ASH Clinical News Hematology Pipeline Update: Drug Updates from the | Page 10

LEUKEMIA

New Antibody-Drug Conjugate Demonstrates
Anti-Leukemic Activity in CD33-Positive AML
CD33 is expressed on myeloblasts in approximately 90
percent of acute myeloid leukemia (AML) cases – regardless
of patient age, prior therapies, or mutational heterogeneity
– making it a promising target for treatment. According to
results from a phase I trial presented at the 2015 ASH Annual Meeting, a novel CD33-directed monoclonal antibody,
SCN-CD33a, demonstrated anti-leukemic activity in newly
diagnosed and relapsed AML patients.
Anthony S. Stein, MD, from City of Hope National Medical Center
in Duarte, California, presented the findings of the dose-escalation
study, which evaluated the agent’s safety, tolerability, pharmacokinetics, and anti-leukemic activity.
At the time of study presentation, 87 patients (62 percent male)
had been treated with SGN-CD33A. Patients had a median age of
74 years (range = 27-89 years). Only those with CD33-positive AML
were eligible for study inclusion, and patients had either relapsed
disease following first complete remission (CR) of more than three
months (n=34), or had declined conventional induction/consolidation therapy (n=52).
Forty of these patients received prior low-intensity therapies with
one or two agents – primarily hypomethylating agents.
Most patients had intermediate stage I-II (51%) or adverse (31%)
risk, according to European Leukemia Network classification, and 54
percent of patients had evidence of underlying myelodysplasia.
SGN-CD33A monotherapy was administered intravenously every
three weeks for up to two cycles, followed by an optional low-dose
maintenance treatment for patients who achieved CR or CR with
incomplete blood count recovery (CRi). Dose levels ranged from 5 to
60 mcg/kg (n=75) and also included fractionated dosing of 20 mcg/kg
on day 1 and day 4 (n=12) of each cycle.
Investigators observed six dose-limiting toxicities in the
dose-escalation cohorts: two cases of grade 4 bone marrow failures
(at 40 and 60 mcg/kg); two cases of grade 3 mucositis (at 50 mcg/kg
and at fractionated 20+20 mcg/kg); one case of grade 3 pulmonary
embolism (20 mcg/kg), and one case of grade 5 sepsis (50 mcg/kg).
The most common grade ≥3 adverse events (AEs) were febrile
neutropenia (69%), thrombocytopenia (29%), and anemia (23%).
Other common treatment-emergent AEs included fatigue (48%),
decreased appetite (28%), constipation, diarrhea, dyspnea, nausea
(26% each), and peripheral edema (25%). Patients treated with
SGN-CD33A at doses higher than 40 mcg/kg and in the fractionated
dosing cohort experienced increased myelosuppression, including
febrile neutropenia (68%) and sepsis (26%).
“AEs were generally manageable, and often were associated with
underlying myelosuppression,” Dr. Stein reported. The rate of 30-day
mortality was low at six percent.
Response was assessed according to International Working Group
criteria. CRi (CR with incomplete recovery of blood counts) required
either platelet count of ≥100,000/µL or neutrophils of ≥1,000/µL.
Twenty-one patients in the 40 mcg/kg dose cohort were evaluable
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Hematology Pipeline Update

for efficacy. Median overall survival in patients treated at this dose
was 10 months, with 17 patients alive at the data cut-off point. Best
clinical responses were CR in three patients, CRi in four patients,
and morphologic leukemia-free state in five patients. “SGN-CD33A
has demonstrated favorable anti-leukemic activity, with 33 percent of
study patients achieving a CR/CRi at the 40 mcg/kg dose level,” the
authors observed. The rate of CR/CRi was further improved, to 60
percent, in the five treatment-naïve patients.
Response occurred rapidly in patients across all dose levels, the
authors noted, with a mean time to full count recovery of five weeks
for neutrophils (≥1,000/µL) and six weeks for platelets (≥100,000/µL).
“The rapid clearance of marrow blasts in patie