ASH News Daily 2016 - Issue 3 - A-3

ASH News Daily

Monday, December 5, 2016

Page A-3
®

HEMOPHILIA

A Vector of Hope for the Future of Hemophilia
By Leslie Skeith, MD

ne family living in Padua,
Italy, has changed the face of
hemophilia care as we know
it. In 2009, a 23-year-old man with an
unprovoked deep vein thrombosis
was found to have a gain-of-function
FIX mutation (FIX-Padua) resulting
in an eight-fold increase in Factor IX
activity compared to antigen levels.
Yesterday in the third Plenary Scientific Session, Dr. Lindsey George
presented encouraging results of a
Phase I/IIa study of a hemophilia
B gene therapy that harnesses the
FIX-Padua transgene using a bioengineered adeno-associated virus
(AAV) capsid that has specificity to
target liver cells (hepatocytes).
Dr. George reported data on nine
subjects with hemophilia B who had

Dr. Lindsey George

baseline FIX levels less than or equal
to 2 percent, and who received a onetime infusion of the investigational
product SPK-9001 at a low dose of
5 × 1011 vg/kg. The subjects varied
in age (18-52 years) and in whether
they had liver disease or not. Patients

with advanced liver fibrosis or hightiter AAV neutralizing antibodies
were excluded from the study. The
mean FIX level achieved in all subjects was 28.3 percent (± 10%). With
the exception of one subject who had
two suspected joint bleeds requiring
factor replacement, all other subjects
stopped their prophylaxis, did not
require any factor replacement, and
had no breakthrough bleeding in
238 cumulative weeks of follow-up.
For example, the first enrolled subject still has FIX levels of 33 percent
after one year of follow-up, with no
joint bleeds or rescue factor required
in the year. Dr. George commented,
"What makes the study remarkable
is that we're using a lower dose, and
these are the highest levels of sustained FIX activity that have been
reported, with relative consistency

of the results across the patients
treated."
Dr. George is cautiously optimistic
about the results of SPK-9001. "First
and foremost, there have been no
adverse events related to the vector.
We will need to continue to monitor
treated patients to determine the durability of transgene expression and
ensure no adverse effects emerge on
long-term follow up." One subject
had a transient grade 1 transaminase
toxicity, and two subjects required a
short course of immunosuppressive
steroids.
One major limitation to previous
studies in hemophilia gene therapy
has been the immune response by
capsid-specific cytotoxic T-cells, leading to clearance of the FIX-transduced
»» HEMOPHILIA Page A-22

F O L L I C U L A R LY M P H O M A

It's Element-ary! GALLIUM Study Shows
Superiority With Obinutuzumab
By R. Frank Cornell, MD

ir Arthur Conan Doyle's fictional
detective,
Sherlock
Holmes, was known for his
skills in deductive reasoning and
observation. Although Doyle never
penned the phrase: "Elementary,
my dear Watson," Holmes often
used the word "elementary" when
explaining his deductive reasoning
to his famed partner. As an expert
chemist, Holmes would surely have
recognized the element Gallium, famous for its unique melting point
just above room temperature, allowing it to melt when held by a human
hand, yet refreeze when removed.
It's elementary that Dr. Robert Marcus, who, like Holmes, hails from
London, used his deductive reasoning powers to reach this year's ASH
Plenary Session.
Dr. Marcus presented primary
results of the randomized phase
III GALLIUM Study, which compares the efficacy of two anti-CD20
monoclonal antibodies: rituximab
(R) and obinutuzumab (GA101; G).
This compelling research could be
practice-changing for the newly diagnosed patients with follicular lymphoma (FL).
This study was an open-label,
randomized phase III trial evaluating the efficacy of induction with
G plus chemotherapy (institutional
choice bendamustine, CHOP, or
CVP) followed by G maintenance,
compared with R-based chemoimmunotherapy and R maintenance

Dr. Robert Marcus

in untreated FL. Of the study's 1,202
total patients, most had aggressive
FL, and the most commonly used
combination was with bendamustine (57% patients). Patients received
two years of maintenance therapy. In
this international trial, the primary
endpoint was investigator-assessed
progression-free survival (PFS) by
CT scan criteria. CT scan imaging
was selected due to regulatory issues
because many participating centers
did not have validated PET/CT. Molecular data assessing responses will
be presented today by Dr. Christiane
Pott at 7:00 a.m. (abstract #613). Due
to high levels of enthusiasm, the
study completed enrollment quicker than anticipated. Fewer patients
withdrew from the trial in the G-arm

compared with the R-arm from early
disease progression. The overall response rate was 85 percent in both
arms. After a median follow-up of 34
months, a clinically meaningful PFS
benefit was seen in the G arm, with
a 34 percent decrease in progression
or death compared to R-chemotherapy (HR, 0.66; 95% CI, 0.51 - 0.85; p
=.001).
Time to next therapy was also superior with use of G. The overall survival data have yet to mature. Lymphoma expert Dr. Brad Kahl said,
"It is a potentially practice-changing
study that clearly shows about an
8 percent absolute improvement in
PFS at two years for the patients getting obinutuzumab versus rituximab.
Obinutuzumab may get front-line indication for FL based on the study."
Important safety signals include a slightly higher infusion reaction rate with use of G versus R.
There was also a higher incidence
of fatal adverse events and an approximately 4 percent higher rate of
non-lymphoma-related mortality in
the G group. This is predominantly
in patients receiving treatment in
combination with bendamustine
where the non-lymphoma-related
mortality was 5 percent with bendamustine therapy versus less than 2
percent with CHOP or CVP therapy.
There is also a small signal for secondary malignancies in both arms.
Dr. Olalekan Oluwole commented,
"The higher incidence of infection
was not unexpected due to enhanced
antibody-dependent cell-mediated

cytotoxicity. It will be important for
there to be an awareness of this risk
and take precautions when using
bendamustine combinations."
For newly diagnosed FL, Dr. Marcus concluded, "Obinutuzumab
with chemotherapy is a better approach than with rituximab. One
should take precautions when using
bendamustine due to risk of infection." He does not believe that differences in dosing between G and
R should affect outcomes as there
is a "different mechanism of action
with G and there are no data to suggest that increased rituximab dosage
leads to improved efficacy."
Dr. Cornell indicated no relevant conflicts of interest.

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Table of Contents for the Digital Edition of ASH News Daily 2016 - Issue 3