FEATURE
Drawing First Blood
“We know
that transplant is
tough on
patients, so
we need
to focus
on those
who do
not need a
transplant.”
—ALAN K. BURNETT, MD
REFERENCES
1. Koreth J, Schlenk R, Kopecky
KJ, et al. Allogeneic stem
cell transplantation for
acute myeloid leukemia in
first complete remission:
systematic review and
meta-analysis of prospective
clinical trials. JAMA.
2009;301:2349-61.
2. Burnett AK, Goldstone A,
Hills RK, et al. Curability of
patients with acute myeloid
leukemia who did not
undergo transplantation in
first remission. J Clin Oncol.
2013;31:1293-1301.
3. Burnett AK, Hills RK,
Wheatley K, et al. Sensitive
risk score for directing
treatment in younger
patients with AML. Blood.
2006;108:10a (Abstract 18).
46
ASH Clinical News
Now, while transplant was clearly
beneficial to event-free survival, when
we start looking at the overall survival, I
think that benefit becomes less clear.
Obviously, there is some risk associated
with forgoing transplant at CR1 because
the patient may not reach second complete
remission (CR2). The literature points to
several features as predictive of relapse risk,
but we must be careful not to assume that
presence of these features means a patient
will automatically benefit from transplant.
For example, would a patient with the
monosomal karyotype benefit from transplant? This karyotype is associated with a
very poor prognosis, but does a transplant
help? It is our only treatment option, so we
will go ahead with transplant, but I’m not
sure it does our patients any good.
Yes, there are very few data suggesting
that intermediate-risk patients undergoing transplant will have shorter survival,
but we do know that a transplant is tough
on patients. It can leave them with chronic
debilitating problems. Therefore, we also
need to focus in on the patients who do
not need a transplant.
In that vein, residual disease measurement is a very influential predictor of outcome of transplant. The data tell us that if a
patient is negative for minimal residual disease (MRD) and undergoes transplant, he
or she will likely have a very good outcome;
if a patient is positive with MRD, he or she
won’t. MRD is also particularly interesting
because it allows you to tailor treatment
to the individual patient – rather than to
use information about average outcomes.
I think this could be a very important step
forward in defining who needs what in
terms of further treatment.
Dr. Majhail: Now, speaking of the literature on this topic, I wanted to look
at a 2013 paper in the Journal of Clinical
Oncology that analyzed outcomes and survival in patients in the Medical Research
Council AML10, 12, and 15 trials, which
included 3,415 patients who entered CR1
(2,029 were intermediate-risk patients).2
Of the total population, one-third
received a transplant in CR1. Overall,
1,271 patients (60%) who did not receive
transplant in CR1 relapsed (61% of these
patients were considered intermediate-risk
according to their cytogenetic profile).
Only half of these patients (642 people)
eventually achieved CR2 (59% of whom
were intermediate-risk patients). Essentially, of all patients who relapsed without a
transplant in CR1, only one-third went on
to receive a transplant in CR2. The numbers were similar when considering the
specific subgroup of intermediate-risk patients, in which, again, only one-third of all
patients who relapsed received a transplant.
When patients were transplanted in CR2,
their survival was lower than what might
be expected for transplantation in CR1.
Keeping in mind that these data
represent patients enrolled on those trials,
I can deduce that many intermediate-risk
AML patients will eventually relapse and,
among those who relapse, only half will
eventually achieve CR2. At the end of the
day, a majority of patients do not end up
getting to a transplant and are not able to
receive any of the procedure’s potential
benefits. Even if you disagree with universal transplant in CR1 in these patients,
you have to agree that there is value in at
least considering it for appropriate patients.
Dr. Burnett: Our interpretations of those
data are a bit different: You are correct that
only about 50 percent of patients with intermediate risk will achieve CR2 and about
one-third of the patients got a transplant
in CR2. Generally speaking, about 20 to 25
percent of patients can be rescued if there is
a donor readily available. To me, these data
tell me that a proportion of intermediaterisk patients can be salvaged. In an eventfree analysis this group is excluded. These
numbers have to be added to the numbers
of patients who survive with chemotherapy
in CR1. This illustrates why overall survival
is an important endpoint to consider,
rather than just event-free survival.
Dr. Majhail: One has to keep in mind
that survival after transplant in general
has improved considerably over the past
few decades. The relatively high rates of
transplant-related mortality that were
reported in historical studies are really
not reflective of the supportive care we
routinely offer patients today. We are
getting better at choosing patients for
transplantation, including incorporating
newer factors into the decision process.
Of course, the decision gets even more
complex in older patients. AML is typically a disease of older patients, who carry
more comorbidities than younger patients
do. Newer instruments, like the HCTComorbidity Index and the EBMT risk
score, are helping us better classify the risk
of transplant-related mortality. Also, availability of a donor is no longer a barrier to
transplantation; with an increasing pool of
unrelated donors and with umbilical cord
blood and haploidentical donor sources
becoming more mainstream, essentially
all patients who need an allogeneic transplant have a potential donor.
To change direction a bit, we should
discuss older patients with AML – a group
that has universally poor outcomes with
chemotherapy only and should be considered, if appropriate, for transplant in CR1.
Reduced-intensity conditioning (RIC)
transplantation offers a relatively low risk
of transplant-related mortality and opens
up the possibility of allogeneic transplantation for older patients with AML. RIC
transplant seems to produce lower relapse
and better leukemia-free survival than
chemotherapy alone. One can argue that
transplant should be strongly considered
for appropriately selected older patients
with intermediate-risk AML in CR1.
Dr. Burnett: For an older patient who is
in otherwise good condition, there is no
question in my mind that RIC transplant
should be considered. In our experiences
with older patients – in about 100 to 150
patients older than 60 years – there is
little evidence that these patients benefit
from consolidation chemotherapy. The
odds of any level of survival after relapse
are low for these patients, so, obviously,
delaying a transplant when the opportunity is there is inadvisable.
However, when our investigators
looked into RIC transplants in older
patients, they found that, in fact, less than
10 percent of older patients in remission
end up going down this route. I do think a
proportion of older patients could benefit
from the RIC transplant but are not currently being offered it due to many factors
– perhaps the comorbidity burden rules
out this approach, or the donor might not
be medically suitable.
People used to believe that RIC transplant would never work in AML, citing
its poor graft-versus-leukemia effect and
the fact that it takes time for RIC transplant to produce some effect – by which
time the patient has probably relapsed. I
think we are at a point now where we can
control leukemia, and RIC transplant is a
feasible way to do so. Ultimately, though,
the choice will depend on what we learn
in future years about the best conditioning
schedule for RIC transplant.
Dr. Majhail: With all the new research in
the field of AML, I think we can expect
perspectives in this debate to continue
to change. Newer therapies, including
FLT3-inhibitors and IDH2 inhibitors, may
change the “control arm” for transplant.
We can at least agree that all patients with
intermediate-risk disease should get a
transplant consult early in their disease
course. The last thing we want is a delayed
transplant in a transplant-eligible patient,
or to see a patient relapse while waiting for transplant. So, treatment of these
patients should be a collaborative effort
between the leukemia physician and the
transplant physician.
Dr. Burnett: I agree – the feasibility of
transplant has to be known very e arly
in a patient’s management. Perhaps the
discussion we need to have with patients
is not “to transplant or not to transplant,”
but whether he or she needs the transplant
now or later, after demonstrating an absolute need for it. ●
Navneet Majhail, MD, is director of the
Blood & Marrow Transplant Program at
Cleveland Clinic Taussig Cancer Institute in
Cleveland, Ohio.
Alan K. Burnett, MD, is head of the department of hematology at the Cardiff University School of Medicine in Cardiff, United
Kingdom.
January 2015