H e m a t o lo g y E d u c a t io n - European Hematology Association

H. Kantarjian
J. Cortes
Leukemia Department,
The University of Texas,
M.D. Anderson Cancer Center,
Houston, TX, USA
Hematology Education:
the education program for the
annual congress of the European
Hematology Association
2011;5:127-131
Chronic myeloid leukemia
Imatinib-resistant chronic myeloid leukemia.
Definitions and management
Imatinib mesylate, a selective BCR-ABL1
tyrosine kinase inhibitor (TKI), has revolutionized
the treatment of patients with
Philadelphia (Ph)-positive chronic myeloid
leukemia (CML). In newly diagnosed patients
in chronic phase, imatinib therapy is associated
with a cumulative best complete cytogenetic
response (CCyR) rate of 85%, an estimated
5-year CCyR rate of 67%, and an estimated
7–10 year survival rate of 80–85%; 90–
93% if only CML-related deaths were
accounted for. 1–5 Despite this success, about 2–
5% of patients develop imatinib resistance
requiring alternative therapies. This failure
rate figure varies depending on how failure is
defined; for example, whether it includes only
patients who develop hematologic resistance
or transformation to accelerated or blastic
phase (AP-BP), or whether it includes additional
other events, such as loss of complete or
major cytogenetic response, TKI related toxicities
preventing further continuation of imatinib,
or other events. In the original IRIS trial,
the reported failure rate, defined as progression
to AP-BP or death on imatinib, or loss of
complete hematologic or major cytogenetic
response on imatinib, was 2–4% annually. 3 In
recent trials, randomizing patients to nilotinib
versus imatinib, or dasatinib versus imatinib,
the early rate of being off TKI therapy was
surprisingly high, in the range of 8–20%. 6,7
This may be due to the particulars of the study
protocols, the definitions of events resulting in
patients not continuing on the TKI, or the
availability of multiple TKIs, which lowered
the threshold for changing therapy by both
the treating physicians and the patients.
Several treatment options are highly effective
in patients with CML after failure of
imatinib therapy. However, the strict definition
of imatinib failure, either resistant disease
clearly associated with worse long-term
outcome, or severe intolerance to imatinib
precluding further therapy even after dose
adjustments and maximum supportive care,
is important. This is in order not to discard
an effective therapy, imatinib, which soon
will become available in generic formulations
at a lower cost. In this review, the definition
of imatinib failure versus resistance,
and the treatment options, including second
and third generation TKIs, non-TKI therapies,
and allogeneic stem cell transplantation
(SCT) will be discussed.
Definitions of imatinib failure
Aside from imatinib severe or moderatechronic
toxicity interfering with patient
quality of life, imatinib failure should be
defined as an event that predetermines a
worse long-term outcome. The latter could
be measured by overall survival, progression-free
survival (PFS), event-free survival
(EFS), transformation-free survival, survival
without AP-BP, or other clinically relevant
definitions. These definitions have become
extremely confusing, accounting for progressions,
events, or even deaths in different
ways. For example, deaths could be reported
as all-cause, or CML-related. Also, progression/event
may not be accounted for in
patients who discontinue TKI therapy for
toxicities, if progression/event, or even
death, occur beyond 1–2 months after discontinuation
of TKI therapy. 8,9 In the classic
definition of EFS by the IRIS (event = death
from any cause on imatinib, development of
AP-BP, loss of complete hematologic
response (CHR), loss of major cytogenetic
response, increasing white blood cell count), 2
the 8-year EFS rate was 81%. With more
inclusive definitions of EFS (event = any
occurrence resulting in discontinuation of
TKI; intention to treat analysis), the estimated
5-year EFS rates ranged from 63–80%. 8,10
Achievement of CCyR has been clearly
associated with improved long-term outcome,
measured by survival, PFS, and EFS
with interferon alpha therapy and with
TKIs. 1,11 Therefore, achievement of CCyR, in
our opinion, is the only reproducible surrogate
endpoint for long-term prognosis in
patients who have received imatinib therapy
for more than 1 year. The European
Leukemia Network (ELN) guidelines clearly
define imatinib resistance (Table 1). Patients
who do not achieve CHR (or perhaps a
minor cytogenetic response) at 6 months, a
major cytogenetic response (Ph-positive less
than 35%) at 12 months, or CCyR beyond 1
year of therapy, or who lose CCyR or CHR
at any point beyond this, are clearly patients
with imatinib resistance requiring a change
of therapy 12 (Table 1).
The question of when to change imatinib
therapy has been muddied by the proposal
of definitions of sub-optimal versus optimal
response. A sub-optimal response is a status,
Hematology Education: the education programme for the annual congress of the European Hematology Association | 2011; 5(1) | 127 |