Chronic Myeloid Leukemia

1. ChronicMyeloidLeukemia CML

2. CML :Chronic Myeloid Leukemia-Summary- • Clonal myeloproliferative disorder of pluripotent stem cells •  proliferation, apoptosis,defective adhesion • Cytogenetic hallmark: Ph chromosomeMolecular hallmark: BCR/ABL • BCR/ABL initiation-causative event in CML

3. CML • Epidemiology: • 20% of allleukemiasare CML. • < 2 / 100.000-year . • Medianage:50-60,<10% are <20 years • M / F : 3 / 2 • Etiology: • Radiation • Benzene ? • t(9:22)

4. BCR / ABL fusion gene => p 210 p210 =>increasedthyrosinekinaseactivity, => Myeloproliferation Proliferation Adhesion defect p210 Proliferationand cellcyclusabnormalitiy İnhibition of apoptosis

5. Bcr/abl T H.StemCell Lymphoidstemcell B G M Myeloidstemcell E P

6. CML is a diseasewiththree phases Chronic Phase 3-5 years < 18 months 3-9 months Accelerated Phase • Blasts >20% • Extramedullary disease with localized immature blasts • Blasts  10-15% • Bl + pros  30% • Basophils  20% • Plts < 100,000/mcl • Clonal evolution • Asymptomatic (if treated) • None of criteria for accelerated or blast blast phase Blast Phase Theblastic (acuteleukemicphase ) is inevitableif 1-thepatient is not treated Or 2- there is no responsetotreatment

7. Clinical Features-1 Clinical Features of CMLMira Farquharson and Pat Shepherd in J.V. Melo · J.M. Goldman. Hematologic Malignancies: Myeloproliferative Disorders Springer Berlin Heidelberg 2007 • I-Chronic Phase • Symptoms : • Asymptomatic : 20-45% • Tiredness : 33-68% • Weight loss : 17-24% • Abdominal fullness : 28-36% • Easy bruising/bleeding : 21-35% • Abdominal pain : 33% • Others::Bone pain ,night sweats,gout etc,

8. Clinical Features-2 • Splenomegaly : 60-95 (70) % • Hepatomegaly : 45-50 % • Sternal tenderness : 78 % • Purpura : 27 % • Retinal bleeding : 21 % • LAP’s > 1 cm : 8 % • 40 - 70 % of the patients have splenomegaly > • 10 cm below the left costal margin. • Sudden onset LUQ pain may indicate splenic infarct

9. Less common features • Thrombosis • Leukostasis • Myocardial infarct.,priapismus, resp. distress, eye and CNS changes, • Granulocytic Sarcoma : Extramedullary leukemic tumors • Gout/stones

10. Lab. Findings in Chronic Phase • Neutrophylic Leukocytosis : • In some cases it may be > 100.000 / mm3 • Eosinophyls or basophyls may also increase • (the amount of increase is more prominent in accelerated phase) • Anemia :Mild to moderate in some cases • Thrombocytes : • Normal , increased or less commonly decreased. • There may be functional plt defects.

11. Peripheral blood smear: • All of the stages of maturation of the granulocytic cells (mainly neutrophyls) may be seen . • Erythroblasts are not seen or few if any.

12. Lab. Findings in CP • Bone marrow: • Hypercellular, • Myeloid activity increased, • Megakaryocytes normal / increased • Red cell precursors relatively decreased , • Myelofibrosis may also occur in late stage.

13. Blood counts of a CML case ? WBC x109/L 122.0 Hb g/dL 9.8 MCV fL 87 Platelets x109/L 843

14. CML:Peripheralbloodsmear Granulocytosiswith a leftshift

15. Leukocyte alkaline phosphatase activity: • 0 or decreased • Ph chromosome + • Conventional cytogenetics/FISH • BCR/ABL + • Molecular methods (PCR) • Serum levels of • K+, uric acid, LDH,Transcobalamin I: increased

16. CML; Diagnosis Clinicalfindings BloodCounts Smearandwhitecelldifferential Leuk.Alk.Phosp Geneticandmolecularanalysis

17. Differential diagnosis • Leukemoid reactions • Other myeloproliferative diseases • PV • ET • IMF • CMML t(9:22) , bcr/ablabsent

18. MyeloidLeukemoidReaction A WBC count >30000-50000/mm3 whichmimicsleukemia but is duetoreasonsotherthanleukemia Sometimesmaypresentwithyoungmyeloidcells in theperipheralblood (leftshift) • Somecauses of myeloidleukemoidreaction • Severe infections • Severe acutehemolysis • Metastaticmalignancy leukemoidreaction CML An obviouscauseforleukocytosis+ - Symptoms++++ -/+ Splenomegaly NO/rarely+Usually+ Neutrophyl alkaline phosphatase HIGH LOW/Absent Phchromosome/bcr-abl+ -

19. CML Chronic Phase • Bone marrow or peripheral blood • Blasts < % 10 (IBMTR and WHO) • Peripheral blood • Blasts < % 15 (German CML study group)

20. General characteristics of • Accelerated or Blastic Phases • Fever,weight loss, bone pain, fatique • Treatment resistant • Further increase in the dimensions of spleen, liver or LAP’s • LAB: • WBC further increased, • Plt’s further increased or decreased • Blasts, eosinophyls and/or basophils increase. • Bone marrow: Blast count increases and/or fibrosis. • Extra chromosomal changes

21. CML-Accelerated Phase

22. CML-Blastic Phase • Blasts ≥ 20 % (WHO classification) • Acute leukemia • ANLL mostly • ALL : about 20%

23. CML- Prognosis Parameters • WBC count • Ph chromosome and other chromosome abnormalities • Basophyl count ( blood ≥ 7% , BM ≥ 3 %) • Organomegaly( spm ≥ 10 cm) • Cytopenia (anemia/thrombocytopenia ) • Thrombocytosis (≥ 700.000/mm3 ) • Blast count (blood ≥ 3 %, BM ≥ 5 %) • Age ≥ 60

24. Sokal Risk Groups/Survival • Age • Spleen size • Thrombocyte count • Blast count (%) Risk group 4 year survival Low % 62 Medium % 43 High risk % 33

25. Hasford score Age :<50 : 0 , ≥ 50 :1 Spleen: subcostal , cm Basophyl: <3%: 0 , ≥ 3 % :1 Thrombocyte: <1.500.000 :0, ≥1.500.000:1 Score Risk Group 5 years survival ≤ 780 low % 76 780-1480 medium % 55 >1480 high % 25

26. CML-Goals of treatment • Normal blood values and spleen • Hematologic response MRD • Cytogenetic : normal/better • (lower Ph1 + cell ratio or absence of Ph1 + cells) • Cytogenetic response • Decreased or absent p210 • Molecular response

27. CML - Treatment 2-Supportive Hydration Allopurinol Leukopheresis etc • 1- Spesifictreatment • Chronicphase: • ThyrosineKinaseInhibitors (TKI): • Imatinibmesylate • Ordasatinib , nilotinib • Stemcelltransplantation • Interpheron ( IFN ) • IFN + ARA-C or • IFN +HU • Busulphan • Radiotherapy • Hydroxyurea(HU) : Rapidcontrol of toohigh WBC counts • Acuteblasticphase: • Acuteleukemiatypetreatment+ ImatiniborotherTKI’s • oralternativetreatments Oldtreatmentmodalities