Medical Marijuana
Giving GVHD a Run
for Its Money
Graft-versus-host disease (GVHD) is a serious
obstacle to successful allogeneic hematopoietic
cell transplantation (alloHCT), and cannabidiol
(CBD) may decrease GVHD incidence and
severity after alloHCT, according to results of a
phase II study conducted in Israel. 1
The investigators, led by Moshe Yeshurun,
MD, of the Institute of Hematology at the
Rabin Medical Center in Petah-Tikva, enrolled
48 patients, most of whom had acute leuke-
mia or myelodysplastic syndromes. Of those,
nearly three-fourths underwent a pre-alloHCT
myeloablative conditioning regimen.
GVHD prophylaxis consisted of cyclospo-
rine and short-course methotrexate, and
all patients receiving a transplant from an
unrelated donor were given low-dose anti–
T cell globulin. Patients received oral CBD
300 mg/day, starting seven days before
alloHCT until 30 days post-alloHCT.
After a median follow-up of 16 months,
none of the patients developed acute GVHD
while consuming CBD. The cumulative
incidence rates of grades 2-4 and grades 3-5
acute GVHD by day 100 were 12.1 percent and
5 percent, respectively, the authors reported.
Compared with 101 historical control patients
who received standard GVHD prophylaxis
alone, the addition of CBD reduced the risk
of developing grades 2-4 acute GVHD by 70
percent (p=0.0002).
One year after alloHCT, researchers found
that rates of non-relapse mortality at 100 days
were 8.6 percent and 13.4 percent, respectively.
Among patients who survived longer than 100
days, the cumulative incidences of moderate to
severe chronic GVHD at 12 and 18 months were
20 percent and 33 percent, respectively.
The investigators reported good compliance,
with 70 percent of patients taking 100 percent
of CBD doses. The main reasons for noncompli-
ance were mucositis and nausea, and no grade
3-4 toxicities were attributed to CBD.
Although the study had some limitations
– a single-arm design and retrospective
comparison with historical controls – the
results highlight “the potential role of CBD
in the prevention of GVHD,” according to the
investigators. The same investigators are
planning another phase II study evaluating
the efficacy of oral CBD for the treatment of
severe (grades 3/4) acute GVHD. That inter-
ventional study will assign patients to one of
three arms: oral CBD (150 mg up to 90 days),
intravenous methylprednisolone (2 mg/kg/day),
and cyclosporine (dose adjusted based on
drug trough levels; 200-400 ng/mL) or tacro-
limus (dose adjusted on drug trough levels;
5-15 ng/mL). 2
The trial’s primary outcome will be the pro-
portion of patients with complete remission of
acute GVHD at 90 days. As of November 2017,
the study was not yet open for patient recruit-
ment, but the estimated primary completion
date is April 2018.
REFERENCES
1. Yeshurun M, Shpilberg O, Herscovici C, et al. Cannabidiol for
the prevention of graft-versus-host-disease after allogeneic
hematopoietic cell transplantation: results of a phase II study. Biol
Blood Marrow Transplant. 2015;21:1770-5.
2. ClinicalTrials.gov. “Cannabidiol for the treatment of severe (grades
III/IV) acute graft-versus-host disease.” Accessed November 2, 2017,
from https://clinicaltrials.gov/ct2/show/study/NCT02392780.
110
ASH Clinical News
other health-care professionals and researchers about
medical marijuana for patients with hematologic diseases,
including patient and provider attitudes and the chal-
lenges of answering clinical questions about the therapy.
Cannabis: A Wacky Tobacky
According to the FDA, the term “medical marijuana”
refers to using the whole, unprocessed marijuana plant
or its basic extracts to treat symptoms of illnesses. 5
Although the FDA has not recognized or approved the
botanical marijuana plant or any product containing it
as a medicine, researchers have studi ed the medicinal
value of cannabinoids (the chemicals in marijuana) and
cannabinoid-based products.
Scientists have identified more than 525 constituents
in the cannabis plant, including about 100 different can-
nabinoids. 1 The most psychoactive cannabinoid is delta-
9-tetrahydrocannabinol (THC), and the second most
active component is cannabidiol (CBD). The cannabis
plant has two main subspecies: Cannabis indica, which
has the higher CBD content, and Cannabis sativa, which
has the higher THC content. 5
When a person ingests cannabis, the active ingredi-
ents attach to binding sites (cannabinoid receptor type
1 and type 2 [CB1R and CB2R]) throughout the body.
CB1R sites are primarily located in the brain, but they
also appear in the liver, thyroid, bones, peripheral ner-
vous system, and testicles; CB2R sites are mostly found in
immune cells, the spleen, and the gastrointestinal system,
but they also appear in the brain and peripheral nervous
system. The receptors have also been shown to play a role
in regulating serotonin transporter activity.
Although the medical marijuana community has
come up with creative ways to deliver the agent, the most
common is through inhalation: Cannabis is smoked or
vaporized, and the THC enters the bloodstream and
quickly makes its way to the brain. However, the effects of
inhaled marijuana generally fade just as quickly.
Cannabis can also be delivered in “edibles” – baked
goods, candies, and other foods infused with cannabis
extracts and tinctures. With ingested cannabis, THC
absorption can take hours. Once it is absorbed, THC is
processed in the liver, producing a substance that acts on
the brain to alter mood or consciousness. 6
“[Patients] need
... palliative care
delivered alongside
aggressive treatment;
medical cannabis
represents one option
for palliative care.”
—DAVID CASARETT, MD
The Wonder Drug?
The effects of cannabis’ psychoactive compounds make it
an obvious candidate for managing the side effects of can-
cer treatment. “Cannabis is useful in combatting anorex-
ia, chemotherapy-induced nausea and vomiting, pain,
insomnia, and depression,” explained Donald Abrams,
MD, chief of hematology/oncology at San Francisco
General Hospital in California. “[It] might be less potent
than other available anti-emetics, but for some patients, it
is the only agent that works, and it is the only anti-emetic
that also increases appetite.”
In a trial of patients with advanced cancer and impaired
chemosensory perception, those who received THC
capsules reported that they had enhanced chemosensory
perception, better pre-meal appetite, and that food “tasted
better.” 7
A systematic review of cannabis-derived products
indicated that cannabinoids were more effective than
several anti-emetics; patients also preferred to use can-
nabinoids over traditional anti-emetics for future che-
motherapy cycles. 8 However, another review found that
adverse events (AEs) were more intense and occurred
more frequently in patients using cannabinoids versus
traditional anti-emetics. 9
The FDA has approved two cannabinoid-based
drugs for the treatment of chemotherapy-related nausea
and vomiting: dronabinol and nabilone. 3,4 The active
ingredient in each is a synthetic version of delta-9-
THC, a cannabinoid naturally occurring in Cannabis
sativa. Dronabinol is also approved for the treatment
of anorexia-associated weight loss in patients with
AIDS. The approval language states that dronabinol and
nabilone be used to manage nausea and vomiting only
after patients have tried conventional anti-emetic agents.
Researchers also have high hopes for cannabinoids’ pal-
liative effects in other diseases, including sickle cell disease
(SCD), characterized by chronic pain. In a study presented
at the 2016 ASH Annual Meeting, Nene Kalu, MSW, a so-
cial worker at the Center for Sickle Cell Disease at Howard
University in Washington, D.C., and colleagues assessed
the prevalence of marijuana use and hydroxyurea use (the
only FDA-approved therapy for SCD at the time of study)
in 103 SCD patients. 10 Patients completed questionnaires
about their use of marijuana or hydroxyurea during steady
states and during moderate to severe pain crises.
More than half of patients (56%) said they had used
both drugs, whereas 44 percent said they had only
used marijuana. Thirty percent stated they had used
marijuana within the past 12 months to relieve symp-
toms associated with SCD, such as boosting appetite,
improving sleep, elevating mood and concentration,
relieving stress and anxiety, and alleviating pain. How-
ever, 80 percent of participants stated that marijuana
was not as effective as hydroxyurea in managing their
SCD-related pain.
For a closer look at an emerging indication for pa-
tients with hematologic malignancies, see the SIDEBAR .
High and Dry
To gather clinical data on cannabis’ therapeutic uses,
researchers need to conduct more studies – a point the
DEA agrees with – but the agency also firmly believes
that cannabis has no medicinal value.
To expand research opportunities, though, the agency
said it “will allow additional entities to apply to become
registered with [the] DEA so that they may grow and
distribute marijuana for FDA-authorized research.” The
DEA will oversee the new growers and ensure that trials
are “scientifically valid and well-controlled.” 2
Because of the lack of long-term, randomized clinical
trials of cannabis in patient populations, a full under-
standing of how and why natural cannabis works still
eludes investigators. The restrictions have also hampered
further development of synthetic cannabinoid-based
products.
Given the federal government’s continued chokehold
on cannabis use, “to do randomized, placebo-controlled
clinical trials is very difficult,” Dr. Abrams said, adding
December 2017