patients with newly diagnosed AML who could not tolerate or chose
not to receive intensive chemotherapy were randomized to receive
GO or best supportive care. The median OS was 4.9 months in those
receiving GO, compared with 3.6 months in those receiving best
supportive care (p value not reported). In the second monotherapy
trial (MyloFrance-1), which was a single-arm study of 57 patients
with relapsed CD33-positive AML, 26 percent of patients achieved
a CR that lasted a median of 11.6 months (range not reported) after
receiving a single course of GO.
The most common AEs associated with GO included pyrexia,
nausea, infection, vomiting, bleeding, thrombocytopenia, stomatitis,
constipation, rash, headache, elevated liver function tests, and neu-
tropenia. Severe AEs included leukopenia, infection, liver damage,
hepatic veno-occlusive disease (VOD), infusion-related reactions,
and hemorrhage.
GO previously received orphan-drug designation and carries a
boxed warning that severe or fatal hepatotoxicity (including VOD
and sinusoidal obstruction syndrome) has occurred in some patients.
Dasatinib
On November 9, 2017, the FDA expanded the indication of the
tyrosine kinase inhibitor (TKI) dasatinib to include children
with Philadelphia chromosome–positive (Ph+) chronic-phase
chronic myeloid leukemia (CP-CML). The drug was previously
approved to treat adults with Ph+ CP-CML.
The decision was based on the results of two studies (one
open-label, non-randomized, dose-ranging trial and one
open-label, non-randomized, single-arm trial) of 97 pediat-
ric patients with Ph+ CP-CML. Fifty-one patients (from the
single-arm trial) were newly diagnosed with CP-CML, and 46
patients (17 from the dose-ranging trial and 29 from the single-arm
trial) were imatinib resistant or intolerant. Ninety-one partic-
ipants were treated with dasatinib 60 mg/m 2 once-daily. After
approximately five years of follow-up across both trials, the
median duration of response (including the efficacy endpoints
complete cytogenetic response [CCyR], major cytogenetic
response [MCyR], and major molecular response [MMR]) could
not be estimated.
Among the newly diagnosed cohort, the response duration
ranged from 2.5 to 66.5 months for CCyR, 1.4 to 66.5 months
for MCyR, 5.4 to 72.5 months for patients who achieved MMR
by month 24, and 0.03 to 72.5 months for those who achieved
MMR at any time. Among the imatinib-resistant or -intolerant
group, durations of response ranged from 2.4 to 86.9 months for
CCyR, 2.4 to 86.9 months for MCyR, and 2.6 to 73.6 months for
MMR.
AEs were reported in 14.4 percent of patients, the most
common (occurring in >15% of patients) of which included my-
elosuppression, headache, nausea, diarrhea, skin rash, and pain
in the abdomen and extremities.
Bosutinib
On December 19, 2017, the FDA granted accelerated approval to
the oral TKI bosutinib for the treatment of adults with newly di-
agnosed Ph+ CP-CML. Bosutinib was first approved in September
2012 for the treatment of adult patients with relapsed or refractory
chronic-, accelerated-, or blast-phase Ph+ CML.
The decision was based on results of the multinational, open-
label, randomized, phase III BFORE (Bosutinib trial in First Line
Chronic Myelogenous Leukemia Treatment) study, which includ-
ed 536 patients with Ph+ CP-CML who were randomized 1:1 to
receive bosutinib 400 mg or imatinib 400 mg.
At 12 months, a higher percentage of patients receiving
bosutinib achieved MMR (47.2% vs. 36.9%; p=0.02). People
treated with bosutinib also had a significantly higher rate of
CCyR at 12 months (77.2% vs. 66.4%; p=0.008).
The most common AEs associated with bosutinib included
diarrhea (70%), nausea (35%), thrombocytopenia (35%), rash
(34%), increased alanine aminotransferase (ALT; 31%), abdominal
pain (25%), and increased aspartate aminotransferase (AST; 23%).
Nilotinib
On March 22, 2018, the FDA approved nilotinib for the treatment
of children (≥1 year) with Ph+ CP-CML that is newly diagnosed
or resistant or intolerant to prior TKI therapy. On December 22,
2017, the product label for nilotinib was also updated to include
information on nilotinib discontinuation, post-discontinuation
monitoring criteria, and guidance for treatment re-initiation in
patients taking nilotinib for Ph+ CML who have achieved a sus-
tained molecular response.
The March approval was based on results from two open-label,
single-arm, multicenter trials: The CAMN107A2120 trial enrolled
pediatric patients with Ph+ CP-CML that was resistant or intolerant
to imatinib or dasatinib, while the CAMN107A2203 trial included
pediatric patients with Ph+ CP-CML resistant or intolerant to ima-
tinib or dasatinib, and newly diagnosed Ph+ CP-CML.
At cycle 12, the MMR was 40.9 percent in patients with resis-
tant or intolerant Ph+ CP-CML and 60.0 percent in those with
newly diagnosed Ph+ CP-CML. The cumulative MMR rates were
47.7 percent and 64.0 percent, respectively.
The common AEs (occurring in >20% of patients) were
hyperbilirubinemia, thrombocytopenia, rash, neutropenia,
lymphopenia, increased ALT, headache, anemia, pyrexia, nausea,
upper respiratory tract infection, increased AST, and vomiting;
the most common grade 3/4 AEs were increased ALT and hyper-
bilirubinemia.
The drug carries a boxed warning for risk of QT prolongation
and sudden death. ●
May 2018
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