ASH News Daily 2013 - Day 3 - (Page A-16)
Page A-16
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ASH NEWS DAILY
Monday, December 9, 2013
Sickle Cell Disease: New Answers Come With New Questions
SICKLE CELL
BY JULIE KANTER, MD
O
ne hundred years ago, Dr.
James Herrick first identified
sickle cells on a pe-
ripheral blood smear from a West
Indies dental student. Despite its
relatively high prevalence among
rare diseases, sickle cell disease
(SCD) has remained underfunded
and underserved. Patients with
SCD are living longer with average
lifespans approaching the fifth
decade of life. However, the question
remains whether quality of life
has improved as much as quantity?
This year's SCD presentations suggest
we have some answers.
Dr. Jean Raphael, Baylor College
of Medicine, Houston, TX, presented
at Saturday's Education Program
(repeated Monday at 7:00 a.m.) on
the merits of applying the patientcentered
medical home (PCMH) to
SCD. He described the triple aim of
a PCMH: improve quality of care,
reduce cost of care, and include the
patient experience. Dr. Raphael also
explained how pain, the hallmark
of SCD, can be managed more ef-
CLL
«« From Page A-1
Dr. Valentin Goede, German CLL
Study Group,
presented practice-
changing results from the CLL11
trial. Dr. Goede eloquently shared
the head-to-head comparison of two
chemoimmunotherapy regimens:
GA101 plus chlorambucil (GClb)
versus rituximab plus Clb (RClb),
and an updated analysis of GClb or
RClb compared with Clb alone in
patients with CLL and comorbidities.
Dr. Goede, from the Department
of Internal Medicine at the University
Hospital Cologne, Cologne,
Germany, focuses his research on
the prediction and management of
age-related vulnerability in elderly
lymphoma and leukemia patients.
During yesterday's session, Dr.
Goede presented the results of this
large pivotal phase III trial that enrolled
previously untreated CLL patients
with significant comorbidities.
Patients were randomly assigned to
six cycles of 1) Clb alone, 2) GClb, or
3) RClb. The primary endpoint was
progression-free survival and the
secondary endpoints were response
rate, minimal residual disease
(MRD), and overall survival (OS).
In the final stage-two analysis of
GClb versus RClb, treatment arms
were similar for baseline characteristics.
At a median follow-up of
19 months GClb proved superior
fectively in a PCMH. Published articles
have already demonstrated
that patients with SCD who receive
comprehensive care have less acute
hospitalization needs. However, as
commented by several attendees,
problems remain with identifying
enough PCMH available to care for
the growing adult SCD population.
Thus, the PCMH appears to be an
answer but also begs further questions.
Also on Saturday, Dr. Stella Chou,
University of Pennsylvania, Philadelphia,
PA, presented her research
on the "balancing act" of transfusion
therapy in SCD. Dr. Chou described
recent results on high-resolution Rh
genotyping that helps to explain
why allo-immunization has continued
in SCD patients receiving blood
transfusions despite enhanced antigen
matching. Furthermore, she
explained that 40 percent of the Rh
antibodies found in antigen-positive
patients were associated with a delayed
transfusion reactions. To prevent
these complications, Dr. Chou
proposed we should move toward
genotyping the Rh antigen. The
question becomes whether we will
be left with any donors?
Until recently, affected patients
had only one option (hydroxyurea).
However, several presenters
revealed early successes in novel
therapeutics for SCD. As explained
by Dr. Paul Frenette, Albert Einstein
College of Medicine, NY, there is
an enhanced understanding of the
pathophysiology of SCD that has
led to new developments in targeted
therapies. This augmented
understanding of the relationship
between the sickled RBC and the microcirculation
has led to several new
categories of medications. These include
anti-adhesion molecules such
as GMI-1070, a pan-selectin inhibitor
(being presented at 7:15 a.m. on
Tuesday by Dr. Laura De Castro,
Duke University, Durham, NC) and
SelG1, a p-selectin inhibitor (abstract
970 by Dr. Johnathan Stocker, Selexys
Pharmaceuticals), and new drugs
to target inflammation, including regadenoson,
an A2A receptor agonist
shown to reduce iNKT cell activation
in phase I studies in SCD (abstract
975 by Dr. Joel Linden, La Jolla
paring Clb monotherapy to each of
the aforementioned chemoimmunotherapy
regimens with a median
observation of 23 months. Either
GClb or RClb was superior to Clb in
terms of PFS (GClb versus Clb: HR
0.18, CI 0.13-0.24; RClb vs. Clb: HR
0.44, CI 0.34-0.57). However, most
importantly, GClb demonstrated a
significant OS advantage over Clb
(HR 0.41,CI 0.23-0.74), while RClb
did not.
The CLL11 trial is pivotal for sevDr.
Valentin Goede
to RClb in PFS (median PFS 26.7
months vs. 15.2 months, p<0.0001)
and achievement of no MRD. Further,
a trend toward improved OS
was seen with GClb over RClb (HR
0.66, CI 0.41-1.06). Neutropenia was
more common with GClb compared
with RClb (33% vs. 28%), but no increased
risk of infection was noted.
Grade three to four infusion-related
reactions occurred in 20 percent of
the GClb arm compared with 4 percent
in the RClb arm and was limited
to the first infusion of GClb.
Dr. Goede next shared with us
the updated stage one analysis of
CLL 11, originally presented at the
2013 ASCO Annual Meeting, com-
eral reasons. Dr. John Gribben, Barts
Cancer Institute in Queen Mary University
of London, who introduced
this Plenary talk, said, "The investigators
are to be commended for the
rapid accrual of patients that many
thought would be very difficult to
enroll into clinical trials." Until now,
no other CLL treatment regimen has
demonstrated a survival advantage
over Clb monotherapy. Dr. Goede
and colleagues have unlocked the
door to provide an understudied elderly
CLL population with safe and
effective treatment. Dr. Goede believes
that "CLL11 is now reporting
on a CLL patient population that is
typical for patients treated in routine
practice." Surely, most practicing
hematologists and oncologists will
find the CLL11 trial has an immediate
impact in their clinical practice.
Dr. Rajasekhar and Dr. Zumberg indicated
no relevant conflicts of interest.
Institute for Allergy and Immunology.
Rounding out treatment options,
Dr. Eliane Gluckman, Hospital Saint
Louis, Paris, France, reminded attendees
that hematopoetic stem cell
transplantation (HSCT) is a cure for
SCD. Her presentation cited impressive
outcomes in sibling-matched
transplantations (96% survival) as
well as current trials using alternative
donors, including matched unrelated
donors, umbilical cord blood,
and hapoloidentical donors. While
HSCT offers immense potential, barriers
still remain including the need
to expand transplant options to low
resource areas, spare fertility, and decrease
toxicity. Dr. Jeffrey Chell, the
CEO of the NMDP "Be The Match"
program and the executive director
of the CIBMTR is committed to
supporting patients throughout the
transplant process so that "financial
and social barriers don't prevent curative
options." Hopefully this promise
will deliver for patients with SCD
as we move forward.
Dr. Kanter indicated no relevant conflicts
of interest.
Genes
«« From Page A-4
well before an individual is exposed
to cancer therapies.
The investigators identi-
fied seven patients with specific
TP53 mutations for whom
banked samples were available
from several years before the
onset of the t-AML/t-MDS.
They were then able to identify
the specific mutations in
these early samples, albeit at
very low levels. This important
observation suggests a very
different model where genotoxic
therapies do not necessarily
induce TP53 mutations, but
rather provide them a selective
growth advantage, allowing
the clone to expand and potentially
further evolve. However,
it remains unclear if the
patients at risk for cancer may
have an enhanced predisposition
to develop these random
mutations, and thus may start
with a higher burden of TP53mutated
cells than an average
person. These findings open
up new opportunities for prevention
and potentially early
detection of t-MDS and t-AML,
which can have a profound effect
on patient outcomes.
Dr. Kumar indicated no relevant
conflicts of interest.
Table of Contents for the Digital Edition of ASH News Daily 2013 - Day 3
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ASH News Daily 2013 - Day 3
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