years before progressing

33. III. Blast Crisis defined by • ≥20% blasts in blood or bone marrow • Extramedullaryblastic infiltration (Chloroma) • Resembles acute leukemia • 2/3 transform to myeloid blastic phase and 1/3 to lymphoid blasticphase • Infection and bleeding common • Abdominal pain, bone pain • Survival is 6-12 months (worse for myeloid phenotype) Course of the disease

35. Special Clinical situations NeutrophilicCML • A rare variant of BCR-ABL–positive CML with elevated white cell count principally of mature neutrophils • WBC count lower than that of classic CML • Basophilia, myeloid immaturity in the blood, prominent splenomegaly, or low leukocyte alkaline phosphatase scores – are all absent! • Larger fusion protein than in classic CML • Usually has an indolent course • Now classified separately

36. Special Clinical situations Hyperleukocytosis (15% of cases) • Intravascular flow-impeding effects of white cell counts greater than 3,00,000/µL (upto 8 lakh) • Impaired circulation of the lung, central nervous system, special sensory organs, and penis • resulting in some combination of • Tachypnea, dyspnea, cyanosis, • Dizziness, slurred speech, delirium, stupor, • Visual blurring, diplopia, retinal vein distention, retinal hemorrhages, papilledema, • Tinnitus, impaired hearing, • And priapism Course of the disease

37. Special Clinical situations Concurrence of Lymphoid Malignancies • CML years after irradiation of non-Hodgkin or Hodgkin lymphoma • Accelerated phase dedifferentiation of the CML clone  acute lymphoblastic transformation • Plasmacytic malignancies – positive association • Patients may present with Ph+ ALL, after chemotherapy-induced remission, develop the features of typical CML

38. Differential Diagnosis • Polycythemia vera • Essential thrombocythemia • Primary myelofibrosis • Leukemoid reactions

39. Treatment • Initial CytoreductionTherapy • Tyrosine Kinase Inhibitor Therapy • Interferon therapy • Chemotherapy • Allogeneic Stem Cell Transplantation • Treatment of accelerated/blast phases • Treatment of CML in pregnancy • Treatment cessation

40. Initial therapy • Allopurinol 300 mg/day orally with adequate hydration  Rasburicase0.2 mg/kg i.v (one doses) for Hyperuricemia* • Leukapheresis – helps reduce leucocyte burden, only in conjunction with definitive therapy • Hydroxyurea - Reversible suppression of hematopoiesis 1 to 6 g/day orally (titre based on counts) • Anagrelide – to reduce the platelet burden Treatment

41. Tyrosine Kinase inhibitor therapy First generation Second generation Dasatinib Nilotinib Bosutinib Ponatinib Bafetinib Imatinib Treatment

42. Treatment

43. Conclusion • CML- 3 phases: Chronic phase, accelerated phase, blast phase. • Lab P.smear and Bone marrow findings are typical. • Anemia and splenomegaly. • Imatinibhas revolutionized the management of CML

44. CMLThe average age at presentation is 45 yrs (rare in children)Death is usually secondary to blast crisis, marrow failure or marrow fibrosis.