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More complete cytogenetic responses at
12 months with radotinib than imatinib
BY MARY JO DALES
Frontline Medical News
R
adotinib was associated with significantly
higher complete cytogenetic responses and
major molecular responses than imatinib
was at a minimum 12 months of follow-up in a
randomised, open-label, phase III clinical trial of
patients with newly diagnosed chronic myeloid
leukaemia-chronic phase (CML-CP).
Radotinib, an investigational BCR-ABL1 ty-
rosine kinase inhibitor developed by IL-YANG
Pharmaceuticals, is approved in Korea for the
treatment of CML-CP in patients who have failed
prior TKIs.
Dr Jae-Yong Kwak of Chonbuk National Uni-
versity Medical School and Hospital, Jeonju,
South Korea, and his colleagues randomised 241
patients to either radotinib 300 mg twice daily
(n = 79), radotinib 400 mg twice daily (n = 81),
or imatinib 400 mg once daily (n = 81). All three
study groups were balanced in regard to baseline
age, gender, race, and Sokal risk score.
At a minimum follow-up of 12 months, the
proportions of patients receiving a study drug
were 86% (69/79) in the radotinib 300 mg twice-
daily group, 72% (58/81) in the radotinib 400 mg
twice-daily group, and 82% (66/81) in the imatinib
400 mg once-daily group.
The rates of major molecular response at 12
months were significantly higher in patients re-
ceiving radotinib 300 mg b.i.d. (52%, P = 0.0044)
and radotinib 400 mg b.i.d. (46%, P = 0.0342),
compared with imatinib (30%), Dr Kwak reported
at the annual meeting of the American Society of
Haematology in Orlando.
Among responders, the median times to major
molecular response were shorter on radotinib
300 mg b.i.d. (5.7 months) and radotinib 400 mg
b.i.d. (5.6 months) than on imatinib (8.2 months).
The MR
4.5
rates by 12 months were also higher for
both radotinib 300 mg b.i.d. (15%) and 400 mg
b.i.d. (14%), compared with imatinib (9%).
The complete cytogenetic response rates by 12
months were 91% for radotinib 300 mg b.i.d. (P =
0.0120), compared with imatinib (77%). None
of the patients in the study had progressed to
accelerated phase or blast crisis at 12 months.
Drug discontinuation due to adverse events
(AEs) or laboratory abnormalities occurred in
9% of patients on radotinib 300 mg b.i.d., 20%
on radotinib 400 mg b.i.d., and 6% on imatinib.
The major side effects included grade 3/4
thrombocytopenia in 16% of patients receiving
radotinib 300 mg b.i.d., 14% on radotinib 400 mg
b.i.d., and 20% receiving imatinib. Grade 3/4
neutropenia occurred in 19%, 24%, and 30%
for radotinib 300 mg b.i.d., 400 mg b.i.d., and
imatinib, respectively.
Overall, grade 3/4 nonlaboratory AEs were
uncommon in all groups. The most common
nonlaboratory AEs in the radotinib groups were
skin rash (about 33% in both), nausea/vomiting
(about 23% in both), headache (19% and 31%),
and pruritus (19% and 30%). In the imatinib
group, the most common adverse events were
oedema (35%), myalgia (28%), nausea/vomiting
(27%), and skin rash (22%).
Dr Kwak had no relevant disclosures. Some of his
colleagues received research funding from IL-YANG
Pharmaceutical Co. and Alexion Pharmaceuticals.
First shot across the bow for CAR
T cells in multiple myeloma
BY PATRICE WENDLING
Frontline Medical News
C
himeric antigen receptor (CAR) T cells tar-
geting BCMA eradicated myeloma cells in a
patient with a heavy burden of chemotherapy-
resistant multiple myeloma.
The patient had received three prior myeloma
therapies and relapsed with myeloma making up
more than 90% of his bone marrow cells just 3
months after autologous transplant.
CD138-positive plasma cells were completely
absent, however, one month after infusion of CAR
T cells directed against the B-cell maturation anti-
gen (BCMA), and remain undetectable 14 weeks
after infusion.
“We have demonstrated for the first time that
CAR T cells can have powerful activity against
measurable multiple myeloma,” Dr James N.
Kochenderfer of the National Cancer Institute
in Bethesda, Maryland, said at the annual meeting
of the American Society of Haematology.
A second patient, who had five prior lines of
myeloma therapy and myeloma in 80% of his
bone marrow cells, also experienced a dramatic
reduction in myeloma, resulting so far in a partial
response. The patient has returned to full-time
work and myeloma cells continue to decrease
6 weeks after infusion.
The two ongoing responses, however, were as-
sociated with the most severe clinical signs of
cytokine release syndrome in the late-breaking
abstract study (LBA-1), Dr Kochenderfer said.
The complete responder experienced cytokine
release toxicities including fever, tachycardia, hy-
potension, elevated liver enzymes, and elevated
creatinine kinase that resolved. The patient was
also platelet transfusion-dependent for 9 weeks
after infusion and a baseline absolute neutrophil
count of less than 500 microliters remained at
that level for 40 days after infusion. All symptoms
resolved within two weeks, he said.
The ongoing partial responder experienced fe-
ver, tachycardia, hypotension, acute kidney injury,
dyspnea, delirium, and prolonged thrombocyto-
penia and all completely resolved.
Both patients had much higher serum levels of
interleukin-6 than the other patients, he noted.
Both patients also received the highest dose
level of anti-BCMA CAR T cells. Going forward,
that dose will now only be administered to pa-
tients with less than 50% bone marrow plasma
cells, Dr Kochenderfer said.
Other responses among the 12 patients treated
thus far include 1 transient very good partial re-
sponse of 8-week duration, 1 transient partial
response lasting 2 weeks, and 8 responses of
stable disease.
While three new drugs (elotuzumab, dara-
tumumab, ixazomib) were approved for the
treatment of multiple myeloma in the month of
November alone, this is early days for CAR T-cell
therapy in multiple myeloma.
“Almost all of the CAR T-cell work has been in
B-cell malignancies, acute lymphocytic leukae-
mia, and chronic lymphocytic leukaemia, so is
this the right antigen, we don’t know? Is this the
right construct, we don’t know? But there’s clearly
activity and that is very exciting,” session comod-
erator Dr David P. Steensma of the Dana-Farber
Cancer Institute in Boston, said in an interview.
Dana-Farber is conducting a CAR T cell trial
in myeloma using a different target and NKG2D
ligands. Other centres are also using CAR T cells
with different targets. “So maybe other targets
would have different results and a better safety
profile,” he added.
BCMA is an appropriate target for CAR T cell
therapy for multiple reasons, Dr Kochenderfer
said. Multiple myeloma is still an incurable dis-
ease and BCMA, a member of the tumour necro-
sis factor superfamily, is uniformly expressed in
60% to 70% of cases.
Preclinical studies by the team also show that
BCMA is not detectable in normal human tis-
sues, but is selectively expressed only in bone
marrow, lymphoid organs, and organs known to
have plasma cells in their lamina propria and by
plasma cells and a small fraction of B cells.
The investigators genetically modified autolo-
gous T cells to express an anti-BCMA CAR and
ligated it into a replication-incompetent gamma
retrovirus. The T cells were stimulated with the
anti-CD3 monoclonal antibody OKT3 before
transduction, with the entire culture process tak-
ing 9 days from start to finish. T cells expressing
this CAR recognize BCMA with great specificity,
Dr Kochenderfer observed.
The 12 patients received 300 mg/m
2
of cyclo-
phosphamide and 30 mg/m
2
of fludarabine daily
for 3 days before a single infusion of anti-BCMA
CAR at dose levels of 0.3 x 10
6
to 9 x 10
6
T cells/
kg. All patients had at least 3 prior therapies and
normal organ function. Five had amyloid light
chain only, 4 had immunoglobulin gamma disease,
and 4 patients, including the complete responder,
had immunoglobulin alpha disease.
It’s unclear why only a few patients responded
to the CAR T cells, but dose level was likely a
big factor and there is a lot of patient variability
with T-cell therapies, Dr Kochenderfer said at a
press briefing.
“I wish we knew exactly why some patients
respond and some don’t,” he added. “The CAR T
cells have shown remarkable activity against re-
ally previously refractory diseases like acute lym-
phocytic leukaemia,” noted Dr George Daley of
Harvard Medical School, Boston, in an interview
at the meeting. “There’s been a lot of excitement
that maybe we can extend the principles that work
in leukaemia to other types of diseases.”
The study is still ongoing and accruing patients,
but a multicentre trial is also being initiated in my-
eloma with Bluebird Bio using “a closely related,
but slightly different CAR,” Dr Kochenderfer said.
Prasugrel does
not reduce vaso-
occlusive crises in
sickle cell anemia
BY BIANCA NOGRADY
Frontline Medical News
P
latelet inhibitor prasugrel has
failed to show a significant re-
duction in the rate of vaso-oc-
clusive crises events in children and
adolescents with sickle cell anaemia,
according to data presented at the
annual meeting of the American
Society of Haematology.
The phase III randomised placebo-
controlled trial of 341 children and
adolescents (aged 2–17 years),
known as the Determining Effects of
Platelet Inhibition on Vaso-Occlusive
Events (DOVE) trial – simultane-
ously published in the
New England
Journal of Medicine
– showed the rate
of vaso-occlusive crises was 2.30 per
person-year in the prasugrel group
and 2.77 in the placebo group (rate
ratio 0.83, 95% confidence interval
0.66-1.05, P = 0.12), with a slightly
greater but still nonsignificant reduc-
tion among the older patients aged
12–17 years.
Treatment with prasugrel did not
achieve any significant reductions
in secondary outcomes of hospi-
talisations for vaso-occlusive crises,
red-cell transfusions, pain rate or
intensity, analgesic use, or school
absences, compared with placebo.
Platelet reactivity, however, was
significantly lower in the prasugrel
group (
N Engl J Med
2015, Dec 8.
doi: 10.1056/NEJMoa1512021).
“Sickle cell anaemia is a hetero-
geneous and complex disease in
which platelet activation is only one
of several mechanisms of vascular
injury, which perhaps explains why
prasugrel was ineffective,” wrote
Dr Matthew M. Heeney of Dana-
Farber/Boston Children’s Cancer
and Blood Disorders Centre, and
his coauthors.
“However, the nonsignificant ef-
fect of prasugrel in the oldest age
group may suggest that platelet ac-
tivation is relatively more important
in these older patients, a hypothesis
that is consistent with the fact that
endothelial dysfunction in sickle cell
disease is progressive.”
Daiichi Sankyo and Eli Lilly funded
the study. Several authors disclosed
ties with Eli Lilly or other pharmaceu-
tical companies. Three authors were
employees of Eli Lilly, and one was an
employee of Daiichi Sankyo.
The rates of major molecular response
at 12 months were significantly higher
in patients receiving radotinib 300
mg b.i.d. and radotinib 400 mg b.i.d.,
compared with imatinib.
Almost all of the CAR T-cell work has been
in B-cell malignancies, acute lymphocytic
leukaemia, and chronic lymphocytic
leukaemia, so is this the right antigen, we
don’t know? Is this the right construct, we
don’t know? But there’s clearly activity
and that is very exciting.
By Prof Osaro Erhabor via Wikimedia Commons,
Creative Commons license.
Vol. 9 • No. 1 • 2016 •
H
aematology
& O
ncology
N
ews
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ASH 2015