chronic myloid leukemia overview (cml)

A Long Story with a Happy End ?

Mustafa Selim

Chronic Myloid Leukemia

Give me one word about CML?

also known as

chronic myelocytic,

chronic myelogenous, or

chronic granulocytic leukemia

A myeloproliferative neoplasm

characterized by the dysregulated production&

uncontrolled proliferation of mature and maturing granulocytes

with fairly normal differentiation.

Philadelphia (Ph) chromosome BCR-ABL1 fusion proteinA reciprocal translocation

CML has

a triphasic or

biphasic clinical courses

splenomegaly

Absolute basophilia is a universal finding in

the blood smears

Fluorescence in situ hybridization analysis

(FISH)

Reverse transcription polymerase chain reaction (RT-PCR)

Allogeneic stem cell transplants

TKI

ObjectivesObjectives

1-Biology

2-History

3-Epidemiology

4-Pathohysiology

5-Diagnosis

6-Current treatment approaches

Hematopoiesis: Blood cell Lineages

Hematopoiesis: process by which blood-cell lineages are produced by bone marrow

Granulocytes----expand to CML

Stem cells --- capable of • Self-renewal • Differentiation

Proliferation and differentiationcontrolled by molecular signals

Biology

• Cancer of blood cells.

• Involves acquistion of growth

advantage by single cell.

•Uncontrolled growth results in

expansion of clonal population of cells.

•Neoplastic transformations initiated by

Point mutation

Chromosolmal loss, dupllication, or

inapproprite recombination.

Loss of expression of a gene that inhibits

cell proliferation or promotes apoptosis.

Biology

• Leukemia classified according to: Cell linage (myloid or lymphoid) Degree of terminal differentiation

• Acute (eg AML, ALL) Primitive progenitor cell with limited capacity for further maturation. Evolves rapidally, requires prompt intervention

• Chronic (eg, CML) Primitive progenitor cell with capacity for further maturation Generally progresses in indolent manner

Biology


John described Case of Hypertrophy of the Spleen and Liver

While Bennett thought that the disease represented an infection

Virchow recognized its cancerous nature and described it “leukemia.”

The next big step came, when Ernst Neumann recognized that leukemia originated in the bone marrow.

1845

1872

Arsenicals had been in use for this cancerIn the Lancet 'a patient with the clinical presentation

of CML who achieved a partial response to arsenicals'1882


The introduction of interferon-α. interferon-α led to complete cytogenetic responses only in a subset of patients.

1982

1990

Revolution in therapy

“The magic bullet” to cure cancer by TIME magazine

TKI "Imatinib"

A second generation of Bcr-Abl TKI was subsequently developed to combat the initial resistance that emerged

Nilotinib Dasatinib Bosutinib Ponatinib

TKIs have altered the landscape of therapy

2003-FDA approves Gleevec for children

2006

2001-FDA approves Gleevec for adults


The introduction of interferon-α. interferon-α led to complete cytogenetic responses only in a subset of patients.

1982

Revolution in therapy1990

“The magic bullet” to cure cancer by TIME magazine

TKI "Imatinib"

A second generation of Bcr-Abl TKI was subsequently developed to combat the initial resistance that emerged

Nilotinib Dasatinib Bosutinib Ponatinib

TKIs have altered the landscape of therapy

2003-FDA approves Gleevec for children2006

2001-FDA approves Gleevec for adults

Summary

CML accounts for 15-20% of all adult leukaemias

1-2 cases /100,000 population {adults}

1-2 cases /million population <19 years

Ocuurs slightly more in men than women {1.4-2.2:1}

The average age diagnosis “55-60 years".

Epidemiology

• Reciprocal Translocation between chromosome 9 and 22• Detected in 95% of patients with CML

Fusion between the Abelson (Abl) tyrosine kinase gene at chromosome 9 and the break point cluster (Bcr) gene at chromosome 22, resulting in a chimeric oncogene (Bcr-Abl)

Results in the formation of the BCR-ABL1 fusion protein. This protein product includes an enzymatic domain from the normal ABL1 with tyrosine kinase catalytic activity.

A constitutively active Bcr-Abl tyrosine kinase that has been implicated in the pathogenesis of CML

Pathohysiology

11 33X

11

33

22

11

Detected in 5-10% of patients with CML.Due to additional translocation masking Ph chromosome or

Due to Break of 9q without reciprocal break 22q.

30 % has trisomy 8

Complex karytyping 3%

Translocation not involving 9q 3%

Additional karyotyping abnormalities 3

Pathohysiology

IS THERE CML without Ph chromosome ???

IS THERE other chromosomal translocations in CML???

2nd Ph chrom2nd Ph chromTrisomy 8Trisomy 8 Iso chro 17 qIso chro 17 q

3311 X

11

33

11

22

33

22

Detected in 3-10% of pediatric ALL.

Detected in 25-35% adult ALL.

Poor porgnosis.

Pathohysiology

IS THERE ALL with Ph chromosome ???

Favourable groupFavourable group Intermediate groupIntermediate group

3311 X

11

33

11

22

3322

Poor groupPoor group

< 10 Y,

<50.000

50%

1-Age

2-TLC

3-EFS

> 10 Y, or

50.000 -100.000

30%

Any age,

>100.000

20%

Pathohysiology

How to differentiat CML (blastic) from ALL (Ph +ve) ???

CML (blastic)CML (blastic) ALL (Ph +ve)ALL (Ph +ve)

>

>

additional

P 210

ph persist

1- basophiles

2- spleen

3- Cytogentic

4- Product protein

5- BM post TTT

<

<

no

p 190

ph revert to N

Pathohysiology

How to differentiat CML (chronic) from JMML ???

CML (chronic)CML (chronic) JMMLJMML

usually >2 Y

+ve

>

<

1-age

2- Ph chromosome

3-spleenomegally

4-monocytes

usually <2 Y

-ve

<

>

The normal Abl protein is involved in

The regulation of the cell cycle,

In the cellular response to genotoxic stress,

In the transmission of information about the cellular

environment through integrin signaling.

Carries the tyrosine kinase function It is tightly regulated under

physiologic conditions.

For interaction with other proteins.

Pathohysiology

inhibitory process

The breakpoints within the ABL gene at 9q34 can occur anywhere over a large area at its 5′ end, either upstream of the first alternative exon Ib, downstream of the second alternative exon Ia, or, more frequently, between the two.

Breakpoints within BCR localize to breakpoint cluster regions (bcr).

Pathohysiology

3311 X

1) The major breakpoint cluster region (M-bcr): In most patients with CML and in approximately one third of patients with Ph-

positive acute lymphoblastic leukemia (ALL). A 210-kilodalton weight (kd) chimeric protein (P210BCR-ABL) is derived from

this mRNA.

3) A third breakpoint cluster region (μ-bcr) Associated with the rare Ph-positive chronic neutrophilic leukemia. Giving rise to a 230-kilodalton weight (kd) fusion protein (P230BCR-ABL)

2) The minor breakpoint cluster region (m-bcr): In the remaining patients with ALL and rarely in patients with CML. The resultant mRNA is translated into a 190-kd protein (P190BCR-ABL). 5 folds higher in tyrosine kinase activity than P210

Pathohysiology

3311 X

Abl tyrosine kinase activity is tightly regulated under physiologic conditions.

inhibitory process

The SH3 domain play a critical role in this inhibitory process.

carries the tyrosine kinase function

Pathohysiology

inhibitory process

Abi-1

Abi-2

Several proteins {Abi-1 and Abi-2} have been identified that bind to the

SH3 domain & activate the inhibitory function of the SH3 domain.

On exposure of cells to oxidative stress such as ionizing radiation, this small

protein is oxidized and dissociates from Abl, whose kinase is in turn

activated.

carries the tyrosine kinase functionX

• So deletion or positional alteration SH3 domain activates the kinase.

Pathohysiology

• Most important, autophosphorylation,

• There is a marked increase of phosphotyrosine on Bcr-Abl itself,

• which creates binding sites for the SH2 domains of other proteins.

Pathohysiology

Pathohysiology

Tyrosine kinases are enzymes responsible for the activation of many proteins by signal transduction cascades.

The proteins are activated by adding a phosphate group to the protein (phosphorylation).

Increase proliferation & cytokine-independent

growth

Pathohysiology

3311 X

• Adhesion to stroma negatively regulates cell proliferation.• An important role for β-integrins in the interaction between stroma

and progenitor cells.

Progenitor

CMLCML

CML

β-integrins-ve

Progenitor

β1-integrinsCML

CML

• CML progenitor cells exhibit decreased adhesion to bone marrow stroma cells and extracellular matrix.

• CML cells express an adhesion-inhibitory variant of β1 integrin that is not found in normal progenitors.

Altered Adhesion

20 to 50 % of patients are asymptomatic

When u suspect in CML?

• The disease suspected from examination (-_-_-_-_-_-_-_-).

• The disease suspected from routine blood tests.

The symptoms of chronic myeloid leukemia (CML) are often vague and are more often caused by other things.

• Asymptomatic• Abdominal enlargment • Acute gouty arthritis

• Weakness• Weight loss

• Fatigue• Fever• Feeling full after eating even a small amount of food

• Bone pain• Night sweats• Involvement of extramedullary tissues such as the lymph nodes, skin,

and soft tissues is generally limited to patients with blast crisis.

COMPLICATIONS

TLS

Hyperleukocytosis

Thrombocytosis

Priapism

COMPLICATIONS

TLS

Hyperleukocytosis

When to treat ? If it is symptomatic or TLC >200000 or blasts>50000

How to treat ? Hydroxyurea (20-30 mg/kg/d) Leukapharesis

COMPLICATIONS

TLS

Hyperleukocytosis

Thrombocytosis

When to treat ? If persistant after treatment

How to treat ? Anagrelide (phosphodiesterase 3 inhibitor >>>decrease plat

production. Thiotepa (alkylating agent)>>>inhibit protein synthesis

COMPLICATIONS

TLS

Hyperleukocytosis

ThrombocytosisPriapism

Why it happend? Mechanical obstruction by leukemic cells. Thrombocytosis (coagulation in corpara). Pressure of spleen on abdominal veins and nerves.

How to treat ? Analgesics, hydration, hydroxyurea, warm compression +/- Radiotherapy (penis & spleen)

• A leukocytosis with a median white count of

250,000/microL.

• Anemia {normochromic, normocytic} is seen in 45

to 60 %.

• Thrombocytosis {it can be normal}.

• The disease suspected from examination (spleenomegally).

• The disease suspected from routine blood tests

• Absolute basophilia is a universal finding.

• Absolute eosinophilia is seen in about 90 % of cases.

• Absolute monocytosis (>1000/microL) is not

uncommon.Prominent monocytosis and a low neutrophil/monocyte ratio in the peripheral blood of patients with CML who have an alternate breakpoint in chromosome 22, producing a p190 BCR-ABL1 fusion protein.

Courtesy of John K. Choi, MD, PhD, University of Pennsylvania.

Normal Chronic phase CML

CML: Peripheral Blood Smear

Routine tests

CBC, LDH LFT, KFT, electrolytes

BMA

CXRP/A US

Routine tests

Bone marrow aspiration demonstrates granulocytic hyperplasia.

BMA

CBC

•A leukocytosis with a median white count of 100,000/microL.

•A normochromic, normocytic anemia is seen in 45 to 60 %.

•The platelet count can be normal or elevated.

•Platelet >600,000/microL are seen in 15 to 30 % of patients.

•Absolute basophilia is a universal finding.

•Absolute eosinophilia is seen in about 90 % of cases.

•Absolute monocytosis (>1000/microL) is not uncommon.

ChemistryRisk for tumor lysis syndrome

P/A U/S Organomegally mainly spleenomegally

Diagnostic criteria BMA

CXR

Genetic testing for the Philadelphia chromosome, the BCR-ABL1

fusion gene or the fusion mRNA gene product is done by

conventional cytogenetic analysis (karyotyping),

fluorescence in situ hybridization (FISH) analysis,or by

reverse transcription polymerase chain reaction (RT-PCR).

• The majority of patients (90 to 95 %) demonstrate the

t(9;22)(q34;q11.2) reciprocal translocation.

• The remaining minority have variant translocations such as

complex translocations involving other chromosome (eg,

t(9;14;22)).

• The rest have cryptic translocations of 9q34 and 22q11.2

that cannot be identified by routine cytogenetics. These are

referred to as "Ph-negative".

When u suspect CML

"the typical findings in the blood and bone marrow"

U should confirm by molecular dettection of T (9:22)

The "gold standard"

for the diagnosis

Chronic phase: Hyper prolipheration ↑ production of nature

of hematopoeitic cells.



3311 XPh chromsomePh chromsome

• Progression to accelerated phase or blast crisis requires the

acquisition of other chromosomal or molecular changes.

• Additional cytogenetic abnormalities develop in over 80 % of

patients, most commonly: trisomy 8, trisomy 19, duplication of the Ph chromosome, and isochromosome 17q (leading to the loss of the P53 gene on

17p).

• These can be seen singly in addition to the Ph chromosome or in

any combination.





Accelerated phase: Progressive maturation defect→AL-like.Accelerated phase: Progressive maturation defect→AL-like.


• It ocures in 50% of patients.• Uncommen in 1st 3 years.• Usually lymphoblastic

morphology.





Accelerated phase: Progressive maturation defect→AL-like.Accelerated phase: Progressive maturation defect→AL-like.

Blastic phase: Leukemic clone loses its capacity to differentiate.Blastic phase: Leukemic clone loses its capacity to differentiate.


• Myeloblastic 60-70% of patients.• Lymphoid morphology 35-40% (usually B).• If lymphoid T-cell

usually no chronic phase, marked lymph node enlargment.

These additional cytogenetic aberrations may

also be found at the time of diagnosis in

approximately 7 % of patients and are associated

with"

A lower response rate to tyrosine kinase inhibitors.

Inferior survival.

Diagnostic criteria

WHO criteria

European Leukemia Net "ELN" criteria

WHO criteria Chronic Accelerated Blast crisis

Blast < 10%10-19%

blood or marrow

≥ 20% blood or marrow

Large foci or clusters of blasts

in BMB biopsy

Basophiles ↑ ≥20% blood

Platletes Normal or ↑Persistent ↓

(<100 X 109/L)unrelated to therapy

WBCS ↑ ↑

Extramedullaryblast proliferation apart from spleen

Spleen size ↑↑

unresponsive to TTT

Ph CCA/Ph1 on treatment

ELN criteria Chronic Accelerated Blast crisis

Blast < 10%15-29%

blood or marrow

≥ 20% blood or marrow

Large foci or clusters of blasts

in BMB biopsy

Basophiles ↑ ≥20% blood

Platletes Normal or ↑Persistent ↓

(<100 X 109/L)unrelated to therapy

WBCS ↑ ↑

Extramedullaryblast proliferation apart from spleen

Spleen size ↑↑

unresponsive to TTT

Ph CCA/Ph1 on treatment

Treatment options

Monitionring responseInitial treatment

Summary & recommendation

1845 1974

1975Potential cure with

allogeneic hematopoietic cell transplantation (HCT)

1990

Disease control without cure using (TKIs)

1

3

2

Palliative therapy with cytotoxic agents

The only option for cure is allogeneic hematopoietic stem cell

transplantation (HCT)

The response to TKI is the most important prognostic factor.

Disease phase at the time of HCT is the most

important prognostic factor for survival following

allogeneic HCT for CML.

Factors influencing the choice of therapy ?

IS THERE A ROLE FOR TKI before-HCT ?

IS THERE A ROLE FOR TKI post-HCT ?

Can we discontinue TKI therapy ?

A number of issues must be addressed when transplantation is considered:

Patient eligibility

Choice of donor

Closeness of match

Method of hematopoietic cell collection

Preparative regimen

Disease phase

Age Medical comorbidities

HaploidenticalMatched

Unrelated

Mismatched

PB

Myeloablative Non myeloablative

Identical twin Relative (eg, sibling, parent)

BM Blood

Disease phase at the time of HCT is the

most important prognostic factor for

survival following allogeneic HCT for CML.

The ability of allogeneic HCT to cure CML is related to th the conditioning regimen and the GVL effect of the donor lymphocytes. Myeloablative conditioning are preferred whenever possible. Intravenous busulfan and cyclophosphamide (BU/CY)

1)An HLA-matched sibling donor

2)Matched unrelated donor

3)Haploidentical donors &umbilical cord blood

Treatment options

Treatment options

Patients who received imatinib before transplantation had

significantly lower risk of death compared with patients who did not

receive imatinib.

TKI leads to lower disease burden at time of transplantation,

decrease the likelihood of relapse after transplantation.

Lee SJ., et al 2008

IS THERE A ROLE FOR TKI before-HCT ?

Treatment options

Initial studies suggest that there may be a role for imatinib maintenance therapy

after allogeneic HCT. Olavarria et al., Blood 2007

IS THERE A ROLE FOR TKI POST-HCT ?

Chronic phase CML no benefit if a molecular remission has been achieved.

Myeloid or lymphoid blast crisis, they suggest the use of a TKI for two years

after allogeneic HCT {if tolerable}, rather than postponing its use until the

emergence of MRD positivity, especially if nonmyeloablative conditioning is

used.

Treatment options

Treatment options

It is a pharmaceutical drugs that inhibits tyrosine kinases.

Treatment options

Clinical uses

•CML & ALL (Ph+ acute lymphoblastic leukemia).

• Gastrointestinal stromal tumors (GIST).

• Aggressive systemic mastocytosis (ASM) with eosinophilia.

• Dermatofibrosarcoma protuberans (DFSP).

• Hypereosinophilic syndrome (HES) and/or chronic eosinophilic

leukemia (CEL).

• Myelodysplastic/myeloproliferative disease (MDS/MPD).

• Chordoma (progressive, advanced, or metastatic expressing

PDGFRB and/or PDGFB).

• Desmoid tumors (unresectable and/or progressive).

• Melanoma (advanced or metastatic with C-KIT mutation).

Administration: Imatinib is associated with a moderate emetic potential

antiemetics may be recommended to prevent nausea and vomiting.

(Dupuis, 2011; Roila, 2010)

Should be administered with a meal and a large glass of water.

It is not recommended to crush or chew tablets due to bitter taste.

Tablets may be dispersed in water or apple juice (using ~50 mL for

100 mg tablet,~200 mL for 400 mg tablet); stir until dissolved and

administer immediately.

Treatment optionsImatinib

Dosing: Pediatric Oral: 340 mg/m2/day;maximum: 600 mg daily.

Drug information

Dosing in children may be once or twice daily for (CML) and once daily for

Philadelphia chromosome–positive (Ph+) ( ALL).

Absorption: Rapid

Protein binding: ~95% to albumin and alpha1-acid glycoprotein.

Metabolism: Hepatic via CYP3A4.

Bioavailability: 98%; may be decreased in patients who have had

gastric surgery (eg, bypass, total or partial resection).

Half-life elimination: Adults: ~18 hours; Children: ~15 hours.

Time to peak: 2 to 4 hours

Excretion: Feces (68% primarily as metabolites, 20% as

unchanged drug); urine (13% primarily as metabolites, 5% as

unchanged drug).

ImatinibTreatment

optionsPharmacodynamics and Pharmacokinetics

Inhibits Bcr-Abl tyrosine kinase, the

constitutive abnormal gene product of

the Philadelphia chromosome in

chronic myeloid leukemia (CML).

Also inhibits tyrosine kinase for

platelet-derived growth factor (PDGF),

stem cell factor (SCF), c-Kit, and

cellular events mediated by PDGF and

SCF.

ImatinibTreatment

optionsMechanism of Action


Cardiovascular: Edema.

Adverse Reactions Significant

Gastrointestinal: Nausea, diarrhea & vomiting.

Dermatologic: Skin rash, pruritus & night sweats.

Central nervous system: Fatigue, headache.

Hematologic & oncologic: Anemia, Neutropenia &Thrombocytopenia.

Hepatic: Increased serum transaminases,alkaline phosphatase&bilirubin.

Neuromuscular & skeletal: Muscle cramps, arthralgia & myalgia.


Avoid concomitant use of strong CYP3A4 inducers (eg, dexamethasone,

carbamazepine, phenobarbital, phenytoin, rifampin).

Drug interactions

If concomitant use cannot be avoided, increase imatinib dose by at least 50% with careful monitoring.

Ibuprofen may decrease intracellular concentrations of imatinib, leading to decreased clinical response.


Dosing: Renal Impairment

• Mild impairment (CrCl 40-59 mL/minute): Maximum recommended

dose: 600 mg.

• Moderate impairment (CrCl 20-39 mL/minute): Decrease dose by

50%.

• Severe impairment (CrCl <20 mL/minute): Decrease dose by 75%.

(Gibbons, 2008)

Dose adjustment

Dosing: Hepatic Impairment

• If elevations of bilirubin >3 times ULN or transaminases >5 times ULN

occur:

Withhold treatment until bilirubin <1.5 times ULN and

transaminases <2.5 times ULN.

Resume treatment at a reduced dose (25% reduction)


1- Over expressionof

MDR-1protein

(transe memberane protein)

>>efflux of drug.

Mechanism of resistance

2- Human organic cation

transporter (HOCT)>>>

influx of imatinib.

Polymorphism of HOCT>>>

decreased activity>>>

decrease influx

Administration:

Administer once daily (morning or evening).

Swallow whole; do not break, crush, or chew tablets.

May be taken without regard to food.

If GI upset occur take with a meal or with a large glass of

water.

Treatment optionsDasatinib

Dosing: Pediatric Oral: 100 mg once daily.

Drug information

Dosing :Sprycel: 20 mg, 50 mg, 70 mg, 80 mg, 100 mg, 140 mg.

Spectrum :binds active & inactive conformation of ABL-kinase, SRC family

kinase, C-KIT & PDGFR.

Side effects:

Fluid retension & edema

Treatment optionsNilotinib

Dosing (Tasigma): Pediatric Oral: 400 mg /12 h.

Drug information

Spectrum : highly selective binding of ABL-kinase, C-KIT & PDGFR.

Discontinuing CML treatment is not recommended unless part of a clinical trial (Baccarani, 2009).

Can we discontinue TKI therapy ?

Treatment options

The phase of CML.

Vailability of a donor for HCT.

Patient age.

The presence of medical co-morbidities affecting patient suitability for

HCT.

The response to treatment with TKIs.

Factors influencing the choice of therapyALLO BMT vs TKIs ?

Initial treatment

TKIs are the initial treatment of choice for the majority of patients with

CML.

Second generation TKIs (eg, dasatinib or nilotinib) produce faster and deeper

responses than imatinib.

Careful follow-up of response is critically important to predict when other

therapies,

such as alternative TKIs or transplantation, should be considered.

Data at eight years of follow-up show that the response to imatinib have been

very durable, with very few relapses after three to four years of follow-up.

Definition of response to treatment

Time landmarks and response criteria to TKI

1>23

Monitionring response

3 M 18 M6 M 12 M

Complete:

WBC < 10 X103/L,

Platelets < 450 X 109/L,

Differential no immature granulocytes and

Basophils <5%

Effectiveness of TKI therapy is determined by the achievement of landmark

responses {hematologic, cytogenetic, and molecular} at specific time.

Monitoring response

Ph metaphases:

Monitoring response

÷ 10

Molecular response is best assessed according to the International Scale (IS)

– As the ratio of BCR-ABL1 transcripts to ABL1 transcripts, or

– Other internationally recognized control transcripts and

– It is expressed and reported as BCR-ABL1 % on a log scale.

10%, 1%, 0.1%, 0.01%, 0.0032% 0.001%.

1 log, 2 log, 3 log,4 log,4.5 log,5 log.

correspond to a decrease

100% N LOG reduction

= Major molecular response (MMR)

= Deep molecular response (MR)

The term complete molecular response should be avoided and substituted with the term molecularly undetectable leukemia.

Monitoring response

N LOG reduction

Monitoring response

Summary

Monitoring response

The responses are defined as

Optimal

Warning Zone

Faiure

Primary Faiure

Secondary Faiure

Optimal response is associated with the best long-term outcom

The patient should receive a different treatment to limit

the risk of progression and death.

Failure to achieve a given response at a given time

Loss of response

Warning implies that the characteristics of the disease and the

response to treatment require more frequent monitoring to

permit timely changes in therapy in case of treatment failure.

Monitoring response

Optimal Warning Zone Faiure

NA High risk NABaseline Or

CCA/Ph1, major route

3 months

BCR-ABL1 >10%and/or

Ph1 36-95%

BCR-ABL1 ≤10% and/or

Ph1 ≤35%

Non-CHRand/or

Ph1 >95%

6 months

BCR-ABL1 1-10%and/or

Ph1 1-35%

BCR-ABL1 <1% and/or

Ph1 0 %

BCR-ABL1 >10%and/or

Ph1 .35%

12 months

BCR-ABL1 > 0.1-1%BCR-ABL1 ≤ 0.1%

and/or Ph1 0 %

BCR-ABL1 >1%and/orPh1 >0

Monitoring response

At any time

Loss of CHR

Loss of CCyR

Confirmed loss of MMR

Mutations

CCA/Ph1

Monitoring response

0 M 3 M 6 M 12 M

≥1 log reduction and/or Ph1 ≤35%

Non-CHRand/or

Ph1 >95%

<1 log reduction and/or Ph1 36-95%

>2 log reduction and/or

Ph1 0 %

<1 log reductionand/or

Ph1 .35%

1-2 log reductionand/or

Ph1 1-35%

≥ 3log reduction and/or

Ph1 0 %

<2 log reductionand/orPh1 >0

<3---≥2 log reductionAt any time

≥ 3log reduction

Loss of CHRLoss of CCyR

Confirmed loss ofMMR*

MutationsCCA/Ph1

Start with imatinib or nilotinib or dasatinib

Monitoring response

They recommend as initial treatment --- imatinib or nilotinib,or dasatinib.

• Jeffrey R., et al Blood. 2012; recommend that front line therapy for

pediatric CML in chronic phase is TKI therapy without transplantation.

R

R

The response to TKI is the most important prognostic factor.F

In the previous versions of the ELN recommendations to the response to first line

treatment was limited to imatinib. Now they do not recommend which TKI should be

used but which response should be achieved, irrespective of the TKI that is used.

Response is assessed with :

Quantitative PCR and/or cytogenetics

At 3, 6, and 12 M.

R

In case of warning, it is recommended to repeat all tests,

cytogeneticand & molecular, more frequently, even monthly.

R

In case of treatment failure or of progression to AP or BP,

cytogenetics of marrow cell metaphases, PCR and mutational analysis

should be performed.

R

• Only in case of baseline warnings (high risk, major route CCA/Ph1)

HLA type patients and siblings should be done.

• Patients should pursue stem cell transplantation in:

Accelerated or blast crisis or

Who fail to reach landmarks on TKIs either because of intolerance

or resistance. {Jeffrey R., et al Blood. 2012}

R

R

Patients should be monitored after transplant by RQ-PCR.R

chronic myloid leukemia overview (cml)

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