MYELOPROLIFERATIVE DISEASES CHRONIC MYELOGENOUS LEUKAEMIA By DR. FATIMA AL-QAHTANI CONSULTANT HAEMATOLOGIST

WHO Classification Chronic Myeloproliferative Disease Chronic Myelogenous Leukaemia [Ph chromosome, t(9;22)(q34;q11), BCR/ABL- positive ] Chronic Neutrophilic Leukaemia Chronic Eosinophilic Leukaemia (and the hypereosinophilic syndrome) Polycythaemia Vera Chronic Idiopathic Myelofibrosis (with extramedullary haematopoiesis) Essential Thrombocythaemia Chronic Myeloproliferative Disease, Unclassifiable

WHO Classification Myelodysplastic / Myeloproliferative Diseases Chronic Myelomonocytic Leukaemia Atypical Chronic Myeloid Leukaemia Juvenile Myelomonocytic Leukaemia Myelodysplastic/Myeloproliferative Disease, Unclassifiable

Myeloid Disorders Usual Features at Diagnosis Disease BM Cellularity % Marrow Blasts Maturation Morphology Haemato- poiesis Blood count (s) Organo- megaly Myeloproliferatie disorder Usually increased Normal or slightly increased (<10%) PresentRelatively normal EffectiveOne or more myeloid cell lines increased Common Myelodysplastic syndromes Usually increased, occasionally decreased Normal or increased (<20%) PresentDysplasia of one or more myeloid lineage IneffectiveCytopenia (S)Uncommon Myelodysplastic/ myeloproliferative disease Usually increased Normal or increased (<20%) PresentDysplasia of one or more myeloid lineages frequent Effective or ineffective; may vary among involved lineages VariableCommon Acute myeloid leukaemia Usually increased, occasionally decreased Increased (≥ 20%) Varies, frequently minimal May or may not be associated with dysplasia in one or more myeloid lines Ineffective or effective Variableuncommon

Myeloproliferative Disease Recurring Genetic Abnormalities and Their Frequency (%) at diagnosis DiseaseSpecific abnormalities(%)Recurring, nonspecific cytogenetic/genetic abnormalities (%) CML, CPt(9;22)(q34;q11), BCR/ABL100 CML, AP/BP t(9;22)(q34;q11), BCR/ABL100+8, +9Ph,+19,i(17q), t(3;21)(q26;q22)(EVI1/AML1)80 CNLNone+8, +9, del(20q), del(11q14)~10 CELNone+8, t(5;12)(q33;p13)(TEL/PDGFβR), dic(1;7), 8p11 (FGFR1) ? PVNone +8, +9, del(20q), del(13q), del(1p11)~15 CIMFNone+8, del(20q), -7/del(7q), del(11q), del(13q)~35 ETNone+8, del (13q)~5 CML, CP = Chronic myelogenous leukaemia, chronic phase; CML, AP/BP= Chronic myelogenous leukaemia, accelerated or blast phase; CNL = Chronic neutrophilic leukaemia; CEL = Chronic eosinophilic leukaemia; PV = Polycythaemia Vera; EVI-1 = ecotropic viral integration site 1 CIMF = Chronic idiopathic myelofibrosis; ET = Essential thrombocythaemia ? = Insufficient data available

Chronic Myelogenous Leukaemia Presenting Manifestations Common Anaemia Splenomegaly Less Common Symptoms due to the raised metabolic rate Haemorrhagic Manifestations, especially bruising

Chronic Myelogenous Leukaemia Presenting Manifestations (Cont…) Occasional Acute abdominal pain Bone or joint pains Menstrual disturbances Neurological symptoms Priapism Gout Skin disorder Disturbances of vision or hearing Accidental discovery on routine blood examination

Chronic Myelogenous Leukaemia Evolution of the disease Chronic Phase Accelerated Phase Blastic Transformation (AML) (ALL)

Chronic Myelogenous Leukaemia Laboratory Investigations CBC Neutrophil Alkaline Phosphatase Bone Marrow Examination. Serum B 12 & B 12 binding capacity Cytogenetic Studies (Ph 1 ) chromosome [ t ( 9 : 22 ) ] DNA restriction enzyme analysis BCR-ABL (Breakpoint Cluster Region)

CML

Chronic Myelogenous Leukaemia Accelerated Phase Blasts 10% to 19% of peripheral blood white cells or bone marrow cells Peripheral blood basophiles at least 20% Persistent thrombocytopenia ( 1000X10 9 L) unresponsive to therapy Increasing spleen size and increase WBC count unresponsive to therapy

Chronic Myelogenous Leukaemia Accelerated Phase (Cont…) Cytogenetic evidence of clonal evolution (i.e., the appearance of an additional genetic abnormality that was not present in the initial specimen at the time of diagnosis of chronic phase CML) Megakaryocytic proliferation in sizable sheets and clusters, associated with marked reticulin or collagen fibrosis, and/or severe granulocytic dysplasia, should be considered as suggestive of CML-AP These findings have not yet been analyzed in large clinical studies, however, so it is not clear if they are independent criteria for accelerated phase. They often occur simultaneously with one or more of the other features listed

Chronic Myelogenous Leukaemia Blastic Phase (BP) Diagnosis is established if one or more of following is present: Blasts 20% or more of peripheral blood white cells or bone marrow cells Extramedullary blast proliferation Large foci or clusters of blasts in bone marrow biopsy

FAP Proposal Guidelines for distinguishing Chronic Granulocytic (CGL), atypical Chronic Myeloid (aCML) and Chronic Myelomonocytic Leukaemia (CMML) ParametersCGLaCMLCMML Basophiles≥ 3%<2% Monocytes<3%3 – 10%≥ 3 – 10% (Usually >10%) Granulocytic Dysplasia Immature granulocytes >20%10 – 20%≤ 10% Blasts≤ 2%>2%<2% Erythroids--+

Chronic Myelogenous Leukaemia Chronic Phase (BP) Treatment  Hydroxyurea (HU): WBC/ulHU (mg/kg BW/DAY) >50, ,00030 – 40 <15,00025  Busulphan  Alpha – Interferon: 5 MU/DAY 7.5 MU/DAY if WBC > 10,000/mcl 10 MU/DAY if WBC > 20,000/mcl 3 MU/DAY if cytopenia develops  BMT, ABMT & STEM CELL HARVEST  Gleevec

Diagnosis of chronic eosinophilic leukaemia and hypereosinophilic syndrome. Required: Persistent eosinophilia ≥ 1.5X10 9 /L in blood, increased numbers of bone marrow eosinophils, and myeloblasts <20% in blood or marrow. 1.Exclude all causes of reactive eosinophilia secondary to: Allergy Parasitic disease Infectious disease Pulmonary diseases (hypersensitivity pneumonitis, Loeffler’s, etc.). collagen vascular diseases.

2.Exclude all neoplastic disorders with secondary, reactive eosinophilia: T cell lymphomas, including mycosis fungoides, Sezary syndrome. Hodgkin lymphoma. Acute lymphoblastic leukaemia/lymphoma Mastocytosis. 3.Exclude other neoplastic disorders in which eosinophils are part of the neoplastic clone: chronic myelogenous leukaemia (Ph chromosome or BCR/ABD fusion gene positive). Acute myeloid leukaemia, including those with inv(16), t(16;16) (p13;q22). Other myeloproliferative disease (PV,ET,CIMF) Myelodysplastic syndromes.

4.Exclude T cell population with aberrant phenotype and abnormal cytokine production. 5.If there is no demonstrable disease that could cause the eosinophilia, no abnormal T-cell population, and no evidence of a clonal myeloid disorder, diagnose HES. 6.If all of the requirements, including conditions 1-4, have been met, and if the myeloid cells demonstrate a clonal chromosomal abnormality or are shown to be clonal by other means, or if blast cells are present in the peripheral blood (>2%) or are increased in the bone marrow (>5% but less than 19% of nucleated bone marrow cells), diagnose CEL.

Diagnostic criteria for chronic neutrophhilic leukaemia. 1.Peripheral blood leukocytosis ≥ 25X10 9 /L. Segmented neutrophils and bands >80% of white blood cells. Immature granulocytes (promyelocytes, myelocytes, metamyelocytes) <10% of white blood cells. Myeloblasts <1% of white blood cells. 2.Hypercellular bone marrow biopsy. Neutrophilic granulocytes increased in percentage and number. Myeloblasts <5% of nucleated marrow cells. Neutrophilic maturation pattern normal.

Diagnostic criteria for chronic neutrophhilic leukaemia. (Continued) 3.Hepatosplenomegaly. 4.No identifiable cause for physiologic neutrophilia. No infectious or inflammatory process. No underlying tumour, or if present, demonstration of clonality of myeloid cells by cytogenetic or molecular studies. 5.No Philadelphia chromosome or BCR/ABL fusion gene.

Diagnostic criteria for chronic neutrophhilic leukaemia. (Continued) 6.No evidence of another myeloproliferative disease. -No evidence of Polycythaemia Vera, i.e., normal red cell mass. -No evidence of chronic idiopathic myelofibrosis, i.e., no abnormal megakaryocytic proliferation, no reticulin or collagen fibrosis, no marked red blood cell poikilocytosis. -No evidence of essential thrombocythaemia, i.e., platelets <600X10 9 /L, no proliferation of mature, enlarged megakaryocytes. 7.No evidence of a myelodysplastic syndrome or a myelodysplastic/myeloproliferative disorder. -No granulocytic dysplasia. -No myelodysplastic changes in other myeloid lineages. -Monocytes <1X10 9 /L.