Accepted Manuscript Cannabidiol for the Prevention of Graft-Versus-Host-Disease after Allogeneic Hematopoietic Cell Transplantation: Results of a Phase II Study Moshe Yeshurun, MD, Ofer Shpilberg, MD, MPH, Corina Herscovici, MD, Liat Shargian, MD, Juliet Dreyer, Anat Peck, Moshe Israeli, PhD, Maly Levy-Assaraf, PhD, Tsipora Gruenewald, M.Ph.Sc, Raphael Mechoulam, PhD, Pia Raanani, MD, Ron Ram, MD PII:
S1083-8791(15)00375-4
DOI:
10.1016/j.bbmt.2015.05.018
Reference:
YBBMT 53871
To appear in:
Biology of Blood and Marrow Transplantation
Received Date: 31 March 2015 Accepted Date: 21 May 2015
Please cite this article as: Yeshurun M, Shpilberg O, Herscovici C, Shargian L, Dreyer J, Peck A, Israeli M, Levy-Assaraf M, Gruenewald T, Mechoulam R, Raanani P, Ram R, Cannabidiol for the Prevention of Graft-Versus-Host-Disease after Allogeneic Hematopoietic Cell Transplantation: Results of a Phase II Study, Biology of Blood and Marrow Transplantation (2015), doi: 10.1016/j.bbmt.2015.05.018. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Cannabidiol for the Prevention of Graft-Versus-Host-Disease after Allogeneic
1
Hematopoietic Cell Transplantation: Results of a Phase II Study
2
3
Moshe Yeshurun, MD1,2, Ofer Shpilberg, MD, MPH1,2, Corina Herscovici,
4
MD1,2, Liat Shargian, MD1,2, Juliet Dreyer1, Anat Peck1, Moshe Israeli, PhD3,
5
Maly
Levy-Assaraf,PhD4,2,
Tsipora
Gruenewald,
RI PT
Running title: Cannabidiol for the prevention of GVHD
M.Ph.Sc5,
Raphael
SC
Mechoulam PhD6 , Pia Raanani, MD1,2, Ron Ram, MD1,2 1
M AN U
Bone Marrow Transplantation Unit, Institute of Hematology, Davidoff Center,
Beilinson Hospital, Rabin Medical Center, Petah-Tikva, Israel; School of Medicine, Tel Aviv University, Tel Aviv, Israel;
2
Sackler
3
6 7
8 9
Tissue typing
10
laboratory, Rabin Medical Center, Petah-Tikva, Israel; 4Felsenstein Medical
11
Research Center, Beilinson Hospital, Sackler School of Medicine, Tel Aviv
12
Pharmacy Services, Rabin Medical Center,
13
Petah-Tikva, Israel; 6Institute for Drug Research, Medical Faculty, Hebrew
14
University, Jerusalem, Israel.
15
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5
Address for correspondence: Moshe Yeshurun, MD, Bone Marrow
16
Transplantation Unit, Institute of Hematology, Rabin Medical Center, Petah-
17
Tikva 49100, Israel.
18
Tel: 972-3-9378127
19
Fax: 972-3-9378130
20
e-mail: [email protected]
21
Pages: 29
22
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University, Tel Aviv, Israel;
Tables: 2
Figures: 5
23 1
ACCEPTED MANUSCRIPT Abstract:
1
Background: Graft-versus-host-disease (GVHD) is a major obstacle to
2
successful
(alloHCT).
3
Cannabidiol (CBD), a non-psychotropic ingredient of Cannabis sativa
4
possesses potent anti-inflammatory and immunosuppressive properties. We
5
hypothesized that CBD may decrease GVHD incidence and severity after
6
alloHCT.
7
hematopoietic
cell
transplantation
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allogeneic
8
GVHD prophylaxis consisted of cyclosporine and a short course of
9
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Methods: We conducted a prospective phase II study (NCT01385124).
10
dose anti-T-cell globulin (Fresenius). CBD 300 mg/day was given orally
11
starting 7 days before transplantation until day 30.
12
Results: Forty-eight consecutive adult patients undergoing alloHCT were
13
enrolled. Thirty-eight patients (79%) had acute leukemia or MDS and 35
14
patients (73%) were given a myeloablative conditioning. The donor was either
15
an HLA-identical sibling (n=28), a 10/10 matched unrelated donor (n=16) or a
16
one antigen mismatched unrelated donor (n=4). The median follow-up was 16
17
(range, 7-23) months. There were no grade 3-4 toxicities attributed to CBD.
18
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methotrexate. Patients transplanted from an unrelated donor were given low
None of the patients developed acute GVHD while consuming CBD. In an
19
intention-to-treat analysis, we found that the cumulative incidence rates of
20
grade 2-4 and grade 3-4 acute GVHD by day 100 were 12.1% and 5%,
21
respectively. Compared to 101 historical control subjects given standard
22
GVHD prophylaxis, the hazard ratio of developing grade 2-4 acute GVHD
23
among subjects treated with CBD plus standard GVHD prophylaxis was 0.3
24
(p=0.0002). Rates of non-relapse mortality at 100 days and at 1 year after
25
2
ACCEPTED MANUSCRIPT 1
more than 100 days, the cumulative incidence of moderate-to-severe chronic
2
GVHD at 12 and 18 months were 20% and 33%, respectively.
3
Conclusions: The combination of CBD with standard GVHD prophylaxis is a
4
safe and promising strategy to reduce the incidence of acute GVHD. A
5
randomized double blind controlled study is warranted.
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transplantation were 8.6% and 13.4%, respectively. Among patients surviving
3
7
ACCEPTED MANUSCRIPT 1
Despite prophylactic immunosuppressive treatment, graft-versus-host disease
2
(GVHD) remains a major cause of morbidity and mortality after allogeneic
3
hematopoietic cell transplantation (alloHCT), affecting 30-50% of patients
4
transplanted from an HLA-matched sibling donor and 50–70% of patients
5
transplanted from an HLA-matched unrelated donor (1-4). The ability to
6
prevent GVHD is of utmost importance, since treatment for established GVHD
7
remains suboptimal. In a recent survey, GVHD and its consequences were
8
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Introduction:
9
developing innovative strategies to prevent and treat GVHD is a major unmet
10
need.
11
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the most important physician restraint from transplantation (5). Thus,
12
potent anti-inflammatory and immunosuppressive properties. Cannabis use in
13
healthy subjects has been associated with a decrease in lymphocyte
14
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Cannabis sativa, commonly known as marijuana, possesses a wide range of
15
increase in IL-10 and TGFβ1 levels (6). In a recent prospective placebo-
16
controlled study, cannabis smoking induced a significant clinical response in
17
patients with refractory Crohn's disease (7). Cannabis contains more than 60
18
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proliferative response to mitogenic stimulation and IL-2 levels, and an
chemical compounds classified as cannabinoids (8). Two cannabinoids in
19
particular have been subjects of most studies examining medical uses: ∆9-
20
tetrahydrocannabinol (THC) and cannabidiol (CBD). In an experimental
21
murine model, THC, the main psychoactive ingredient of marijuana, was
22
shown to be effective in both the prevention and treatment of GVHD (9). Its
23
administration led to reduced tissue injury to the liver and intestine, to early
24
recovery from body weight loss associated with GVHD and to increased mice
25
4
ACCEPTED MANUSCRIPT 1
and INFγ. On a cellular level, THC treatment reduced the expansion of donor
2
derived effector T cells and increased the number of Foxp3+ regulatory T
3
cells. Nevertheless, despite its promising therapeutic potential, the unwanted
4
psychoactive effects of THC limit its consideration as a potential medication
5
for GVHD prophylaxis.
6
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survival. THC-treated GVHD mice had significantly decreased levels of IL-2
7
produce psychoactive effects and is well tolerated by humans even when
8
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CBD, in contrast, which contributes up to 40% of cannabis extract, does not
9
research and therapeutic use (10-17). Similar to THC, CBD possesses potent
10
anti-inflammatory and immunosuppressive properties. Its administration
11
results in attenuation of clinical disease in animal models of various
12
inflammatory diseases including multiple sclerosis, rheumatoid arthritis,
13
inflammatory bowel disease and diabetes mellitus (18-23). These effects are
14
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taken over extended periods of time and thus has the potential for both clinical
15
cytokine release (TNFα, INFγ, IL-1β, IL-6, and IL-17) and stimulation of anti-
16
inflammatory cytokine production (IL-4, IL-5, IL-10 and IL-13) (19-25).
17
Furthermore, cannabinoids have recently been shown to reduce the capacity
18
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mediated by T cell attrition, as well as by inhibition of pro-inflammatory
of dendritic cells to migrate to secondary lymphoid organs and activate naive
19
T cells (26).
20
Based on these experimental and clinical observations, we conducted a
21
phase II study to assess the safety and efficacy of CBD in the prevention of
22
acute GVHD.
23 24 25 5
ACCEPTED MANUSCRIPT 1
This prospective single center phase II clinical trial was approved by the
2
institutional review board of the Rabin Medical Center (RMC). Written
3
informed consent was obtained before patient enrollment.
4
Inclusion and exclusion criteria
5
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Patients and Methods:
6
available 10/10 HLA-matched or one antigen mismatched related or unrelated
7
donor. Patients were excluded if they had a mental disorder, were actively
8
SC
Patients were eligible for the study if they were 18 years or older and had an
consuming illicit drugs, or were consuming cannabis during the 3 months prior
9
to
10
Patients
transplantations were excluded. Conditioning regimens
receiving
cord
blood
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transplantation.
or
haploidentical
11 12 13
plus intravenous (IV) cyclophosphamide 120 mg/kg or IV busulfan 12.8 mg/kg
14
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Myeloabaltive conditioning (MAC) included total body irradiation (TBI) 12 Gray
15
Reduced intensity conditioning (RIC) comprised of IV fludarabine 150 mg/ m2
16
with either IV busulfan 6.4 mg/kg or IV melphalan 100 mg/ m2. Non-
17
myeloablative (NMA) conditioning comprised of TBI 2 Gray plus IV fludarabine
18
90 mg/ m2.
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plus either IV cyclophosphamide 120 mg/kg or IV fludarabine 160 mg/m2.
All patients received G-CSF mobilized peripheral blood stem cell grafts.
20
GVHD prophylaxis
21
All patients received standard GVHD prophylaxis consisting of cyclosporine
22
twice daily starting on day -1 with target trough levels of 200-400 ng/mL and a
23
short course of methotrexate (MTX) (15 mg/ m2 on day 1 and 10 mg/ m2 on
24
6
ACCEPTED MANUSCRIPT 1
cell globulin (ATG, Fresenius) at a low dose of 5 mg/kg on days -3 to -1 (27).
2
The investigational agent, CBD (STI Pharmaceuticals, Essex, UK) was
3
dissolved in olive oil at a concentration of 2.5% and was orally administered at
4
a fixed dose of 150 mg twice daily, starting 7 days before transplantation until
5
day 30. Dose and duration of CBD administration were based upon doses
6
previously safely used in several clinical trials in the non-transplant setting
7
(10-17).
8
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days 3 and 6). Patients transplanted from unrelated donors received anti-T-
Supportive care
9 10
day 7 until neutrophil engraftment, infection prophylaxis according to
11
institutional guidelines (28), and ursodeoxycholic for sinusoidal obstruction
12
syndrome prevention.
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End points
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All patients received filgrastim (G-CSF) at a dose of 5 microgram/kg/day from
14 15
endpoints were safety and cumulative incidence rates of grade 2-4 and grade
16
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End points were assessed based on intention-to-treat analysis. Primary
17
incidence rates of acute GVHD by day 200, overall and moderate to severe
18
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3-4 acute GVHD by day 100. Secondary end points were cumulative
chronic GVHD, non-relapse mortality (NRM), relapse incidence (RI) and
19
overall survival (OS).
20
Acute GVHD was assessed by using the consensus grading system and
21
suspected cases of GVHD were histologically confirmed (29). Chronic GVHD
22
was assessed according to the National Institutes of Health (NIH) consensus
23
criteria (30).
24
7
ACCEPTED MANUSCRIPT 1
hybridization analysis in sex-mismatched pairs and by DNA amplification of
2
polymorphic microsatellite regions in sex-matched pairs as previously
3
described (31,32).
4
We compared the outcomes of the study group to a control group comprising
5
101 adult patients who would have met the protocol inclusion and exclusion
6
criteria and consecutively underwent alloHCT and were treated by the same
7
medical team at the RMC between 05/2007 and 8/2012. This historical cohort
8
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Donor chimerism in bone marrow was measured by XY– fluorescence in situ
9
a short course of methotrexate without CBD.
10
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received the same standard GVHD prophylaxis consisted of cyclosporine and
Side effects possibly attributed to CBD were graded according to the Common
11
Terminology Criteria for Adverse Events (CTCAE v4.0) classification.
12 13
14
Cohort sample size (n=48) was calculated to demonstrate a reduction of 50%
15
in the occurrence of grade 2-4 acute GVHD by day +100 with a power of 80%
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Statistical considerations
17
Neutrophil and platelet recovery were defined as the first of 3 days with
18
absolute neutrophil count ≥ 500/microliter and the first of 7 days with an
19
unsupported platelet count ≥ 20,000/microliter.
20
NRM was defined as death in remission. Death was treated as a competing
21
risk in the analyses of relapse and progression and acute and chronic GVHD.
22
Relapse and progression were treated as a competing risk when analyzing
23
NRM. Probabilities of OS and DFS were calculated using the Kaplan-Meier
24
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and a type I error of 0.05.
8
ACCEPTED MANUSCRIPT 1
variables of study and historical cohorts were compared using the chi-square
2
or Fisher Exact test, as appropriate. All p values are two sided. Statistical
3
analyses were performed using SPSS ver. 21 and Prism ver. 5.0.
4
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estimates. The log-rank test was used for univariate comparisons. Categorical
Results Patients
SC
From September 2012 through January 2014, 50 consecutive unselected
5 6 7 8 9
consent. Among 48 enrolled patients, one patient with acute leukemia
10
declined informed consent 2 days after starting CBD; a second patient with
11
aplastic anemia had primary graft failure and received a second transplant for
12
which CBD was not administered. These 2 patients were included in the
13
intention-to-treat analyses. Baseline characteristics and transplantation
14
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adult patients were evaluated for enrollment. Two patients refused informed
15
patients was 56 (range, 22 to 73) years and 19 patients (40%) were 60 years
16
or older. Most patients (n=38, 79%) had acute leukemia or myelodysplastic
17
syndrome (MDS). Among 47 patients with hematological malignancies, 4%
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parameters of the 48 patients are depicted in table 1. The median age of
(n=2), 51% (n=24), 32% (n=15) and 13% (n=6) had low, intermediate, high
19
and very-high risk disease, respectively, according to the refined Disease Risk
20
Index (DRI) for allogeneic stem cell transplantation (table 1) (33). Four
21
patients underwent a prior autologous stem cell transplantation (multiple
22
myeloma, n=1, NHL, n=2, Hodgkin's lymphoma, n=1). Thirty five patients
23
(73%) received a myeloablative conditioning and 20 patients (42%) received
24
allografts from unrelated donors (10/10 match, n=16; 9/10 match, n=4). Seven
25
9
ACCEPTED MANUSCRIPT 1
median follow-up of survivors was 16 (range 7 to 23) months.
2
Compliance and toxicity
3
The overall compliance with the protocol was good, with 32 patients (70%)
4
taking 100% of the doses. Median dose adherence among non-compliant
5
patients was 86% (range, 43%-96%). Non-compliance with study medication
6
was mainly due to mucositis and nausea. No grade 3-4 non-hematologic
7
toxicities related to CBD were observed.
8
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male patients (15%) received allografts from a female donor (table 1). The
Engraftment and chimerism
9 10
with aplastic anemia had a primary graft failure. This patient subsequently
11
had a second transplant from the same donor without reconditioning and
12
engrafted properly. She did not receive MTX and CBD during the second
13
transplant.
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In all, 47 patients (98%) achieved primary engraftment. One female patient
15
10 to 22) days. The median time to unsupported platelet count ≥
16
20,000/microliter was 16 (range, 13 to 33) days. None of the patients
17
experienced secondary graft failure. Excluding the patient with primary graft
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The median time to absolute neutrophil count ≥ 500/microliter was 11 (range,
failure, the median percentage of donor whole marrow chimerism was 99%
19
(range, 91% to 100%) on day 30, and 100% (range, 95% to 100%) on day
20
200.
21
Graft-versus-host-disease
22
All 48 patients were evaluable for acute GVHD. None of the patients
23
developed acute GVHD while consuming CBD (i.e. before day 30). One
24
patient developed grade 1 acute GVHD and 7 patients developed grade 2-4
25
10
ACCEPTED MANUSCRIPT 1
gastrointestinal tract (GIT) only, 3 patients had involvement of the GIT and
2
skin, 1 patient had involvement of the GIT and liver and 1 patient had
3
involvement of the GIT, skin and liver. Among the 7 patients with GIT
4
involvement, 2 patients had only involvement of the lower GIT and 5 patients
5
had involvement of both the upper and lower GIT. Organ-specific stages of
6
acute GVHD are depicted in Table 2. Median time to onset of grade 2-4 acute
7
GVHD was 60 (range, 41 to 150) days. Based on an intention-to-treat
8
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acute GVHD after CBD discontinuation. Two patients had involvement of the
9
and 200 were 12.1% (95% CI, 1% to 41%) and 14.8% (95% CI, 1% to 45%),
10
respectively (Figure 1).
Four patients developed grade 3-4 acute GVHD.
11
Among them, one patient developed steroid refractory grade 3 acute GVHD
12
on day 46, which was subsequently treated with extra-corporal photopheresis
13
and gradually improved. A second patient developed grade 3 acute GVHD on
14
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analysis, cumulative incidence rates of grade 2-4 acute GVHD by days 100
15
leukemia and died on day 186 post alloHCT. A third patient with aplastic
16
anemia stopped CBD on day 8 due to severe mucositis, had primary graft
17
failure and hence received a second transplant on day 32 for which MTX and
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day 71 from which he recovered. This patient subsequently had a relapse of
CBD were not administered. The patient developed grade 4 acute GVHD on
19
day 106 and died from sepsis on day 138 post alloHCT. The fourth patient
20
developed grade 4 acute GVHD on day 150, upon cessation of cyclosporine
21
and died of sepsis on day 179 post alloHCT. Cumulative incidence rates of
22
grade 3-4 acute GVHD by days 100 and 200 were 5% (95% CI, 1% to 45%)
23
and 8% (95% CI, 2% to 51%), respectively (Figure 1).
24
11
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GVHD occurred in 15 patients (overlap, n=3 and classic, n=12), with a median
2
time to onset of 159 (range, 110 to 486) days. Chronic GVHD was classified
3
as mild, moderate and severe in 7, 1 and 7 patients, respectively. Notably, 6
4
out of 7 patients with severe chronic GVHD had moderate (score 2) lung
5
involvement.
6
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Among patients surviving more than 100 days after alloHCT (n=41), chronic
7
GVHD at 1 year were 49.7% (95% CI, 26% to 65%) and 20% (95% CI, 5% to
8
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The cumulative incidence rates of overall and moderate-to-severe chronic
9
moderate-to-severe chronic GVHD at 18 months were 58% (95% CI, 36% to
10
69%) and 33% (95% CI, 12% to 57%), respectively (Figure 2).
11
Comparison of acute GVHD incidence between study and control groups
12
There was no significant difference between subjects treated with CBD and
13
the historical control patients treated at the RMC with respect to baseline
14
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52%), respectively (Figure 2). The cumulative incidence rates of overall and
15
rates of grade 2-4 and grade 3-4 acute GVHD by day 100 among the 101
16
historical control patients were 46% and 10%, respectively. Compared to
17
subjects given standard GVHD prophylaxis, the hazard ratios of developing
18
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characteristics and risk factors for GVHD (Table 1). The cumulative incidence
grade 2-4 and grade 3-4 acute GVHD by day 100 among subjects treated with
19
CBD plus standard GVHD prophylaxis were 0.3 (95% CI: 0.2-0.6; p=0.0002)
20
and 0.6 (95% CI: 0.2-1.8; p=0.3), respectively. Nevertheless, this did not
21
translate into statistically significant difference in NRM at 12 months (13.4%
22
vs. 20 %, p=0.95). Median time for developing acute GVHD in the control
23
group was 20 (range, 9-137) days. The median time to onset of acute GVHD
24
was significantly shorter in the control group compared to the CBD group (20
25
12
ACCEPTED MANUSCRIPT 1
respect to organ specific involvement by acute GVHD as depicted in table 2.
2
Patients treated with CBD had less often skin (p=0.0033), upper
3
gastrointestinal tract (p=0.0057) and lower gastrointestinal tract (p2 (%)
10 (21)
*12 (39)
0.13
CMV +/+ (%)
35 (73)
84 (84)
0.8
Acute Leukemia AML ALL MDS
33 (69)
74 (74)
26
63
7
11
5
(10.5)
6 (6)
7
(14.5)
12 (12)
(6)
9 (9)
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LPD
Other
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Disease (%)
RI PT
Age - years (median, range)
3
0.9
DRI (%)
2 (4)
10 (10)
Intermediate
24 (51)
38 (38)
High
15 (32)
45 (45)
Very high
6 (13)
8 (8)
28 (58)
58 (58)
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Low
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Disease risk according to the refined
0.19
Donor characteristics Matched sibling
24
1
ACCEPTED MANUSCRIPT Full matched unrelated
16 (33)
41 (41)
1
1 allele/antigen mismatched
4 (9)
2 (2)
0.18
7 (15)
18 (18)
0.5
Myeloablative (TBI/Cy or Bu/Cy)
11 (23)
26 (26)
Myeloablative reduced toxicity
24 (50)
42 (42)
Reduced Intensity
13 (27)
33 (33)
ATG
20 (42)
unrelated (%) Female to Male (%)
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Preparative Regimen
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43 (43)
Transfused CD34x10^6/kg (median, range)
6 (2.7-13)
6.8 (2.1-9)
0.6
1 0.8
1
Index; TBI – total body irradiation; Cy – cyclophosphamide; Bu- busulfan;; CMV –
2
cytomegalovirus; AML – acute myeloid leukemia; ALL – acute lymphoblastic
3
leukemia; MDS – myelodysplastic syndrome; LPD – lymphoproliferative disease
4
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HCTCI – hematopoietic cell transplantation comorbidity index; DRI – Disease Risk
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*out of 31 patients with available data
25
5 6
ACCEPTED MANUSCRIPT Table 2 – Organ-specific involvement by acute graft-versus-host disease
1 2
Datum
% of patients in the CB cohort (n=48)
% of patients in the control cohort (n=101)
0.0033
0
12
Stage 2
6
17
Stage 3
6
5
Stage 4
0
1
12
33
Upper GIT
4
Stage 2
0
Stage 3
4
Stage 4
4
Liver
4 2 4
0.34
2
3
Stage 2
0
3
Stage 3
0
1
2
3
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Stage 1
Stage 4
< 0.0001
34
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Stage 1
0.0057
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Lower GIT
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Stage 1
RI PT
Skin
P
GIT – gastrointestinal tract
26
3
ACCEPTED MANUSCRIPT
Figure 1
1 2 3 4
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Figure 2
27
6 7 8 9 10
ACCEPTED MANUSCRIPT
Figure 3
1 2 3
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Figure 3
Figure 4
6 7 8 9 10 11 12 13 14 15
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Figure 4
5
16 17 18 19 20 28
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Figure 5
2 3
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4
29
5 6 7
ACCEPTED MANUSCRIPT
Cannabidiol for the Prevention of Graft-Versus-Host-Disease after Allogeneic Hematopoietic Cell Transplantation: Results of a Phase II Study
RI PT
Highlights
Cannabidiol (CBD) is a non-psychotropic ingredient of Cannabis sativa.
CBD possesses potent anti-inflammatory and immunosuppressive properties.
Its efficacy in the prevention of acute GVHD was assessed in a phase
SC
2 study.
No severe toxicities were attributed to CBD.
The incidence of acute GVHD of 12% by day 100 was lower than
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expected.
S1083-8791(15)00375-4
DOI:
10.1016/j.bbmt.2015.05.018
Reference:
YBBMT 53871
To appear in:
Biology of Blood and Marrow Transplantation
Received Date: 31 March 2015 Accepted Date: 21 May 2015
Please cite this article as: Yeshurun M, Shpilberg O, Herscovici C, Shargian L, Dreyer J, Peck A, Israeli M, Levy-Assaraf M, Gruenewald T, Mechoulam R, Raanani P, Ram R, Cannabidiol for the Prevention of Graft-Versus-Host-Disease after Allogeneic Hematopoietic Cell Transplantation: Results of a Phase II Study, Biology of Blood and Marrow Transplantation (2015), doi: 10.1016/j.bbmt.2015.05.018. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Cannabidiol for the Prevention of Graft-Versus-Host-Disease after Allogeneic
1
Hematopoietic Cell Transplantation: Results of a Phase II Study
2
3
Moshe Yeshurun, MD1,2, Ofer Shpilberg, MD, MPH1,2, Corina Herscovici,
4
MD1,2, Liat Shargian, MD1,2, Juliet Dreyer1, Anat Peck1, Moshe Israeli, PhD3,
5
Maly
Levy-Assaraf,PhD4,2,
Tsipora
Gruenewald,
RI PT
Running title: Cannabidiol for the prevention of GVHD
M.Ph.Sc5,
Raphael
SC
Mechoulam PhD6 , Pia Raanani, MD1,2, Ron Ram, MD1,2 1
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Bone Marrow Transplantation Unit, Institute of Hematology, Davidoff Center,
Beilinson Hospital, Rabin Medical Center, Petah-Tikva, Israel; School of Medicine, Tel Aviv University, Tel Aviv, Israel;
2
Sackler
3
6 7
8 9
Tissue typing
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laboratory, Rabin Medical Center, Petah-Tikva, Israel; 4Felsenstein Medical
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Research Center, Beilinson Hospital, Sackler School of Medicine, Tel Aviv
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Pharmacy Services, Rabin Medical Center,
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Petah-Tikva, Israel; 6Institute for Drug Research, Medical Faculty, Hebrew
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University, Jerusalem, Israel.
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Address for correspondence: Moshe Yeshurun, MD, Bone Marrow
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Transplantation Unit, Institute of Hematology, Rabin Medical Center, Petah-
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Tikva 49100, Israel.
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Tel: 972-3-9378127
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Fax: 972-3-9378130
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e-mail: [email protected]
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Pages: 29
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University, Tel Aviv, Israel;
Tables: 2
Figures: 5
23 1
ACCEPTED MANUSCRIPT Abstract:
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Background: Graft-versus-host-disease (GVHD) is a major obstacle to
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successful
(alloHCT).
3
Cannabidiol (CBD), a non-psychotropic ingredient of Cannabis sativa
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possesses potent anti-inflammatory and immunosuppressive properties. We
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hypothesized that CBD may decrease GVHD incidence and severity after
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alloHCT.
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hematopoietic
cell
transplantation
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allogeneic
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GVHD prophylaxis consisted of cyclosporine and a short course of
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Methods: We conducted a prospective phase II study (NCT01385124).
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dose anti-T-cell globulin (Fresenius). CBD 300 mg/day was given orally
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starting 7 days before transplantation until day 30.
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Results: Forty-eight consecutive adult patients undergoing alloHCT were
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enrolled. Thirty-eight patients (79%) had acute leukemia or MDS and 35
14
patients (73%) were given a myeloablative conditioning. The donor was either
15
an HLA-identical sibling (n=28), a 10/10 matched unrelated donor (n=16) or a
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one antigen mismatched unrelated donor (n=4). The median follow-up was 16
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(range, 7-23) months. There were no grade 3-4 toxicities attributed to CBD.
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methotrexate. Patients transplanted from an unrelated donor were given low
None of the patients developed acute GVHD while consuming CBD. In an
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intention-to-treat analysis, we found that the cumulative incidence rates of
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grade 2-4 and grade 3-4 acute GVHD by day 100 were 12.1% and 5%,
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respectively. Compared to 101 historical control subjects given standard
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GVHD prophylaxis, the hazard ratio of developing grade 2-4 acute GVHD
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among subjects treated with CBD plus standard GVHD prophylaxis was 0.3
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(p=0.0002). Rates of non-relapse mortality at 100 days and at 1 year after
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more than 100 days, the cumulative incidence of moderate-to-severe chronic
2
GVHD at 12 and 18 months were 20% and 33%, respectively.
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Conclusions: The combination of CBD with standard GVHD prophylaxis is a
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safe and promising strategy to reduce the incidence of acute GVHD. A
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randomized double blind controlled study is warranted.
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transplantation were 8.6% and 13.4%, respectively. Among patients surviving
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Despite prophylactic immunosuppressive treatment, graft-versus-host disease
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(GVHD) remains a major cause of morbidity and mortality after allogeneic
3
hematopoietic cell transplantation (alloHCT), affecting 30-50% of patients
4
transplanted from an HLA-matched sibling donor and 50–70% of patients
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transplanted from an HLA-matched unrelated donor (1-4). The ability to
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prevent GVHD is of utmost importance, since treatment for established GVHD
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remains suboptimal. In a recent survey, GVHD and its consequences were
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Introduction:
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developing innovative strategies to prevent and treat GVHD is a major unmet
10
need.
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the most important physician restraint from transplantation (5). Thus,
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potent anti-inflammatory and immunosuppressive properties. Cannabis use in
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healthy subjects has been associated with a decrease in lymphocyte
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Cannabis sativa, commonly known as marijuana, possesses a wide range of
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increase in IL-10 and TGFβ1 levels (6). In a recent prospective placebo-
16
controlled study, cannabis smoking induced a significant clinical response in
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patients with refractory Crohn's disease (7). Cannabis contains more than 60
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proliferative response to mitogenic stimulation and IL-2 levels, and an
chemical compounds classified as cannabinoids (8). Two cannabinoids in
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particular have been subjects of most studies examining medical uses: ∆9-
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tetrahydrocannabinol (THC) and cannabidiol (CBD). In an experimental
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murine model, THC, the main psychoactive ingredient of marijuana, was
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shown to be effective in both the prevention and treatment of GVHD (9). Its
23
administration led to reduced tissue injury to the liver and intestine, to early
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recovery from body weight loss associated with GVHD and to increased mice
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and INFγ. On a cellular level, THC treatment reduced the expansion of donor
2
derived effector T cells and increased the number of Foxp3+ regulatory T
3
cells. Nevertheless, despite its promising therapeutic potential, the unwanted
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psychoactive effects of THC limit its consideration as a potential medication
5
for GVHD prophylaxis.
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survival. THC-treated GVHD mice had significantly decreased levels of IL-2
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produce psychoactive effects and is well tolerated by humans even when
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CBD, in contrast, which contributes up to 40% of cannabis extract, does not
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research and therapeutic use (10-17). Similar to THC, CBD possesses potent
10
anti-inflammatory and immunosuppressive properties. Its administration
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results in attenuation of clinical disease in animal models of various
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inflammatory diseases including multiple sclerosis, rheumatoid arthritis,
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inflammatory bowel disease and diabetes mellitus (18-23). These effects are
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taken over extended periods of time and thus has the potential for both clinical
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cytokine release (TNFα, INFγ, IL-1β, IL-6, and IL-17) and stimulation of anti-
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inflammatory cytokine production (IL-4, IL-5, IL-10 and IL-13) (19-25).
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Furthermore, cannabinoids have recently been shown to reduce the capacity
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mediated by T cell attrition, as well as by inhibition of pro-inflammatory
of dendritic cells to migrate to secondary lymphoid organs and activate naive
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T cells (26).
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Based on these experimental and clinical observations, we conducted a
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phase II study to assess the safety and efficacy of CBD in the prevention of
22
acute GVHD.
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This prospective single center phase II clinical trial was approved by the
2
institutional review board of the Rabin Medical Center (RMC). Written
3
informed consent was obtained before patient enrollment.
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Inclusion and exclusion criteria
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Patients and Methods:
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available 10/10 HLA-matched or one antigen mismatched related or unrelated
7
donor. Patients were excluded if they had a mental disorder, were actively
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Patients were eligible for the study if they were 18 years or older and had an
consuming illicit drugs, or were consuming cannabis during the 3 months prior
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to
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Patients
transplantations were excluded. Conditioning regimens
receiving
cord
blood
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transplantation.
or
haploidentical
11 12 13
plus intravenous (IV) cyclophosphamide 120 mg/kg or IV busulfan 12.8 mg/kg
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Myeloabaltive conditioning (MAC) included total body irradiation (TBI) 12 Gray
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Reduced intensity conditioning (RIC) comprised of IV fludarabine 150 mg/ m2
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with either IV busulfan 6.4 mg/kg or IV melphalan 100 mg/ m2. Non-
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myeloablative (NMA) conditioning comprised of TBI 2 Gray plus IV fludarabine
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90 mg/ m2.
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plus either IV cyclophosphamide 120 mg/kg or IV fludarabine 160 mg/m2.
All patients received G-CSF mobilized peripheral blood stem cell grafts.
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GVHD prophylaxis
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All patients received standard GVHD prophylaxis consisting of cyclosporine
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twice daily starting on day -1 with target trough levels of 200-400 ng/mL and a
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short course of methotrexate (MTX) (15 mg/ m2 on day 1 and 10 mg/ m2 on
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cell globulin (ATG, Fresenius) at a low dose of 5 mg/kg on days -3 to -1 (27).
2
The investigational agent, CBD (STI Pharmaceuticals, Essex, UK) was
3
dissolved in olive oil at a concentration of 2.5% and was orally administered at
4
a fixed dose of 150 mg twice daily, starting 7 days before transplantation until
5
day 30. Dose and duration of CBD administration were based upon doses
6
previously safely used in several clinical trials in the non-transplant setting
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(10-17).
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days 3 and 6). Patients transplanted from unrelated donors received anti-T-
Supportive care
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day 7 until neutrophil engraftment, infection prophylaxis according to
11
institutional guidelines (28), and ursodeoxycholic for sinusoidal obstruction
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syndrome prevention.
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End points
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All patients received filgrastim (G-CSF) at a dose of 5 microgram/kg/day from
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endpoints were safety and cumulative incidence rates of grade 2-4 and grade
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End points were assessed based on intention-to-treat analysis. Primary
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incidence rates of acute GVHD by day 200, overall and moderate to severe
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3-4 acute GVHD by day 100. Secondary end points were cumulative
chronic GVHD, non-relapse mortality (NRM), relapse incidence (RI) and
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overall survival (OS).
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Acute GVHD was assessed by using the consensus grading system and
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suspected cases of GVHD were histologically confirmed (29). Chronic GVHD
22
was assessed according to the National Institutes of Health (NIH) consensus
23
criteria (30).
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hybridization analysis in sex-mismatched pairs and by DNA amplification of
2
polymorphic microsatellite regions in sex-matched pairs as previously
3
described (31,32).
4
We compared the outcomes of the study group to a control group comprising
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101 adult patients who would have met the protocol inclusion and exclusion
6
criteria and consecutively underwent alloHCT and were treated by the same
7
medical team at the RMC between 05/2007 and 8/2012. This historical cohort
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Donor chimerism in bone marrow was measured by XY– fluorescence in situ
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a short course of methotrexate without CBD.
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received the same standard GVHD prophylaxis consisted of cyclosporine and
Side effects possibly attributed to CBD were graded according to the Common
11
Terminology Criteria for Adverse Events (CTCAE v4.0) classification.
12 13
14
Cohort sample size (n=48) was calculated to demonstrate a reduction of 50%
15
in the occurrence of grade 2-4 acute GVHD by day +100 with a power of 80%
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Statistical considerations
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Neutrophil and platelet recovery were defined as the first of 3 days with
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absolute neutrophil count ≥ 500/microliter and the first of 7 days with an
19
unsupported platelet count ≥ 20,000/microliter.
20
NRM was defined as death in remission. Death was treated as a competing
21
risk in the analyses of relapse and progression and acute and chronic GVHD.
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Relapse and progression were treated as a competing risk when analyzing
23
NRM. Probabilities of OS and DFS were calculated using the Kaplan-Meier
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and a type I error of 0.05.
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variables of study and historical cohorts were compared using the chi-square
2
or Fisher Exact test, as appropriate. All p values are two sided. Statistical
3
analyses were performed using SPSS ver. 21 and Prism ver. 5.0.
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estimates. The log-rank test was used for univariate comparisons. Categorical
Results Patients
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From September 2012 through January 2014, 50 consecutive unselected
5 6 7 8 9
consent. Among 48 enrolled patients, one patient with acute leukemia
10
declined informed consent 2 days after starting CBD; a second patient with
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aplastic anemia had primary graft failure and received a second transplant for
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which CBD was not administered. These 2 patients were included in the
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intention-to-treat analyses. Baseline characteristics and transplantation
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adult patients were evaluated for enrollment. Two patients refused informed
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patients was 56 (range, 22 to 73) years and 19 patients (40%) were 60 years
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or older. Most patients (n=38, 79%) had acute leukemia or myelodysplastic
17
syndrome (MDS). Among 47 patients with hematological malignancies, 4%
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parameters of the 48 patients are depicted in table 1. The median age of
(n=2), 51% (n=24), 32% (n=15) and 13% (n=6) had low, intermediate, high
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and very-high risk disease, respectively, according to the refined Disease Risk
20
Index (DRI) for allogeneic stem cell transplantation (table 1) (33). Four
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patients underwent a prior autologous stem cell transplantation (multiple
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myeloma, n=1, NHL, n=2, Hodgkin's lymphoma, n=1). Thirty five patients
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(73%) received a myeloablative conditioning and 20 patients (42%) received
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allografts from unrelated donors (10/10 match, n=16; 9/10 match, n=4). Seven
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median follow-up of survivors was 16 (range 7 to 23) months.
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Compliance and toxicity
3
The overall compliance with the protocol was good, with 32 patients (70%)
4
taking 100% of the doses. Median dose adherence among non-compliant
5
patients was 86% (range, 43%-96%). Non-compliance with study medication
6
was mainly due to mucositis and nausea. No grade 3-4 non-hematologic
7
toxicities related to CBD were observed.
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male patients (15%) received allografts from a female donor (table 1). The
Engraftment and chimerism
9 10
with aplastic anemia had a primary graft failure. This patient subsequently
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had a second transplant from the same donor without reconditioning and
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engrafted properly. She did not receive MTX and CBD during the second
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transplant.
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In all, 47 patients (98%) achieved primary engraftment. One female patient
15
10 to 22) days. The median time to unsupported platelet count ≥
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20,000/microliter was 16 (range, 13 to 33) days. None of the patients
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experienced secondary graft failure. Excluding the patient with primary graft
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The median time to absolute neutrophil count ≥ 500/microliter was 11 (range,
failure, the median percentage of donor whole marrow chimerism was 99%
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(range, 91% to 100%) on day 30, and 100% (range, 95% to 100%) on day
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200.
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Graft-versus-host-disease
22
All 48 patients were evaluable for acute GVHD. None of the patients
23
developed acute GVHD while consuming CBD (i.e. before day 30). One
24
patient developed grade 1 acute GVHD and 7 patients developed grade 2-4
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gastrointestinal tract (GIT) only, 3 patients had involvement of the GIT and
2
skin, 1 patient had involvement of the GIT and liver and 1 patient had
3
involvement of the GIT, skin and liver. Among the 7 patients with GIT
4
involvement, 2 patients had only involvement of the lower GIT and 5 patients
5
had involvement of both the upper and lower GIT. Organ-specific stages of
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acute GVHD are depicted in Table 2. Median time to onset of grade 2-4 acute
7
GVHD was 60 (range, 41 to 150) days. Based on an intention-to-treat
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acute GVHD after CBD discontinuation. Two patients had involvement of the
9
and 200 were 12.1% (95% CI, 1% to 41%) and 14.8% (95% CI, 1% to 45%),
10
respectively (Figure 1).
Four patients developed grade 3-4 acute GVHD.
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Among them, one patient developed steroid refractory grade 3 acute GVHD
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on day 46, which was subsequently treated with extra-corporal photopheresis
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and gradually improved. A second patient developed grade 3 acute GVHD on
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analysis, cumulative incidence rates of grade 2-4 acute GVHD by days 100
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leukemia and died on day 186 post alloHCT. A third patient with aplastic
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anemia stopped CBD on day 8 due to severe mucositis, had primary graft
17
failure and hence received a second transplant on day 32 for which MTX and
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day 71 from which he recovered. This patient subsequently had a relapse of
CBD were not administered. The patient developed grade 4 acute GVHD on
19
day 106 and died from sepsis on day 138 post alloHCT. The fourth patient
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developed grade 4 acute GVHD on day 150, upon cessation of cyclosporine
21
and died of sepsis on day 179 post alloHCT. Cumulative incidence rates of
22
grade 3-4 acute GVHD by days 100 and 200 were 5% (95% CI, 1% to 45%)
23
and 8% (95% CI, 2% to 51%), respectively (Figure 1).
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GVHD occurred in 15 patients (overlap, n=3 and classic, n=12), with a median
2
time to onset of 159 (range, 110 to 486) days. Chronic GVHD was classified
3
as mild, moderate and severe in 7, 1 and 7 patients, respectively. Notably, 6
4
out of 7 patients with severe chronic GVHD had moderate (score 2) lung
5
involvement.
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Among patients surviving more than 100 days after alloHCT (n=41), chronic
7
GVHD at 1 year were 49.7% (95% CI, 26% to 65%) and 20% (95% CI, 5% to
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The cumulative incidence rates of overall and moderate-to-severe chronic
9
moderate-to-severe chronic GVHD at 18 months were 58% (95% CI, 36% to
10
69%) and 33% (95% CI, 12% to 57%), respectively (Figure 2).
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Comparison of acute GVHD incidence between study and control groups
12
There was no significant difference between subjects treated with CBD and
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the historical control patients treated at the RMC with respect to baseline
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52%), respectively (Figure 2). The cumulative incidence rates of overall and
15
rates of grade 2-4 and grade 3-4 acute GVHD by day 100 among the 101
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historical control patients were 46% and 10%, respectively. Compared to
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subjects given standard GVHD prophylaxis, the hazard ratios of developing
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characteristics and risk factors for GVHD (Table 1). The cumulative incidence
grade 2-4 and grade 3-4 acute GVHD by day 100 among subjects treated with
19
CBD plus standard GVHD prophylaxis were 0.3 (95% CI: 0.2-0.6; p=0.0002)
20
and 0.6 (95% CI: 0.2-1.8; p=0.3), respectively. Nevertheless, this did not
21
translate into statistically significant difference in NRM at 12 months (13.4%
22
vs. 20 %, p=0.95). Median time for developing acute GVHD in the control
23
group was 20 (range, 9-137) days. The median time to onset of acute GVHD
24
was significantly shorter in the control group compared to the CBD group (20
25
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respect to organ specific involvement by acute GVHD as depicted in table 2.
2
Patients treated with CBD had less often skin (p=0.0033), upper
3
gastrointestinal tract (p=0.0057) and lower gastrointestinal tract (p2 (%)
10 (21)
*12 (39)
0.13
CMV +/+ (%)
35 (73)
84 (84)
0.8
Acute Leukemia AML ALL MDS
33 (69)
74 (74)
26
63
7
11
5
(10.5)
6 (6)
7
(14.5)
12 (12)
(6)
9 (9)
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Disease (%)
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Age - years (median, range)
3
0.9
DRI (%)
2 (4)
10 (10)
Intermediate
24 (51)
38 (38)
High
15 (32)
45 (45)
Very high
6 (13)
8 (8)
28 (58)
58 (58)
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Disease risk according to the refined
0.19
Donor characteristics Matched sibling
24
1
ACCEPTED MANUSCRIPT Full matched unrelated
16 (33)
41 (41)
1
1 allele/antigen mismatched
4 (9)
2 (2)
0.18
7 (15)
18 (18)
0.5
Myeloablative (TBI/Cy or Bu/Cy)
11 (23)
26 (26)
Myeloablative reduced toxicity
24 (50)
42 (42)
Reduced Intensity
13 (27)
33 (33)
ATG
20 (42)
unrelated (%) Female to Male (%)
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Preparative Regimen
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43 (43)
Transfused CD34x10^6/kg (median, range)
6 (2.7-13)
6.8 (2.1-9)
0.6
1 0.8
1
Index; TBI – total body irradiation; Cy – cyclophosphamide; Bu- busulfan;; CMV –
2
cytomegalovirus; AML – acute myeloid leukemia; ALL – acute lymphoblastic
3
leukemia; MDS – myelodysplastic syndrome; LPD – lymphoproliferative disease
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HCTCI – hematopoietic cell transplantation comorbidity index; DRI – Disease Risk
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*out of 31 patients with available data
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ACCEPTED MANUSCRIPT Table 2 – Organ-specific involvement by acute graft-versus-host disease
1 2
Datum
% of patients in the CB cohort (n=48)
% of patients in the control cohort (n=101)
0.0033
0
12
Stage 2
6
17
Stage 3
6
5
Stage 4
0
1
12
33
Upper GIT
4
Stage 2
0
Stage 3
4
Stage 4
4
Liver
4 2 4
0.34
2
3
Stage 2
0
3
Stage 3
0
1
2
3
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Stage 1
Stage 4
< 0.0001
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Stage 1
0.0057
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Lower GIT
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Stage 1
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Skin
P
GIT – gastrointestinal tract
26
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Figure 1
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Figure 2
27
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Figure 3
1 2 3
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Figure 3
Figure 4
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Figure 5
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Cannabidiol for the Prevention of Graft-Versus-Host-Disease after Allogeneic Hematopoietic Cell Transplantation: Results of a Phase II Study
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Highlights
Cannabidiol (CBD) is a non-psychotropic ingredient of Cannabis sativa.
CBD possesses potent anti-inflammatory and immunosuppressive properties.
Its efficacy in the prevention of acute GVHD was assessed in a phase
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2 study.
No severe toxicities were attributed to CBD.
The incidence of acute GVHD of 12% by day 100 was lower than
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expected.
