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Souza CA, Pagnano KB, Bendit I, Conchon M, Freitas CM, Coelho AM, Funke VA, Bernardo WM
Rev Bras Hematol Hemoter. 2012;34(5):367-82
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 (IC
50
) defines three groups of sensitivity (low, intermediate
and high concentrations) of the mutation to: dasatinib (IC
50
≤ 3 nM,
3-60 nM and > 60 nM) and nilotinib (IC
50
≤ 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 IC
50
(25%
and 25%, respectively) compared to low IC
50
(96% and 54%,
respectively). In the accelerated phase there is also a reduction
in the cytogenetic response for mutations with 10% reduction
in intermediate IC
50
and 31% reduction in low IC
50
,
(78)
(B). In the
chronic phase, the disease-free survival and overall survival are
lower in patients with mutations with high IC
50
(0% and 75%,
respectively), when compared with mutations with low IC
50
(78%
and 100%, respectively)
(78)
(B). The T315I mutation is associated
with high IC
50
(resistance) but there is no difference comparing
dasatinib and nilotinib
(78)
(B).
Other specific mutations associated with high IC
50
(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).