FEATURE
Drawing First Blood
We invite two experts to debate controversial
topics in hematology and health care.
Teaching Old Drugs New Tricks?
Harry Erba, MD, PhD
Richard Stone, MD
Disclaimer:
The following positions were assigned
to the participants and do not
necessarily reflect ASH opinions, the
participants’ opinions, or what they
do in daily practice.
Agree? Disagree? We want to hear
from you! Send your thoughts and
opinions on this controversial
issue to ashclinicalnews@
hematology.org.
ASHClinicalNews.org
When the U.S. Food and Drug
Administration (FDA) approved
CPX-351 (a fixed combination of
daunorubicin and cytarabine),
it appeared that everything old
was new again. The drug, which
is a combination of two existing
generic drugs encased in a lipo-
some, received breakthrough-
therapy designation in August
2017 for the treatment of
adults with newly diagnosed,
therapy-related acute my-
eloid leukemia (AML) or AML
with myelodysplasia-related
changes (MRC). Its safety and
efficacy were demonstrated
in a phase III trial comparing
CPX-351 with the standard 7+3
regimen of cytarabine and dau-
norubicin in patients aged 60 to
75 years.
In this edition of Drawing
First Blood, ASH Clinical News
invited Harry Erba, MD, PhD,
and Richard Stone, MD, to de-
bate the question, “Can CPX-351
be used with other therapies, or
outside of the approval study
group, in AML?” Dr. Erba, director
of the UAB Hematologic Malig-
nancy Program at the University
of Alabama at Birmingham, will
argue on the “pro” side, and Dr.
Stone, clinical director of the
Adult Leukemia Program at
Dana-Farber Cancer Institute in
Boston, will argue on the “con”
side.
Harry Erba, MD, PhD: In AML, the
trouble is that while we’ve been giving 7+3
for the last 40 years, the schedule by which
we give this regimen does not ensure a
constant molar ratio of these two agents.
We also know that the molar ratios of
cytotoxic agents given in combination are
important to achieve optimal cytotoxicity.
CPX-351 was developed based on pre-
clinical and murine model observations
that a 1:5 molar ratio of daunorubicin to
cytarabine appeared to provide the most
synergistic cytotoxic combination. 1 The
only way to do that would be to encap-
sulate these agents in a fixed–molar ratio
in a liposome. In the preclinical murine
AML studies, these liposomes appeared
to be more preferentially taken up by
leukemic blasts, as opposed to normal
stem cells. 2
Next, a subset analysis of a randomized,
phase II study comparing CPX-351 and
7+3 in adults with previously untreated
AML found a safety and efficacy signal in
older patients with secondary AML, either
following myelodysplastic syndromes
(MDS) or treatment-related AML. This
came in the form of a higher complete
response rate and improved event-free
and overall survival (OS), but with a lower
induction mortality. 3
However, these comparisons were
underpowered and not statistically
significant. That’s what launched the
pivotal, phase III study in patients aged
60 to 75 years with secondary AML who
were fit for chemotherapy. 4 This trial met
its primary endpoint for OS, which was
statistically significantly improved with
CPX-351 (9.6 vs. 6 months; p=0.005).
This is not necessarily a less toxic way of
giving 7+3, but it does appear to be a more
efficacious way of giving it in this patient
population. 3 We don’t know if, for example, patients
with p53 mutations will benefit from
CPX-351. We also don’t know much about
the different patient subgroups enrolled
in the trial. For example, did participants
who had MDS that was treated with a
hypomethylating agent (HMA) before
receiving CPX-351 benefit from the new
formulation or from 7+3? Although I
agree with everything Dr. Erba said about
CPX-351 being more efficacious than the
7+3 in the 60- to 75-year-old subgroup,
there are still some important unanswered
questions about the trial itself.
Richard Stone, MD: That’s an excellent
summary of CPX-351’s history, and I have
a couple of points to add: First, in terms
of its mechanism of action, models of
CPX-351 suggest that it delivers the com-
pounds in a prolonged fashion in the bone
marrow (BM), which may be good for pa-
tients with intrinsically resistant disease.
Second, unfortunately, the trial sponsor
did not prospectively collect biologic data
on the type of AML being treated or the
patients’ genetic profile. Dr. Stone: Understanding the role of he-
matopoietic cell transplantation (HCT) in
CPX-351–treated patients may be the key
to getting answers to questions about who
can and should receive this treatment.
One analysis looked at preliminary data
from the phase III trial of people in first
remission who had an HCT; compared
with those receiving 7+3, patients receiv-
ing CPX-351 had a longer OS after HCT. 5
There are also questions about con-
solidation therapy following CPX-351
“[CPX-351] is not
necessarily a
less toxic way of
giving 7+3, but
it does appear
to be a more
efficacious way
of giving it in this
... population.”
—HARRY ERBA, MD, PhD
Dr. Erba: That’s true, and I’m concerned
because we have seen data for the subset
of patients with treatment-related AML,
but we have not seen CPX-351 showing a
benefit over 7+3 in patients with poor-risk
cytogenetics or molecular profiles.
ASH Clinical News
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