Dr.Papri Nasrin

Resident phase-B

Haematology

BSMMU

Chronic myeloid leukemia:2020 update on diagnosis,therapy & monitoring

American journal of haematology

Author-Elias jabbour,Hagop

Published on-18^th march,2020

INTRODUCTION

• CML is a myeloproliferative neoplasm with an incidence of 1-2 case per 100000 adults.
• It accounts for approximately 15% newly diagnosed cases of leukemia in adults.
• The defining characteristics of CML is presence of Philadelphia chromosome and/or BCR/ABL gene in all neoplastic cells.
• It is the most common of the myeloproliferative diseases.

OBJECTIVES

• Use of each of the available TKIs.
• How to select an agent under various circumstances & phases of the disease.
• Allo-SCT is an important treatment option in CML-CP, post TKIs failure & advanced CML cases.
• Cytogenetic & molecular biomarkers for pt on therapy.
• Appropriate monitoring strategies.

PATHOGENESIS

• Central to the pathogenesis of CML is the fusion of the Abelson murine leukemia (ABL1) gene on chromosome 9 with breakpoint cluster region (BCR) gene on chromosome 22.
• This result in expression of an oncoprotein termed BCR-ABL1 is a constitutively active tyrosine kinase that promotes growth & replication through downstream signaling pathway such as RAS,RAF, JUN kinase, MYC & STAT.

Manifestations & Staging

• About 50% of patients diagnosed with CML in the united states are asymptomatic.
• The diagnosis of CML often occurs during a routine physical examination or blood tests.
• CML can be classified into 3 phases-

1.Chronic phase (CP)

2.Accelerated phase (AP)

3.Blast phase (BP)

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• 90% to 95% patients present in CML-CP.
• Common signs & symptoms of CML-CP….

Fatigue,malaise,weight loss,

Easy satiety,

Left upper quadrant fullness/pain

Thrombosis (associated with thrombocytosis or marked leukocytosis)

Gouty arthritis (elevated uric acid level)

Priapism(marked leukocytosis/Thrombocytosis)

Upper GI bleeding & ulceration

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• Splenomegaly is the most consistent physical sign.

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• CML-AP….

might be insidious/present with worsening anemia,splenomegaly & organ infiltration.

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• CML-BP….

present as an acute leukemia( myeloid 60%,lymphoid 30%,megakaryocytic/undifferentiated 10%) with worsening constitutional symptoms,bleeding,fever & infections.

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DIAGNOSIS

• The diagnosis of typical CML is simple & consists of documenting…..

1.Peripheral blood examination

2.Bone marrow examination

3.Neutrophil alkaline phosphatase

4.Cytogenetic analysis

5.BCR-ABL1 analysis

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3. NAP score: low in CML-CP & increase in CML-AP,CML-BP.

4. Cytogenetic analysis:

from peripheral blood & BM shows the Ph’ chromosome in >95% of patients .

In CML-AP –cytogenetic evidence of clonal evolution occur ( duplication of Ph’ chromose,trisomy 8,trisomy19,isochromosome 17q)

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3.BCR-ABL1 analysis: by fluorescence in situ hybridization/by molecular studies

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DIFFERENTIAL DIAGNOSIS

1. Leukamoid reaction
2. Other myeloproliferative disorders
3. Chronic neutrophilic leukemia

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Leukamoid reaction

• Can occur in infections,inflammations & non-myeloid malignancy.
• Leukocytosis is modest & shift to the left,usually upto metamyelocytes/myelocyte stages.
• Occasional blast may be seen.
• Absence of splenomegaly,basophilia.
• Toxic granules in neutrophil.
• Normal/increased NAP score.
• Ph’chromosome absent.

Chronic neutrophilic leukemia

• Rare neoplasm.
• Persistent neutrophilia in PBF without neutrophilic precursor or basophilia.
• Hepatosplemegaly common.
• Absence of Ph’chromose & BCR-ABL1 fusion gene.
• CSF3R gene mutation

TREATMENT

• Hydroxycarbamide (cytoreduction)
• Allopurinol (blunt any raise of uric acid)
• Leucapharesis ( leukostasis/priapism)
• Monotherapy with a TKI for CML-CP & CML-AP.
• TKI alone or in combination with chemotherapy for CML-BP
• Allogenic HSCT

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• Commercially available TKIs for the frontline treatment of CML include-

Imatinib,Dasatinib,Nilotinib & Bosutinib

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• Imatinib :

> 1^st FDA approved drug.

>it acts via competitive inhibition at the ATP-binding site of the BCR-ABL1 oncoprotein,which results in the inhibition of phosphorylation of proteins involved in cell signal transduction.

>it inhibits the BCR-ABL1 kinase but also blocks the PDGFR, C-KIT tyrosine kinase.

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• Most common starting dose of Imatinib is 400mg.a dose of 600mg may lead to higher molecular resposes.
• More common toxicities of Imatinib are…

GI disturbances (nausea,vomiting,anorexia,diarrhoea,dyspepsia) and edema(periorbital,facial,pedal),haematological toxicities( anemia,thrombocytopenia,neutropenia)

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• Dasatinib :

>second generation TKI & dual Src/ABL inhibitor.

>approved for treatment of CML-CP,resistant to or intolerant to atleast one prior TKI.

>Dose : 100mg daily for CP & 140mg for advanced phase.taken with or without food.

>Dasatinib is active against a range of Imatinib-resistant mutations,although inactive against T3151/A,V299L,F317V/C

>Idiosyncratically Dasatinib may cause pleural effusion,pulmonary HTN,pericardial effusion,lymph node follicular hyperplasia & peripheral blood lymphocytosis.

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• Nilotini:

>A second generation TKI.indicated for treatment of CML-CP &CML-AP,who have resistance or intolerent to atleast 1 TKI at a dose of 400mg BD.

>in addition to BCR-ABL1,also inhibits PDGFR<C-kit.

> is active against a range of Imatinib-resistant mutations except T3151,F359V/C,E255K/V,Y253H/F

>twice daily dose on an empty stomach.

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• common associated biochemical abnormalities are-raise liver enzymes,lipase,amylase,hyperbilirubinaemia.
• Although all TKIs causes prolong QT interval,the effect of Nilotinib best documented when it is taken with fatty meal.

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• Bosutinib:

A second generation TKI.indicated for treatment of CML-CP &CML-AP,who have resistance or intolerent to atleast 1 TKI.

• Administered as a single daily dose of 500mg daily.
• Common toxicities are- rash,headache,raised liver enzyme,diarrhoea,vomiting,nausea,abdominal pain.

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• Ponatinib:

A third generation TKI.

• Only drug active against T3151 mutation.
• Compound mutation especially involving the E255K/V mutation,are potentially resistant to this drug.
• Non haematological toxicities are-rash,elevated lipas,pancreatitis,headache.
• 27% of pts who have participated in early clinical studies having had either venous or arterial thrombotic events.

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TKI RESISTANCE

Treatment resistance may be encountered in 10-20% pts receiving TKIs….

1. A common mechanism of resistance involves point mutations in the kinase domain of BCR-ABL1, which impairs the activity of the available TKIs.
2. Varying degree of toxicities & intolerance
1. Before defining a pt as having TKIs resistance- compliance & drug interactions must be assed.

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• Second generation TKIs overcome most of the mutations that confer resistance to imatinib.
• Second-line treatment with Nilotinib,Dasatinib or Bosutinib can yeild high rates of response in pt who have inadequate response to Imatinib,including high rates of MMR
• One important mutation ,T3151,known as the “gatekeeper” mutation,displays resistance to all currently available TKIs except ‘Ponatinib’.

PROGNOSTIC SCORE

1. Sokal score- based on…

Age,spleen size,platelet count & percentage of blasts in blood at diagnosis.

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• Low risk= <0.8
• Intermediate risk= 0.8-1.2
• High risk= >1.2

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2. Hasford calculation-

effects of basophilia & eosinophilia at diagnosis; based on pt treated with interferon alpha.now outdated.

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3.EUTOS score

4.Early cytogenetic response to imatinib-

PCyR at 6 months,80% probability of CCyR at 2 yrs.minor/minimal CyR at 6 m-50% probability,no CCyR at 6m -15% probability

DISEASE MONITORING & RESPONSE TO TREATMENT

• Response is assesed by-

1. Haematological

2.Cytogenetic &

3.Molecular parameters

Definition of treatment response

Definition of failure, optimal, suboptimal response

When to switch therapy

• If complete haematological response do not achieve by 3 months.
• If BCR-ABL1 transcript >10% at 6 months.
• If BCR-ABL1 transcript >1% after 12 months.
• At any time loss of major molecular response,CCyR or complete haematological response.

Treatment duration & discontinuation

Advanced stage CML

• TKI monotherapy is much less effective.
• Second generation TKI should be superior to Imatinib in CML-AP.
• In CML-BP TKIs are of benefit when used prior to or in combination with chemotherapy.
• Transplant eligible pt should proceed to allogenic HSCT,once a second chronic phase has been established.
• Monotherapy with TKIs or in combination with chemotherapy may serve as a good option for those who are not candidate for HSCT or as a bridge to allo-SCT.

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Conclusions & future directions

• Most pts with CML would expected to have a normla life span though molecularly not cured.
• Future directions will focus on the potential molecular cure of CML.( achievement of durable CMR & its persistence after discontinuation of TKI therapy)
• Durable CMR can be achieved with current more potent TKIs alone or in combination with other available.( Bcl-2 inhibitors,pegylated interferon alpha2,omacetaxine,decitabine) or investigational therapies.

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