SAN DIEGO, Dec. 1, 2018 /PRNewswire/ -- Today at the
60th American Society of Hematology (ASH) Annual Meeting and
Exposition in San Diego,
researchers will announce findings from four studies that could
greatly expand access to both curative and supportive treatments
for individuals living with sickle cell disease (SCD)
worldwide.
The results of two first-in-human trials suggest promising
initial results for ground-breaking approaches to stem cell
transplantation and gene therapy for SCD. Another, the largest
prospective trial of hydroxyurea ever conducted in Africa, suggests that this drug –– long the
standard of care for SCD in developed countries ––is safe and
effective and can confidently be used in low-resource countries.
Additionally, a large-scale study of in-hospital death rates
provides reassurance that opioid medications may safely be used to
treat acute SCD-related pain in the hospital.
"Taken together, these results will enhance clinicians' ability
to offer a range of therapeutic options to patients living with SCD
in all parts of the world," said press briefing moderator
Ifeyinwa Osunkwo, MD, MPH, of Atrium
Health's Levine Cancer Institute in Charlotte, NC. "They show that investment in
SCD research has the potential to improve the lives of millions of
affected individuals across the globe."
Individuals with SCD, an inherited blood disease, produce
abnormal hemoglobin, a protein in red blood cells that attaches to
oxygen in the lungs and carries it to all parts of the body. Red
blood cells that contain normal hemoglobin are donut-shaped and
flexible so that they can travel smoothly through the smallest
blood vessels. In SCD, however, the red blood cells are
sickle-shaped and rigid and can get stuck in these vessels,
blocking the flow of blood and oxygen to the body and leading to
intense pain and other serious issues such as stroke, infection,
pulmonary complications, and even death.
Supporting SCD research and access to care is a chief priority
for ASH, which in 2016 launched a multifaceted initiative to
address the burden of this disease both in the United States and globally. "ASH is
committed to accelerating the development of new therapies for this
community, which currently has had very few treatment modalities
and even fewer curative options," said Dr. Osunkwo. "The results
being presented today demonstrate that we are indeed on the brink
of a new era in SCD research and treatment."
This press conference will take place on Saturday, December 1, at 7:30 a.m. PST in Room 22, San Diego Convention Center.
Novel Parental-Donor Stem Cell Transplant Technique Shows
Promise in Sickle Cell Disease
Significantly Improved
Long Term Health Related Quality of Life (HRQL) and
Neurocognition Following Familial Haploidentical Stem Cell
Transplantation (HISCT) Utilizing CD34 Enrichment and
Mononuclear (CD3) Addback in High Risk Patients with Sickle
Cell Disease (SCD) [162]
In a new study, ninety percent of young people with SCD who
received blood-forming stem cells from a parent were alive and
healthy one year later, free of symptoms and complications. They
did not need to take immune-suppressive medications, and in some
instances their cognitive processing speed — that is, how quickly
they were able to learn, think, and communicate — in some instances
improved.
With a median follow-up of over three years, there have been no
recurrences of sickle cell pain crises, no patients have required
blood transfusions, and no new patients have developed
graft-versus-host disease (GVHD), a complication in which
transplanted cells attack healthy tissues and organs, said lead
study author Mitchell Cairo, MD, of
New York Medical College in
Valhalla, NY.
"These individuals have a completely new lease on life," Dr.
Cairo said. "They're either stable or better in every organ system.
What's more, this could mean that every person with SCD who has a
living parent could have a potential donor in their family."
Currently, the only cure for SCD is a stem cell transplant using
cells donated by a brother or sister who has the same tissue type,
has the same mother and father, and is SCD-free. According to Dr.
Cairo, only about one in six patients with SCD has a suitable
sibling donor.
This study focused on a newer, modified form of stem cell
transplant in which the donor's bone marrow needs to be only 50
percent the same as the recipient's. In this type of transplant,
known as a haploidentical transplant, the patient's mother or
father can be the stem cell donor. In previous studies of
haploidentical transplants for SCD, however, the rate of transplant
failure has been high.
Dr. Cairo and his team sought to reduce both the rate of
transplant failure and the risk of serious post-transplant
complications by enriching stem cells with a type of protein called
CD34 that is understood to be important in promoting the acceptance
of transplanted blood-forming cells. In addition, they added back
the patients' T cells (after the transplant). T cells are a type of
immune cell that has also been shown to promote the acceptance of
transplanted blood-forming cells while not increasing rates of
GVHD.
In this study, 19 patients age 3-20 with frequent or severe SCD
symptoms received transplanted stem cells; 15 patients received
cells from their mothers, and four from their fathers.
Engraftment, wherein the transplant recipient's body accepts the
new stem cells and the stem cells begin to produce new blood and
immune cells, is one of the first steps in a successful stem cell
transplant, and it occurred in all 19 patients in the study.
Chimerism is a measure of the durability of engraftment. Full
donor chimerism means that 100 percent of the cells in the
patient's bone marrow and blood have developed from the donor's
stem cells. Mixed chimerism means that some of the transplant
recipient's own cells are also present in the bone marrow and
blood. At one year following the transplant, the rate of chimerism
was 97 percent. One patient developed acute GVHD within 100 days of
the transplant and another developed chronic GVHD more than 100
days after the transplant.
Follow-up tests performed two years after the transplant showed
that patients had stable or improved heart and lung function.
Imaging tests showed no evidence of strokes or inflammation of
blood vessels in the brain, two potentially serious complications
of SCD. Tests of memory, language, intellectual functioning, and
ability to plan, focus on tasks, and manage emotions all showed
stability or improvement.
These results suggest that nearly 90 percent of patients (17 of
19) with SCD will go on to lead normal lives after undergoing a
stem cell transplant that incorporates the techniques researchers
used in this study, Dr. Cairo said. He cautioned, however, that the
procedure is not successful in all patients, adding that whether
patients will develop late adverse effects is not yet known. Dr.
Cairo and his team have received funding to continue to follow this
group of patients for another three years to assess the risk of
long-term complications.
This study was supported by the U.S. Food and Drug
Administration.
Mitchell Cairo, MD,
New York Medical College, will
present this study during an oral presentation session on
Saturday, December 1, at 12:00
noon PST, Room 24B, San Diego
Convention Center.
Novel Approach to Gene Therapy for SCD Shows Promise in Pilot
Trial
Flipping the Switch: Initial Results of Genetic
Targeting of the Fetal to Adult Globin Switch in Sickle Cell
Patients [1023]
One adult patient with SCD is doing well after receiving an
infusion of his own stem cells in which a genetic "switch" was
flipped on to induce the cells to both start producing healthy
hemoglobin and stop producing unhealthy (sticky or harmful)
"sickle" hemoglobin, according to a new study. This first-in-human
pilot study provides a proof of principle for this novel approach
to gene therapy for SCD, said lead study author Erica B. Esrick, MD, hematologist at
Dana-Farber /Boston Children's
Cancer and Blood Disorders Center.
"This is the first gene therapy trial in any disease –– not just
in SCD –– to use this novel engineering strategy," Dr. Esrick said.
"Although only one patient has so far completed treatment, the
results we're seeing are very encouraging and support the promising
preclinical data that were the basis for this trial."
Currently, the only established cure for SCD is a transplant of
healthy stem cells from a matched sibling donor. However, many
patients with SCD do not have a suitable sibling donor and
sometimes stem cell transplants may fail. Gene therapy is an
alternative approach that uses the patient's own stem cells and
does not rely on the availability of a compatible donor.
This novel technique for gene therapy for SCD is inspired by
changes observed in hemoglobin before and after birth. Fetuses in
the womb need to extract oxygen from their mother's circulation.
For this purpose, they have a special type of hemoglobin known as
fetal hemoglobin that accepts and releases oxygen at lower
blood and tissue oxygen levels compared with adult hemoglobin. Soon
after birth, a switch is turned off and fetal hemoglobin begins to
be replaced by adult hemoglobin –– or, in infants with SCD, with
sickle hemoglobin.
Researchers have long recognized that fetal hemoglobin inhibits
the development of sickle hemoglobin polymers, the basis of sickled
cells, from forming. More recently, preclinical research from
Boston Children's Hospital has shown that suppressing the action of
a protein known as BCL11A can reverse SCD by reactivating fetal
hemoglobin production.
In the current study, David
Williams, MD, chief scientific officer at Boston Children's
Hospital, and colleagues devised a technique to genetically
engineer an inactivated virus to deliver a gene that blocks the
action of BCL11A in red blood cells using the cell's own machinery
called a microRNA. The key feature of the new approach is targeting
BCL11A with a structure they named a shMIR.
"We are in effect providing the cells with instructions to stop
producing sickle hemoglobin and start producing fetal hemoglobin
instead," Dr. Esrick said.
To date, four adult patients have been enrolled in the trial,
with one having received this gene therapy. This patient, who,
prior to transplant, required monthly blood transfusions to
alleviate SCD symptoms, has required only a single transfusion in
the six months following treatment, with no transfusions required
following engraftment. Blood tests show high levels of fetal
hemoglobin in this patient.
"He has had no pain or other symptoms that could be attributed
to SCD," Dr. Esrick said. "He's back to his normal life."
Two other patients are awaiting transplant, with the fourth
patient set for stem cell collection by year-end.
This study was funded by the National Institutes of
Health.
Erica B. Esrick, MD,
Dana-Farber/Boston Children's
Cancer and Blood Disorders Center, will present this study during
an oral presentation session on Monday,
December 3, at 6:15 p.m. PST,
Room 6B, San Diego Convention Center.
Large Single-Arm Trial Finds Hydroxyurea for SCD Feasible,
Safe, and Beneficial for Children in Sub-Saharan Africa
Realizing Effectiveness Across Continents with Hydroxyurea
(REACH): A Prospective Multi-National Trial of Hydroxyurea for
Sickle Cell Anemia in Sub-Saharan Africa [3]
The largest prospective trial of hydroxyurea for sickle cell
anemia (SCA), a severe form of SCD, has shown that this drug — long
the standard of care for treating SCA in developed countries — is
feasible, accepted, well tolerated, and safe for children living in
sub-Saharan Africa. Researchers report that there are distinct
clinical benefits for children receiving hydroxyurea.
After a median of 2.5 years of treatment, children in the trial
experienced less pain and anemia, fewer episodes of malaria and
other infections, and lower rates of transfusions and death
compared with rates during the pre-treatment screening phase of the
trial.
"Because of its positive impact on anemia, clinical events, and
quality of life, hydroxyurea can now be considered for routine care
of children with sickle cell anemia in Africa," said lead study author Leon Tshilolo,
MD, PhD, of the Centre Hospitalier Monkole in Kinshasa, Democratic
Republic of the Congo.
Though some previous studies had suggested that hydroxyurea
treatment might put children at higher risk for malaria by
suppressing the immune system, which defends the body against
infections, this study found that not to be the case.
"We're very encouraged by the fact that we saw reductions in the
rates of malaria and other infections," said Dr. Tshilolo. "This
suggests that hydroxyurea doesn't cause suppression of the immune
system in treated children and therefore doesn't increase their
risk for malaria or other infectious diseases."
Ample data support the value of hydroxyurea treatment for
children with SCA who live in high-resource countries such as
the United States, the
United Kingdom, and European
countries, Dr. Tshilolo said. However, prior to this study, data
were lacking on the drug's benefits for children living in
sub-Saharan Africa, where the burden of SCA is highest and rates of
malaria and other infectious diseases, as well as undernutrition
and poverty, are extremely high.
A total of 635 children ages between 1-10 from four African
countries — Angola, the
Democratic Republic of the Congo,
Kenya, and Uganda — were enrolled in the trial. Four
children died during a two-month screening period before treatment
began; 25 other children withdrew from the trial for other reasons
during the screening period.
The remaining 606 children began six months of treatment with a
modest dose of hydroxyurea. After six months, if no adverse effects
were observed, the dose was gradually increased, based on weight
and other criteria, to a maximum tolerated dose (MTD), or the
highest dose that could be given without adverse effects being
seen.
Five percent of treated patients dropped out of the trial or
died. Ninety-seven percent of the remaining completed all scheduled
study visits and 94 percent completed all the required laboratory
tests. The rate of toxicities was similar between the screening
period and the treatment phase. Patients received the hydroxyurea
capsules, all lab tests, and transportation to clinic visits at no
charge, which may have contributed to the high rates of retention
and adherence to treatment. The close monitoring for adverse
effects that children received throughout the trial may also have
contributed to the benefits of treatment observed in the study, Dr.
Tshilolo said.
Dr. Tshilolo and his colleagues plan to continue to follow the
children in this study for several years to observe the effects of
hydroxyurea treatment on their growth and sexual development, as
well as on the function of organs such as the brain, liver, spleen,
and kidneys, and the children's intellectual performance as they
get older.
The costs of hydroxyurea treatment and associated laboratory
monitoring will be a major factor limiting more widespread use of
the drug to treat SCA in Africa.
"The current cost of treatment is beyond the daily wage of most
families living in sub-Saharan Africa," Dr. Tshilolo said. "We hope
that treatment will be made available to more patients through
outside financial support, as is the case with treatment for HIV
infection in several African countries."
This study was supported by the National Heart, Lung, and
Blood Institute (a component of the National Institutes of Health)
and the Cincinnati Children's Research Foundation.
Bristol-Myers Squibb donated the
hydroxyurea capsules.
Leon Tshilolo, MD, PhD, Centre Hospitalier Monkole,
Kinshasa, Democratic Republic of the Congo, will present
this study during the Plenary Scientific Session on Sunday, December 2 at 2:00
p.m. PST, Hall AB, San
Diego Convention Center.
Study Finds No Link Between Opioid Use and Death in Patients
Hospitalized for Sickle Cell Disease
Opioid Use Is Not
Associated with in-Hospital Mortality Among Patients with Sickle
Cell Disease in the United States:
Findings from the National Inpatient Sample [315]
Attacks of excruciating pain are the most common cause of
hospital admission among patients with SCD, and opioid medications
are a mainstay of treatment for these attacks, known as pain
crises. Researchers at Boston University
School of Medicine wanted to know whether the U.S. opioid
epidemic, which has resulted in a marked increase in opioid-related
overdoses and deaths over the past two decades, may have affected
the death rate among people with SCD who were treated with opioids
in the hospital to relieve these pain crises.
A new study analyzing data from a large database on hospital
inpatients appears to show that the use of opioid medications for
pain control in patients with SCD is relatively safe, said lead
investigator Oladimeji A. Akinboro,
MBBS, of the Boston University School of
Medicine.
In-hospital death rates among those with SCD did not increase
over a 15-year period despite an increase in hospitalization rates
for most adults with SCD over the same period, Dr. Akinboro
said.
"We do not see a relationship between opioid use and death in
patients who are hospitalized for SCD," he said, adding that the
overwhelming majority of patients with SCD need strong pain
medication to control acute pain during crises.
"Adults with SCD are hospitalized frequently," he added. "We
expected that if opioid-related mortality had increased in this
population, the increase would be apparent in hospital inpatient
mortality data. It is reassuring to find that opioid use during
acute pain crisis does not seem to have led to higher mortality in
this population."
The hallmark of SCD is stiff, sickle-shaped red blood cells that
don't flow smoothly through the blood vessels as normal red blood
cells do. A pain crisis occurs when these sickle-shaped red blood
cells get stuck in blood vessels, slowing or blocking blood flow
and preventing oxygen from reaching all parts of the body.
Dr. Akinboro and his colleagues analyzed data from the National
Inpatient Sample, the largest publicly available all-payer
inpatient health care database in the
United States, which contains data from more than 7 million
hospital stays each year. They identified more than 1.7 million
hospitalizations for patients with SCD between 1998-2013. They
examined rates of hospitalization and in-hospital death both for
this entire patient population and for specific age groups (0-17
years, 18-44 years, 45-64 years, and 65 years and over) and by the
region of the country where patients were hospitalized (Northeast,
Midwest, South, or West).
The analysis found no significant increase in the rate of
in-hospital death among those with SCD over the 15-year period
examined. By contrast, the death rate related to prescription
opioids among the U.S. population without SCD increased 350 percent
between 1999-2013.
Overall, the hospitalization rate for patients with SCD declined
from 39 per 100,000 people in 1998 to 27 per 100,000 in 2002 and
did not change significantly from 2002-2013. Among adults in the
18–44 age group, however, the hospitalization rate increased
significantly, from 43 per 100,000 in 2002 to 71 per 100,000 in
2013. For adults ages 65 and over, the hospitalization rate also
increased significantly, from 2.7 per 100,000 in 1998 to 5.4 per
100,000 in 2013.
According to subgroup analysis, the rates of opioid-related
hospitalizations relative to the total number of hospitalizations
in the sickle cell population were stable over time and similar to
the relative rates in the general population. However, unlike in
the general population in which inpatient deaths from
opioid-related admissions increased over time, inpatient deaths
related to opioid toxicity and/or overdose were almost non-existent
over the entire study period. This further reinforces the study
conclusions that opioid use for pain control should be considered
safe in the sickle cell disease population, according to Dr.
Akinboro.
Dr. Akinboro said further research is needed to clarify the
reasons why hospitalization rates climbed in these two age groups,
but he suspects one reason may be lack of coordination of medical
care for adults with SCD. Another possible explanation is that
people with SCD are now living longer than they did in the past and
are developing other health problems as they age, he
said.
"One important message from this study is that health care
providers need to keep tabs on their patients with SCD and make
sure that their care is coordinated," he said.
Oladimeji A. Akinboro, MBBS,
Boston University School of Medicine,
will present this study during an oral presentation session on
Sunday, December 2, at 7:30 a.m. PST, Room 28D, San Diego Convention Center.
The study authors and press program moderator will be available
for interviews after the press conference or by telephone.
Additional press briefings will take place throughout the meeting
on large-scale practice-changing clinical trials, lasting results
in CAR T-cell therapies, and looking to the future in the era of
personalized medicine. For the complete annual meeting program and
abstracts, visit http://www.hematology.org/annual-meeting. Follow
@ASH_hematology and #ASH18 on Twitter and Instagram, and like ASH
on Facebook for the most up-to-date information about the 2018 ASH
Annual Meeting.
The American Society of Hematology (ASH) (www.hematology.org) is
the world's largest professional society of hematologists dedicated
to furthering the understanding, diagnosis, treatment, and
prevention of disorders affecting the blood. For 60 years, the
Society has led the development of hematology as a discipline by
promoting research, patient care, education, training, and advocacy
in hematology. The Society publishes Blood
(www.bloodjournal.org), the most cited peer-reviewed publication in
the field, as well as the newly launched, online, open-access
journal, Blood Advances.
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SOURCE American Society of Hematology