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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
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.