1. CHRONIC MYELOGENOUS LEUKEMIA

2. Definition, History & Epidemiology Etiology and Pathogenesis Clinical Features Diagnosis Course and special clinical situations Differential Diagnosis Therapy 2 3. The 2008 World Health Organization Classification System for Myeloproliferative Neoplasms 4. DEFINITION Chronic myelogenous leukemia (CML) - pluripotential stem cell disease characterized by Anemia Extreme blood granulocytosis and granulocytic immaturity Basophilia Thrombocytosis Splenomegaly Characteristic genetic change - Reciprocal translocation between chromosomes 9 and 22 (Philadelphia (Ph) chromosome) 4 5. HISTORY In 1845, Bennett in Scotland and Virchow in Germany described splenic enlargement, severe anemia, and leukocytosis at autopsy Virchow proposed the term leukmie In 1878, Neumann proposed marrow origin for leukemia myelogene (myelogenus) Nowell and Hungerford in 1960 identified the culprit gene at the Perelman School of Medicine, Philadelphia Dr. Rowley identified the BCR-ABL translocation 1998 Discovery of targeted TKI therapy 5 6. EPIDEMIOLOGY CML - 15 %of all cases of Leukemia US Incidence ~ 2 per lakh persons for men and 1.1 per lakh persons for women Sparse Indian data - 0.82.2/lakh in men and 0.6 1.6/lakh in women 50-70% of leukemias in India Male predominance (1.4:1) Average age at presentation 50 yrs Incidence is least in Swedes 6 7. EPIDEMIOLOGY 7 8. ETIOPATHOGENESIS 1. Environmental Leukemogens Very high doses of ionizing radiation* Chemical leukemogens - benzene and alkylating agents are not causative increased incidence of AML No concordance of the disease between identical twins Several large studies no links with smoking/diet/lifestyle 8 9. Etiopathogenesis 9 2. The stem cell 10. 2. The stem cell Etiopathogenesis 10 CML Stem Cell 11. 2. The stem cell Acquisition of the BCR-ABL fusion gene in a single multipotential hematopoietic cell CML stem cell Majority of these cells would be in G0 phase of the cell cycle These BCR-ABL stem cells favor differentiation over self- renewal Ph chromosome is found on myeloid, monocytic, erythroid, megakaryocytic, B-cells and sometimes T-cell proof that CML derived from pluripotent stem cell Etiopathogenesis 11 12. 2. The stem cell The CML stem cells have no regulation of proliferation Mediated by IL3 GCSF autocrine loop Immature granulocytes >> mature granulocytes Etiopathogenesis 12 13. 3. BCR-ABL protein (Tyrosine Kinase) BCR (breakpoint cluster region) gene on chromosome 22 fused to the ABL (Ableson leukemia virus) gene on chromosome 9 The fusion protein derived from the BCR-ABL gene is a tyrosine kinase enzyme This particular protein is seen in small amounts normally* The ABL gene regulated tyrosine kinase BCR-ABL unregulated tyrosine kinase Etiopathogenesis 13 14. 3. BCR-ABL (Tyrosine Kinase) Etiopathogenesis 14 Altered adhesion No adhesion to marrow stroma Reduced regulation by marrow factors Mitogenic activation Activation of various pathways proliferation Inhibition of apoptosis Upregulation of Bcl-2 Uninhibited proliferation 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 15 16. A. Symptoms Uncommon symptoms Night sweats Heat intolerance Gouty arthitis Left upper-quadrant and left shoulder pain* Urticaria Hyperleukocytic Syndrome dyspnea, tachypnea, hypoxia, lethargy, slurred speech Clinical features 16 Mimics thyrotoxicosis 17. Clinical features 17 Acute febrile neutrophilic dermatosis (Sweet syndrome) A. Symptoms 18. B. Signs Pallor Splenomegaly Sternal tenderness Rarely hepatomegaly, lymphadenopathy Poor prognostic indicators Clinical features 18 19. DIAGNOSIS A. Laboratory studies Blood counts and blood smear Hemoglobin concentration is decreased Nucleated red cells in blood film The leukocyte count above 25,000/l (even > 1,00,000/l), Hypersegmented neutrophils The basophil and eosinophil counts are increased (Absolute) The platelet count is normal or increased Blast cells ~ 3 % (10 ULN) Serum uric acid increased Lactate dehydrogenase increased Mean histamine levels increased Diagnosis 23 24. B. 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 24 25. B. Cytogenetics Diagnosis 25 90% 26. C. Molecular Probes i. FISH (Fluorescence In Situ Hybridization) Detect the BCR-ABL fusion gene on chromosome 22 Qualitative Diagnosis 26 27. C. Molecular Probes ii. 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 27 28. COURSE OF THE DISEASE CML has 3 phases 28 I. Chronic Phase Most patients are asymptomatic Incidental leukocytosis/splenomegaly Bleeding and infectious complications are uncommon in the chronic phase 29. 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 () New clonal chromosome abnormalities Anemia progresses and cause fatigue, loss of sense of well-being Splenomegaly Ranges from 4-5 years before progressing Course of the disease 29 30. III. Blast Crisis defined by 20% blasts in blood or bone marrow Extramedullary blastic infiltration (Chloroma) Resembles acute leukemia 2/3 transform to myeloid blastic phase and 1/3 to lymphoid blastic phase Infection and bleeding common Abdominal pain, bone pain Survival is 6-12 months (worse for myeloid phenotype) Course of the disease 30 31. Special Clinical situations Neutrophilic CML A rare variant of BCR-ABLpositive 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 Course of the disease 31 32. Special Clinical situations Hyperleukocytosis (15% of cases) Intravascular flow-impeding effects of white cell counts greater than 3,00,000/L (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 32 33. Special Clinical situations Concurrence of Lymphoid Malignancies 1. CML years after irradiation of non-Hodgkin or Hodgkin lymphoma 2. Accelerated phase dedifferentiation of the CML clone acute lymphoblastic transformation 3. Plasmacytic malignancies positive association 4. Patients may present with Ph+ ALL, after chemotherapy-induced remission, develop the features of typical CML Course of the disease 33 34. DIFFERENTIAL DIAGNOSIS Polycythemia vera Essential thrombocythemia Primary myelofibrosis Leukemoid reactions 34 35. TREATMENT 1. Initial Cytoreduction Therapy 2. Tyrosine Kinase Inhibitor Therapy 3. Interferon therapy 4. Chemotherapy 5. Allogeneic Stem Cell Transplantation 6. Treatment of accelerated/blast phases 7. Treatment of CML in pregnancy 8. Treatment cessation 35 36. 1. Initial therapy Allopurinol 300 mg/day orally with adequate hydration Rasburicase 0.2 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 36 37. 2. Tyrosine Kinase inhibitor therapy Treatment 37 First generation Second generation Imatinib Dasatinib Nilotinib Bosutinib Ponatinib Bafetinib 38. 2. Tyrosine Kinase inhibitor therapy Imatinib Mesylate Approved for use in Ph+ CML in 2001 Preliminary studies showed a remarkable cytogenic remission Hematological remission was seen in 95% Now the treatment of choice for CML Treatment 38 39. 2. Tyrosine Kinase inhibitor therapy Imatinib Mesylate Treatment 39 40. 2. Tyrosine Kinase inhibitor therapy Imatinib Mesylate Dosage 400 mg/day orally 400 mg BD Well tolerated Myelosuppression is common in CML patients Elevated hepatic transaminases (Acute liver failure described) Periorbital edema Cutaneous reactions Osteoporosis Treatment 40 41. 2. Tyrosine Kinase inhibitor therapy Imatinib Mesylate Treatment 41 42. 2. Tyrosine Kinase inhibitor therapy Imatinib Mesylate Treatment 42 90-96% 43. 2. Tyrosine Kinase inhibitor therapy Imatinib Mesylate Treatment 43 ~63% 44. 2. Tyrosine Kinase inhibitor therapy Imatinib Mesylate Treatment 44 National Comprehensive Cancer Network 45. 2. Tyrosine Kinase inhibitor therapy Imatinib Mesylate Treatment 45 European Leukemia Net 46. 2. Tyrosine Kinase inhibitor therapy Imatinib Mesylate Four mechanisms of resistance (1) Gene amplification (2) Mutations at the kinase site (3) Enhanced expression of multidrug exporter proteins (4) Alternative signaling pathways compensating imatinib-sensitive mechanisms. Treatment 46 47. 2. Tyrosine Kinase inhibitor therapy 2nd Generation TKI 1. Dasatinib Used in imatinib resistance or intolerance 325-fold more potent than imatinib 100 mg/day, administered in chronic phase CML Unlike imatinib, dasatinib penetrates the bloodbrain barrier Cytopenia, followed by fluid retention, diarrhea, and skin rash Treatment 47 48. 2. Tyrosine Kinase inhibitor therapy 2nd Generation TKI 2. Nilotinib Used in imatinib resistance or intolerance 30 times more potent than imatinib ATP-competitive inhibitor of BCR-ABL 400 mg every 12 hours Neutropenia, hyperbilirubinemia, hypophosphatemia, QT interval prolongation Imatinib and nilotinib in combination may have additive or synergistic effects Treatment 48 49. 3. Interferon IFN was the initial therapy before TKI therapy Complete cytogenetic response uncommon (13%) 50% responders long term survival 3-5 million units/m2 five times per week Neurotoxicity, thrombocytopenia, fatigue, and liver dysfunction dose limiting effects Single dose of 450 g pegylated IFN comparable IFN was combined with Cytarabine Some patients intolerant to a Imatinib may be treated successfully with INF Treatment 49 50. 4. Chemotherapeutic Agents and other modalities i. Cytarabine IFN combined with cytarabine (20 mg/m2/day -10 days per month better than IFN alone Replaced by TKI ii. Busulfan Once the mainstay of treatment now almost never used Use limited to the preparative regimen for allografting or autografting Treatment 50 51. 4. Chemotherapeutic Agents and other modalities iii. Splenectomy* Delay the onset of the accelerated phase Enhance sensitivity to chemotherapy Prolong survival of patients But, does not prolong the chronic phase iv. Radiotherapy Splenic irradiation - extreme splenomegaly with splenic pain, perisplenitis may be useful for extramedullary tumors (bone/soft tissue) Treatment 51 52. 4. Chemotherapeutic Agents and other modalities v. Omacetaxine (formerly Homoharringtonine) Protein translation inhibitor Still in Phase 2 trials Showed promise in TKI intolerant/resistant cases 18% major cytogenetic response in TKI failed cases vi. Experimental Lonafarnib and tipifarnib Berbamine Adaphostin Third-generation TKIs Treatment 52 53. 5. Allogeneic Stem Cell Transplantation Allogeneic HSCT - complicated by mortality owing to the procedure (1) The patient (2) The type of donor (3) The preparative regimen (myeloablative or reduced- intensity) (4) Graft versus Host Disease (5) Post-transplantation treatment Treatment 53 54. 6. Treatment of accelerated/blast phases Goal achieve remission Else aim to reduce to chronic phase TKI bridging therapy to permit allogenic SCT Dasatinib and nilotinib achieve better molecular remission in accelerated phase Imatinib+mitoxantrone+etoposide Imatinib+cytarabine Ultimately Stem cell transplant Treatment 54 Blast crisis 55. 7. Treatment of CML in pregnancy Untreated CML placental insufficiency (leukostasis) Risk of teratogenicity with Imatinib IFN is safe can be used Leukapheresis 1st trimester Hydroxyurea 2nd and 3rd trimester Restart TKI therapy soon after delivery Treatment 55 56. 8. Treatment cessation Despite achieving deep and lasting remissions CML is not curable Patients with remissions still have residual CML cells (PCR) Available evidence suggests that people who receive TKIs may remain in remission for very long periods Research still underway Treatment 56 57. 57 Treatment 58. CONCLUSION Imatinib has revolutionized the management of CML Long term survival is a reality now TKI therapy is still not curative 3rd generation TKI and newer drugs in the pipeline show some promise at achieving a possible cure 58