C H R O N I C L E U K E M I C H R O N I C L E U K E M I AA

IRZA WAHIDIRZA WAHID

5-02-20155-02-2015

SUBDIVISION OF HEMATOLOGY & MEDICAL ONCOLOGYSUBDIVISION OF HEMATOLOGY & MEDICAL ONCOLOGY

DEPARTEMENT OF INTERNAL MEDICINEDEPARTEMENT OF INTERNAL MEDICINE

FACULTY OF MEDICINE ANDALAS UNIVERSITYFACULTY OF MEDICINE ANDALAS UNIVERSITY

Leukaemias Leukaemias

What are LeukemiasWhat are Leukemias– Neoplasm of white blood cell and its Neoplasm of white blood cell and its

precursorprecursor– Clonal proliferations and Clonal proliferations and

accumulation of cells in marrow accumulation of cells in marrow – Classify as Classify as

Acute leukaemias Acute leukaemias AML - AML - ALLALL

Chronic leukaemiasChronic leukaemias CML - CLL CML - CLL

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PluripotentStem Cell

Myeloid Stem Cell

LymphoidStem Cell CFU-T

CFU-B

CFU-Eosin

CFU-Bas

CFU-GM

CFU-MEG

BFU-E

T-Cell

B-Cell

eosinophil

basophil

neutrophil

platelets

monocyte

macrophage

erythrocyte

Genesis of Blood Products

Copyright © 2006 by Elsevier, Inc.

Hemocytoblast

CFU-L

CFU-M

CHRONIC MYELOID CHRONIC MYELOID LEUKEMIA (CML)LEUKEMIA (CML)

Clonal malignant myeloproliferative disorder Clonal malignant myeloproliferative disorder (MPD) (MPD) characterized by increased proliferation characterized by increased proliferation of the granulocytic cell line without the loss of of the granulocytic cell line without the loss of their capacity to differentiate their capacity to differentiate

Results in increases in myeloid cells, erythroid Results in increases in myeloid cells, erythroid cells and platelets in peripheral blood and cells and platelets in peripheral blood and marked myeloid hyperplasia in the bone marked myeloid hyperplasia in the bone marrow marrow

Originate in a single abnormal haemopoietic Originate in a single abnormal haemopoietic stem cellstem cell

Introduction- CMLIntroduction- CML

Incidence :1 per 100,000 (UK)Incidence :1 per 100,000 (UK) Accounts for 7-15% of all Accounts for 7-15% of all

leukaemia in adultsleukaemia in adults Median age : 53 yearsMedian age : 53 years All age groups, including children, All age groups, including children,

can be affectedcan be affected

Introduction- CMLIntroduction- CML

EtiologyEtiology– Not clearNot clear– Little evidence of genetic factors Little evidence of genetic factors

linked to the diseaselinked to the disease– Increased incidence Increased incidence

Survivors of the atomic disasters at Survivors of the atomic disasters at Nagasaki & HiroshimaNagasaki & Hiroshima

Post radiation therapyPost radiation therapy

LeukaemogenesisLeukaemogenesis

Philadelphia Philadelphia chromosome is an chromosome is an acquired cytogenetic acquired cytogenetic anomaly that is anomaly that is characterizes in all characterizes in all leukaemic cells in leukaemic cells in CMLCML

90-95% of CML pts 90-95% of CML pts have Ph have Ph chromosomechromosome

Reciprocal Reciprocal translocation of translocation of chromosome 22 and chromosome 22 and chromosome 9chromosome 9

LeukaemogenesisLeukaemogenesis

BCR (breakpoint cluster region)BCR (breakpoint cluster region) gene gene on chromosome 22 fused to the on chromosome 22 fused to the ABL ABL (Ableson leukemia virus)(Ableson leukemia virus) gene on gene on chromosome 9chromosome 9

Ph chromosome is found on myeloid, Ph chromosome is found on myeloid, monocytic, erythroid, monocytic, erythroid, megakaryocytic, B-cells and megakaryocytic, B-cells and sometimes T-cell proof that CML sometimes T-cell proof that CML derived from pluripotent stem cellderived from pluripotent stem cell

LeukaemogenesisLeukaemogenesis

Molecular consequence Molecular consequence of the t(9;22) is the of the t(9;22) is the fusion protein BCR–ABL, fusion protein BCR–ABL, which has increased in which has increased in tyrosine kinase activitytyrosine kinase activity

BCR-ABL protein BCR-ABL protein transform hematopoietic transform hematopoietic cells so that their growth cells so that their growth and survival become and survival become independent of cytokinesindependent of cytokines

It protects hematopoietic It protects hematopoietic cells from programmed cells from programmed cell death (apoptosis) cell death (apoptosis)

ClinicalClinical FeaturesFeatures

Clinical features - symptomsClinical features - symptoms

Asymptomatic in > 20%FatigueBleedingWeight lossSplenic discomfort/fullness

Clinical features - signsClinical features - signs

Splenomegaly (75%)Hepatomegaly (2%)Purpura (16%)Priapism (1% of males)

Lab featuresLab features

Peripheral blood filmPeripheral blood film– Leukocytosis (usu >25 x 10Leukocytosis (usu >25 x 1099/L, freq> /L, freq>

100 x 10100 x 1099/L/L– WBC differential shows granulocytes WBC differential shows granulocytes

in all stages of maturationin all stages of maturation– BasophiliaBasophilia– thrombocytosisthrombocytosis

Lab Lab featuresfeatures Bone marrowBone marrow

– Hypercellular (reduced Hypercellular (reduced fat spaces)fat spaces)

– Myeloid:erythroid ratio Myeloid:erythroid ratio – 10:1 to 30:1 (N : 2:1)– 10:1 to 30:1 (N : 2:1)

– Myelocyte predominant Myelocyte predominant cell, blasts less 10%cell, blasts less 10%

– Megakaryocytes Megakaryocytes increased & dysplasticincreased & dysplastic

– Increase reticulin Increase reticulin fibrosis in 30-40%fibrosis in 30-40%

Lab Lab featuresfeatures Other lab features :Other lab features :

– Serum B12 and transcobalamin Serum B12 and transcobalamin increasedincreased

– Serum uric acid increasedSerum uric acid increased– Lactate dehydrogenase increasedLactate dehydrogenase increased– Cytogenetic : Philadelphia Cytogenetic : Philadelphia

chromosomechromosome– PCR : Fusion of BCR ABL genePCR : Fusion of BCR ABL gene

PhasesPhases

Accelerated phaseAccelerated phase– Median duration is 3.5 – 5 yrs before Median duration is 3.5 – 5 yrs before

evolving to more aggressive phasesevolving to more aggressive phases– Clinical featuresClinical features

Increasing splenomegaly refractory to chemoIncreasing splenomegaly refractory to chemo Increasing chemotherapy requirementIncreasing chemotherapy requirement

– Lab featuresLab features Blasts>15% in bloodBlasts>15% in blood Blast & promyelocyte > 30% in bloodBlast & promyelocyte > 30% in blood Basophil 20% in bloodBasophil 20% in blood ThrombocytopeniaThrombocytopenia Cytogenetic: clonal evolutionCytogenetic: clonal evolution

Phases Phases

Blastic phase Blastic phase – Resembles acute leukaemiaResembles acute leukaemia– Diagnosis requires > 20% blast in Diagnosis requires > 20% blast in

marrowmarrow– 2/3 transform to myeloid blastic 2/3 transform to myeloid blastic

phase and 1/3 to lymphoid blastic phase and 1/3 to lymphoid blastic phasephase

– Survival : 9 mos vs 3 mos (lym vs Survival : 9 mos vs 3 mos (lym vs myeloid)myeloid)

General General ManagementManagement Discussion with familyDiscussion with family

– The disease & diagnosisThe disease & diagnosis– Prognosis Prognosis – Choices of treatmentChoices of treatment

Cytotoxic drug vs bone marrow Cytotoxic drug vs bone marrow transplanttransplant

Side effectSide effect

CML - principles CML - principles of treatmentof treatment Relieve symptoms of hyperleukocytosis, Relieve symptoms of hyperleukocytosis,

splenomegaly and thrombocytosissplenomegaly and thrombocytosis– HydrationHydration– Chemotherapy (bulsuphan, Hydoxyurea)Chemotherapy (bulsuphan, Hydoxyurea)

Control and prolong chronic phase Control and prolong chronic phase (non-curative)(non-curative)– alpha interferon+chemotherapyalpha interferon+chemotherapy– imatinib mesylate imatinib mesylate – chemotherapy (hydroxyurea)chemotherapy (hydroxyurea)

CML - principles CML - principles of treatmentof treatment

Eradicate malignant clone Eradicate malignant clone (curative)(curative)– allogeneic transplantationallogeneic transplantation– alpha interferon ?alpha interferon ?– imatinib mesylate/STI 571 ?imatinib mesylate/STI 571 ?

(Thyrosine kinase inhibitor)(Thyrosine kinase inhibitor)

Chronic lymphocytic Chronic lymphocytic leukemia leukemia

Is characterised by the accumulation of Is characterised by the accumulation of nonproliferating mature-appearing nonproliferating mature-appearing lymphocytes in the blood, marrow, lymphocytes in the blood, marrow, lymph nodes, and spleenlymph nodes, and spleen

In most cases, the cells are monoclonal In most cases, the cells are monoclonal B lymphocytes that are CD5+ B lymphocytes that are CD5+

T cell CLL can occur rarelyT cell CLL can occur rarely

Chronic lymphocytic leukemia Chronic lymphocytic leukemia

Is the most common form of leukemia Is the most common form of leukemia in North America and Europe, but is in North America and Europe, but is extremely rare in the Orientextremely rare in the Orient

Typically occurs in older patients, with Typically occurs in older patients, with the highest incidence being in those the highest incidence being in those aged 50 to 55 yearsaged 50 to 55 years

Affects men twice as often as womenAffects men twice as often as women

Etiology Etiology

The cause of CLL is unknownThe cause of CLL is unknown

There is increased incidence in farmers, There is increased incidence in farmers, rubber manufacturing workers, asbestos rubber manufacturing workers, asbestos workers, and tire repair workersworkers, and tire repair workers

Genetic factors have been postulated to Genetic factors have been postulated to play a role in high incidence of CLL in play a role in high incidence of CLL in some families some families

Clinical Clinical findings findings Approximately 40% of CLL patients are Approximately 40% of CLL patients are

asymptomatic at diagnosisasymptomatic at diagnosis In symptomatic cases the most In symptomatic cases the most

common complaint is fatiguecommon complaint is fatigue Less often the initial complaint are Less often the initial complaint are

enlarged nodes or the development of enlarged nodes or the development of an infection (bacterial)an infection (bacterial)

Clinical Clinical findings findings

Most symptomatic patients have Most symptomatic patients have enlarged enlarged lymph lymph nodes (more commonly cervical and nodes (more commonly cervical and supraclavicular) and splenomegalysupraclavicular) and splenomegaly

Hepatomegaly may occureHepatomegaly may occure Less common manifestation are infiltration Less common manifestation are infiltration

of tonsils, mesenteric or retroperitoneal of tonsils, mesenteric or retroperitoneal lymphadenopathy, and skin infiltration lymphadenopathy, and skin infiltration

Patients rarely present with features of Patients rarely present with features of anemia, and bruising or bleeding anemia, and bruising or bleeding

Laboratory Laboratory findingsfindings

The blood lymphocyte count above 5,0 G/LThe blood lymphocyte count above 5,0 G/L In most patients the leukemic cells have In most patients the leukemic cells have

the morphologic appearance of normal the morphologic appearance of normal small lymphocytessmall lymphocytes

In the blood smears are commonly seen In the blood smears are commonly seen ruptured lymphocytes (“basket” or ruptured lymphocytes (“basket” or “smudge” cells)“smudge” cells)

Careful examination of the blood smear can Careful examination of the blood smear can usually differentiate CLL, and the diagnosis usually differentiate CLL, and the diagnosis can be confirmed by immunophenotypingcan be confirmed by immunophenotyping

Laboratory Laboratory findings findings

Clonal expansion of B (99%) or T(1%) lymphocyteClonal expansion of B (99%) or T(1%) lymphocyte– In B-cell CLL clonality is confirmed by In B-cell CLL clonality is confirmed by

the expression of either the expression of either or or light chains on the cell surface light chains on the cell surface membrane membrane

the presence of unique idiotypic specificities on the the presence of unique idiotypic specificities on the immunoglobulins produced by CLL cellsimmunoglobulins produced by CLL cells

by immunoglobulin gene rearrangementsby immunoglobulin gene rearrangements typical B-cell CLL are unique in being CD19+ and CD5+typical B-cell CLL are unique in being CD19+ and CD5+

Hypogammaglobulinemia or agammaglobulinemia Hypogammaglobulinemia or agammaglobulinemia are often observed are often observed

10 - 25% of patients with CLL develop 10 - 25% of patients with CLL develop autoimmune hemolytic anemia, with a positive autoimmune hemolytic anemia, with a positive direct Coombs’ testdirect Coombs’ test

The marrow aspirates shows greater than 30% of The marrow aspirates shows greater than 30% of the nucleated cells as being lymphoidthe nucleated cells as being lymphoid

The diagnostic criteria for The diagnostic criteria for CLLCLL1) A peripheral blood lymphocyte count 1) A peripheral blood lymphocyte count

of greater than 5 G/L, with less than of greater than 5 G/L, with less than 55% of the cells being atypical55% of the cells being atypical

2) The cell should have the presence of 2) The cell should have the presence of Bcell-specific differentiation antigens Bcell-specific differentiation antigens (CD19, (CD19, CD20,CD20, and CD24) and be and CD24) and be CD5(+)CD5(+)

3) A bone marrow aspirates showing 3) A bone marrow aspirates showing greater than 30% lymphocytesgreater than 30% lymphocytes

Differential Differential diagnosisdiagnosis

Infectious causesInfectious causes– bacterial (tuberculosis)bacterial (tuberculosis)– viral (mononucleosis)viral (mononucleosis)

Malignant causesMalignant causes– B-cellB-cell– T-cellT-cell

leukemic phase of non-Hodgkin lymphomasleukemic phase of non-Hodgkin lymphomas Hairy-cell leukemiaHairy-cell leukemia Waldenstrom macroglobulinemiaWaldenstrom macroglobulinemia large granular lymphocytic leukemialarge granular lymphocytic leukemia

StaginStaging g Rai Classification for CLLRai Classification for CLL

– 0 - lymphocytosis (>5 G/L)0 - lymphocytosis (>5 G/L)– I - lymphocytosis + lymphadenopathyI - lymphocytosis + lymphadenopathy– II - lymphocytosis + splenomegaly +/-II - lymphocytosis + splenomegaly +/-

lymphadenopathylymphadenopathy– III - lymphocytosis + anemia (Hb <11g%) +/-III - lymphocytosis + anemia (Hb <11g%) +/-

lymphadenopathy or splenomegalylymphadenopathy or splenomegaly– IV - lymphocytosis + thrombocytophenia (Plt IV - lymphocytosis + thrombocytophenia (Plt

<100G/L) +/- anemia +/-lymphadenopathy +/- <100G/L) +/- anemia +/-lymphadenopathy +/- splenomegalysplenomegaly

Staging Staging

Binet Classification for CLLBinet Classification for CLL– A. < 3 involved areas, Hb > 10g%, Plt > A. < 3 involved areas, Hb > 10g%, Plt >

100G/L100G/L– B. > 3 involved areas, Hb > 10g%, Plt > B. > 3 involved areas, Hb > 10g%, Plt >

100G/L100G/L– C. - any number of involved areas, Hb < C. - any number of involved areas, Hb <

10g%, 10g%,

Plt < 100G/LPlt < 100G/L

PrognosisPrognosis

Rai classificationRai classificationstagestage median survivalmedian survival

(years)(years)00 >10>10II > 8> 8IIII 6 6IIIIII 2 2IVIV < 2< 2

Binet classificationBinet classificationstagestage median median

survivalsurvival(years)(years)

AA > 10> 10BB 7 7CC 2 2

TreatmentTreatment

– Alkylating agents (chlorambucil, Alkylating agents (chlorambucil, cyclophosphamide)cyclophosphamide)

– Nucleoside analogs (cladribine, fludarabine)Nucleoside analogs (cladribine, fludarabine)

– Monoclonal antibodiesMonoclonal antibodies

– Bone marrow transplantationBone marrow transplantation

– And systemic complications requiring therapyAnd systemic complications requiring therapy antibioticsantibiotics immunoglobulinimmunoglobulin steroidssteroids blood productsblood products

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