ASH News Daily 2013 - Day 2 - (Page A-13)
Sunday, December 8, 2013
TRANSPLANTATION
To B or Not to B: Two Faces of the B Lymphocyte
BY SHAJI KUMAR, MD
the human body, playing a crucial
role in health and disease. While
the classic approach to the study
of the immune system attempts
to compartmentalize the cellular
and humoral aspects, we are just
starting to realize the intricate and
complex relationship of the effector
and regulator cells of the B- and Tcell
compartments. In yesterday's
Scientific Committee Session, Burgeoning
Roles of B Cells in Transplant,
attendees were well rewarded
by three great speakers covering
a lesser known aspect of B-cells -
its active contribution to pathology
and disease.
In the first presentation of the session,
Dr. Ann Marshak-Rothstein,
University of Massachusetts, provided
a compelling story on the active
role played by wayward B cells
in the development of autoimmune
disorders. She elucidated the complex
interplay between the B-cell
receptors and the toll-like receptors
in the development of auto-reactive
B cells. In the context of knockout
mouse models lacking specific
TLRs, Dr. Marshak-Rothstein also
highlighted the complex interac-
T
LEUKEMIA
Taking a BiTE Out of Acute Lymphocytic Leukemia
BY MARK M. UDDEN, MD
record for the treatment of adults
with acute lymphocytic leukemia
(ALL). Pediatric hematologists can
take pride in their superior long-
N
othing is more discouraging
and downright depressing
than the track
term remission rate of 85 percent
compared with only a 45 percent
rate in most studies of adult ALL.
Why is adult ALL so intractable?
Is it the disease itself, the inability
of adults to tolerate high-dose chemotherapy,
or both? The answers
to these questions and a glimpse of
promising new treatment strategies
ASH attendees traverse the lobby of the Ernest N. Morial Convention
Center during the 55th ASH Annual Meeting and Exposition.
that might override poor-risk factors
for all patients was the topic
of discussion in yesterday's session,
Changing Paradigms in Acute
Lymphocytic Leukemia: From the
Genome to the Patient. According
to Dr. Anjali Advani, Cleveland
Clinic, Ohio, the session chair, there
is hope that "our depression will
be alleviated - for the following
reasons: 1) the use of pediatric inspired
regimens for younger adults
will likely improve outcomes; 2)
the addition of novel treatments to
standard therapy; and 3) targeting
specific pathways." If you were unable
to attend this session, it will be
repeated from 7:30 to 9:00 a.m. in La
Nouvelle Ballroom C in the convention
center.
Dr. Christine Harrison, Newcastle
University Leukemia Research Cytogenetics
Group, United Kingdom,
began by sorting out the bewildering
array of genetic mayhem in ALL.
She stated, "To achieve the goal of
curing all patients with ALL and
reducing toxicity there is a need for
new therapies to target underlying
molecular pathology of the disease,
he immune system is arguably
the most complex system
of checks and balances in
tion between the environment and
the BCR/TLR-mediated generation
of auto-reactive B cells, which in
turn may play a crucial role in the
development of autoimmune disorders
such as lupus.
This was followed by a very
stimulating presentation by Dr.
Thomas Tedder, Duke University,
Durham, NC, on the regulatory role
of B cells, a function commonly attributed
to T-cell subsets. While the
traditional concept is that of B cells
regulating the immune function
through production of antibodies,
he presented convincing evidence
of cytokine-mediated regulation of
the immune response by the B cells.
Work from his laboratory has identified
a rare subset of B cells that
secrete IL-10 and negatively regulate
inflammation in autoimmune
disease, as well as normal immune
response. These cells introduce an
antigen-specific aspect to the regulation
of the immune response and
interaction between these B cells
and T cells further modulate the
antigen-specific responses. From a
therapeutic perspective, the ability
of autologous IL-10 secreting B
cells to blunt the immune response
opens up an entirely new approach
to therapy in patients with autoimmune
disease as well as transplant
rejection.
An increasing wealth
of data demonstrates
that the donor B cells play
an important role in
maintaining the finely
orchestrated balance
between GVHD and GVL.
The topic of allogeneic stem cell
transplantation often conjures up
images of T cells running amok and
unleashing the terrible manifestations
of GVHD, or of the benevolent
T cells trying to mop up the tumor
cells through a wide variety of immunologic
mechanisms, depending
on individual perspective. T-cellspecific
agents such as the calcineurin
inhibitors have remained the
mainstay for transplanters trying to
maintain the fine balance between
GVHD and GVL. With all the attention
given to reining in donor T
cells, B cells have not been on most
people's radar screen. An increasing
wealth of data demonstrates that the
donor B cells play an important role
in maintaining the finely orchestrated
balance between GVHD and
GVL.
In the third topic of yesterday's
session, Dr. Jerome Ritz, Dana-
ASH NEWS DAILY
Page A-13
®
Farber Cancer Institute, Boston,
MA, presented an overview of the
current understanding of the less
recognized but important role of B
cells in the development of graftversus-host
disease. It has been
recognized that the donor B cells
can mount an immune response
and generate antibodies to minor
histocompatibility antigens as well
as tumor-specific antigens, and development
of these antibodies is
associated with reduced risk of relapse.
Less well understood is the
role of donor B cells in the development
of GVHD. Unlike T cells,
which clearly play a role in the development
of acute GVHD, B cells
seem to be contributing primarily
to the chronic GVHD; this is understandable
given the delayed reconstitution
of the B-cell compartment post
stem cell transplantation. Clearly, this
is not another exotic finding restricted
to animal models, as is evident from
the beneficial effects of rituximab in
the treatment as well as prevention of
GVHD. Dr. Ritz's ended the session
with a discussion of the importance
of the B-cell activating factor (BAFF)
in generating and maintaining this
hitherto unanticipated activity of B
cells.
Dr. Kumar indicated no relevant
conflicts of interest.
which forms the crux of leukemia
research at this time." In addition to
reviewing established good and bad
prognostic chromosomal and genetic
predictors for pre B-cell ALL,
Dr. Harrison delivered an update on
newly recognized abnormalities in
signaling pathways. These included
iAMP21, CRLF2, IKZF1, MLL, JAK2,
and the BCR-ABL-like ALL leukemias.
According to Dr Harrison, "A
subgroup of BCR-ABL1-like geneexpression
signature accounts for
10 to 15 percent of childhood and
25 percent of adult B-cell precursor
ALL, and there is evidence for sensitivity
to TKI when incorporated into
therapy."
Next, Dr. Mary Relling, St. Jude
Children's Hospital, Memphis, TN,
focused on how pharmacogenomic
variation affects efficacy and toxicity
of ALL treatment. For example,
there are ethnic differences that
may affect responses to therapy
and relapse rates of ALL. There are
also differences in drug metabolism
that may limit effect or enhance
»» LEUKEMIA Page A-14
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ASH News Daily 2013 - Day 2
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