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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
the presence of 1% to 19% blasts in the blood or bone marrow,
basophils > 20%, thrombocytosis or thrombocytopenia not related
to therapy and clonal evolution in cytogenetic evaluation. The
blast crisis phase is characterized by blasts > 20% of peripheral
blood white cells or extramedullary blast proliferation
(1-3)
(D).
Recommendation:
Diagnosis of CML depends on the
identification of the Philadelphia chromosome or the
BCR-ABL rearrangement.
Is there any difference in the prognosis of CML patients
with p210 e13a2(b2a2) and e14a2(b3a2) or (e1a2)
p190 rearrangements?
The prevalence of the e1a2 BCR-ABL fusion transcript
in CML patients is 1%. This rearrangement is associated with
decreased therapeutic response to tyrosine kinase inhibitors
(TKIs) as complete hematologic response is attained in only 30%
of cases, complete cytogenetic response in 20% (3 to 18 months)
and major molecular response in 10% of cases. Progression to
other phases (accelerated or blast crisis) occurs in 60% of chronic
phase patients
(4)
(C).
The response of treatment-naïve CML patients to imatinib
treatment is different for the b3a2(e14a2) and b2a2(e13a2)
transcripts. In 12 months of treatment, patients with the
b3a2(e14a2) transcript have a 29% increase in complete
cytogenetic response, which is faster, and greater disease-free
survival
(5)
(B).
In CML patients on imatinib treatment for six months, the
number of b2a2(e13a2) transcripts is lower when compared to the
number of b3a2(e14a2) transcripts, suggesting greater sensitivity
of the b2a2(e13a2) transcripts to imatinib and consequently
prognosis is better
(6)
(B).
Imatinib treatment in chronic-phase CML patients with the
BCR-ABL b2a2(e13a2) transcript has better results compared to
those with the b3a2(e14a2) transcript with a 31% increase in the
major cytogenetic response and a smaller number of BCR-ABL
transcripts
(7)
(B).
Recommendation:
the (e1a2)p190 transcript is associated
to a reduced therapeutic response; there is controversy as
to whether there is difference in response between the
p210 e13a2(b2a2) and p210 e14a2(b3a2) transcripts.
At diagnosis, do the Philadelphia chromosome and 9q
deletion have prognostic significance?
There is no difference in survival between CML patients
with the chromosome 9q deletion on interferon alpha treatment
and those without this deletion. However, there is a reduction in
the survival of patients with the deletion spanning the BCR-ABL
junction compared to those without this deletion. The survival
rate is 44% higher in chronic phase patients submitted to bone
marrow transplantation who do not have the deletion (Number
needed to treat - NNT: 2)
(8)
(B). There is evidence that the
disease-free survival, overall survival and cytogenetic response
is reduced in CML patients with the chromosome 9q34 deletion
under treatment with interferon alpha
(9,10)
(B).
A comparison of first-generation (imatinib) or second-
generation (nilotinib or dasatinib) TKIs in the treatment of CML
patients with chromosome 9 deletion shows that there is no
significant difference in the overall survival, disease-free survival
or in cytogenetic response between patients with and without
the chromosome 9 deletion over a two-year follow-up
(11,12)
(B).
There is, however, evidence that there is a reduction in survival
of patients with derivative chromosome 9 deletions
(13)
(B).
The ABL deletion on derivative 9 (15.1%) in CML patients
reduces disease-free survival, the BCR deletion reduces overall
survival and combined ABL and BCR deletions reduce the
overall and disease-free survival
(14,15)
(B). There is evidence that
only the ABL deletion reduces the survival time and the duration
of the chronic phase
(16)
(B).
Over a 5-year follow up of imatinib treatment, CML patients
with variant Philadelphia chromosome translocations do not
demonstrate significant differences in overall survival, disease-free
survival, progression-free survival, completehematological response,
cytogenetic response or molecular response compared to patients
without variant Philadelphia chromosome translocations
(17,18)
(B).
Other studies have shown that Philadelphia chromosome mosaicism
increases mortality in 3.3 years by 21% (NNH: 5) and translocation
variations reduce cytogenetic response
(19,20)
(B).
Recommendation:
Despite controversy on whether
chromosome 9q, BCR deletions and variant Philadelphia
chromosome translocations confer worse prognoses,
there is evidence of reductions in overall and disease-
free survival and in therapeutic response of CML
patients treated with interferon alpha or first-generation
and second-generation TKIs. ABL deletion reduces the
overall and disease-free survival of patients. The presence
of variant Philadelphia chromosome translocations and
mosaicism also seem to confer worse prognosis in CML.
Do cytogenetic abnormalities in addition to the
Philadelphia chromosome at diagnosis have prognostic
significance?
In CML patients under treatment using first-generation
(imatinib) and second-generation (dasatinib or nilotinib) TKIs,
the presence of additional chromosomal abnormalities reduces
disease-free and overall survival at 5 years
(21)
(B).
The presence of additional chromosomal aberrations in
CML patients under treatment with nilotinib increases mortality
by 28% due to disease progression (NNH: 4). In addition,
mortality is increased by 38% at 2 years in chronic phase patients
with additional chromosomal aberrations (NNH: 3)
(22)
(B).
Aberrations reduce the survival time of these patients
(23,24)
(B).
The presence of additional chromosomal aberrations increases