FEATURE
Drawing First Blood
are more targeted. None of them, though, are free
of side effects. Three of these drugs in development
– quizartinib, gilteritinib, and crenolanib – have
unique toxicity profiles and targeting abilities. Each
has been studied in relapsed disease and has induced
a leukemia-free state with tolerable toxicity.1,2,3
They are now being studied in randomized trials in
patients with relapsed disease and are, or soon will
be, evaluated as part of induction chemotherapy in
patients with untreated AML. Hopefully, these trials
will provide more information about the role of
FLT3 inhibition in patients with AML.
To date, no FLT3 inhibitor has – as a single
agent – resulted in a complete remission or normal
hematopoiesis in patients with AML, and no
FLT3 inhibitor combined with other drugs has
contributed to an overall survival (OS) benefit in
older patients in a randomized trial. Right now, we
are at the “tolerable” stage, rather than the “superior”
stage with these data.
Dr. Stone: True, we do not have much data in the
setting of older AML. The only real data to suggest
that we should be using a FLT3 inhibitor, along
with chemotherapy, in older patients are from the
RATIFY trial, which I presented at the 2015 ASH
annual meeting.4 Only patients aged 18 to 60 years
old, with a median age of 48 years, were included
in the trial, but, in the absence of definitive data, we
have to extrapolate from the data we do have.
In this phase III trial, 717 patients (341 FLT3ITD with low mutant fraction; 214 FLT3-ITD with
high mutant fraction; 162 with FLT3-TKD) were
randomized to receive a standard 7+3 regimen
with placebo or the investigational FLT3 inhibitor
midostaurin (administered orally at a dose of 50 mg
twice-daily on days 8-22). Post-remission therapy
consisted of high-dose cytarabine, plus midostaurin
or placebo. Patients then received one year of
maintenance therapy with midostaurin or placebo.
There was a survival benefit for patients who
received midostaurin compared with those who
received placebo. The median OS was significantly
longer (74.7 months vs. 25.6 months; p=0.007), and
the median event-free survival more than doubled
(8 months vs. 3 months; p=0.004).
Again, older patients were excluded, but the
finding that midostaurin improved outcomes in
all different subtypes of the FLT3 mutation was
promising, and suggests that we could explore the
safety and efficacy of midostaurin in different AML
populations.
Dr. Luger: RATIFY was a remarkable study for
patients with FLT3-mutated AML, who desperately
need more treatment options. There are still many
unanswered questions, though.
For example, we do not know exactly how
midostaurin worked – whether it worked primarily
as a FLT3 inhibitor or if it worked by enhancing
the effect of the anthracycline. Therefore, we do not
know whether these targeted drugs are really the
best approach for this patient population. And, even
if we had data that showed midostaurin exerted its
effect through FLT3 inhibition, we do not know if it
is the right FLT3 inhibitor to use.
And, since treatment toxicity is a primary
concern in older patients with AML, the fact that we
do not know whether midostaurin’s toxicity profile
changes in older patients versus younger patients is
another issue.
54
ASH Clinical News
Dr. Stone: We will have to conduct multivariate
analyses of different age groups to see if patients
benefitted similarly. If we find that the older RATIFY
patients (40-60 years old) benefitted equally to the
younger adults (18-40 years old), then we could
easily make the case that patients up to age 70 might
benefit similarly when midostaurin is added to the
standard 7+3 regimen.
Midostaurin is a multi-kinase inhibitor, and,
as we mentioned earlier, we won’t know whether a
more targeted FLT3 inhibitor would be better until
we have head-to-head trials comparing these agents.
Also, we don’t know if midostaurin works in patients
with low ITD burden; based on the available data, it
is possible that it could be effective in patients with
zero mutant FLT3. That’s not to mention the older
patient question, which is still wide open.
Midostaurin is not yet approved by the U.S.
Food and Drug Administration, but I would expect
that it will soon be approved in patients with FLT3mutated AML who are 18 to 60 years old. Future
trials will have to answer the questions, “Does it
make sense to extend the drug label to include
older people who are already planning to receive
chemotherapy? Should the label include any patient
who is going to receive 7+3, or only patients younger
than 60?”
Dr. Luger: Without answers to these questions,
we have to rely on the standard approaches for
FLT3-mutated AML, including 7+3 chemotherapy
and allogeneic hematopoietic cell transplantation
(alloHCT). AlloHCT is reserved for a certain group
of eligible patients, but we need to explore how old
is too old for a patient to undergo transplant? The
accepted limit seems to be up to 75 years, which
is similar to the cut-off age for induction therapy.
A retrospective analysis looking at FLT3-ITDmutated patients actually provided data that these
patients have a survival benefit when they undergo
alloHCT.5
The potential benefit of transplant in these
patients leads to another unanswered question about
FLT3 inhibitors: Is one of their benefits that these
agents can get patients to transplant? Transplant
ultimately may be what these patients need, and we
should use whatever agents we have to maximize
their chances to get to transplant.
Dr. Stone: I agree that these patients need to be
transplanted. Virtually all patients with the FLT3ITD mutation in first remission should receive a
transplant, no matter their age. There is a caveat
revealed by European data that showed that patients
with a low FLT3-ITD ratio and an NPM1 mutation
might not need to be transplanted.6 Again, hopefully
we will get more data about FLT3-TKD mutations
and transplant from the RATIFY trial.
I would note that the RATIFY data showed that
midostaurin benefited patients even if they had
received transplant at first remission. To achieve
maximum therapeutic benefit, according to the
RATIFY data, it still might be a good idea to use a
FLT3 inhibitor like midostaurin in these patients.
But, for the time being, I would say that transplant
is still part of the equation for patients with FLT3mutated AML.
Dr. Luger: We simply need more studies. We know
FLT3-ITD-mutated AML, whether in young or old
patients, carries a poor prognosis, and we know we
“Is it time to routinely
add a kinase inhibitor
to the standard
chemotherapy given
to [these patients]?” I
think the answer is a
qualified ‘yes,’ but not
a very strong one.”
—RICHARD M. STONE, MD
need to find new therapies. If the FLT3 inhibitors fill
that need, that would be wonderful, but we need to
continue the search for ways to improve on the AML
therapies we have.
Dr. Stone: I agree – every clinical question surround-
ing FLT3 inhibitors in older patients with AML
still needs to be answered. Even though we think
we have proven that midostaurin should be added
to chemotherapy in the younger population in the
RATIFY trial, it was not powered to look at patient
subsets, so we are still going to ask if this treatment
benefits everyone equally when the final data are
available.
Dr. Luger: The number of clinical questions remain-
ing highlights the challenges of doing these types
of studies in this patient population. These are very
complicated trials that require a lot of resources. For
example, we used to make decisions based on age,
organ function, and cytogenetics. Now, we need to
know patients’ FLT3 status to decide if they should
be enrolled in an FLT3 inhibitor trial, then we
need to know whether they have a high or low ITD
burden and what their NPM1 mutation status is. The
more we learn, the more we want to know. ●
REFERENCES
1. Hills RK, Gammon G, Trone D, Burnett AK. Quizartinib significantly improves overall
survival in FLT3-ITD positive AML patients relapsed after stem cell transplantation
or after failure of salvage chemotherapy: a comparison with historical AML database
(UK NCRI data). Blood. 2015;126:2557.
2. Altman JK, Perl AE, Cortes J, et al. Antileukemic activity and tolerability of ASP2215
≥80 mg in FLT3 mutation-positive subjects with relapsed or refractory acute myeloid
leukemia: results from a phase 1/2, open-label, dose-escalation/dose-response.
Abstract #321. Presented at the American Society of Hematology Annual Meeting,
December 6, 2015; Orlando, FL.
3. Cortes JE, Kantarjian HM, Kadia TM, et al. Crenolanib besylate, a type I pan-FLT3
inhibitor, to demonstrate clinical activity in multiply relapsed FLT3-ITD and D835
AML. Abstract #7008. Presented at the American Society of Clinical Oncology Annual
Meeting, June 4, 2016; Chicago, IL.
4. Stone RM, Mandrekar S, Sanford BL, et al. The multi-kinase inhibitor midostaurin
(M) prolongs survival compared with placebo (P) in combination with daunorubicin
(D)/cytarabine (C) induction (ind), high-dose C consolidation (consol), and as
maintenance (maint) therapy in newly diagnosed acute myeloid leukemia (AML)
patients (pts) age 18-60 with FLT3 mutations (muts): an international prospective
randomized (rand) P-controlled double-blind trial (CALGB 10603/RATIFY [Alliance]).
Abstract #6. Presented at the 2015 ASH Annual Meeting, December 6, 2015; Orlando,
FL.
5. Brunet S, Labopin M, Esteve J, et al. Impact of FLT3 internal tandem duplication
on the outcome of related and unrelated hematopoietic transplantation for adult
acute myeloid leukemia in first remission: a retrospective analysis. J Clin Oncol.
2012;30:735-41.
6. Gale RE, Hills R, Kottaridis PD, et al. No evidence that FLT3 status should be
considered as an indicator for transplantation in acute myeloid leukemia (AML): an
analysis of 1135 patients, excluding acute promyelocytic leukemia, from the UK MRC
AML10 and 12 trials. Blood. 2015;106:3658-65.
July 2016