Journal of Cancer Therapy, 2013, 4, 747-764
http://dx.doi.org/10.4236/jct.2013.43092 Published Online May 2013 (http://www.scirp.org/journal/jct)

747

Mexican Guidelines for the Diagnosis and Treatment ofChronic Myeloid Leukaemia
Eduardo Cervera1, Federico Godínez2, Rosa Sosa3, Ramón Rivas4, Carlos Best5, Juan Hernández6,
Adrián Morales7, Hugo Zurita8, Ivette Carrasco9, Jorge Cruz10, Álvaro Aguayo11, José Espinoza1,
Juan Labardini1, Luis Valero1, Judith Cruz1, Diana Arcos1, Diego Limón1, Omar López-Navarro1,
Daniela Gordillo-Bastidas1, Myrna Candelaria1, Francisco Torres12, Juan Kassack13,
Oscar de Jesús Pérez Ramírez14, Jorge Aquino15, Guillermo Díaz16, Mariela Cardiel17,
Margarita Rodríguez18, Patricia Montoya1, Juan Contreras1, María Chávez1, Sandra Chávez1,
David Gómez19, Olga Cantú19, Jorge Duque20, Luis Pita21, Eduardo Lobato22, Julio López23,
Antonio López24, Pedro González25, Jorge Cortés26
1

Haematology Department, Cancerology National Institute (INCan), Mexico City, Mexico; 2Internal Medicine, Haematology, Hospital
ISSSTECALI, Tijuana, Mexico; 3Haematology Department, General Hospital of Sonora State, Sonora, Mexico; 4Haematology Department,
Blood Bank and Unit of Aphaeresis, General Hospital of Culiacán, Health Ministry, Culiacán, Mexico; 5Haematology, Hospital General de
Occidente SSA, Guadalajara, Mexico; 6Haematology, Haematology Service, Hospital General Regional SSG, León, Mexico; 7Haematology,
Oncology Unit, SSEP, Puebla, Mexico; 8Haematology Department, Bone Marrow Transplant, and Blood Bank from Hospital Regional de
Alta Especialidad “Dr. Juan Graham Casassus”, Villahermosa, Mexico; 9Haematology, Hospital General de Especialidades, Campeche,
Mexico; 10Haematology Deparment from Hospital Juárez, Mexico City, Mexico; 11Haematology and Oncology Department, National Institute of Medical and Nutrition Sciences “Dr. Salvador Zubirán”, Mexico City, Mexico; 12Haematology, Hospital “Aranda de la Parra”, León,
Mexico; 13Haematology, Hospital General de México, Mexico City, Mexico; 14Haematology, Head of Haematology Service, School of
Medicine, Autonomous University of San Luis Potosí, San Luis Potosí, Mexico; 15Haematology, Hospital Regional de Alta Especialidad deOaxaca, Oaxaca, Mexico; 16Leukaemias Clinic at ISSEMyM, Toluca, Mexico; 17Haematology Department, Centenario Hospital, MiguelHidalgo, Health Ministry, Aguascalientes, Mexico; 18Haematology, Mérida Clinic, Yucatán, Mexico; 19Haematology Department, Hospital
Universitario UANL, Monterrey, Mexico; 20State Council for AIDS Prevention and Control, Chihuahua, Mexico; 21Renaissance Clinic, Morelia, Mexico; 22Hospital Betania, Puebla, Mexico; 23Los Mochis General Hospital, Sinaloa, Mexico; 24Hospital of the Poblano Child, Puebla,
Mexico; 25Universidad Autónoma de Yucatán, Mérida, Mexico; 26Leukemia Department, MD Anderson Cancer Center, Houston, Mexico.
Email: eduardocerverahematol@yahoo.com.mx, eduardocer@yahoo.com
Received December 29th, 2012; revised January 31st, 2013; accepted February 8th, 2013
Copyright © 2013 Eduardo Cervera et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

ABSTRACT
Background: This document includes recommendations and guidelines issued by a group of Mexican researchers andspecialists gathered in the First National Colloquium for the Diagnosis and Management of Chronic Myeloid Leukaemia (CML) by initiative of Instituto Nacional de Cancerología and with the support of the Leukaemia Department of the
MD Anderson Cancer Center. Mexico lacks of updated information taken from its own reality on the diagnosis andtreatment of CML and other haematological disorders; besides, there are no national guidelines. Aim: To publish aconsensus document with guidelines for the management of CML adjusted to the national environment and overallcharacteristics. Method: The participants answered a DELPHI questionnaire about the overall aspects of the disease,aiming to target controversial topics, discuss them in the colloquium, and to agree on the best ones. After those meetings, a final document was drawn up. Results: The group presents recommendations for definition, diagnosis, prognosis,
monitoring, and treatment of CML in Mexico. Conclusions: Having consensus guidelines for the clinical managementof CML in our country will enable the consensual practice of Mexican specialists regarding the clinical approach to
CML, as well as optimize the resources which allow the rational planning of the medical care strategies.
Keywords: Chronic Myeloid Leukaemia; Management Guidelines; Diagnosis; Treatment.

1. Introduction
Chronic Myeloid Leukaemia (CML) is a clonal and
Copyright © 2013 SciRes.

myeloproliferative expansion of the transformed haematopoietic stem cells. Such expansion includes the myeloid stem cells lineage, and others. The CML was the
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Mexican Guidelines for the Diagnosis and Treatment of Chronic Myeloid Leukaemia

first human disease related to a genetic disorder (Philadelphia chromosome, Ph chromosome and/or Ph+ chromosome [positive]). The most reliable incidence statistics
may be the American one, which reports 1 to 2 cases of
CML per 100 thousand people every year. This disease
stands for 15% of leukaemias among adults [1]. Mexicolacks of a reliable incidence rate, although such leukaemia is regarded as the most treated one. In Mexico, CML
seems to appear earlier—between 37 and 40 years old—than in Caucasian populations, where it is frequent tofind among adults in their 66 years old [2].
The CML classification proposed by the World HealthOrganization is functional; nevertheless, other classifications are used. Such classifications are based on clinical
trials findings with tyrosine kinases inhibitors (TKI),
particularly with imatinib mesylate which has proven tobe effective in the treatment of a sound proportion ofpatients with CML. The classification based on experience with imatinib is much more operationally objective
and supports proper updated expectations for every stageof the disease [3]. Recently, European Leukemia Net(ELN) used this classification system to group the disease within the context of its guidelines for the treatmentof the CML [4].
The international recommendations about CML may
be applied to Mexico, but there are characteristics which
demand local guidelines. At diagnosis, it is recommended to show the presence of Ph+ and/or the BCR/ABL transcript. The methods which may be used are
karyotype, FISH (Fluorescence in situ hibridization), andqRT-QRT-PCR (quantitative real time polymerase chain
reaction). Nevertheless, there is disagreement on performing them when they are used to diagnose and in thefollow-up. It is recommended to classify the patients witha Sokal score.
Imatinib is the first line treatment in patients in chronic
phase. Dasatinib and nilotinib should also be considered
as effective first line treatment. Choosing TKI as thefront-line treatment for CML in chronic phase must be adecision taken according to age, risk disease, comorbidity, security profile, cost, and availability [5].
When treatment with imatinib fails or the patient does
not tolerate it, second line treatment includes nilotinib or
dasatinib. When the outcome is suboptimal or nilotinib
and dasatinib are not available, alternative doses ofimatinib are 600 mg or 800 mg. The stem cell transplantation (SCT) is a second or third line treatment when
there is resistance to second generation TKIs. The accelerated or blastic phases must be treated with TKI plus
chemotherapy and SCT.
There are definitions of haematological, cytogenetic,
and molecular outcomes which may be accomplished ina pre-established period of time to reach the best outcome to treatment. It is not recommended to frequently
Copyright © 2013 SciRes.

determine mutations or serum levels of TKI [6,7].

MethodThe most important bibliography was analyzed; including
the latest versions (when this document was being drawing up) of the most followed recommendations aroundthe world: the European Leukemia Net (ELN) [1] and the
National Comprehensive Cancer Network (NCCN) [2].
A group of experts in diagnosis and treatment of CML
was chosen to represent a certain geographical area,
among entire Mexico. They were distributed in 5 teams
as follows:
1) Epidemiology and natural history of CML;
2) Diagnosis and follow-up;
3) Management in first and second lines;
4) Transplantation;5) Management in blastic and accelerated phases.
A coordinator was assigned for every topic. The coordinators’ duties consisted of giving bibliography to theirgroups, moderate team work during the session; monitor
members meet the programme deadlines, and name asecretary who will properly draw up the conclusions of
the team discussion during the colloquium. Delphi questionnaires were developed for groups 2, 3, and 5 with the
purpose of reaching a consensus on controversial issues
which will be discussed by the group. The clinical trials,
laboratories and reference institutions were analysed. For
the main recommendations proposed, a GRADE classification is provided to identify the level and the scope ofthe sentences.

2. Epidemiology and Natural History of
CML
The American reported incidence of CML is 1 to 2 cases/
100,000/year, which stands for 15% of the leukaemias inadults [7]. Mexico lacks of information about this disease;nevertheless, chronic leukaemia is the most frequent diagnosis in clinical practice. Most of the cases (86%) arediagnosed in chronic phase, 7% in accelerated phase, and
7% in the blastic one. Likewise, median age at diagnosis
is different from the age in Caucasian countries—medianage is 66 years old (SEER) [8]—mainly between 37 and40 years old [9-11]. Therefore, this indicates the diseaseaffects the most economically productive population.
Even though prevalence of CML has not been definedaltogether, in 2008 Corn informed that in the North ofFrance the prevalence increased 4.1% annually from1998 to 2002; and 9.3% from 2003 to 2007. This rise
responds to the administration of imatinib therapy, which
in turn had an effect on patients’ survival. This is somehow similar with moderate therapies based in TKI in
Mexico and the rest of the world [12]. The most common
findings are anaemia, haemorrhage, fever, splenomegaly,JCTMexican Guidelines for the Diagnosis and Treatment of Chronic Myeloid Leukaemia

and hepatomegaly. Only 20% of the patients is asymptomatic; thus, it seems that in Mexico there are more patients with high Sokal risk, compared with the information obtained in USA and Europe [9]. The disease ischaracterized by a natural triphasic or biphasic course[10]. Before the management with TKIs, survival inchronic phase was estimated in 3 to 5 years; the accelerated one in less than a year; and the blastic one in 3 to 6
months [13].

2.1. CML Phases and Definitions
The existing criteria for distinguishing every phase of thedisease are rather different and are divided into: WHOclassification system and the classification based onclinical trials with TKIs. The difference is so critical that
it is likely to reclassify the cases using one or the othersystem [14]. In this document, we recommend the system
based in clinical trials with imatinib because it is much
more objective, easy to find, and reflects the pathologicalclinical status of CML; besides, it is supported by prospective clinical trials with the current therapy whichallow the establishment of expectations for every phase.
Recently, ELN applied this classification system inorder to group the disease according to the recommendations for the management of CML (Table 1 [15]) [16].

2.2. Physiopathology (Molecular Biology)
On the whole, the diagnosis of CML is based on theidentification of the Philadelphia chromosome. This abnormality was described in 1960 as a short chromosome
22; then, in 1973 as a translocation t(9;22) [17], which ispresent in 95% of the patients [18].
The increase in expression of BCR/ABL1 is related tothe disease progress to an accelerated phase. Although
this is not well-understood, it may derive in mechanisms
which favour the expansion of differentiated leukaemia
cells. The over expression and /or activation of genes andmetabolic pathways as SFK, HCK, LYN y FYN have749

been associated with progression of CML and resistanceto imatinib. The consequence of BCR/ABL1 is a DNA
chronic oxidative damage, cell cycle arrest at phases S
and G2/M, which enables mutagenesis. About 80% of
the patients with CML develops cytogenetic aberrations(non-randomized in positive Ph), known as clonal evolution, which imply a genetic instability and characterised
the transition to advance phases. One of the most common mutations, related to progression on CML, includes
the p53 tumour-suppressor gene and is present in 25% 30% of the patients with myeloid blastic phase [19-31].

2.3. Molecular Biology
CML is characterised by the presence of the Philadelphia
chromosome, which is a shortening of the chromosome
22 and product of a translocation t(9;22) (q34;q11). Suchtranslocation adds a region 3’ of the ABL gene in the
9q34 chromosome to the region 5’ of the BCR gene in
the q11 region in the chromosome 22. Consequently, ahybrid gene BCR/ABL1is created and transcribed in achimeric mRNA (BCR/ABL1) which encodes a tyrosine
kinase-like protein.
The breakpoints of the ABL gene are located at exons a2
to 11, while the ones in the BCR are in exons 12 and 16(exon b1 to exon b5). Depending on the breakpoints involved, there will be 4 different variables: a1a2, b2a2, b3a2,
and e19a2, closely related to CML (Figure 1 [32]) [16].
ABL gene has a binding domain to DNA and a Y-Cinase domain, while BCR gene contains an autophosphorylation domain. When the fusion BCR/ABL1 takes
place, the result is a tyrosine kinase-like protein type Cwith autophosphorylation capacity, which enables survival and cell proliferation signals (Figure 2[33]) [16].
As a consequence of a high tyrosine kinase activity,
protein BCR/ABL1 may phosphorylate several substrates
which will activate different signaling pathways and affect the cell growth and differentiation. These substrates
include CRKL, p62Dok, paxiline, CBL, and RIN which
activate pathways involving RAS, RAF, P13K, AKT,

Table 1. Clinical phases of Chronic Myeloid Leukaemia[Adapted from 15].
Accelerated phase
Blasts in peripheral blood orbone marrow 15 to 29%
Summation of blasts plus
promyelocytes in peripheral
blood or bone marrow > 30%,
but with blasts cells < 30%
Basophiles in peripheral blood≥ 20%

Blastic phase

Chronic phase

Blasts in peripheral
blood or bonemarrow ≥ 30 orextramedullary
infiltrates of
blasts cells

The chronic
phase definition
implies thatnone of thecriteria for
accelerated
and blastic
phases aremet.

Persistent thrombocytopenia(platelets < 100,000),
not related with treatment

Figure 1. Breakpoints of the ABL gene [Adapted from 32].

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Mexican Guidelines for the Diagnosis and Treatment of Chronic Myeloid Leukaemia

Figure 2. Survival and cellular proliferation signalling pathways promotion [Adapted from 33].

JUN kinase, MYC, and STAT. Such pathways have notbeen well-defined; nevertheless, it is known that BCR/ABL1 activates the same signaling pathways, which are
triggered by cytosines and control the growth and differentiation of normal hematopoietic cells.
Unlike other fusion oncogenes, which are associated tohuman leukaemia (MLL-ELN or MOZ-TIF2), BCR/ABL1
may transform hematopoietic stem cells (HSC), but it is
not enough to transform the compromised myeloid progenitors when there is a lack of self-renewal capacity.
In CML, the leukaemic stem cells (CD34+, CD38-Lin-)
express high levels of transcripts BCR/ABL1. During thetransition from chronic phase to the blastic one, leukaemic
stem cells acquire genetic and/or epigenetic abnormalities which lengthen survival, resistance to a programmed
death, and a more extended replication.
These data suggest that the blastic phase may be theproduct of genetic alterations inside the progenitor hematopoietic cell lineage, which gives self-renewal properties [34-36].

3. CML Diagnosis and Prognosis
3.1. Disease Progression
Acquiring additional chromosomal changes is related tothe accelerated and blastic phases of the disease. They include monosomy of chromosome 7, translocation (3;21),extra copies to the translocation (9;22), trisomy of chromosome Y, and abnormalities of chromosome 17, among
others.
Recent clinical trials have suggested a prognostic importance at the loss of the chromosomal region which
derives from the long arm of chromosome 9q. Patientswith losses at breakpoints in this chromosome have amore aggressive disease, with a fast development to a
blastic crisis; nevertheless, imaninib treatment reduces
the prognostic importance of this abnormality [16]. Abnormalities in chromosome 17 are the result of mutations
at p53, which have been found only in the blastic myeCopyright © 2013 SciRes.

loid crisis.
The progressive fibrosis of bone marrow is associatedwith transformation and may produce progressive bonemarrow failure. It has been informed that bone marrow
fibrosis, at diagnosis and confirmed by means of reticulin
staining, is severe in 40% of the cases and is usually associated with a poor prognosis [37]. Nevertheless, in theimatinib era, the importance of fibrosis—as prognosis—
has decreased.
As a rule, the most common cause of death is thetransformation to the accelerated or blastic phase. In theaccelerated phase, citopenias may develop and, in turn,cause much more morbidity, but the main cause of deathis the transformation to the blastic phase: 50% of thepatients present a myeloid blastic crisis, 25% have alymphoid phenotype, and 25% have a not well-differentiated phenotype.
The CML diagnosis should be establish by means ofrecognition of Ph positive or the rearrangement of BCR/ABL.
It is recommended that the presence of Ph positive
and/or BCR/ABL transcript must be identified in every
patient with clinical suspicion of CML.
Category of evidence: A Recommendation grade: 1.

3.2. Methods
The methods used to diagnose are karyotype, FISH, and
QRT-PCR. Recommendations to use these methods may
differ according to the moment they are performed: at
diagnosis or in the follow-up.
Karyotype. The main advantage of karyotype is that it
enables the identification of cytogenetic alterations,besides the Ph positive, which influence prognosis. It is
recommended to:Go to certified laboratories with experience in
cytogenetics protocols for oncological diseases.
Preferably, this test should be performed in bonemarrow with 10% of sodium heparin or lithium heparin, and keep the sample at room temperature.

The laboratory must receive the sample optimally inthe first 24 hours after being drawn, with a minimum
volume of 2 ml.

The test must include, at least, 20 analyzable metaphases. When positivity is confirmed, two outstanding
cytogeneticists must review it independently. Images
must be printed or kept in an electronic format for
future reference.

Some treatments, like interferon, may alter the cellproliferation and decrease the number of analyzable
metaphases; thus, it is suggested to perform the test
before administering a cytoreductive treatment or
wait for a “washing” period, at least one week
before the test is carried out again. This does notJCTMexican Guidelines for the Diagnosis and Treatment of Chronic Myeloid Leukaemia

happen with TKI. At the moment of performing thetest, the patient must indicate if she or he receives adrug which may alter the results. The report must be
drawn up according to the recommendations of theinternational system of human cytogenetic nomenclature 2009 (ISCN 2009) [1].

In patients with secondary myelofibrosis, it isrecommended to collect the sample and use FISH
test to identify the fusion gene BCR/ABL.
FISH. It is the only test which identifies loss of derivative 9; however, it does not detect associated cytogenetic
alterations. It may give false positives between 1% and10%, depending on the used probe. It is performed ininterphase cells (FISH-I); thus, it is not necessary that thecells be in metaphase.
It is recommended at diagnosis when the karyotype
is not an option because of an absence or poor quality of the test.
It may be successfully performed in peripheral
blood, even if the patient is receiving an antileukaemic treatment.

It is recommended to use dual probes for BCR and
ABL, as well as to analyse a minimum of 200 nuclei.
QRT-PCR. It detects transcripts of mRNA in BCR/ABL.

It cannot replace karyotype or FISH at diagnosis.

Its availability is not enough in our country. Sometimes, it may give false negatives when there arevariants of the non-detectable transcript BCR/ABL.

So far, it has not been considered essential toperform it at diagnosis.

While FISH positive confirms disease, it has notbeen accepted as a test to confirm cytogenetic response, which is performed by means of karyotype.

3.3. Complementary Tests to the Diagnosis
The complementary tests are useful to determine the
CML stages and specify the prognosis.
In all the patients it is recommended to perform:Complete Blood Count with peripheral blood smear
because knowing the number of basophiles, eosinophiles and blasts is useful. Likewise, it is recommended to perform a complete biochemical profile
as a record to evaluate the toxicity criteria with theused treatment.

Measure of spleen. The prognostic scores use theclinical measure of the spleen, taking into accountits costal margin.
The bone marrow aspirate is necessary to group
CML and to perform karyotype. Above all, thenumber of blasts and basophiles are taken into account.
Category of evidence: B. Recommendation grade: 1.
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751

3.4. Other Test at Diagnosis
Bone biopsy. Although there is information about
its usefulness, most of it comes from the previous
time to the administration of TKIs treatment.
Nowadays, its value has decreased mainly because
fibrosis may be reversed with imatinib [37]. It may
be considered a convenient test, but not indispensable.
Category of evidence: C Recommendation grade: 2.
Mutations at the region BCR/ABL. There is no current
evidence of its usage at diagnosis. Besides, as it is notavailable in our country and it is very expensive, it is notregarded as an initial test.

3.5. Recommendations to Establish Diagnosis
At diagnosis, there is no practice prognostic score proposed during treatment with TKIs. Nevertheless, thescores previously established, like Hasford and Sokal,
have demonstrated an impact on treatment response withinterferon and even with imatinib in chronic phase.
The results of the IRIS trial confirmed it at the 12month follow-up with complete cytogenetic response(CCR) of 78%, 68%, and 51% for the groups of low,intermediate, and high risk of Sokal, as well as major
molecular remissions (MMR) among the CCR of 66%,
45%, and 38%, respectively [38]. The influence of the
prognostic group of Sokal is also observed in the overall
survival (OS), progression-free survival (PFS) to accelerated or blastic phases, and event-free survival (EFS)
within 6 years with 94%, 97%, and 91% for the low risk
group; 87%, 92%, and 81% for the intermediate risk; and76%, 83%, and 64% for the poor prognostic group, respectively [39]. Nevertheless, once the CCR is accomplished, the Sokal score influence disappears (PFS of
99%, 95%, and 95% (p=0.2)) [40].
The poor prognostic group is the one which has more
influence in response and survival, since the low andintermediate groups overlap, above all when imatinib isadministered. Since most of the studies have used Sokal
score, it is recommended if no other score shows clinicalutility.
The time between diagnosis and treatment withimatinib or transplantation may influence prognosis, as it
is shown in some trials [41]. Thus, it is recommended to
begin with specific treatment as soon as diagnosis is established. The presence of other additional chromosomal
alterations to the Philadelphia chromosome predicts a
briefer OS and a PFS [42].
Using Sokal score as a predictive system would allow
a better uniformity when analyzing the results of different regions of our country. If this score is wanted to be
used, there is information on the web or in electronic
devices which can automatically work out the risk.
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Mexican Guidelines for the Diagnosis and Treatment of Chronic Myeloid Leukaemia

It is recommended to use the prognostic Sokal score at
diagnosis in every patient with CML in chronic phase.
Category of evidence: B Recommendation grade: 1.
Recently, the European group has validated a predictive response score to TKI (EUTOS Score). Although it
is simple, practical, and reproducible it has not been approved for our population. Thus, it is suggested to evaluate it in our patients.

3.6. Follow-Up
Once established the CML diagnosis, the detailed followup of the evolution of the patient is crucial to choose theproper treatment. The careful monitoring response andtoxicity is the base for a better medical practice.

3.7. Types of Response in CML
There are three types of response in CML: haematological, cytogenetic, and molecular. The first therapeutic
objective of CML is acquisition, as soon as possible, of
cytogenetic response which in patients in chronic phaseis usually preceded of complete haematological response.
Category of evidence: A Recommendation grade: 1.
However, the molecular response has acquired anoteworthy magnitude. It takes place after CCR, and its
importance lies on the fact that no patient with complete
molecular response progress to accelerated and blastic
phases.

3.8. Haematological Response
The haematological tests and blood counts are the earliest and most common ways of monitoring. They are thekey to detect severe (but fortunately rare) case of primary
resistance to treatment (when imatinib is used as firstline therapy). This follow-up continues during the all thetreatment for monitoring toxicity, and it is not the first
relapse indicator (in reverse to acquisition of relapse, thehaematological recurrence is usually preceded by cytogenetic relapse, which in turn is preceded by relapse ormolecular progression). Needless to say, the importanceof careful morphological review of peripheral blood isdeterminant from diagnosis, as well as the value of review of bone marrow with specific identification of basophiles, eosinophiles, and myeloid cells in different
stages.
The loss of complete haematological response (CHR)
in patients who receive imatinib and did not have molecular cytogenetic response (MCR) or complete cytogenetic response (CCR) is an ominous sign and must betreated in an effective way, usually with second generation TKI.
Category of evidence: A Recommendation grade: 2.
Copyright © 2013 SciRes.

3.9. Cytogenetic Response
The cytogenetic response (CR) is characterized by gradual decrease of positive Ph metaphases number, workedout by means of bone marrow aspiration and cytogenetic
evaluation. Chromosomal monitoring is the most widelyused test for the response follow-up in patients with
CML. It is becoming the golden standard because of its
availability, consistency, and meaningful difference insurvival, among the patients with CR vs. the patients who
do not present it.

3.10. Types of Cytogenetic Response
As the treatment continues, there must be a gradual decrease in the number of metaphases positive to Philadelphia chromosome. Likewise, time to assess response has
been agreed in order to establish specific features which
relate positive Ph metaphases/time by means of extrapolating the number of positive Ph cells as leukaemic residual mass. Thus, based on 100% of original Ph positive
cells at diagnosis, some defining criteria have been proposed to identify the different types of cytogenetic response.
Category of evidence: A Recommendation grade: 1.
The capacity of conventional cytogenetic of detecting
the clonal cytogenetic evolution (CCE) is quite importantbecause it may be predictive when it is obtained in presence of the Philadelphia clone, and when conspicuously
appears in the evolution of advanced stages of the disease(accelerated phase by CCE and/or blastic phase).
On the contrary, the presence of additional cytogenetic
alterations (ACA)—in the context of a karyotype without Ph—may seem not to imply a poor prognosis; andthe only recommendation is to monitor their evolution bykaryotype. The most common alteration is trisomy 8 andthe one with the worst prognosis is the loss of −7 chromosome, with a potential myelodysplastic syndrome [43].

3.11. Frequency of Cytogenetic Evaluation
Cytogenetic assessment is recommended every six months,
after front-line treatment with imatinib. Recently, it has
been suggested that the first assessment be performed atthree months, particularly when administering effective
drugs like second generation TKIs [1]. In the case of
imatinib, it is important to consider that, although new
ELN recommendations suggest performing karyotype inbone marrow at three months, this test is convenient, but
not indispensable because of its poor availability in
Mexico and because if there is no CR (Ph positive > 95%)
it would be interpreted as a suboptimal response and not
as a failure. Then, it would not be necessary to change
treatment, just maintaining imatinib in the same or higher
doses. Once CCR is reached, it is recommended toJCTMexican Guidelines for the Diagnosis and Treatment of Chronic Myeloid Leukaemia

monitor every 12 months or when suspecting failure orcytopenias (ELN).
Category of evidence: B Recommendation grade: 2.
Cytogenetic relapse. In any moment, a cytogenetic response may be lost. This indicates treatment failure,
which leads to modify it. In these cases is critical to regard the compliance to treatment. If this is the correctone, an effective treatment must be administered: increasing imatinib dose, or ideally administering nilotinib
or dasatinib. Cytogenetic relapse must be prevented toprogress to haematological relapse, because the prognosis worsens.
Besides a clinical trial, the best recommendation inthis moment is limiting the chromosomal surveillance inpatients who have CCR and present increase in transcripts BCR/ABL1 by quantitative real time polymerase
chain reaction (qRT-QRT-PCR) or with persistent or
recently acquired cytopenias.
Category of evidence: C Recommendation grade: 2.
FISH. The CR may be assessed by more sensitive tests
like the molecular cytogenetic FISH, both in peripheral
blood and in bone marrow. It is an important diagnostic
tool used mainly for diagnosing CML. Several trials haveconfirmed a good correlation between cytogenetics of thebone marrow and FISH, particularly in retrospective trials as well as in correlation trials.
Nevertheless, ELN does not recommend this technique
because in the prospective response trials with TKIs, thecytogenetic assessment is performed with karyotype.
Therefore, FISH is recommended as a complimentary
technique to the conventional cytogenetics; thus, every
laboratory must establish the cut-off point of the usedprobe for the detection of the fusion gene BCR/ABL.
After that, FISH is regularly recommended unless:
It is not possible to obtain bone marrow aspirations
or metaphase cells enough to karyotype;
There is no good-quality conventional cytogenetics
which assures a satisfactory outcome, (for instance,lack of proper metaphases for the analysis);
There is no access to good qRT-QRT-PCR;
Possibility of false positives and lack of information
about other chromosome alterations.
Category of evidence: C Recommendation grade: 2.

3.12. Molecular Response
Once the CCR is obtained, the scope of the response may
be measured by taking into the account the number ofchimeric BCR/ABL mRNA transcripts. This implies theperformance of molecular techniques like qRT-QRTPCR. The molecular response is determined by the gradual decrease in the amount of transcripts. The major molecular response (MMR) indicates decrease in at least
three algorithms (or more) of chimeric RNA related tothe basal quantification (but with detectable transcripts).
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The complete molecular response (CMR) takes place
when, in spite of the current qRT-QRT-PCR, there is no
detection of chimeric RNA transcripts.
The qRT-QRT-PCR technique may be performed in aqualitative way, and its results are regarded as positive or
negative. When this technique is used with nested
QRT-PCR is very useful. The qRT-QRT-PCR advantage
is that it reveals the real percentage of BCR/ABL transcripts; thus, it is the most reliable result related to residual leukaemic mass. Another advantage is that qRTQRT-PCR has a remarkable correlation between results
obtained from peripheral blood and from bone marrow,
which prevents bone marrow punctures and aspirations.
However, they are not equivalent; then it is always recommended to use peripheral blood.
The qRT-QRT-PCR is the most used technique aroundthe world to detect BCR/ABL transcripts in peripheral
blood or in bone marrow. It can detect a CML cellamong 100,000 normal cells.
Most of the patients treated with imatinib acquire CCR,
but only a small percentage acquires MCR. As a rule, the
BRC/ABL transcripts diminish slowly after CCR. The
patients who accomplish molecular, major or complete
response have a better diagnosis. Consequently, qRTQRT-PCR has demonstrated its usefulness for monitoring molecular response, after CCR. Due to the potential
different variables which may participate in the qRTQRT-PCR, a world effort has been made to determine aninternational conversion to homologate the results fromall the participating health centres as well as uniform thecriteria for molecular response.
Category of evidence: A. Recommendation grade: 1.
Countless efforts are made to improve the standardization of qRT-QRT-PCR. Once some certain quality requirements are met, the individual laboratories will beable to use their own technology, but they must apply a
specific conversion tool with the purpose of expressing
their data in an “international score”. A value of 100% insuch score would be close to the median leukaemic loadin BCR/ABL transcripts at diagnosis (obtained from thebasal data of the IRIS trial). Then, 0.1% corresponds toreduction of three algorithms and defines MMR. Nowadays, it is recommended to use this international score
and to count on world standardized reference laboratories,
because when this technique is not approved, it may givewrong results which disorient the physician, rather thanhelp him/her.
With respect to cytogenetic and molecular response,
several trials have demonstrated that MMR is associatedwith long-term remission rates and an excellent freeprogression survival with imatinib. Likewise, the earlymolecular response is a favourable prognostic factor toprevent the disease progression.
In consequence, MMR is the ideal goal, since it places
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Mexican Guidelines for the Diagnosis and Treatment of Chronic Myeloid Leukaemia

the patient in a “high-security” response which prevents
the disease progression.
Category of evidence: A. Recommendation grade: 1.
Molecular relapse. The continuous increase in thenumber of transcripts may suggest resistance or treatment
failure. However, when there is no resistance data, anyrise in the number of transcripts must be confirmed witha second sample, particularly in the case of low levels of
BCR/ ABL1, where the imprecision in the quantificationof BCR/ABL1 is evident.
Category of evidence: C Recommendation grade: 2.
It is strongly advised that, when haematological, chromosomal or molecular results be bordering or conflicting,a second analysis must be performed.

3.13. Optimal Response to First-Line Imatinib
Treatment
The optimal, suboptimal, and treatment failure to imatinib
have already been defined in previous lines, as well as
the second generation TKIs. These protocols have been
recommended in several consensus and guidelines,
manly in the NCCN guidelines and in the ELN consensus [1,44].

However, there is neither international consensus norenough data in the literature to approve monitoringplasma levels as part of routine follow-up [45].
It is not recommendable to routinely measure plasma
levels.
Only certain chosen cases may benefit from this measure, such as patients with resistance, with severe andunusual adverse effects, and the ones with poor compliance or pharmacological interference.
Category of evidence: C Recommendation grade: 2.

3.16. Haematological, Cytogenetic, andMolecular Response Criteria
It is recommended to follow the NCCN guidelines for theclinical oncologic practice in Chronic Myeloid Leukaemia V.2.2011.

4. First and Second Lines Treatment
4.1. Chronic Phase Treatment

The typical mutations (change of an amino acid for another one) in the final sequence of the resulting oncoprotein may be a common finding. Nevertheless, many of
those changes are not crucial in the clinical context. At
present, there is no justification for the routine determination of mutations in the kinase domain, nor at diagnosis (basal) or periodically during the follow-up, particularly in patients with a good response. In fact, the findingof transient mutations in patients with stable CCR has
been reported and it does not alter the prognosis or disease progression which suggests that detecting a mutation is not essential for the therapeutic failure, when there
is no increase in leukaemic mass.
Taking all this into account, besides the fact that Mexico does not have a reference health centre which performs it, it is not recommended to detect mutations
unless treatment with TKIs fails.
Category of evidence: C Recommendation grade: 2.

First-line treatment with imatinib. IRIS trial results, at 7
years, show a sound superiority of imatinib over the
combination of IFN-α/cytarabine [46]. None of the patients who reached MMR at 12 months has progressed toadvanced phases. At 7 years, 86% of the patients havereached MMR. The progression rate at 4 and 7 years has
been 0.9%, 0.5%, 0%, and 0%, respectively [46].
These results are expressed in terms of survival and asignificant reduction of progression, with less adverse
effects than IFN-α/cytarabine combination: OS 85%;
PFS 92%, and FDS 81%.
The first-line treatment recommended for patients with
CML in chronic phase has been imatinib mesylate (400
mg/day) in just one dose. Its low cost, effectiveness in aconsiderable number of patients and follow-up time withimatinib, compared with second generation TKIs, proves
it is the best choice as first-line treatment. Nevertheless,every patient must receive a treatment according to her/
his clinical condition.
Category of evidence: A. Recommendation grade: 1.
Nevertheless, in 2010, the FDA and the European
regulatory agencies authorized nilotinib and dasatinib as
the first-line treatment, and they are also approved as
first-line treatment since 2011 in Mexico.

3.15. Imatinib Plasma Levels Determination

4.2. Response to Imatinib

A recent trial showed that patients with high levels of
imatinib in plasma had a correlation with high rates of
CCR and MMR. In a subanalysis of the IRIS trial, patients with low concentrations of imatinib on day 29 were
not so prone to acquire CCR and MMR. This suggeststhat the measure of the plasma concentrations may identify patients, where the adjustment of doses was useful.

The response to imatinib is defined according to European Leukaemia Net (ELN) recommendations [1].

3.14. Mutation Determination in Tyrosine
Kinase Domain

Copyright © 2013 SciRes.

4.3. Optimal Response
The optimal response indicates that the treatment is being
successful and there is no need of modification.
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4.4. Suboptimal Response
The suboptimal response is, by definition, a transient
response. It may progress to optimal response or to failure [47,48].
Dose adjustment is recommended; daily dose of 400
mg of imatinib may be adjusted to 600 or 800 mg when apatient meets with suboptimal response. Doses higher
than 800 mg are not recommended.
Category of evidence: B. Recommendation grade: 2.
A therapeutic option may be second generation TKIs
like dasatinib or nilotinib (see second generation inhibittors section).
Nevertheless, there are no prospective data about thelong-term benefit of the dose adjustment of imatinib or
the second generation inhibitors in case of suboptimal
response.
Category of evidence: C Recommendation grade: 3.
Imatinib must be stopped in case of failure (according
to ELN criteria) [1] or intolerance with toxicity (grades 3to 4) and to change to second generation treatment.

4.5. Failure
There may be primary (response with imatinib was neverachieved) or secondary (after a kind of response withimatinib) resistance. The secondary resistance is much
more frequent. The most common resistance mechanismis the development of mutations in the BCR/ABL1
kinase domain. Some others are: clonal cytogenetic evolution, over-expression or amplification of the gene, anddecrease of bioavailability or in the cellular exposition toimatinib [49,50].
Resistance to imatinib turns up 2% to 4% a year. In the
IRIS trial, the frequency was 3.3% in the first year, 7.5%in the second year, 4.8% in the third year, 1.5% in the
fourth year, 0.8% in the fifth, 0.4% in the sixth; 1.4% in
the seventh, and 1.3% in the eight year of treatment [51].
In case of failure, the use of second generation TKIs
(like nilotinib and dasatinib) must be considered in thefirst place, but not when mutation T315I is present because it is resistant to both drugs.
If second generation TKIs are not available, imatinib
800 mg may be administered, as well as its combination
with other drugs. The second generation inhibitors havedemonstrated to be more effective than high doses ofimatinib; and they are associated with less adverse effects. However, CCRs may be obtained even in 50%,
particularly in patients who have had cytogenetic response before imatinib.
Failure may be classified according to the inability ofreaching response or loss of any of the three responses:
haematological, cytogenetic, and molecular.
The one with the worst prognosis is the haematological failure; thus, it must be changed to a second generaCopyright © 2013 SciRes.

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tion TKI as soon as possible, as long as there is no mutation T315I. New therapies are being developed for thismutation [52].
In cases of cytogenetic failure (primary or secondary),timely intervention offers the best possibilities of a favourable outcome. Then, it is not recommended to continue with the same management and expect loss of haematological response.
The lack or loss of MMR is just a suboptimal response,
not failure. There are no clinical data which support
therapeutic changes in these cases, not even in cases of
CMR. In our country, the use of cytogenetic response
will be ideal as the main technique; nevertheless, molecular tests must be developed.

4.6. Intolerance
Intolerance is related to the presence of haematologicalor non-haematological adverse effects.
Most of the times, the secondary effects to imatinib are
mild to moderate, grades 1 to 2, and treated withsymptomatic therapy, depending on the case. Adverse
effects grade 1 to 2 must be treated; on the contrary, they
may affect the long-term compliance. They must be
timely solved to prevent, if possible, stopping imatinib
treatment [53].
When toxicity was grade 3 to 4, there are recommendations to solve it and to determine the moment
when imatinib should be stopped temporarily or permanently [54]. As a rule, in cases of grades 3 or 4, theadministration of imatinib is stopped. Therapy is reinitiated with 300 mg/day or the same dose of 400 mg
when neutropenia or thrombocytopenia is solved in two
weeks or less.
The adverse effects treatment depends on the grade of
response of the patient, grade of toxicity, and availabilityof alternatives.

4.7. Pharmacological Interactions
Imatinib is metabolised in the liver, mainly by the P450,
CY-P3A4 or CYP3A5 cytochrome enzymes. The drugs
that induce increase of the group of enzymes CYP3A4/5(like anticonvulsants and steroids) may reduce theimatinib therapeutic concentrations. On the contrary,drugs which inhibit CYP3A4 enzymatic activity (likeclarithromycin and itraconazole) and the ones metabolized by CYP3A4/5 may cause high plasma levels of
imatinib. Imatinib is also a mild inhibitor of the isoenzymes CYP2D6 and CYP2C9; thus, the drugs metabolized by these enzymes (like warfarin) must be usedcarefully.
In consequence, it is fundamental that in the assessment of toxicity and imatinib effectiveness, the potential
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Mexican Guidelines for the Diagnosis and Treatment of Chronic Myeloid Leukaemia

cause they may modify both efficacy and toxicity [46].

4.8. Imatinib High doses as First-line Treatment
Imatinib high doses and second generation of inhibitors
have been studied as the first-line treatment for CML in
chronic phase. In spite of achieving earlier responses
with doses of 800 mg, nowadays, it cannot be affirm that
this means better outcomes related to progression diseaseor survival because more follow-up is needed. This happens because of the frequency of interruptions and doses
reductions when high doses are administered. Patients,
who managed to keep a higher tolerability to the dose,
seem to have a better long-term prognosis (Data fromTIDEL, TOPS/24 months, and CML IV) [54-56].
Dose of 800 mg is not recommended as first-line treatment in chronic phase.
Category of evidence: B. Recommendation grade: 1(There is no unanimous consensus).

4.9. Pregnancy
Mesylate imatinib is teratogenic in animal models; then,a double-contraception in reproductive age women isrecommendable. There are no concise treatment guidelines for pregnant patients who have CML and receive
imatinib [46,55-57]. When there is suspicion of pregnancy or confirmation in women who receive imatinib, it
is recommendable to immediately stop the treatment until
the organogenesis has concluded (ending of the firstquarter, approximately), and then begin with hydroxylurea or IFN-α until the pregnancy ends. If organogenesis
has not concluded and blood count is required, an option
is leukapheresis until chemotherapy may be applied withsecurity. When pregnancy finishes, lactation must be
prevented and begin treatment with imatinib, since 60%of the patients present an increase in Ph positive metaphases when they stop receiving imatinib [57].
In animal models, spermiogenesis may be damaged,
but in the clinical experience, male fertility is preserved,
although there are isolated reports of oligospermia [58].
An effective method of birth control is recommended toprevent pregnancy in women who receive imatinib. Patients who suspect pregnancy must not be administeredimatinib or any other second generation kinase inhibitor.
It must be consciously considered to continue treatment
with these drugs, after the second quarter of pregnancy.
A useful alternative is IFN-α or leukapheresis.
Category of evidence: B. Recommendation grade: 1.

4.10. Second Generation of TKI as First-line
Treatment in Chronic Phase
The activity of the second generation inhibitors nilotinib
and dasatinib has been assessed as first-line treatment.
Responses are superior to the historical control groups
Copyright © 2013 SciRes.

with 400 mg and 800 mg of imatinib.
Nilotinib is an oral tyrosine kinase inhibitor with ahigh specificity for BCR/ABL1 and potency 10 to 50
higher than imatinib to inhibit the proliferation andautophosphorylation of cell lines of BCR/ABL1 native
type. It also inhibits 32 to 33 mutant cell lines of
BCR/ABL1, but it is not effective in mutation T315I. It
also inhibits the activity of Arg, Kit, and PDGFR, but notkinases in the family Src [59,60].
The bioavailability of nilotinib increase with food(particularly the fatty ones); so, it should not be taken
along with food.
Since phase II trials, results prove to be effective[61,62]. In a recent phase III trial, imatinib (dose 400
mg/day) was compared to nilotinib (150 mg/BID), or 200
mg. Albeit the results with nilotinib were not so good
like in the phase II trials, that does demonstrate better
efficacy with both doses. There was no significant difference in adverse effects [63,64].
Dasatinib is a dual oral tyrosine kinase inhibitor withan in vitro potency of about 300 times higher thanimatinib to inhibit the proliferation and autophosphorylation of BCR/ABL1 cell lines native type, as well as mostof the BCR/ABL1 mutations, except T315I. It also inhibits the Scr family, among others.
Likewise, the results of dasatinib in phase II trials arepromising [57]. In the latest phase III trial, imatinib (400
mg/day) is randomly compared against dasatinib (100 mg
every 24 hours). Like in the nilotinib trial, the results
were not so satisfactory like the phase III trials, but
dasatinib was more effective than imatinib [64].
TKIs showed faster and better responses (for instance,
MMR at 12 months) than imatinib, until the publicationof the phase III trials.
Due to the celerity and scope of the response to thesecond generation TKIs, it is possible that in a future, theproposed response criteria for imatinib change and new
criteria come into view for the second generation of TKIs
in first line.
The adverse effects are less common when dasatinib
or nilotinib are administered in first line than in second
one (see security profile in TKIs in second line). However, cardiotoxicity must be assessed, as well as the QTcinterval.
It is recommended to consider nilotinib or dasatinib as
the first line treatment for CML in chronic phase, recently diagnosed. Nilotinib recommended dose is 300 mg
every 12 hours, 2 hours before and one hour after meals.
Dasatinib recommended dose is 100 mg every 24 hours.
Choosing among imatinib, nilotinib or dasatinib mustbe personalized according to age, disease risk, comorbidity, security profile, cost, and availability.
Nilotinib and dasatinib have been approved in Mexico
as first-line treatment.
JCTMexican Guidelines for the Diagnosis and Treatment of Chronic Myeloid Leukaemia

Category of evidence: A. Recommendation grade: 1.

4.11. Second-Line Treatment. CML in Chronic
Phase (Resistant or Intolerant to Imatinib)
Second line tyrosine kinase inhibitors as second-line
treatment. Resistance or primary failure to reach haematological response (at three months) or cytogenetic one(some grade al 6 months) is rare with the administrationof imatinib.
Primary or secondary resistance to imatinib causes
therapeutic failure, which is present in 15% - 25% of thepatients. In the IRIS trial, 14% had poor therapeutic effect in the 8-year follow-up.
According to the molecular perspective, the secondary
resistance is the result of the stimulation of the BCR/
ABL activity; nevertheless, it happens because of thepoor compliance to imatinib treatment. Therefore, before
switching to a second generation TKIs, the complianceshould be assessed in order to find if it is causing awrong response.
Intolerance to imatinib may cause stopping its administration, even in 5% of the patients, as it has happened in
the IRIS trial, after an 8-year follow-up.
Both dasatinib (approved by the FDA in June 2006)
and nilotinib (approved by the FDA in October 2007)
have demonstrated to be very potent and effective drugs
for patients resistant or intolerant to imatinib. Both areavailable in Mexico.
Dasatinib. At the beginning, the dose was 70 mg every
12 hours and the responses were good [59,60,64]. Then,a phase III trial was carried out to establish the optimal
dose. It was demonstrated that each 100 mg every 24
hours have the same efficacy, but less adverse effects [65,66].
Taking that into account, dasatinib optimal dose is 100
mg (once a day) in the chronic phase [67].
Nilotinib. In chronic phase, the nilotinib optimal doseis 400 mg/BID and has been confirmed in phase II trials[57,68,69].
In Mexico (October 2006), the Compassionate Access
Program (CAP) began [64]. It enabled the generation of anational experience in patients with CML Ph positive,
resistant or intolerant to imatinib in chronic, accelerated
or blastic phases with 57 patients in Mexico, out of a 940.
Most of them (60%) had progressed to an accelerated
phase (45%) or blastic (15%). The CHR rate was 79%
with a CCR of 23%, and a MR of 10%. The detectedbasal mutations included E355G, T315I, M351T,
F359V/F, F317L, F486S/F, G250E, M315T/M, E453K,
and F486S/F in 13 (32%) of the patients [70,71].
The results with dasatinib and nilotinib have beenquite satisfactory as rescue treatment or second line inpatients with failure or intolerance to imatinib. The reCopyright © 2013 SciRes.

757

sponse is better after intolerance rather than after failure
with imatinib. In most of the cases, the response is longlasting.
Usually, there is no crossed intolerance between
imatinib and the second generation TKIs with respect tonon haematological effects. Nevertheless, there is a certain degree of crossed toxicity for the haematological
toxicity (tendency to develop cytopenias).
The adverse effects may have different profiles indasatinib (mainly in lungs), compared with nilotinib (inpancreas, increase in billirubin level, and rash), but there
is a potential of cardiotoxicity risk with both of them,besides a prolongation of QT interval. Thus, the treatment must be personalized according to every patient’s
status related to these clinical conditions.
There are criteria for the treatment of adverse effects
with dasatinib and nilotinib, the same happens withimatinib.
Choosing one or another drug depends on the availability and cost evaluation. With respect to efficacy, informed results with both are similar; there are just somemutations which are more sensitive to one or anotherdrug. These in vitro data may or not correlate with theclinical response in the patients, with the exception of
mutation T315I which implies resistance to TKIs [72].
What must be evaluated, to choose the best option, isevery drug security profile in relation to background andcomorbidity in every patient.
The second generation of TKIs is less dependent oftransporters. For instance, they do not depend on OCT-1.
Nevertheless, they are also metabolized in the hepatic
microsomal system and present pharmacological interacttions which may modify their efficacy or security profile.
It is recommended to have those interactions at close
hand during the treatment with TKIs.
It is recommended to administer dasatinib 100 mg/
daily, along with or without food.
Nilotinib is recommended 400 mg/BID. Tablets must
be taken two hours before and one hour after meals.
So far, availability and costs of these drugs limited
their use in Mexico. Taking the decision of administering
one or another must be individual, because there is alack of a trial which compares them prospective and directly [55].
Category of evidence: B. Recommendation grade: 1.

4.12. Treatment Adjustment According to
Response
The definitions of suboptimal response are only applicable to imatinib and according to European Leukemia Net;
for NCCN only complete and partial responses are assessed in the use of second generation inhibitors [58,73].
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lotinib treatment in chronic phase must continue withclinical control and serial CBC every two weeks until thestabilization of the counting takes place; after CHR,
every four weeks; and after CCR every six weeks. Patients must undergo liver function tests twice a weekduring four weeks, then every six weeks.
Evaluation of the second generation TKIs responsemust be carried out earlier because their efficacy (orresistance) is evident prematurely. Therefore, it is recommended to perform the first cytogenetic assessment inbone marrow at three months. Likewise, evaluation of the
BCR/ABL transcripts, by means of QTR-PCR in real time,must be carried out at three months because it has aprognostic value.
Category of evidence: A. Recommendation grade: 1[74].
When there is failure or suboptimal response to second generation TKIs during treatment, HCT must be considered [75]. There are criteria to early evaluate the response to these drugs and to decide if the patient should
undergo HCT.
Category of evidence: A. Recommendation grade: 1.

4.13. Imatinib High Doses as Second-Line
Treatment
The results of imatinib at high doses as second-line
treatment are not as good as the ones with second generation TKIs. The cause of that are adverse effects ofimatinib high doses (see imatinib high doses in first-line
treatment).
Nevertheless, in cases of suboptimal response or failure (when there is no access to second generation of
TKIs), high doses of imatinib must be regarded either bylack of them or by their high cost. Ideally, in case of failure, mutations must be carried out in order to demonstrate the presence of a non-sensitive mutation like
T315I.

5. Transplantation
The allogenic stem cell transplantation (ASCT) is thepotentially curative treatment for CML; nevertheless, theexcellent outcomes with first and second TKIs haveplaced this treatment as a second alternative.
The outcomes with ASCT in chronic phase are quite
superior to advanced and blastic phases. In the era ofTKIs, survival after transplantation in patients in chronic
phase is 91% at three years globally. When they are classified by risk, according to the European Group for
Blood Marrow Transplantation (EBMT) is 88.2%, 94%,
and 59% for groups I, II, and III, respectively [76].
The results of International Blood and Marrow Transplantation (IBMTR) from 1998 to 2008 showed that thesurvival at three years is 70% - 72% for patients in
Copyright © 2013 SciRes.

chronic phase; 45% - 56% for patients in accelerated
phase, and 16% for patients in blastic phase [77].

5.1. Donors Search for Bone Marrow
Transplantation
The next patients are regarded high risk; then, it is necessary to look for HLA-compatible donors.
Chronic phase with high Sokal;
Low Sokal with therapeutic failure to the first-line
TKIs;
Identify the patients with therapeutic failure to TKIs
to take them to second-line treatment and who havepoor risk, according to the Hammersmith index [78];Patients who reach accelerated and blastic phase.

5.2. Indications for Transplantation
Chronic phase [79]:Patients with failure to the first-line with TKIs or
who are being assessed for the response to second
generation TKIs (see criteria response in indications
for second line).

Nowadays, ASCT is an excellent option as first-line
treatment when patients are in accelerated and blastic phases at diagnosis, and have mutation T315I,
patients with intolerance or failure to TKIs.
Advanced disease [79]:Accelerated phase: patients with failure to second
generation TKI.
Blastic phase [79]:Patients who experience complete remission to the
induction protocol with QT alone or TKI.
Conditioning protocols [80]:Busulfan/cyclophosphamide in patients who require
myeloablative protocols;
Fludarabine/cyclophosphamide in patients whoneed reduced intensity protocol.


5.3. Post-Transplantation Treatment
Use of Donor Lymphocyte Infusion (DLI) after transplantation. Patients who underwent a reduced intensity
protocol, do not have Graft-versus-host-disease, and present haematological and/or cytogenetic relapse may
reach remission in 60% - 90% with the lymphocyte infusion. When choosing this treatment, it is recommended toadjust the dose [81].
Monitoring of minimal residual disease after transplantation. Several relapses have been observed after
donor allogenic transplantation related to chronic phaseof CML in 8% to 26%.
The lymphocyte infusion, imatinib induction, andelimination of immunosuppression are some alternatives
to relapse after ASCT.
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Mexican Guidelines for the Diagnosis and Treatment of Chronic Myeloid Leukaemia

sponse to TKIs and relapse possibility with these treatments. Although the kinetics of transcript BCR/ABL1
after transplantation has not been examined, some studies
have suggested that the increase in the transcript levels—before the transplantation—predict relapse.
A molecular monitoring must be performed by meansof qRT-QRT-PCR technique, in the months 1, 2, 3, 6, 9,
and 12. Later on, every six months, minimal residual
disease must be considered in case of:
BCR/ABL1/ABL > 0.02% in three monthly tests.

BCR/ABL1/ABL > 0.05% in two monthly tests.
Nevertheless, there is no international standardization
for monitoring. Additionally, conventional chromosomal
study and FISH must be carried out.
TKIs after transplantation. The beginning of the TKIs
treatment will depend on several factors and clinicalstatus of the patient after transplantation, as conditioning
protocol, immunosupressor drug, infectious complications, and persistence of transcript BCR/ABL (minimal
residual disease).
The patient will begin TKIs when the complete immunosuppression was stopped, as long as the minimal
residual disease is not informed. In case of presence ofminimal residual disease, TKIs must be administered[82].

6. Advanced Phases Treatment (Accelerated
and Blastic)
6.1. Accelerated Phase
The definition of the accelerated phase may be controversial (see Phases and Definitions). The most used definition is the WHO one. The treatment depends on the
progression (or absence of it) to these phases in presenceof a TKI [56-59]. The results shown with dasatinib andnilotinib occurred in patients resistant or intolerant toimatinib.
1) First line. When there has not been previous treatment with TKIs, imatinib 600 mg to 800 mg/day is recommended, followed by ASCT [83].
2) In case of resistant mutations to imatinib, nilotinib
400 mg every 12 hours or dasatinib 140 every 24 hours[84].
Second line. In case of previous treatment withimatinib, ASCT is recommended, followed by dasatinib
or nilotinib at the aforementioned doses.
As it was discussed, in patients with CML in advanced
phases, the possibility of allogenic stem cell transplantation must be considered (ASCT) [85].
Recommendation in Mexico. The first-line treatment inpatients with CML in accelerated phase may be imatinib
600 mg/day, followed by ASCT. When the second generation of TKIs are available, dasatinib and nilotinib arerecommended, followed by ASCT.
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Category of evidence: B. Recommendation grade: 1.

6.2. Blastic Phase
In the blastic phase, global responses are obtained withimatinib from 55% to 70%, with complete responses of
11% - 20% of these patients [86].
1) In a II phase trial of CML in blastic phase (myeloid
phenotype = 74 and lymphoid = 42 patients) with an 8month follow-up, dasatinib induced haematological responses in 33% and 31%, and cytogenetic remissions
higher in 31% and 50%, respectively. However, only 31%
and 13% of the patients remain in the same follow-up[87].
Nilotinib. In phase II trials of CML in myeloid andlymphoid phases, nilotinib showed CHR in 11% and13%, respectively; in CCR 29% and 32%, respectively[88].
Given that in the three TKIs the responses in blastic
phase are rather brief; chemotherapy (lymphoid or myeloid) is recommended, depending on the corresponding
cell lineage [89].
An ASCT must be regarded as consolidation therapy.
Imatinib 600 mg - 800 mg/day + suitable chemotherapy. Dasatinib 70 mg /BID + suitable chemotherapy
Category of evidence: B. Recommendation grade: 1.
In Mexico, the combination of imatinib 600 mg to 800
mg or a second generation of TKIs (dasatinib or nilotinib)
is recommended for patients with blastic phase of the
CML. Such treatments are associated with the corresponding chemotherapy to the leukaemia phenotype(lymphoid or myeloid), followed by allogenic stem celltransplantation.
Category of evidence: B. Recommendation grade: 1.

7. Acknowledgements
The authors of the Mexican Guidelines for the Diagnosis
and Treatment of Chronic Myeloid Leukaemia would
like to state our acknowledgment to Bristol-Myers Squibb
for the support given to the consensus.

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