The Hematologist - January-February 2008

Transcription

Hematologist
THE
A S H! N E W S A N D R E P O R T S
JANUARY/FEBRUARY 2008
VOLUME 5 ISSUE 1
FEATURES
A Yearlong Celebration for ASH’s 50th
KENNETH KAUSHANSKY, MD, FACP
Dr. Kaushansky is Helen M. Ranney Professor and Chair of the Department of Medicine at the University of California, San Diego. Dr.
Kaushansky is President of ASH.
t is my great pleasure and honor as President to welcome
you to the 50th year of the American Society of
Hematology, a year that promises to be our best in terms of
promoting translational and clinical hematology, teaching its art
and science, and advancing our understanding of normal and
pathological blood formation and function. As you will see from
perusing the cover and content of this issue of The Hematologist
and the Januar y 1 issue of Blood, we are celebrating this milestone through images, historical narratives, and timely review
articles. Throughout the year, our members will be treated to
historical reviews in ever y issue of Blood, and historical biographies in the pages of The Hematologist. The education sessions
at the annual meeting and the meeting book, Hematology 2008,
will be splashed with historical introductions and images of the
topics that practicing hematologists find most interesting. The
meeting rooms and common areas of our 2008 annual meeting
I
site, Moscone Center in San Francisco, will be filled with banners featuring photographs of pioneers in hematology and information about the first annual meeting and milestones in both
hematology and ASH. Video vignettes of past presidents and
pioneers in hematology will be featured throughout the meeting
and will bring our attendees a sense of the excitement that is
hematology. A special brochure, titled Conquering Blood
Diseases – From Research to Patient Care, will be available and
will make the progress of hematology more accessible to our
patients, friends, and family. You will even notice our special
50th anniversar y meeting bags will be worthy of collection!
And please don’t miss the ASH Bash on Monday evening of
the annual meeting, “A Taste of San Francisco.” So enjoy
2008, the year of the Hematologist!
THE ENVELOPE PLEASE:
THE ASH MEETING TOP
TEN LIST – Dr. Margaret
Ragni recounts some of the
highlights of the recent meeting.
2
ASK THE HEMATOLOGIST
– Dr. Thomas Loughran
evaluates a patient with
large granular lymphocytes.
5
6
ASH EFFORTS IMPACT
CMS MODIFICATIONS OF
RULES FOR MEDICARE
COVERAGE OF CLINICAL
TRIALS – Dr. John Leonard and
ASH Research Advocacy
Manager Tracy Roades discuss
reimbursement for patients in
clinical trials.
MINI REVIEW: NATURAL
KILLER CELLS:
DEVELOPMENT,
RECEPTOR BIOLOGY, AND
THEIR ROLE IN CANCER
IMMUNOTHERAPY – Dr.
Michael Caligiuri and Bradley
Blaser provide an overview of
natural killer cells.
7
WALLACE H. COULTER
AWARD FOR LIFETIME
ACHIEVEMENT IN
HEMATOLOGY: INAUGURAL
AWARD WINNER ERNEST
BEUTLER, MD – Drs. Marshall
Lichtman, Josef Prchal, and Karl
Blume profile the inspiration for
and winner of ASH's newest honorific award.
12
April 7, 1957
1st Organizational Meeting of the
American Society of Hematology
Geraldine P. Schechter, MD, Chief of
the Hematology Section at Washington
VA Medical Center and Professor of
Medicine at George Washington
University, kindly sent ASH a copy of
the Program of the First Organizational
Meeting of the American Society of
Hematology held on April 7, 1957, at
the Har vard Club in Boston, MA.
She writes: “It was given to me by my
mentor Dr. William McFarland a couple
of years ago, framed with the note on the
back in which he explains that he had it
copied in color because the bracket
drawn around the first group of papers
had been done by Bill Dameshek [pictured above] with his ‘futuristic’ pen,
which I took to be a ball point pen.”
OSCAR D. RATNOFF:
CHAMPION OF
CLOTTING – Drs.
Stanton Gerson and Nathan
Berger reflect on the prodigious
career of this groundbreaking
hematologist.
15
DEPARTMENTS
3
NEWS AND REPORTS
5
THE PRACTICING
HEMATOLOGIST
6
8
15
DIFFUSION
ASH’S 50TH ANNIVERSARY:
PROFILES IN HEMATOLOGY
16
Join us in San Francisco, December 2008
THE HEMATOLOGIST
ADVOCATE
MARK YOUR CALENDAR
N E W S
A N D
R E P O R T S
The Envelope Please:
The ASH Meeting Top Ten List
MARGARET V. RAGNI, MD, MPH
Dr. Ragni is Professor of Medicine in the Department of Medicine, Division Hematology/Oncology at the University of Pittsburgh and Director, Hemophilia
Center of Western Pennsylvania. She was also the Editor -in-Chief of ASH News Daily 2007.
C
ontinuing in the rich tradition of ASH meetings, the 49th annual meeting in
Atlanta was notable for outstanding presentations on new genetic mechanisms
of disease, inhibitors of novel molecular pathways, host response in gene
transfer, new targeted therapies in clinical trials, and pressing public health issues.
Among the firsts were a phenomenal Trainee Day, a one-hour “Best of ASH” meeting summar y, and late-breaking abstracts. The emphasis on young physicians and
scientists in workshops and sessions about writing a successful grant, finding a good
mentor, and landing the ideal career was outstanding. Perhaps not coincidentally,
three of the six late-breaking abstracts were authored by a fellow or medical student!
And, in a new tack, a French edition of ASH News Daily was published.
On behalf of the dedicated ASH News Daily authors, Drs. Jay Coghill, Naomi
Galili, Irene Ghobrial, Xavier Leleu, Alice Ma, Ruben A. Mesa, Vida Almario
Passero, Azra R aza, and Robert L. Redner, the top ten hits at the ASH meeting
are…The envelope please…
#
10
#
#
#
Targeting P13K/AKT for T-ALL may be a NOTCH above the
rest.
New targets for T-ALL include the activating mutations in the NOTCH1 receptor.
Among these, the gamma-secretase inhibitors (GSIs), which block NOTCH1 activation, have been of great interest. Their use is limited, however, by the development
of resistance. In his presentation, Dr. Adolfo Ferrando described the molecular
sequelae of resistance to NOTCH inhibitor therapies in T-ALL and the molecular
basis for use of the alternative inhibitors of the P13K/AKT pathway, which are now
in clinical trial.
Elizabeta Nemeth, PhD, talks about “Ferropor tin Function and Ferropor tin
Disease” during the Scientific Committee session on Iron and Heme.
9
Hepcidin regulation of dietary iron absorption is unmasked.
Investigating the role of hepcidin in the regulation of iron absorption, Dr. Bruce
Beutler (standing in for his father) described elegant studies of mice with the Mask
phenotype. These mice have iron deficiency and regional alopecia of truncal hair,
which is corrected with iron supplementation. In contrast to typical iron deficiency in
which the iron regulator hepcidin is greatly decreased, and with it, hepcidin inhibition of iron absorption and iron release from macrophages, Mask mice have elevated
hepcidin and profound iron deficiency. Utilizing positional cloning, Dr. Beutler ’s
group (along with his father ’s research group) identified a splicing error in the
Tmprss6 gene as the cause of the Mask phenotype. TMPRSS6 is required for normal absorption of dietar y iron. In mice with the Mask phenotype, the hepcidin gene
transcription is inhibited, resulting in inhibition of hepcidin upregulation and the
Mask phenotype.
8
RNAi identifies RPS14 as the cause of 5q- MPD.
In a tour de force, Dr. Benjamin Ebert reported at the Plenar y Session on exciting
research using RNA interference that led his team to identify the causal gene of the
5q- syndrome, a subset of MPD. Patients with this disorder have a block in RBC
maturation. Thus, by assessing each of 41 candidate genes for capacity to induce
hematopoietic differentiation in CD34+ cells, RPS14 gene, which encodes for ribosomal protein, was identified as the causal gene. Subsequent simultaneous sessions
described targeted therapeutics taking advantage of these findings, such as lenalidomide, which has eliminated transfusion dependence in up to 75 percent of individuals with the 5q- MPD syndrome.
7
Imatinib for childhood ALL comes of age.
The successes of the tyrosine kinase inhibitor imatinib in CML have led to studies of
the drug in childhood Ph+ ALL. In this Plenar y abstract, Dr. Kirk Schultz
detailed the results of his Children’s Oncology Group protocol in which imatinib was
given, with high-dose chemotherapy, for 42 to 280 days. What the group found was
that the longer imatinib was used, the better the event-free sur vival: 84.7 percent
among those receiving imatinib for 280 continuous days, as compared with 41.2 percent among those given imatinib for the shortest duration.
(Cont. on Page 4)
2
Highlights of ASH®
Mark your calendar for the third annual Highlights of ASH.
Join ASH February 1-2, 2008, in Seattle, WA, or February
8-9, 2008, in Austin, TX, for the official Highlights of ASH.
You’ll hear renowned experts present their analyses of the
most influential abstracts from the 2007 ASH annual meeting. The meeting is geared toward practitioners and is the
only “Highlights” meeting produced by ASH in collaboration
with the ASH program committee.
The co-chairs of Highlights of ASH, Jane N. Winter, MD,
from the Robert H. Lurie Comprehensive Cancer Center at
Northwestern University, and Ari M. Melnick, MD, from the
Albert Einstein College of Medicine, served as co-chairs of
the 2007 ASH Education Program and the 2007 ASH
Scientific Program, respectively. It is from this vantage point
that Highlights of ASH has been developed. Together, they
identified topics and speakers based on the most important
information presented at the ASH meeting, without limitation by topic or institutional affiliation. In addition to hearing
analysis of groundbreaking research presented at the 2007
ASH annual meeting, attendees will discuss real cases with
leaders in the field, network with colleagues, and earn CME
credits. For more information, visit www.hematology.org/
meetings/highlights/index.cfm.
The Hematologist: ASH NEWS AND REPORTS
N E W S
Hematologist
THE
A N D
R E P O R T S
ASH Moves Forward with Sickle Cell Research Agenda
ASH ® NEWS AND REPORTS
ISSN 1551-8779
GEORGE BUCHANAN, MD, and MARILYN TELEN, MD
Dr. Buchanan is Children’s Cancer Fund Distinguished Chair in Pediatric Oncology and Hematology, and Director of
Pediatric Hematology-Oncology at the University of Texas Southwestern Medical Center.
Dr. Telen is Wellcome Clinical Professor in Medicine, Division of Hematology, at the Duke Comprehensive Cancer
Center, and Chief of the Hematology Division.
Editor-in-Chief
Peter Emanuel, MD
Winthrop P. Rockefeller Cancer Institute
Little Rock, AR
Contributing Editors
Charles Abrams, MD
University of Pennsylvania
School of Medicine
Philadelphia, PA
Kenneth Anderson, MD
Dana-Farber Cancer Institute
Boston, MA
Nelson Chao, MD
Duke University Medical Center
Durham, NC
Steven Grant, MD
Virginia Commonwealth University
Richmond, VA
Diane Krause MD, PhD
Yale University School of Medicine
New Haven, CT
Michael Linenberger, MD
Seattle Cancer Center Alliance
Seattle, WA
Robert Lowsky, MD
Stanford University Medical Center
Stanford, CA
Lilli Petruzzelli, MD, PhD
Millennium Pharmaceuticals
Cambridge, MA
t the end of 2007, the Society released a summar y of
recommendations titled Toward a New Research
Paradigm: Building A New Sickle Cell Disease
(SCD) Research Agenda. The document captures the discussions of the ASH Workshop on Sickle Cell Disease in May
2007. The Workshop’s goal was to explore new SCD
research objectives and create a real-world model to achieve
them. The Workshop document presents a synopsis of the
new research priorities identified and a blueprint for execution of the new sickle cell research strategy.
A
Five research areas were identified and prioritized by workshop participants. In rank order, they are: 1) development of
improved and new treatments, 2) identification of predictors
of SCD outcomes, 3) improved pain management and quality of life, 4) elucidation of the pathophysiology of organ
complications (kidneys, brain, heart, and lungs), and 5) initiation of international strategies for collaborative SCD
research.
The document identifies barriers to a new research agenda,
acknowledging the psychosocial, economic, and clinical care
deliver y problems that affect people with SCD, especially
adults. The document also recognizes that NIH’s funding
and organizational structure does not optimally support
multi-disciplinar y and longitudinal approaches to SCD, and
notes that the lack of cohesive interaction among the many
SCD stakeholders hampers new research initiatives.
In an effort to avoid fragmentation and disengagement, workshop participants recommended that NIH assemble a single
national DHHS-funded, multi-center collaborative research
group. Children and adults with SCD residing in areas of
the United States not ser ved by current government-funded
programs or who do not have access to care for financial or
other reasons must be included. The research agenda
describes two models for the NHLBI and other agencies to
consider.
New research should focus on multi-disciplinar y approaches
to characterize the genetic and environmental factors that
contribute to the heterogeneity of disease phenotype and
response to therapy. Continued improvement in drug therapies and pain management techniques remains a high priority. Additional study must also focus on preventing and
reducing organ complications for those with SCD.
To maximize quality SCD treatment, ASH emphasizes the
need to align the efforts of SCD stakeholders, including government entities, physicians, scientists, foundations, community advocates, and SCD patients and their families. ASH
recommends the creation of a new Sickle Cell Research
Group. This group would be composed of clinicians and scientists at academic medical centers that ser ve a large number
of SCD patients.
ASH has responded to the NHLBI’s Request for
Information (RFI): Defining a Research Agenda for Sickle
Cell Disease and Other Hemoglobinopathies by submitting
this document and has also distributed it to other Federal
Agencies and the sickle cell community. View the full text of
ASH’s sickle cell research agenda at www.hematology.org.
Josef Prchal, MD
University of Utah
Salt Lake City, UT
N EW H ONORIFIC AWARD
Jerald Radich, MD
Fred Hutchinson Cancer Research Ctr.
Seattle, WA
The Wallace H. Coulter Award for Lifetime Achievement in
Hematology is bestowed on an individual who has demonstrated a lifetime commitment and outstanding contribution to hematology, and who has made a significant impact
on education, research, and/or practice. The first
Wallace H. Coulter Award for Lifetime Achievement was
presented at the 2007 ASH annual meeting. It was presented to Ernest Beutler, MD. Wallace Henry Coulter was
a prolific inventor who made important contributions to
hematology and to ASH. (Editor’s note: For more on Mr.
Coulter and Dr. Beutler, please see pages 12-13.)
Roy Silverstein, MD
Lerner Research Institute
The Cleveland Clinic Foundation
Cleveland, OH
Gérard Socié, MD, PhD
St. Louis Hospital-1
Paris, France
Michael Williams, MD
University of Virginia Health System
Charlottesville, VA
Abisola Ayodeji, a Doctor of Medicine candidate at VCU School
of Medicine, speaks at the MMSAP reception held during the
2007 annual meeting.
Managing Editor
Karen Learner
Graphic Designer
Michael Kelly
American Society of Hematology
1900 M Street, NW, Suite 200
Washington, DC 20036
[email protected]
©2008 by the American Society of
Hematology.
All materials contained in this newsletter
are protected by copyright laws and may
not be used, reproduced, or otherwise
exploited in any manner without the express
prior written permission of The Hematologist:
ASH News and Reports. Any third party
materials communicated to The
Hematologist become its copyrighted property and may be used, reproduced, or otherwise exploited by The Hematologist.
Contributing authors have declared any
financial interest in a product or in potentially competing products in cases where
financial compensation is above the level of
$10,000 per year or ownership of stock
exceeds the fair market value of $10,000.
Any such financial interest is noted with the
author byline.
ASH Minority Medical Student Award
Program (MMSAP) Application Available
The MMSAP is an eight- to 12-week summer
research experience for first- and second-year minority medical students. The benefits of this program
include the guidance of two mentors, a research
stipend, and an allowance for travel to the ASH annual meeting. The application deadline is March 14,
2008, and the deadline to request ASH’s assistance
to match an applicant with a host institution and
research mentor is February 1, 2008. For more
information, please visit the ASH Web site at
www.hematology.org/education/awards/mmsap.cfm
or contact Courtney Krier via e-mail at [email protected], or by phone at 202-776-0544.
Nominate a colleague, mentor, or friend for this new prestigious award by submitting a nomination (including full
name, institution, and reason for the nomination) by
February 1, 2008. This award will be presented at the
50th ASH annual meeting in December 2008.
ASH Members Awarded Membership in the Institute of
Medicine of the National Academies
Katherine A. High, MD
Division of Hematology
Howard Hughes Medical Institute
The Children’s Hospital of Philadelphia
Ronald Levy, MD
Professor and Chief, Division of Oncology, Stanford
University School of Medicine
Jeffrey V. Ravetch, MD, PhD
Theresa and Eugene M. Lang Professor and Head of the
Leonard Wagner Laboratory of Molecular Genetics and
Immunology, Rockefeller University
David T. Scadden, MD
Gerald and Darlene Jordan Professor of Medicine, CoChair, Department of Stem Cell and Regenerative Biology,
and Co-Director, Harvard Stem Cell Institute, Harvard
University
Director, Center for Regenerative Medicine,
Massachusetts General Hospital
3
N E W S
A N D
R E P O R T S
ASH Meeting Top Ten
(Cont. from Page 2)
#
#
#
#
#
#
4
6
AMG 531 does for platelets what EPO does for RBCs.
AMG 531, the novel thrombopoietin (TPO) receptor stimulating agent, garnered
great attention. In a phase III randomized, double-blind, placebo-controlled trial in
splenectomized ITP patients reported by Dr. Terr y Gernsheimer, AMG 531
increased platelet counts to a significantly greater degree than placebo. The primar y
endpoint, maintaining a platelet count greater than 50,000/ul for at least six weeks
of the last eight weeks on study, was achieved by 38 percent of those treated versus
none of the placebo group. The drug was considered safe, although one patient
developed thrombosis. More studies are warranted for this promising agent.
5
Oral agent prevents clots at the Xa intersection.
Among the hot topics of discussion at the Plenar y Session was the new oral anti-Xa
inhibitor, rivaroxaban, currently in phase III clinical trials. This new oral anticoagulant requires no monitoring and has no interaction with food. When compared with
enoxaparin for thromboprophylaxis following hip arthroplasty, rivaroxaban showed a
four-fold lower incidence of VTE, PE, and all-cause mortality, with a similar safety
profile. Review by the FDA is projected for late 2009.
Above: Terry Gernsheimer, MD, delivers her presentation during the
Plenary Scientific Session.
4
Hematologists and consumer groups aggregate to prevent
thrombosis.
Venous thromboembolism (VTE) headlined several special sessions at the annual
meeting, bringing together advocacy groups, grassroots organizations, and hematologists. The presentations made from diverse perspectives underscored the heavy toll
VTE disorders take and the major advances that are needed to bring new understanding and new treatment to the field. With more than 600,000 individuals developing VTE each year in the United States, this disorder is a major cause of morbidity and mortality. There are ongoing epidemiologic studies to determine VTE risk,
based on age, race, and gender, which will be useful in the development of optimized prevention and treatment approaches. Mechanistic studies of age-related cellular and molecular changes that affect the vascular epithelium are also in study.
Health-care deliver y, outreach and education programs, development of multidisciplinar y teams, and heath-ser vices research are among the programs already underway.
3
The formidable partners, infection and inflammation, assume a
malignant role.
A discussion of molecular mechanisms of infectious agents in cancer development
was highlighted at the ASH/ASCO Joint Symposium. Dr. Francis Megraud discussed the role of genetic mutations and epigenetic changes in malignant transformation, using the examples of Helicobacter pylori and inflammation in the development
of gastric cancer. Dr. Maura Gillison focused on the malignant transformation with
human papillomavirus (HPV) and orophar yngeal squamous cell carcinoma. Dr. Eric
Klein completed the session with a talk on the new gamma retrovirus XMRV in
patients with prostate cancer who have a common polymorphic variant of the
RNASEL gene, which is involved in antiviral activity of interferons. Understanding
the pro-inflammator y pathways activated by these pathogens should lead to potential
new targeted treatments and preventions of some of these common cancers.
Above: A full audience enjoys one of the Friday Satellite Symposia.
Below: Radek Skoda, MD, presents the Ham-Wasserman Lecture.
2
Getting to know JAK opens up the world of MPD.
The Ham-Wasserman Lecture was presented by Dr. R adek Skoda in recognition of
his seminal work with c-MPL and hereditar y thrombocythemia. It was his initial
report with Dr. Kralovics of the JAK2 V617F defect that generated the explosion of
myeloproliferative disorders (MPDs) research. In his talk, Dr. Skoda provided an
exciting journey through mutated genes, delineating, on a molecular basis, why some
MPDs affect red cells, others white cells, and still others platelets. Further, these
findings at the bench have provided molecular markers for disease as well as targets
for treatment, and will also be the basis for the upcoming revised WHO diagnostic
criteria for MPDs.
1
Cutting the cord launched the field of stem cell transplantation.
In recognition of his research leading to the first ever cord blood stem cell transplant
that launched the field of cord blood transplantation, Hal E. Broxmeyer, PhD, was
awarded the E. Donnall Thomas Lecture and Prize. He was honored for his prescient work on stem cells and its profound influence on research. His research has
revolutionized clinical outcomes for many hematologic diseases and has provided
hope for many previously considered untreatable.
T H E
P R A C T I C I N G
H E M A T O L O G I S T
ASK THE HEMATOLOGIST
THOMAS P. LOUGHRAN, JR., MD
Dr. Loughran is Director at Penn State Cancer Institute and Professor of Medicine at Penn State Milton S.
Hershey Medical Center, Penn State College of Medicine.
THE PATIENT
A 56-year-old man has a one- to two-year histor y of
recurrent infections including sinusitis and peri-rectal
abscess. He has been diagnosed for several years with
seropositive rheumatoid arthritis, with involvement of
bilateral metacarpophalangeal and proximal interphalangeal joints. Physical examination is also notable
for splenomegaly. He has had documented neutropenia for one year and has been considered as having
Felty ’s syndrome. Current CBC shows WBC of
10,000/µl, with an absolute neutrophil count of
100/µl and a total lymphocyte count of 9,500/µl.
EVALUATION
Review of the peripheral blood smear shows that most
of the lymphocytes had morphology typical of large
granular lymphocytes (LGLs). This case illustrates
the importance of careful review of the blood smear in
patients with neutropenia and/or rheumatoid arthritis.
The recognition of LGL leukemia as a distinct entity
was based on demonstrating increased numbers of circulating LGL, by examining the blood smear. In this
era of translational medicine, typically defined as
bench-to-bedside research, it is important to emphasize that clinical obser vations can also lead to new
knowledge and trigger laborator y investigations.
LGL leukemia results most often from a clonal
expansion of T cells with a typical CD3+ CD8+
CD57+ phenotype. Clonality is proven by T-cell
receptor gene rearrangement studies. The typical
workup then, in addition to review of the smear,
includes flow cytometr y and T-cell receptor gene
rearrangement studies. Less commonly, the expanded
LGLs are of natural killer (NK) lineage.
PATHOPHYSIOLOGY
Current evidence indicates that leukemic LGLs are
most likely antigen-driven cytotoxic T lymphocytes
(CTLs). Leukemic LGLs are characterized as terminal-effector memor y cells as defined by a CD45RA
positive and CD62 ligand negative phenotype. Gene
expression data showing extensive upregulation of
perforin and cytotoxic proteases resembles patterns of
gene expression obser ved in activated CTLs.
Molecular analyses of the antigen-specific portion of
the T-cell receptor show a non-random clonal selection consistent with an antigen-driven process.
Normally activated CTLs are downregulated by Fasmediated apoptosis. In contrast, leukemic LGLs are
Fas-resistant. Constitutive activation of multiple survival pathways, including STAT3/Mcl-1,
MAPK/ERK, and PI3Kinase, appears central to the
pathogenesis of LGL leukemia.
HEMATOLOGIC AND AUTOIMMUNE
DISEA SES A SSOCIATED WITH LGL
LEUKEMIA
ized by a CTL attack on the marrow, including aplastic anemia, pure red cell aplasia, and some cases of
MDS. The most commonly identified association with
pure red cell aplasia is not thymoma, but LGL
leukemia. A recent study identified clonal LGL in 50
percent of patients with MDS. Autoimmune hematologic presentations, such as hemolytic anemia or ITP,
can also occur with LGL leukemia. Rheumatoid
arthritis is a common feature of LGL leukemia. As
with the case presented here, the diagnosis of Felty ’s
syndrome is often considered. It is my opinion that
Felty ’s syndrome and LGL leukemia/RA are part of
the same disease process. Clinical, immunologic,
pathologic, molecular, and genetic data support this
contention.
TREATMENT OPTIONS
Immunosuppressive regimens are the treatment of
choice. However, there are no large prospective studies available to establish standard of care.
Methotrexate, cyclosporine, and oral cytoxan all
appear effective as single agents in about 50 percent
of patients. Treatment should be continued for at
least four months before considering alternative therapies because of lack of response. Participation in clinical trials should be encouraged. ECOG 5998 is
investigating use of methotrexate/prednisone as initial
therapy. A phase II trial sponsored by NHLBI is
examining alemtuzumab treatment. Humanized MiKbeta1 monoclonal antibody directed at CD122, the
IL-2 receptor gamma chain, is undergoing testing in a
phase I trial. A phase II trial of tipifarnib, a farnesyltransferase inhibitor, is under way. This trial is sponsored by CTEP and the R are Diseases Clinical
Research Network. Patients with LGL leukemia are
also encouraged to participate in the LGL Leukemia
Registr y (www.hmc.psu.edu/cancer/research/
index.htm).
FURTHER READING
Sokol L, Loughran TP Jr. Large granular lymphocyte leukemia. Oncologist. 2006;11:263-73.
Wlodarski MW, O’Keefe C, Howe EC, et al.
Pathologic clonal cytotoxic T-cell responses:
Nonrandom nature of the T-cell-receptor restriction in
large granular lymphocyte leukemia. Blood.
2005;106:2769-80.
Epling-Burnette PK, Painter JS, Rollison DE, et al.
Prevalence and clinical association of clonal T-cell
expansions in myelodysplastic syndrome. Leukemia.
2007;21:659-67.
Osuji N, Matutes E, Tjonnfjord G, et al. T-cell large
granular lymphocyte leukemia: A report on the treatment of 29 patients and a review of the literature.
Cancer. 2006;107:570-8.
2008 ASH-AMFDP
Application
Deadline Approaching
The ASH-AMFDP award is a
partnership between ASH and
the Harold Amos Medical Faculty
Development Program (AMFDP)
of the Robert Wood Johnson
Foundation. The ASH-AMFDP
award provides four years of
postdoctoral research support,
including an annual stipend of up
to $75,000 and an annual grant
of $30,000 toward the support
of research activities. The deadline for the 2008 ASH-AMFDP
Award is March 19, 2008. To
apply for this award, trainees
should visit the AMFDP Web site
at www.amfdp.org/
applicat.htm.
C ALL
FOR
H ONORIFIC AWARD
N OMINATIONS
ASH members are invited to
submit nominations for the
William Dameshek Prize, Henry
M. Stratton Medal, E. Donnall
Thomas Lecture and Prize, and
Wallace H. Coulter Award for
Lifetime Achievement in
Hematology for 2008.
Nominations must include the
nominee’s full name, institution,
current bio-sketch or CV, and a
brief paragraph summarizing his
or her contributions to hematology. Nominations are due by
February 1, 2008, and should
be sent by postal mail to the
American Society of Hematology,
Attn: Courtney Krier, 1900 M
Street, NW, Suite 200,
Washington, DC 20036, or via
e-mail to [email protected].
More information and nomination forms can be found on the
ASH Web site at www.hematology.org/education/awards/honorific.cfm.
There is growing appreciation of a considerable overlap of LGL leukemia and other disorders character-
5
T H E
H E M A T O L O G I S T
A D V O C A T E
ASH EFFORTS IMPACT CMS
MODIFICATIONS OF RULES FOR
MEDICARE COVERAGE OF CLINICAL
TRIALS
JOHN P. LEONARD, MD, and TRACY ROADES
Dr. Leonard is the Richard T. Silver Distinguished Professor of Hematology and Medical Oncology, Director of
Hematology/Oncology Clinical Research Program, and Professor of Medicine at Weill Cornell Medical College.
Ms. Roades is the Research Advocacy Manager at ASH.
L
ast spring, CMS initiated several rounds of proposed revisions to the rules governing
Medicare coverage of ser vices provided to beneficiaries enrolled in clinical research
studies.
Under the Medicare Clinical Trial Policy, first developed in September 2000, Medicare will
pay for certain items and ser vices for Medicare beneficiaries involved in clinical trials. In
April, CMS issued proposed revisions to this policy. Some of these had the potential to
impact the ability of patients to participate in clinical trials, and therefore could have affected
clinical trial accrual and operations in significant ways. ASH submitted comments expressing
concern with a number of the proposed revisions.
In commenting on CMS’s proposed revisions to its coverage policy, ASH sought to ensure
that Medicare beneficiaries are not, in any way, discouraged from participating in clinical trials. ASH’s comments to CMS took into account comments and input from the
Reimbursement Subcommittee, the Committee on Government Affairs, and the general ASH
membership. These comments detailed concerns about proposed new requirements for publication of research study information, the generalization of studies to the Medicare population,
and self-certification and deeming (to verify that studies meet certain qualifying criteria). In
some of these areas, individual investigators and institutions potentially would have been held
responsible for ensuring that new and higher standards were met to ensure that Medicare beneficiaries could participate in trials. Some of these were not fully
defined or were beyond the scope
of expected conduct of clinical
TAKE ACTION
research practice, and therefore
had the potential to hinder activiThis year, ASH will continue its advocacy efforts on
ties in a significant way.
several important research and practice-related
As a result of the comments submitted by ASH and other organizations during the agency ’s first
reconsideration of the policy,
CMS announced in a July 9
Decision Memorandum that it
was backing away from the proposed changes and indicated that
the agency was “issuing this
national coverage determination
in order to preser ve the status
quo with the exception of two
changes” — clarifying that items
or ser vices under investigation in
a clinical trial will be covered by
Medicare if they would be otherwise covered outside of a clinical
trial and adding language indicating that Medicare could cover
routine costs in connection with
clinical trials required as a result
of a National Coverage Decision
(NCD) based on a Coverage
with Evidence Development
(CED) determination.
At the end of December, Congress and the President agreed to provide physicians with a temporar y reprieve from the scheduled 10.1
percent payment rate cut that was to go into effect Januar y 1, 2008,
and increase Medicare physician fees by .5 percent until July 1,
2008. The legislative fix comes as a part of the Medicare, Medicaid
& SCHIP Extension Act of 2007 (S. 2499), which extends several
programs that provide higher Medicare reimbursement rates to rural
health-care providers and hospital laboratories. The legislation, however, does not address future physician fee cuts, which means the 10.1
percent cut will go back into effect after six months in the absence of
additional Congressional action. For a complete update on this important issue, please visit the ASH Web site at www.hematology.org.
Congress Approves $133 Million Increase for NIH
After much debate, the Congress and the President finally agreed on
an omnibus budget package for fiscal year 2008 that “hews closely to
the White House’s budget limits but shifts billions of dollars to the
Democratic majority ’s priorities.” Under the package, NIH receives
$28.942 billion, an increase of $133 million (+.46 percent). This
includes a $294.7 million transfer to the Global AIDS Fund. The
legislation provides $495.6 million for the NIH Common Fund, an
increase of $12.6 million (+2.61 percent). These budget numbers
are disturbing as they do not even keep pace with biomedical inflation
(expected to be 3.7 percent).
Institute
FY 2007
Comparable
FY 2008
President’s
Request
NCI
$4,792,624
$4,782,114
NHLBI
2,922,391
2,925,413
• Seeking increased federal funding for
research
NIDDK
1,852,996
1,858,045
• Seeking appropriate physician reimbursement
NCRR
1,131,633
1,112,498
• Supporting legislation to expand federally funded embryonic research
NIA
1,045,468
1,047,148
issues, such as:
• Supporting legislative initiatives concerning
sickle cell treatment and research
• Advocating for genetic information nondiscrimination legislation
The Society needs the help of all ASH members to
bring issues important to the future of hematology
to the attention of the U.S. Congress and other
governmental agencies. Members of the
Grassroots Network receive action alerts and information about issues in which they indicate an interest. At times, Grassroots Network members are
invited to represent hematology in Washington
activities, such as visits with Congress, NIH leadership, and other federal regulatory agencies. Visit
the ASH Advocacy Center at www.hematology.org/
takeaction.
However, after issuing the Decision Memorandum, CMS reopened the Clinical Trial Policy
for a second reconsideration. ASH once again submitted comments on the proposed revisions
and again focused on concerns about proposed new requirements for public release of research
study information and self-certification requirements. In mid-October, CMS announced that
the final policy would maintain the revisions contained in the July 9 final Decision
Memorandum on the policy but negate all of the other proposed changes to the Clinical Trial
Policy.
The fact that CMS has, in the end, not made major modifications to how it handles participation for Medicare beneficiaries seems to be good news for ASH members, in that clinical
research in hematology and hematologic malignancies should be able to continue without new
hurdles to overcome. However, CMS has indicated that it may again reopen the Clinical Trial
Policy for another reconsideration in the future and that the agency may still issue one or
more proposed rules to modify Medicare regulations pertaining to coverage and payment in
connection with clinical trials. ASH members should be alert to updates from the ASH leadership in this area. It is clearly important to both the clinical and research missions of hematologists that clinical research efforts are facilitated rather than hindered and that Medicare
beneficiaries have the opportunity to participate in clinical trials both now and in the future.
6
Congress Passes Six-Month Delay of Physician Payment Cut
FY 2008
$4,805,088
(+12,464)
2,922,928
(+537)
1,853,248
(+252)
1,149,446
(+17,813)
1,047,260
(+1,792)
In Februar y, President Bush will release his proposed FY 2009 budget. ASH will launch grassroots campaigns to increase NIH funding
appropriately and will keep the membership abreast of all developments through The Hematologist, the ASH Web site, and the electronic newsletter The Advocacy Update.
NIH Issues Anemia of Inflammation and Chronic Disease
Program Announcement
Four Institutes of the NIH have joined together in a program
announcement (PAS-08-019) on “Anemia of Inflammation and of
Chronic Disease” (AICD). The announcement was published in the
NIH Guide to Grants and Contracts (November 2, 2007).
Responsive R01 applications will be accepted on standard receipt
dates, beginning in Februar y 2008. The National Institute of
Diabetes and Digestive and Kidney Diseases (NIDDK) has been
joined by the National Heart, Lung, and Blood Institute (NHLBI),
the National Cancer Institute (NCI), and the National Institute on
Aging (NIA) in announcing this program. The purpose of the program is to promote research that will lead to a better understanding of
the pathophysiology of AICD and improved methods of detection,
prevention, and treatment of this common form of anemia.
The program’s objective is to support research that leads to a better
understanding of signaling pathways and regulator y mechanisms that
affect the expression of hepcidin, ferroportin, hemojuvelin, DMT-1,
and other factors involved in iron metabolism, and the development of
new therapeutic strategies for AICD that may overcome er ythropoietin
resistance in this disorder. Other research objectives include a better
understanding of how aging affects er ythroid cell response to er ythropoietin, iron metabolism, and red blood cell sur vival, and clearance,
as well as a better understanding of the causes of anemia associated
with hematologic and solid tumor malignancies, unrelated to cancer
chemotherapy. Details on the program announcement may be viewed
at http://grants.nih.gov/grants/guide/pa-files/PAS-08-019.html.
M I N I
R E V I E W
Natural Killer Cells: Development, Receptor Biology,
and Their Role in Cancer Immunotherapy
MICHAEL A. CALIGIURI, MD, and BRADLEY W. BLASER
Dr. Caligiuri is Director, The Ohio State University Comprehensive Care Center. Mr. Blaser attends The Ohio State University College of Medicine.
ferent HLA alleles, 10,16 Velardi and others at the University of Perugia, Italy,
showed that NK cells could efficiently lyse allogeneic leukemic blasts in vitro if
KIR-HLA incompatibility were present. 17 They have subsequently asked whether
an NK-mediated graft-versus-leukemia (GVL) effect could be obser ved in vivo in
recipients of haploidentical (multiply mismatched) allogeneic stem cell transplantation. 18 Patients with AML in any complete remission or in chemo-resistant relapse
were transplanted with highly T-cell-depleted and CD34+ stem-cell-enriched haploidentical allografts. Recipients with NK graft-versus-host alloreactivity as predicted by HLA-typing had significantly longer relapse-free sur vival and event-free
sur vival than recipients of non-alloreactive NK. Strikingly, graft-versus-host NK
alloreactivity did not increase the incidence of acute graft-versus-host disease
(GVHD). Donor NK cells ignore non-hematopoietic tissues and preferentially
eliminate recipient antigen-presenting cells, which are known to be the primar y
source of antigenic stimulation for donor-derived T cells. 19-21 In addition to improving the relapse rate and preventing acute GVHD, alloreactive NK cells may also
Two immunophenotypically distinct subsets of NK cell can be found in human
improve engraftment of HLA-incompatible hematopoietic stem cells (HSCs) by
peripheral blood based on expression of
eliminating recipient T cells with the
CD56, a neural cell adhesion molecule
potential for graft rejection. 19 Figure 1
Effect
of
NK
Alloreactivity
in
T-Cell-Depleted
Haploidentical
Stem
Cell
Transplantation
(NCAM) and ligand for fibroblast growth
summarizes these effects. The impressive
factor receptor 1 (FGFR1): CD56 bright and
results of the Perugia group have been
Recipient
Donor
Result
CD56 dim NK. 3,4 CD56 dim cells produce more
attempted by others using various modificytotoxic granules and are more effective in
cations to the protocol with mixed
Lower risk of relapse
Graft versus Leukemia
antibody-dependent cellular cytotoxicity
results, but more recent studies have used
AML
+
and natural (antibody-independent) cytoalternative T-cell depletion and stem-cellBlast
Less priming of residual
toxicity than CD56 bright NK cells. 5 In conenrichment strategies with increasing sucdonor-derived T cells and
trast, CD56 bright cells that are stimulated by
cess. 22
improved engraftment of
NK
HLA-mismatched
HSC
monocyte-derived cytokines produce more
+
interferon gamma, GM-CSF, IL-10, and
Ongoing translational and clinical
APC
No direct cytotoxicity
IL-13 consistent with a role in regulating
research aims to bring the benefits of
Graft versus Host Immunity
against non-hematopoietic
the immune response to infectious insult. 6
NK-cell anti-leukemic activity to a wider
tissues
T
population of patients than only those
Development
who are candidates for allogeneic stem
HSC
cell transplantation. By modulating the
Prevention of acute GVHD
Epithelium
Like all hematopoietic cells, NK cells arise
activity of KIRs or other families of NK
and improved survival
from pluripotent stem cells in the bone
cell receptors, it may be possible to
marrow. Early progenitor cells traffic to
induce a controlled level of NK autoimFigure 1: Alloreactive donor-derived NK cells preferentially target AML blasts, T cells, and antigen presenting cells (APC) remaining in the recipient after conditioning for transplantation. Recipients of
secondar y lymphoid tissues where they pass
munity that could reproduce the GVL
alloreactive NK demonstrate lower rates of acute GVHD, graft rejection, leukemic relapse, and death
through discrete developmental stages to
effect without the associated risk of transafter transplantation compared with recipients of non-alloreactive NK.
bright
7
the CD56
NK-cell stage. A recent
plantation. In addition, our expanding
study has provided evidence for what may
knowledge of the immunologic and genetbe the terminal event in NK-cell developic control of NK developmental pathways
ment. 4 CD56 bright NK cells were sorted and cultured on synovial or dermal fibrobmay permit further manipulation of these cells through genetic, small molecule, or
last layers that express FGFR1. After several days in culture, the NK cells
antibody-based approaches.
became CD56 dim , had lost the ability to produce IFN-γ in response to cytokine
stimulation, and had significantly increased capacity to participate in natural cytoConclusion
toxicity. This result was independent of NK-cell proliferation but was dependent
upon direct contact between the NK cells and the fibroblast layers. It was also
Once known primarily for what it could not do, the NK cell is now recognized as
inhibited by antibody blockade of the CD56-FGFR1 interaction. Although these
a unique and important part of the immune system with roles in infectious disease
findings have yet to be confirmed, a model has emerged wherein relatively immaand tumor sur veillance. Studies focused on the mechanisms of NK-target recogniture CD56 bright NK cells reside primarily in secondar y lymphoid tissues and regution have led to encouraging findings at the clinical level. As the basic and translate local immune responses through cytokine production. These cells then migrate
lational studies of today tell us more, our knowledge of the role NK cells in cancer
to the peripher y where they differentiate into CD56 dim NK and acquire the capaciimmunotherapy will continue to unfold.
ty for natural cytotoxicity.
References
Receptor Biology
atural killer cells are large granular lymphocytes that comprise approximately 10 percent of the peripheral blood mononuclear cell compartment.
Despite sharing a close developmental relationship and similar cytolytic
mechanisms with T cells, they are considered a part of the innate immune system.
The designation “innate” is primarily one of exclusion; NK cells do not express
the T-cell receptor or surface immunoglobulin, nor do they undergo V(D)J recombination, and consequently they are not part of the “adaptive” immune system.
This and the obser vation that NK-like cells exist in more primitive animals while
T and B cells can only be obser ved in vertebrates has led to the perception that
NK cells are evolutionar y forerunners of T and B cells. 1,2 However, recent
advances in our knowledge of NK-cell development, cellular interactions, and
receptor biology have uncovered an entirely unexpected level of complexity in the
biology of NK cells, which has important implications for the future of cancer
immunotherapy.
N
19
18,19
The elucidation of the mechanism of NK-cell recognition of target cells dates back
to their identification as lymphocytes that could kill “naturally ” or without the
need for prior antigenic exposure. 8 In 1986, K arre provided a mechanism for these
findings with his proposal of the “missing self hypothesis”: NK cells are activated
by target cells that downregulate expression of MHC class I, 9 an event that often
is associated with viral infection or malignant transformation. This hypothesis
implies that NK cells express receptors for MHC class I that inhibit activation.
Several groups identified expression of such receptors by both mouse and human
NK cells. 10-13 In humans, killer-cell Ig-like receptors (KIRs) are the primar y
inhibitor y receptors for MHC class I. It appears that KIRs play an active role in
the acquisition of cytolytic capacity during NK-cell development. 14 In addition to
inhibitor y KIRs, there are a number of activating forms of KIR as well as activating and inhibitor y receptors of the C-type lectin family including NKG2D and
CD94/NKG2A. 15 The integrated sum of activating and inhibitor y inputs seems to
determine the final outcome of the interaction between NK and target cell. 15
Clinical Application
More than thirty years of investigation into the biology of NK-cell development
and signaling have led to important advances in clinical research in the treatment
of leukemia. Based on pioneering work identifying the specificity of KIR for difThe Hematologist: ASH NEWS AND REPORTS
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
Janeway CA. Nature. 1989;341:108.
Cooper MD, Alder MN. Cell. 2006;124:815-22.
Cooper MA, Fehniger TA, Caligiuri MA.Trends Immunol. 2001;22:633-40.
Chan A, Hong DL, Atzberger A, et al. J Immunol. 2007;179:89-94.
Nagler A, Lanier LL, Cwirla S, Phillips JH. J Immunol. 1989;143:3183-91.
Cooper MA, Fehniger TA, Turner SC, et al. Blood. 2001;97:3146-51.
Freud AG, Yokohama A, Becknell B, et al. J Exp Med. 2006;203:1033-43.
Kiessling R, Klein E, Wigzell H. Eur J Immunol. 1975;5:112-7.
Kärre K, Ljunggren HG, Piontek G, Kiessling R. Nature. 1986;319:675-8.
Colonna M, Samaridis J. Science. 1995;268:405-8.
Litwin V, Gumperz J, Parham P, et al. J Exp Med. 1994;180:537-43.
Moretta A, Bottino C, Pende D, et al. J Exp Med. 1990;172:1589-98.
Karlhofer FM, Ribaudo RK, Yokoyama WM. Nature. 1992;358:66-70.
Anfossi N, André P, Guia S, et al. Immunity. 2006;25:331-42.
Lanier LL. NK cell recognition. Annu Rev Immunol. 2005;23:225-74.
Colonna M, Brooks EG, Falco M, et al. Science. 1993;260:1121-4.
Ruggeri L, Capanni M, Casucci M, et al. Blood. 1999;94:333-9.
Ruggeri L, Mancusi A, Capanni M, et al. Blood. 2007;110:433-40.
Ruggeri L, Capanni M, Urbani E, et al. Science. 2002;295:2097-100.
Teshima T, Ordemann R, Reddy P, et al. Nat Med. 2002;8:575-81.
Duffner UA, Maeda Y, Cooke KR, et al. J Immunol. 2004;172:7393-8.
Koh LP, Chao NJ. Blood Cells Mol Dis. 2007. [Epub ahead of print]
7
Targeting Multiple RTKs in Cancer
Monoallelic Gene Expression in Health and Disease
Stommel JM, Kimmelman AC, Ying H, et al.
Coactivation of receptor tyrosine kinases affects
the response of tumor cells to targeted therapies.
Science. 2007;318: 287-90.
Alexander MK, Mlynarczyk-Evans S, Royce-Tolland M, et al. Differences between homologous
alleles of olfactory receptor genes require the Polycomb Group protein Eed. J Cell Biol.
2007;179:269-76.
herapies targeting receptor tyrosine kinases (RTKs) have provided remarkable
responses in both hematologic cancers and
solid tumors, but their clinical efficacy has been
limited in many cases, and few, if any, patients
are cured. In a recent seminal work that has
identified obstacles to meaningful responses to
single-agent therapies targeting RTKs, Stommel
and colleagues have utilized a glioblastoma
(GBM) model to examine coactivation of RTKs
triggering downstream phophatidylinositol 3kinase (PI3K) signaling in cell lines, xenotransplants, and primary patient tumor cells.
Remarkably, using an antibody array to assess
for phosphorylation of 45 RTKs, they found
three or more activated RTKs in each tumor,
and up to 10 activated RTKs in some cases. In
elegant experiments to assess the biologic and
clinical relevance of this upstream multiple RTK
coactivation, they utilized combinations of RTK
inhibitors and/or RNA interference to examine
the effects on PI3K signaling, cell sur vival, and
anchorage-independent GBM growth.
Impor tantly, combinations of RTK inhibitors, but
not single agents, inhibited PI3K signaling and
these functional sequelae.
lthough most genes in the genome of diploid organisms are expressed from both
alleles, genes in some tissues are transcribed preferentially from a single allele. Sex
chromosome gene dosage compensation is the first described and best known example of such monoallelic expression. In order to balance expression of X-linked genes, which
are present in two copies in females, the majority of one of the X-chromosome genes are
transcriptionally silenced in a process called X-chromosome inactivation; however, it has
subsequently been shown that monoallelic expression also occurs in some autosomal
genes. Genomic imprinting, another example of monoallelic expression, is characterized by
transcription in a parent-of-origin-dependent manner. There is clinical relevance of imprinting since a parenteral location of the same genetic lesion may be associated with disorders of entirely different phenotypes. Yet another mechanism of preferential allele usage is
allelic exclusion, which occurs in specialized cell types (e.g., B-lymphocytes express only a
single heavy and light chain and each olfactory neuron expresses a single odorant receptor
gene from greater than 1,300 genes). In the examples given above, allele-specific transcription is not fully understood but may be attained by one or a combination of mechanisms, including asymmetric DNA methylation, replication timing, chromatin structure,
non-coding RNAs, and nuclear localization.
T
These studies have fundamental implications for
our translational studies to treat cancer. First,
in the laboratory, they suggest that individual
patients’ tumor cells may need to be profiled in
order to identify specific activated RTKs and
then select cocktails of targeted therapies in
order to achieve meaningful inhibition of cell signaling. Alternatively, it may be possible to
choose a single agent targeting multiple RTKs
selected for individual patients. A third possibility
is to target downstream molecules in cell signaling cascades, thereby theoretically resulting in
significant inhibition of relevant signaling pathways and sequelae, regardless of the number of
upstream RTKs coactivated. Impor tantly, translation of these findings will inform the design of
clinical trials to evaluate targeted therapies in
patients most likely to respond, avoiding the
development of drug resistance and allowing for
fewer side effects.
The paradigm of combination therapies to cure
childhood acute lymphocytic leukemia, Hodgkin
lymphoma, non-Hodgkin lymphoma, and testicular
cancer is well established. Most impor tantly, the
current study suggests that combinations of targeted therapies directed at activated RTKs, or
single agents targeting multiple activated RTKs,
may allow for more broad application of this paradigm of successful combination therapies in
cancer.
8
Scholl C, Bansal D, Döhner K, et al. The homeobox gene CDX2 is aberrantly expressed in most
cases of acute myeloid leukemia and promotes leukemogenesis. J Clin Invest. 2007;117:1037-48.
A
Two recent papers have contributed to the elucidation and significance of the mechanism
by which two homologous alleles will be targeted for inactivation in so-called random
monoallelic expression. Alexander and colleagues employed mouse embryonic stem cell
lines that have yet to choose the allele for inactivation and used fluorescence in situ
hybridization probes targeted to specific genes. These investigators could then detect and
differentiate between the active and inactive states of specific loci during the S-phase by
the presence of a single fluorescent pinpoint in replicated loci that was characteristic of
the active state, while a doublet on the homologous chromosome indicated its tendency
for inactivation. In their paper, Alexander, et al. noted that alleles subjected to monoallelic
expression on both autosomes and X-chromosomes often flipped between the active and
inactive states in the embryonic stem cells. The inability to assay the state of activity of
monoallelic loci in methanol fixed cells suggested a requirement for intact chromatin structure. Based on this, the authors investigated whether embryonic stem cells carrying mutations in either Eed or Dnmt1, proteins that are known to play a role in chromatin modification, would affect the allelic inactivation, and their results showed a pivotal role for Eed
gene in the establishment of the active/inactive state.
A second paper by Scholl and colleagues unveiled a pivotal role for the clustered homeobox (HOX) genes in normal hematopoiesis and obser ved their abnormal expression in the
majority of patients with acute myeloid leukemia (AML). A normal human genome carries
39 HOX transcription factors clustered on four chromosomes (HOXA - 7p15, HOXB 17q21, HOXC - 12q12, and HOXD - 2q31); expression of the genes within each cluster is
developmentally, temporally, and spatially correlated to their location within each loci. Gene
expression from these loci is under complex transcriptional and epigenetic regulation. One
family of transcription factors, the Caudal-like homeobox genes (CDX1, CDX2, and CDX4),
plays a critical role in regulating expression of HOX genes. Normal expression of CDX2 is
restricted to intestinal development in the adult, while aberrant expression has been linked
to gastrointestinal malignancies. The authors of this repor t first showed that the ectopic
expression of CDX2 in a mouse was sufficient to induce malignant leukemic transformation. In their study of human AML, they showed that 153 of 170 patients (90 percent)
and eight of 15 human myeloid leukemia cell lines (53 percent) expressed CDX2 regardless of their cytogenetic status. These investigators then studied the mechanism of aberrant CDX2 expression and discovered that six of seven patients expressed CDX2 from a
single allele. However, the molecular basis of this monoallelic expression of CDX2 remains
unclear as no mutations in the promoter, its exons, or hypomethylation of CpG island of
CDX2 exon-1 were found.
These two papers contribute to our understanding of the cellular mechanism of mono- or
bi-allelic gene expression and also show that deregulation of these processes can have
profound organismal consequences. The discovery that CDX2 is aberrantly expressed from
a single allele in the majority of AML patients underscores the impor tance of disturbances
in monoallelic and bi-allelic gene expression and, in addition, its novelty as a mechanism of
disease pathophysiology, about which much more remains to be learned.
KENNETH ANDERSON, MD
ROBERTO H. NUSSENZVEIG, PHD, AND JOSEF T. PRCHAL, MD
Dr. Anderson indicated no relevant conflicts of interest.
Drs. Nussenzveig and Prchal indicated no relevant conflicts of interest.
Improved Resolution of Stem and Progenitor Cells
Reveals Increased Complexity Within the
Hematopoietic Hierarchy
NF-κB Profiling in Multiple Myeloma
Pronk C, Rossi D, Månsson R, et al. Elucidation of the phenotypic, functional,
and molecular topography of a myeloerythroid progenitor cell hierarchy. Cell
Stem Cell. 2007;1:428-42.
Annunziata CM, Davis RE, Demchenko Y, et al. Frequent engagement of
the classical and alternative NF-kappaB pathways by diverse genetic
abnormalities in multiple myeloma. Cancer Cell. 2007;12:115-30.
his manuscript defines the surface phenotype of different
hematopoietic stem and progenitor cell subpopulations with higher
resolution than achieved previously. With this fur ther refinement,
the investigators reveal more plasticity within the hematopoietic differentiation hierarchy than has been previously recognized.
he NF-κB pathway involves a family of transcription factors
(p50, p52, c-Rel, p65/RelA, and RelB) involved in the regulation of diverse cellular processes, including sur vival, proliferation, differentiation, and inflammatory responses, among numerous
others. This cascade can be subdivided into three components: the
classical or canonical pathway, the alternative or non-canonical
pathway, and the atypical pathway. In the classical pathway, an
inciting stimulus, such as activation of TNF-related cell surface
receptors, leads to activation of the IKK complex, which phosphorylates the IκBα protei n, resul ti ng i n i ts proteasomal degradati on. Under
normal condi ti ons, I κBα traps p65/Rel A i n the cy topl asm; hence, I κBα
degradati on resul ts i n Rel A nucl ear transl ocati on and DNA bi ndi ng, culminating i n the transcri pti on of numerous NF- κB-dependent genes,
including those encoding sur vival (for example, XIAP, Bcl-x L ) and
antioxidant proteins (for example, MnSOD2), among others. The NFκB pathway is hyperactivated in diverse neoplastic diseases, par ticularly those of hematopoietic origin. For example, human leukemia
cells and leukemia stem cells have been shown to require an intact
NF-κB pathway for sur vival. Notably, the sur vival of multiple myeloma cells appears to be par ticularly dependent upon NF-κB signaling,
and it has long been suggested that targeting the NF-κB pathway
might represent a very logical therapeutic strategy in this disease.
The success of the proteasome inhibitor bor tezomib, which among
other actions spares IκBα from proteasomal degradati on, i n pati ents
wi th adv anced mul ti pl e my el oma prov i des strong support for thi s noti on.
T
Prior excellent studies have shown enrichment for murine hematopoietic
stem cells (HSCs) and various par tially committed progenitor cells, such
as common lymphoid progenitors and common myeloid progenitors.
These investigators fur ther purify these populations using additional cell
surface proteins, including CD105 (endoglin) and CD150 (signaling lymphocytic activation molecule family member 1, SLAM1), which play roles
in signal transduction. HSCs, previously known to be Lin-Kit+Sca+, were
recently shown by Sean Morrison’s group to be fur ther enriched by selection for CD150 expression. To test the hypothesis that CD105 and
CD150 might also be differentially expressed within hematopoietic progenitor subsets, the investigators used flow cytometry to sor t subpopulations based on surface expression of lineage markers Sca, Kit, CD150,
CD105, and CD41. They extensively analyzed each subpopulation for morphology, in vitro and in vivo function, and gene expression profile.
Among the impor tant findings presented, they show that the LinKit+Sca1- population, which was previously known to be enriched for
bipotent megakaryocytic erythroid precursors (MEPs), is CD41- and is
comprised of at least three subpopulations based on CD105 and CD150
expression. The CD105+CD150- and CD105+CD150+ cells within this
population are already erythroid-committed, and the CD105-CD150+ cells
are truly biphenotypic with the ability to differentiate down the erythroid
and megakaryocytic lineages. This CD105-CD150+ population represents
less than 20 percent of the cells previously called MEP and is referred to
as PreMegE. In vitro assays of colonies expanded from single PreMegE
cells, a highly rigorous and labor-intensive approach, demonstrated that
they were biphenotypic megakaryocytic and erythroid precursors. It
remains to be seen whether the corresponding human hematopoietic subpopulations share the phenotypes identified.
Additional analysis of the different blood cell types that differentiated
from single cells of the different sor ted subpopulations adds to the complexity of current models of the hematopoietic hierarchy. For example,
Lin-Kit+Sca+CD150+ cells, which are highly enriched for HSC, would be
expected to be polyploid, and thus give rise to multiple different cell
types. However, 25 percent of the time, these cells differentiated exclusively into megakaryocytes. This doesn’t fit with our current understanding of hematopoietic lineage steps and suggests that megakaryocytes
may differentiate from HSCs without going through multiple intermediate
stages.
Gene expression analyses were consistent with the lineage commitments
obser ved in vitro. However, one surprising obser vation was that common
myeloid and common lymphoid progenitors had many genes in common,
which could underlie the lineage plasticity that has been found during initial phases of lineage commitment.
The improved ability to identify and purify specific hematopoietic subpopulations will help investigators to better understand hematopoietic differentiation in general, and myelopoiesis specifically. The identification of
successive lineage-restricted progenitors can be used to study the mechanisms of proliferation and maturation down specific lineages. For example, the highly purified biphenotypic PreMegE population can be purified
to study lineage fate decisions and to design approaches for enhancing
growth and differentiation of erythrocytes and/or megakaryocytes for in
vivo enhancement of these lineages or for transfusion therapy.
T
In a recent study appearing in Cancer Cell, Annunziata, et al. surveyed a large number of myeloma cell lines and patient samples for
evidence of NF-κB-activating mutations. They found a very high incidence of such mutations (i.e., 15-20 percent), which took multiple
forms, including translocations involving or amplifications of NF-κBactivating genes such as NIK, or mutations, deletions, or silencing
of NF-κB negative-regulatory genes such as TRAF3 or CYLD.
Interestingly, there was a correlation between the presence of such
genetic abnormalities and NF-κB hyperactivation with the susceptibility of cells to the antiproliferative and death-inducing effects of
agents, such as IKKβ i nhi bi tors (e.g., MLN120B), or proteasome
i nhi bi tors (e.g., bortezomi b). I n a compani on study i n the same j ournal ,
Keats, et al . reported a hi gh percentage (e.g., ~ 20 percent) of such mutations i n pri mary pati ent sampl es, parti cul arl y those i nvol v i ng TRAF3,
many of which were associated with activation of the non-canonical
NF-κB pathway. 1
The significance of these studies lies not only in their implications
for our understanding of the pathogenesis of multiple myeloma and
related hematologic malignancies, but also in their potential to have
profound ramifications for attempts to develop more rational targeted therapy in these disorders. In this context, genetic profiling of
diffuse lymphocytic B-cell lymphoma (DLBCL) has recently identified
specific subtypes (for example, GC vs. ABC), which differ in their
response to therapy, and perhaps not coincidentally, their dependence upon the NF-κB pathway. 2 It is therefore plausible to propose
that in the future, genetic profiling of multiple myeloma will not only
provide us with impor tant prognostic information, but may also
facilitate the development of more rational targeted approaches.
References
1.Keats JJ, Fonseca R, Chesi M, et al. Cancer Cell. 2007;12:131-44.
2.Bea S, Zettl A, Wright G, et al. Blood. 2005;106:3183-90.
DIANE KRAUSE, MD, PhD
STEVEN GRANT, MD
Dr. Krause indicated no relevant conflicts of interest.
Dr. Grant indicated no relevant conflicts of interest.
9
A Stake Through the Heart of Cardiolipin
A Bank Without Assets: Ex Vivo Storage Depletes
RBC NO Bioactivity
Galli M, Borrelli G, Jacobsen EM, et al. Clinical significance of different antiphospholipid antibodies in the WAPS (warfarin in the antiphospholipid syndrome) study.
Blood. 2007;110:1178-83.
Reynolds JD, et al. S-nitrosohemoglobin deficiency: A mechanism for loss
of physiological activity in banked blood. Proc Natl Acad Sci USA.
2007;104:17058-62.
Bennett-Guerrero E, et al. Evolution of adverse changes in stored RBCs.
Proc Natl Acad Sci USA. 2007;104:17063-8.
ome patients with
antiphospholipid antibodies have a clinical
syndrome composed of
thrombosis, fetal wastage,
and, frequently, autoimmune cytopenias, livedo
reticularis, and marantic
endocarditis. In this repor t
by Galli and colleagues, the
authors analyzed the significance of a variety of antibodies found in patients
with persistent antiphospholipid antibodies who par ticiFigure 1: Anticardiolipin antibodies alone are not a risk
factor for thrombosis. Some patients with lupus anticoagupated in an international
lants have thrombi and some also have anticardiolipin antiand prospective registry.
bodies. Anticardiolipin antibodies are not associated with
thrombi unless a lupus anticoagulant is also present.
Confirming the obser vations
of previous studies, this
analysis found that antibodies directed against ß2-glycoprotein I (ß2-GPI), or prothrombin, were associated
with recurrent thrombosis and pregnancy loss. This analysis also confirmed
some, but not all, previous studies demonstrating that anticardiolipin antibodies
were not significantly associated with either of these two adverse events.
S
Antiphospholipid antibodies are a heterogenous group of autoantibodies
directed against phospholipid-binding proteins. Some antiphospholipid antibodies
will induce their target protein to soak up the small amount of phospholipid
added to plasma during the PT and aPTT assays. These par ticular antibodies
will prolong phospholipid-dependent coagulation tests and are called lupus anticoagulants. Other phospholipid antibodies are directed against cardiolipin, a
phospholipid component of mitochondria originally described in bovine cardiac
cells.
Approximately five to 10 percent of healthy people will have detectable
antiphospholipid antibodies in their blood, although only a minority of people will
have the persistent presence of these antibodies and have thrombotic or
adverse pregnancy events. Since only a minority of patients with antiphospholipid antibodies have symptoms, several studies have investigated whether certain types of phospholipid antibodies better predict the subset of patients that
will develop the full syndrome. The study by Galli, et al. confirms previous studies showing that the correlation between the antiphospholipid antibody syndrome and autoantibodies is most prevalent for lupus anticoagulants and antiß2-GPI (a common phospholipid-binding protein). But, what is the significance of
antibodies against cardiolipin?
The Physicians’ Health Study produced the most widely quoted evidence that
anticardiolipin antibodies are associated with venous thrombosis (Annals of
Internal Medicine 1992;117:997-1002). In this large cohor t of 22,071 male
physicians, subjects with anticardiolipin antibody titers greater than the 95th
percentile had an approximately five-fold increased risk of DVTs and PEs. Since
this publication, the significance of these antibodies has been readdressed in
numerous trials. Several of these trials are quite notewor thy because of their
large size and findings that contradicted the Physicians’ Health Study. The LITE
study, another very large trial of 21,680 subjects, found no increased risk of
venous thrombosis in par ticipants with greater than the 95th percentile of anticardiolipin antibodies (Br. J. Haematology 2002;119:1005-1010). Also notable
is the lack of association between anticardiolipin antibodies and venous thrombosis in the HUNT trial that derived data from the 66,140 par ticipants in the
Health Study of Nord-Trondelag in Nor way (J. Thrombosis and Haemostasis
2006;4:44-49). In a meta-analysis, again anticardiolipin antibodies were not
associated with venous thrombosis (Blood 2003;101:1827-1832).
What should we do with patients who have anticardiolipin antibodies and thrombosis? Cer tainly, in patients with recurrent thrombosis, fetal loss, livedo reticularis, and autoimmune cytopenias, the presence of anticardiolipin antibodies
merely confirms the clinical diagnosis of an autoimmune-mediated thrombotic
disorder. A much tougher decision has to be made when we find the presence
of anticardiolipin antibodies in patients who have their first DVT, but no other
laboratory tests or symptoms consistent with the antiphospholipid syndrome. If
we let evidence be our guide, there is little to suppor t treating such a patient
any differently from the patient with a DVT and no laboratory abnormalities.
issue oxygen
(O 2 ) delivery is
dependent on
two interacting
processes: red
blood cell (RBC) O 2
content and microcirculatory blood
flow. Under normoxic conditions,
vasomotor tone
and tissue perfusion are regulated
by endotheliumderived nitric oxide
(NO). In hypoxic tissues, RBCs transfer bioactive NO to the vessel wall
to cause vasodilation and increase oxygenation. The chemistry of NO
biosynthesis and expor t from RBCs is not yet completely understood;
however, the mechanistic roles of hemoglobin (Hb) have recently been
clarified. 1,2 Impor tant intermediates in the process include S-nitrosothiol (SNO) adducts and S-nitrosohemoglobin (SNO-Hb), the concentration
of which directly correlates with the ability of RBCs to transfer NO and
induce vasodilation in laboratory models of tissue hypoxia. Reynolds, et
al. and Bennett-Guerrero, et al. were prompted by obser vational studies showing an association between worse clinical outcomes in critically
ill medical and surgical patients who had received RBC transfusions or
transfusions of RBC units with prolonged storage times. 3 They sought
to determine whether collection and storage of blood under standard
blood bank conditions resulted in changes in the content of RBC NO
equivalents and hypoxic vasodilatory function, which, in turn, might
explain a loss of efficacy for RBC transfusions in patients at high risk
for ischemic tissue injury.
T
Both of these studies demonstrated rapid depletion of RBC SNO-Hb
and membrane SNO concentrations that began as early as three hours
after blood draw (prior to leukofiltration and processing) and persisted
for six weeks. In concer t with SNO-Hb depletion, stored RBCs exhibited
significantly impaired vasodilatory activity in hypoxic rabbit aor tic ring
bioassays. The mechanism for rapid SNO-Hb loss was not defined nor
was a direct correlation between SNO-Hb depletion and other biochemical RBC storage lesions identified. Bennett-Guerrero, et al. did obser ve
a slow decline in RBC deformability that became more marked at two
to six weeks of storage, possibly relevant to repor ts of adverse outcomes after transfusion with older banked blood. 3 Reynolds, et al.
showed that RBCs stored for up to six weeks could be renitrosylated by
exposure to aqueous NO and adjustment of pH, and this reconstituted
the SNO-Hb concentrations and hypoxic vasodilatory functions in organ
chamber and live-animal canine coronary ar tery models.
These obser vations identify an impor tant storage lesion in banked
blood that profoundly affects the ability of RBCs to function as an O 2 responsive vasoregulator. The reason for rapid SNO-Hb loss ex vivo is
not defined nor is it known whether SNO-Hb levels and functional activity can be recovered in RBCs after transfusion. For patients with critical illness and tissue hypoxia, transfusion of SNO-Hb depleted RBCs
could theoretically displace enough native RBCs to impair normal
vasodilatory function and augment ischemic injury, resulting in
increased morbidity and mor tality. Altered RBC SNO-Hb levels have
been implicated in the vasculopathic processes associated with sickle
cell disease, diabetes, and pulmonary hyper tension. Transfusion practices for these patients, and perhaps others with chronic cardiac, pulmonary, and vascular diseases, should be re-evaluated in light of these
findings. The obser vation that SNO-Hb levels and experimental vasodilatory activity could be reconstituted by renitrosylation raises the intriguing notion that blood banks in the future might be able to provide
“recharged” RBCs for anemic critically ill patients, for red cell
exchange to treat severe sickle cell crisis, and for other transfusion
indications in selected high-risk individuals.
1. Angelo M, Singel DJ, Stamler JS. Proc Natl Acad Sci USA. 2006;103:8366-71.
2. Basu S, Grubina R, Huang J, et al. Nat Chem Biol. 2007;3:785-94.
3. Tinmouth A, Fergusson D, Yee IC, et al. Transfusion. 2006;46:2014-27.
CHARLES ABRAMS, MD
MICHAEL LINENBERGER, MD
Dr. Abrams indicated no relevant conflicts of interest.
Dr. Linenberger indicated no relevant conflicts of interest.
10
Transplantation Leads to Fertility
Autologous Stem Cell Transplantation for
Follicular Lymphoma: Evolution or Extinction?
Lee HJ, Selesniemi K, Niikura Y, et al. Bone marrow transplantation generates
immature oocytes and rescues long-term fertility in a preclinical mouse model of
chemotherapy-induced premature ovarian failure. J Clin Oncol. 2007;25:3198-204.
Montoto S, Canals C, Rohatiner AZ, et al. Long-term follow-up of highdose treatment with autologous haematopoietic progenitor cell support in 693 patients with follicular lymphoma: an EBMT registry study.
Leukemia. 2007; 21:2324-31.
nfer tility is a devastating adverse
effect of systemic chemotherapy.
Hematopoietic cell transplantation
(HCT) is now a treatment for
chemotherapy-induced ovarian failure. HCT is the treatment of choice
for many malignancies and non-cancerous conditions. Full donor
chimerism is frequently seen in the
hematopoietic system. Recent experimental models and studies in HCT
recipients have documented donor
cells in vascular endothelium, various
organs, and even in the recipient’s
fingernails. This recent repor t from
Lee, et al. adds another twist to
these obser vations.
ollicular lymFigure 1
phoma (FL) is
an indolent
non-Hodgkin lymphoma responsive
to a variety of
chemoimmunotherapeutic approaches. However, the
lack of cure with
these treatments
has led to a number of clinical trials over the past
20 years investigating the role of high-dose therapy (HDT) and autologous stem
cell transplantation (ASCT) in first or subsequent remission, with
no consensus benefit for overall sur vival (OS) and with concerns
regarding early and late toxicities. Montoto and colleagues repor t
a retrospective analysis and long-term follow-up of 693 patients
with FL from the European Blood and Marrow Transplantation
Registry who received HDT-ASCT in first remission or after
relapse and subsequent treatment. As a registry-based analysis,
induction treatments and the type of HDT conditioning regimens
varied. Fifty-eight percent received total-body irradiation (TBI) as
par t of HDT, 81 percent of patients were treated after 1990,
and all patients in the analysis had at least five years of followup; 30 percent of patients had received only a single line of
treatment prior to HDT-ASCT, and 19 percent were in first complete remission (CR1). Half of the patients relapsed following
HDT-ASCT at a median of 1.5 years, with lower relapse rates
among those patients who received TBI conditioning regimens (53
percent vs. 43 percent; p=.05). Progression-free sur vival (PFS)
and OS were improved for patients transplanted in CR1 (Figures
1a and 1b). Ninety-three patients (13 percent) died within one
year of HDT from a cause other than lymphoma, most due to
infection, and 40 (6 percent) died of a non-lymphoma cause more
than one year post-HDT, most due to second malignancy. The latter was significantly more common in TBI-treated patients and
contributed to an inferior long-term sur vival for TBI versus nonTBI conditioning regimens despite the lower relapse rates.
I
Figure 1
We have known that the preparatory
regimens for HCT are associated
with near absolute ovarian failure
and infer tility due to the ablative regimens utilized (although, there have
been repor ts of pregnancies especially in younger women). The current
dogma is that women are born with
a fixed number of oocytes that are
not replenished and that the
chemotherapy with or without radiation destroys the oocytes. This
dogma was challenged in 2005 when
investigators repor ted in a controver(A) Percentage of mice receiving vehicle
sial manuscript that adult mice con(n = 10), nonlethal chemotherapy (CTxtinued to produce new eggs and that
low, n = 13), or nonlethal CTx followed by
these eggs could have arisen from
bone marrow (BM) transplantation (BMT)
1 week later (CTx-low + BM/1 week, n =
bone marrow cells. 1 In this current
10) that achieved the indicated number of
study, Lee, et al. tested if and how
successful (live-bir th) pregnancies over a
HCT (in this case using murine mar7-month period when mating was initiated
coincident with BMT.
row cells) could restore fer tility in
mice treated with chemotherapy.
Figure from Lee HJ, Selesniemi K, Niikura
Y, et al. J Clin Oncol. 2007;25:3198Females administered nonlethal
204. Reprinted with permission from the
doses of chemotherapy (12 mg/kg of
American Society of Clinical Oncology.
busulfan and 120 mg/kg of
cyclophosphamide) without HCT
became infer tile, with the majority (10 of 13 mice) achieving three or fewer
live-bir th pregnancies and none achieving six live-bir th pregnancies. On the
other hand, 90 percent of the mice that received HCT one week after the
same chemotherapy achieved at least four live-bir th pregnancies, 80 percent (eight of 10 mice) achieved five pregnancies, and 70 percent (seven of
10 mice) achieved six pregnancies. It is impor tant to note that in this preclinical model, the mice were six to 10 weeks old. (They were quite young.)
The data demonstrate that if HCT is performed within one week of the
chemotherapy, the procedure leads to restoration of long-term fer tility. To
the investigators’ surprise, while they were able to track a few donorderived oocytes in the ovaries, the pups were of recipient origin (none were
of donor origin). What happened in these studies? Is the ovary similar to
the testes where the germ cells continuously generate new gametes? The
data suggest that the infusion of donor bone marrow cells led to the rescue
of a significant number of recipient follicles. These data are reminiscent of
effects of other cell populations, such as mesenchymal stem cells, where
the effect is that of repair or recruitment of endogenous host cells that
allow for repair of the cell of interest or of the stromal suppor t cells. The
data raise many questions. Is the infusion of bone marrow cells simply
enhancing clearance of damaged cells, decreasing inflammation, re-establishing stromal/nurse cells, enhancing overall health, recruiting impor tant
host cells to help with fer tility, or restar ting the production of oocytes?
Regardless of the answers that will come with fur ther research, if bonemarrow-derived cells can help preser ve fer tility, this could go a long way in
mitigating one of the most devastating adverse events for young women
receiving systemic chemotherapy.
F
These results suppor t previous findings that HDT-ASCT may result
in durable remission and possible cure for a subset of patients
with FL. Patients who received a transplant in CR1, and those
who had received fewer lines of pre-transplant chemotherapy or
were younger than 45 at transplant, had improved outcomes. The
analysis also verifies excess late mor tality due to second malignancies including MDS/AML, primarily in those treated with TBI;
as such, TBI should no longer be utilized in conditioning regimens
and has been largely abandoned. Although this is the largest
series to date evaluating HDT-ASCT in FL and having the benefit
of very long follow-up, caveats include the retrospective and nonrandomized nature of this study, the lack of central pathology
review, and the varying induction and conditioning regimens utilized. Previous prospective randomized clinical trials of HDT-ASCT
for FL in CR1 failed to show a benefit in OS and also showed
excess late, second malignancies. 1 However, these prospective
trials and the current retrospective analysis only included
patients treated in the pre-chemoimmunotherapy era. Fur ther
prospective clinical trials will be necessary to assess whether
HDT-ASCT will evolve to become a reliably curative approach via
induction chemoimmunotherapy and “in vivo purging” with monoclonal antibody therapy prior to stem cell collection, or will
become extinct if comparably long PFS and OS is achievable with
more effective and less toxic induction therapies, consolidative
immunotherapy with monoclonal antibodies or idiotype vaccines,
or the availability of more effective regimens for patients who
relapse.
1. Bowles K, Hodson D, Marcus R. Follicular lymphoma. Lymphoma: Pathology,
Diagnosis and Treatment, R Marcus et al., Eds. pp 119-122. Cambridge Univ. Press,
1. Powell, K. Skeptics demand duplication of controversial fer tility claim. Nat Med. 2005:11;911.
2007
.
NELSON CHAO, MD
MICHAEL WILLIAMS, MD
Dr. Chao indicated no relevant conflicts of interest.
Dr. W illiams indicated no relevant conflicts of interest.
11
Wallace H. Coulter Award for Lifetime Achievement in Hematology:
MARSHALL A. LICHTMAN, MD
Dr. Lichtman is Professor of Medicine, Biochemistry and Biophysics, at the University of Rochester Medical Center in Rochester, NY.
he establishment of The Wallace H. Coulter Award for Lifetime
Achievement in Hematology by the Coulter Foundation and the American
Society of Hematology ’s naming Ernest Beutler, MD, as its first recipient
is the happy convergence of two people who are among the most important contributors to hematology in the last 50 years.
T
The science and practice of hematology is dependent on blood-cell enumeration.
The methods for cell counting through the first half of the 20th centur y were
manual, tedious, laborious, and subject to frequent error. In the late 1950s, a
transformation in particle, including cell, counting occurred. This transformation
was the result of the genius of Wallace Coulter who patented the method he
developed to count and measure the volume of particles electronically.
Mr. Coulter had a strong interest in electronics in
high school and attended the Georgia Institute of
Technology with a major interest in electrical engineering. He worked for a series of electronics firms,
including General Electric and R aytheon. After
World War II, he began to consider methods of measuring industrial and biological particles electronically
to improve accuracy and ease of measurement. In the
mid-1950s, he and his brother Joseph produced prototype models of the Coulter Counter. The Model A
was the first instrument put into practice, and in 1958
the brothers established Coulter Electronics. Over the
next 40 years, the company grew to employ 5,000
people and operate in 20 countries, and the instruments it developed revolutionized particle counting,
sizing, and more. I was a happy beneficiar y of this
landmark work when I dispensed with my diluting
pipette and used a Model B Coulter Counter rigged to
a computer, with an oscilloscope interpolated, permitting tallies of cell counts and Polaroid photos of their
volume distribution cur ve. Who in clinical or research
hematology throughout the world has not benefited
from Mr. Coulter ’s innovations?
Mr. Coulter ’s ideas and instruments were among the
most important innovations in diagnostic and investigative medicine in the 20th centur y when one considers
their impact on the disciplines of cell biology, hematology, immunology, and oncology, and also on industrial
processes.
Wallace H. Coulter
The Coulter Principle, which formed the basis for future developments and
advanced instruments, is that cells are poor conductors of electricity as compared
to a salt solution. If cells are diluted in a saline solution and drawn through a
tiny aperture carr ying a current, each cell produces slight impedance to current
flow. The pulse created by the resistance to current flow of each particle flowing
through the aperture can be amplified and counted. Moreover, the size of the
pulse can be made proportional to cell volume. Thus, the number and size distribution of particles in a measured volume of a dilute suspension of cells can be
converted electronically to the blood cell count and volume. Thousands of cells
can be counted per second. Since platelets, white cells, red cells, and contaminating particles are sufficiently different in frequency and size, they can be discriminated. It is an irony of progress that the red cell count and volume is measured so
precisely that the packed cell volume (hematocrit), theretofore the most simple
and accurate measure of red cell concentration in the blood, has become a derived
value, the product of the red cell count and the mean red cell volume.
The early device and its successors provided an unparalleled level of accuracy,
efficiency, and breadth of application for enumerating and measuring the size of
cells from any tissue source. Those readers who labored over red cell and white
cell counts using a diluting pipette and hemacytometer chamber have some sense
of the effect of Coulter ’s instrument and its later multi-parameter output on
hematology and related disciplines.
The development of flow cytometr y and sorting has had a stunning and incalculable impact on research, diagnosis, and therapy. Adaptations that permit characterizing the phenotype or DNA content of cells and sorting and isolating cells by
their physical or surface properties have advanced studies of cells dramatically.
This remarkable instrument evolved from Joseph and Wallace Coulter ’s earliest
developments. A small subsidiar y owned by Coulter, Los Alamos Particle, Inc.,
in collaboration with the Health Physics Division of the Los Alamos National
Laboratories, used the ideas that had evolved to develop the prototype flow
12
cytometer. The instrument developed used the Coulter Principle to separate fluid
droplets containing cells by differences in cell volume. They could electrically
charge droplets with cells of the desired volume and deflect them electrostatically
into a collecting reser voir. Later, workers at Stanford advanced this technology by
using cells stained with fluorescent dyes and measured cell size by light scatter
and the fluorescence intensity generated by a laser. The cell-containing droplets
could be charged based on size and on the conversion of the laser-generated optical signal into an electronic pulse. These two variables (dual parameters) could
be used to decide whether to deflect the cell into a collecting reser voir. The addition of laser light scatter to the Coulter Principle of electronic counting and sizing
resulted in VCS (volume, conductivity, scatter of laser light) technology.
Dr. Beutler ’s contributions were of a different nature.
He provided scientific insight into a remarkable range
of hematologic diseases. He is a foremost student of
blood storage, red cell metabolism, hemolytic anemias,
iron metabolism and its disorders, lipid storage diseases (Gaucher disease, in particular), and a range of
clinical genetic disorders, and has contributed to many
other areas in insightful ways (e.g. hematopoietic stem
cell transplantation, leukocyte disorders, platelet transfusion, and others). He contributed to refined methodologies of measurement (e.g. red cell enzymes) and
diagnostic tests of importance for clinical genetic and
hematologic disorders. His contributions have been
highlighted in an article written by Drs. Josef Prchal
and K arl Blume in this issue of The Hematologist (see
page 13) and in a short biography published in
Leukemia. 1 A singular contribution of his was the first
demonstration of the human female as a mosaic of Xchromosome gene expression. Dr. Beutler had already contributed extensively to
our understanding of red cell glucose-6-phosphate dehydrogenase (G6PD) and
the clinical impact of its deficiency. He used this enzyme as an X-chromosome
marker to establish the mosaic state of X-chromosome gene expression in the
human female. Coat color genes are on the X chromosome in mice but not in
humans, making Dr. Beutler ’s discover y applicable to human genetics. Thus, the
work was of profound importance for the understanding of gene regulation and for
other biologic processes. For example, the concept was used to demonstrate that
human tumors were monoclonal, providing the once elusive definition of a neoplasm as a tissue abnormality arising from the genetic alteration in a single cell.
In parallel to Mr. Coulter, who in hematology around the world has not benefited
from Dr. Beutler ’s enormously productive career; his insights into human disease
and its diagnosis and management; his gifted writings; his contributions to agencies, organizations, and institutions; and his mentoring of innumerable disciples?
His warm friendship and gentle humor have also been shared by the lucky ones
among us who have had the opportunity to interact with him more intimately.
“In choosing a Nobel prize winner, there is usually no unambiguous or incontestable best choice,” said Arne Tiselius, himself a Nobel Laureate in Chemistr y,
and later President of the Nobel Foundation. “One can only hope the selection is
worthy,” he continued. Here, I would argue we have an unambiguous and incontestable best choice, Ernest Beutler.
1. Lichtman MA. An Introduction of Ernest Beutler. Leukemia.
2001:15;656-657.
Inaugural Award Winner Ernest Beutler, MD
JOSEF PRCHAL, MD, and KARL BLUME, MD
Dr. Prchal is Professor of Medicine and Genetics at the University of Utah.
Dr. Blume is Professor of Medicine at Stanford University.
rnest Beutler, MD, Chairman of the Department of Molecular &
Experimental Medicine at The Scripps Research Institute, was
the inaugural recipient of The Wallace H. Coulter Award for
Lifetime Achievement in Hematology in December 2007. This award is
bestowed on an individual who has demonstrated a lifetime of contributions to the field of hematology and who had a significant impact on
research, education, and practice. One cannot think of anyone more
deser ving of this new award than Ernest Beutler. His accomplishments
in academic hematology and the biologic sciences over the last five
decades are singular.
E
Dr. Beutler ’s original discoveries in science and the art of hematology
span a wide spectrum, involving many areas
of biochemistr y, molecular biology, genetics,
cell biology, pathophysiology, diagnosis, and
therapy. His contributions not only have
given us new insights into the mechanisms of
diseases but have also changed the way we
practice medicine in general and hematology
in particular.
He proposed the phenomenon of X-chromosome inactivation in human females, based on
his work with glucose-6-phosphate dehydrogenase (G6PD), concurrently and independent of the studies of the mouse geneticist Dr.
Mar y Lyon. This insight represented the first
example of the modulation of expression of
genes by an epigenetic mechanism. This brilliant obser vation provided an explanation of
the remarkable heterogeneity of the phenotype expressed by heterozygous females for
G6PD deficiency, hemophilia, and other Xlinked disorders. Following the studies by
Drs. Gartler and Linder on the clonality of
myomas, Dr. Beutler promptly demonstrated
the clonality of malignant human tumors that
changed the way we understand carcinogenesis.
In 1975, in his role as a clinical hematologist, Dr. Beutler initiated a
ver y successful clinical bone marrow transplantation program. Inspired
by the findings of Dr. E. Donnall Thomas
and his group that patients with advanced
leukemia enjoy sur vival superior to that seen
with chemotherapy, Dr. Beutler and his transplant team at the City of Hope National
Medical Center became one of the first to
successfully explore transplantation in acute
leukemia patients in complete first remission.
Above: Ernest Beutler, MD. Below: 2007 ASH
President Andrew Schafer, MD, presents the
Wallace H. Coulter Award for Lifetime
Achievement in Hematology, accepted on Dr.
Beutler's behalf by his son, Bruce.
With his typical rigorous approach, Dr.
Beutler established and standardized methods
for measurements of red blood cell enzymes
that provided the explanation for several
heretofore mysterious hemolytic anemias. He
also developed a simple and accurate method
for the early identification of newborns with
galactosemia using small samples of er ythrocytes. This method has since been used on
millions of newborns for early detection and
institution of dietar y treatment, making possible the avoidance of the debilitating complications of galactosemia. His critical knowledge of red cell metabolism led to improvement in blood storage preser vation that increased the shelf life of blood
— a major contribution to transfusion medicine with immeasurable benefits to the general public.
Dr. Beutler is a true clinician-scientist who has taken care of patients
most of his career. He also has made many innovative clinical obser vations demonstrating that the fusion of knowledge of basic science and the
art of medicine often leads to pioneering discoveries. In 1959, he was
the first to propose that sickle cell disease could be treated by altering
the hemoglobin in patients’ er ythrocytes, either by increasing methemoglobin levels or inducing the formation of fetal hemoglobin. The latter
approach bore fruit 40 years later with the introduction of the treatment
of sickle cell disease with hydroxyurea. Dr. Beutler has also been a
major contributor to the understanding of the biochemical genetics,
molecular biology, and treatment of hereditar y lipid storage diseases. He
developed the first clinically practical biochemical method for the diagnosis of Gaucher disease and for identifying carriers. His group cloned
the glucocerebrosidase gene and identified most of the mutations that
cause Gaucher disease. He pioneered enzyme replacement therapy for
Gaucher disease in the 1970s. When enzyme replacement became commercially available, his careful studies showed that the dose of the ver y
costly enzyme that was being used for treatment was recommended at
nearly 10 times the effective dose.
Dr. Beutler repeatedly seized on lessons
learned from genetic diseases to devise better
treatments. When Dr. Dennis Carson, then
an assistant professor in his new department
at The Scripps Research Institute, designed
2-chlorodeoxyadenosine (cladribine) as a
promising anti-lymphocyte compound, Dr.
Beutler initiated and directed clinical studies
that established this agent as the most effective treatment for hair y cell leukemia. Most
recently, Dr. Beutler has revolutionized our
thinking about the clinical penetrance of
hereditar y hemochromatosis, thought to be
“the most common disease of Europeans.”
Dr. Beutler organized what was probably the
largest DNA-based epidemiology study to
date, comprising more than 41,000 participants. This study demonstrated that although
the hereditar y hemochromatosis genotype was
common, the clinical phenotype was rare.
Initially received with skepticism, since they
ran counter to common belief, his findings
have now been extensively confirmed.
Among his many contributions to hematology
has been to ser ve as an editor of a leading
hematology textbook of which seven editions
have appeared since its inception in 1970.
He was the President of ASH in 1979 and
has ser ved on the editorial board of the
Society ’s journal, Blood. He also established
the first combined online and print biomedical journal, Blood Cells, Molecules and
Diseases. He was elected to the National Academy of Sciences and the
Institute of Medicine, has been a consultant to many scientific and medical organizations, ser ved on the Editorial Board of numerous scientific
and medical journals, and has received many prestigious awards including an Honorar y Doctor of Sciences from the Tel Aviv University.
One can only hope that all trainees in academic hematology may have
the good fortune of the attentive, generous, and superior intellectual
guidance that we experienced as trainees of Dr. Beutler.
13
N E W S
A N D
R E P O R T S
Emergency Preparedness: Looking Forward Five Years After SARS
MICHAEL GARDAM, MD, LEAH GITTERMAN, MHSc, and ARMAND KEATING, MD
Dr. Gardam is Director, Infection and Prevention Control Unit, UHN.
Ms. Gitterman is the Pandemic Planning Strategist with the Infection Prevention and Control Unit, UHN.
Dr. Keating is Professor of Medicine and Director, Division of Hematology, University of Toronto. He is Secretary of ASH.
t has been almost five years since Toronto experienced its outbreak of severe
acute respirator y syndrome (SARS). The outbreak, which occurred during the
spring of 2003, resulted in 25 1 cases and 43 deaths. Unlike some other countries that identified a significant number of cases in the community setting,
SARS in Toronto was spread predominantly in hospitals. Indeed, 43 percent of
the SARS cases occurred in health-care workers — the highest percentage of any
countr y that experienced an outbreak. It is important to note, however, that
almost all the mortality occurred not in health-care workers, but in patients who
had the misfortune of being admitted to the hospital for some other medical problem when SARS appeared.
I
nificant impact on our ability to provide care. Most current planning models
assume a “moderate” pandemic like that experienced in 1957. Unlike SARS,
which only affected local hospitals, a pandemic will be far more per vasive, involving a large segment of the world’s population over a period of months. Toronto
hospitals were able to access staff and supplies from surrounding areas during the
SARS outbreak, and the health-care system outside the city was still reasonably
able to care for patients; this option would not be available during a pandemic as
all health-care systems would be affected at roughly the same time.
Along with the stockpiling of supplies and the development of policies and
screening tools, cancer hospitals are also grappling with continuing to provide
care in a setting where their clinical programs, emergency departments, and intenFortunately, the worldwide spread of SARS was a limited phenomenon and
aggressive control measures were able to eventually halt its spread in all the coun- sive care units will be inundated with influenza patients. Some of the issues that
need to be addressed include the adequacy of intensive care beds for critically ill
tries that developed cases. The control measures used in Toronto were unprececancer patients, the desirability and ethical considerations of giving marrow-abladented in their scope and were imposed upon hospitals in the form of provincial
tive chemotherapy when influenza is widespread, protecting patients from acquirgovernment directives. Within hospitals, additional infection control precautions
ing influenza while in the hospital, the use of antiviwere used for all patients, outpatient and inpatient
ral agents and vaccines, and the necessity of freeing
ser vices were scaled back as were hospital staffing
up inpatient and outpatient space to care for influenlevels, and patients and staff were routinely surOur patients are highly vul- za patients which will require limiting cancer care to
veyed for symptoms of febrile respirator y illness.
The two main reasons for scaling back patient-care nerable to infectious diseases, certain patient populations. This last issue is particuactivities were to free up resources in the event
and it is a cruel irony that the larly contentious as we are not used to prioritizing
that additional cases occurred and required admis- very places patients go for care to this extent, and one can imagine the chaos if
hospitals develop different prioritization crision, and to provide less “fuel for the fire” as
t r e at m e n t m i gh t b e w h e r e different
teria. In order to help provide some guidance on this
SARS spread to patients in hospitals. In the
they acquire a deadly infec- issue, the provincial cancer care agency, Cancer Care
Toronto region overall, medical admissions were
tious disease.
Ontario, has recently published the results of an
decreased by 10 to 12 percent, while elective surextensive consultative process with its membership on
gical admissions decreased by 15 to 22 percent. 2
prioritizing cancer care during a pandemic. 6 These
Elective cardiac procedures, on the other hand,
were decreased by 66 percent and high acuity visits to emergency departments
are the first disease-specific guidelines developed for the deliver y of care during a
decreased by 37 percent. 2 Outside the hospital, more than 20,000 contacts of
pandemic. Central to this process was the use of an ethical framework based on
SARS cases were placed in home quarantine. 3
patient need and the efficacy of treatment to help guide decision-making. 7 These
guidelines divide patient care into three priority groups:
The impact of SARS on Toronto’s Princess Margaret Hospital (PMH),
• Priority A patients are those who are deemed critical and require
Canada’s largest facility for the treatment of hematologic and solid tumors, was
ser vices/treatment even in the event of a pandemic because their situation is
mixed. Staff and patients were extremely fortunate that no known patients with
immediately life-threatening.
SARS were admitted to PMH or made outpatient visits. This was despite many
cases being admitted to adjacent and neighboring facilities, including the two
• Priority B patients are those who require ser vices/treatment but whose situaother hospitals – Toronto General and Toronto Western – which, with PMH,
tion is deemed non-life-threatening; in the event of a pandemic,
make up the University Health Network. This being said, PMH administrators
ser vices/treatment could be discontinued for the period of the pandemic
and staff, like all Toronto health-care workers, were faced with the stress of the
wave (6-8 weeks).
outbreak and of complying with governmental directives that required scaling
back ser vices. Furthermore, as PMH is dependent upon other hospitals for inten• Priority C patients are those whose condition is deemed as non-life-threatsive care ser vices, there was the added concern amongst patients and staff that
ening and who can be deferred; those ser vices would be discontinued while
patients who required ICU care would be transferred to neighboring units that
there is pandemic activity in the province.
were caring for SARS patients. Early experience with SARS had suggested that
solid organ transplant recipients had ver y poor outcomes when infected; 4 hence,
Each priority group is then subdivided into multiple categories. The guidelines
there was reason to believe that bone marrow transplant recipients, especially
recognize that local or regional circumstances may influence a cancer program’s
those who had received allogeneic transplants, would have a poor prognosis.
ability to follow the criteria. If some regions are harder hit than others, a re-referConsequently, the admission of new allotransplant candidates was curtailed at
ral system is recommended for patients with potentially life-threatening or rapidly
PMH for several weeks because there was no assurance that the patients who
progressive cancers. This plan will help to ensure that Ontario’s cancer system
might require critical care would be transferable to the ICU of other hospitals.
and PMH will be in the best position to provide critical cancer care.
Nonetheless, short-term admissions for chemotherapy administration were minimally affected, except for a week’s delay for new cases. Overall, however, the
It is our hope that the lessons learned from the Toronto SARS outbreak can be
caseload was maintained, despite the challenges faced by PMH staff in screening
translated into improved health preparedness response planning for future health
all patients and distinguishing the symptoms and signs of SARS from chemother- emergencies such as pandemic influenza. Our patients are highly vulnerable to
apy effects, especially among those with febrile neutropenia.
infectious diseases, and it is a cruel irony that the ver y places patients go for
treatment might be where they acquire a deadly infectious disease.
While morale among staff was high initially, the need for gowning and masking at
all times became burdensome, and for some, debilitating. A further unexpected
During the SARS outbreak, Michael Gardam, MD, was Director of Infection
consequence was the cessation of formal education programs for residents and fel- Prevention and Control at UHN, Leah Gitterman, MHSc, was a patient escort
lows, largely because there was a moratorium on meetings in hospitals and no
and helped screen PMH staff for febrile respirator y illness, and Armand
movement of staff and trainees from hospital to hospital.
Keating, MD, was Chief of Medical Ser vices at PMH.
“
”
As horrible and surreal as the SARS experience was, it helped identify some
ver y significant weaknesses in the health-care system that we now have the opportunity to strengthen. Certainly, years of underfunding and neglect had left the
Ontario public health system in disarray and unable to deal with significant public health emergencies. Closer to home, it also identified that advanced hospital
planning to deal with infectious diseases and other emergencies is essential; one
of the reasons for the aggressive control measures was because hospitals did not
have any experience or plans to deal with this type of event.
Currently PMH, like most hospitals in North America, is in the midst of planning for the next influenza pandemic. No one can accurately predict what a
future pandemic will look like; however, even a mild pandemic would have a sig14
1. World Health Organization. www.who.int/csr/sars/country/table2004_04_21/en/index.html.
2. Schull MJ, Stukel TA, Vermeulen MJ, et al. CMAJ. 2007;176:1827-32.
3. Lim S, Closson T, Howard G, Gardam M. Lancet Infect Dis. 2004;4:697-703.
4. Kumar D, Tellier R, Draker R, et al. Am J Transplant. 2003;3:977-81.
5. Walker D, Keon W, Laupacis A, et al. Ministr y of Health and Long-Term Care; 2004.
6. Cancer Care Ontario. www.cancercare.on.ca/OntarioCancerNews/index_710.htm.
7. Upshur R, Faith K, Gibson J, et al. University of Toronto Joint Centre for Bioethics. 2005.
www.utoronto.ca/jcb/home/documents/pandemic.pdf.
ASH’s 50th Anniversary: Profiles in Hematology
Oscar D. Ratnoff: Champion of Clotting
STANTON L. GERSON, MD, and NATHAN A. BERGER, MD
Dr. Gerson is Director, Case Comprehensive Cancer Center; Director, Ireland Cancer Center; and Director of the Center for Stem Cell and Regenerative Medicine,
Case Western Reserve University and University Hospitals Case Medical Center.
Dr. Berger is Hanna-Payne Professor of Experimental Medicine; Professor of Medicine, Biochemistry and Oncology; and Director of the Center for Science, Health,
and Society at Case Western Reserve University School of Medicine.
scar D. R atnoff, MD, we might presume,
stood in his office in late 1964 with his biochemist colleague, Earl Davie, at Case
Western Reser ve University and in a moment of
chalkboard brilliance, devised the coagulation waterfall, published later that year in the journal, Science.
His obser vations, along with those of Robert
Macfarlane, also published in 1964 in Nature, provided the guiding light for research and education into
the clotting process for decades to come. (See Figure
1.) Dr. R atnoff, by his own hand, used painstaking
efforts to partially purify clotting factors, and then
used blood products from patients with deficits in one
or more factors to establish mixing experiments and
deduced the complexity of blood clotting by simple glass tube experiments timed
with a stopwatch. For those of us lucky enough to have laboratories nearby, we
watched patients come to his research office, and we provided countless blood
samples as healthy donors until we turned 40, at which time he recognized that
our own clotting waterfalls became more complex and were perhaps not suitable
as controls.
O
Dr. R atnoff and his colleagues, including residents and fellows, continued in their
efforts to understand patients with other evidence of defective clotting, including
von Willebrand disease. While the elucidation of the relationship between von
Willebrand factor and factor VIII proved to be complicated, Dr. R atnoff ’s development, with Ted Zimmerman, MD, of an immunoassay to differentiate classic
hemophilia factor VIII from von Willebrand factor provided a critical tool to distinguish and characterize the two disorders.
Later, as a result of his drive to let no clinical puzzle go uninvestigated, Dr.
R atnoff described psychogenic purpura, typically seen in women with some level
of hysterical mood disorder, who have self-inflicted bleeding of unclear etiology
and clinical course. Perhaps one of the greatest public health impacts that Dr.
R atnoff ’s work has had was his decision to boldly proclaim that the blood supply,
especially preparations of factor concentrate, should not be used because it had
been contaminated with HIV from the donor pool of the early 1980s. With Mike
Lederman, MD, he identified hemophilia as a risk factor for AIDS when he
noticed first a drop in lymphocyte counts among his patients with hemophilia, and
then their propensity to opportunistic infections
associated with impaired cellmediated immunity and the
occurrence of “immune”
thrombocytopenic purpura. As
a result, he strongly advocated
for use of cr yoprecipitates from
selected, screened donors.
The son of a New York general
practitioner, Dr. R atnoff was
trained, first at Columbia College
of Physicians and Surgeons, then at
Johns Hopkins, Har vard Medical
School, and Montefiore Hospital in
Through all of these endeavors,
New York, before coming in 1952
Dr. R atnoff has cherished his
to what are now Case Western
role as educator, research precepReser ve University School of
tor, and article reviewer. For those
Medicine and University Hospitals,
of us so lucky, receipt of his eruCase Medical Center. Dr. R atnoff
dite reviews of what we considered our final
was excited about pursuing laboradrafts, strewn with corrections marked in red
tor y research and investigating
ink, was a sure sign of an acceptable manupatient problems, usually with synscript submission, pending grant award, or
ergism. He was a paragon of transacademic promotion statement. We also
lational research before the term
remember his stern disdain for the term “comwas ever popularized. While he
plete remission,” his 10-line rule for assuring
ser ved as chair of hematology and
a slide’s legibility and impact, and his love of
interim chair of medicine, he much
preparing fellows for presentations at scientific
preferred his laborator y and clinical
meetings. Dr. R atnoff, like many of his generpractice, taking greater pleasure
ation, is guided by the principle of academic
with residents and fellows, all of
medicine in its purest sense, of handwritten
Fig. 1 from Davie, EW, Ratnoff, OD. Waterfall Sequence for Intrinsic Blood Clotting.
whom had productive experiences
notes and personal obser vations. No one could
Science. 1964;145:1310-2. Reprinted with permission from AAAS.
in his laborator y.
escape his infectious enthusiasm, when Dr.
R atnoff ran down the hall showing ever yone his latest lab results drawn out on
Dr. R atnoff had a prepared mind when John Hageman, MD, came to his lab for
green graph paper. He instills in his colleagues a love of discover y and a care for
evaluation of an asymptomatic prolonged glass tube clotting time. This led to his
a well-crafted spoken and written phrase. Above all, he brought logic and order
discover y of Hageman factor (Factor XII), which helps to initiate clotting on a
to a coagulation field mired in complex obser vations and laid the foundation for
glass surface but was not required to form a clot in vivo. This finding and other
today ’s research advances in the field.
studies with partially purified factor preparations in plasma led to the hypothesis
that a clot formation consisted of a series of inactive factors or zymogens activated References:
in sequence, dubbed a waterfall sequence, and that the balance of clotting in the
Davie EW, Ratnoff OD. Waterfall sequence for intrinsic blood clotting. Science. 1964; 145:1310-2.
body was mediated by factor levels and initiators of the clot. Although deciphering the complexity of these initiating factors remains an active area of research,
Kellermeyer RW, Ratnoff OD. Abolition of the permeability enhancing properties of Hageman factor by speDr. R atnoff clearly recognized the impact of illness and age, perhaps explaining
cific antiserum. J Lab Clin Med. 1967;70:365-71.
why Dr. Hageman died of a pulmonar y embolus and why he did not want those
Ratnoff OD, Agle DP. Psychogenic purpura: A re-evaluation of the syndrome of autoerythrocyte sensitization.
over 40 years of age considered for collection of normal plasma or the study of
Medicine. 1968;47:475-500.
vascular abnormalities as mediators of clotting initiation. Later, with Hidehiko
Saito, MD, this approach led to the discover y of Fitzgerald factor, also associated
Niwano H, Embury PB, Greenberg BD, et al. Inhibitory action of amyloid precursor protein against human
with prolonged clotting times, and then, together with Virginia Donaldson, MD,
Hageman factor (factor XII). J Lab Clin Med. 1995;125:251-6.
they identified Fitzgerald factor as high-molecular-weight kininogen, thus linking
clotting to inflammation.
15
W H A T ’ S
O N
T H E
W E B
MARK YOUR CALENDAR
The ASH Web site offers a convenient way for ASH members to find information relating to upcoming Society events and provides easy access to the many
valuable products and ser vices offered by ASH.
Participate in ASH’S 50TH ANNIVERSARY and learn more about the rich
histor y of ASH and hematology by visiting www.hematology.org/about/
50thanniversary. Here you can:
•Meet legends in hematology and hear their insights about the field and
the development of ASH.
•Sign the Legends Guestbook and pay tribute to these leaders in hematology.
•Download a 2008 calendar for your home or office that colorfully encapsulates the histor y of the Society.
•View the Galler y of ASH Presidents.
•Read the 50th anniversar y review articles to be featured in Blood
throughout the year about advances in hematology.
Return to this section to meet the featured legend of the month and view new
content, including video clips, a report on the top advances made in the field
over the last 50 years, and details about the celebration planned for the 2008
ASH annual meeting.
FEBRUARY
1
Nominations due for ASH Honorific Awards
Washington, DC
www.hematology.org
1–2
Highlights of ASH
Seattle, WA
www.hematology.org
7 – 10
The International Conference on Fixed Combination in the Treatment of
Hypertension and Dyslipidemia
Budapest, Hungary
wwww.paragon-conventions.com/fixed
8–9
10th International Symposium on Febrile Neutropenia
Brussels, Belgium
www.imedex.com
8–9
Highlights of ASH
Austin, TX
www.hematology.org
15 – 19
Scripps Cancer Center’s Clinical Hematology and Oncology Conference
San Diego, CA
www.scripps.org/conferenceservices
MARCH
2–7
Gordon Research Conference: Molecular Mechanisms in Lymphatic
Function and Disease
Ventura, CA
www.grc.org
14
Deadline for MMSAP applications
Washington, DC
www.hematology.org
19
Deadline for ASH-AMFDP Award applications
Washington, DC
The ASH JOB BANK brings together hematologists and open positions online
and is searchable by keyword, state, countr y, type of employment, salar y range,
or education requirement. The Job Bank is free to all job seekers. Job posters
can now enjoy a host of new features such as the ability to post, edit, remove,
and replace their own job, lower posting fees, and a more user-friendly jobposting system. To view these new features, visit the ASH Job Bank at
www.hematology.org/education/jobs.
www.hematology.org

The Hematologist - January-February 2008

Transcription

Similar documents

M Esteira Deck Freixo Termotratado (24)

WET-TO-DRY CONVERSIONS FOR COAL POWER GENERATION

Ash tree dieback – autumn and winter signs

Marshalls Seedless Ash(CMYK)

File - THE VORPAL CHAINSWORD

Ash Rememberance - Aug 2000 to Nov 2015

Hematologist - Southlake Regional Health Centre

kentuckiana farm - Justice Real Estate