Introduction
The guidelines project is a joint initiative of the Associação Médica Brasileira and
the Conselho Federal de Medicina. It aims to bring together information in medicine
to standardize conduct in order to help decision-making during treatment. The data
contained in this manuscript were prepared by and are recommended by the Associação
Brasileira de Hematologia, Hemoterapia e Terapia Celular. Even so, all possible conducts
should be evaluated by the physician responsible for treatment depending on the patient's
setting and clinical status.
Description of the method used to gather evidence:
These guidelines were drafted after constructing 19 questions relevant to the diagnosis
and treatment of Chronic myeloid leukemia (CML). The questions were structured using
the PICO (patient-intervention-comparison-outcome) methodology, thus enabling the
creation of strategies to search for evidence (Appendix 1) in the main scientific
electronic databases (Medline/PubMed, Embase, Lilacs/SciELO, Cochrane Library, PreMEDLINE
via OVID). Moreover a manual search for evidence in dissertations and theses was carried
out (Biblioteca Digital de Teses e Dissertações do Instituto Brasileiro de Informação
em Ciência e Tecnologia - BDTD/IBICT). Evidence was selected by critical evaluation
using discriminatory instruments (scores) according to the category of question: diagnosis
(Quality in Diagnostic and Screening tests - QADAS) or therapy (JADAD for randomized
clinical trials and Newcastle-Ottawa scale for non-randomized studies). After identifying
potential studies to substantiate recommendations, the level of evidence and degree
of recommendation were calculated using the classification of Oxford (available at
www.cebm.net).
Summary of the degree of recommendation and level of evidence:
A: Major experimental and observational studies.
B: Minor experimental and observational studies.
C: Case reports (non-controlled studies).
D: Opinion without critical evaluation based on consensus, physiological studies or
animal models.
Aims
To set parameters for clinical diagnosis, evaluate severity and standardize treatment,
maintenance and monitoring options for CML patients. The target audience of these
guidelines is the hematologist with the aim of contributing to decision making in
the diagnosis and treatment of CML.
What are the diagnostic criteria for Chronic myeloid leukemia?
The diagnosis of CML is based on leukocytosis and often also thrombocytosis, and on
the differential blood count (immature granulocytes, metamyelocytes, myeloblasts and
basophilia). Diagnosis depends on the identification of the Philadelphia chromosome
(22q) resulting from the t(9;22)(q34;q11) resulting in the head to tail fusion of
Breakpoint Cluster Region (BCR) and the Abelson Murine Leukemia (AML) genes or identification
of the result of this translocation in peripheral blood or bone marrow cells. In some
cases, the Philadelphia chromosome cannot be detected and diagnosis is made by molecular
methods. The typical clinical course has three stages: the chronic phase, the accelerated
phase and the blast crisis phase. Most diagnoses are made in the chronic phase. The
accelerated phase is defined as the presence of 1% to 19% blasts in the blood or bone
marrow, basophils > 20%, thrombocytosis or thrombocytopenia not related to therapy
and clonal evolution in cytogenetic evaluation. The blast crisis phase is characterized
by blasts > 20% of peripheral blood white cells or extramedullary blast proliferation(1-3)(D).
Recommendation: Diagnosis of CML depends on the identification of the Philadelphia
chromosome or the BCR-ABL rearrangement.
Is there any difference in the prognosis of CML patients with p210 e13a2(b2a2) and
e14a2(b3a2) or (e1a2)p190 rearrangements?
The prevalence of the e1a2 BCR-ABL fusion transcript in CML patients is 1%. This rearrangement
is associated with decreased therapeutic response to tyrosine kinase inhibitors (TKIs)
as complete hematologic response is attained in only 30% of cases, complete cytogenetic
response in 20% (3 to 18 months) and major molecular response in 10% of cases. Progression
to other phases (accelerated or blast crisis) occurs in 60% of chronic phase patients(4)(C).
The response of treatment-naïve CML patients to imatinib treatment is different for
the b3a2(e14a2) and b2a2(e13a2) transcripts. In 12 months of treatment, patients with
the b3a2(e14a2) transcript have a 29% increase in complete cytogenetic response, which
is faster, and greater disease-free survival(5)(B).
In CML patients on imatinib treatment for six months, the number of b2a2(e13a2) transcripts
is lower when compared to the number of b3a2(e14a2) transcripts, suggesting greater
sensitivity of the b2a2(e13a2) transcripts to imatinib and consequently prognosis
is better(6)(B).
Imatinib treatment in chronic-phase CML patients with the BCR-ABL b2a2(e13a2) transcript
has better results compared to those with the b3a2(e14a2) transcript with a 31% increase
in the major cytogenetic response and a smaller number of BCR-ABL transcripts(7)(B).
Recommendation: the (e1a2)p190 transcript is associated to a reduced therapeutic response;
there is controversy as to whether there is difference in response between the p210
e13a2(b2a2) and p210 e14a2(b3a2) transcripts.
At diagnosis, do the Philadelphia chromosome and 9q deletion have prognostic significance?
There is no difference in survival between CML patients with the chromosome 9q deletion
on interferon alpha treatment and those without this deletion. However, there is a
reduction in the survival of patients with the deletion spanning the BCR-ABL junction
compared to those without this deletion. The survival rate is 44% higher in chronic
phase patients submitted to bone marrow transplantation who do not have the deletion
(Number needed to treat - NNT: 2)(8)(B). There is evidence that the disease-free survival,
overall survival and cytogenetic response is reduced in CML patients with the chromosome
9q34 deletion under treatment with interferon alpha(9,10)(B).
A comparison of first-generation (imatinib) or second-generation (nilotinib or dasatinib)
TKIs in the treatment of CML patients with chromosome 9 deletion shows that there
is no significant difference in the overall survival, disease-free survival or in
cytogenetic response between patients with and without the chromosome 9 deletion over
a two-year follow-up(11,12)(B). There is, however, evidence that there is a reduction
in survival of patients with derivative chromosome 9 deletions(13)(B).
The ABL deletion on derivative 9 (15.1%) in CML patients reduces disease-free survival,
the BCR deletion reduces overall survival and combined ABL and BCR deletions reduce
the overall and disease-free survival(14,15)(B). There is evidence that only the ABL
deletion reduces the survival time and the duration of the chronic phase(16)(B).
Over a 5-year follow up of imatinib treatment, CML patients with variant Philadelphia
chromosome translocations do not demonstrate significant differences in overall survival,
disease-free survival, progression-free survival, complete hematological response,
cytogenetic response or molecular response compared to patients without variant Philadelphia
chromosome translocations(17,18)(B). Other studies have shown that Philadelphia chromosome
mosaicism increases mortality in 3.3 years by 21% (NNH: 5) and translocation variations
reduce cytogenetic response(19,20)(B).
Recommendation: Despite controversy on whether chromosome 9q, BCR deletions and variant
Philadelphia chromosome translocations confer worse prognoses, there is evidence of
reductions in overall and disease-free survival and in therapeutic response of CML
patients treated with interferon alpha or first-generation and second-generation TKIs.
ABL deletion reduces the overall and disease-free survival of patients. The presence
of variant Philadelphia chromosome translocations and mosaicism also seem to confer
worse prognosis in CML.
Do cytogenetic abnormalities in addition to the Philadelphia chromosome at diagnosis
have prognostic significance?
In CML patients under treatment using first-generation (imatinib) and second-generation
(dasatinib or nilotinib) TKIs, the presence of additional chromosomal abnormalities
reduces disease-free and overall survival at 5 years(21)(B).
The presence of additional chromosomal aberrations in CML patients under treatment
with nilotinib increases mortality by 28% due to disease progression (NNH: 4). In
addition, mortality is increased by 38% at 2 years in chronic phase patients with
additional chromosomal aberrations (NNH: 3)(22)(B).
Aberrations reduce the survival time of these patients(23,24)(B). The presence of
additional chromosomal aberrations increases mortality by 36% (NNH: 3) and reduces
the mean overall survival of CML patients submitted to stem cell transplantation(25)(B).
CML-related disease-free and overall survival at 5 years is different in patients
with cytogenetic changes compared to those without. The presence of major cytogenetic
aberrations (major route abnormalities) (such as a second Philadelphia chromosome,
trisomy 8, isochromosome 17q, or trisomy 19) reduces disease-free and overall survival
at 5 years by 40%(26)(B).
Recommendation: The presence of additional chromosomal aberrations at diagnosis (major
route abnormalities) reduces the overall and disease-free survival and increases mortality
by 36% to 40%.
Are the criteria of the World Health Organization comparable to other criteria to
classify CML phases (chronic, accelerated and blast crisis phases)?
The use of the World Health Organization (WHO) classification of CML stratifies patients
into chronic, accelerated and blast crisis phases at approximate rates of 77.8%, 15.5%
and 6.7%, respectively(27)(C). The appropriate classification allows the establishment
of adequate estimates of response(28)(D).
In the treatment of CML patients with imatinib, there is no difference in the overall
classification of patients in the chronic, accelerated and blast crisis phases between
the standard method and the WHO criteria. The distribution of patients according to
the standard classification is about 60% in the chronic phase, 28% in the accelerated
phase and 12% as blast crisis. Although there is no significant difference between
the two classifications, 6% of patients classified in the chronic phase by the standard
classification were reclassified in the accelerated phase (WHO). Similarly, 9% of
patients classified in the accelerated phase were reclassified as blast crisis (WHO),
and 7% in the chronic phase(29)(B).
There are differences between the M. D. Anderson Cancer Center (MDACC), International
Bone Marrow Transplant Registry (IBMTR) and WHO classifications and definitions of
the accelerated phase of CML particularly in respect to the percentages of blasts
and platelets (Table 1)(30)(D):
Table 1
A comparison between the M. D. Anderson Cancer Center, International Bone Marrow Transplant
Registry and World Health Organization classifications and definitions of the accelerated
phase of CML
Characteristic
MDACC
IBMTR
WHO
Blasts (%)
> 15
> 10
10 - 19
Platelets
< 100
No response
< 100 or > 1000
MDACC: M. D. Anderson Cancer Center; IBMTR: International Bone Marrow Transplant Registry;
WHO: World Health Organization (main differences)
Recommendation: The WHO classification for the chronic, accelerated and blast crisis
phases of CML are similar to the IBMTR and MDACC classifications.
Is it important to define risk in CML patients using the Sokal and Hasford scores?
The Sokal score can be determined using an online calculator (www.pharmacoepi.de).
The score takes into account the size of the spleen (in centimeters) palpable below
the left costal border, the platelet count, the percentage of blasts and the age,
where a result < 0.8 corresponds to low risk, from 0.8 to 1.2 intermediate risk and
> 1.2 high risk. The Sokal score has a predictive value in CML patients treated with
imatinib, where molecular and cytogenetic responses are higher in low-risk patients.
High-risk, intermediate-risk and low-risk patients who achieve cytogenetic response
within 12 months have probabilities of survival of 90%, 94% and 97%, respectively.
The Hasford score considers the age, the percentage of eosinophils and basophils,
platelet count, spleen size in centimeters and percentage of blasts; the patient has
low risk when the result is < 780, intermediate risk between 780 and 1480 and high
risk > 1480. The 5-year survival rate corresponding to each risk group is 76%, 55%
and 25%, respectively(31)(D)(32)(B).
The Sokal score predicts treatment response of CML patients on interferon alpha therapy.
The high-risk, intermediate-risk and low-risk groups include 48%, 29% and 23% of the
cases with mean survival rates of 45, 76 and 105 months, respectively. The 10-year
survival is 8%, 28% and 34%, respectively(33)(B).
After the introduction of imatinib treatment, the Sokal score identified an increase
in the 5-year survival rate of low-risk CML patients of 11%, intermediate-risk patients
of 40% and of high-risk patients of 38%(34)(B). Moreover, it is known that high-risk
patients are more likely to evolve to the accelerated or blast crisis phases even
on imatinib therapy(35)(A). The Sokal score is also inversely related to cytogenetic
response in high-risk patients(36)(B), as, for high-risk patients, there is a 30.4%
reduction in cytogenetic response(37)(B).
The Hasford score identifies patients at low risk, with probability of survival at
9 years of 41%, intermediate risk, with probability of 0.16%, and high-risk, with
a probability zero at 9 years. The Sokal and Hasford scores classify 23% and 9% of
all patients as high-risk, respectively. Patients with low or intermediate risk who
achieve complete hematological response, have probabilities of survival of 51% and
23%, respectively; those without complete hematologic response have probabilities
of 26% and 12%, respectively. High-risk patients who achieve cytogenetic response
have prognoses similar to those with low risk(38)(B). Of the different groups as classified
by Hasford, 57% of low-risk patients present complete cytogenetic response and 27%
of intermediate-risk and high-risk patients achieve complete cytogenetic responses(39)(B).
The Hasford and Sokal scores predict complete hematological responses mainly in low-risk
patients(40)(B).
Recommendation: The Sokal and Hasford scores are prognostic predictors of CML patients.
Is imatinib better than second-generation tyrosine kinase inhibitors as first-line
treatment of chronic phase CML?
A comparison between dasatinib (100 mg) and imatinib (400 mg) as first-line treatment
in chronic phase CML patients demonstrates that complete hematologic response is 11%
higher, cytogenetic response is 11% higher and molecular response is 18% higher with
dasatinib (NNT: 9)(41)(B). The two-year follow-up of these patients upholds the higher
beneficial effect of dasatinib compared to imatinib(42)(B).
Initial treatment of chronic phase CML patients using nilotinib (300 mg or 400 mg
twice daily) compared to imatinib (400 mg once daily) increases the molecular response
at 12 months by 22% (NNT: 5), increases the cytogenetic response by 15% (NNT: 7) and
reduces the likelihood of progression to the accelerated and blast crisis phases(43)(A).
In the two-year follow up, the effect of nilotinib increases the molecular response
to 27% (NNT: 4), the cytogenetic response is 10% higher than imatinib (NNT: 10) with
this difference being 5% lower than the evaluation at 12 months. The reduction in
progression to the accelerated and blast crisis phases is maintained(44)(A).
Recommendation: Dasatinib and nilotinib provide greater benefits than imatinib in
the first-line treatment of chronic phase CML patients in respect to the molecular,
cytogenetic and hematologic responses as well as to the progression of the disease.
Does the time between diagnosis and start of treatment with imatinib have prognostic
importance?
In chronic phase CML patients, imatinib treatment may be started after diagnosis (early),
or may be started after 24 months of treatment with interferon (late), leading to
different results regarding toxicity and effectiveness. Early treatment reduces the
risk of grade I and II adverse effects by 52% (NNT: 2) and grade III and IV adverse
effects by 81% (NNT: 1), although it increases the risk of neutropenia and thrombocytopenia
by 5% (NNH: 20). After one year of follow-up in patients who have not achieved complete
cytogenetic response, early treatment produces a reduction in the risk of grade I
adverse events by 3% (NNT: 33), grade II by 8% (NNT: 12) and grades III and IV by
7% (NNT: 14)(45)(B).
In early treatment, there is a 16% increase in complete cytogenetic response (NNT:
7), a 2% reduction in the risk of relapse (NNT: 50) and a 15% increase in disease-free
survival (NNT: 7)(45)(B).
There is reduction in the risk of non-hematological adverse events with early treatment,
including weight gain (11%), periorbital edema (12%), rash (9%), diarrhea (11%), and
infections (19%), but there is increased risk of hemorrhage (5%) and bone pain (8%)(45)(B).
Imatinib treatment at diagnosis of chronic phase CML (early treatment) increases the
likelihood of major molecular response by 20% (NNT: 5) and increases the likelihood
of response maintenance at 30 months by 36% (NNT: 3) compared to beginning treatment
one year after diagnosis (late treatment). After one year of imatinib treatment, the
likelihood of loss of or not achieving molecular response is 58% lower than patients
treated early (NNT: 2)(46)(B).
Treatment with 400 mg imatinib produced higher major and complete cytogenetic response
rates compared to the interferon and cytarabine combination in chronic phase CML patients
(87.1% vs. 34.7%) and higher progression-free survival to the accelerated and blast
crisis phases (96.7% vs. 91.5%; p-value < 0.001)(32)(A).
Recommendation: Imatinib treatment of chronic phase CML patients should be started
as early as possible after diagnosis.
Does the cytogenetic evaluation have an impact on prognosis?
The identification of CML patients on imatinib treatment with cytogenetic clonal evolution
provides some information on the prognosis that depends on the disease phase. The
presence of this change in the chronic and accelerated phases is not associated to
a different cytogenetic response, however it reduces the survival rate of patients.
Cytogenetic response after three months of treatment is an independent prognostic
factor. The absence of complete or partial response is associated with lower survival
rates(47)(B).
In CML patients on imatinib treatment, the presence of a cytogenetic response increases
4-year survival by 23% (NNT: 4) and disease-free survival by 38% (NNT: 3)(48)(B).
The rate of cytogenetic response in patients in late chronic phase CML after interferon
alpha intolerance or resistance was 55%. After 6 years of treatment with imatinib,
77% of the patients were still with stable complete cytogenetic response, with a survival
rate of 91%. Among the 124 patients who never achieved a complete cytogenetic response,
54 (44%) progressed to the accelerated or blast crisis phases(49)(B).
The expected loss of cytogenetic response in the first year of imatinib treatment
is 0.6%, with the mortality rate at 2 years of patients who achieved response being
lower. The estimated 8-year mortality rate of these patients is 4.8%(50)(B).
For CML patients unresponsive to imatinib and thus treated with second-generation
TKIs (dasatinib and nilotinib), a cytogenetic response confers 20% greater survival
(NNT: 5), and when associated with hematological response, the increase in the survival
rate is 42% (NNT: 2)(51)(B).
The presence of minor or major cytogenetic response in chronic phase CML patients
under treatment with second-generation TKIs, increases event-free survival, overall
survival and disease-free survival by about 25% (NNT: 4)(52)(B).
Recommendation: the cytogenetic evaluation of patients under TKI treatment can predict
the prognosis by complete or partial response, associated or not to other factors.
Does molecular evaluation by quantitative real time polymerase chain reaction have
an impact on prognosis?
The BCR-ABL/ABL ratio is almost always below 2% in chronic phase CML patients who
attain cytogenetic response on imatinib treatment. Patients with the BCR-ABL/ABL ratio
below 0.0001% are regarded as having complete molecular response. For patients who
lose the cytogenetic response within 24 months (2.5%) the mean value of the ratio
is 0.12%. Some relapsed patients evolve with disease progression (15.4%) with BCR-ABL/ABL
ratios that vary from 0.3% to 0.0075%, which, within the usefulness of quantitative
real time PCR (qPCR) in molecular evaluation defines the extremes of positive or negative
residual disease, but with a great variability in the mean(53)(B).
In CML patients investigated using qPCR, the estimated 5-year major molecular response
rate is 67.1% and the cytogenetic response is 81.7%. In respect to event-free survival,
including transformation to accelerated and blast crisis phases, death from any cause,
loss of adherence to treatment or loss of cytogenetic response, patients who attain
molecular response have a higher response compared to those who do not. Patients with
major molecular response have better survival than patients with complete cytogenetic
response, who do not achieve major molecular response(54)(B).
The estimated molecular response obtained by PCR analysis in CML patients treated
with imatinib, also allows a comparison with hematologic and cytogenetic responses
over time. Thus, in an 18-month follow-up, the molecular, cytogenetic and hematologic
responses were 79%, 83% and 93%, respectively(55)(B).
Cytogenetic progression (loss of response, clonal evolution, 20% increase of the Philadelphia
clone) occurs in 13% of CML patients under imatinib treatment in 2 years of follow-up.
At the time of progression, none of these patients had major molecular response (reduction
> 3log in BCR-ABL). Thus, there is a suggestion that cytogenetic analysis should be
restricted to cases that do not attain or lose molecular response as measured by qPCR(56)(B).
To evaluate changes in the levels of BCR-ABL transcripts as prognostic markers by
qPCR, monitoring during 4 years demonstrates major molecular response (> 3-log reduction)
and predicts higher disease-free survival rates. A minimal increase of 0.5-log predicts
shorter relapse-free survival. Loss of molecular response (< 2.5-log reduction) also
defines reduction in disease-free survival. A complete molecular response (PCR undetectable)
corresponds to an increased disease-free survival(57)(B).
Recommendation: the prognosis (survival, relapse, progression) of CML patients under
imatinib treatment can be predicted using qPCR.
Can cytogenetics be replaced by quantitative real-time polymerase chain reaction to
monitor CML patients taking tyrosine kinase inhibitors who attain complete cytogenetic
response?
There is a correlation between the levels of transcripts in the bone marrow and peripheral
blood at 3 months of treatment and obtaining molecular response at 6 months(58)(B).
The comparison between qPCR, cytogenetics and fluorescence in situ hybridization (FISH)
to monitor response to treatment using TKIs in CML patients demonstrates the following
correlations and/or concordances: qPCR in bone marrow and peripheral blood; cytogenetics
in the bone marrow, FISH in peripheral blood and qPCR in peripheral blood(59)(B).
Despite the correlation between qPCR and cytogenetic analysis, other prognostic factors
may be associated with molecular or cytogenetic responses, affecting the outcomes
during TKI treatment of chronic phase CML patients. This shows the need of multivariate
analyses that estimate the impact of the interaction of prognostic factors present
in the medical practice. However in multivariate analysis, just the 3-month cytogenetic
response is predictive of the response at 6 months and disease-free survival at 2
years(58)(B).
Relapse occurs at 24 months in 2.5% of patients who have obtained cytogenetic response
and these patients may experience disease progression to the accelerated and blast
crisis phases. The correlation between PCR analysis and cytogenetic response may contain
a raneg of values that hamper interpretation and thus not favor the substitution of
methods(53)(B).
Three-monthly monitoring using qPCR may provide the prognostic data needed for decision
making in CML patients thereby reducing the need of bone marrow aspirations. The reasons
that PCR monitoring is sufficient include: the level of log reduction in the BCR-ABL/ABL
ratio correlates with cytogenetic response; in the 12 -month follow-up, no patient
has disease progression without there being an indication in the risk by qPCR (half-log
increase or 5-fold increase in the previous value of the BCR-ABL/ABL ratio); and no
patient has cytogenetic progression when they have molecular response(56)(B).
Recommendation: qPCR in peripheral blood can be used as the examination of choice
to monitor chronic-phase CML patients under imatinib treatment. Cytogenetics is a
fundamental option for monitoring that may be used in association with PCR, or may
be reserved for cases where either there is no molecular response or the molecular
response was lost.
What is the treatment of choice for chronic-phase CML patients resistant to imatinib
400 mg?
A comparison of treatment with dasatinib 140 mg and an increase in the dose of imatinib
(800 mg) in chronic phase CML patients resistant to imatinib 400 mg (lack of complete
hematological response at 3 months or lack of cytogenetic response at 6 months, or
lack of major cytogenetic response at 12 months of treatment) demonstrates the following
results: complete hematologic response increases in 11% of patients (NNT: 9), complete
cytogenetic response increases by 23% (NNT: 4) and major molecular response increases
by 12% (NNT: 8). Moreover, there are 27% and 15% reductions in the risk of swelling
and water retention, respectively with dasatinib 140 mg. However, the risk of neutropenia
and thrombocytopenia increases by 22% (NNH: 5) and 42% (NNH: 2), respectively(60)(B).
These results remain constant at 18 months of follow-up with an increase in disease-free
survival(61)(B).
The treatment of these patients (CML in chronic phase, resistant to imatinib) with
dasatinib 100 mg/day compared to 140 mg/day leads to a similar clinical response in
6 months and 2 years of follow-up (complete hematologic response, cytogenetic response
and disease-free survival), however the risk of pleural effusion is reduced by 9%
(NNT: 11), of thrombocytopenia by 15% (NNT: 7) and of discontinuity of treatment(62,63)(A).
The response rate of chronic phase CML patients under nilotinib treatment (400 mg
b.i.d) is no different to patients resistant or intolerant to imatinib (600 mg/day).
The lack of response to imatinib (hematologic or cytogenetic) predicts absence of
response to nilotinib(64)(B). Patients who attain a response with nilotinib remain
with 96% to 98% of the response (hematologic or cytogenetic) at 6 months of follow-up(65)(B).
The mean time to obtain a complete hematologic response is 2.8 months and complete
cytogenetic response is 3.2 months, with disease-free survival and overall survival
at 24 months being estimated at 64% and 87%, respectively(66)(B). Patients resistant
to imatinib or dasatinib treatment attain 79% complete hematologic response and 24%
complete cytogenetic response at 12 months(67)(C).
In chronic phase CML patients resistant to imatinib and dasatinib, treatment with
bosutinib (500 mg/day) produces complete hematological and complete cytogenetic responses
in 62% and 31% of the cases, respectively. Patients resistant to imatinib and nilotinib
treatment achieve complete hematological and complete cytogenetic responses in 75%
and 35% of cases taking bosutinib (500 mg/day). In cases of resistance to imatinib
or dasatinib, the likelihood of maintaining response, disease-free survival and overall
survival from 12 months on are 27%, 32.4% and 72.9%, respectively. In patients resistant
to imatinib and nilotinib treated with bosutinib, the odds of maintaining response,
disease-free survival and overall survival from 12 months, are 22.2%, 44.4% and 77.7%,
respectively(68)(B).
Recommendation: Chronic phase CML patients, who are resistant to imatinib at a dose
of 400 mg, should be treated with dasatinib (100 mg/day), nilotinib (800 mg/day) or
bosutinib (500 mg/day).
Are there differences in the toxicity profiles of second-generation tyrosine kinase
inhibitors (dasatinib and nilotinib)?
The difference in adverse effects between imatinib with nilotinib or dasatinib is
expressed as the NNT; when these latter two drugs produce a reduction in the risk
of adverse effects and the number needed to harm (NNH) when the risk of a particular
adverse effect increases.
The use of nilotinib (at any dose) as first-line therapy of patients with newly diagnosed
CML reduces the rates of nausea (NNT: 8), diarrhea (NNT: 7), vomiting (NNT: 6), muscle
spasm (NNT: 6), edema (NNT: 11) and neutropenia (NNT: 3) when compared to imatinib.
However, the rates of rash (NNH: 4), headache (NNH: 8), pruritus (NNH: 8) and alopecia
(NNH: 11) are increased and there are increases in liver enzymes (NNH: 2), total bilirubin
(NNH: 2) and glucose (NNH: 5)(43)(A).
When nilotinib is given as second-line therapy in chronic phase CML patients, cardiotoxicity
can occur with increases in the QT interval (QTc - 1% of cases) and thrombocytopenia
(29% of cases)(65)(B).
In a comparison of dasatinib and imatinib as first-line therapy for CML, the main
non-hematological adverse effects including nausea (NNT: 9), myositis (NNT: 8) and
water retention (NNT: 4) are reduced with dasatinib. However, there are increases
in pleural effusion in 10% (NNH: 10), thrombocytopenia in 9% (NNH: 11) and cardiotoxicity
in 0.4%(41)(B).
As second-line therapy in chronic-phase CML patients, dasatinib produces increases
in the rates of pleural effusion (NNH: 6), neutropenia (NNH: 5), thrombocytopenia
(NNH: 2), dyspnea (NNH: 6) and headache (NNH: 7)(60)(B).
Recommendation: With regards to most expected adverse effects using this class of
medication, dasatinib and nilotinib have similar results but with slight differences
in the degree. However, nilotinib seems to cause more hepatotoxicity and dasatinib
causes more water retention (pleural effusion).
Does adherence to imatinib treatment have prognostic impact?
CML patients on imatinib treatment who have suboptimal response are less adherent
to treatment (do not take the medication) than patients with optimal response. Patients
treated for more than 12 months who have complete cytogenetic response also have better
compliance than those with partial cytogenetic response. There is no difference in
the hematologic response between adherent and non-adherent patients(69)(B).
There is a direct correlation between adherence (< 90% or > 90%) of CML patients to
imatinib treatment and the likelihood of major molecular response at 6 years (an increase
in 66.1% of response in adherence > 90%). When adherence is less than 80% there is
no molecular response. Patients who need to increase the dose of imatinib have 12.8%
reduction in adherence(70)(B).
In the treatment of CML with imatinib, < 85% adherence increases the risk of loss
of complete cytogenetic response by 34.9% (NNH: 3). No patients with adherence > 95%
lose cytogenetic response. Patients with adherence level < 85% who never attained
molecular response, have low adherence as a predictor of loss of cytogenetic response.
Adherence of < 85% reduces the disease-free survival by 37% (NNH: 3). Adherence rates
of more than 85% confer a similar prognosis as patients who have major molecular response(71)(B).
The 5-year disease-free survival in chronic phase CML patients who adhere to imatinib
treatment is 16.9% higher than for non-adherent patients. Non-compliance reduces the
possibility of complete cytogenetic response by 18% (NNH: 6). The greatest cause of
cessation of imatinib treatment (29.6%) is related to noncompliance. Complete cytogenetic
response is correlated to adherence to treatment, with a reduction in the response
in noncompliant patients by 20%(72)(B).
Recommendation: adherence to imatinib treatment is directly correlated to the probability
of molecular and cytogenetic responses and disease-free survival.
Are prior cytogenetic response to imatinib and performance status prognostic factors
for response to second-line tyrosine kinase inhibitors in imatinib-resistant patients?
The best cytogenetic response (0% positive Philadelphia chromosome) during treatment
with imatinib is predictive of response to dasatinib and nilotinib, with an increase
in cytogenetic response by 21% when compared to no cytogenetic response during treatment
with imatinib, i.e. Philadelphia > 95% (52)(B).
The response to second-line TKI of Imatinib-resistant CML patients is associated with
some other prognostic factors such as: 1. low-risk Sokal: 25.5% increase in cytogenetic
response and 27.0% in disease-free survival; 2. percentage of positive Philadelphia
chromosome at the beginning of treatment < 95%: 43.8% increase in the cytogenetic
response and 27.3% in disease-free survival; 3. time to therapeutic failure of imatinib
< 6 months: 37.2% increase in cytogenetic response, 24.3% increase in overall survival
rate and 13.8% increase in progression-free survival(52)(B).
The prognosis of treatment using second-line TKIs (nilotinib or dasatinib) in Imatinib-resistant
CML patients can be predicted by prior cytogenetic response (imatinib), giving an
estimated 37% increase in disease-free survival at 3 years and in the cytogenetic
response at 1 year. A performance status (European Cooperative Oncology Group - ECOG)
of "0" at the beginning of treatment with second-line TKIs, predicts an 18% increase
in disease-free survival and a 32% increase in overall survival at 3 years(73)(B).
Other prognostic factors may be associated with response to treatment with nilotinib
or dasatinib such as: age greater than 55 years with a 24% reduction in cytogenetic
response at 1 year, a 20% reduction in disease-free survival at 3 years and a 6% reduction
in overall survival at 3 years; > 90% Philadelphia chromosome-positive metaphases
at start of treatment with second-line TKIs with a 30% reduction in the cytogenetic
response and a 21% reduction in disease-free survival(73)(B).
Recommendation: Information related to cytogenetic response and performance status
(ECOG) should be used to assess prognosis on starting second-line treatment with TKIs
such as nilotinib or dasatinib in Imatinib-resistant CML patients. Additionally age
and cytogenetic response prior to treatment with second-generation TKIs should be
taken into account.
When is it necessary to make an analysis of BCR-ABL mutations in CML patients under
treatment with tyrosine kinase inhibitors?
BCR-ABL mutations are associated to 100% resistance to imatinib treatment in accelerated-phase
CML patients and in 79% of chronic-phase patients(74)(C).
The presence of BCR-ABL mutations increases the risk by 52% of chronic-phase CML patients
evolving to the accelerated or blast crisis phases within 9 months (NNH: 2). These
mutations, especially P-loop mutations, also reduce the time free of disease progression
and survival of these patients(75)(B).
In the follow-up of CML, BCR-ABL mutations occur at different times in patients under
treatment with imatinib and are correlated with lower survival rates. For patients
in the early phase of the disease, mutations are associated with increases in transformation
to the accelerated (32%) and blast crisis phases (16%) and a reduction in the complete
cytogenetic response (24%). Regardless of the stage of the disease, mutations reduce
hematologic response(76)(B).
BCR-ABL mutations in CML patients under imatinib treatment predict, within about 20
months, loss of complete cytogenetic response and progression to the advanced stages
of the disease(77)(B).
Hematologic and cytogenetic responses are similar in patients with and without BCR-ABL
mutations under treatment with second-generation TKIs (dasatinib and nilotinib). Moreover
disease-free survival and overall survival are not significantly different between
these two groups of patients(78)(B).
In the four-year follow-up of chronic phase CML patients, the time from the beginning
of imatinib treatment to the progression of the disease to the accelerated or blast
crisis phases is worse in patients with mutations than those without mutations. The
overall survival of patients without mutations and those with mutations is 51 and
10 months, respectively but this varies according to the type of mutation (P-loop
type - 13 months and T315I - 9 months)(79)(B).
Among chronic phase CML patients under nilotinib treatment, the two-year overall survival
is reduced by 38% in the presence of BCR-ABL mutations. In addition, the presence
of mutations is associated with a 34% reduction in the cytogenetic response(80)(B).
T315I mutations occur more often in patients treated with dasatinib. The presence
of mutations during nilotinib or dasatinib treatment is predictive of a worse prognosis
in these patients(21)(B).
Recommendation: BCR-ABL mutations should be investigated in CML patients resistant
to TKIs (suboptimal response or failure) regardless of the stage, because their presence
predicts the greater risk of resistance and shorter survival.
Does the diagnosis of mutations guide the choice of treatment in imatinib-resistant
patients?
In imatinib-resistant CML patients, mutations can assist in the choice of second-generation
TKIs (nilotinib or dasatinib). An evaluation of the sensitivity of mutations to inhibitors
in
in vitro
studies (IC50) defines three groups of sensitivity (low, intermediate and high concentrations)
of the mutation to: dasatinib (IC50 < 3 nM, 3-60 nM and > 60 nM) and nilotinib (IC50
< 50 nM, 50-500 nM and > 500 nM) with the worst case scenario (resistance) corresponding
to high concentrations(78)(B).
Hematologic and cytogenetic responses at one year are significantly lower in patients
with mutations and in the chronic phase, particularly for mutations with intermediate
IC50 (25% and 25%, respectively) compared to low IC50 (96% and 54%, respectively).
In the accelerated phase there is also a reduction in the cytogenetic response for
mutations with 10% reduction in intermediate IC50 and 31% reduction in low IC50,(78)(B).
In the chronic phase, the disease-free survival and overall survival are lower in
patients with mutations with high IC50 (0% and 75%, respectively), when compared with
mutations with low IC50 (78% and 100%, respectively)(78)(B). The T315I mutation is
associated with high IC50 (resistance) but there is no difference comparing dasatinib
and nilotinib(78)(B).
Other specific mutations associated with high IC50 (resistance) in the chronic phase
of CML treated with dasatinib are: T315I/A, F317L/I/V/C and V299L(81-83)(B), and with
nilotinib: T315I, Y253H, E255K/V and F359V/C(82,84)(B). The G250E mutation also has
an impact on resistance common in the two forms of treatment(83)(B).
Mutations associated with resistance to dasatinib such as V299L, T315A and F317I may
be sensitive to nilotinib, while the mutation V299L may be resistant to bosutinib(83-85)(B).
Complete cytogenetic response subsequent to treatment using dasatinib or nilotinib
is lower in patients with resistant mutations [mutations detected by sequencing that
confer resistance to the inhibitor received (0%) - T315I, F359V/C, F317L, Y253H, E255V/K]
compared to patients with other mutations (mutations detected by sequencing or spectrometry
of masses sensitive to the inhibitor received) or without mutations (41% and 49%,
respectively). The survival of chronic phase CML patients when resistant mutations
are detected is 0% compared with 51% and 45% in patients with other mutations or without
mutations, respectively(86)(B).
Recommendation: the identification of mutations, especially resistant mutations, can
assist in the choice of the TKI, allowing the definition of which therapeutic option
will provide the best response.
How should monitoring of CML patients taking tyrosine kinase inhibitors be performed?
Reports state that monitoring of chronic-phase CML patients for BCR-ABL mutations
during imatinib treatment can be achieved with PCR in peripheral blood (BCR-ABL/ABL
ratio) correlating this with the result obtained through the usual cytogenetic study
of bone marrow. This identifies responsive, partial responsive and unresponsive patients
in respect to BCR-ABL/gene control of up to 0.08%, of 0.08% to 10% and of above 10%,
respectively(87)(B).
In a randomized trial, 1106 CML patients were treated with interferon or imatinib
as first-line treatment. All patients who achieved cytogenetic remission performed
qPCR for BCR-ABL mutations. The results were expressed in terms of the logarithmic
reduction in relation to the median level of transcripts in 30 newly-diagnosed patients.
Patients who achieved complete cytogenetic remission and at least a 3-log reduction
in the level of transcripts, had progression-free survival of 100% at 24 months compared
to 95% for those with complete cytogenetic remission and less than a 3-log reduction
in the level of transcripts and 85% for patients without complete cytogenetic response(88)(B).
Thus, this form of monitoring also allows you to identify the 2-year progression-free
survival with the low values of transcripts(58,88)(B).
Using samples from 38 international centers, one study validated the use of an international
scale of BCR-ABL values that established 0.1% as a 3-log reduction(89)(B).
It is possible to stratify patients by PCR during the 3 years follow-up as patients
whose indexes reflect increases, stability or reduction, or even loss of cytogenetic
response(53)(B).
Plasma imatinib levels are significantly higher in patients with molecular and cytogenetic
responses compared to patients without response. The level that differentiates the
difference between molecular response and lack of response with the greatest accuracy
(77% sensitivity and 71% specificity) is 1002 ng/mL(90)(B).
The use of FISH to monitor CML patients on imatinib treatment enables the use of peripheral
blood to identify cytogenetic response. A positive result points to the absence of
cytogenetic response and a negative result identifies its presence. The association
with PCR allows the molecular response to be monitored. In a study published by Reinhold
et al., the estimated cytogenetic and molecular responses at 5 years were 81.7% and
67.1%, respectively(54)(B). However, the comparison between the results of FISH using
peripheral blood leukocytes and the cytogenetics of the bone marrow may not establish
an appropriate correlation in the measurement of CML activity during imatinib treatment(91)(B).
The existence or occurrence of mutations in CML patients under TKI treatment, when
identified, enables an estimation of the prognosis and guides treatment. High-performance
liquid chromatography (HPLC) is a practical and sensitive method to identify mutations
to clinically monitor patients(92)(B).
Some mutations can be identified by direct sequencing during the follow-up of patients
including: T315T, T315I, F317L, V339L, M351T, E355G, Y253F and F359V; these are associated
with different responses to available inhibitors. A 31% reduction in the overall survival
of patients with mutations is identified in the 3-year follow-up(74)(B).
Recommendation: The monitoring of CML patients treated with TKIs can be accomplished
by bone marrow cytogenetics and qPCR for the BCR-ABL gene in peripheral blood, thereby
allowing an estimation of prognosis and the definition of therapeutic strategies.
Mutational analysis should be performed in patients with suboptimal response or loss
of response to TKIs.
When should bone marrow transplantation be indicated for CML patients?
Imatinib may be used as treatment for relapse after allogeneic hematopoietic stem
cell transplantation, the prevalence of which ranges from 40% to 70% at 5 months.
In the chronic phase, the cytogenetic and hematologic response rates obtained and
survival at 9 months are 58%, 84% and 100%, respectively(93,94)(B). Imatinib came
to be used as first-line treatment in the chronic phase of CML demonstrating increased
survival when used before bone marrow transplant(95)(B).
Due to the lower cost, resistance to imatinib or advanced stages of the disease (accelerated
and blast crisis phases), some series of cases of transplant in CML have been reported
with comparative results or in association to imatinib, demonstrating similar disease-free
survival, overall survival and cardiotoxicity(96)(C).
The previous use (before transplantation) of imatinib in patients with advanced stages
of CML, produces hematological response in 73% and cytogenetic response in 40% of
patients, and 3 years after the transplant, 66.7% of patients have complete molecular
response(97)(C).
In a prospective study, Jiang et al. compared accelerated phase patients treated either
with imatinib (n = 87) or allogeneic transplantations (n = 54). In this study, multivariate
analysis established hemoglobin < 10.0 g/dL, blasts in peripheral blood < 5% and disease
duration of less than 12 months as independent risk factors for survival. High-risk
(two risk factors or more) or intermediate-risk patients (one risk factor) had better
overall survival and progression-free survival with allogeneic transplant. No difference
was seen with low-risk patients(98)(BII).
The mortality of CML patients on imatinib treatment associated to hematopoietic stem
cell transplant is 9.7% and the relapse rate is 5.0% at one year(99)(C).
Despite the new options in imatinib-resistant patients, such as dasatinib and nilotinib,
non-comparative case series that associate TKIs and transplant are still being performed(100)(C).
Data are still limited for the pediatric population, but the results with imatinib
are similar to those seen in adults. Millot et al. published their experience in 44
children with newly diagnosed CML treated with imatinib. With a median follow-up of
31 months, the estimated progression-free survival at 36 months was 98%. The rates
of complete cytogenetic response and major molecular response at 12 months were 61%
and 31%, respectively. About 30% of the children discontinued the use of medication,
mainly due to lack of effectiveness. There are adverse effects of TKIs on the growth
of children and this aspect should be monitored(101)(BII).
Moreover, researchers reported the results of a prospective study involving 200 CML
children and adolescents treated by allogeneic transplantation according to donor
availability. The probability of survival at five years was 87 ± 11% for matched related
donors, 52 ± 9% for matched unrelated donors and 45 ± 16% for unmatched donors. The
likelihood of relapse at 5 years was 20 ± 12%(102)(BII).
Recommendation: Bone marrow transplantation is a therapeutic option to treat CML but
it should be reserved for cases resistant to TKI treatment and patients in the advanced
stages of the disease after an initial course of TKIs.