ASH NEWS AND REPORTS®
JANUARY/FEBRUARY 2016
VOLUME 13 ISSUE 1
What We Carried on Christmas
Fiction for the Year’s Best in Hematology
JASON GOTLIB, MD, MS, Editor-in-Chief
Editor’s Note: The characters in the following story are fictionalized versions of patients we have
managed on the hematology service. The title “What We Carried on Christmas” is a tribute to “The Things
They Carried,” Tim O’Brien’s critically acclaimed short story from 1987 that uses the list as a writing
form to tell a powerful story of a platoon in Vietnam. The commentary following this piece provides my
perspective on how hematology advances, including 2015 Year’s Best selections, weave together with the
compelling narratives of our patients’ lives.
My Christmas morning commute to Stanford Hospital felt like a post-apocalyptic odyssey. I didn’t spot a single car or
human being on the eight-mile stretch of Interstate 280. However, shortly after taking the off-ramp to Sand Hill Road, I
came upon a freshly struck deer lying in the left lane. I slowed down and surveyed the carnage. Its warm entrails formed
an accidental palette with the shoulder’s yellow border. Along this corridor of venture capital firms, a Tesla sped off
from the scene. It carried dollops of the deer on its front grille, while leaving an electric hum in its wake. The driver
would hide this accident from his family so it couldn’t taint the splendor of the holiday. I drove away, carrying the
vicissitudes of this deer’s life with me to inpatient hematology rounds, along with my stethoscope and iPhone.
On Christmas morning, Paul carried an extra 5 kg of fluid from his AML induction. The edema made little difference on
the 6’6”, 120-kg frame that he sculpted during Army Special Forces training in the early 1990s. His physique blended
a perfect combination of slow-twitch and fast-twitch muscle memory that made it easy to double-tap a target while
hanging upside down in the dark. Paul carried the tip of the spear as a member of Delta Force during two Gulf wars
and numerous clandestine ops around the globe. The team stared at his massive figure when he lapped around the
hematology unit with his diminutive IV pole; the nurses and other patients gawked, too, like rubberneckers transfixed
by that swirl-cake of a deer. When United Airlines flight 77 tore into the Pentagon, Paul had scooped up workers and
carried them to safety before the ceiling of their office collapsed. For a few hours, he inhaled a plume of super-heated
dust consisting of incinerated concrete, fuselage, and parts of people’s souls. His lungs carry the scars of that day. A few
months after 9/11, he developed pneumonitis and lost a quarter of his pulmonary function. It’s possible the toxic brew
also corrupted his bone marrow.
During morning rounds, Paul shared tidbits from some of his Delta Force missions, including Operation Gothic Serpent
in Mogadishu and Operation Enduring Freedom against the Taliban. During treatment, his waning appetite made him
think of meals at home and abroad. He joked about the similar textures and tastes of combat MREs and our cafeteria’s
selections. He reminisced about toppings that presaged the dinner menu at his base in Kabul: horseradish on the tables
was followed by prime rib, and applesauce heralded pork chops. For worsening trismus related to mucositis, ENT
had him bite down on a stack of tongue blades to exercise his jaw. This wasn’t very difficult for him. Muscle memory.
I imagined a celluloid version of Paul clenching the blade of a knife between his teeth while scaling a wall just before
snatching a high-value target.
Paul’s three children and wife spent Christmas day with him in his room. He hopes that his illness will bring them
closer together. In two weeks, he’ll leave the hospital. When I have the results of his remission marrow, he’ll be
(Cont. on page 6)
Advances in
aplastic anemia
LEUKEMIA
2
PRESIDENT’S COLUMN – ASH President
Dr. Charles S. Abrams highlights how ASH
will continue to grow in 2016.
3
PET-directed therapy
in lymphoma
Boosting HSC
engraftment
Reversal agents for DOACs
Clonal
Hematopoiesis
Hope
Myeloma antibodies
NEWS AND REPORTS – Meet the
four contributing editors that joined The
Hematologist’s Editorial Board in 2016.
New frontiers in
sickle cell disease
6
57th ASH Annual Meeting
Wrap-Up: Hematology’s Own
Cambrian Explosion
LAURA C. MICHAELIS, MD
Associate Professor of Medicine, Division of Hematology and Oncology,
Medical College of Wisconsin, Milwaukee, WI; ASH News Daily Editor,
2015
Harvard paleontologist Dr. Stephen Jay Gould
was best known for his theory of “punctuated
equilibrium,” which, as a neophyte like me
understands it, argues that evolution is not
the smooth upward trajectory envisioned by
Charles Darwin. Instead, the fossil record
shows evolution to be a bumpy road characterized by very
long periods of developmental stasis followed by stretches of
remarkably rapid changes as natural selection gallops forward.
As I look back on another year of results and ideas presented
at the 2015 ASH Annual Meeting, I wonder if our profession’s
accomplishments are showing a similar pattern. If so, it seems
that we are in the midst of one of those epochs of rapid change.
Take lymphoma treatment, for example. For decades, tumor
growth rate was the sole target with which to approach
therapy — the clearest way to leverage the difference between
normal cells and the cancer cell. In 1997, after decades of
improvements in the tools and trade of molecular biology, better
understanding of cellular processes led to the approval of
rituximab, one of the initial landmark “targeted” agents in cancer
care.
Less than 20 years have passed since that approval, and now
most of the treatments that are being tested in lymphoma
capitalize on our growing understanding of the molecular
behavior of the cancer cell. Translational research, for example,
is responsible for remarkable gains in the treatment of chronic
lymphocytic leukemia (CLL). This year, the Late-Breaking
Abstracts (LBA) session included results from two studies of
novel agents for relapsed/refractory CLL. One study presented
YEAR’S BEST – The Hematologist lists
rankings from the 2015 Year’s Best in
Hematology reader survey.
(Cont. on page 4)
14
IN MEMORIAM – Colleagues reflect on
the life and professional accomplishments
of the late Dr. Zucker-Franklin.
President’s Column
Hematologist
THE
ASH NEWS AND REPORTS®
ISSN 1551-8779
PUBLISHED BIMONTHLY
Editor-in-Chief:
A New Year Full of Promise for ASH
Jason Gotlib, MD, MS
Stanford Cancer Institute
Stanford, CA
A
s we enter into the New Year, I would like to acknowledge the support and leadership that Dr. David Williams has
provided ASH and its members throughout 2015.
Contributing Editors:
In the past several years, the January/February issue of The Hematologist has looked back at the previous year’s
achievements and has celebrated the way in which ASH’s annual meeting convenes the best minds in the discipline. This year
in Orlando, I was impressed with the rapid rate of progress and discovery that the field of hematology is currently enjoying
and the unique and enticing opportunities where ASH could play a leading role.
Pamela S. Becker, MD, PhD
University of Washington
Seattle, WA
Theresa Coetzer, PhD
University of the Witwatersrand
Johannesburg, South Africa
Some of the most meaningful ways ASH can lead is by steadily growing, and refining, the Society’s content offerings. With
each issue of Blood, there continues to be a drive toward high-quality, cutting-edge research, resulting in novel therapies
across a wide variety of subspecialties. Additionally, in 2016, these efforts will continue with the launch of a new journal from
ASH, designed to keep both researchers and clinicians abreast of topics in emerging areas, including, but not exclusive to,
immunotherapies and gene editing.
Adam Cuker, MD, MS
University of Pennsylvania
Philadelphia, PA
David Garcia, MD
University of Washington
Seattle, WA
In addition to publications, ASH will launch new educational offerings in 2016 that are in line with the explosive
breakthroughs in hematology. To shed continued light on the latest advances in basic and translational lymphoma
research, the second Meeting on Lymphoma Biology will take place in June in Colorado Springs, Colorado, while the second
ASH Meeting on Hematologic Malignancies in September will feature clinical breakthroughs and cutting-edge treatment
approaches to lymphomas, leukemias, and other malignant conditions. Furthermore, because training is so pivotal to our
ongoing progress and mission, ASH will launch the Medical Educator’s Institute, which will equip medical educators with a
“boot camp” that will cover teaching techniques, as well as proper evaluation of trainees and programs.
Tracy I. George, MD
University of New Mexico
Albuquerque, NM
Jonathan Hoggatt, PhD
MGH/Harvard University
Cambridge, MA
It is impossible to discuss the influx of innovation without also mentioning new drugs and precision medicine. At the 2015 Annual
Meeting, there were two sessions (one delivered in partnership with the U.S. Food and Drug Administration) devoted to the
recent introduction of exciting new drugs available in benign and malignant hematology. With regard to precision medicine,
ASH’s newly defined Agenda for Hematology Research has prioritized the areas of genomic profiling and chemical biology and
has also created a task force on precision medicine to identify and capitalize on the opportunities in hematology. Building on
the research that has been conducted by our members, 2016 is gearing up to be an exciting year in which developments in new
drugs and novel treatments based on the human genome will continue on the path to becoming clinically meaningful.
Peter Johnson, MD
Southampton General Hospital
Southampton, United Kingdom
Mark J. Koury, MD
Vanderbilt University
Nashville, TN
Impressive momentum abounded all throughout hematology last year, and sickle cell disease (SCD) was no exception. From
promising improvements in gene therapy, to new approaches for vaso-occlusion, SCD researchers saw some incredible
advancements. To strengthen the pace of innovation, ASH announced a new “Call to Action” for SCD during an April 2015
Summit, and in 2016, the Society will expand on the strategies identified, to create new work groups focused on access to
care, research, and global outreach.
Ann LaCasce, MD, MSc
Dana-Farber Cancer Institute
Boston, MA
Charles T. Quinn, MD, MS
Cincinnati Children’s Hospital Medical
Center
Cincinnati, OH
Finally, 2016 will be another year in which ASH continues to expand outreach and growth on a global scale. To begin with, we
were excited to announce, after the close of the 2015 annual meeting, a newly approved category of membership that gives
International members the right to vote, and that gives the Nominating Committee the flexibility to nominate international
candidates to run for a Councillor position, as appropriate for the needs of the Society, at any given time. Another bylaws
amendment has created a membership category for International Associate members, which allows trainees outside of North
America to join and enjoy a member benefits package similar to that of Associate members in North America.
Elizabeth Raetz, MD
University of Utah
Salt Lake City, UT
Noopur Raje, MD
Massachusetts General Hospital
Boston, MA
I am incredibly proud to help realize the promise of the new year as president of ASH, as our Society continues to
demonstrate its leadership in some of the most thrilling areas of scientific and clinical exploration.
Managing Editor
Juana Llorens, MS
Editorial Associate
Laura M. Santini
Graphic Designer
grayHouse design
Charles Abrams, MD
American Society of Hematology
2021 L Street, NW, Suite 900
Washington, DC 20036
jllorens@hematology.org
I N
©2016 by the American Society of Hematology.
Contributing authors have declared any financial
interest in a product or in potentially competing
products, regardless of the dollar amount. Any such
financial interest is noted at the bottom of the article.
Dr. Gotlib has no relevant conflicts of interest to
disclose.
The material published in The Hematologist is for
informational purposes only. The opinions of the
authors and editors of The Hematologist are their
own and do not necessarily represent official policy
of the American Society of Hematology. ASH does
not recommend or endorse any specific tests,
physicians, products, procedures, or opinions, and
disclaims any representation, warranty, or guaranty
as to the same. Reliance on any information
provided in this publication is solely at your own risk.
Bernard G. Forget, MD (1939-2015)
PHOTO BY JOHN CURTIS, YALE MEDICINE
All materials contained in this newsletter are
protected by copyright laws and may not be used,
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without the express prior written permission of The
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become its copyrighted property and may be
used, reproduced, or otherwise exploited by The
Hematologist.
Dr. Bernard G. Forget died on November
6, 2015, at the age of 76, after a threeyear battle with cancer. The hematology
community has lost one of its most beloved
and esteemed colleagues.
Bernie was born in Fall River, Massachusetts,
where his French Canadian father served
as a dedicated general practitioner. After
undergraduate training at the University
of Montreal, Bernie received an MD in
1963 from McGill University where he was
class valedictorian. Following a medical internship and residency at
Massachusetts General Hospital, he received training in hematology
at the National Institutes of Health (NIH) and at Children’s Hospital in
Boston. His early scientific development was fostered by the mentoring
of Drs. Roger Monier, Sherman Weissman, and David Nathan.
In 1976, Bernie joined the Departments of Medicine and Human
Genetics at Yale University where he devoted the remainder of his
career. He was chief of Yale’s Section of Hematology from 1976 to
1987, and again from 1993 to 2005. During this 30-year span, he made
landmark research contributions and oversaw the training and mentoring
of a generation of students, residents, and fellows, many of whom have
become leaders in hematology research and clinical practice.
Bernie and his research team pioneered studies of molecular
pathogenesis of congenital red cell disorders. He was the first to use
specific ribonucleases to prepare two-dimensional maps of globin
mRNA that enabled sequence information to be generated on both
coding and noncoding segments. This early work was critically important
2
M E M O R I A M
in facilitating the cloning of globin genes. His studies of the flanking
regions of the human γ-genes provided insight into the physiologically
and clinically important switch from γ- to β-gene expression.
Subsequently, Bernie’s lab focused on the molecular genetics of red
blood cell (RBC) membrane proteins. His lab was the first to clone and
sequence genes encoding α- and β-spectrins, the major proteins of the
RBC cytoskeleton. These studies paved the way toward a molecular
understanding of the assembly of red cell membrane proteins. Bernie’s
work on the globin genes and on those encoding RBC membranes have
clear-cut relevance to important blood disorders such as thalassemia,
sickle cell disease, and congenital hemolytic anemias due to mutations
in red cell membrane proteins.
During his long and remarkably productive career, Bernie received
many honors, including membership in the American Society for Clinical
Investigation, the Association of American Physicians, and the American
Academy of Arts and Sciences. He was awarded the Henry M. Stratton
Medal from ASH in 1996 and was the recipient of the Yale Cancer
Center Lifetime Achievement Award in 2013.
A happy and fulfilling family life was a huge contributor to Bernie’s
remarkable record of leadership and discovery. During their time
together in New Haven, his wife Bernadette held a position of
comparable responsibility in nursing at the Yale-New Haven
Hospital. She and Bernie were blessed with three children and three
grandchildren. The Forget family cherished time together at their seaside
home in Rhode Island as well as frequent trips to France, which helped
sustain Bernie’s Gallic pride and temperament.
–H. Franklin Bunn, MD, Hematology Division, Brigham and Women’s
Hospital, Harvard Medical School
The Hematologist:
ASH NEWS AND REPORTS
President’s Column
N E W S
A N D
R E P O R T S
Register for the First-Ever ASH
Workshop on Genome Editing
The Hematologist Board of Contributing Editors
Maintains the Cycle of Excellence in 2016
The ASH Workshop on Genome Editing will take place July
14-15, 2016, at the Omni Shoreham Hotel in Washington,
DC. This workshop was created to provide a forum that
focuses on the mechanistic aspects, and possible clinical
implications of genome editing for blood disorders. Academic
researchers, industry scientists, regulators involved in the
clinical application of the technology, and other interested
individuals are encouraged to attend. Learn about the basic
science of genome editing, its application in clinic, current
scientific challenges in using this tool for research purposes,
application of the technology to hematologic disorders,
as well as regulatory issues. There will also be ample
opportunities to network with colleagues and world-class
experts, and to explore possible collaborations. For a list of
speakers and additional information, and to register online,
visit www.hematology.org/genome-editing.
The yearly convening of The Hematologist Editorial Board at the ASH annual meeting always marks a time of
transition. In December 2015 in Orlando, we expressed our gratitude to four outgoing Contributing Editors:
Drs. Mark Koury, Peter Johnson, Pamela Becker, and Charles Quinn. Both Drs. Koury and Johnson served for
consecutive terms.
Since first joining the editorial board in 2012, Mark, with his wealth of expertise in erythropoiesis along with 30
years of experience in research and clinical practice at Vanderbilt University, has endowed this publication with
dozens of challenging, thought-provoking contributions. We will greatly miss the enthusiasm of Southampton
General Hospital’s Peter Johnson, whose thoughtful Diffusion selections brought us the most significant
developments in topics from lymphoma, to molecular diagnostics, to emerging antibody therapeutics. We also
had the benefit of working with Pamela Becker of the University of Washington. Pam’s incredible expertise in a
wide range of areas across malignant and nonmalignant hematology, particularly in acute myeloid leukemia and
stem cell and regenerative medicine, filled a great need and served our readership well. Finally, we owe a great
debt to Charles Quinn of Cincinnati Children’s Hospital Medical Center. With his deep knowledge of sickle
cell disease and thalassemia, Charles provided ASH and its members with precise and steadfast coverage of
these increasingly vital topics.
Four new contributing editors have been appointed to fill the vacancies left by the
departures of Drs. Koury, Johnson, Becker, and Quinn.
Register for the 2016 ASH Meeting
on Lymphoma Biology
The ASH Meeting on Lymphoma Biology will take place June
18-21 at The Broadmoor in Colorado Springs, Colorado. This
meeting will bring together experts from around the world to
discuss the latest breakthroughs in basic and translational
lymphoma research, address current challenges in the field
and steps to address them, and promote efforts to accelerate
the development of new therapeutic strategies. The event
spans four days and features didactic sessions, abstract
presentations, interactive workshops, and panel discussions.
For registration fees, speaker information, and more, please
visit www.hematology.org/lymphoma-biology. Remember to
register online by the advance registration deadline of May 27.
Learn More about the New ASH
Medical Educators Institute
This new program provides hematologists who are new to
medical education with a “boot camp” for teaching techniques,
medical education scholarship, and trainee and program
evaluation. Topics that will be discussed include educational
research design in hematology, use of technology in medical
education, adding value to your institution as a hematology
educator, small group instruction, and the ins and outs
of promotion and tenure. ASH will subsidize participation
in the program by covering costs of travel, lodging, and
meals. For additional information, visit www.hematology.org/
educators/4692.aspx.
Dr. Omar Abdel-Wahab is an assistant attending physician on the leukemia service
at Memorial Sloan-Kettering Cancer Center and a member of the Human Oncology
and Pathogenesis Program. His laboratory is focused on the functional understanding
of genetic alterations in patients with chronic myeloid and lymphoid leukemias.
One of his main areas of interest is in understanding the biological and therapeutic
significance of epigenetic and transcriptional alterations in patients with leukemia. He
also serves on the editorial board of Blood.
Dr. Michael DeBaun is professor of pediatrics and medicine, JC Peterson Endowed
Chair in Pediatrics, vice chair of clinical and translational research in pediatrics, and
the founder and director of the Vanderbilt-Meharry Center for Excellence in Sickle
Cell Disease at Vanderbilt University School of Medicine. He is an internationally
recognized physician-scientist whose research has resulted in fundamental advances
in the genetics of cancer predisposition syndromes and the epidemiology and optimal
treatments of stroke and lung disease in sickle cell disease. Dr. DeBaun has mentored
numerous medical and graduate students and postdoctoral fellows, several of whom
have gone on to receive multiple investigator-initiated federal grants and foundation
awards. Dr. DeBaun is an elected member of the American Society for Clinical
Dr. Michael R. DeBaun Investigation, the Association of American Physicians, the Institute of Medicine of the
National Academy of Sciences, and the American Association for the Advancement of
Science. In 2014 he was honored by ASH with the Ernest Beutler Lecture and Prize in Clinical Science.
Dr. Paul Moss is professor of hematology and director of medical research at the
University of Birmingham, UK. He is also chair of the Infections & Immunity Board at
the Medical Research Council, and previously served as Chair of the Cancer Research
UK Clinical and Translational Research Committee. Professor Moss has a clinical
interest in lymphoproliferative and immunological disorders. His research program
focuses on translational immunology within cancer, transplant, and viral disorders. He
is author of Essential Haematology, one of the most popular international textbooks on
hematology.
Dr. Sioban Keel
Speakers for the 2016 Meeting on
Hematologic Malignancies Have
Been Announced
The 2016 ASH Meeting on Hematologic Malignancies
will take place September 15-17 at the Fairmont Chicago,
Millennium Park, in Chicago, Illinois. Hear the top experts in
hematologic malignancies discuss the latest developments in
clinical care and answer some of your most challenging patient
care questions. There will be lectures on topics including
leukemia, lymphoma, myelodysplastic syndromes, myeloma,
and myeloproliferative neoplasms. For more information about
the meeting and to see the full list of sessions and speakers,
visit www.hematology.org/malignancies.
Follow Blood on Twitter!
Stay up to date with Blood, the official journal of ASH, and
the most cited peer-reviewed publication in the field of
hematology. Follow the journal on Twitter through the handle
@BloodJournal.
The Hematologist:
ASH NEWS AND REPORTS
Dr. Omar Abdel-Wahab
Dr. Sioban Keel is a clinician-scientist at the University of
Washington in Seattle. Her research centers on defining the
Dr. Paul Moss
phenotypic spectrum and genetic and molecular mechanisms
regulating hematopoiesis and marrow failure in inherited bone marrow failure
syndromes and inherited predisposition to leukemia and myelodysplastic syndromes.
She brings research expertise in the molecular and cellular events that control red
blood cell development, which synergizes with her active clinical practice. Dr. Keel
cares for adult patients with inherited and acquired marrow failure, intrinsic red blood
cell disorders, and unexplained cytopenias at the Seattle Cancer Care Alliance, and
both directs and attends on the inpatient hematology consult service at the University
of Washington.
We look forward to having Omar, Michael, Paul, and Sioban lend their unique viewpoints regarding the
molecular underpinnings of leukemia, hemoglobinopathies, immunotherapeutics, and marrow failure states,
respectively. The benchtop, clinical, and translational interests of The Hematologist board of Contributing
Editors mirror the education, research, and patient care missions of ASH — malignant and non-malignant
hematology, pediatric disease, genomic/precision medicine, stem cell biology, hematopathology, and global
health. Through our popular Diffusion articles, Ask the Hematologist, and Mini Review pieces, as well as
multimedia platforms such as podcasts, our goal is share the dynamic developments in our field while speaking
to the broad demographics of our Society. We are always interested in readers’ ideas so that our content can
best serve the voices and passions of ASH’s membership.
— Jason Gotlib, MD, MS, Editor-in-Chief
Save the Date for the 2016 International
Highlights of ASH
Highlights of ASH provides a summary of the top hematology research presented
at the 57th annual meeting in Orlando, to help improve patient management and
care strategies. Look out for this year’s International Highlights of ASH:
• Latin America: April 29-30 – Natal, Brazil
• Asia-Pacific: March 5-6 – Brisbane, Australia
For more information, visit www.hematology.org/highlights.
3
57th ASH Annual Meeting Wrap-Up
(Cont. from page 1)
by Dr. Andrew Zelenetz demonstrated what happens when
an inhibitor of the PI3 Kinase pathway, idelalisib, is added
to bendamustine and rituximab (BR). In a randomized,
double-blind, placebo-controlled phase III study, the threedrug combination showed an impressive improvement in
progression-free and overall survival over BR alone. In that
same session, Dr. Stephen Stilgenbauer presented results from
a phase II study, which used a BCL-2 inhibitor (venetoclax;
ABT-199), in patients with del(17p) relapsed or refractory CLL,
also with impressive results in this notoriously challenging
subset.
Multiple myeloma (MM), which was long known as a specialty
of therapeutic nihilism, has become a poster child for rapid
translation of molecular discoveries into the clinic. In 2015,
the FDA approved four agents for the disease, panobinostat,
ixazomib, daratumumab, and elotuzumab, each of which
takes advantage of a different mechanistic vulnerability of the
myeloma cell. At this year’s meeting, attendees were presented
with numerous new studies that incorporated these agents
either alone or in combination with established therapies. For
example, Dr. Saad Usmani presented combined results of two
studies that treated a total of 148 patients with late-stage MM
with daratumumab, a monoclonal antibody to CD138, for an
overall response rate of 31 percent. In the LBA session, the
first in-human results using chimeric-antigen receptor (CAR)
T-cells that target the B-cell maturation antigen in patients with
advanced MM were presented. Dr. Syed Abbas Ali led the
study, which showed similar types of toxicities that have been
observed with anti-CD19 CAR T-cells (e.g., cytokine release
syndrome) and impressive antimyeloma activity, including
clearance of bone marrow plasma cells, and a stringent
complete remission at the highest dose level.
Targeted therapy is beginning to reach the myeloid world
as well. Long held out as “too heterogeneous” for a
targeted approach, the last two ASH annual meetings
have demonstrated the important role that inhibitors of the
constitutively activated FLT3 receptor play in the treatment of
acute myeloid leukemia (AML). During the Plenary Scientific
Session, Dr. Richard Stone revealed the important findings
of the RATIFY study, a CALGB/Alliance effort that took years
of work in accrual and logistical management. This study
randomly assigned patients (ages 18 to 60 years) with newly
diagnosed, FLT3-mutated (ITD or TKD) AML to 7+3 alone or
in conjunction with the FLT3/multikinase inhibitor, midostaurin.
The study showed that addition of midostaurin improved the
event-free and overall survival of patients (whether censored or
uncensored for transplantation), with this genetically defined
subgroup of AML. These data pave the way for drug approval,
and may herald an end to the four-decade period of relative
stasis in the field of AML therapeutics.
The momentum is not limited to areas of malignant disease.
Since the discovery of thrombopoietin (TPO) more than
20 years ago, numerous biologic insights have been made
regarding its interaction with its receptor c-mpl. This signaling
pathway’s role in megakaryocyte production and regulation
of platelet mass has been therapeutically exploited, leading
to drug approvals of the TPO mimetics romiplostim and
eltrombopag in patients with idiopathic thrombocytopenic
purpura. TPO also has an established role in regulating
hematopoietic stem cells, which led Drs. Cynthia Dunbar and
Neal Young of the National Institutes of Health (NIH) to first
evaluate its efficacy in patients with refractory severe aplastic
anemia (SAA). This year, presenting results of a NIH–led
phase II study, Dr. Danielle Townsley outlined the benefits of
the TPO agonist eltrombopag on count recovery and response
rates when added to up-front immunosuppressive therapy for
patients with SAA (see Dr. Tracy George’s Year’s Best article
for a more in-depth review of this subject).
of therapies. Researchers elegantly
demonstrated how control over
the gene for fetal hemoglobin is
exerted by the transcription factor
leukemia/lymphoma–related factor
(LRF)/ZBTB7A. The next step is to
determine whether one can safely
modulate LRF’s usual suppression
of fetal hemoglobin to mitigate the
clinical consequences of sickle cell
disease. Similarly, the first in vitro
evidence on how to modulate the
spliceosome in myeloid malignancies
was presented by Dr. Stanley ChunWei Lee on behalf of the laboratory of
Dr. Omar Abdel-Wahab at Memorial
Sloan Kettering Cancer Center.
For the myriad blood cancers with driver mutations in the
spliceosome, such progress bodes well for future therapies.
Recognizing the challenges of keeping up with changes
in the diseases we treat, in the last several years ASH has
added several additional in-depth sessions that cut across
diseases. This year, there were two well-attended Friday
scientific workshops: one on myeloid diseases and the other
on hematology and aging. On Saturday, there was a special
interest session on newly approved drugs, shedding light on
the right time and place to utilize drugs like blinotumumab,
panobinostat, and idarucizumab. Attendees even had an
hour-long educational session on social media and Twitter,
and the many ways these ubiquitous technologies might be
productively used by physicians and patients.
We will never know, limited in perspective as we are by time,
just what these past few years mean in the whole of our
profession’s trajectory. However, I’m sure that I’m not alone in
being grateful to have the opportunity to treat patients during
a period “punctuated” by a breakneck pace of approvals of
rationally designed therapeutics borne from the knowledge and
tools of precision medicine.
Thank You for Participating in the 2015 ASH Foundation Run/Walk!
The 2015 ASH Foundation Run/Walk, which took place during the 57th ASH Annual Meeting, marked another big sprint
toward success! For the third consecutive year, a wave of support from corporate sponsors as well as the dedication and
enthusiasm of meeting attendees helped ASH reach 1,200 registered run/walk participants, while the foundation raised
more than $90,000 to help fund programs in research, career development, and quality care and education.
The final race results were as follows:
Dr. Jordan Zwick, Top Male 5K
Dr. Kinjal Parikh, Top Female 5K
Dr. Chris Gregory, Top Male 3K
Dr. Molly Hein, Top Female 3K
Team Janssen Oncology had the highest number of
participants as well as the highest team fundraising total,
while Dr. Linda Burns achieved the highest fundraising total
among individual donors. To see all results and to view
the leaderboard, visit www.hematology.org/runwalk. ASH
appreciates the generosity of all participants and donors
and looks forward to next year’s Run/Walk, taking place
December 4, 2016, in San Diego, California.
The ASH Foundation thanks the 2015 Run/Walk Sponsors
Seattle Genetics, Gilead Sciences, Incyte Corporation,
and Freeman. To learn more and to donate to the ASH
Foundation, visit www.hematology.org/Foundation.
The Plenary Scientific Session also highlighted biologic and
molecular discoveries that may pave the way for the next wave
4
The Hematologist:
ASH NEWS AND REPORTS
T H E
H E A D L I N E S
F R O M
H E M A T O L O G I S T
A D V O C A T E
Washington
End of 2015 Sees Research Advocacy Victory:
Congress Provides $2 Billion Increase for NIH
ASH Continues Advocacy to Ensure Patient Access to Safe
and Effective Hematologic Drugs
After partisan disputes about “policy riders,” ranging from the defunding of Planned
Parenthood to changes to the President’s refugee resettlement program due to the current
situation with ISIS/L and Syria, Congress finally reached an agreement in mid-December
to fund federal programs and agencies, including the National Institutes of Health (NIH),
through the remainder of fiscal year (FY) 2016.
While oral and patient self-administered forms of chemotherapy have become more
prevalent, and represent the standard of care for many types of cancers, they are covered
differently than intravenous drugs, leaving many patients responsible for unsustainable,
high monthly co-payments.
The final funding bill, known as an “omnibus,” avoided a government shutdown and
contained very good news for NIH: Advocacy efforts by ASH and the biomedical research
community were successful in gaining a significant increase in funding for the agency.
Under the terms of the agreement, NIH will receive $32.084 billion in FY 2016, an increase
of approximately $2 billion (6.6%) over FY 2015 levels. The agreement also fully funds
the Obama Administration’s Precision Medicine Initiative at $200 million. Additionally,
the bill maintains FY 2015 funding levels for the numerous blood programs within the
National Center on Birth Defects and Developmental Disabilities (NCBDDD) at the Center
for Disease Control and Prevention’s (CDC’s) Division of Blood Disorders, which had seen
drastic cuts in recent years.
With 2015 now behind us, it’s time to take a look at some of the advocacy and policy
initiatives that were important to hematology and to the ASH membership throughout
the year. In addition to advocating for raising NIH funding levels, ASH also advocated
for expanding access to safe and effective hematologic drugs and supporting physician
payment. 2015 was also a time of heightened attention to patients with sickle cell disease
and sickle cell trait. For additional information about these initiatives and all of ASH’s 2015
advocacy highlights, visit the Policy News section of the ASH website at www.hematology.
org/Advocacy/Policy-News.
ASH will continue its advocacy efforts on issues of importance to hematology research
and practice throughout 2016. The Society needs the help of all ASH members to bring
these issues to the attention of the U.S. Congress and other U.S. governmental agencies.
Members of the ASH Grassroots Network receive action alerts and information about
issues in which they indicate interest. At times, Grassroots Network members are
also invited to represent hematology in activities such as visits to Capitol Hill, with
NIH leadership, and with other regulatory agencies. To learn more about how you can
participate in ASH’s advocacy efforts, visit the ASH website at www.hematology.org/
Advocacy, or contact ASH Legislative Advocacy Manager Tracy Roades at troades@
hematology.org.
ASH Submits Comments in Response to Proposed
Rulemaking on the “Common Rule”
The Obama Administration released a Notice of Proposed Rulemaking (NPRM) to
modernize, and strengthen the Federal Policy for the Protection of Human Subjects,
otherwise known as the “Common Rule.” By way of background, in 2011, the Obama
administration published an Advance Notice of Proposed Rulemaking (ANPRM), “Human
Subjects Research Protections: Enhancing Protections for Research Subjects and Reducing
Burden, Delay, and Ambiguity for Investigators,” to seek more information on how the
Common Rule might be improved and revised to be more effective. The current NPRM
proposal, which was published in the Federal Register on September 8, 2015, incorporates
the feedback received from the ANPRM. The proposed rule is designed to streamline
federal oversight of human subjects protections while reducing administrative burden,
delay, and confusion for researchers. Once promulgated, the regulations would impact
every research discipline funded by every federal agency, as well as clinical trials,
regardless of funding source.
As part of the Patients Equal Access Coalition (PEAC), ASH has advocated for legislation in
the U.S. House of Representatives and the U.S. Senate (H.R. 2739/S. 1566, the Cancer Drug
Coverage Parity Act) to ensure that cancer patients have equality of access (and equality
of insurance coverage) to all approved anticancer regimens including, but not limited
to, oral and intravenous drugs. Several ASH committees, as well as members of the ASH
Advocacy Leadership Institute, advocated for the legislation throughout 2015 and secured
the support of a number of members of Congress. The sponsors of the legislation in both
the House and Senate remain committed to the issue and are working to urge committees
in both houses to hold hearings, with the ultimate goal of passing the bills before the
conclusion of the 114th Congress in December 2016. Visit the ASH Advocacy Center at
www.hematology.org/TakeAction to send an email to your Senators and Representative
urging them to support the Cancer Drug Coverage Parity Act.
Although only federal legislation will ensure coverage for all cancer patients, 40 states
plus the District of Columbia have passed legislation to limit patient out-of-pocket costs
for oral anticancer medications. ASH has supported legislative efforts at the state level as
well, and will continue to work with stakeholders and advocacy groups to support ongoing
legislative efforts in a number of additional states in 2016, including Michigan, Tennessee,
Alabama, North Carolina, and Pennsylvania. If you live in one of these states and are
interested in working with ASH to help ensure your patients have affordable access to oral
chemotherapy drugs, please contact ASH Legislative Advocacy Manager Tracy Roades at
troades@hematology.org.
NIH Unveils FY 2016-2020 Strategic Plan
In mid-December 2015, NIH released the NIH-Wide Strategic Plan, Fiscal Years 2016–2020:
Turning Discovery Into Health, a detailed plan that seeks to ensure the agency remains
well positioned to capitalize on new opportunities for scientific exploration and address
new challenges for human health. Developed after hearing from hundreds of stakeholders
and scientific advisers, and in collaboration with leadership and staff of NIH’s Institutes,
Centers, and Offices (ICOs), the plan is designed to complement the ICOs’ individual
strategic plans that are aligned with their congressionally mandated missions.
The plan focuses on four essential, interdependent objectives that will help guide NIH’s
priorities over the next five years as it pursues its mission of seeking fundamental
knowledge about the nature and behavior of living systems and applying that knowledge
to enhance health, lengthen life, and reduce illness and disability.
Over the next five years, NIH leadership will evaluate the agency’s progress in meeting the
objectives laid out in the strategic plan, which will be a living document that will be open
to refinements throughout its life cycle.
The complete strategic plan can be found on the NIH website at www.nih.gov/sites/default/
files/about-nih/strategic-plan-fy2016-2020-508.pdf.
One of the most fundamental changes in the Common Rule as proposed in the NPRM is
the inclusion of biospecimens in the definition of human subjects research. The focus
of the NPRM is to require informed consent for research involving biospecimens in all
but a limited number of circumstances. The consent would not need to be obtained for
each specific study using the biospecimen, but instead would be obtained through broad
consent for future unspecified research.
ASH solicited feedback on the NPRM from the ASH Committee on Government Affairs and
the Committee on Scientific Affairs, and submitted final comments to the government on
January 6, 2016. The Society’s complete comments may be found on the ASH website at
www.hematology.org/Advocacy/Testimony. At the time of publication, it is unclear when a
final rule will be published.
The Hematologist:
ASH NEWS AND REPORTS
5
What We Carried on
Christmas
(Cont. from page 1)
studying my face for clues about good or bad news. Reading
microexpressions is part of his training. Paul carries the
unflinching faith that he’ll dodge another bullet. He visualizes a
military retirement, lounging at his beachside home, out from
the shadows and cured of AML. In this future, he’ll make the
choice to sport a buzz cut, despite it occasionally reminding
him of the time when nurses carried away clumps of his hair.
Olivia is a 32-year-old blonde with television good looks who
came in carrying a new quilt of bruises. She and her husband,
owner of a private equity firm, live in an 8,000-square-foot home
in Atherton. They are warm and soft-spoken. Their two girls,
ages three and six, are angelic clones of their mother. Photos
of the kids and their crayon drawings blanket the walls of her
hospital room. When the resident and first-year fellow first spied
her D-dimer of >20,000 ng/mL, fibrinogen of 42 mg/dL, platelet
count of 19 × 109/L, and white blood cell count of 77 × 109/L, they
understandably carried apprehension and urgency. I felt the
same. They heard of the head bleeds; I managed them; our APL
patients died of them. We started ATRA and successfully FISHed
for t(15;17).
Olivia steadied her shaky voice; she carried guilt, fear, and many
questions about things she was afraid to ask since she first
heard the word “leukemia.”
“I dyed my hair,” she said. “Did this cause my
leukemia?” “No,” I firmly replied.
“Six months ago I went vegan.”
I almost cut her off. “No connection,” I replied.
She inspected her bruises. She was unconvinced that she wasn’t
to blame. Tears welled in her eyes.
“Am I going to give this to my kids?” she asked.
“No. None of this is your fault. This is an acquired blood cancer.
You can’t pass this on to your children,” I comforted her.
We commenced a protocol for high-risk APL and reassured her
that she has an excellent chance of being cured. However, we all
knew that she wasn’t out of the woods.
A year ago, I lost a mother of three young kids to relapsed acute
lymphocytic leukemia. Soon after, her husband reconnected
with me. While he was thankful and trying to move on, Olivia’s
case reminded me that I hadn’t. I still carried an insidious
melancholy that bubbled to the surface. It hung on to my
conscience the way dried silicone gel sticks to jeans despite
repeated washings.
I felt that this was a good time for bargaining. I rationalized that
if all creatures are equal in God’s eyes, maybe he would agree
to a zero-sum arrangement: Olivia for the deer. I turned to her
husband to make sure there would be no last-minute hiccups:
“Do you drive a Tesla?”
Commentary: Our patients remind us daily of what we are
fighting for. While there may be “eight million stories in the
naked city,”1 we are privileged to be witnesses to a few thousand
of them during our careers. In some cases, we can extend
patients’ quantity and quality of life so that new epilogues and
second chances can be written.
2015’s Year’s Best in Hematology is a subjective list that
highlights the achievements of our profession. Our choices mark
time and allow different arcs of progress to reveal themselves.
However, these choices are most relatable and personal when
we can identify specific patients who are beneficiaries of these
breakthroughs. Olivia’s promising outlook reflects a narrative
of incremental progress in APL throughout the past 30 years. I
remain hopeful for Paul. Genomic studies are helping to inform
druggable pathways for different subsets of patients with AML.
Separately, a day before Christmas, a man with a white blood
cell count greater than 100 × 109/L walked into our emergency
department. He left a day later with a diagnosis of chronic
phase CML, a TKI prescription, and unexpected hope. The
transformative success of CML therapy could not have been
fleshed out nor appreciated in a single Year’s Best article. I am
curious to see how studies of clonal hematopoiesis, myeloma
antibodies/immunotherapy, techniques to enhance stem cell
engraftment, and the other Year’s Best selections featured
herein pay dividends for our patients over the long haul. I will
let you know when I am on service again during Christmas 2025.
From Jules Dassin’s “The Naked City”
1
6
RAN KI NG S FROM TH E H E MATOLOGI ST
R EAD E R SU RVEY
1)
Anti-CD19 CAR T-cells for refractory DLBCL
2)
Antibodies and immunotherapy for multiple myeloma
3)
Reversal agents for direct oral anticoagulants
4)
Age-related clonal hematopoiesis in normal individuals
5)
Reprogramming of Ph+ ALL cells into nonleukemic macrophages
6)
PET-directed therapy for early Hodgkin lymphoma
7)
Novel mechanisms of regulation of blood production
8)
Boosting hematopoietic stem cell engraftment
9)
Perioperative bridging anticoagulation and atrial fibrillation
10)
Mutation order and myeloproliferative neoplasms
11)
Biologic insights into malaria infection and resistance
12)
Practice-defining trials: fresher blood and IVC filters
13)
New therapeutic frontiers in sickle cell disease
14)
Optimizing maintenance therapy in ALL
15)
Somatic mutations in aplastic anemia
Reprinted with permission from Nat Rev Drug Discov. 2013;12:229-243.
This ranking reflects the results of a survey in which readers of The Hematologist scored several topics from
“most influential” to “least influential.” The following articles reflect the top choices of the Editor-in-Chief and
individual Contributing Editors.
The Hematologist:
ASH NEWS AND REPORTS
Clonal Hematopoiesis: The Seeds of Leukemia or Innocuous Bystander?
PAMELA S. BECKER, MD, PhD
Professor of Medicine, Division of Hematology, Institute for Stem Cell and Regenerative Medicine and Center for Cancer Innovation, University of Washington, Seattle, WA
The topic of age-related clonal
hematopoiesis in normal individuals
emerged as a compelling story
in late 2014 and dominated 2015
as a subject hematologists are
still grappling to understand. It
has become clear that in some
individuals, these somatic clones
might not always remain quiescent
or harmless. Instead, they may contribute to clonal
expansion and overt development of myeloid neoplasms
with the acquisition of additional cooperating mutations.
One year ago, in the January/February 2015 Year’s Best
issue of The Hematologist, Dr. Ravi Majeti authored the
article titled “Pre-Leukemic Hematopoietic Stem Cells
in Human Acute Myeloid Leukemia.” He highlighted
the seminal findings, published concurrently by three
groups,1-3 that some of the typical recurrent mutations
found in acute myeloid leukemia (AML) could also be
found in the peripheral blood of patients without a prior
diagnosis of hematologic disease. Dr. Majeti raised the
question of whether these individuals could be followed
with the goal of detecting overt disease earlier, allowing
for early treatment and/or prevention.
The studies by Dr. Siddhartha Jaiswal,1 Dr. Giulio
Genovese,2 and Dr. Mingchao Xie3 and their respective
colleagues established that these acquired mutations
occurred with normal aging and were akin to precursor
conditions such as monoclonal gammopathy of
undetermined significance
(MGUS) or monoclonal
Figure
B-cell lymphocytosis (MBL).
A
Analysis of mutations in
12,380 individuals in a
Swedish study2 revealed that
10 percent of those older than
65 years had such mutations,
compared with 1 percent
younger than 50 years. The
most frequent mutations in
this study and in a similar
study of 17,182 individuals in
the United States and abroad1
were in the DNMT3A, ASXL1,
and TET2 genes. Mutations
in the genes JAK2, TP53,
SF3B1, CBL, and SRSF2 were
less common. Longitudinal
follow-up of several cohorts
revealed that individuals
with clonal hematopoiesis
exhibited an increased risk for
development of hematologic
cancers and all-cause
mortality.
In 2015, we saw that these
“seeds” could remain
dormant, in a state of
“clonal hematopoiesis of
indeterminate potential
(CHIP).”4 CHIP is defined as at
least 2 percent variant allele
frequency (VAF) of somatic
mutations known to be
associated with hematopoietic
neoplasms, but without
fulfilling diagnostic criteria
for the malignancy (e.g., MDS
or AML).4 There is a 0.5 to 1
percent risk of progression
to overt malignancy per year
(Figure), with increased rates
in patients with a higher VAF
of the somatic mutation.
Instead of remaining dormant,
such clones may demonstrate
opportunistic tendencies.
In patients undergoing
chemotherapy, clones may
The Hematologist:
ASH NEWS AND REPORTS
expand under the selective pressure of treatment and
contribute to the development of therapy-related MDS
or AML (t-MDS/t-AML).5 Historically, it was believed
that chemotherapy and radiation led to therapy-related
hematologic cancers because of increased numbers of
mutations induced by treatment. However, contrary
to this dogma, Dr. Terrence Wong and colleagues’
analysis5 of t-AML patient samples showed that there
was not an increased number of mutations compared
with de novo AML. Moreover, the same AML-associated
mutations could be detected long before the diagnosis
of cancer, and resistant clones simply expanded after
treatment of the cancer.5 For example, in one patient with
Hodgkin lymphoma, two TP53 mutations were detected
in leukapheresis samples at a VAF of 0.5 percent six
years prior to development of t-AML, and both TET2 and
NUP98 mutations subsequently arose as potential driver
mutations, only detectable later at the time when the
leukemia was diagnosed.
(ICUS or IDUS, respectively) who do not meet diagnostic
criteria for MDS. And what do we tell the otherwise normal
individual who is referred to our clinic with one or more
“hits” uncovered on a myeloid gene panel that should not
have been ordered in the first place? We have much to
learn ourselves before we can confidently guide patients
through this maze of genetic complexity.
Notably, two of the three most commonly observed
mutated genes in normal individuals, DNMT3A and TET2,
were also found to be the most frequent mutations that
failed to clear by day 30 after induction chemotherapy for
AML. Patients in whom these mutations persist exhibit
a worse outcome, even in complete remission.6 Clearly,
these mutations are not always innocuous. It will be our
task as hematologists to contextualize the prognostic
importance of these molecular abnormalities, not only
patients with MDS or AML, but also in individuals with
mild cytopenias or dysplasia of unknown significance
4. Steensma DP, Bejar R, Jaiswal S, et al. Clonal hematopoiesis of
indeterminate potential and distinction from myelodysplastic
syndromes. Blood. 2015;126:9-16.
Dr. Becker indicated no relevant conflicts of interest.
1. Jaiswal S, Fontanillas P, Flannick J, et al. Age-related clonal
hematopoiesis associated with adverse outcomes. New Engl J
Med. 2014;371:2488-2498.
2. Genovese G, Kähler A, Handsaker RE, et al. Clonal hematopoiesis
and blood-cancer risk inferred from Blood DNA sequence. New
Engl J Med. 2014;371:2477-2487.
3. Xie M, Lu C, Wang J, et al. Age-related mutations associated with
clonal hematopoietic expansion and malignancies. Nat Med.
2014;20:1472-1478.
5. Wong TN, Ramsingh G, Young AL, et al. Role of TP53 mutations
in the origin and evolution of therapy-related acute myeloid
leukaemia. Nature. 2015;518:552-555.
6. Klco JM, Miller CA, Griffith M, et al. Association between mutation
clearance after induction therapy and outcomes in acute myeloid
leukemia. JAMA. 2015;314:811-822.
Model of Clonal Expansion and Clonal Evolution from Normal Hematopoeisis to
Myelodysplasia and Myeloid Leukemia
Clonal hematopoiesis of indeterminate potential (CHIP) as a precursor state for hematologic neoplasms. The figure depicts a model for evolution
from normal hematopoiesis to CHIP and then, in some cases, to myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Hematopoietic
progenitor cells or stem cells commonly acquire mutations throughout the human lifespan; most of these are passenger mutations that have no consequence
for hematopoiesis. Certain mutations, however, confer a survival advantage to the mutated cell and its progeny and allow clonal expansion. Serial acquisition
of mutations in an expanded clone can lead to a disease phenotype and ultimately, morbidity and mortality. CHIP can also directly progress to AML without an
intervening MDS stage, and CHIP can progress to other conditions such as myeloproliferative neoplasms or lymphoid neoplasms. The majority of patients with
CHIP will never develop an overt neoplasm, and patients will eventually die of unrelated causes.
From Steensma et al. Blood. 2015;126:9-16, with permission.
7
or double refractory multiple myeloma (MM): 54767414MMY2002
(Sirius). J Clin Oncol. 2015;33:LBA8512.
Novel Drugs Push the Envelope in Multiple Myeloma
ANDREW J. YEE, MD, 1 ELIZABETH O’DONNELL, MD, 2 AND NOOPUR S. RAJE, MD 3
1. Instructor in Medicine, Harvard Medical School, Center for Multiple Myeloma, Massachusetts General Hospital Cancer Center, Boston, MA
2. Instructor, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA
3. Associate Professor of Medicine, Harvard Medical School; Director of the Multiple Myeloma Center at Massachusetts General Hospital Cancer Center, Boston, MA
The year 2015 has been truly remarkable
for the treatment of multiple myeloma
(MM). The first oral proteasome inhibitor,
ixazomib, is now approved for the treatment
of MM. Data from the Tourmaline-MM1 study
presented at the 57th ASH Annual Meeting demonstrated
the benefit of ixazomib when combined with lenalidomide
and dexamethasone in relapsed and/or refractory MM, with
improvement in progression-free survival (20.6 months
vs. 14.7 months for patients receiving lenalidomide and
dexamethasone) and without significant toxicity.1
While there have been continued advances in novel drugs for
MM, this has easily been the year where immuno-oncology and
monoclonal antibodies (MoABs) have stolen the spotlight. A
few days prior to and after ixazomib approval, two new MoABs
were approved by the U.S. Food and Drug Administration
(FDA): daratumumab and elotuzumab. Daratumumab, a MoAB
directed against CD38, was approved for the treatment of MM
patients who have received at least three prior lines of therapy
including a proteasome inhibitor and an immunomodulatory
agent, or those who are refractory to both these classes of
drugs (i.e., double-refractory). In a pivotal phase I/II study,
daratumumab demonstrated striking effectiveness as a
single agent in heavily pretreated patients including doublerefractory patients.2 The overall response rate in this group
was 36 percent, including two patients who had a complete
response and two patients with a very good partial response.
Furthermore, responses were durable, and 65 percent of
patients who had a response were free of progression at one
year. These observations were corroborated by the Sirius
study, in a similar refractory MM population.3 At the 2015 ASH
Annual Meeting, we heard about early-stage trials combining
daratumumab with lenalidomide4 or pomalidomide,5 with
encouraging data demonstrating deeper responses. These
studies will inform use of daratumumab as a partnering agent
in the evolving MM treatment landscape.
Elotuzumab is a humanized recombinant IgG1 MoAB that
targets signaling lymphocyte activation molecule (SLAMF7),
also known as CS1 (CD2-subset-1). In a phase III study,
ELOQUENT-2, the combination of elotuzumab, lenalidomide,
and dexamethasone was compared with lenalidomide and
dexamethasone in patients with relapsed disease.6 Patients
with one to three prior lines of therapy were eligible to
participate. This trial enrolled 646 patients with a median of
two prior lines of therapy. A significant proportion had highrisk cytogenetics (32% with del[17p] and 9% with t[4;14]).
The elotuzumab-containing arm had superior progressionfree survival (19.4 months vs. 14.9 months in the control
group; p<0.001), and the overall response rate was also
higher (79% vs. 66%; p<0.001). Based on these findings,
elotuzumab was approved in combination with lenalidomide
and dexamethasone in patients with one to three prior lines of
treatment. These studies with elotuzumab and daratumumab
are among the first to show promising activity for MoAB
therapy in MM, and they will be practice-changing additions
to our arsenal against MM.
Cellular therapies such as chimeric antigen receptor-T
(CAR-T) cell therapy are now being actively studied in MM.
Although still in the early days of development, the promising
data presented this year with the use of CD19-directed CAR-T
cells in a heavily pretreated MM patient with nine prior lines
of therapy provide proof of concept for the promise of this
strategy.7 During the Late-Breaking Abstracts session at
the 2015 ASH Annual Meeting, early data on a series of MM
patients undergoing CAR-T cell therapy directed against a
different target, B-cell maturation antigen, may translate into
the use of personalized cellular therapy with the potential for
long-term disease control.8
Continuing the theme of immuno-oncology, data from solid
tumors highlight the successful paradigm of using checkpoint
inhibitors to target inhibitory mechanisms of the immune
system. Nivolumab and pembrolizumab, MoABs targeting
the programmed death 1 checkpoint, have shown activity in
melanoma and lung cancer and were recently approved by
the FDA. In relapsed MM, trials studying the use of immune
checkpoint blockade with MoABs such as pembrolizumab
are showing promise when the drug is combined with
lenalidomide9 or pomalidomide.10 Exploring the full potential
of MoABs in the treatment of myeloma is an area of great
interest for 2016.
8
Drs. Yee, O'Donnell, and Raje indicated no relevant
conflicts of interest.
1. Moreau P, Masszi T, Grzasko N, et al. Ixazomib, an investigational
oral proteasome inhibitor (PI), in combination with lenalidomide
and dexamethasone (IRd), significantly extends progression-free
survival (PFS) for patients (Pts) with relapsed and/or refractory
multiple myeloma (RRMM): the phase 3 tourmaline-MM1 study
(NCT01564537). Blood. 2015;126:727.
2. Lokhorst HM, Plesner T, Laubach JP, et al. Targeting CD38 with
daratumumab monotherapy in multiple myeloma. N Engl J Med.
2015;373:1207-1219.
3. Lonial S, Weiss BM, Usmani SZ, et al. Phase II study of daratumumab
(DARA) monotherapy in patients with ≥ 3 lines of prior therapy
4. Plesner T, Arkenau HT, Gimsing P, et al. Daratumumab in
combination with lenalidomide and dexamethasone in patients with
relapsed or relapsed and refractory multiple myeloma: updated
results of a phase 1/2 study (GEN503). Blood. 2015;126:507.
5. Chari A, Lonial S, Suvannasankha A, et al. Open-label, multicenter,
phase 1b study of daratumumab in combination with pomalidomide
and dexamethasone in patients with at least 2 lines of prior therapy
and relapsed or relapsed and refractory multiple myeloma. Blood.
2015;126:508.
6. Lonial S, Dimopoulos M, Palumbo A, et al. Elotuzumab therapy
for relapsed or refractory multiple myeloma. N Engl J Med.
2015;373:621-631.
7. Garfall AL, Maus MV, Hwang WT, et al. Chimeric antigen receptor
T cells against CD19 for multiple myeloma. N Engl J Med.
2015;373:1040-1047.
8. Ali SA, Shi V, Wang M, et al. Remissions of multiple myeloma during
a first-in-humans clinical trial of T cells expressing an anti-B-cell
maturation antigen chimeric antigen receptor. Blood. 2015;126:LBA-1.
9. San Miguel J, Mateos MV, Shah JJ, et al. Pembrolizumab in
combination with lenalidomide and low-dose dexamethasone for
relapsed/refractory multiple myeloma (RRMM): keynote-023. Blood.
2015;126:505.
10. Badros AZ, Kocoglu MH, Ma N, et al. A phase II study of anti PD-1
antibody pembrolizumab, pomalidomide and dexamethasone in
patients with relapsed/refractory multiple myeloma (RRMM). Blood.
2015;126:506.
Flipping a Switch: Advances in DOAC Reversal in 2015
ADAM CUKER, MD, MS
Assistant Professor of Medicine, Assistant Professor of Pathology & Laboratory Medicine, Director, Penn Comprehensive Hemophilia and Thrombosis
Program; Clinical Director, Penn Blood Disorders Center; Associate Director, Penn-CHOP Blood Center for Patient Care and Discovery, University of
Pennsylvania, Philadelphia, PA
The direct oral anticoagulants (DOACs)
dabigatran, rivaroxaban, apixaban, and
edoxaban, are associated with reduced major
bleeding, intracranial hemorrhage, and fatal
bleeding compared with warfarin.1 Nevertheless,
reversal of these agents may be warranted in patients who have
serious bleeding or who require an emergent procedure.
At this time last year, there was no standard of care for
emergent DOAC reversal. Hospital committees grappled with
low-quality evidence to define institutional protocols for
reversal. Clinicians lacked guidance on how to manage patients.
The best available options, prothrombin complex concentrate
and activated prothrombin complex concentrate, were
supported primarily by data from animal and healthy volunteer
studies, and raised concerns about thrombotic risk. No data
were available on the efficacy and safety of these agents in
DOAC-treated patients with a clinical indication for emergent
reversal.2
2015 was a year of great forward momentum on the reversal
front. In the RE-VERSE AD study, dabigatran-treated patients
who have serious bleeding or who require an emergent
procedure are treated with idarucizumab, a monoclonal
antibody fragment that binds and neutralizes dabigatran. An
interim analysis of the first 90 patients (51 with bleeding, 39
requiring a procedure) showed normalization of coagulation
tests within minutes of infusion. Among patients requiring an
emergent procedure, 92 percent were judged to have normal
surgical hemostasis. Clinical outcomes, including cessation of
bleeding, were more difficult to assess in the group with serious
hemorrhage. Idarucizumab was well tolerated. Only one patient
had a thrombotic event within 72 hours of administration.3
Based on the favorable results of RE-VERSE AD, idarucizumab
was approved in the United States and Europe in autumn of
2015 and is now the standard of care for emergent dabigatran
reversal in jurisdictions where it is available.
Not far behind idarucizumab in development is andexanet alfa,
a modified recombinant factor Xa molecule that lacks catalytic
and membrane-binding activity but retains the ability to bind
and neutralize factor Xa inhibitors. In the recently published
ANNEXA-A and ANNEXA-R trials, healthy volunteers taking
apixaban and rivaroxaban, respectively, were randomized
to receive andexanet or placebo. Rapid and profound
reduction in anti-Xa activity was observed within minutes
of bolus administration of andexanet. A continuous infusion
following the bolus was necessary to sustain the reversal
effect. Andexanet was well tolerated. Plasma samples from
some subjects showed increased D-dimer and prothrombin
1+2 fragments.4 The clinical relevance of this observation
is unknown. ANNEXA-4 (ClinicalTrials.gov Identifier:
NCT02329327), an ongoing phase IIIb-IV study, will provide
data on the efficacy and safety of andexanet in patients taking a
factor Xa inhibitor who have serious bleeding.
Other DOAC-reversal agents are in earlier stages of
development. Ciraparantag is a small, positively-charged
molecule that binds to, and neutralizes factor Xa inhibitors
through noncovalent interactions. It corrected coagulation
tests in healthy edoxaban-treated volunteers within minutes
of administration.5 Factor XaI16L, a zymogen-like variant of
factor Xa, and superFVa, a variant of factor Va engineered
to resist inactivation by activated protein C, both rapidly
reversed the anticoagulant effect of rivaroxaban in vitro and
in animal studies.6,7
A remarkable feature of DOAC reversal agents is the rapidity
with which they normalize coagulation parameters. Hours
are required for full reversal of the anticoagulant effect of
warfarin by vitamin K or plasma. Correction is achieved
more quickly with prothrombin complex concentrate, but 40
percent of patients have a persistently elevated INR (≥ 1.4)
30 minutes after infusion.8 In contrast, DOAC-reversal agents
correct coagulation tests within minutes of administration,
suggesting their potential to turn off anticoagulation almost
instantly, like flipping a light switch.
Whether the effect of DOAC reversal agents on laboratory
endpoints leads to improved clinical outcomes remains to be
proven. Continued progress in the field of DOAC reversal in
2016 and beyond is expected to shed light on this and other
crucial questions. Clinical observations from RE-VERSE AD
and ANNEXA-4 will teach us more about the efficacy and
safety of idarucizumab and andexanet alfa, respectively, in
patients with DOAC-associated bleeding. Real world data on
idarucizumab will be reported and recommendations for its
use will be incorporated into clinical practice guidelines and
institutional protocols.
Dr. Cuker indicated no relevant conflicts of interest.
1. Chai-Adisaksopha C, Crowther M, Isayama T, et al. The impact of
bleeding complications in patients receiving target-specific oral
anticoagulants: a systematic review and meta-analysis. Blood.
2014;124:2450-2458.
2. Siegal DM, Cuker A. Reversal of target-specific oral anticoagulants.
Drug Discov Today. 2014;19:1465-1470.
3. Pollack CV Jr, Reilly PA, Eikelboom J, et al. Idarucizumab for
Dabigatran Reversal. N Engl J Med. 2015;373:511-520.
4. Siegal DM, Curnutte JT, Connolly SJ, et al. Andexanet alfa for the
reversal of factor Xa inhibitor activity. N Engl J Med. 2015. DOI:
10.1056/NEJMoa1510991. [Epub ahead of print].
5. Ansell JE, Bakhru SH, Laulicht BE, et al. Use of PER977 to
reverse the anticoagulant effect of edoxaban. N Engl J Med.
2014;371:2141-2142.
6. Thalji NK, Ivanciu L, Jasuja R, et al. Zymogen-like FXa is a potent
bypassing agent for reversal of direct FXa inhibitors in vivo.
Blood. 2014;124:582.
7. Bhat V, Gale AJ, Griffin JH, et al. Reversal of novel oral
anticoagulant (NOAC)-induced bleeding in mice by engineered
superfactor Va. Blood. 2014;124:695.
8. Sarode R, Milling TJ Jr, Refaai MA, et al. Efficacy and safety of a
4-factor prothrombin complex concentrate in patients on vitamin K
antagonists presenting with major bleeding: a randomized, plasmacontrolled, phase IIIb study. Circulation. 2013;128:1234-1243.
The Hematologist:
ASH NEWS AND REPORTS
Using Interim PET to Direct Therapy for Early Hodgkin Lymphoma: Results from the Trials
ANN LACASCE, MD, 1 AND PETER JOHNSON, MD 2
1. Program Director, Fellowship in Hematology/Oncology; Assistant Professor of Medicine, Lymphoma Program, Dana-Farber Cancer Institute, Boston, MA
2. Professor of Medical Oncology, Cancer Research UK Centre, University of Southampton, UK
In 2015, the vast majority of patients with
Hodgkin lymphoma (HL) will be cured of
their disease using standard treatments.
Despite high rates of long-term disease
control, late therapy-related toxicities (most
importantly, secondary malignancies and cardiovascular
disease) remain a source of significant morbidity and
mortality among survivors. In 2015, results from a trio
of important risk-adapted trials in early-stage HL were
reported on, designed to maintain efficacy while reducing
the risk of late effects.
All three trials took the approach of using interim positron
emission tomography (PET) scanning to determine how
well treatment was working, allowing escalation of therapy
for individuals in whom the initial response appeared poor,
or reduction of therapy for those with an early metabolic
response.
In the RAPID trial from the United Kingdom (Figure 1),
patients with newly diagnosed stage IA and IIA nonbulky
HL underwent PET imaging after three cycles of ABVD
(doxorubicin, bleomycin, vinblastine, and dacarbazine).1
PET-positive patients received an additional cycle of ABVD
followed by IFRT. Patients who were PET-negative, defined
by a Deauville score of 1 or 2 (fluorodeoxyglucose [FDG]
uptake was less than the mediastinal blood pool) were
randomized to no further therapy versus involved-field
radiation therapy (IFRT) to 30Gy. The randomization was
designed to exclude a 7 percent or greater difference in
three-year progression-free survival (PFS) between the
two arms. After two cycles of ABVD, 75 percent of patients
were PET-negative, and 420 patients were ultimately
randomized. Although the 95 percent CI for the difference
in risk crossed 7 percent (−8.8% to +1.3%), the outcome
in both arms was excellent, with a three-year PFS of 94.6
percent in the radiotherapy (RT) arm versus 90.8 percent
in the observation arm. There was no difference in overall
survival.1
RAPID trial schema
ELIGIBILITY
Histologically confirmed classic HL
Stage IA/IIA by CT scan
No mediastinal bulk or B symptoms
No prior treatment
PET +ve
ABVD
x 3 cycles
Response
PET scan
R
PET –ve
CALGB/Alliance 50604 trial schema
ELIGIBILITY
Histologically confirmed classic HL
Stage I/II, A or B
No mediastinal bulk
No prior treatment
PET +ve
ABVD
x 2 cycles
Response
PET scan
PET –ve
Preliminary results of
EORTC/LYSA/FIL H10 trial schema
the U.S. Intergroup study
Figure 3
(Figure 2) of risk-adapted
therapy in patients
H10
with nonbulky stage I
2 ABVD
PET
1 ABVD + INRT 30 Gy (+ 6 Gy)
F
and II classical HL were
presented at the 57th
ASH Annual Meeting
–
2 ABVD
in December.2 In this
2 ABVD
PET
study, Deauville scores
+ 2 escBEACOPP + INRT 30 Gy (+ 6 Gy)
of 1 to 3 (FDG uptake
less than liver) were
considered negative.
Patients who were PETH10
2 ABVD
PET
2 ABVD + INRT 30 Gy (+ 6 Gy)
negative after two cycles
U
of ABVD received two
more cycles without
RT. Individuals who
–
4 ABVD
were PET-positive were
2 ABVD
PET
treated with two cycles
+ 2 escBEACOPP + INRT 30 Gy (+ 6 Gy)
of escalated BEACOPP
(doxorubicin, bleomycin,
vinblastine, and
dacarbazine) followed by
of interim PET imaging as a biomarker in patients with
IFRT to 30Gy. The group treated 164 patients, 91 percent of
early-stage HL. Overall, they suggest that escalation of
whom were interim PET-negative. With a median follow-up
chemotherapy for PET-positive patients is effective, and
of two years, the estimated 3-year PFS was 92 percent
they provide evidence to support the idea of omitting RT
in the PET-negative arm. In the PET-positive group, the
for those with an early metabolic response. This does not
estimated three-year PFS was 66 percent.2 This figure may
seem to compromise overall survival, though there is a
seem lower than in the PET-positive arm of RAPID, where
small increase in the risk of recurrence. It is notable that in
one further cycle of ABVD followed by 30Gy IFRT yielded
all three studies the proportion of patients dying from HL
87 percent PFS at five years, but it is important to note that
was less than 3 percent overall, emphasizing the need to
the “PET-positive” group in that trial contained 90 patients
take a holistic view of the data and not focus exclusively on
with a Deauville score of 3, from a total of 145, which is
disease control.
likely to have increased the PFS substantially.
R
R
During the 13th International Conference on Malignant
Lymphoma in June 2015, results from the H10 study by
the European Intergroup (EORTC/LYSA/FIL; Figure 3)
were presented.3 Patients with stage I and II disease were
randomized between PET-adapted therapy and standard
treatment with ABVD for
three cycles (favorable
patients per the EORTC
Figure 1
criteria: age 50 years or older,
large mediastinal mass, B
symptoms and erythrocyte
sedimentation rate [ESR] > 30,
ESR > 50 without B symptoms,
> 2 nodal sites of involvement)
4th cycle ABVD
or four cycles (unfavorable
then IFRT
patients) plus involved-node
RT (INRT) to 30Gy. In the PETadapted arm, PET-negative
patients (Deauville score of
IFRT 30 Gy
1-3) received a total of four
cycles (favorable) or six
cycles (unfavorable) of ABVD.
Interim PET-positive patients
No further
received intensified therapy
treatment (NFT)
with escalated BEACOPP
for two cycles followed by
INRT to 30Gy. In total, 1,950
patients were enrolled, and
interim PET was positive in
11 percent and 22 percent for
Figure 2
the favorable and unfavorable
groups, respectively. With
a median follow-up of 4.5
years, among 361 patients
who were PET-positive, the
5-year PFS was 91 percent
2 escBEACOPP
in those on the PET-adapted
then IFRT
arm who received BEACOPP,
compared with 77 percent
in the standard ABVD group.
There was also a trend toward
improved overall survival
in the PET-adapted arm: 96
percent compared with 89
percent (p=0.062).3
ABVD x 2 cycles
No RT
The Hematologist:
ASH NEWS AND REPORTS
Many hematologists/oncologists and patients alike are
willing to accept a small increased likelihood of disease
recurrence to avoid the risk of secondary cancers
and cardiovascular disease associated with RT. To
identify patients who may benefit from intensified or
novel approaches, interim PET, and possibly molecular
predictors, such as the recently described gene expression
signature, may be useful tools.4 Additionally, with the
availability of novel agents with impressive activity, such
as brentuximab vedotin and nivolumab, therapeutic
options for high-risk patients will continue to evolve, and
trials of these approaches are already underway.
Drs. LaCasce and Johnson indicated no relevant
conflicts of interest.
1. Radford J, Illidge T, Counsell N, et al. Results of a trial of PETdirected therapy for early-stage Hodgkin’s lymphoma. N Engl J
Med. 2015;372:1598-1607.
2. Straus D, Pitcher B, Kostakoglu L, et al. Initial results of
US Intergroup trial of response-adapted chemotherapy or
chemotherapy/radiation therapy based on PET for non-bulky
stage I and II Hodgkin lymphoma (HL) (CALGB/Alliance 50604).
Blood. 2015;126:578.
3. Raemaekers J. Early FDG-PET adapted treatment improved
the outcome of early FDG-PET positive patients with stages I/
II Hodgkin lymphoma (HL): final results of the randomized
Intergroup EORTC/LYSA/FIL H10 trial. Presented at the 13th
International Conference on Malignant Lymphoma, June 17-20,
2015, Lugano, Switzerland.
4. Scott DW, Chan FC, Hong F, et al. Gene expression-based model
using formalin-fixed paraffin-embedded biopsies predicts overall
survival in advanced-stage classical Hodgkin lymphoma. J Clin
Oncol. 2013;31:692-700.
These three studies
demonstrate the utility
9
Acquired Aplastic Anemia: Somatic Mutations and Eltrombopag Take the Spotlight
MELODY K. HARRISON, MD, 1 AND TRACY I. GEORGE, MD 2
1. Hematopathology Fellow, University of New Mexico School of Medicine, Albuquerque, NM
2. Associate Professor of Pathology; Hematopathology Division Chief and Hematopathology Fellowship Director, University of New Mexico and TriCore Reference Laboratories, Albuquerque, NM
Acquired aplastic anemia (AA) results from
autoimmune destruction of hematopoietic
progenitor cells, and a significant
proportion of these patients develop a
myelodysplastic syndrome (MDS) and/or
acute myeloid leukemia (AML) as a late complication
of their disease.1,2 Recent studies have demonstrated
clonal hematopoiesis (CH) in the majority of cases of
AA, including pediatric patients and those in whom MDS
and AML do not ultimately develop, and these clones are
generally detectable early in the course of the disease.1,2
The distribution and types of mutations (frame-shift,
nonsense, and splice site changes) identified in AA show
significant overlap with those observed in association with
MDS and AML but with a much lower allelic burden in the
former.1,2,3 Comparison of diagnostic samples with those
obtained after six months of immunosuppressive therapy
shows no significant difference in the numbers of different
mutations present; the levels, however, are significantly
increased after treatment.1
The specific genes involved in AA show significant
differences from, but also a good deal of overlap with,
MDS and AML. Alterations of BCOR, BCORL1, and PIGA
are more prevalent in AA, while JAK2, RUNX1, TET2, and
TP53 are less so. Mutations of DNMT3A and ASXL1 are
noted in both.1,2 Dr. Tetsuichi Yoshizato and colleagues2
suggest discrete mechanisms of clonal selection at play
in these processes. In other words, CH in general seems
to originate from a small clone present early in the
disease course, and its evolution is dependent on the
progressive accumulation of additional mutations and
subsequent clonal selection.1-4 Thus, CH appears to signify
leukemogenesis at a very early stage.
It is generally accepted that stem cells in all tissues,
including the bone marrow, tend to accumulate somatic
mutations throughout life, most of which are of no clinical
significance. Occasionally though, a disease-initiating
alteration occurs.4-6 Recent studies suggest that clones
with mutations in certain genes seem to have a survival
advantage in bone marrow failure.1,2 This seems to occur
through either escape from immune-mediated destruction,
as with loss-of-function mutations in HLA class I genes,
from a relative increase in proliferation, or both.1
Neal Young, and colleagues from the National Institutes
of Health (NIH) showed that eltrombopag elicited
a 44 percent response rate, including multilineage
responses, in patients with severe AA (sAA) refractory
to immunosuppression.8 This led to U.S. Food and Drug
Administration approval of eltrombopag in this patient
population. In the Late-Breaking Abstracts session, Dr.
Danielle Townsley, on behalf of colleagues from the
same NIH group, presented data that extended these
initial results. She presented data from a phase II trial
of 88 treatment-naïve sAA patients, where eltrombopag
was added to horse antithymocyte globulin (ATG) and
cyclosporine (CSA). Eltrombopag was administered
starting at day 14 (due to potential concerns for liver
toxicity) for six months (cohort 1) or three months
(cohort 2), or from day 1 for six months (cohort 3).
The combination was well tolerated, and no increased
marrow fibrosis was observed. Among the three treatment
cohorts, the combination of eltrombopag with ATG + CSA
yielded overall response rates at three and six months
of 80 percent and 85 percent, respectively; complete
response rates were 28 percent and 34 percent at these
time points. The addition of eltrombopag yields response
rates that are 20 percent to 30 percent higher than
historical rates with ATG + CSA alone in sAA (p < 0.001).
Clonal cytogenetic evolution occurred in seven of 88
patients, similar to prior rates observed with standard
immunosuppression. No baseline factors were predictive
of outcome.
2015 was a breakthrough year for AA. The marriage
of clinical breakthroughs with a more sophisticated
understanding of the mutational landscape of AA is certain
to catalyze robust translational research opportunities
moving forward. Additional investigation is needed to
correlate both baseline mutation status and temporal
Drs. Harrison and George indicated no relevant
conflicts of interest.
1. Babushok DV, Perdigones N, Perin JC, et al. Emergence of clonal
hematopoiesis in the majority of patients with acquired aplastic
anemia. Cancer Genet. 2015;208:115-128.
2. Yoshizato T, Dumitriu B, Hosokawa K, et al. Somatic mutations
and clonal hematopoiesis in aplastic anemia. N Engl J Med.
2015;373:35-47.
3. Genovese G, Kähler AK, Handsaker RE, et al. Clonal
hematopoiesis and blood-cancer risk inferred from blood DNA
sequence. N Engl J Med. 2014;371:2477-2487.
4. Xie M, Lu C, Wang J, et al. Age-related mutations associated with
clonal hematopoietic expansion and malignancies. Nat Med.
2014;20:1472-1478.
5. Jaiswal S, Fontanillas P, Flannick J, et al. Age-related clonal
hematopoiesis associated with adverse outcomes. N Engl J Med.
2014;371:2488-2498.
6. Steensma DP, Bejar R, Jaiswal S, et al. Clonal hematopoiesis of
indeterminate potential and its distinction from myelodysplastic
syndromes. Blood. 2015;126:9-16.
7. Zeigler FC, de Sauvage F, Widmer HR, et al. In vitro
megakaryocytopoietic and thrombopoietic activity of c-mpl
ligand (TPO) on purified murine hematopoietic stem cells.
Blood. 1994;84:4045-4052.
8. Olnes MJ, Scheinberg P, Calvo KR, et al. Eltrombopag and
improved hematopoiesis in refractory aplastic anemia. New Engl
J Med. 2012;367:11-19.
9. Townsley DM, Dumitriu B, Scheinberg P, et al. Eltrombopag
added to standard immunosuppression for aplastic anemia
accelerates count recovery and increases response rates. Blood.
2015;126:LBA-2.
Progression of Disease, Patient NIH075
Figure
Progression of Disease, Patient NIH075
Immune-mediated
destruction of HSCs
An understanding of the genes involved can provide some
insight into the mechanism of disease. For instance, the
most commonly detected mutation in these series results
in a loss of function of DNMT3A, which appears to impede
stem cell differentiation and results in accumulation of the
abnormal cells within the bone marrow. TET2 mutations
(also one of the most frequently identified) facilitate selfrenewal and give rise to a competitive growth advantage.
It is worth noting that candidate driver mutations,
alterations that occur in a subset of genes known to be
drivers of hematopoietic neoplasms, are relatively rare
among young patients with AA and seem to be enriched in
older individuals.3,5
The differences in involved genes are not only of interest
for understanding the evolution of disease, but some have
also been shown to have prognostic implications. For
instance, BCOR, BCORL1, and PIGA mutations generally
portend a better response to immunosuppressive therapy
and improved overall survival, while abnormalities of
ASXL1, CSMD1, DNMT3A, RUNX1, and TP53 tend to herald
inferior treatment response and shortened survival. In
a similar vein, clones with aberrancies in the former
(good prognostic) group of genes tend to remain small
or diminish in size over time, whereas clones involving
mutations of the latter (poor prognostic) group are more
likely to grow in size and progress to MDS and/or AML.
changes in clonal architecture (Figure) with disease
natural history and response to immunosuppression and
hematopoietic stem cell transplantation.
Recovery
ASXL1
TSC22D1
YTHDF2
FZD8
OR51A4 TET2
BCOR
COG1
SETBP1
EHD2
Onset of
Aplastic
Anemia
Base- 1
line
2
3
4
5
6
7
8
9
10
11
12
Years
Chronologic history of clonal evolution from the onset of disease to the last follow-up in Patient NIH075. Each mutated
gene is depicted in the representative cells. The vertical axis indicates the absolute volume of the clones. Representative
mutations in each clone are also shown. From Yoshizato T, Dumitriu B, Hosokawa K, et al. Somatic mutations and clonal
hematopoiesis in aplastic anemia.
N Engl J Med. 2015;373:35-47.
On the clinical front, data presented at the 57th ASH
Annual Meeting continue to highlight the promise of the
eltrombopag in patients with severe AA. The rationale for
using such agents is based on the expression of c-mpl,
the receptor for thrombopoietin, on hematopoietic stem
and progenitor cells, and the finding that the addition
of recombinant thrombopoietin expands the pool of
these cells in culture.7 In 2012, Drs. Cynthia Dunbar and
10
The Hematologist:
ASH NEWS AND REPORTS
Practice-Defining Clinical Trials in Nonmalignant Hematology
DAVID GARCIA, MD
Professor of Medicine, Division of Hematology, University of Washington, Seattle, WA
During 2015, two important myths from the
nonmalignant hematology world were busted
(to use a verb from the title of a recently
popular television series, “Myth Busters”). In
both cases, the myth was based on biological
theory and observational data from uncontrolled studies,
while the definitive evidence emerged from one or more
prospective, randomized controlled trials.
The first myth consists of the idea that patients
who are anticoagulated for so-called high-risk (but
hemodynamically stable) pulmonary embolism (PE) might
benefit from the placement of a retrievable inferior vena
cava (IVC) filter. Indeed, the general notion that more
aggressive interventions (over and above anticoagulant
therapy) might benefit high-risk PE patients is not new.
For example, more than one randomized controlled trial of
thrombolysis plus anticoagulation versus anticoagulation
alone has been conducted in this population. For some
clinicians, the retrievable IVC filter, an intervention with
no bleeding risk that theoretically could protect an already
tenuous right ventricle from the next embolism, seemed
even more attractive, especially after an observational
study in PE patients documented an association between
IVC filter placement and improved survival.1 Thankfully, a
group of investigators was able to carry out a prospective,
randomized controlled trial in which patients with highrisk PE were randomly assigned to have (or not have)
a retrievable IVC filter placed; all participants received
anticoagulation.2 The patients who received a filter had
no improvement on any of the efficacy outcomes, and a
handful experienced some of the complications known
to occur after IVC filter placement such as access site
hematoma, filter thrombosis, and retrieval failure. This
study, by Dr. Patrick Mismetti and colleagues, should serve
as a reminder to all hematologists that, when administered
with careful monitoring at a high-quality center,
anticoagulation therapy is as effective as more expensive
and potentially hazardous treatment options, sometimes
considered for patients with high-risk pulmonary
embolism. I suspect that Drs. D.W. Barritt and Stanley
C. Jordan, the authors who performed the landmark
randomized trial of heparin vs. no heparin in patients with
PE more than 50 years ago,3 would be pleased to learn that
the therapy they tested remains the gold standard in 2015.
The second myth to be challenged was that, among
patients who require red cell transfusions, those who
receive “fresher” units of packed red blood cells (RBCs)
fare better than patients who receive RBC units of
“standard” age. This idea that fresher blood might be
better has a basis in biology4 and observational data.5
However, in 2015, two randomized trials involving a
cumulative total of more than 3,500 patients6,7 failed to
demonstrate any evidence of a mortality (or other clinical)
benefit among those who received “fresher” RBCs. In one
study, the mean ages of RBCs were six versus 22 days,
and in the other, the median ages were seven versus 28
days. The studies involved critically ill adult patients and
patients (12 years or older) undergoing complex cardiac
surgery; all RBCs administered were leukoreduced. Like
any data from a clinical trial, the evidence provided by
these large trials can certainly be criticized: What if more
RBC units older than 35 days had been tested? Should the
variable of interest (age of RBCs) have been treated as
continuous rather than categorical (dichotomous)? Those
reservations notwithstanding, the sheer size of these trials,
along with the degree to which the findings agree with
previous controlled studies, indicates that if there is any
benefit from RBCs with storage time longer than 28 days,
it is small, and the additional costs of providing “fresher”
blood to all patients would be very difficult to justify.
Dr. Garcia indicated no relevant conflicts of interest.
1. Kucher N, Rossi E, De Rosa M, et al. Massive pulmonary
embolism. Circulation. 2006;113:577-582.
2. Mismetti P, Laporte S, Pellerin O, et al. Effect of a retrievable
inferior vena cava filter plus anticoagulation vs anticoagulation
alone on risk of recurrent pulmonary embolism: a randomized
clinical trial. JAMA. 2015;313:1627-1635.
3. Barritt DW, Jordan SC. Anticoagulant drugs in the treatment
of pulmonary embolism. A controlled clinical trial. Lancet.
1960;1:1309-1312.
4. Zimring JC. Established and theoretical factors to consider in
assessing the red cell storage lesion. Blood. 2015;125:2185-2190.
5. Wang D, Sun J, Solomon SB, et al. Transfusion of older
stored blood and risk of death: a meta-analysis. Transfusion.
2012;52:1184-1195.
6. Lacroix J, Hébert PC, Fergusson DA, et al. Age of transfused blood
in critically ill adults. N Engl J Med. 2015;372:1410-1418.
7. Steiner ME, Ness PM, Assmann SF, et al. Effects of red-cell storage
duration on patients undergoing cardiac surgery. N Engl J Med.
2015;372:1419-1429.
New Therapeutic Frontiers in Sickle Cell Disease
CHARLES T. QUINN, MD, MS
Associate Professor of Clinical Pediatrics, University of Cincinnati College of Medicine and Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
A panoply of potential new therapies for sickle
cell disease (SCD) has emerged in just the
past five years. Pharmaceutical companies
are now actually interested in SCD. Many
sickle cell centers now run more than one
clinical trial at the same time, and even decline participation
in others because of limited resources and competing
enrollment. While this may be unsurprising to many readers
of The Hematologist, especially those who treat patients
with hematologic malignancies, this is a strange, new world
for the sickle cell community. This column highlights three
publications from 2015 that reported new therapeutic
frontiers in different stages of development: gene therapy,
antiadhesive therapy, and modulation of coagulation.
Gene therapy for SCD has always been ‘just around the
corner.’ Now it is actually here for humans, albeit in an
extremely limited and experimental basis. Five individuals
with SCD have undergone some form of gene transfer
therapy to date, but the durability of clinical benefit of the
current generation of gene therapy methods remains to
be demonstrated. Even so, next-generation gene therapy
techniques are already being studied in preclinical models.
An ideal gene therapy for SCD would avoid the problems
of insertional mutagenesis and difficulty achieving proper
spatiotemporal expression of a transgene by permanently
correcting the sickle mutation in situ. In an effort to
achieve this goal, Dr. Megan Hoban and colleagues used
specifically engineered zinc-finger nucleases and a donor
nucleotide template to effect cleavage of the β-globin
locus and homology-directed repair of the sickle mutation
in hematopoietic stem and progenitor cells (HSPCs).1
These modified HSPCs could engraft in immunodeficient
mice and produce cells from multiple lineages. Moreover,
gene-corrected CD34+ cells from the bone marrow of
individuals with SCD could produce wild-type hemoglobin
tetramers. Clearly, more work needs to be done until
this gene correction technique is ready for studies in
humans, including elimination of off-target cleavage
and nonhomologous end joining. Different gene editing
techniques (e.g., TALEN- and CRISPR-based systems) are
The Hematologist:
ASH NEWS AND REPORTS
also being actively studied. So, while gene therapy for SCD is
“already here,” even better gene therapy is “just around the
corner.”
prothrombin is a modifier of end-organ damage in SCD in
mice and support the study of dabigitran and other direct
thrombin inhibitors for the treatment of SCD.
Until gene therapy delivers a universal cure, the painful
vaso-occlusive episode (VOE) will remain a vexing
therapeutic challenge. A number of studies have
demonstrated a key role for intercellular adhesive
interactions in the pathophysiology of vaso-occlusion, and
several antiadhesive therapies are being tested for VOE.
Among these is the pan-selectin inhibitor, GMI-1070, now
known as rivipansel. Dr. Marilyn Telen and colleagues
reported the results of a prospective, multicenter,
randomized, placebo-controlled, double-blind, phase II study
of 76 patients with VOE.2 Although the time to resolution
of VOE was not statistically different between the groups,
the medication appeared to be safe, and a secondary
analysis showed a significant reduction in opioid usage in
the GMI-1070 group. These results provided support for
a phase III study of GMI-1070 that is currently recruiting
(NCT02187003). GMI-1070 exemplifies the renewed optimism
that exists for alternative therapeutic options beyond
hydration, analgesics, and supportive care for VOE and
related complications of SCD.
While promising new therapies and cures for SCD such as
these are hotly pursued and eagerly anticipated, we must
not forget what we can do for our patients now: Prescribe
hydroxyurea.4 Hydroxyurea decreases SCD-related morbidity
and mortality and improves quality of life. It is effective
and has very few serious side effects. Sadly, it is still not
prescribed as broadly as it should be. Looking forward
to 2016, we will certainly see expanded indications for
hydroxyurea. In particular, the results of the TWiTCH Trial
were presented at the Plenary Scientific Session of the 2015
ASH Annual Meeting but not published in time for this Year’s
Best in Hematology.5,6 The TWiTCH trial demonstrated that
hydroxyurea was not inferior to chronic transfusions for
primary stroke prevention in select children with SCD. I
predict that these practice-changing findings will top next
year’s list.
SCD is characterized by activation of the coagulation system
and chronic inflammation. This knowledge has prompted
a handful of trials of anticoagulant and anti-inflammatory
therapies. None had resounding success, perhaps because
these agents (e.g., heparins, corticosteroids) have targets
that are too broad. As a specific therapeutic target for
SCD, thrombin is attractive because it is both a central
effector and regulator of coagulation and a key modifier
of inflammation. Dr. Paritha Arumugam and colleagues
demonstrated that targeted reduction of prothrombin
levels, using both antisense oligonucleotides and genetic
diminution techniques, significantly ameliorated vasoocclusion, vasculopathy, and inflammation in sickle cell
mice.3 Importantly, these benefits were achieved with only
a modest increase in the prothrombin time and without
hemorrhagic complications. These findings indicate that
1. Hoban MD, Cost GJ, Mendel MC, et al. Correction of the sickle cell
disease mutation in human hematopoietic stem/progenitor cells.
Blood. 2015;125:2597-2604.
Dr. Quinn indicated no relevant conflicts of interest.
2. Telen MJ, Wun T, McCavit TL, et al. Randomized phase 2 study of
GMI-1070 in SCD: reduction in time to resolution of vaso-occlusive
events and decreased opioid use. Blood. 2015;125:2656-2664.
3. Arumugam PI, Mullins ES, Shanmukhappa SK, et al. Genetic
diminution of circulating prothrombin ameliorates multiorgan
pathologies in sickle cell disease mice. Blood. 2015;126:1844-1855.
4. Quinn CT. Do not leave for tomorrow what you can do today.
Pediatr Blood Cancer. 2015;62:1879-1880.
5. Quinn CT. TWiTCH: itching to find an alternative to transfusions
for prevention of stroke in sickle cell anemia. The Hematologist.
2013;6:13.
6. Ware RE, Davis BR, Schultz WH, et al. TCD with transfusions
changing to hydroxyurea (TWiTCH): hydroxyurea therapy as
an alternative to transfusions for primary stroke prevention in
children with sickle cell anemia. Blood. 2015;126:3.
11
Therapeutically Enhancing Stem Cell Engraftment
JONATHAN HOGGATT, PhD
Assistant Professor, Cancer Center and Center for Transplantation Sciences, Massachusetts General Hospital/Harvard Medical School, Boston, MA
Hematopoietic stem cell transplantation is
often the only curative treatment modality for
a number of hematologic diseases. There are
more than 50,000 bone marrow transplants
performed each year worldwide. Despite
this fact, there are virtually no therapies in clinic today to
support or enhance the engraftment of transplanted stem
and progenitor cells. In 2015, several high-profile studies
were published, which have begun adding to the toolkit of
potential therapies to enhance stem cell engraftment.
One therapeutic option that is currently being explored
is treating the stem cell graft ex vivo with 16,16-dimethyl
prostaglandin E2 (dmPGE2)1 — a long-acting analogue of the
naturally occurring prostaglandin, which is derived from
arachidonic acid via the cyclooxygenase enzymes, COX1 and
COX2 (Figure). Two articles in 2015 have now expanded the
realm of manipulating arachidonic acid-derived eicosanoids
to enhance stem cell engraftment. Work published from the
laboratory of Dr. Leonard Zon utilized a novel competitive
transplantation system in transparent zebrafish, allowing for
direct visualization of stem cell engraftment.2 They screened
480 chemicals with known biologic activity for the ability
to alter hematopoietic stem cells, and several hits targeted
eicosanoids, including 11,12 epoxyeicosatrienoic acid (11,12EET) and 14,15-EET, which are derived from arachidonic acid
via cytochrome P450 epoxygenases (Figure). Mouse bone
marrow was treated ex vivo with 11,12-EET for four hours
and then washed away (similar to the dmPGE2 protocol),
prior to transplantation into lethally irradiated recipients.
This short pulse with 11,12-EET resulted in enhanced homing
and in increases in both short and long-term hematopoietic
reconstitution. These studies highlight the broad role of
eicosanoids in regulating stem and progenitor function,
and they suggest yet another potential therapeutic strategy
utilizing short, ex vivo pulses with small molecules to
enhance engraftment. In the future it may be possible to
treat a hematopoietic graft with a cocktail of various factors
targeting multiple pathways leading to super enhancements.
While the 11,12-EET strategy followed the aforementioned
concept of an ex vivo pulse, a team of collaborators at
Case Western and UT Southwestern utilized an approach
of altering the environment within the recipient of a
transplant.3 Many therapeutics that we have today, most
notably nonsteroidal anti-inflammatory drugs (NSAIDs),
focus on inhibiting COX enzyme activity to decrease
PGE2 levels. However, as PGE2 enhances stem cell
function, the authors evaluated methods
to increase the natural levels of PGE2. They
accomplished this enhancement with the
small molecule SW033291, which inhibits
15-hydroxyprostaglandin dehydrogenase
(15-PGDH), a key enzymatic step in the
breakdown of PGE2 (Figure). When mice
were treated with SW033291 prior to
transplantation, there were enhancements
to the microenvironment, including
elevated stromal derived factor-1 (SDF-1), a
chemoattractant and supportive molecule for
stem cells, and the growth factor c-kit ligand
(stem cell factor [SCF]). Additionally, there
was improvement in stem and progenitor
cell homing to the bone marrow niche,
accelerated recovery of neutrophils and
platelets, and enhanced survival in a limited
cell transplantation assay. These studies
outline a potential therapeutic strategy to
augment engraftment by altering the recipient
environment those cells are entering, rather
than altering the stem cell graft itself.
Figure
Arachidonic Acid Cascade
Arachidonic
Acid
NSAIDs
Cyclooxygenases
Lipoxygenases
Cytochrome P450
epoxygenases
Prostaglandin E2
Leukotrienes
EETs
15-PGDH
SW033291
Shown is a simplified version of the arachidonic acid cascade. After
arachidonic acid is released by phospholipase A2, it can then be converted
to numerous other eicosanoid molecules by a variety of enzymatic reactions.
Cyclooxygenase enzymes convert arachidonic acid into thromboxanes,
prostacyclins, and prostaglandins, notably Prostaglandin E2. These enzymes
are the target of many nonsteroidal anti-inflammatory drugs (NSAIDs), such
as aspirin and ibuprofen. Prostaglandin E2 is then rapidly degraded by
15-hydroxyprostaglandin dehydrogenase (15-PGDH), which is the target
of the small molecule inhibitor SW033291. Arachidonic acid can also be
converted into leukotrienes, many of which are mediators of allergy, and into
the epoxyeicosatrienoic acids (EETs) by the cytochrome P450 epoxygenases.
This past year has not only brought
exciting new studies showing that stem cell
engraftment can be enhanced by ex vivo
manipulation of the hematopoietic graft,
or by in vivo enhancement of the recipient
environment, but also by simply harvesting
the graft with enhancing protocols. Earlier
this year in The Hematologist,4 we highlighted
work from the Broxmeyer lab that demonstrated exposure
to ambient air could lead to a phenomenon they termed
“extraphysiologic oxygen shock/stress” or EPHOSS, which
led to reductions in stem cell function.5 When bone marrow
was harvested in the continuous presence of Cyclosporin A,
there was a reversal of the deleterious effects of ambient air
exposure, with significant increases in stem cell number and
competitive transplantation. These results also extended
to human cord blood samples harvested in Cyclosporin
A. Given the recurring interest in stem cell expansion and
ex vivo manipulation (i.e. gene therapy), the discovery of
EPHOSS effects, and more importantly, strategies to mitigate
the negative effects on stem cells, represented important
contributions to therapeutic enhancement of stem cell
engraftment in 2015.
Dr. Hoggatt indicated no relevant conflicts of interest.
1. Cutler C, Multani P, Robbins D, et al. Prostaglandin-modulated
umbilical cord blood hematopoietic stem cell transplantation.
Blood. 2013;122:3074-3081.
2. Li P, Lahvic JL, Binder V, et al. Epoxyeicosatrienoic acids enhance
embryonic haematopoiesis and adult marrow engraftment.
Nature. 2015;523:468-471.
3. Zhang Y, Desai A, Yang SY, et al. Tissue regeneration: inhibition of
the prostaglandin-degrading enzyme 15-PGDH potentiates tissue
regeneration. Science. 2015;348:aaa2340.
4. Rasmussen HK, Hoggatt J. Hematopoietic stem cells should hold
their breath. The Hematologist. 2015;12(5):9.
5. Mantel CR, O’Leary HA, Chitteti BR, et al. Enhancing
hematopoietic stem cell transplantation efficacy by mitigating
oxygen shock. Cell. 2015;161:1553-1565.
Malaria: Progress in the Host-Pathogen Arms Race
THERESA COETZER, PhD
Co-Director of Wits Research Institute for Malaria; Associate Professor, University of the Witwatersrand, Johannesburg, South Africa
The 2015 Nobel Prize in Physiology or Medicine
was awarded to three scientists for their
discoveries on novel therapies against
parasitic infections. Youyou Tu from China
was honored for isolating artemisinin, the active
ingredient from the Chinese herb Artemesia annua, which
rapidly kills malaria parasites. Artemisinin combination
therapy is the current gold standard treatment for malaria,
and it has had a major impact on diminishing the burden of
the disease. Malaria parasites are transmitted to humans by
female Anopheles mosquitoes, and, after initial replication
in the liver, they invade and subsequently destroy red
blood cells (RBCs), which triggers the clinical symptoms
of the disease. The complex parasite lifecycle in both the
human host and the mosquito vector has necessitated a
multipronged approach in global efforts to eliminate this
remarkably successful pathogen. Preventive measures,
including the use of insecticide-treated bed nets and indoor
residual spraying with insecticides, have been combined
with rapid diagnostic test kits in order to detect malaria as
early as possible. These interventions, followed by immediate
and appropriate treatment of the patient, have contributed
to a dramatic global decline in malaria since 2000 and to
achievement of the United Nations’ Millennium Development
Goal by 2015.1
12
Despite this progress, 3.2 billion people remain at risk of
contracting malaria. According to the latest World Health
Organization report,2 an estimated 214 million new cases and
approximately 438,000 deaths were reported in 2015. SubSaharan Africa continues to bear the brunt of the disease,
accounting for 88 percent of the morbidity and 90 percent of
the mortality, mainly in children younger than five years.
The gains that have been achieved are threatened by the
development of insecticide resistance in African vector
species and by the alarmingly rapid development and spread
of drug-resistant parasites, which have rendered several
antimalarial drugs useless. Resistance to artemisinin by
Plasmodium falciparum, the most deadly of the five species
of Plasmodium parasites that infect humans, has recently
been detected in five countries in the Greater Mekong region.
This threat has accelerated research into the biology of P.
falciparum and its interaction with the human host, and has
fueled efforts to develop new drugs and a vaccine. Several
major advances have been reported this year, and results
from four studies are highlighted here.
In a multi-institutional collaboration3 led by Dr. Kasturi
Haldar, the specific molecular target of artemisinin
in early ring-stage P. falciparum was identified as
phosphatidylinositol-3-kinase (PfPI3K). However, PfPI3K
polymorphisms were not detected in all resistant strains,
and previous genome-wide association studies (GWAS)
revealed selective pressure on chromosome 13, in particular
on the pfkelch13 gene. The mammalian orthologue is a
substrate adaptor for an E3 ubiquitin ligase; the putative
substrate binding domain of the parasite PfKelch13 protein
has a characteristic kelch propeller domain, and mutations
in this region correlated with artemisinin resistance. In an
elegant series of biochemical and cell biology experiments,
the researchers demonstrated that one of the most prevalent
mutations, C580Y, inhibited the binding of PfKelch13 to
PfPI3K, which decreased ubiquitination of the enzyme and
limited subsequent proteasomal degradation, resulting
in increased amounts of enzyme and its lipid product,
phosphatidylinositol-3-phosphate (PI3P). It is hypothesized
that artemisinin resistance is mediated by PIP3-induced
amplification of downstream targets that are currently
unknown. This study is important since it provides a tool to
screen and monitor clinical parasite isolates for the presence
of artemisinin resistance, and it identifies a target that can
be exploited for novel drug development.
The invasion of RBCs by P. falciparum is a complex process,
and interactions between host receptors and parasite ligands
The Hematologist:
ASH NEWS AND REPORTS
millenniumgoals/ne
are not fully understood. Genetic manipulation experiments
to identify host factors influencing susceptibility to infection
have been hampered by the absence of a nucleus in mature
erythrocytes. To overcome this challenge, Dr. Elizabeth Egan
and colleagues4 exploited two recent technological advances
of RNA interference and ex vivo production of RBCs to design
a forward hematopoietic stem cell-based genetic screen.
They identified CD55 or decay-accelerating factor (DAF)
as an essential host receptor and verified their laboratory
findings by demonstrating that RBCs from a patient lacking
CD55 were refractory to invasion by P. falciparum. CD55
is a membrane-bound glycoprotein that regulates the
complement system, and these findings suggest that the role
of complement in parasite invasion and pathogenesis should
be re-examined. The study also identifies CD55 as a potential
target for the development of novel antimalaria therapeutics.
P. falciparum is a highly virulent parasite that can cause
severe disease, including cerebral malaria. Features that
contribute to virulence include binding of infected RBCs
to the microvasculature and also to other RBCs to form
rosettes. These host-pathogen interactions are poorly
understood. Dr. Mats Wahlgren and colleagues5 used
molecular and cell biology approaches to demonstrate that
P. falciparum expressed repetitive interspersed families of
polypeptides (RIFINs) on the surface of infected RBCs and
formed rosettes by preferentially binding to blood group
A erythrocytes. RIFINs also mediated microvasculature
sequestration by interacting with A antigens on endothelial
cells. These findings indicate that RIFINs play a major
role in the pathogenesis of severe malaria and that blood
group A predisposes to the development of severe disease,
which correlates with previous clinical studies on African
children. This study highlights the impact of malaria on the
human genome and suggests that RIFINs contributed to
the evolutionary pressure that led to the emergence of the
protective blood group O and the variable global distribution
of human ABO blood groups.
The development of a malaria vaccine has been actively
pursued for several decades but has been an elusive and
frustrating target. The RTS,S Clinical Trials Partnership
published the final results6 of an individually randomized,
controlled phase III trial on the most advanced malaria
vaccine candidate RTS,S/AS01. More than 15,000
participants, including young children (ages 5 to 17 months)
and infants (ages 6 to 12 weeks) were enrolled in seven
sub-Saharan African countries representing different levels
of malaria transmission. The vaccine was administered
at months 0, 1, and 2, with a booster at 20 months. The
results showed modest protection against clinical P.
falciparum malaria throughout 48 months, with a vaccine
efficacy of 36.3 percent in young children and 25.9 percent
in infants, and illustrated the importance of the booster
to sustain the protective effect. Recent recommendations
from international expert committees who evaluated the
trial are to conduct three to five real-world demonstration
pilot studies with 200,000 African children each time over
the next few years to assess the impact and feasibility of
implementing the four-dose vaccine strategy.
In conclusion, despite the major advances reported in these
four studies, they have highlighted our lack of in-depth
understanding of the complex interplay between the
malaria parasite and its human host. Numerous challenges
remain and it will require an enhanced effort not only by
researchers, but also by political leaders and funders, to
ensure that the current momentum is not lost in the battle
against this formidable pathogen.
Dr. Coetzer indicated no relevant conflicts of interest.
1. The Millennium Development Goals Report 2015. United Nations.
Available at www.un.org/millenniumgoals/news.shtml. Accessed
January 3, 2016.
2. Malaria World Report. World Health Organization. Available at
www.who.int/malaria/publications/world_malaria_report/en/.
Accessed December 22, 2015.
3. Mbengue A, Bhattacharjee S, Pandharkar T, et al. A molecular
mechanism of artemisinin resistance in Plasmodium falciparum
malaria. Nature. 2015;520:683-687.
4. Egan ES, Jiang RHY, Moechtar MA, et al. Malaria. A forward genetic
screen identifies erythrocyte CD55 as essential for Plasmodium
falciparum invasion. Science. 2015;348:711-714.
5. Goel S, Palmkvist M, Moll K, et al. RIFINs are adhesins implicated in
severe Plasmodium falciparum malaria. Nat Med. 2015;21:314-317.
6. RTS,S Clinical Trials Partnership. Efficacy and safety of RTS,S/
AS01 malaria vaccine with or without a booster dose in infants
and children in Africa: final results of a phase 3, individually
randomised, controlled trial. Lancet. 2015;386:31-45.
A New Roadmap for Optimizing Thiopurine Therapy in
Acute Lymphocytic Leukemia
ELIZABETH RAETZ, MD, 1 AND JULIA MEYER, PhD 2
1. P
rofessor in the Division of Pediatric Hematology/Oncology; Director of High-Risk Leukemia and Lymphoma Program, University of Utah/Huntsman
Cancer Institute, Salt Lake City, UT
2. Postdoctoral Fellow, University of Utah School of Medicine, Salt Lake City, UT
The treatment of childhood acute lymphocytic
leukemia (ALL) has been a success story,
with the majority of patients now achieving
cure; however, there is still a steep learning
curve with regard to our understanding of
how to most effectively and safely deliver conventional
chemotherapeutic drugs. The bulk of childhood ALL
therapy is the approximately two-year maintenance
phase, the backbone of which is daily administration of
6-mercaptopurine (6MP). Questions still remain regarding
how best to fine tune dosing of 6MP in individual patients
and how to enhance compliance with daily oral 6MP during
the several-year trajectory of an ALL treatment course.
Further, despite overall high cure rates for childhood
ALL, some patients develop resistance to 6MP; efforts at
early detection of resistance are underway, so preemptive
changes can be made to avert relapse. 6MP has been a
mainstay of ALL therapy for the past six decades; however,
three seminal articles published in 2015 lent critical insights
into why optimal delivery of this drug is critical to the
success of patient outcomes.
Expanding on prior studies, which have demonstrated that
nonadherence to 6MP increases relapse risk,1 Dr. Smita
Bhatia and colleagues reported their results from a large
prospective multiyear study examining the effects of high
intra-individual variability of 6MP exposure on the risk of
relapse.2 The authors assessed adherence in 742 children
throughout a six-month period during the maintenance
phase of therapy on Children’s Oncology Group (COG)
treatment regimens. The authors observed that patients
with a mean 6MP adherence rate of less than 95 percent
were at a 2.7-fold increased risk of relapse compared with
those having 95 percent or greater adherence. Adherence
was measured in this study using a special bottle cap
with an electronic monitoring device to record the date
and time of bottle opening for medication administration.
The authors examined several other variables related to
mediation adherence to determine their impact on relapse
risk, including erythrocyte thioguanine (TGN) levels, 6MP
dose intensity (number of prescribed 6MP doses divided
by the number of planned protocol doses), thiopurine
methyltransferase (TPMT) genotype, and absolute
neutrophil count (ANC). Interestingly, dose intensity and
TGN levels were not associated with the risk of relapse.
Notably, however, among adherent patients, high intraindividual variability in TGN levels increased relapse risk
by 4.4 fold. This variability in TGN levels was the result of
varying 6MP dose intensity and drug treatment interruptions.
in COG protocols, 6MP dose adjustments are made in an
effort to target an ANC range of 1 to 1.5 × 109/L, and 6MP is
held when the ANC and/or platelet count are lower than 0.5 ×
109/L and 50 × 109/L, respectively. Once blood counts recover,
6MP is reintroduced at a reduced dose with incremental
dose increases, as tolerated. Patients tend to experience
fluctuations in their blood counts that require 6MP dosing
modifications, and given the association of TGN variability
and relapse, this raises the question of whether modifications
to current dosing guidelines should be considered in an effort
to reduce drug interruptions and maintain more consistency
in TGN levels.
The work by Dr. Bhatia and colleagues also ties in well
with other influential reports this year describing a new
host polymorphism impacting tolerance of 6MP and new
discoveries on mechanisms of thiopurine resistance.
While adherence to 6MP is key to minimizing relapse risk,
understanding how inherited variants contribute to 6MP
intolerance is also important so that consistent exposure can
be maintained and excessive toxicity can be avoided. In early
2015, Dr. Jun Yang and colleagues identified a novel germline
variant in the gene NUDT15, which was strongly associated
with 6MP intolerance and which was most frequently found
in patients of East Asian and Hispanic descent.3 The newly
identified variant is hypothesized to lead to a loss-of-function
phenotype for NUDT15, causing extensive DNA damage and
cytotoxicity. Patients that were homozygous for the TT
genotype only tolerated 8.3 percent of planned 6MP doses.
This discovery, coupled with existing data on the role that
TPMT variant alleles also play in 6MP intolerance,4 will help
to identify a significant number of children spanning different
racial and ethnic groups for individualized 6MP dosing.
Since the first reports that relapse-specific acquired
mutations in the gene NT5C2 cause overt resistance to
6MP,5,6 two new studies published in 2015 have helped to
expand our knowledge of genes contributing to maintenance
therapy resistance. Dr. Xiaotu Ma and colleagues showed
that the prevalence of mutations in NT5C2 may be as high as
45 percent in patients with early ALL relapses, and further,
that these mutations were often acquired in the founding
relapse clone.7 They also observed that patients can acquire
multiple mutations in NT5C2, albeit in different subclones,
demonstrating the selective pressure on leukemia cells to
evade 6MP cytotoxicity. Additionally, Dr. Benshang Li and
colleagues reported that another mechanism of thiopurine
resistance can occur through the acquisition of relapsespecific mutations in the gene PRPS1.8 PRPS1 is an enzyme
involved in the de novo purine biosynthesis pathway, and
These findings raise important questions about how best to
the acquired mutations were shown to reduce nucleotide
administer 6MP during ALL maintenance therapy. Presently,
feedback inhibition, causing a reduction in the conversion of
6MP into its active metabolite. Mutations
were found in 6.7 percent of the B-lineage
Figure
ALL samples examined and were mutually
Strategies for optimizing the delivery
exclusive of NT5C2 mutations. Taken
of thiopurine therapy
together, these studies suggest that
resistance to 6MP is a commonly observed
mechanism of ALL relapse.
While continued advances in the field of
pediatric ALL are envisioned with precision
medicine initiatives and the development
of new targeted agents, the improved
utilization of conventional chemotherapy
drugs also falls within the spirit of these
efforts. The report by Dr. Bhatia and
colleagues and the aforementioned studies
published in 2015 converge on a central
theme of employing different approaches
to optimize 6MP delivery during ALL
maintenance therapy (Figure). These
studies raise important considerations
for the development of future prospective
ALL trials and suggest that measures to
enhance adherence and reduce treatment
interruptions will need to be carefully
considered. In concert, prospective
assessment for TPMT and NUDT15 variants
to identify individuals at risk for 6MP
(Cont. on next page)
The Hematologist:
ASH NEWS AND REPORTS
millenniumgoals/news.shtml. Accessed January 3, 2016.
13
Clinical Implications of Novel Regulatory Mechanisms for Production of Platelets,
Neutrophils, and Erythrocytes
MARK J. KOURY, MD
Professor of Medicine, Vanderbilt University, Nashville, TN
Several 2015 publications involving mouse
models that examined blood counts and
underlying hematopoietic events have
advanced our understanding of both steadystate and emergency production rates for
platelets, neutrophils, and erythrocytes. These studies
provided insights that were specific to each of the three
bone marrow lineages. These newly identified regulatory
mechanisms suggest potential new approaches for treating
diseases that result in abnormal numbers of platelets,
neutrophils, or erythrocytes.
A newly described mechanism for rapid platelet production,
which occurs in emergency situations such as low circulating
platelet levels due to enhanced destruction or increased
platelet numbers from intense inflammation or infection,
is megakaryocytic rupture induced by interleukin-1α (IL1α).1 Sudden IL-1α–mediated release of larger-than-normal
platelets increases production rates by more than an order
of magnitude over the pro-platelet shearing mechanism
of steady-state platelet production.1 Both of these release
mechanisms require development of mature megakaryocytes
located adjacent to the vascular sinuses of the marrow, a
process regulated by thrombopoietin (TPO), the principal
growth factor for megakaryocytes that is produced mainly by
the liver. Aging of circulating platelets has been associated
with desialylation of surface glycoproteins, which in turn
leads to platelet removal from the circulation after binding
by asialoglycoprotein receptors on hepatocytes.2 The
bound asialoglycoprotein receptors in turn signal through
the JAK2-STAT3 pathway inducing TPO transcription,
thereby completing a feedback loop that maintains steadystate platelet numbers.2 Megakaryocyte rupture provides
explanations for increased platelet size and rapid recovery,
with potential overshoot thrombocytosis following correction
of platelet destruction processes. The asialoglycoproteinmediated removal of aged platelets and JAK2-STAT3-linked
production of TPO help explain thrombocytopenia associated
with JAK inhibitor therapy and rapid normalization of platelet
numbers after overshoot thrombocytosis. Both of these newly
described mechanisms may allow for future approaches to
treating thrombocytopenia with sequential TPO mimetics and
inducers of megakaryocytic rupture.
Despite brief intravascular life spans, neutrophils were
found to age in the circulation in response to products of
the gut microbiota that signal through Toll-like receptors
and myeloid differentiation factor-88.3 The more aged
neutrophils had increased tissue adhesiveness and proinflammatory activity, and their expanded population in
the chronic inflammation of a murine model of sickle cell
disease was reversed by antibiotic treatment of microbiome
organisms.3 During acute inflammation or infection, the
myeloid progenitor cell pool was shown to expand in
response to interstitial reactive oxygen species (ROS)
generated by phagocytic NADPH oxidase activity emanating
from adjacent mature myeloid cells in the marrow.4 This
ROS-mediated emergency granulopoiesis is related to PTEN
oxidation/inactivation and does not involve granulocyte
colony-stimulating factor (G-CSF).4 Therefore, it has
therapeutic potential beyond that provided by G-CSF and
granulocyte macrophage colony-stimulating factor (GM-CSF)
to raise neutrophil counts in acute situations of increased
demand such as sepsis. These new insights provide an
opportunity to test two hypotheses: 1) whether antibioticmediated suppression of gut microbiota can improve
chronic inflammatory states, and 2) whether pharmacologic
manipulation of the ROS-PTEN pathway can improve
emergency granulopoiesis in chronic granulomatous disease,
in which defective myeloid NADPH oxidase activity increases
susceptibility to bacterial infections.
Transferrin receptor-2 (TFR2) plays a role in hepcidin
transcription in liver when iron saturation of transferrin
is increased. TFR2’s function in erythroid cells, where it
had been shown to associate with erythropoietin (EPO)
receptors, was not known. However, CBCs of mice with
TFR2-deficient erythroid cells showed increased hemoglobin
owing to increased numbers of RBCs that had decreased
MCHs and MCVs, indicating that TFR2 restricts steady-state
erythropoiesis and maintains normal RBC size during iron
sufficiency, presumably by decreasing EPO responsiveness.5
In iron sufficiency therefore, TFR2 restricts both
erythropoietic iron supply via hepcidin-mediated control of
iron flux and erythropoietic use of iron. Conversely, in iron
deficiency, instability of unbound TFR2 leads to increased
iron absorption and flux via decreased hepcidin and
increased EPO responsiveness of erythroid cells. The method
by which increased EPO responsiveness coordinates with
other regulators of erythropoiesis in iron deficiency (such as
iron regulatory protein-1 (IRP-1) limiting EPO production and
heme-regulated inhibitor (HRI) limiting hemoglobin synthesis)
is unknown, but multiple levels of control are present in the
erythropoietic response to this common cause of anemia.
The emergency situation in anemia is tissue hypoxia, and
the erythropoietic response to anemia is termed “stress
erythropoiesis.” Renal EPO production has been extensively
studied in stress erythropoiesis. However, beginning at the
burst-forming unit-erythroid (BFU-E) stage and extending
to the proerythroblast stage of differentiation, non-EPO
mediators such as glucocorticoid hormones, stem cell factor,
and bone morphogenetic protein-4, can expand erythroid
progenitor cell populations without inducing differentiation.
Glucocorticoid-induced expansion of BFU-Es was shown to
involve a direct synergistic interaction between dexamethasone
and peroxisome proliferator-activated receptor-α (PPAR-α),6
whereas expansion of EPO-dependent erythroid progenitors,
colony-forming units-erythroid (CFU-Es) and proerythroblasts,
did not involve PPAR-α, suggesting that other mechanisms
are involved in glucocorticoid-mediated expansion of these
later differentiation stages. From the clinical standpoint,
enhancement of glucocorticoid-mediated erythropoietic activity
by PPAR-α agonists6 indicates that, when steroidal side effects
become problematic, PPAR-α agonists may allow reduced doses
of glucocorticoids. Such agonists could be particularly useful
in bone marrow failure syndromes such as Diamond-Blackfan
anemia, in which glucocorticoids are the mainstay of treatment.
Dr. Koury indicated no relevant conflicts of interest.
1. Nishimura S, Nagasaki M, Kunishima S, et al. IL-1α induces
thrombopoiesis through megakaryocyte rupture in response to
acute platelet needs. J Cell Biol. 2015;209:453-466.
2. Grozovsky R, Begonja AJ, Liu K, et al. The Ashwell-Morell receptor
regulates hepatic thrombopoietin production via JAK2-STAT3
signaling. Nat Med. 2015;21:47-54.
3. Zhang D, Chen G, Manwani D, et al. Neutrophil ageing is regulated
by the microbiome. Nature. 2015;525:528-532.
4. Kwak HJ, Liu P, Bajrami B, et al., Myeloid cell-derived reactive oxygen
species externally regulate the proliferation of myeloid progenitors in
emergency granulopoiesis. Immunity. 2015;42:159-171.
5. Nai A, Lidonnici MR, Rausa M, et al. The second transferrin
receptor regulates red blood cell production in mice. Blood.
2015;125:1170-1179.
6. Lee HY, Gao X, Barrasa MI, et al. PPAR-α and glucocorticoid
receptor synergize to promote erythroid progenitor self-renewal.
Nature. 2015;522:474-477.
I N
(Cont. from previous page)
intolerance so that their dosing can be refined, and periodic
monitoring for the emergence of acquired resistance so
that regimens could be modified to avert relapse, may be
additional beneficial strategies.
Dr. Raetz and Dr. Meyer indicated no relevant conflicts
of interest.
1. Bhatia S, Landier W, Hageman L, et al. 6MP adherence in a
multiracial cohort of children with acute lymphoblastic leukemia: a
Children’s Oncology Group study. Blood. 2014;124:2345-2353.
2. Bhatia S, Landier W, Hageman L, et al. Systemic exposure
to thiopurines and risk of relapse in children with acute
lymphoblastic leukemia: a Children’s Oncology Group study. JAMA
Oncol. 2015;1:287-295.
3. Yang JJ, Landier W, Yang W, et al. Inherited NUDT15 variant is a
genetic determinant of mercaptopurine intolerance in children
with acute lymphoblastic leukemia. J Clin Oncol. 2015;33:1235-1242.
4. Relling MV, Hancock ML, Rivera GK, et al. Mercaptopurine
therapy intolerance and heterozygosity at the thiopurine
S-methyltransferase gene locus. J Natl Cancer Inst.
1999;91:2001-2008.
M E M O R I A M
Dorothea Zucker-Franklin, MD (1929 – 2015)
Dr. Dorothea Zucker-Franklin, National Academy of Medicine member, pioneer in electron microscopy
of blood cells at New York University School of Medicine, and third female president of ASH (1995),
passed away November 24, 2015, at the age of 86. Dottie was born in Berlin, Germany, but fled to the
Netherlands with her family in 1936 to escape Nazism. There she attended the same school as Anne
Frank and was forced into hiding in 1943. Arriving destitute in New York in 1948, Dottie graduated
from Hunter College as class valedictorian and proceeded to attend New York Medical College on a
scholarship. Dottie and her husband, immunologist Dr. Edward Franklin, who was a childhood neighbor
from Berlin, enjoyed a close professional partnership until his death in 1982. The Franklins required
separate home offices since, when together, their constant conversation precluded working effectively.
However, together Dottie and Ed were able to accomplish a great deal. Aside from their professional
accomplishments, they raised their daughter Deborah, cared for their much loved farm in the Berkshires,
travelled internationally, and collected pre-Columbian sculptures. When visiting fellow Dr. Mordechai
Pras showed Dottie amyloid tissue, her fascination with amyloid’s birefringence convinced Ed that it
would be fun to learn more about this substance together. They jointly penned more than 20 articles
on amyloid, identified its fibrillary nature, and showed that precursor serum amyloid A was cleaved by
monocyte proteases, introducing the concept that cellular proteases modify amyloid in disease.
Dr. Steven D. Douglas of the University of Pennsylvania praised Dottie’s goal of juxtaposing numerous techniques to achieve “molecular
morphology,” as stated in her book, Atlas of Blood Cells. He noted that, “Dottie’s microscopy not only captured spectacular events in the
cell, but was a magnificent form of medical and biologic creative art. Her innovative observations spanned cell biology, hematology, and
immunology. With James Hirsch, she published the first evidence that neutrophil and eosinophil granules released their contents into the
phagocytic vacuole. This remarkable discovery ushered in modern understanding of phagocyte function.” Her later studies explored electron
microscopy of blood cells responding to cytokines, thrombopoietin, and HIV.
7. Ma X, Edmonson M, Yergeau D, et al. Rise and fall of subclones
from diagnosis to relapse in pediatric B-acute lymphoblastic
leukaemia. Nat Commun. 2015;6:6604.
Dr. Barry Coller, ASH president in 1998, wrote, “I was very fortunate to have Dr. Zucker-Franklin as my professor when I was a medical
student, my ward attending when I was a resident, and later (as “Dottie”) as my colleague and friend sharing a love for hematology.
She was an ideal role model as a physician-scientist, devoted to both her elegant electron microscopic studies and to her patients.
Megakaryocytes held a special place in her heart, as in mine! She set and met the highest standards for both research and clinical
activities.” Dr. Ralph Nachman commented that “Dottie was a dedicated perfectionist who took great pride in the clarity of her data,
particularly the impressive electron micrographs of platelets. She combined old fashioned morphology and molecular physiology.” Dr.
Kenneth Kaushansky, ASH President in 2008 added, “Dottie was a passionate hematologist, devoted to understanding the structure and
function of blood cells. Our scientific collaboration taught me a great deal about what many consider the most complicated and beautiful
cell in all of biology, the megakaryocyte.”
8. Li B, Li H, Bai Y, et al. Negative feedback-defective PRPS1 mutants
drive thiopurine resistance in relapsed childhood ALL. Nat Med.
2015;21:563-571.
–Barry Coller, MD, Vice-President for Research, Rockefeller University
–Steven D. Douglas, MD, Professor of Pediatrics, University of Pennsylvania
–Babette Weksler, MD, Professor Emerita of Medicine, Weill Cornell Medicine
5. Meyer JA, Wang J, Hogan LE, et al. Relapse-specific mutations in
NT5C2 in childhood acute lymphoblastic leukemia. Nat Genet.
2013;45:290-294.
6. Tzoneva G, Perez-Garcia A, Carpenter Z, et al. Activating mutations
in the NT5C2 nucleotidase gene drive chemotherapy resistance in
relapsed ALL. Nat Med. 2013;19:368-371.
14
The Hematologist:
ASH NEWS AND REPORTS
Editors’ Choice
SEPTEMBER 24, 2015
NOVE M B E R 5, 2015
Kassim AA, Payne AB, Rodeghier M, et al. Low forced
expiratory volume is associated with earlier death in sickle
cell anemia. Blood. 2015;126:1544-1550.
Kiyasu J, Miyoshi H, Hirata A, et al. Expression of
programmed cell death ligand 1 is associated with
poor overall survival in patients with diffuse large B-cell
lymphoma. Blood. 2015;126:2193-2201.
Pulmonary complications are a known contributor to
mortality in adults with sickle cell disease (SCD). In this
article, Dr. Adetola Kassim and colleagues present data
examining the prognostic significance of decreased
pulmonary function in a large prospective cohort of SCD
patients in the Cooperative Study for Sickle Cell Disease.
They confirm that a decreased forced expiratory volume
in 1 second percent (FEV1%) predicts for earlier death
in patients with SCD. Surprisingly, however, obstructive
or restrictive pulmonary function test abnormalities are
not predictive of earlier death. Further study is needed
to better understand the pathophysiology and negative
impact of decreased FEV1% in SCD patients.
Dr. Bob Löwenberg (Editor-in-Chief) and Dr. Nancy Berliner
(Deputy Editor-in-Chief) have combined efforts to identify some
of the most outstanding Blood articles that have appeared either
in print or online during the two-month interval between issues
of The Hematologist. The goal is to underscore the remarkable
research that is published in Blood and to highlight the exciting
progress that is being made in the field.
SEPTEMBER 10, 2015
Rapetti-Mauss R, Lacoste C, Picard V, et al. A mutation in the
Gardos channel is associated with hereditary xerocytosis.
Blood. 2015;126:1273-1280.
Glogowska E, Lezon-Geyda K, Maksimova Y, et al. Mutations
in the Gardos channel (KCNN4) are associated with
hereditary xerocytosis. Blood. 2015;126:1281-1284.
The Gardos channel is a Ca2+-sensitive potassium
channel that is widely expressed in tissues and cells,
including erythrocytes. It has been widely studied as a
potential regulator of cell volume that may be important
in hemoglobinopathies. In this week’s plenary papers,
Dr. Raphael Rapetti-Mauss and colleagues and Dr. Edyta
Glogowska and colleagues identify mutations in the KCNN4
gene, which encodes the Gardos channel, as the molecular
basis for a subset of hereditary xerocytosis and chronic
hemolytic anemia associated with dehydrated cells. These
studies confirm the importance of the Gardos channel
in maintaining erythrocyte hydration, and they offer a
potential clinical entry point for treatment of this rare
syndrome.
S E P T E M B E R 1 7, 2 0 1 5
Donadieu J, Bernard F, Noesel Mv, et al. Cladribine and
cytarabine in refractory multisystem Langerhans cell
histiocytosis: results of an international phase 2 study.
Blood. 2015;126:1415-1423.
Dr. Jean Donadieu and colleagues present the most
promising treatment data to date in a group of patients
with Langerhans cell histiocytosis (LCH) who historically
have had a notoriously unfavorable survival. The
investigators applied a standardized disease activity
score to follow and evaluate these patients on therapy.
They report their encouraging results of an intensive
chemotherapy regimen of cladribine and cytarabine in
a multicenter trial in children with disease of the bone
marrow, liver, or spleen who were refractory to standard
therapy.
Zhu S, Travers RJ, Morrissey JH, et al. FXIa and platelet
polyphosphate as therapeutic targets during human blood
clotting on collagen/tissue factor surfaces under flow.
Blood. 2015;126:1494-1502.
Factor XIIa (FXIIa) and FXIa contribute to thrombosis in
animal models, while platelet-derived polyphosphate
(polyP) may potentiate contact or thrombin-feedback
pathways. Dr. Shu Zhu and colleagues discovered that
platelet-derived polyP plays a significant role in human
whole blood that is distinct from FXIIa activation and
thrombin generation through feedback activation of FXI.
polyP directly interacts with fibrin in a way that makes the
thrombus less susceptible to lysis by fibrinolytic agents.
The way in which FXIa and polyP contribute to thrombus
formation in human blood and the fact that blocking polyP
reduces thrombus stability and increases lysis of the fibrin
clot suggest that polyphosphate inhibitors are among the
most interesting candidate antithrombotic therapeutic
agents.
The Hematologist:
ASH NEWS AND REPORTS
OCTOB E R 1, 2015
Bernard S, Goldwirt L, Amorim S, et al. Activity of ibrutinib in
mantle cell lymphoma patients with central nervous system
relapse. Blood. 2015;126:1695-1698.
A substantial proportion of patients with aggressive forms
of mantle cell lymphoma develop central nervous system
(CNS) metastasis, which is notoriously difficult to treat. In
their article, Dr. Sophie Bernard and colleagues provide
evidence that ibrutinib, an orally administered inhibitor of
Bruton tyrosine kinase, crosses the blood-brain barrier and
has significant therapeutic activity in CNS disease of mantle
cell lymphoma.
OCTOB E R 22, 2015
Gill JC, Castaman G, Windyga J, et al. Hemostatic efficacy,
safety, and pharmacokinetics of a recombinant von
Willebrand factor in severe von Willebrand disease. Blood.
2015;126:2038-2046.
Dr. Joan Gill and colleagues present the results of a phase
III trial of recombinant von Willebrand factor (rVWF) for
treatment of bleeds in patients with severe von Willebrand
disease (vWD). Their results confirm that rVWF is safe and
highly effective for the control of bleeding. Since patients
with severe vWD are initially factor VIII (FVIII) deficient as
well because VWF stabilizes FVIII, the first dose of rVWF
was administered with FVIII. Later FVIII dosing proved to
be unnecessary, as endogenous stores recovered upon
administration of rVWF. Bleeding control was achieved in
97 percent of bleeds, and only one infusion was required
in more than 80 percent of bleeding episodes. These
encouraging results represent a major breakthrough in the
treatment of vWD.
Moretti D, Goede JS, Zeder C, et al. Oral iron supplements
increase hepcidin and decrease iron absorption from
daily or twice-daily doses in iron-depleted young women.
2015;126:1981-1989.
The appropriate oral treatment of iron deficiency is
codified and rarely questioned, but perhaps it should be.
In this article, Dr. Diego Moretti and colleagues report
on a study of iron administration that is based on the
current understanding of iron metabolism and may be
practice-changing. Since serum iron levels are one factor
regulating hepcidin, they postulate that absorption of iron
supplements could paradoxically induce hepcidin and
inhibit further iron absorption. Using a clever strategy of
differing iron doses labeled with different Fe isotopes, they
document that this is in fact the case. They demonstrate
that iron supplements of 60 mg of iron or more increase
hepcidin for up to 24 hours, impairing subsequent iron
absorption. They suggest that alternate-day single doses
of iron could improve the efficacy of oral iron therapy,
allowing a welcome reduction in gastrointestinal side
effects; confirmation awaits an appropriate clinical trial.
The PD-1/PD-L1 pathway inhibits host antitumor responses
in a wide variety of malignancies. However, since PD-1
is normally expressed on lymphocytes within the lymph
node, the potential role of this pathway in lymphoma
is complex. Dr. Junichi Kiyasu and colleagues report
an in-depth study of the expression of PD-1 and PD-L1
in diffuse large B-cell lymphoma (DLBCL) cells and the
surrounding microenvironment. They demonstrate that
11 percent of DLBCLs manifest PD-L1 expression on the
tumor cells and that this has a negative impact on overall
survival. In contrast, expression of PD-L1 by infiltrating
lymphocytes within the microenvironment does not affect
survival. This suggests that targeting this pathway with
checkpoint inhibitors may be a therapeutic option in this
subset of DLBCL patients.
Sun C, Tian X, Lee YS, et al. Partial reconstitution of
humoral immunity and fewer infections in patients with
chronic lymphocytic leukemia treated with ibrutinib. Blood.
2015;126:2213-2219.
Chronic lymphocytic leukemia (CLL) is associated with
hypogammaglobulinemia and immune dysregulation,
which contribute to increased infections. The Bruton
tyrosine kinase (BTK) inhibitor ibrutinib is a recently
approved novel agent that induces a high rate of response
in CLL. However, congenital loss of BTK results in Bruton
agammaglobulinemia, a severe B-cell defect, suggesting
that BTK is also critical to normal B-cell function. In this
article, Dr. Clare Sun and colleagues assess the impact of
ibrutinib on normal B-cell function in patients with CLL,
and demonstrate that the BTK inhibitor allows partial
reconstitution of normal B cells and humoral immunity at
12 months. Since patients are treated with ibrutinib longterm, further follow-up is needed to assess the full extent
of immune reconstitution and its impact on infectious
outcomes.
NOVE M B E R 12, 2015
Hur WS, Mazinani N, Lu XJD, et al. Coagulation factor XIIIa is
inactivated by plasmin. Blood. 2015;126:2329-2337.
This article resolves years of conflicting results regarding
the inactivation of factor XIIIa (FXIIIa) by plasmin. Dr.
Woosuk Hur and colleagues demonstrate that plasmin
inactivates activated blood coagulation factor XIIIa, but not
zymogen factor XIII (FXIII). They also show that FXIIIa is
inactivated during clot lysis but not during clot formation.
NOVE M B E R 19, 2015
Kwok B, Hall JM, Witte JS, et al. MDS-associated somatic
mutations and clonal hematopoiesis are common in
idiopathic cytopenias of undetermined significance. Blood.
2015;126:2355-2361.
Cargo CA, Rowbotham N, Evans PA, et al. Targeted
sequencing identifies patients with preclinical MDS at high
risk of disease progression. Blood. 2015;126:2362-2365.
Increasingly, clinicians are obtaining molecular genetic
tests when evaluating patients with unexplained
cytopenias. How is one to interpret the detection of clonal
hematopoiesis in the absence of dysplastic changes in
the bone marrow? If a clonal mutation is discovered,
yet diagnostic criteria for a hematological neoplasm are
not met, what is the diagnosis? Dr. Brian Kwok et al and
Dr. Catherine Cargo and colleagues report results of
mutation testing in two series of patients with cytopenia
and nondiagnostic marrows. These two plenary papers
demonstrate that the answer is challenging and that
the appropriate interpretation of positive mutation
testing in patients without evidence of dysplasia is not
straightforward.
15
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The ASH Pocket Guides app includes interactive versions of all the
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guide contents, the app includes tools to aid in clinical decision
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