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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
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 tomost 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).