NEWLY APPROVED DRUGS
in the glasdegib arm and 4.3 months (range= 1.9-5.7 months) in
the cytarabine-alone arm (hazard ratio = 0.46; 95% CI 0.30-0.71;
p=0.0002).
The most common AEs (occurring in ≥20% of patients)
included anemia, fatigue, hemorrhage, febrile neutropenia, mus-
culoskeletal pain, nausea, edema, thrombocytopenia, dyspnea,
decreased appetite, dysgeusia, mucositis, constipation, and rash.
Glasdegib was approved through the priority-review pathway
and was granted orphan-product designation. Studies of glasde-
gib in combination with agents other than low-dose cytarabine,
including DNA hypomethylating agents, are ongoing.
Venetoclax
On November 23, 2018, the FDA approved the BCL2 inhibitor
venetoclax, in combination with azacitidine or decitabine or
low-dose cytarabine, for the treatment of patients with newly
diagnosed AML who are age 75 or older or who have comorbidi-
ties that preclude use of intensive induction chemotherapy.
The approval is based on results from two phase II trials: the
M14-358 and M14-397 studies.
The M14-358 study evaluated venetoclax in combination with
azacitidine (n=67) or decitabine (n=13) in patients with newly di-
agnosed AML. Twenty-five patients who received venetoclax plus
azacitidine achieved a CR, with a median duration of remission
of 5.5 months (range = 0.4-30 months). Seven of the patients who
received venetoclax plus decitabine achieved a CR, with a median
duration of remission of 4.7 months (range = 1.0-18 months).
The M14-387 study evaluated venetoclax in combination
with low-dose cytarabine in patients with newly diagnosed
AML (n=61), including patients with previous exposure to a
hypomethylating agent for an antecedent hematologic disor-
der. When combined with low-dose cytarabine, treatment with
venetoclax induced CR in 13 patients, with a median observed
remission duration of six months (range = 0.03-25 months).
The most common AEs (occurring in ≥30% of patients)
associated with venetoclax were nausea, diarrhea, thrombocy-
topenia, constipation, neutropenia, febrile neutropenia, fatigue,
vomiting, peripheral edema, pneumonia, dyspnea, hemorrhage,
anemia, rash, abdominal pain, sepsis, back pain, myalgia, dizzi-
ness, cough, oropharyngeal pain, pyrexia, and hypotension.
Gilteritinib
On November 28, 2018, the FDA approved gilteritinib, an
oral FLT3/AXL inhibitor, for the treatment of adult patients
with FLT3-mutated relapsed or refractory AML. The FDA also
expanded the indication for the LeukoStrat CDx FLT3 Mutation
Assay, a companion diagnostic to detect the FLT3 mutation.
6
Focus on Myeloid Malignancies
The agency’s decision was based on interim results from
the phase III ADMIRAL trial, which enrolled 138 patients with
relapsed or refractory AML and a confirmed FLT3 mutation.
Gilteritinib was administered orally at a dose of 120 mg daily until
unacceptable toxicity or lack of clinical benefit. After a median
follow-up of 4.6 months (range = 2.8-15.8 months), 29 gilteritinib-
treated patients (21%) achieved CR or CRh. Of the 106 patients
who were RBC or platelet transfusion–dependent at the start
of treatment with gilteritinib, 33 (31.1%) became transfusion-
independent during any 56-day, postbaseline period.
The most common AEs (occurring in ≥20% of patients)
included myalgia/arthralgia, fatigue, and liver transaminase
elevation.
Gilteritinib was approved through fast-track and priority-
review pathways and received orphan-product designation.
Studies of gilteritinib in combination with chemotherapy or
as maintenance therapy after allogeneic hematopoietic cell
transplantation are ongoing.
Tagraxofusp-erzs
On December 21, 2018, the FDA approved tagraxofusp-erzs
(formerly SL-401), a CD123-directed cytotoxin, for the treat-
ment of adults and children (≥2 years of age) with blastic plas-
macytoid dendritic cell neoplasm (BPDCN). This marks the first
approval for this rare disease.
The efficacy of tagraxofusp-erzs was evaluated in two cohorts
of patients in a single-arm clinical trial. In the first cohort, which
included 13 patients with untreated BPDCN, seven (53.8%)
achieved a CR or CR with a skin abnormality not indicative of
active disease (CRc). The median response duration was not
reached in this cohort. In the second cohort, which included 15
patients with relapsed or refractory BPDCN, one patient each
achieved a CR (which lasted for 111 days) and a CRc (which
lasted for 424 days).
The most common clinical AEs (occurring in ≥30% of
patients) associated with tagraxofusp-erzs included capillary
leak syndrome, nausea, fatigue, peripheral edema, pyrexia, chills,
and weight increase. The most commonly observed laboratory
abnormalities (identified in ≥50% of patients) were decreases
in lymphocytes, albumin, platelets, hemoglobin, and calcium,
as well as increases in glucose and liver enzymes. Given this
observation, the approval letter advises health-care providers
to monitor patients’ liver enzyme levels and ensure an albumin
level ≥3.5 g/dL before starting therapy.
Tagraxofusp-erzs was approved with a boxed warning about
the increased risk of capillary leak syndrome, which may be
life-threatening or fatal.
This agent was approved through the priority-review
pathway and was granted breakthrough therapy and orphan-
product designations. Studies of tagraxofusp-erzs in other
myeloid malignancies are ongoing. ●