ASH News Daily - Tuesday, December 13, 2011 - (Page A-3)
Tuesday, December 13, 2011
TRANSFUSION
ASH NEWS DAILY
Can We Take Neutrophils Out
Of the Driver Seat of TRALI?
By aManda BRandow, do, MS
T
ransfusion-related acute lung
injury (TRALI) is the leading
cause of transfusion-related
death. TRALI is defined as a new
episode of acute lung injury within
six hours of a transfusion and is
characterized by hypoxemia, fever,
dyspnea, and bilateral pulmonary
infiltrates. The pathophysiology of
TRALI is not entirely clear; however,
neutrophil activation is thought
to play an important role. Intriguing
studies that focused on the
role of neutrophils in TRALI were
presented at the Oral session titled
“Basic Science and Clinical Practice
in Blood Transfusion: RBC Storage
Lesion and TRALI,” on Sunday, December
11.
Dr. Grace Thomas, Children’s
Hospital, Boston, discussed the role
of neutrophil extracellular traps
(NETs) in TRALI (abstract #37).
NETs are DNA fibers decorated
with histones and antimicrobial proteins
contained in neutrophil granules.
NETs protect against infection
but can cause tissue injury, activate
platelets, and contribute to inflammatory
diseases. The authors demonstrated
that NETs biomarkers are
present in the blood of patients with
TRALI and that TRALI-inducing antibodies
purified from blood donors
activate neutrophils and stimulate
NETs generation. Dr. Thomas used
a TRALI mouse model to demonstrate
that NETs are also abundantly
found in TRALI-affected alveoli.
Furthermore, the authors showed
that pretreatment of mice with intranasal
DNase1 prevented alveoli
NETs accumulation and improved
lung function. “These results support
the hypothesis that NETs are
indeed formed in the inflamed lungs
during TRALI and contribute to the
disease process and, thus, could be
targeted to prevent or treat TRALI,”
Dr. Thomas stated.
Dr. Behnaz Bayat and colleagues
at Justus-Liebig University, Giessen,
Germany, were the first to prove
a TRALI mechanism involving
the pulmonary endothelium (abstract
#40). Their data revealed that
1-HNA-3a antibodies can directly
bind to pulmonary endothelial cells
and induce breakdown of the endothelial
barrier, subsequently causing
lung edema. “This is the first report
to prove a previously suspected
mechanism of TRALI in which a
transfused mediator induces TRALI
by directly affecting the pulmonary
endothelium,” Dr. Bayat stated.
Dr. Christopher Silliman, Bonfils
Blood Center, Denver, presented
data focused on antibody filtration
as a preventive measure for TRALI
(abstract #41). Dr. Silliman and colleagues
hypothesized that filtration
of plasma with leukocyte antibodies
will decrease antibody-mediated
priming of PMNs and TRALI. To
test this hypothesis, an antibody filter
capable of removing two to three
logs of donor IgG was developed
and shown to successfully remove
antibodies to HLA and HNA antigens
as evidenced by loss of priming
activity in in vitro assays using
PMNs that express the cognate antigen;
these filters, tested in a rodent
model, also appear to inhibit antibody-mediated
TRALI. “Such filters
would represent the first PRBC
mitigation step to prevent TRALI,”
Dr. Silliman stated. This work was
further discussed in a poster presentation
by Dr. Silliman, titled
“Characterization of Packed Red
Blood Cells Prepared with Experimental
Multifunctional Leukocyte
Antibody-Reduction Filters,” on
Sunday.
Dr. John Semple, Keenan Research
Center, St. Michael’s Hospital, Toronto,
Ontario, discussed using
IVIg infusions to prevent antibodymediated
TRALI (abstract #42). Dr.
Semple and colleagues induced
TRALI in mice that received no
pre-treatment with IVIg, were pretreated
with IVIg, or received IVIg
after TRALI symptoms developed.
The authors found IVIg pre-treatment
was protective against shock,
lung edema, and mortality and significantly
reduced production of
neutrophil reactive oxygen species.
Moreover, mice that received IVIg
after TRALI induction had significant
protection against lung damage
and mortality. In contrast, mice
that did not receive IVIg suffered
reduced body temperature, pulmonary
neutrophil accumulation, and
death. “This animal model may be
the first to demonstrate a successful
therapy for antibody-mediated
TRALI. It is a proof-of-concept, at
least, that IVIg is effective in antibody-mediated
acute lung injury,
and it may have a benefit in certain
at-risk patient populations. Hopefully,
clinical trials may confirm this
exciting observation,” Dr. Semple
stated.
The important insights offered
by these scientists bring us one step
closer to determining how the neutrophil
gets its license to drive the
TRALI and the ways in which this
license can be revoked!
Dr. Brandow indicated no relevant
conflicts of interest.
Page A–3
®
EHA President Dr. Ulrich Jäger, far left, and ASH President Dr. J. Evan
Sadler look on as Dr. Alan Bernstein delivers his presentation at the
ASH-EHA Joint Symposium on Sunday.
MYELOMA
More Flavors For Multiple
Myeloma
By heatheR landau, Md and
Michael a. RoSenzweiG, Md
T
he last decade has been
characterized by significant
progress with respect to the
treatment of patients with multiple
myeloma (MM), predominantly
due to the activity and availability
of novel agents (thalidomide,
lenalidomide, and bortezomib).
But despite deeper responses and
prolonged progression-free and
overall survival, the overwhelming
majority of patients eventually relapse
on these agents and salvage
treatment is required. Fortunately
at this year’s meeting, not only did
several groups identify resistance
mechanisms to immune modulating
agents (IMiDs) and proteosome
inhibitors, but high response rates
to second- and third-generation
agents were demonstrated. A handful
of new drugs and strategies with
promising activity were also introduced,
and chocolate and vanilla
may no longer be the only flavors
around.
Translational efforts focusing on
drug resistance were presented in
several Oral sessions Sunday afternoon.
Dr. Xiao Zhu (abstract #127)
from the Mayo Clinic in Scottsdale,
Arizona, presented data on
an important mechanism of IMiD
resistance, decreased cereblon expression
that will be studied as a biomarker
to identify patients destined
to fail IMiD therapy. In a murine
model of MM, Enrique M. Ocio (abstract
#134) from University Hospital
of Salamanca, Spain, showed that
pERK, pMEK, pRAF, and RAS were
upregulated in MM cells that became
resistant to lenalidomide and
pomalidomide. This was consistent
with the clinical data presented. Dr.
Paul G. Richardson (abstract #634)
from Dana-Farber Cancer Institute,
reported that in patients who were
refractory to both lenalidomide and
bortezomib, 16 percent and 30 percent
had at least a PR to single agent
pomalidomide and pomalidomide/
dexamethasone, respectively. Dr.
Xavier Leleu (abstract #812) from
Hôpital Claude Hurez, Lille, France,
on behalf of the IFM also showed a
35 percent response rate to pomalidomide/dexamethasone
in patients
refractory to both lenalidomide and
bortezomib. Triplet combinations
that included pomalidomide were
even more active in heavily pretreated
patients. Dr. Antonio Palumbo
(abstract #632) University of
Torino, Torino, Italy, reported that
in patients refractory to lenalidomide
the combination of pomalidomide,
cyclophosphamide, and
dexamethasone resulted in > PR
in 73 percent of patients. Despite
the limitations of cross-trial comparisons,
the antibiotic clarithromycin
does seem to potentiate the
combination of pomalidomide/
dexamethasone since Dr. Tomer
M. Mark (abstract #635) from Weill
Cornell Medical College, New York,
also showed that the combination of
clarithromycin, pomalidomide, and
dexamethasone (ClaPD) resulted in
responses > PR in 60 percent of patients
compared with the ORR of 34
percent reported by Dr. Richardson.
Bortezomib resistance has also
been investigated and based on the
work by Dr. Linda Baughn (abstract
#129) from the University of Minnesota
in Minneapolis, proposed targeting
B-cell differentiation in order
to overcome resistance.
Combination chemotherapy with
lenalidomide, bortezomib and dexamethasone
(RVD) is known to be
highly effective, but at this meeting
Dr. Andrzej Jakubowiak (abstract
»» MULTIPLE MYELOMA Page A-6
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ASH News Daily - Tuesday, December 13, 2011
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