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RECOGNIZING AND MANAGING HIGH-RISK CML
Diagnosing and Managing Advanced Chronic Myeloid Leukemia
Michael W. Deininger, MD, PhD
OVERVIEW
Clinical staging of chronic myeloid leukemia (CML) distinguishes between chronic phase (CP-CML), accelerated phase (AP-CML), and
blastic phase (BP-CML), reflecting its natural history in the absence of effective therapy. Morphologically, transformation from CP-CML
to AP/BP-CML is characterized by a progressive or sudden loss of differentiation. Multiple different somatic mutations have been
implicated in transformation from CP-CML to AP/BC-CML, but no characteristic mutation or combination of mutations have emerged.
Gene expression profiles of AP-CML and BP-CML are similar, consistent with biphasic evolution at the molecular level. Gene expression
of tyrosine kinase inhibitor (TKI)–resistant CP-CML and second CP-CML resemble AP/BP-CML, suggesting that morphology alone is a poor
predictor of biologic behavior. At the clinical level, progression to AP/BP-CML or resistance to first-line TKI therapy distinguishes a good
risk condition with survival close to the general population from a disease likely to reduce survival. Progression while receiving TKI
therapy is frequently caused by mutations in the target kinase BCR-ABL1, but progression may occur in the absence of explanatory
BCR-ABL1 mutations, suggesting involvement of alternative pathways. Identifying patients in whom milestones of TKI response
fail to occur or whose disease progress while receiving therapy requires appropriate molecular monitoring. Selection of salvage
TKI depends on prior TKI history, comorbidities, and BCR-ABL1 mutation status. Despite the introduction of novel TKIs, therapy
of AP/BP-CML remains challenging and requires accepting modalities with substantial toxicity, such as hematopoietic stem cell
transplantation (HSCT).
It is thought that CML is initiated when a hematopoietic
stem cell acquires the t(9;22)(q11;34) reciprocal translocation,
which the cytogenetic correlate is the Philadelphia chromosome
(Ph). Based on the increase in CML incidence in
survivors of the atomic bombings on Japan, the latency between
this initial event to the clinical manifestation is estimated
to be approximately 8 years. 1 Whether or not a clonal
genetic lesion predates the acquisition of Ph or whether additional
genetic abnormalities are required to produce CP-
CML is a matter of debate. However, recent next-generation
sequencing studies suggest both scenarios are possible. 2
Without effective therapy, CP-CML invariably progresses to
an acute leukemia termed BP-CML, sometimes through an
intermediate stage referred to as AP-CML. BP-CML may
have a myeloid (70%), B-lymphoid (20%), or mixed phenotype
(10%). 3 Observations from the 1920s, when therapeutic
options were limited to splenic irradiation and arsenic trioxide,
suggest that the natural duration of CP-CML may be approximately
2.5 years. In the developed world, the vast
majority of patients are diagnosed in the chronic phase, frequently
when an abnormal complete blood count leads to a
diagnostic workup. Presentation with AP/BP-CML is more
common in countries with lower socioeconomic status,
probably reflecting delays in diagnosis as a result of insuffıcient
access to medical care. The term “advanced CML” is not
clearly defıned and variably used to include AP/BP-CML
only or also CP-CML resistant to standard therapy.
DEFINING ADVANCED CHRONIC MYELOID
LEUKEMIA: CHRONIC PHASE, ACCELERATED PHASE,
AND BLASTIC PHASE
Several different classifıcation systems have been developed
to defıne the phases of CML based on morphologic and clinical
criteria, including the International Bone Marrow Transplant
Registry (IBMTR), The University of Texas MD
Anderson Cancer Center (MDACC), and World Health Organization
(WHO) classifıcations (Table 1). The simultaneous
use of different systems has generated considerable
confusion, as different classifıcations may assign patients to
different disease phases and some of the criteria lack a precise
defınition. For example, the WHO defınition of AP-CML
uses increasing white blood cells and spleen size unresponsive
to therapy as defıning criteria. Another important discrepancy
is the bone marrow or blood blast percentage that
defınes BP-CML. Whereas the WHO classifıcation uses 20%
or greater as the cutoff (in line with acute myeloid leukemia
[AML]), MDACC and IBMTR classifıcations use 30% or
greater. The MDACC criteria defıning AP-CML were prospectively
validated as independent prognostic variables, and
From the Huntsman Cancer Institute, Division of Hematology and Hematologic Malignancies, University of Utah, Salt Lake City, UT.
Disclosures of potential conflicts of interest are found at the end of this article.
Corresponding author: Michael W. Deininger, MD, PhD, Huntsman Cancer Institute, Room 4280, 2000 Circle of Hope, Salt Lake City, UT 84112-5550; email: michael.deininger@hci.utah.edu.
© 2015 by American Society of Clinical Oncology.
asco.org/edbook | 2015 ASCO EDUCATIONAL BOOK
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