NEWLY APPROVED DRUGS
The Year in FDA Approvals
In the past year, the U.S. Food and Drug Administration
(FDA) approved several therapies for the treatment of
myeloid malignancies, including drugs approved for multiple
indications. We review the regulatory approvals since our last
“Focus on Myeloid Malignancies” special edition published
in May 2017. In addition, midostaurin was approved for
FLT3-mutated acute myeloid leukemia (AML) and aggressive
systemic mastocytosis in April 2017.
Enasidenib
On August 1, 2017, the FDA approved enasidenib for the treat-
ment of adults with relapsed or refractory AML with an isocitrate
dehydrogenase-2 (IDH2) mutation. The drug is approved for use
with the RealTime IDH2 Assay, a companion diagnostic that can de-
tect specific mutations in the IDH2 gene in this patient population.
The approval was based on the results of the single-arm, phase
I/II AG221-C-001 study that included 199 patients (median age = 68
years; range = 19-100 years) with relapsed/refractory IDH2-mutated
AML that was detected by the RealTime IDH2 Assay. Patients had
received a median of two prior therapies (range = 1-6 therapies).
After a minimum of six months of treatment, 19.3 percent of
patients (95% CI 13.8-25.9) who received enasidenib experienced a
complete remission (CR) for a median of 8.2 months, and 4 percent
of patients experienced a CR with partial hematologic recovery for
a median of 9.6 months. Of the 157 patients who required blood
or platelet transfusions at baseline, 34 percent no longer required
transfusions after receiving enasidenib.
The most common adverse events (AEs) associated with enasid-
enib included nausea, vomiting, diarrhea, and hyperbilirubinemia.
The drug carries a boxed warning that differentiation syn-
drome can occur and can be fatal if left untreated. Differentiation
syndrome is associated with fever; dyspnea; acute respiratory
distress; radiographic pulmonary infiltrates; pleural or pericardial
effusions; rapid weight gain; peripheral edema; or hepatic, renal,
or multi-organ dysfunction.
CPX-351
On August 3, 2017, the FDA approved CPX-351, a fixed com-
bination of cytarabine and daunorubicin, for the treatment of
adults with newly diagnosed therapy-related AML (t-AML) or
AML with myelodysplasia-related changes (AML-MRC). This is
the first FDA-approved treatment specifically for patients with
t-AML or AML-MRC – both of which are considered high-risk
leukemia subtypes.
Approval was based on results from the CLTR0310-301 study,
in which 309 patients with newly diagnosed t-AML or AML-MRC
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Focus on Myeloid Malignancies
received daunorubicin and cytarabine either in the liposomal,
fixed-combination formulation (CPX-351) or as separate treat-
ments (standard 7+3 regimen). Patients who received CPX-351
had a longer median overall survival (OS), compared with those
who received separate treatments (9.56 months vs. 5.95 months).
Common AEs associated with CPX-351 included hemorrhage,
febrile neutropenia, rash, edema, nausea, mucositis, diarrhea,
constipation, musculoskeletal pain, and fatigue– which occur
frequently with other cytarabine/anthracycline induction chemo-
therapy regiments for AML. Blood count recovery was slower with
CPX-351 than with 7+3, but 60-day induction mortality was lower.
Patients who have a history of serious hypersensitivity to dauno-
rubicin, cytarabine, or any component of the formulation should
not use the drug. The prescribing information also includes a boxed
warning not to interchange CPX-351 with other daunorubicin- or
cytarabine-containing products, in part because the dose of CPX-351
is different from that of other approved products.
Gemtuzumab Ozogamicin
On September 1, 2017, the FDA approved gemtuzumab ozogami-
cin (GO) for two patient populations: adults with newly diagnosed
CD33-positive AML and children (≥2 years) with relapsed or re-
fractory CD33-positive AML. GO may be used in combination with
daunorubicin and cytarabine for adults with newly diagnosed AML
or as a stand-alone treatment for certain adult and pediatric patients.
GO originally received accelerated approval in May 2000 as
monotherapy for older patients with relapsed CD33-positive AML.
In June 2010, the drug was voluntarily withdrawn from the market
after subsequent confirmatory trials failed to verify clinical benefit
and demonstrated safety concerns, including early deaths.
This recent approval includes a lower recommended dose
(3 mg/m 2 , or up to a cap of one 4.5 mg vial, on days 1, 4, and 7 of
induction), compared with the initial 2000 approval (9 mg/m 2 in 2
doses separated by 2 weeks) and new patient populations. “We are
approving [GO] after a careful review of the new dosing regimen,
which has shown that the benefits of this treatment outweigh the
risk,” said Richard Pazdur, MD, director of the FDA’s Oncology
Center of Excellence. and acting director of the Office of Hematolo-
gy and Oncology Products in the FDA’s Center for Drug Evalua-
tion and Research.
The approval was based on outcomes from three clinical
trials – one pivotal trial investigated GO in combination with
chemotherapy (ALFA-0701) and two other trials investigated
GO as a single agent. In the combination study, adult patients
treated with daunorubicin and cytarabine with GO had longer
median event-free survival than those treated with daunorubicin
and cytarabine without GO (17.3 months vs. 9.5 months; p value
not reported).
In the first monotherapy study (EORTC-GIMEMA AML-19),