Chronic Myloid Leukemia

Give me one word about CML?

Reverse transcription polymerase Fluorescence in situ

chain reaction (RT-PCR) hybridization analysis
(FISH)
splenomegaly
also known as
Absolute basophilia is
chronic myelocytic, CML has
a universal finding in
the blood smears chronic myelogenous, or a triphasic or

Allogeneic stem chronic granulocytic leukemia biphasic clinical courses

cell transplants
TKI
A myeloproliferative neoplasm
characterized by the dysregulated production&
uncontrolled proliferation of mature and maturing granulocytes
with fairly normal differentiation.

Philadelphia (Ph) chromosome A reciprocal translocation BCR-ABL1 fusion protein

 Objectives

1-Biology

2-History

3-Epidemiology

4-Pathohysiology

5-Diagnosis

6-Current treatment approaches

 Biology

Hematopoiesis: Blood cell Lineages

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

bone marrow

Stem cells --- capable of

• Self-renewal
• Differentiation

Proliferation and differentiation

controlled by molecular signals

Granulocytes----expand to CML
 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
 A Long Story with a Happy End ?

John described Case of Hypertrophy of the Spleen and Liver

1845
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
1872 leukemia originated in the bone marrow.

Arsenicals had been in use for this cancer

1882 In the Lancet 'a patient with the clinical presentation
of CML who achieved a partial response to arsenicals'
 A Long Story with a Happy End ?

1982 The introduction of interferon-α. interferon-α led to complete

cytogenetic responses only in a subset of patients.

TKIs have altered the landscape of therapy

TKI "Imatinib" Revolution in therapy

1990 “The magic bullet” to cure cancer by TIME magazine

2001-FDA approves Gleevec for adults

2003-FDA approves Gleevec for children

2006
Nilotinib Dasatinib Bosutinib Ponatinib
A second generation of Bcr-Abl TKI was subsequently
developed to combat the initial resistance that emerged
 A Long Story with a Happy End ?

Summary
1982 The introduction of interferon-α. interferon-α led to complete
cytogenetic responses only in a subset of patients.

TKIs have altered the landscape of therapy

TKI "Imatinib"
1990 Revolution in therapy

2001-FDA approves Gleevec for adults

Nilotinib
“The Dasatinib
magic bullet” Bosutinib
to cure cancer Ponatinib
by TIME magazine
2006 A second generation of Bcr-Abl TKI was subsequently
2003-FDA approves Gleevec for children
developed to combat the initial resistance that emerged
 Epidemiology

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".

 Pathohysiology
11 X 3

• Reciprocal Translocation between chromosome 9 and 22

1
• Detected in 95% of patients with CML

Fusion between the Abelson (Abl) tyrosine

kinase gene at chromosome 9 and the break
2
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
3
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
1 X 3

IS THERE CML without Ph chromosome ???

1 Detected in 5-10% of patients with CML.
 Due to additional translocation masking Ph chromosome or
2
 Due to Break of 9q without reciprocal break 22q.
3 30 % has trisomy 8

IS THERE other chromosomal translocations in CML???

1
 Complex karytyping 3%
2 Translocation not involving 9q 3%

3 Additional karyotyping abnormalities 3


Trisomy 8 2nd Ph chrom Iso chro 17 q

 Pathohysiology
1 X 3

IS THERE ALL with Ph chromosome ???

1 Detected in 3-10% of pediatric ALL.

2 Detected in 25-35% adult ALL.

3 Poor porgnosis.
1 2 3

Favourable group Intermediate group Poor group

1-Age < 10 Y, > 10 Y, or Any age,

2-TLC <50.000 50.000 >100.000

-100.000
3-EFS 50% 30% 20%
 Pathohysiology

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

CML (blastic) ALL (Ph +ve)

1- basophiles > <

2- spleen > <

3- Cytogentic additional no

4- Product protein P 210 p 190

5- BM post TTT ph persist ph revert to N

 Pathohysiology

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

CML (chronic) JMML

1-age usually >2 Y usually <2 Y

2- Ph chromosome +ve -ve

3-spleenomegally > <

4-monocytes < >

 Pathohysiology

For interaction Carries the tyrosine kinase function

with other It is tightly regulated under
proteins. physiologic conditions.

inhibitory process

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.
 Pathohysiology
1 X 3

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
1 X 3

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.

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

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)
 Pathohysiology

inhibitory process

carries the tyrosine

kinase function

Abl tyrosine kinase activity is tightly regulated under physiologic conditions.

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

 Pathohysiology

inhibitory process

X
Abi-1
carries the tyrosine
Abi-2 kinase function

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.

• 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

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).
 Pathohysiology

1 X 3

Increase proliferation &

cytokine-independent
growth
Altered Adhesion
CML
CML
CML
Progenitor
CML
Progenitor
β1-integrins
β-integrins CML
-ve

• Adhesion to stroma negatively regulates cell proliferation.

• An important role for β-integrins in the interaction between stroma
and progenitor cells.

• 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.
 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

Thrombocytosis
Priapism
 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)
• The disease suspected from examination (spleenomegally).
• The disease suspected from routine blood tests

• 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}.

• 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.
 CML: Peripheral Blood Smear

Normal Chronic phase CML

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

 CBC, LDH LFT, KFT,
electrolytes

Routine tests
BMA

P/A US
CXR
Routine tests
•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.
CBC •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.

Chemistry
Risk for tumor lysis syndrome

P/A U/S Organomegally mainly spleenomegally

BMA Bone marrow aspiration demonstrates granulocytic

hyperplasia.
 When u suspect CML
The "gold
"the typical findings in the blood and bone marrow" standard" for
the diagnosis
U should confirm by molecular dettection of T (9:22)

• The majority of patients (90 to 95 %) demonstrate the t(9;22)

(q34;q11.2) reciprocal translocation.
Diagnostic
•
criteria
The remaining minority have variant translocations
BMA such as complex
Genetic testing for the Philadelphia chromosome, the BCR-ABL1 fusion gene
translocations involving other chromosome (eg, t(9;14;22)).
or the fusion mRNA gene product is done by
• The rest have cryptic translocations of 9q34 and 22q11.2 that
 conventional cytogenetic analysis (karyotyping),
cannot be identified by routine cytogenetics. These are referred to
 fluorescence in situ hybridization (FISH) analysis,or
CXR by
as "Ph-negative".
 reverse transcription polymerase chain reaction (RT-PCR).
Ph chromsome 1 X 3

Chronic phase: Hyper prolipheration ↑ production of nature

of hematopoeitic cells.

• 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.
Ph chromsome 1 X 3

Chronic phase: Hyper prolipheration ↑ production of nature

of hematopoeitic cells.

Accelerated phase: Progressive maturation defect→AL-like.

• It ocures in 50% of patients.

• Uncommen in 1st 3 years.
• Usually lymphoblastic morphology.
Ph chromsome 1 X 3

Chronic phase: Hyper prolipheration ↑ production of nature

of hematopoeitic cells.

Accelerated phase: Progressive maturation defect→AL-like.

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

10-19% ≥ 20%
Blast < 10%
blood or marrow blood or marrow

Basophiles ↑ ≥20% blood

Large foci or
Persistent ↓ clusters of blasts
Platletes Normal or ↑ (<100 X 109/L) in BMB biopsy
unrelated to therapy

WBCS ↑ ↑

↑
Spleen size ↑
unresponsive to TTT Extramedullary
blast proliferation
apart from spleen
Ph CCA/Ph1 on treatment
ELN criteria Chronic Accelerated Blast crisis

15-29% ≥ 20%
Blast < 10%
blood or marrow blood or marrow

Basophiles ↑ ≥20% blood

Large foci or
clusters of blasts
Persistent ↓ in BMB biopsy
Platletes Normal or ↑ (<100 X 109/L)
unrelated to therapy

WBCS ↑ ↑

Extramedullary
↑
Spleen size ↑ blast proliferation
unresponsive to TTT
apart from spleen
Ph CCA/Ph1 on treatment
Treatment options Initial treatment Monitionring response

Summary & recommendation

1845 1974
1
Potential cure with
1975 allogeneic hematopoietic
cell transplantation (HCT)
2
Disease control without
cure using (TKIs)
1990
3
Palliative therapy with cytotoxic agents
The only option for cure is allogeneic hematopoietic stem cell
transplantation (HCT)

Disease phase at the time of HCT is the most

important prognostic factor for survival following
allogeneic HCT for CML.

The response to TKI is the most important

prognostic factor.
 IS THERE A ROLE FOR TKI before-
HCT ?

IS THERE A ROLE FOR TKI post-HCT ?

Factors influencing the choice of therapy ?

Can we discontinue TKI therapy ?

 Treatment
options
1)An HLA-matched sibling donor
2)Matched unrelated donor
3)Haploidentical donors &umbilical cord blood
A number of issues must be addressed when transplantation is considered:
Patient eligibility Age Medical comorbidities
Choice of donor Identical twin Relative (eg, sibling, parent) Unrelated
Closeness of match Matched Haploidentical Mismatched
Method of hematopoietic cell collection
BM PB Blood
Preparative regimen
Myeloablative Non myeloablative
Disease phase
The ability of allogeneic HCT to cure CML is
Disease phase at the time of HCT is the related to th the conditioning regimen and the
GVL effect of the donor lymphocytes.
most important prognostic factor for Myeloablative conditioning are preferred
whenever possible. Intravenous busulfan and
survival following allogeneic HCT for CML.
cyclophosphamide (BU/CY)
 Treatment
options

IS THERE A ROLE FOR TKI before-HCT ?

 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

 Treatment
options

IS THERE A ROLE FOR TKI POST-HCT ?

Initial studies suggest that there may be a role for imatinib maintenance therapy
after allogeneic HCT. Olavarria et al., Blood 2007

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
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).

 Treatment
Imatinib Drug information options

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

Dosing in children may be once or twice daily for (CML) and once daily for
Philadelphia chromosome–positive (Ph+) ( ALL).

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
Imatinib options
Pharmacodynamics and Pharmacokinetics
 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).
 Treatment
Imatinib Mechanism of Action options

 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.
 Treatment
Imatinib options
Adverse Reactions Significant
Gastrointestinal: Nausea, diarrhea & vomiting.

Dermatologic: Skin rash, pruritus & night sweats.

Central nervous system: Fatigue, headache.

Cardiovascular: Edema.

Hematologic & oncologic: Anemia, Neutropenia &Thrombocytopenia.

Hepatic: Increased serum transaminases,alkaline phosphatase&bilirubin.

Neuromuscular & skeletal: Muscle cramps, arthralgia & myalgia.

 Treatment
Imatinib options
Drug interactions

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

carbamazepine, phenobarbital, phenytoin, rifampin).

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.
 Treatment
Imatinib Dose adjustment options

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)
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)
 Treatment
Imatinib options
Mechanism of resistance

1- Over expressionof
MDR-1protein
(transe memberane protein)
>>efflux of drug.

2- Human organic cation

transporter (HOCT)>>>
influx of imatinib.
Polymorphism of HOCT>>>
decreased activity>>>
decrease influx
 Treatment
Dasatinib Drug information options

Dosing: Pediatric Oral: 100 mg once daily.

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.

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
Nilotinib Drug information options

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

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

Side effects:
 Fluid retension & edema
 Treatment
options

Can we discontinue TKI therapy ?

Discontinuing CML treatment is not recommended unless

part of a clinical trial (Baccarani, 2009).
 Factors influencing the choice of therapy
ALLO BMT vs TKIs ?

 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.
 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.
 Monitionring response

Definition of response to treatment

3 >2 1

Time landmarks and response criteria to TKI

3M 6M 12 M 18 M
 Monitoring response

Effectiveness of TKI therapy is determined by the achievement of landmark

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

Complete:
 WBC < 10 X103/L,
 Platelets < 450 X 109/L,
 Differential no immature granulocytes and

 Basophils <5%
 Monitoring response

Ph metaphases:
 Monitoring response

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 correspond to a decrease The term complete molecular response

should be avoided and substituted with the
100% N LOG reduction term molecularly undetectable leukemia.
10%, 1 log,

= Major molecular response (MMR)

1%, 2 log,
3 log, = Deep molecular response (MR)
4 log,
0.1%, 4.5 log,
 Monitoring response

N LOG reduction
 Monitoring response

Summary
 Monitoring response

The responses are defined as

Optimal Optimal response is associated with the best long-term outcom

Warning implies that the characteristics of the disease and the

Warning Zone response to treatment require more frequent monitoring to
permit timely changes in therapy in case of treatment failure.

Faiure The patient should receive a different treatment to limit

the risk of progression and death.

Primary Faiure Failure to achieve a given response at a given time

Secondary Faiure Loss of response

 Monitoring response

Optimal Warning Zone Faiure

NA High risk NA
Baseline Or
CCA/Ph1, major route

BCR-ABL1 ≤10% BCR-ABL1 >10% Non-CHR

3 months and/or and/or and/or
Ph1 ≤35% Ph1 36-95% Ph1 >95%

BCR-ABL1 <1% BCR-ABL1 1-10% BCR-ABL1 >10%

6 months and/or and/or and/or
Ph1 0 % Ph1 1-35% Ph1 .35%

BCR-ABL1 ≤ 0.1% BCR-ABL1 >1%

12 months and/or BCR-ABL1 > 0.1-1% and/or
Ph1 0 % Ph1 >0
 Monitoring response

At any time
Loss of CHR
Loss of CCyR
Confirmed loss of MMR
Mutations
CCA/Ph1
 Monitoring response

≥1 log reduction
and/or Ph1 ≤35%
Start with >2 log reduction
imatinib or and/or
≥ 3log reduction
nilotinib or Ph1 0 %
and/or ≥ 3log reduction
dasatinib
Ph1 0 %
1-2 log reduction
<1 log reduction
3M At any
<3---≥2 log reduction
0M 6 M
and/or Ph1 36-95% and/or12 M
time
Ph1 1-35%
<2 log reduction
Loss of CHR
and/or
Loss of CCyR
Ph1 >0
<1 log reduction Confirmed loss of
and/or MMR*
Ph1 .35% Mutations
CCA/Ph1
Non-CHR
and/or
Ph1 >95%
R
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.

R 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.

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

R
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.

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