chronic myeloid leukemia hammad

8/10/2019 Chronic Myeloid Leukemia Hammad

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AGHA MUHAMMAD HAMMAD KHANHOUSE OFFICER

ONCOLOGY (WARD- 4)

Chronic Myeloid Leukemia


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Hem atop o iet ic Prog eni to rs


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Leukemias:What are Leukemias?

Neoplasm of white blood cell and itsprecursor.Clonal proliferations andaccumulation of cells in marrow.Classify as:

Acute leukemiasChronic leukemias


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Types of Leukemia

Acute : NoMaturation beyondblast

Chronic :Maturation beyondblast

Lymphocytic (B or Tlineage) ALL CLLMyeloid granulocytesErythroidsMonocytesPlatelets

AML CML


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What is CML ?Chronic Myelogenous Leukemia (CML) isdefined as,

a malignant cancer of the bone marrow.

It causes rapid growth of the blood-forming cells (known as myeloidprecursors) in the bone marrow, peripheral

blood, and body tissues.


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Epidemiology of CML Approximately 5,050 cases in the U.S. in 2009 (11%of all leukemias) with an incidence that increases

significantly with age (median age ~ 55)

Risk Factors include:

prior high dose radiation exposure exposure to certain organic solvents (benzene) age gender (male > female)

A very small percentage (< 0.1%) of individuals canexpress Bcr-Abl but not develop CML (wrong cellof origin, multiple genetic mutations leading tonon-viability, immune surveillance)


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CML Pathophysiology the Philadelphia Chromosome

CML was the firstmalignancy to be linkedto a clear geneticabnormality, thechromosomaltranslocation known asthe Philadelphiachromosome . This

chromosomalabnormality is sonamed because it wasfirst discovered anddescribed in 1960


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DIAGNOSIS


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CML Peripheral Blood and BMFindings

Peripheral smear canonly give a presumptive

1) leukocytosis with aleft shift 2) normocytic anemia. 3) thrombocytosis in50% of pts. 4) absoluteeosinophilia with anormal % of Eos. 5) absolute and relative

increase in basophils


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Bone marrowBone marrow

Hypercellular(reduced fatspaces).Myeloid:erythroidratio 10:1 to 30:1(N : 2:1).Myelocytepredominant cell,blasts less 10%.Megakaryocytesincreased &dysplastic.Increase reticulinfibrosis in 30-40%.


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Diagnosing Chronic Myeloid

Leukemia

Karyotyping in CML : ( 1-10%).

Fluorescence in-situ hybridization(FISH): ( 0.5-5%).

Quantitative RT-PCR for Bcr-Abl: ( 0.0001-0.001%)


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Diagnostic Criteria for the 3Phases of the Disease

Patients who have CML are said to be in one ofthe following three phases (in order ofoccurrence):

the chronic phase (between 1 and 15%blasts) the accelerated phase (between 15% - 30%blasts) the blast phase (more than 30% blasts).


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PHASES


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Chronic phase 85% of patients with CML are in the chronic

phase at the time of diagnosis. Asymptomatic or have only mild symptomsof fatigue, left side pain, joint and/or hippain, or abdominal fullness. myleoblast cell


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Accelerated phase Median duration is 3.5 5 yrs beforeevolving to more aggressive phases.Clinical features

Increasing splenomegaly refractory tochemoIncreasing chemotherapy requirement

Lab features: (WHO CRITERIA)1. 10 19% myeloblasts in the blood or bone

marrow.2. >20% basophils in the blood or bone marrow.

3. Platelet count 1,000,000, unresponsive to

therapy.5. Cytogenetic evolution with new

abnormalities in addition to the Philadelphia


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Blastic PhaseResembles acute leukaemia.Diagnosis requires > 30% blast in

Large clusters of blasts in the bonemarrow on biopsy .Development of a chloroma (solidfocus of leukemia outside the bonemarrow).


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Discussion with family The disease & diagnosis

Prognosis Choices of treatment

General Management


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CML - principles of treatment1. Relieve symptoms of

hyperleukocytosis, splenomegaly andthrombocytosis.

HydrationChemotherapy (bulsuphan,Hydoxyurea)

2. Control and prolong chronic phase(non-curative).alpha interferon+chemotherapyImatinib mesylateChemotherapy (hydroxyurea)


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CML - principles of treatment

3) Eradicate malignant clone(curative).

Allogeneic transplantationImatinib mesylate/STI 571(Thyrosine kinase inhibitor)


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Treatment Milestones for CML Definitions of Responses to Treatments Hematologic Response Complete Hematologic response 1) Normal PB counts (WBC < 10 and plt < 450) 2) Normal WBC differential 3) No Dz symptoms 4) Normalization of the size of the liver and spleenCytogenetic Responses : Ph + Metaphases 1) complete: 0% 2) partial: 1% - 35% 3) minor: 36% - 65%

4) minimal: 66% - 95% 5) none: 96% - 100%Molecular Responses: ratio of Bcr-Abl/Abl Major Molecular Response 3-log 10 reduction from initial diagnosis sample (i.e. 25 0.025)


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ChemotherapyBusulphan

Alkylating agentPreferred in older pts (not candidate

for transplant)Side effect :prolonged myelosuppressionPulmonary fibrosisSkin pigmentationinfertility


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ChemotherapyHydoxyures

Fewer side effectActs by inhibiting the enzyme

ribonucleotide reductaseHaematological remissions obtain in80% for both drugsHowever disease progression notaltered and persistence of Phchromosome containing clone


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ChemotherapyRecombinant human - Interferon

Prolong chronic phase and increasesurvival

Haematogical and cytogeneticremissionSide effect

Flu like symptomsFever and chillsAnorexiaDepression


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Imatinib Mesylate:Mechanism of Action

Imatinib mesylate occupies the ATPbinding pocket of the Abl kinase domainThis prevents substrate phosphorylation

and signalingA lack of signaling inhibits proliferationand survival


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Imatinib has Revolutionizedthe Treatment of CML IRIS Trial


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Imatinib Mesylate in ChronicPhase CML Following IFN- Failure: Overall Survival*

Seventy-five percent of patients remain alive

on imatinib mesylate therapy after a medianfollow-up of 45 months .Patients who received imatinib mesylate hadsignificantly improved survival rates , with anestimated 4-year survival rate of 86% vs 43%(P


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Treatment Options for ResistantDisease1) Dose Escalation of imatinib

2) Second Generation TKIs

3) Bone Marrow Transplant


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Dose Escalation of imatinibSTART-R Trial Patients resistant to 400mg-600 mg of imaitnib weretreated with either 70 mg BID of dasatinib or 800 mg of

imaitnib primary endpoint of the trial was the rate of

MCyR(major cytogenetic response )at 12 weeks andthis was equal

(D=36%; IM=29%; p = .40)

At a minimum follow-up of 2 years, dasatinibdemonstrated higher rates of: complete hematologic response (93% vs 82%; P

= .034) major cytogenetic response (MCyR) (53% vs

33%; P = .017) complete cytogenetic response (44% vs 18%; P =

.0025)

The depth of the previous response to imatinib may beassociated with the proportion of patients respondingto dose escalation. Patients having achieved a priormajor cytogenetic response (MCyR) with imatinibreported a greater than 50% chance of reachieving thatresponse with high-dose imaitnib, yet only 7% of


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Second GenerationTyrosine Kinase Inhibitors (TKIs) The FDA has approved 2 additional oral TKIs for the treatment

ofimatinib relapsed/refractory or imatinib intolerant CML

1. Dasatinib

2. Nilotinib


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Bone Marrow TransplantationAllogeneic bone marrow transplant remains the onlyknown curative option in CML

Associated with an increased morbidity and mortality.

Therefore, not typically applied for upfront therapy forCML considered only in cases of matched-related

extremely young pts (pediatrics)

However, often considered in those withrelapsed/refractory disease to TKI based therapies efficacy of the transplant dependent upon the

phase of the disease at the time of thetransplant: CP>AP>BP


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CML - prognosisMedian survival 3.5 yrs (range 2-8 yrs).Interferon + chemotherapy :6 years.Transplant : 5+ years.

Imatinib mesylate : 8.9 years.(5yr: 86%;10yr:68%).


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chronic myeloid leukemia hammad

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