Chronic leukaemias Chronic myelogenous leukaemia Chronic myelogenous leukaemia Chronic lymphocytic leukaemia Chronic lymphocytic leukaemia

Chronic leukaemias Chronic myelogenous leukaemia Chronic myelogenous leukaemia Chronic lymphocytic leukaemia

Chronic myelogenous leukaemia A Myeloproliferative disorder A Myeloproliferative disorder A clonal disorder where 95% of patients have a distinctive cytogenetic abnormality “the Philadelphia (Ph) chromosome” A clonal disorder where 95% of patients have a distinctive cytogenetic abnormality “the Philadelphia (Ph) chromosome” Median age of ph+ CML is 67 yrs(30- 80yrs) Median age of ph+ CML is 67 yrs(30- 80yrs) Medial survival is 4-6 yrs, (range 1-10yrs) Medial survival is 4-6 yrs, (range 1-10yrs) Curative only by BMT Curative only by BMT

Myeloproliferative disorders Chronic myelogenous leukaemia Chronic myelogenous leukaemia Polycythemia Vera Polycythemia Vera Myelofibrosis Myelofibrosis Essential thrombocythemia Essential thrombocythemia

CML – Natural History Chronic phase: Chronic phase: Disease respond to treatment Disease respond to treatment < 5% of blasts and promyelocytes in the peripheral blood and bone marrow < 5% of blasts and promyelocytes in the peripheral blood and bone marrow Accelerated phase Accelerated phase > 5% in either peripheral blood or bone marrow and 5% in either peripheral blood or bone marrow and < 20% in both peripheral blood and bone marrow. Blast crisis  acute leukaemia Blast crisis  acute leukaemia > 20% blasts are present in peripheral blood or bone marrow > 20% blasts are present in peripheral blood or bone marrow 70% AML 70% AML 30% ALL 30% ALL

CML- Symptoms Fatigue Fatigue Abdominal fullness and discomfort Abdominal fullness and discomfort Symptoms of anaemia Symptoms of anaemia Night sweating Night sweating Low grade fever Low grade fever When WBC count is very high “leukostasis” When WBC count is very high “leukostasis” Blurred visionBlurred vision Respiratory distressRespiratory distress priapismpriapism

CML- Signs Splenomegaly ; Splenomegaly ; mild to gross, usually marked mild to gross, usually marked 10% have normal spleen 10% have normal spleen Sternal tenderness Sternal tenderness Signs of anaemia Signs of anaemia

Philadelphia chromosome A cytogenetic abnormality A cytogenetic abnormality Due to reciprocal translocation between the long arm of chromosomes 9(9q) and 22(22q) (9:22 translocation) Due to reciprocal translocation between the long arm of chromosomes 9(9q) and 22(22q) (9:22 translocation) It is found in all haematopoietic precursors of CML patients. It is found in all haematopoietic precursors of CML patients. This result in the transfer of the Abelson's (abl) oncogene to an area of chromosome 22 termed the break-point cluster region (bcr) This result in the transfer of the Abelson's (abl) oncogene to an area of chromosome 22 termed the break-point cluster region (bcr) This results in a fused bcr-abl gene and production of an abnormal tyrosine kinase protein. This results in a fused bcr-abl gene and production of an abnormal tyrosine kinase protein. This protein causes disordered myelopoiesis in CML This protein causes disordered myelopoiesis in CML

CML- Investigations Complete blood count Complete blood count Peripheral blood film smear Peripheral blood film smear Bone marrow aspiration Bone marrow aspiration Ph chromosome analysis Ph chromosome analysis Others Others

CML- Investigations Complete blood count Complete blood count Peripheral blood film smear Bone marrow aspiration Southern Blot analysis Ph chromosome analysis NAP score Others

Complete blood count  WBC counts  WBC counts It may reach up to 500 x 10 9 /l It may reach up to 500 x 10 9 /l Usually around 150 x 10 9 /l Usually around 150 x 10 9 /l Anaemia Anaemia Platelets N or  Platelets N or 

CML- Investigations Complete blood count Peripheral blood film smear Peripheral blood film smear Bone marrow aspiration Ph chromosome analysis Others

Peripheral blood film smear Shift to left of myeloid series with more myelocytes in PBF than mature WBCs Shift to left of myeloid series with more myelocytes in PBF than mature WBCs Blast cells are < 5% Blast cells are < 5% Basophilia Basophilia

PBF in CML

CML- Investigations Complete blood count Peripheral blood film smear Bone marrow aspiration Bone marrow aspiration Assess cellularity Assess cellularity Assess fibrosis Assess fibrosis Cytogenetic studies for Ph chromosome analysis Cytogenetic studies for Ph chromosome analysis Others

CML - Bone marrow aspiration Hyper cellular bone marrow Hyper cellular bone marrow Shift in the myeloid series to immature forms, this increase in number as patients progress to blastic phase of the disease. Shift in the myeloid series to immature forms, this increase in number as patients progress to blastic phase of the disease. Myeloblast count <5% of myeloid cells in chronic phase. Myeloblast count <5% of myeloid cells in chronic phase. Elevated myeloid/ erythroid ratio in the marrow. Elevated myeloid/ erythroid ratio in the marrow.

CML- Investigations Complete blood count Peripheral blood film smear Bone marrow aspiration Assess cellularity Assess fibrosis Cytogenetic studies for Ph chromosome analysis Others  Vitamin B12 level due to  secretion of transcobolamin III  Uric acid

Management of Chronic CML Gleevec ® (Imatinib mesylate) Gleevec ® (Imatinib mesylate) A tyrosine kinase inhibitor A tyrosine kinase inhibitor Tyrosine kinase is required for transforming functioin of the bcr-able fusion protein Tyrosine kinase is required for transforming functioin of the bcr-able fusion protein It induces hematological remission in almost all patients with interferon resistent CML It induces hematological remission in almost all patients with interferon resistent CML Cytogenetic response is seen in 50% of patients. Cytogenetic response is seen in 50% of patients.

Management of Chronic CML Allogenic BMT Allogenic BMT Is the only curative treatment available of CML so far Is the only curative treatment available of CML so far It should be considered in the first year of diagnosis if the patient is <40 yrs of age and has an HLA matched donor. It should be considered in the first year of diagnosis if the patient is <40 yrs of age and has an HLA matched donor. Interferon α Interferon α Used for patients who are not eligible for BMT Used for patients who are not eligible for BMT May induce a cytogenetic response in 20% of patients. May induce a cytogenetic response in 20% of patients.

Management of Chronic CML Hydroxurea Hydroxurea Uses: Uses: Initial treatment to lower WBC count prior to interferon therapy. Initial treatment to lower WBC count prior to interferon therapy. Palliative treatment of patients failing other treatment. Palliative treatment of patients failing other treatment. Splenectomy Splenectomy Hypersplenism Hypersplenism discomfort discomfort

Accelerated phase of CML Features Features  Bone pain  Bone pain  Spleenomegaly  Spleenomegaly  Resistance to current treatment  Resistance to current treatment Progressive anaemia Progressive anaemia Thrombocytopenia or thrombocytosis Thrombocytopenia or thrombocytosis Blast cells >5% in either PB or BM and 5% in either PB or BM and <30% of both PB and BM.

Accelerated phase of CML Treatment Treatment Imatinib mesylate Imatinib mesylate Bone marrow transplantation Bone marrow transplantation High dose cytarabine High dose cytarabine

Blastic phase of CML Features Features Fever Fever Malaise Malaise Progressive splenomgaly Progressive splenomgaly Blast cells >20% in PB or BM Blast cells >20% in PB or BM

Blastic phase of CML Treatment Treatment Imatinib mesylate Imatinib mesylate As in ALL (Vincrisitne and prednisolone + anthracycline) As in ALL (Vincrisitne and prednisolone + anthracycline) Allogenic BMT Allogenic BMT

Chronic lymphocytic leukemia It is a disease of morphologically mature but immunologically less mature lymphocytes. It is a disease of morphologically mature but immunologically less mature lymphocytes. Manifested by progressive accumulation of lymphocytes in the blood, bone marrow and lymphatic tissues. Manifested by progressive accumulation of lymphocytes in the blood, bone marrow and lymphatic tissues.

CLL Epidemiology Epidemiology The most common leukemia in adult The most common leukemia in adult males >females males >females > 45 yrs > 45 yrs Here mature lymphocytes fail to respond to Ag stimulation Here mature lymphocytes fail to respond to Ag stimulation 95% are B cell type 95% are B cell type 5% are T cell type 5% are T cell type The overall 5 year survival is 60% The overall 5 year survival is 60%

CLL Clinical presentation Indolent lymphocytosis (asymptomatic) Indolent lymphocytosis (asymptomatic) Generalized lymphadenopathy Generalized lymphadenopathy Hepato-splenomegaly Hepato-splenomegaly

CLL Clinical presentation Pancytopenia Pancytopenia Anaemia Anaemia Coombs positive hemolysis Coombs positive hemolysis Hypoplastic Hypoplastic Bleeding Bleeding Production thrombocytopenia Production thrombocytopenia Immune thrombocytopenia Immune thrombocytopenia Infection Infection Depressed immunoglobulin levels Depressed immunoglobulin levels

CLL investigations CBC CBC PBF PBF BM aspiration BM aspiration Immunochemistry Immunochemistry Total protein and Ig level Total protein and Ig level

CBC CBC PBF BM aspiration immunochemistry Total protein and Ig level CLL investigations

WBC: WBC: Increased counts Increased counts Mainly lymphocytes Mainly lymphocytes Lymphocyte count >=10 x 10 9 /l Lymphocyte count >=10 x 10 9 /l Hb: Hb: Normal or low Normal or low Hemolytic anaemia Hemolytic anaemia Platelets: Platelets: Normal or low Normal or low Complete blood counts

CBC PBF PBF BM aspiration Immunochemistry Total protein and Ig level CLL investigations

Perioheral blood film Predominantly lymphocytosis Predominantly lymphocytosis Normally looking Normally looking Presence of smudge cells Presence of smudge cells

CBC PBF BM aspiration BM aspiration Immunochemistry Total protein and Ig level CLL investigations

Not necessary for diagnosis Not necessary for diagnosis Infiltration of the bone marrow by lymphocytes. Infiltration of the bone marrow by lymphocytes. Bone marrow aspiration

CBC PBF BM aspiration Immuno chemistry Immuno chemistry Total protein and Ig level Total protein and Ig level CLL investigations

Immunoglobulin levels Low immunoglobulin levels Low immunoglobulin levels Immuno-chemistry CD19 positiveCD19 positive CD20 positiveCD20 positive CD5 positiveCD5 positive

CLL- staging

CLL whom to treat? Stage A  No Treatment Stage A  No Treatment Observation only Observation only Stage B  Treat if symptomatic Stage B  Treat if symptomatic Observation only for asymptomatic Observation only for asymptomatic Chemotherapy for symptomatic lymphadenopathy Chemotherapy for symptomatic lymphadenopathy Stage C  Treat All Stage C  Treat All Should be treated Should be treated Stage A  No Treatment Stage A  No Treatment Observation only Observation only Stage B  Treat if symptomatic Stage B  Treat if symptomatic Observation only for asymptomatic Observation only for asymptomatic Chemotherapy for symptomatic lymphadenopathy Chemotherapy for symptomatic lymphadenopathy Stage C  Treat All Stage C  Treat All Should be treated Should be treated

CLL treatment Supportive treatment Supportive treatment Treat infection Treat infection Herpes zoster Herpes zoster Pseudomonas carinii Pseudomonas carinii Proper hydration + allopurinol Proper hydration + allopurinol Automimmune anaemia or thrombocytopenia Automimmune anaemia or thrombocytopenia corticosteroids corticosteroids Blood transfusion Blood transfusion High dose immuneglobulin High dose immuneglobulin Cyclosporine Cyclosporine Splenectomy Splenectomy Low dose radiation to the spleen Low dose radiation to the spleen

CLL Treatment options Oral alkylating agents + corticosteroids Oral alkylating agents + corticosteroids Chlorambucil + prednisolone Chlorambucil + prednisolone Purine analogues: Fludrabine, Purine analogues: Fludrabine, Combination chemotherapy: Combination chemotherapy: CVP or CHOP CVP or CHOP Involved field radiotherapy: for lymph node areas Involved field radiotherapy: for lymph node areas Splenic radiation for palliation of hypersplenism Splenic radiation for palliation of hypersplenism