NcXHF

MICHAEL W. DEININGER
broad range effıcacy of ponatinib must be balanced against its
substantial cardiovascular toxicity, which is enhanced by
preexisting risk factors such as diabetes, hypercholesterolemia,
and hypertension. 54 Failure of ponatinib indicates a
patient is a candidate for non-TKI therapies, including omacetaxine,
a clinical trial, or HSCT. 44 This is particularly true
for patients with compound mutations that include T315I as
one component and may confer resistance to all currently approved
TKIs. 28 Dense qPCR monitoring is critical for patients
in whom second-generation TKIs failed, and those in
whom multiple TKIs have failed. When to proceed to HSCT
in a patient with CP-CML is a diffıcult clinical decision that
must take into account the transplant risk as well as the risk of
progression to AP/BC-CML. It is good clinical practice to refer
any transplant-eligible patient with progression on fırstline
therapy to a transplant center for an initial evaluation
and preliminary clarifıcation of donor options.
Progression to Accelerated-Phase/Blastic-Phase
Chronic Myeloid Leukemia
Patients who progress to AP/BP-CML are treated with the appropriate
TKI, taking into account prior TKI exposure history
and BCR-ABL1 mutation status. Given the limited therapeutic
options, more TKI toxicity is acceptable. Decisions whether or
not to combine TKI salvage with chemotherapy must be individualized
based on performance status and the availability of
allogeneic stem cell transplant as a potentially curative salvage
strategy. 19 Given the absence of controlled studies in this fortunately
rare patient population, the value of adding chemotherapy
is not completely clear, particularly in patients with myeloid
transformation. All eligible patients should be offered an allogeneic
stem cell transplant, and avoiding unnecessary toxicity in
potential transplant patients is an important consideration.
ALLOGENEIC STEM CELL TRANSPLANTATION
Allogeneic HSCT was the fırst treatment modality that restored
Ph-negative hematopoiesis and induced durable responses.
55 Before the introduction of imatinib, allografting
was recommended to all eligible patients and even today it is
still regarded as the only therapy with curative potential.
Only one study prospectively compared allotransplant versus
drug therapy. Newly diagnosed patients with CML-CP
were biologically randomly assigned to a matched sibling
transplant versus IFN-based drug therapy, the best nontransplant
treatment available when the trial was initiated. 56 Patients
managed with drug therapy had superior survival, with
the biggest difference observed in low-risk patients. After approximately
8 years, the survival curves crossed, suggesting
that transplant would be superior in the long-term if IFN was
the alternative. However, given the effıcacy of TKIs in the
fırst-line setting, and that early transplant-related mortality is
clearly higher than the risk of early disease progression, allotransplant
is no longer justifıable in newly diagnosed patients
with CML-CP, except in unusual circumstances. 57
Risk scores for allografting in CML were developed by the
European Group for Blood and Marrow Transplantation
(EBMT) in the pre-imatinib era and identifıed disease duration
of longer than 12 months, more advanced disease,
higher age, unrelated donor type, and the combination of a
male recipient with a female donor as adverse prognostic factors.
58 Disease phase had the greatest effect on outcome. Although
somewhat historic, the EBMT score is still useful for
prognostication. There is consensus that allotransplant
should be offered to all patients with progression to AP/BP. A
more individualized approach is required for patients in
whom dasatinib or nilotinib have failed in chronic phase,
given that ponatinib is effective, albeit at the cost of cardiovascular
toxicity. 54 Fortunately, there is no evidence that
imatinib or other TKIs before allografting negatively affect
the outcome. On the contrary, for unknown reasons, imatinib
before allotransplant seems to reduce the risk of chronic
graft-versus-host disease and possibly relapse risk. 59-61 Results
from the German CML study group reassert the importance
of transplanting patients while they are still in chronic
phase: 3-year OS was 91% for patients transplanted in CP after
imatinib failed versus 59% for patients transplanted in
AP/BP. 62 There is an emerging consensus that bone marrow
is preferred over peripheral blood stem cells in patients with
CML-CP, in whom graft-versus-host disease is a greater concern
than disease control. 63 This assessment is different for
patients with transformation to AP/BP, even if they have
achieved a second chronic phase. High relapse–risk patients
should receive a TKI post-transplant; BCR-ABL1 mutation
analysis at the time of resistance will help match the optimal
TKI to individual patients. Given the high median age at the
time of diagnosis, many patients will be eligible only for reduced
intensity conditioning regimens. An in-depth discussion
of the various conditioning regimens, selection of bone
marrow versus peripheral blood stem cells, and post-transplant
immunosuppression is presented elsewhere.
PERSPECTIVE
Despite the unparalleled success of TKI in CML, progression
during fırst-line TKI therapy, and transformation to
accelerated- or blastic-phase continue to carry a poor prognosis.
Although BCR-ABL1 mutations are a well-established
mechanism of TKI resistance, many cases of clinical resistance
remained mechanistically unexplained and are thought
to be a result of activation of alternative signaling pathways. In
these patients, salvage therapies are currently nonspecifıc. The
hope is that diverse upstream pathways may activate a limited
set of downstream effector molecules, thus providing an opportunity
for rationally targeted therapies that are applicable to a
wider population of patients. Early identifıcation of patients
with TKI failure or at risk of transformation is critical, so that
therapy can be adjusted in a timely fashion to maximize the
chances of successful salvage therapy. Despite the introduction
of new TKIs such as ponatinib, the prediction is that allogeneic
stem cell transplant will retain its position as the salvage therapy
of choice for patients who progress to AP/BC-CML.
e386
2015 ASCO EDUCATIONAL BOOK | asco.org/edbook