FEATURES
Reframing and Replacing 7+3
The FDA approved two drugs that, when combined with the
7+3 regimen, have been shown to increase CR rates – and
slightly improve overall survival (OS) rates – compared with
7+3 alone: midostaurin and gemtuzumab ozogamicin. 1,2 Both
agents were approved for patients whose disease expresses a
specific therapeutic target.
In April 2017, the oral multitargeted kinase inhibitor mido-
staurin was approved for the treatment of patients with newly
diagnosed FLT3-mutated AML based on results from the
randomized phase III RATIFY trial. Compared with 7+3 alone,
the addition of midostaurin prolonged survival and reduced
the risk of death by 23 percent (median OS=74.7 months vs.
25.6 months; hazard ratio [HR] = 0.77; p=0.0074).
Then, in September 2017, the FDA approved gemtuzumab
ozogamicin, a humanized anti-CD33 monoclonal antibody
attached to calicheamicin, an antitumor anthracycline anti-
biotic, for two patient populations: adults with newly diag-
nosed CD33-positive AML and children aged 2 or older with
relapsed or refractory CD33-positive AML. The approval was
based on results from an open-label phase III clinical trial,
in which the addition of gemtuzumab ozogamicin to chemo-
therapy prolonged event-free survival (17.3 months vs. 9.5
months; HR=0.56; p<0.001).
Gemtuzumab ozagamicin originally received accelerated
approval in May 2000 as monotherapy for older patients with
relapsed/refractory AML, But, in June 2010, the drug was
voluntarily withdrawn from the market after confirmatory
studies showed more toxicity and less benefit in that setting
than suggested by earlier studies. The 2017 approval includes a
lower recommended dose, as well as new patient populations
and a different dosing schedule.
But, in August 2017, it seemed that everything old was new
again: The FDA approved CPX-351, a fixed combination of
daunorubicin and cytarabine. The drug, which is a combina-
tion of these two existing generic drugs encased in a liposome,
received breakthrough-therapy designation in August 2017 for
the treatment of adults with newly diagnosed therapy-related
AML or AML with myelodysplasia-related changes. Its safety
and efficacy were demonstrated in a phase III trial comparing
CPX-351 with the standard 7+3 regimen of cytarabine and
daunorubicin in patients aged 60 to 75 years. 3
The FDA next approved two additional therapies for the
treatment of patients with newly diagnosed AML who were
deemed unfit to undergo standard induction therapy. In No-
vember 2018, both the oral BCL2 inhibitor venetoclax and the
oral hedgehog inhibitor glasdegib received expedited approval
for the treatment of patients aged 75 or older or who have
comorbidities that preclude them from the more intensive 7+3
chemotherapy regimen. 4,5 For details about these FDA deci-
sions, see “The Year in Drug Approvals” on page 5.
New Kids on the Block
The FDA also approved several options for patients with re-
lapsed and/or refractory disease, including those whose disease
22
Focus on Myeloid Malignancies
harbors an IDH mutation.
The IDH2 inhibitor enasidenib was approved for the treat-
ment of adults with relapsed/refractory IDH2-mutated AML,
along with the RealTime IDH2 assay, a companion diagnostic
that can detect specific mutations in the IDH2 gene in this pa-
tient population. 6 In October 2018, the FDA approved another
IDH inhibitor, ivosidenib, for patients with relapsed, refractory
disease that expresses an IDH1 mutation, based on results from
an open-label, phase I clinical trial. 7
The most recent agent to join the AML treatment paradigm
is gilteritinib. This FLT3-targeted oral inhibitor was approved
for the treatment of adult patients with FLT3-mutated relapsed
or refractory AML. The agency’s decision was based on interim
results from the phase III ADMIRAL trial, in which 21 percent
of patients achieved CR or CRh. 8 (More details about these
FDA decisions can be found in “The Year in Drug Approvals”
on page 5.)
An additional FLT3 inhibitor, quizartinib, is currently un-
der review by the FDA for this same patient population. 9
The Old Reliable?
Despite the plethora of new treatment options available, 7+3
induction therapy remains a standard. “I think of the cytotoxic
agents as the first targeted agents, which home in on rapidly
dividing cells,” Dr. Michaelis said. “It would be a mistake to
eliminate these from our arsenal just because we have devel-
oped ones that are based on new biologic targets.”
When deciding on the first course of treatment, clinicians
assess patients’ overall health and ability to tolerate chemother-
apy, as well as whether they have favorable-, intermediate-, or
adverse-risk disease characteristics according to cytogenetic
and molecular testing – including tests for a FLT3 and other
mutations.
For patients who are fit to tolerate induction treatment and
who have favorable-risk disease, 7+3 remains the best option,
according to clinicians who spoke with ASH Clinical News,
possibly with the addition of midostaurin or gemtuzumab for
eligible patients. For patients who cannot tolerate intensive
chemotherapy and who have adverse-risk disease, options
include a clinical trial, venetoclax plus chemotherapy, or glas-
degib plus chemotherapy.
Decisions for the other subgroups of patients, including those
with favorable-risk disease who are unfit for induction chemo-
therapy or those with adverse-risk disease who are healthy enough
to tolerate the 7+3 regimen – are more complicated.
“The biggest challenge at the clinical level is that we don’t
know the best way to integrate these new drugs into clinical
practice because there are not enough randomized data to
know the best choice for all patients,” Dr. Michaelis added.
Dr. Roboz agreed. “For those patients between the ages of
about 50 and 80, the boundaries of decision making for who
should receive intensive versus non-intensive induction regi-
mens are not clear.”
For patients with newly diagnosed AML who are considered
unfit for 7+3 induction, the clinical trial data for glasdegib and