Up Front
Latest & Greatest
A Cheaper, Faster Test FDA “Fast Tracks”
for Sickle Cell?
Experimental AML Drug
Twelve minutes and 50 cents could be
all it takes to diagnose sickle cell disease
(SCD), if the sensitivity and specificity
results seen with a new rapid, low-cost
test hold up in accuracy analyses. The
new density-based test developed by
researchers from Harvard University
takes advantage of the fact that sickle
cells are heavier than healthy red blood
cells. Slightly larger than a toothpick, the
test prototype can be easily administered
in the field: after uncapping the capillary
tube, pricking the patient’s finger for a
blood sample, allowing the blood to wick
into the tube, and placing the tube in a
centrifuge machine to separate the layers,
sickled cells form visibly identifiable layers on the bottom of the thin tube. “The
tests we have today work great, but the
equipment needed to run them costs in
the tens of thousands of dollars, and they
take hours to run,” said Ashok A. Kumar, MD, first author of the paper and
a postdoctoral fellow in chemistry and
chemical biology at the School of Engineering and Applied Sciences at Harvard
University. “That’s not [practical for]
rural clinics, or even some cities where
the medical infrastructure isn’t up to the
standards we see in the United States.”
Sources: Ku mar A, Patton MR, Hennek JW, et al. Density-based
separation in multiphase systems provides a simple method to identify
sickle cell disease. Proc Natl Acad Sci. 2014 September 2. [Epub ahead
of print]
Harvard University press release, September 2, 2014.
Leukemia Drug Shows
Promise for Other
Cancers
Dasatinib, a second-generation tyrosine
kinase inhibitor approved by the FDA
for the treatment of chronic myeloid
leukemia (CML), shows promise for
treating skin, breast, and several other
cancers, according to researchers from
Loyola University Chicago Stritch
School of Medicine. In CML, the drug
targets the protein BCR-ABL; BCR-ABL
is similar to Fyn, a protein that is found
in these other malignancies. When the
drug was used to treat other cancers, researchers found that dasatinib inhibited
Fyn’s cell-cell adhesion and migration
activity, which prevented cancer cells
from migrating and metastasizing.
Source: Fenton SE, Hutchens KA, Denning MF. Targeting Fyn in
Ras-transformed cells induces F-actin to promote adherens junctionmediated cell–cell adhesion. Mol Carcinog. 2014 June 29. [Epub ahead
of print]
14
ASH Clinical News
An experimental IDH2 mutant inhibitor,
AG-221 (Agios Pharmaceuticals, Inc.),
was recently granted the FDA’s “Fast
Track” designation for the treatment of
patients with acute myeloid leukemia.
AG-221 selectively inhibits the IDH2,
or isocitrate dehydrogenase-2, mutation
found in a subset of acute myeloid leukemia (AML) patients. The fast-track status
is given to medications with the potential
to treat serious or life-threatening conditions and address unmet clinical needs.
AG-221 is currently being tested in phase
I clinical trials in patients with advanced
hematologic malignancies. With this new
designation, sections of the New Drug
Application can be submitted on a rolling
basis as data become available.
Source: Agios Pharmaceuticals, Inc. press release. Accessed
from: investor.agios.com/phoenix.zhtml?c=251862&p=irolnewsArticle&ID=1939983
Investigational
Myeloma Drug Shows
Favorable Results
Phase I trial data suggest that treatment
with an investigational oral proteasome
inhibitor, ixazomib, led to stable disease or better response in 76 percent of
patients with heavily pretreated multiple
myeloma. In a study population of 60
patients, 15 percent had a “partial or better response” and 60 percent had “stable
disease.” All patients had undergone
previous treatment with bortezomib and/
or carfilzomib, lenalidomide, or stem
cell transplantation. Twice-weekly oral
ixazomib also appeared tolerable, with
no severe neuropathy seen to date.
Source: Richardson PG, Baz R, Wang M, et al. Phase 1 study of
twice-weekly ixazomib, an oral proteasome inhibitor, in relapsed/
refractory multiple myeloma patients. Blood. 2014 August 14. [Epub
ahead of print]
Engineered T Cells in
Chemotherapy-Resistant B-Cell Lymphoma
Results from a phase I-IIa clinical trial
show successful treatment of diffuse, large
B-cell lymphoma (DLBCL) with engineered autologous anti-CD19 CAR T cells
in patients with chemotherapy-refractory
DLBCL and indolent B-cell malignancies. Of 15 patients with advanced CD19+
B-cell malignancies treated with a single
infusion of anti-CD19 CAR T cells,
eight achieved complete remission, four
achieved partial remissions, one had
stable lymphoma, and two were not evaluable for response, according to a research
team at the National Cancer Institute. The
CAR-expressing T cells were produced
from each patient’s own peripheral blood
mononuclear cells, using a new cell production process that reduced the preparation time from 24 to 10 days.
Source: Kochenderfer JN, Dudley ME, Kassim SH, et al. Chemotherapyrefractory diffuse large B-cell lymphoma and indolent B-cell malignancies can be effectively treated with autologous T cells expressing an anti-CD19 chimeric antigen receptor. J Clin Oncol. 2014 August 25.
[Epub ahead of print]
FDA Expands Approval
of Eltrombopag for
Severe Aplastic Anemia
On August 26, 2014, the FDA expanded
the approved indications for eltrombopag
(Promacta®, GlaxoSmithKline) to include
treatment of patients with severe aplastic
anemia who demonstrated an insufficient
response to immunosuppressive therapy.
The oral thrombopoeitin receptor agonist
has already been approved for the treatment of thrombocytopenia in patients
with hepatitis C, and for chronic immune
thrombocytopenia patients who demonstrated insufficient response to immunoglobins, corticosteroids, or splenectomy.
The FDA’s new approval was based
on results from an NHLBI-conducted
phase 2 study; 40 percent of this patient
population showed hematologic response
in at least one lineage (red blood cells,
white blood cells, or platelets) at week
12. Among responders, the median red
blood cell transfusion–free period was
208 days (range, 15–1,082).
Source: GlaxoSmithKline press release. Accessed from: www.gsk.
com/en-gb/media/press-releases/2014/gsks-promacta-eltrombopagreceives-fda-approval-of-an-additional-indication
Updates on LongerLasting Hemophilia
Treatment Options
Patients with hemophilia A and B may
benefit from the less-frequent dosing
regimens of two recently FDA-approved
fusion protein therapies: recombinant
coagulation factor VIII (FVIII) Fc fusion protein (Eloctate™) for hemophilia
A and recombinant coagulation factor
IX (FIX) Fc fusion protein (Alprolix™)
for hemophilia B.
Margaret Ragni, MD, MPH, discussed the safety, efficacy, and clinical
implications of these new therapies in a
webinar titled “ASH Update on Recent
FDA-Approved Therapies for Hemophilia A and B.”*
rFVIIIFc was approved on the basis
of results from a phase III pivotal trial
that showed that patients with severe
hemophilia A who received individualized prophylaxis (25–65 IU/kg every 3–5
days) and those who received weekly
prophylaxis (65 IU/kg) had lower annualized bleeding rates (ABR) than
those who were treated episodically — to
the tune of 92 percent and 76 percent,
respectively. Thirty percent of patients
who received individualized prophylaxis
were also able to lower their bleeding rate
while on a five-day interval regimen.
In the phase III trial for rFIXFc,
patients with hemophilia B who received 10-day interval dosing (100 IU/
kg) had the lowest ABR (1.4), followed
by patients in the once-weekly dosing
group (50 IU/kg; 3.0). This represented
an 87 percent and 83 percent reduction,
respectively, in bleeding from the episodic treatment group (20–100 IU/kg).
Notably, patients in the 10-day interval
group actually received prophylaxis at a
median interval of 12.5 days.
In terms of safety, both agents were
well-tolerated: adverse events were minor
and unrelated to the product (except
for one case of painful hematuria in the
rFIXFc group).
Both of the agents extended the halflives of their non-Fc protein counterparts:
• rFVIIIFc: 19 hours (vs. 12.4 hours
with rFVIII)
• rFIXFc: 82 hours (vs. 33.8 hours
with rFIX)
Speaking about the clinical implications
for these new fused proteins, Dr. Ragni
noted that the longer duration >1 percent
factor level “means we can reduce our
treatment frequency and perhaps even
avoid ports and ER visits.” The need for
less-frequent injections, she added, will
also encourage some patients who were
not on prophylaxis to consider it.
*ASH, in collaboration with the FDA, offers webinars that feature an unbiased discussion of newly
approved hematology therapies. Access recordings
of these programs at ASHonDemand.org.
October 2014