NcXHF

RECOGNIZING AND MANAGING HIGH-RISK CML
have a higher risk or progression, they are not considered as
having advanced CML. Given that the distinction between
CP-CML and BP-CML can hinge on minute differences in
the white blood differential count, it is obvious that the separation
of high-risk CP-CML from AP-CML may be more
theoretical than practically relevant. Consistent with this,
gene expression profıling studies on CP-CML, using mononuclear
cells or CD34 cells, have revealed overlap between
poor-prognosis CP-CML and BP-CML. 11-13
TABLE 3. Mutations Associated with Blastic-Phase
Chronic Myeloid Lymphoma
Mutation/Mutated Gene
% Prevalence
Double Ph 38%
Isochromosome 17q
30% (myeloid)
Trisomy 8
53% (lymphoid)
Trisomy 19
23% (myeloid)
p53
20–30% (myeloid)
p16
50% (lymphoid)
NUP98-HOXA9
NR
AML1-EVI1
NR
GATA-2
18% (lymphoid)
RUNX1
38% (myeloid)
CDKN2A/B
50% (lymphoid)
IKZF1
55% (lymphoid)
ASXL1
20.5% (myeloid)
TET2
7.7% (myeloid)
WT1
15.4% (myeloid)
NRAS/KRAS
5.1/5.1% (myeloid)
Abbreviation: NR, not reported.
MOLECULAR UNDERPINNING OF BLASTIC
TRANSFORMATION
The salient morphologic feature of BP-CML is loss of cellular
differentiation capacity, which may occur suddenly or
gradually through the intermediate stage of AP-CML. Progression
is frequently associated with clonal cytogenetic evolution.
The distinction between major (8, isochromosome 17q,
additional Ph, 19) and minor route abnormalities (all others)
is of limited clinical signifıcance once transformation has
occurred. However, in newly diagnosed CP-CML major
route abnormalities are associated with a poor outcome with
imatinib treatment. 14 At the molecular level, multiple somatic
mutations have been identifıed upon transformation,
but there is no characteristic molecular abnormality (Table
3). 15 Unsurprisingly, lymphoid BP-CML resembles Ph
acute lymphoblastic leukemia (ALL), whereas mutations
typical for AML and myelodysplastic syndromes are dominant
in myeloid BP-CML. Core binding factor mutations
such as AML1-ETO and CBFB-MYH11 are uncommon in
BP-CML, suggesting that the differentiation block of BP-
CML has a different molecular basis. Epigenetic dysregulation
is likely to play a major role, for example through
increased BCR-ABL1 expression that in turn suppresses the
myeloid transcription factor CEBPA. 16,17
APPROACH TO THE PATIENT PRESENTING WITH
ACCELERATED-PHASE/BLASTIC-PHASE CHRONIC
MYELOID LEUKEMIA
As presentation of CML in AP or BP is uncommon in the
developed world, there is limited data for this group of
patients. However, second-generation TKIs are preferred
over imatinib. In the salvage setting, dasatinib has shown
slightly higher response rates and more durable responses
in CML-AP and is currently the only second-generation
TKI approved for BP-CML. 18 In the case of blastic transformation,
TKIs are usually combined with AML- or ALLtype
multiagent chemotherapy, whereas this is not
typically the case for AP. 19 All patients with AP/BP-CML
should be considered for an allogeneic stem cell transplant,
with TKI therapy used to restore a second chronic
phase and bridge the time to transplant. Therefore, human
leukocyte antigen typing and a transplant consultation are
essential parts of the initial workup for patients who present
in AP/BP. Whether or not to proceed to allografting in
a patient with AP/BP-CML who attained a very good response
to TKI can pose an extremely challenging clinical
decision, and it is wise to discuss this eventuality before
starting TKI therapy. Transplant risk, comorbidities, and
the patient’s personal preferences are critical factors.
DEFINING TREATMENT FAILURE
Resistance to Tyrosine Kinase Inhibitors
Clinical TKI resistance is grouped into primary and acquired
resistance. At a mechanistic level, resistance can be
classifıed as BCR-ABL1–dependent or BCR-ABL1–independent.
In BCR-ABL1–dependent resistance, there is
reactivation of BCR-ABL1 kinase, which implies that responses
may be recaptured if BCR-ABL1 inhibition is restored.
In BCR-ABL1–independent resistance, alternative
pathways substitute for BCR-ABL1 kinase activity. 20
BCR-ABL1 Kinase Domain Mutations
The best characterized mechanism of TKI resistance is
point mutations in the BCR-ABL1 kinase domain that impair
drug binding. 21 Solving the crystal structure of ABL1
in complex with an imatinib analog was instrumental to
understanding how kinase domain mutations cause resistance.
22 In contrast to expectations, imatinib was found to
bind an inactive conformation of ABL1, with the activation
loop of the kinase in a closed position. Additionally,
there was extensive downward displacement of the ATPbinding
loop. Mutations in the kinase domain can cause
resistance by steric hindrance or elimination of hydrogen
bonds, most impressively in the T315I mutation at the
gatekeeper position. A different type of mutation affects
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