Chronic myeloid Chronic myeloid leukemialeukemia

The myeloproliferative diseases (MPDs) are The myeloproliferative diseases (MPDs) are clonal stem cell disorders characterised by clonal stem cell disorders characterised by leukocytosis, thrombocytosis, erythrocytosis, leukocytosis, thrombocytosis, erythrocytosis, splenomegaly, and bone marrow splenomegaly, and bone marrow hypercelularityhypercelularity

They are divided into polycythemia vera (PV), They are divided into polycythemia vera (PV), essential thrombocytosis (ET), agnogenic essential thrombocytosis (ET), agnogenic myeloid metaplasia or myelofibrosis and myeloid metaplasia or myelofibrosis and chronic myelogenous leukemia (CML)chronic myelogenous leukemia (CML)

CML results from a somatic mutation in a CML results from a somatic mutation in a pluripotential hematopoietic cellpluripotential hematopoietic cellCML is a MPD characterized by increased CML is a MPD characterized by increased granulocytic cell line, associated granulocytic cell line, associated often withoften with platelet hyperplasiaplatelet hyperplasiaThe disease usually envolves into an The disease usually envolves into an accelerated phase that often terminates in accelerated phase that often terminates in acute phaseacute phase

--chronic phasechronic phase 3-5 years3-5 years--accelerated phaseaccelerated phase 6-9 months 6-9 months--blastic phaseblastic phase 3-6 months3-6 months

EtiologyEtiology

Exposure to high- dose ionizing radiationExposure to high- dose ionizing radiation

Chemical agents have not been established as Chemical agents have not been established as a ca caauseuse

EpidemiologyEpidemiology

CML accounts for approximately 15 percent of CML accounts for approximately 15 percent of all cases of leukemia and approximately 3 all cases of leukemia and approximately 3 percent of childhood leukemiaspercent of childhood leukemias

The median age of onset is 53 yearsThe median age of onset is 53 years

PathogenesisPathogenesis Hematopoietic abnormalityHematopoietic abnormality

Expansion of granulocytic progenitors and a Expansion of granulocytic progenitors and a decreased sensitivity of the progenitors to decreased sensitivity of the progenitors to regulation – increased white cell countregulation – increased white cell count

Megakaryocytopoiesis is often expandedMegakaryocytopoiesis is often expanded

Erythropoiesis is usually deficientErythropoiesis is usually deficient

Function of the neutrophils and platelets is Function of the neutrophils and platelets is nearly normalnearly normal

PathogenesisPathogenesis Genetic abnormalityGenetic abnormality

CML is the result of an acquired genetic CML is the result of an acquired genetic abnormalityabnormality

A translocation between chromosome 9 and A translocation between chromosome 9 and 22 22 [t(9;22)] – the [t(9;22)] – the Philadelphia chromosomePhiladelphia chromosome

The oncogene BCThe oncogene BCRR-ABL encodes an -ABL encodes an enzyme – tyrosine phosphokinase (usually enzyme – tyrosine phosphokinase (usually p210)p210)

Translocation t(9;22)Translocation t(9;22)(q34;q11)(q34;q11)

Translocation t(9;22)Translocation t(9;22)(q34;q11)(q34;q11)

Philadelphia ChromosomePhiladelphia Chromosome

• More than 95% of patients with CML haMore than 95% of patients with CML haveve Philadelphia (Ph) chromosomePhiladelphia (Ph) chromosome

A subset of patients with CML lack a A subset of patients with CML lack a detectable Ph chromosome but have the detectable Ph chromosome but have the fusion product for the bcr/abl translocation fusion product for the bcr/abl translocation detectable by reverse transcriptase- detectable by reverse transcriptase- polymerase chain reaction (RT-PCR)polymerase chain reaction (RT-PCR)

The bcr/abl fusion proteinThe bcr/abl fusion protein

Uncontrolled kinase activityUncontrolled kinase activity

1.1. Deregulated cellular proliferationDeregulated cellular proliferation

2.2. Decreased adherence of leukemia cells to Decreased adherence of leukemia cells to the bone marrow stromathe bone marrow stroma

3.3. Leukemic cells are protected from normal Leukemic cells are protected from normal programmed cell death (apoptosis)programmed cell death (apoptosis)

Clinical featuresClinical features

30 -50% of patients are asymptomatic at the time of 30 -50% of patients are asymptomatic at the time of diagnosis (90% are diagnosed in chronic phase)diagnosis (90% are diagnosed in chronic phase)Symptoms are gradual in onset:Symptoms are gradual in onset:

fatigue, malaise, anorexia, abdominal discomfort, fatigue, malaise, anorexia, abdominal discomfort, weight loss, excessive sweatingweight loss, excessive sweating

● Less frequent symptomsLess frequent symptoms:: Night sweats, heat intolerance- mimicking Night sweats, heat intolerance- mimicking

hyperthyroidism, symptoms of leukostasis hyperthyroidism, symptoms of leukostasis (tinnitus, stupor), splenic infarction (left upper-(tinnitus, stupor), splenic infarction (left upper-quadrant and left shoulder pain), urticaria (result quadrant and left shoulder pain), urticaria (result of histamine release)of histamine release)

● Physical signsPhysical signs:: Pallor, splenomegaly, sternal painPallor, splenomegaly, sternal pain

Laboratory featuresLaboratory features

The hemoglobin concentration is decreased or normalThe hemoglobin concentration is decreased or normal

Nucleated red cells in blood film can be seenNucleated red cells in blood film can be seen

The leukocyte count above 25000/The leukocyte count above 25000/μl (often above μl (often above 100000/μ100000/μll), granulocytes are at all stages of development ), granulocytes are at all stages of development

Hypersegmentated neutrophilsHypersegmentated neutrophils

The basophiles count is increasedThe basophiles count is increased

The platelet count is normal or increasedThe platelet count is normal or increased

Neutrophils alkaline phosphatase (GAF) activity is low or Neutrophils alkaline phosphatase (GAF) activity is low or absent (90%)absent (90%)

Laboratory features (2)Laboratory features (2)

The marrow is hypercellular (granulocytic hyperplasia)- The marrow is hypercellular (granulocytic hyperplasia)- proportion >10:1 (blasts <10% in chronic phase)proportion >10:1 (blasts <10% in chronic phase)

Reticulin fibrosisReticulin fibrosis

Hyperuricemia and hyperuricosuriaHyperuricemia and hyperuricosuria

Serum vitamin B12-binding proteine and serum vitamin Serum vitamin B12-binding proteine and serum vitamin B12 levels are increasedB12 levels are increased

Pseudohyperkalemia, and spurious hypoxemia and Pseudohyperkalemia, and spurious hypoxemia and hypoglycemiahypoglycemia

Cytogenetic test-Cytogenetic test- presence of the Ph chromosome presence of the Ph chromosome

Molecular testMolecular test – presence of the BCR-ABL fusion gene – presence of the BCR-ABL fusion gene

DiagnosisDiagnosisDiagnosis is based on blood counts (leukocytosis and Diagnosis is based on blood counts (leukocytosis and frequently also thrombocytosis) and differential frequently also thrombocytosis) and differential (immature granulocytes, from the metamyelocyte to (immature granulocytes, from the metamyelocyte to the myeloblast, and basophilia). Splenomegaly is the myeloblast, and basophilia). Splenomegaly is present in >50% of cases of CML in the initial chronic present in >50% of cases of CML in the initial chronic phase, but ₃50% of patients are asymptomatic.phase, but ₃50% of patients are asymptomatic.

Proof of diagnosis is attained by demonstration of the Proof of diagnosis is attained by demonstration of the Philadelphia (Ph) chromosome (22q–) resulting from Philadelphia (Ph) chromosome (22q–) resulting from the balanced translocation t(9; 22) (q34;q11), and/or the balanced translocation t(9; 22) (q34;q11), and/or the BCR–ABL rearrangement in peripheral blood or the BCR–ABL rearrangement in peripheral blood or bone marrow cells. bone marrow cells.

Accelerated phase of CMLAccelerated phase of CML

Most patients eventually became resistant to therapy Most patients eventually became resistant to therapy and the disease enters a more agressive phaseand the disease enters a more agressive phase

Criteria of accelerated phaseCriteria of accelerated phase1.1. Blasts in blood or bone marrow-10-Blasts in blood or bone marrow-10-229%9%2.2. Basophilia Basophilia ≥≥ 20% 20%3.3. Thrombocytopenia <100G/lThrombocytopenia <100G/l4.4. Thrombocytaemia >1000G/lThrombocytaemia >1000G/l5.5. Additional chromosomal aberrationsAdditional chromosomal aberrations6.6. RRefractory splenomegalyefractory splenomegaly or refractory leucocytosis or refractory leucocytosis

BlastBlast phase phase (blast crisis) (blast crisis) of CML of CML

• Criteria of blast phaseCriteria of blast phase1.1. Blasts Blasts ≥≥330%0% in PB or BM in PB or BM2.2. extramedullary tumorsextramedullary tumors

• Phenotype of blastsPhenotype of blasts1.1. Mieloblasts - 50%Mieloblasts - 50%2.2. Limphoblasts - 30%Limphoblasts - 30%3.3. Megakarioblasts – 10%Megakarioblasts – 10%4.4. Acute myelofibrosisAcute myelofibrosis

Differential diagnosisDifferential diagnosis

Polycythemia veraPolycythemia vera

MMyelofibrosisyelofibrosis

EssentialEssential thrombocytemia thrombocytemia

Chronic myelomonocytic leukemia (Mo>1000/µl)Chronic myelomonocytic leukemia (Mo>1000/µl)

Extreme reactive leukocytosis (GAF is increased)Extreme reactive leukocytosis (GAF is increased)

Prognostic factorsPrognostic factors

Sokal scoreSokal score = = = (11= (11xx age + 35 age + 35x x spleen + 89spleen + 89xx blasts + 0,4 blasts + 0,4x x platelet – platelet –

550)/1000550)/1000

Euro scaleEuro scale = = = (0,666= (0,666xx age /0 when age <50, 1 when >/ + 0,0420 age /0 when age <50, 1 when >/ + 0,0420xx

spleen + 0,0584spleen + 0,0584xx blasts + 0,0413 blasts + 0,0413xx eosinophils + eosinophils + 0,20390,2039x x basophils /0 when basophils <3%, 1 when basophils /0 when basophils <3%, 1 when basophils >3%/ + 1,0956basophils >3%/ + 1,0956xx platelet /0 when platelet platelet /0 when platelet <15000G/l, 1 when >/) <15000G/l, 1 when >/) xx 1000 1000

Sokal EuroLow risk <0,8 <780Moderate risk 0,8-1,2 781-1479High risk >1,2 >1480

TreatmentTreatment

Imatinib mesylate (GlivecImatinib mesylate (Glivec) or other TKI-the ) or other TKI-the current standard approachcurrent standard approach

Interferon alfaInterferon alfa

Oral chemotherapeutic agents (hydroxyurea, Oral chemotherapeutic agents (hydroxyurea, busulfan)busulfan)

Allo- SCTAllo- SCT

TreatmentTreatmentAlgorithm for treating CMLAlgorithm for treating CML

DIAGNOSIS

Imatinib for all

Response to imatinib‘Failed” response

to imatinib

ContinueConsider for other TKI

or SCT

TreatmentTreatmentHydroxyurea:Hydroxyurea:

Often used initially for white cell count reductionOften used initially for white cell count reduction

It does not alter long-term prognosiIt does not alter long-term prognosiss

Interferon-alfInterferon-alfaaHematologic improvement – 75% of patients, Hematologic improvement – 75% of patients, cytogenetic remission – 10%cytogenetic remission – 10%Prolong the chronic phase of CML more likely than Prolong the chronic phase of CML more likely than hydroxyureahydroxyurea

Interferon with CytarabineInterferon with Cytarabine

Combined therapy can improve the results of Combined therapy can improve the results of treatmenttreatment

TrTreaeatmenttmentImatinib mesylate (Gleevec)Imatinib mesylate (Gleevec)

• Inhibits activity of mutant tyrosine kinase by Inhibits activity of mutant tyrosine kinase by blocking ATP bindingblocking ATP binding

• Imatinib has less toxicity, is easier to administer , Imatinib has less toxicity, is easier to administer , and induces higher hematologicand induces higher hematologic, , cytogenetic and cytogenetic and molecular types of remissionmolecular types of remission..

• Dose: 400mg/d orally (maximal dose 600-800mg/d Dose: 400mg/d orally (maximal dose 600-800mg/d in two divided doses)in two divided doses)

• Usually after 3-9 months of treatment – cytogUsually after 3-9 months of treatment – cytogeenetic netic responseresponse

Response evaluationResponse evaluation

Time:Time: Optimal response:Optimal response:

3 Months3 Months CHRCHR

6 Months6 Months ‡ ‡ PCgRPCgR

12 Months12 Months CCgRCCgR

18 Months18 Months ‡ ‡ MMolRMMolR

AnytimeAnytime No response lossNo response loss

Criteria of cytogenetic responseCriteria of cytogenetic response

Cytogenetic Cytogenetic responseresponse

% of Ph in bone marrow% of Ph in bone marrow

completecomplete 00

maiormaior 1-351-35

minorminor 36-9536-95

lack of responselack of response >95>95

Criteria of molecular responseCriteria of molecular response

Complete molecular response: Complete molecular response:

BCR/ABL transcript undetectable in PCRBCR/ABL transcript undetectable in PCR

Maior molecular response:Maior molecular response:

≥≥3-log reduction of BCR/ABL transcript in RQ-PCR3-log reduction of BCR/ABL transcript in RQ-PCR

Aditional TAditional Treatmentreatment

Splenic radiation- useful in marked splenomegaly and Splenic radiation- useful in marked splenomegaly and splenic pain (marked splenomegaly usully asociated splenic pain (marked splenomegaly usully asociated with acute transformation of the disease)with acute transformation of the disease)

Splenectomy- Splenectomy- can be can be helpful in patient with helpful in patient with thrombocytopenia and massive splenomegaly thrombocytopenia and massive splenomegaly refractory to therapy (postoperative complications)refractory to therapy (postoperative complications)

Radiotherapy for extramedullary granulocytic tumorsRadiotherapy for extramedullary granulocytic tumors

Leukapheresis – useful in patients in early pregnancyLeukapheresis – useful in patients in early pregnancy

Treatment of patients with Treatment of patients with blast crisis blast crisis ((AML phenotypeAML phenotype))

Start with Imatinib 600mg/d.Start with Imatinib 600mg/d.

If remission develops consider allogeneic stem If remission develops consider allogeneic stem cell transplantcell transplant

If relapse on Imatinib therapy consider an AML If relapse on Imatinib therapy consider an AML drug protocol depending on patientdrug protocol depending on patient´s age and ´s age and conditioncondition

Treatment of patients with Treatment of patients with blast crisis blast crisis ((ALL phenotypeALL phenotype))

Start with Imatinib 600mg/d orally- maximal Start with Imatinib 600mg/d orally- maximal dose 400mg twice a day. If remission develops dose 400mg twice a day. If remission develops consider allogeneic consider allogeneic SCT.SCT.

If relapse after If relapse after IImatinib consider ALL drug matinib consider ALL drug protocoprotocoll

1/31/3 of patiens reenter the chronic phase, but of patiens reenter the chronic phase, but remission lasts usually about 4 monthsremission lasts usually about 4 months

• Allogeneic stem cell transplantation can Allogeneic stem cell transplantation can prolong remission in blasts crisisprolong remission in blasts crisis