ASH News Daily 2012 - Sunday, December 9, 2012 - (Page A-2)
Page A–2
®
ASH News Daily
2012 Editorial Board
Editor
Michael R. Bishop, MD
University of Chicago
Authors
Jose A. Bufill, MD
Michiana
Hematology
Oncology, PC
Jenna D. Goldberg, MD
Memorial SloanKettering
Cancer
Center
Matthew Hsieh, MD
National Institutes
of Health
Marc Kahn, MD,
MBA
Tulane University
School of Medicine
Andrew D. Leavitt, MD
University of
California,
San Francisco
The information contained in ASH
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©2012 by the American Society of
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the author byline.
LYMPHOMA
Chronic Lymphocytic Leukemia:
New Insights, New Challenges
BY JOSE A. BUFILL, MD
quarely at the center of the
process of malignant transformation
in chronic lymphocytic
leukemia (CLL) is the B-cell receptor
and the molecular pathways dependent
upon it. New agents targeting
these pathways have improved and
prolonged the lives of end-stage
patients, an observation that has
generated both great expectations
and a new set of clinical challenges.
These challenges will be addressed
in an Education Program session,
“Chronic Lymphocytic Leukemia:
Can New Prognostic Factors Guide
New Therapeutic
S
Approaches?”
scheduled this morning at 7:30 in
Hall 5, Level 1, Building B (GWCC).
Understanding the difference between
normal and pathologic B-cell
activation is the key to understanding
CLL. In the normal state, B cells
are in constant dialogue with their
microenvironment, acknowledging
the presence of chemical neighbors
as either friends (immune tolerance)
or foes (immune response). When a
threat is detected, the B-cell receptor
is activated, setting off a series
of reactions that ultimately lead to
the generation of antigen-specific
antibodies. The process of antibody
generation – called somatic hypermutation
– involves a frenzy of shuffling
and reshuffling of antibodyproducing
genes, whose products
determine the chemical properties
of the tip of the antibody – the variable
region of the immunoglobulin
heavy chain (IgHV) – enabling the
antibody to bind and neutralize its
corresponding antigen with razorsharp
precision.
In the malignant B cells of CLL,
the presence or absence of hypermutation
is the most reliable determinant
of prognosis. Unmutated
CLL cells are a less mature B cell
whose clinical course is more aggressive
and whose prognosis is
much worse. Mutated CLL cells are
more mature; their clinical course is
usually indolent. The important role
of IgHV and other newer prognostic
markers will be reviewed in detail
by Nicholas Chiorazzi, MD, of The
Feinstein Institute for Medical Research,
North Shore-LIJ Health System.
Dr. Chiorazzi is also the chair
of this session.
Steps in the molecular pathways
activated by the B-cell receptor have
emerged as effective therapeutic targets
in CLL (figure). Adrian Wiestner,
MD, PhD, of the National Institutes
of Health in Bethesda will review a
few of the new drugs that have en-
Figure A: Chemical Structures of Signal Kinase Inhibitors
ASH NEWS DAILY
Sunday, December 9, 2012
Figure B: Kinase Inhibitors and the B-Cell Receptor Pathway
Woyach JA, Johnson AJ, Byrd JC. The B-cell receptor signaling pathway
as a therapeutic target in CLL. Blood. 2012;120:1175-1184.
tered clinical trials. One of these is
ibrutinib (PCI 32765), an agent that
optimists have dubbed “the imatinib
of CLL” after dramatic and durable
responses were observed in patients
with end-stage disease. The exciting,
updated results of a multi-center
phase Ib/II study of ibrutinib in patients
with untreated, relapsed, or
refractory disease (abstract 189) will
be presented by John C. Byrd, MD,
of The Ohio State University today
at 5:00 p.m. in the Thomas Murphy
Ballroom 4, Level 5, Building B.
Among the many striking biologic
observations described with
ibrutinib is the development of
“redistribution lymphocytosis,”
a rapid shift in lymphocytes from
nodes and spleen into peripheral
blood. When it occurs, the lymphocyte
doubling time may be
measured in weeks and may take
weeks to resolve. It is an expression
of benefit rather than progression,
and investigators have emphasized
that response criteria should be re-
vised to take this phenomenon into
account.
The push to redefine response criteria
in CLL has also been prompted
by higher complete response rates
seen with more effective therapy.
Paolo Ghia, MD, PhD, from the
Università Vita-Salute San Raffaele,
Milano, Italy, will highlight promising
new measures of response and
survival in patients with CLL. The
concept of minimal residual disease
(MRD), as defined by PCR- or flow
cytometry-based techniques, may be
a reliable and independent predictor
of outcomes when used in patients
after completion of therapy. Dr. Ghia
will enthusiastically argue for the
use of MRD as a marker of survival
and of therapeutic efficacy. Taken
together, these talks suggest that the
long-term control – if not the “cure”
– of symptomatic CLL may be a realistic
expectation in the near future.
Dr. Bufill indicated no relevant conflicts
of interest.
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