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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
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.