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![3. The European Treatment and Outcome Study
(EUTOS) risk score
• Low risk - <87
• High risk - >87
• Also proposed a formula for predicting probability of
no CCyR at 18 months
• Presently used – ‘Imatinib era’
Risk assessment
38
(7 x basophil [%]) + (4 x spleen size)](https://image.slidesharecdn.com/cmlslideshare-140717103011-phpapp02/75/Chronic-Myelogenous-Leukemia-38-2048.jpg)
Uploaded byAneesh Bhandary
Chronic Myelogenous Leukemia
Chronic myelogenous leukemia (CML) is a pluripotential stem cell disease characterized by anemia, extreme granulocytosis, and a genetic defect known as the Philadelphia chromosome. The treatment landscape for CML has evolved significantly with the introduction of tyrosine kinase inhibitors like imatinib, which have improved patient outcomes, although the disease remains incurable. CML progresses through three phases: chronic, accelerated, and blast crisis, with various risk assessment tools available to guide treatment strategies.
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Chronic Myelogenous Leukemia
- 1.
- 2. Definition, History &Epidemiology Etiology and Pathogenesis Clinical Features Diagnosis Course and special clinical situations Differential Diagnosis Risk assessment and Therapy 2
- 3. The World HealthOrganization Classification System for Myeloproliferative Neoplasms
- 4. DEFINITION • Chronic myelogenousleukemia (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 leukämie • 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 - 0.8–2.2/lakh in men and 0.6–1.6/lakh in women • 50-70% of leukemias in Indian adults • Male predominance (1.4:1) • Average age at presentation – 50 yrs • Incidence is least in Swedes 6
- 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.
- 10. 2. The stemcell Etiopathogenesis 10 CML Stem Cell
- 11. 2. The stemcell • 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 stemcell • 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 (TyrosineKinase) 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 • Uncommonsymptoms • 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 febrileneutrophilic 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 Bloodcounts and blood smear • Hemoglobin concentration - decreased • Nucleated red cells in blood film • Leukocyte count above 25,000/μl (> 1,00,000/μl) • Hypersegmented neutrophils • Basophil and eosinophil counts - increased (Absolute) • The platelet count - normal or increased • Blast cells ~ 3 % (<10% in the chronic phase) 19
- 20.
- 21. A. Laboratory studies Diagnosis 21 Bonemarrow Hypercellular Replacement of fat Granulopoiesis Megakaryocytopoiesis Erythropoiesis
- 22. A. Laboratory studies BoneMarrow studies • Mitotic figures are increased • Macrophages that mimic Gaucher cells * • Macrophages - engorged with lipids - yield ceroid pigment - imparting a granular and bluish cast - sea-blue histiocytes • Increased reticulin fibrosis (Collagen type III) * • Angiogenesis Diagnosis 22
- 23. A. Laboratory studies Otherlab features : • Neutrophil Alkaline Phosphatase reduced • Serum B12 and transcobalamin increased (>10 ULN) • Serum uric acid increased • Lactate dehydrogenase increased • Mean histamine levels increased Diagnosis 23
- 24. B. Cytogenetics • Studyof 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.
- 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 THEDISEASE • 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 definedby • 10%–19% blasts in blood or bone marrow • >20% basophils in blood or bone marrow • Thrombocytosis, thrombocytopenia unrelated to therapy (<1 lakh or >10 lakh) • 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 definedby • ≥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 NeutrophilicCML • A rare variant of BCR-ABL–positive CML – leukocytosis 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 – 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/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 32
- 33. Special Clinical situations Concurrenceof 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 features of typical CML Course of the disease 33
- 34. DIFFERENTIAL DIAGNOSIS • Polycythemiavera • Essential thrombocythemia • Primary myelofibrosis • Leukemoid reactions 34
- 35. RISK ASSESSMENT • 3scores 1. Sokal score - 1984 2. Euro (Hasford) score – 1998 3. European Treatment and Outcome Study (EUTOS) – 2011 35
- 36. 1. Sokal score •Age • Spleen size • Platelet count • Peripheral blood blast percentage • Was used in busulphan or hydroxyurea based therapy • Low risk - <0.8 • Intermediate risk – 0.8 – 1.2 • High risk - >1.2 Risk assessment 36
- 37. 2. Hasford score •Age • Spleen size • Platelets • Blast cell percentage • Eosinophil percentage • Was used in interferon based therapy • Low risk - <780 • Intermediate - 780-1480 • High risk >1480 Risk assessment 37
- 38. 3. The EuropeanTreatment and Outcome Study (EUTOS) risk score • Low risk - <87 • High risk - >87 • Also proposed a formula for predicting probability of no CCyR at 18 months • Presently used – ‘Imatinib era’ Risk assessment 38 (7 x basophil [%]) + (4 x spleen size)
- 39. TREATMENT 1. Initial CytoreductionTherapy 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 39
- 40. 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 40
- 41. 2. Tyrosine Kinaseinhibitor therapy Treatment 41 First generation Second generation Imatinib Dasatinib Nilotinib Bosutinib Ponatinib Bafetinib
- 42. 2. Tyrosine Kinaseinhibitor 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 42
- 43. 2. Tyrosine Kinaseinhibitor therapy Imatinib Mesylate Treatment 43
- 44. 2. Tyrosine Kinaseinhibitor 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 44
- 45. 2. Tyrosine Kinaseinhibitor therapy Imatinib Mesylate Treatment 45
- 46. 2. Tyrosine Kinaseinhibitor therapy Imatinib Mesylate Treatment 46 90-96%
- 47. 2. Tyrosine Kinaseinhibitor therapy Imatinib Mesylate Treatment 47 ~63%
- 48. 2. Tyrosine Kinaseinhibitor therapy Imatinib Mesylate Treatment 48 National Comprehensive Cancer Network
- 49. 2. Tyrosine Kinaseinhibitor therapy Imatinib Mesylate Treatment 49 European Leukemia Net
- 50. 2. Tyrosine Kinaseinhibitor 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 50
- 51. 2. Tyrosine Kinaseinhibitor 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 blood–brain barrier • Cytopenia, followed by fluid retention, diarrhea, and skin rash Treatment 51
- 52. 2. Tyrosine Kinaseinhibitor 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 52
- 53. 3. Interferon α •IFNα 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 µg pegylated IFNα – comparable • IFNα was combined with Cytarabine • Some patients intolerant to a Imatinib may be treated successfully with INFα Treatment 53
- 54. 4. Chemotherapeutic Agentsand other modalities i. Cytarabine • IFNα 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 54
- 55. 4. Chemotherapeutic Agentsand 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 55
- 56. 4. Chemotherapeutic Agentsand 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 56
- 57. 5. Allogeneic StemCell 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 57
- 58. 6. Treatment ofaccelerated/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 58 Blast crisis
- 59. 7. Treatment ofCML 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 59
- 60. 8. Treatment cessation •Despite achieving deep and lasting remissions • CML is not curable • Patients with remissions - have residual CML cells (PCR) • Evidence suggests - people who receive TKIs may remain in remission for very long periods • Research still underway Treatment 60
- 61.
- 62. CONCLUSION • Disease ofolder males • The Philadelphia chromosome BCR-ABL gene and it’s Tyrosine kinase protein – central to the pathogenesis • Occurs in 3 phases • Most patients in the chronic phase - asymptomatic 62
- 63. CONCLUSION • Imatinib hasrevolutionized 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 63
Editor's Notes
- #4 CMML – monocytes >1000, BCR-ABL negative, pdgfra+
- #6 Bennett initially favored an extreme pyemia as the explanation, but Virchow argued against suppuration as a cause TKI – Approved in 2001
- #7 <0.3% patients reported
- #8 <0.3% patients reported
- #9 very high doses of ionizing radiation – 3 major populations Hiroshima Nagasaki 1945 British ankylo spond spine irradiation uterine cervical carcinoma who received radiation therapy
- #11 BCR – breakpoint cluster region ABL – Abelson Leukemia gene
- #13 Granulocyte colony stimulating factor Flt3 ligand Steel factor
- #15 Interferon-α reduces adhesion defects BCL2 is an apoptosis inhibitor
- #16 vague, nonspecific, and gradual in onset (weeks to months) *Attributable to splenic enlargement
- #17 *Splenic infarcts Histamine
- #18 perivascular infiltrate of neutrophils in the dermis fever and painful maculonodular violaceous lesions trunk, arms, legs, and face
- #19 *Massive - and in almost all patients Sternal tenderness – lower part – patient can detect
- #21 Elevated leukocyte count. Characteristic array of immature (myelocytes, metamyelocytes, band forms) and mature neutrophils. Two basophils in the field. Absolute basophilia is a constant finding in CML
- #22 Hypercellular. Replacement of fatty tissue (normally ~60% of marrow volume ) with hematopoietic cells. Intense granulopoiesis and evident megakaryocytopoiesis. Decreased erythropoiesis Granulopoeisis – 10 to 30:1 (N 2-4 :1)
- #23 glucocerebrocidase overload due to high turnover of glucocerebrocide* Collagen type III – correlates with spleen size and megakaryocytosis* Angiogenetic marrow – reduces with treatment
- #24 Neutrophil alkaline phosphatase activity is low or absent (90%) - Activity increases with treatment (limited use) B12 – immature cell leak Uric acid – gout/uropathy Histamine increase with basophil
- #25 90%
- #27 In normal cells, two red and two green signals indicate the location of the normal ABL and BCR genes, respectively. In abnormal cells, the BCR-ABL fusion is visualized through the fusion of the red and green signals. It is frequently detected as a yellow fluorescence (noted by arrows).
- #30 European Society of Medical Oncology (ESMO) 15-29%
- #31 European Society of Medical Oncology (ESMO) >30%
- #34 vPlasmacytic - Multi myeloma, Waldenstroms etc
- #35 Myeloproliferative TC <3 lakh (in 90%) 1 - PV – High Hb - AQUAGENIC PRURITIS, ERYTHROMELALGIA 2- essential thrombocythemia have a platelet count greater than 450,000 3 - Myelofibrosis - teardrop poikilocytes and other severe red cell shape, size, and chromicity changes JAK2 (PV>other MPD > CML) 4 - leukemoid reaction overt inflammatory disease
- #36 *applied at diagnosis before starting treatment
- #37 *applied at diagnosis before starting treatment
- #38 *applied at diagnosis before starting treatment
- #39 *applied at diagnosis before starting treatment
- #41 cell lysis* - Febuxostat – little evidence in CML
- #45 Other uses MDS ALL GI stromal tumours Hyper eosinophillic syndrome Dermatofibrosarcoma protuberans
- #51 All four mechanisms are being targeted in clinical trials.
- #53 Bosutinib Ponatinib (active against T315I)
- #56 Careful selection of the case is a must
- #57 Farnesyltransferase inhibitors
- #58 1 Patient – age and phase 2 Donor - monozygotic twins or hla-compatible allogeneic, related or unrelated
- #62 he T315I mutation results in an amino acid substitution at position 315 in BCR-ABL1, from a threonine (T) to an isoleucine (I)
- #65 Kareem Abdul-Jabbar