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Chronic myeloid leukemia treatment guidelines: Brazilian Association of Hematology, Hemotherapy and Cell Therapy. Brazilian Medical Association Guidelines Project – 2012
Rev Bras Hematol Hemoter. 2012;34(5):367-82
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,