Full text of DOI:10.2165/00003495-200262060-00002

Drugs 2002; 62 (6): 879-889
0012-6667/02/0006-0879/$30.00/0
LEADING ARTICLE
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Novel Pharmacotherapeutic
Approaches to Prevention and
Treatment of GVHD
1
2
David A. Jacobsohn and Georgia B. Vogelsang
1
2
Oncology and Pediatrics, The Johns Hopkins University School of Medicine, Baltimore,
Maryland, USA
Hematologic Malignancies, Department of Oncology, The Johns Hopkins University
School of Medicine, Baltimore, Maryland, USA
Abstract
Acute and chronic graft versus host disease (GVHD) remain the major barriers
to successful hematopoietic cell transplantation. The induction of GVHD may be
divided into three phases: (i) recipient conditioning; (ii) donor T-cell activation;
and (iii) effector cells mediating GVHD. This review examines GVHD preven-
tion and treatment using this conceptual model as framework.
The various pharmacological agents discussed impact on different phases of
the GVHD cascade. For example, keratinocyte growth factor and interleukin
(
IL)-11 are cytokines that may be useful in disrupting phase I of the GVHD
cascade by blocking gastrointestinal tract damage, and lowering serum levels of
lipopolysaccharide and tumour necrosis factor (TNF)-α. Cyclosporin, tacrolimus
(
FK-506) and sirolimus (rapamycin) are some of the main agents that disrupt
phase II (donor T-cell activation). Mycophenolate mofetil and tresperimus prob-
ably act on this phase as well. Other novel drugs that affect phase II are tolerance-
induction agents such as CTLA-4 and anti-CD40–ligand monoclonal antibodies,
and preliminary results using CTLA-4 monoclonal antibody in GVHD prevention
are encouraging. Examples of agents that disrupt phase III are the IL-2 receptor
antagonist daclizumab and the anti-TNFα monoclonal antibody infliximab.
These anti-cytokine antibodies have shown promising results in early studies.
The most effective approach to GVHD prevention will probably be a combi-
nation regimen where the three phases of the GVHD cascade are disrupted. Once
GVHD has occurred, all three phases of the cascade are activated. Developments
of combination therapy for treatment of both acute and chronic GVHD are likely
to yield better results than monotherapy. The numerous new treatment modalities
presented should improve the outlook for patients with acute and chronic GVHD.
This review aims at familiarising the reader
GVHD, a well-supported model of GVHD is dis-
cussed to set the stage. The agents and how they
potentially disrupt the GVHD cascade are then dis-
cussed. Prophylaxis is discussed first, then treat-
with novel approaches to the prevention and treat-
ment of graft-versus-host disease (GVHD). After
explaining the clinical symptoms associated with

8
80
Jacobsohn & Vogelsang
ment. Rather than grouping drugs by mechanism
of action, the review is deliberately structured to
provide information that would be immediately us-
able to the clinician.
thickened, sclerodermatous skin. Patients may de-
velop fasciitis and contractures. Dryness and mu-
cosal ulceration of the eyes and mouth are common.
The respiratory tract, gastrointestinal (GI) tract and
liver can also be affected.[ Patients receiving pe-
ripheral blood stem cell transplants (PBSC) have a
higher incidence of chronic GVHD than those re-
ceiving standard bone marrow transplant.[
2]
1
. Clinical Symptoms and
Pathophysiology
3]
Acute and chronic GVHD remain the major bar-
riers to successful hematopoietic stem cell trans-
plantation (SCT). Skin rash (which may progress
to dermal-epidermal separation), hepatic dysfunc-
tion and abdominal cramping with diarrhoea char-
acterise acute GVHD. Biopsies of affected organs
show lymphocyte infiltration. Most centres now
use the Keystone criteria (table I) for grading GVHD,
although some may make minor modifications.
The majority of patients with grade III to IV acute
GVHD die of their disease.
Chronic GVHD usually begins at least 100 days
after SCT but rarely may start earlier or over a year
after SCT. It can evolve from acute GVHD (pro-
gressive – associated with high mortality), follow
resolution of acute GVHD (quiescent), or start in
patients without history of acute GVHD (de novo).
Chronic GVHD mimics certain rheumatologic dis-
eases such as systemic lupus erythematosus and
Sjogren’s syndrome. Most commonly, patients
have skin involvement in the form of an erythem-
atous lichenoid papular rash that may progress to
The pathophysiology of acute GVHD may be
divided into three phases (figure 1). This model
allows us to understand which pathways can be
blocked to prevent or treat GVHD. In the first
phase, the conditioning regimen causes damage to
the intestinal mucosa and liver that leads to activa-
tion of host cells and release of inflammatory
cytokines such as tumour necrosis factor (TNF)-α,
interferon (IFN)-γ, and interleukin (IL)-1.[ These
cytokines upregulate major histocompatibility
4]
complex (MHC) antigens, thus enhancing their
recognition by donor T cells.[
5-9]
In the second
phase, donor T cells become activated and prolif-
erate in response to host antigens, fueled by the
inflammatory cytokines. Activation of T cells re-
quires two signals: the first from the T-cell receptor-
peptide–MHC interaction [
10,11]
and the second (co-
stimulatory) from contact with antigen-presenting
cells. The binding of B7 on the antigen-presenting
cell to CD28 or CTLA-4 on the T cell usually car-
ries out this signal. Another costimulatory signal is
Table I. Clinical staging and grading of acute graft-versus-host disease[1]
Stage or
Skin
Liver
GI tract
equivalent grade
Stage
1
Rash on <25% of skin
Bilirubin 2-3 mg/dl
Diarrhoea >500 ml/day or persistent
nausea with positive biopsy
2
3
4
Rash on 25-50% of skin
Rash on >50% of skin
Bilirubin 3-6 mg/dl
Bilirubin 6-15 mg/dl
Bilirubin >15 mg/dl
Diarrhoea >1000 ml/day
Diarrhoea >1500 ml/day
Generalised erythroderma with
bulla formation
Severe abdominal pain with or without ileus
Grade
1
Stage 1-2
Stage 3 or
None
None
2
Stage 1 or
Stage 2-3 or
Stage 4
Stage 1
Stage 2-4
3
4
Stage 4 or
GI = gastrointestinal.
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Prevention and Treatment of GVHD
881
(I) Recipient conditioning
Tissue damage
Infliximab
Host tissue
IL-1
Small
intestine
KGF, IL-11
IL-6
TNFα
LPS
Infliximab
MØ
Host
APC
CTLA-4
KGF, IL-11
TNFα
IL-1
Donor
T Cell
MMF; pentostatin;
post-transplant Cy
IL-12
Target cell
apoptosis
CTL
Th1
(III) Effector
IFNγ
IL-2
NK
CsA;
tacrolimus;
sirolimus
MMF; pentostatin
(
II) Donor T cell
activation
Daclizumab
Fig. 1. Acute graft versus host disease (GVHD) pathophysiology and pharmacotherapeutic intervention. The three sequential phases
of GVHD (I, II, III) are detailed. Agents discussed are shown in relation to the phases of GVHD they disrupt (Adapted from Hill and
Ferrara,[ © American Society of Hematology, with permission). APC = antigen-presenting cells; CsA = cyclosporin; CTL = cytotoxic
T cells; CTLA-4 = CTLA-4 monoclonal antibody; Cy = cyclophosphamide; IL = interleukin; IFN = interferon; KGF = keratinocyte growth
factor; LPS = lipopolysaccharide; MØ = monocyte; MMF = mycophenolate mofetil; NK = natural killer cell; Th1 = T helper-1 cell; TNF
13]
=
tumour necrosis factor.
the binding of CD40 to its ligand. Signalling
through the T-cell receptor in the absence of a sec-
ond signal leads to tolerance, whereas absence of
CTLA-4 leads to uncontrolled activation and
cytokine production.[12] Blockade of the costim-
ulatory signal would clearly be a potential way of
preventing GVHD.
can also cause direct injury of skin and intes-
tines.[14-16]
2
. Graft versus Host Disease
(
GVHD) Prophylaxis
The intent of this review is to provide a descrip-
tion of new therapies in the context of the GVHD
cascade to better comprehend where each agent
may fit in within the scope of treatment. A key
point is that for successful prophylaxis, it is likely
that disruption of more than one phase of the
GVHD cascade will be required. Figure 1 explains
how each agent disrupts the GVHD cascade. It
should be noted that certain drugs may affect more
than one phase of the GVHD cascade. Table II
In the third phase, monocytes that have been
primed by lipopolysaccharide (LPS) [secreted by
damaged intestinal mucosa], IL-2 and IFNγ (from
activated T cells), secrete IL-1 and TNFα. TNFα
causes direct tissue damage and causes apoptosis
via the TNFα–Fas pathway. IL-1 also leads to tar-
get cell apoptosis. In addition, cytotoxic Tcells and
natural killer (NK) cells, also activated by IFNγ
[
12]
and IL-2, lead to cellular damage. IFNγ and IL-2
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Jacobsohn & Vogelsang
shows a summary of key GVHD prophylaxis stud-
ies.
cytotoxic T cells, NK cells and monocytes; there-
fore reducing target cell apoptosis. Short-course
2
2
methotrexate (15mg/m on day 1; 10mg/m on
days 3, 6, and 11) plus cyclosporin for 6 months
has become the gold standard against which other
GVHD prophylaxis is measured. [ Controversy
exists as to whether the addition of corticosteroids
2
.1 Disruption of Phase I of the GVHD
Cascade (Recipient Conditioning)
24]
In animal models, IL-11 and keratinocyte
growth factor (KGF) act as ‘cytokine shields’ and,
when administered during the conditioning regi-
men, completely abolish GI tract GVHD. The
agents decrease serum levels of LPS and TNFα.
They appear to block GI tract damage in phase I,
preventing amplification of the cascade. However,
they preserve cytotoxic T cell and NK cell re-
sponses, maintaining the graft-versus-leukaemia
effect. As shown in figure 1, these agents also block
the activity of TNFα and IL-1 and therefore de-
to the regimen decreases the incidence of acute
GVHD.[
25,26]
However, the addition of methyl-
prednisolone increases the risk of bacterial and
fungal infections within the first 2 months after
SCT.[
27]
At some centres tacrolimus (FK-506) has re-
placed cyclosporin on the basis of two phase III
trials that showed a slight decrease in grade II to IV
acute GVHD with tacrolimus plus methotrexate
compared with cyclosporin plus methotrexate.
Overall disease-free survival is not different. Tox-
[
13]
crease target cell apoptosis in phase III. Both of
these agents are currently in clinical trials.
icities are similar except for nephrotoxicity, which
2
.2 Disruption of Phase II of the GVHD
[17,18]
is slightly higher in the tacrolimus group.
The
Cascade (Donor T Cell Activation)
mechanism of action of tacrolimus is similar to that
of cyclosporin but it is a more potent calcineurin
inhibitor,[ allowing lower doses to be used.
Mycophenolate mofetil blocks synthesis of RNA
and DNA by inhibition of inosine monophosphate
dehydrogenase. Lymphocytes do not have a sal-
Before the introduction of cyclosporin, the first
drug developed for purely immunomodulatory ef-
fects, lympholytic drugs such as methotrexate,
antithymocyte globulin, cyclophosphamide and
corticosteroids were used. Cyclosporin has com-
plex effects on the immune system but basically
28]
vage pathway and die in the presence of myco-
[
23]
[29]
acts by inhibiting IL-2 production.
Therefore,
phenolate mofetil.
The use of mycophenolate
cyclosporin acts mainly on phase II of the GVHD
cascade, preventing activation of Tcells. This leads
to disruption of phase III – decreasing activated
mofetil is appealing since it disrupts phases II and
III, where lymphocytes play a key role. It is suc-
cessful at preventing renal transplant rejection.[
30]
Table II. Summary of clinical trials for prophylaxis of acute graft versus host disease (aGVHD)
Drugs
Setting
Incidence aGVHD
Reference
17
Tacrolimus plus methotrexate
HLA-identical donor marrow (unmodified);
myeloablative
32% grade II-IV aGVHD
Tacrolimus plus methotrexate
MMF/CsA
Matched-unrelated donor marrow
56% grade II-IV aGVHD
25% grade II-IV aGVHD
18
(unmodified); myeloablative
HLA-identical PBSC; nonmyeloablative
19
20
CTLA-4 antibody–cultured donor marrow;
cyclosporin plus methotrexate prophylaxis
Mismatched marrow from parents/siblings;
myeloablative
27% grade II-IV aGVHD;
(only GI, no skin or liver)
Campath antibodies (in vitro treatment of
marrow and in vivo during conditioning)
HLA-identical donor marrow; myeloablative
4% grade II-IV aGVHD
21
22
Daclizumab with cyclosporin plus
methotrexate
Matched-unrelated donors; myeloablative
75% grade II-IV aGVHD
(no difference from placebo)
CsA = cyclosporin; GI = gastrointestinal; HLA = human leucocyte antigen; MMF = mycophenolate mofetil; PBSC = peripheral blood stem cell.
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Prevention and Treatment of GVHD
883
In SCT, it has mainly been used for GVHD prophy-
laxis after nonmyeloablative transplants. Born-
couraging initial results. Tolerance-induction drugs
are likely to be more effective without cyclosporin
or tacrolimus, since these agents prevent tolerance
by blocking signal 1.[
[
19]
hauser and colleagues reported 24 patients with
malignancies who received busulfan, fludarabine
and 200 cGy total body irradiation followed by
human leucocyte antigen (HLA)-identical PBSC.
GVHD prophylaxis was cyclosporin plus myco-
phenolate mofetil (1000mg orally twice daily on
days 1 to 40). Only 25% of patients developed
grade II to IV acute GVHD but it is too early to
determine the long-term incidence of chronic
GVHD.
33]
Sirolimus (rapamycin) may play an important
role in GVHD prophylaxis. In contrast to cyclo-
sporin or tacrolimus, this agent inhibits mTOR,
which is essential for T-cell proliferation, and thus
leads to cell cycle arrest.[ In animal models,
sirolimus is synergistic with co-stimulatory block-
ade in producing allograft tolerance.[ Thus, we
will probably see this agent used with tolerance-
induction regimens. Clinical trials are under way
but no results have been reported in marrow trans-
plants.
34]
35]
Another promising agent is tresperimus (15-
deoxyspergualin). One of the mechanisms of ac-
tion of tresperimus is binding to HSP70 in T cells
to inhibit nuclear factor kappa B (NF-κB) and thus
Finally, animal data from Johns Hopkins, Balti-
more, Maryland, USA, indicate that in non-
myeloablative transplants following fludarabine
and total body irradiation, post-transplant cyclo-
phosphamide (48 to 72 hours after transplant) in-
hibits acute GVHD mediated by T cells reactive to
host MHC and minor H antigens.[ The ability
of cyclophosphamide to prevent GVHD without
causing global immunosuppression is consistent
[
31]
prevent IL-2 activation.
This agent selectively
induces anergy post-transplant and has been used
to treat GVHD in animal models. A multicentre
clinical trial using tresperimus as prophylaxis for
GVHD in patients undergoing transplants for high-
risk malignancies is ongoing.
36]
Other interesting agents are those that induce
tolerance by blocking the costimulatory signal
(
signal 2), namely CTLA-4 and anti-CD40–ligand
with the selective toxicity of the drug to T cells
recently activated by antigen recognition.[
37]
A
monoclonal antibodies. These agents preserve T
cell response to other antigens, thus minimising
global immunosuppression. CTLA-4 monoclonal
antibody binds to B7 molecules with high affinity
and blocks signal 2 by preventing the binding of
B7 on the antigen presenting cell to CD28 on the
T cell.[ These agents have significant appeal as
they could potentially obliterate phase II of the cas-
cade, therefore diminishing resultant target cell
apoptosis. Guinan and colleagues[20] transplanted
clinical trial is currently underway examining the
effect of different dosages of post-transplant cyclo-
phosphamide.
Depletion of T cells is an effective way of pre-
venting GVHD but leads to higher relapse rates.
32]
The multiple non-pharmacological modalities of
depleting T cells[
38,39]
are beyond the scope of this
paper. Campath-1M is a rat immunoglobulin (Ig)M
antibody that recognises the human lymphocyte
antigen CD52. Although the use of Campath-1M
is an effective way of purging T cells in vitro by
cell lysis, it leads to higher relapse rates secondary
to ablation of the graft-versus-leukaemia ef-
fect.[
1
2 patients with mismatched marrow, from parents
or siblings, which was cultured with irradiated re-
cipient cells and CTLA-4 monoclonal antibody be-
fore infusion. The preparative regimen consisted
of total body irradiation, cyclosporin and methyl-
prednisolone ± cytarabine; and GVHD prophy-
laxis was cyclosporin plus methotrexate. No pa-
tient died of GVHD, and of 11 evaluable patients,
none had skin or liver GVHD and three had GI tract
GVHD. Larger studies will follow given the en-
40,41]
However, using in vivo with in vitro Campath
antibodies has shown promising results. In 70 pa-
tients receiving HLA-identical transplants for
acute myeloid leukaemia, T-cell depletion was ac-
complished with Campath-1M and immunosup-
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Jacobsohn & Vogelsang
pression consisted of in vivo Campath-1G 20mg/day
over 5 days during conditioning. Campath-1G is a
rat IgG2b CD52 antibody effective in depleting
tion, and there were a number of deaths secondary
to opportunistic infections.[
46,47]
To our knowledge, there is one randomised trial
comparing high- and low-dose methylpredniso-
lone for the treatment of acute GVHD.[ Patients
receiving 2mg/kg/day and 10mg/kg/day had the
same rate of response (70%) and the same 3-year
actuarial survival (62%). Higher morbidity was ob-
served with the higher dose. Therefore, there is no
compelling argument to start with a high dose of
corticosteroids. Initial response to corticosteroids,
either low-dose or high-dose, is very predictive of
future severity of GVHD and other transplant com-
plications.
[
42]
residual host T cells.
The incidence of acute
48]
GVHD was 4% and chronic GVHD was 3%. The
risk of relapse or 5-year leukaemia-free survival
was equal to historical controls receiving cyclo-
[
21]
sporin plus methotrexate. Campath-1G has also
been used in nonmyeloablative transplants with
good results.[
43]
Although longer follow-up is
needed to assess remission status and chronic
GVHD incidence, the use of Campath antibodies
in preparative regimens will be seen in future stud-
ies given positive initial results.
Table III shows a summary of key GVHD treat-
ment studies. Several different anti–IL-2 receptor
antibodies have been investigated as primary treat-
ment of acute GVHD. A study of 69 patients who
received treatment in 13 centres for acute GVHD
showed no benefit in survival or response when
adding an anti–IL-2 receptor antibody (inolimo-
mab; BT-563) to methylprednisolone and cyclo-
sporin, despite successful trials of this antibody in
salvage therapy.[
2
.3 Disruption of Phase III of the GVHD
Cascade (Effector)
Daclizumab or humanised anti-TAC antibody,
the IL-2 receptor antagonist, was studied in a
double-blind, placebo-controlled, multicenter trial
as add-on prophylaxis to cyclosporin and metho-
trexate. Daclizumab did not prevent acute GVHD
nor improve survival compared with placebo.[22]
Other agents that disrupt phase III (i.e. infliximab)
have not been studied in the context of prophylaxis.
If shown to have some benefit in treatment, these
agents should be further studied in this context.
49]
The study with daclizumab is more promising.
Daclizumab is a humanised monoclonal IgG1 that
incorporates the complementarity-determining re-
gions of a murine monoclonal antibody raised
3
. Treatment of Acute GVHD
[56,57]
against the human IL-2 receptor-α chain.
Forty-three patients received treatment at diagno-
sis of severe acute GVHD or after corticosteroid
failure. The dose of daclizumab was 1mg/kg and
was given on days 1, 8, 15, 22 and 29 (regimen 1)
to 24 patients and on days 1, 4, 8, 15 and 22 (regi-
men 2) to 19 patients. All patients were treated con-
currently with methylprednisolone 2mg/kg/day. If
there was no improvement within the first week,
antithymocyte globulin was added. At day 43, the
response rate was 51%. Responses were better in
skin than in GI tract or multiorgan GVHD. Regi-
men 2 yielded a higher complete response rate. Al-
though the drug was well tolerated, three patients
developed Epstein-Barr virus (EBV) lymphopro-
liferative disease.[ Future trials need to study
daclizumab in the absence of antithymocyte glob-
3
.1 Primary Treatment
Once GVHD occurs, all phases of GVHD induc-
tion are active. Successful treatment will ulti-
mately need to work on all phases. Most centres
treat grade II to IV acute GVHD by continuing im-
munosuppression and adding methylprednisolone
at 2 or 2.5 mg/kg/day. However, starting dosages
range from 1 to >20 mg/kg/day.[44] Corticosteroids
are tapered after control of GVHD. A rapid steroid
taper (86 days) is just as effective as a slow taper
(
147 days) in terms of preventing flares of GVHD
[
45]
or chronic GVHD. A few studies have reported
outcomes with high-dose methylprednisolone (20
to 50mg/kg/day). Patients that responded to these
dosages generally had a flare-up after dose reduc-
50]
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Prevention and Treatment of GVHD
885
Table III. Summary of clinical trials in the treatment of acute graft versus host disease (aGVHD)
Drugs
Setting
Response
Reference
Daclizumab
Most HLA-non identical transplants;
most steroid-refractory
51% response at day 43
50
51
52
53
54
55
CD5 immunotoxin plus
methylprednisolone
HLA-identical & unrelated transplants;
primary treatment
44% CR at 6 weeks (same as placebo)
Anti-CD2 monoclonal antibody
HLA-identical & unrelated transplants;
all steroid-refractory
55% improvement in overall aGVHD
grade
(salvage treatment)
Recombinant human IL-1 receptor
HLA-identical & unrelated transplants;
all steroid-refractory
57% improvement in overall aGVHD
grade
Infliximab
HLA-identical & unrelated transplants;
most steroid-refractory
74% overall (CR&PR)
Pentostatin
HLA-identical & unrelated transplants;
all steroid-refractory
67% overall (CR&PR)
CR = complete response; HLA = human leucocyte antigen; IL = interleukin; PR = partial response.
ulin (since 40% of patients in this trial received
antithymocyte globulin) to understand the inde-
pendent contribution of this agent to acute GVHD
therapy.
provement in skin, 15% in liver, and 32% in GI
tract. However, the survival rate was very poor:
median survival for grade II – 4.1 months, grade
III – 3.6 months, and grade IV – 2.7 months.
Ninety-five percent of deaths were attributed to in-
fection.[ Given these data, antithymocyte globu-
lin should not be considered standard therapy for
steroid-refractory GVHD.
Two randomised studies of antithymocyte glob-
ulin for initial therapy of grade II to IV GVHD
showed no difference in efficacy between antithy-
61]
[
58]
mocyte globulin and prednisone,
nor between
antithymocyte globulin plus prednisone and pre-
dnisone alone.[ In fact, given the very high risk
of infectious complications with antithymocyte
globulin use, this drug has a minimal role in
GVHD, particularly for primary treatment. Fur-
thermore, results from a phase III trial comparing
methylprednisolone plus placebo versus methyl-
prednisolone plus a CD5-specific immunotoxin
In an attempt to give more selective immuno-
suppression, many investigators have explored the
use of monoclonal antibodies. Use of an anti-CD2
59]
monoclonal antibody gave a response rate of 55%
[52]
in patients with steroid-resistant GVHD.
Re-
sults from a pilot study testing a recombinant hu-
man IL-1 receptor demonstrate a 57% response
[53]
rate in patients with acute GVHD. These results
(
xomazyme) yielded similar outcomes in both
should be interpreted with caution as there were
few patients enrolled and results from larger stud-
ies have not been reported.
[
51]
groups.
3
.2 Salvage Therapy
A promising agent is infliximab, an anti-TNFα
monoclonal antibody licensed for the treatment of
Crohn’s disease and rheumatoid arthritis. At the
MD Anderson Cancer Center, Houston, Texas,
USA, close to 75% of patients (n = 32) with acute
GVHD demonstrated a response to intravenous in-
fliximab 10mg/kg weekly for 4 weeks. A majority
of these patients had steroid-refractory disease.
The drug appears to work best for skin and GI
tract GVHD and much less so for liver.[ Amulti-
centre, randomised trial is under way to evaluate
the efficacy of this drug. When used for treat-
The response to salvage therapy after failure to
initial therapy (i.e. progression after 3 days, no
change after 7 days, or incomplete response after
1
4 days of corticosteroid therapy) is usually very
poor. The most common agents used as salvage
therapy are antithymocyte globulin, monoclonal
antibodies and higher dosages of corticoste-
[
44,60]
roids.
The review of the experience at Johns
54]
Hopkins’ with antithymocyte globulin shows that
of 69 patients who received antithymocyte globu-
lin for steroid-refractory GVHD, 59% had im-
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8
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Jacobsohn & Vogelsang
ment, infliximab probably impacts phase III most-
ly. Potentially, this drug could also be used prophy-
lactically by decreasing MHC antigen presentation
thus affecting donor T-cell activation (phase I/II).
Finally, pentostatin, a purine analogue that ap-
pears to be less myelosuppressive than fludarabine,
is being explored at Johns Hopkins for the treat-
ment of acute GVHD. Being a lympholytic agent,
this drug is likely to affect both phase II and III of
the GVHD cascade. Out of 15 patients with steroid-
refractory acute GVHD, seven achieved a com-
plete response and three patients achieved a partial
response (overall response 67%). Responses are
mostly in the skin and gut, and less so in the
liver.[ The goal of our study is to determine a
rational dose administration schedule before ad-
vancing the drug in clinical trials. It is most likely
that dose administration schedules different from
chemotherapeutic regimens will be optimal.
and the drug has therefore fallen out of favour with
other newer agents being preferred. Another agent
sometimes used in patients with steroid-refractory
chronic GVHD is azathioprine. However, given its
myelosuppressive effects and high incidence of in-
fections, it is best avoided.[
66]
We are currently studying, in a phase II trial, the
combination of mycophenolate mofetil and tacro-
limus. A retrospective review of 26 patients with
refractory chronic GVHD who received treatment
with this steroid-sparing combination showed that
it was well tolerated, and nearly half the patients
showed an objective response.[
67]
A study using pentostatin is also under way at
55]
2
Johns Hopkins. Patients are receiving 4mg/m in-
travenously every 2 weeks for 6 months. Of 17 pa-
tients treated so far, there have been objective re-
sponses in 65%.[ Particularly encouraging is that
some heavily pre-treated patients with scleroder-
matous skin and fascial changes showed dramatic
responses. The goal after this study is to incorpo-
rate this agent as front-line treatment of chronic
GVHD to avoid corticosteroids and their toxicities.
68]
4
. Treatment of Chronic GVHD
4
.1 Standard Therapy
Although there is no specific ‘standard therapy’,
it seems that most centres start with prednisone
and cyclosporin for the treatment of chronic GVHD.
One regimen that appears to improve survival in
patients with high-risk features such as thrombo-
cytopenia and extensive skin involvement is alter-
nate-day prednisone and cyclosporin.[ At our in-
stitution, patients are evaluated every 3 months and
therapy is continued for 3 months after maximal
response. The 3-month time frame for evaluation
of response to a given therapy is based on our own
observation that 90% of patients who are ulti-
mately going to respond to therapy will show signs
4
.3 Additional Treatment Considerations
Etretinate and acitretin are synthetic retinoids
used in dermatological conditions. In a case series
of 32 patients, these drugs induced improvement in
about 65% of patients with sclerodermatous chronic
GVHD when added on to a chronic GVHD regi-
men.[ The mechanism of action of the retinoids
is not likely to involve modulation of the immune
response to foreign antigen.
Clofazimine is an antimycobacterial drug with
anti-inflammatory activity that, in a recent phase II
trial, yielded an approximately 50% response rate
in patients with skin involvement, flexion contrac-
tures or oral manifestations. The drug was added
on, in most cases, to the immunosuppressive regi-
men of the patient.[
62]
69]
[
63]
of response at that point.
4
.2 Salvage Regimens
70]
An agent initially shown by Vogelsang to have
a role in chronic GVHD is thalidomide. The re-
sponse of patients with high-risk chronic GVHD to
Hydroxychloroquine is an antimalarial agent
that down-regulates MHC. It also appears to have
a role in treating sclerodermatous chronic GVHD
and does not lead to skin drying, flaking or ulcer-
ation (as seen with acitretin).[ A phase III trial of
[
64,65]
thalidomide appears to be 20 to 30%.
Unfor-
tunately, the adverse effects (particularly sedation
and constipation) are intolerable to many patients
71]
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Drugs 2002; 62 (6)

Prevention and Treatment of GVHD
887
initial therapy of patients with chronic GVHD
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Dr Jacobsohn receives funding through NIH/NCI Grant
number 5K12CA01709. Drs Jacobsohn and Vogelsang are
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Correspondence and offprints: Dr David A Jacobsohn, Pe-
diatric Oncology/CMSC800, Johns Hopkins Hospital, 600
North Wolfe Street, Baltimore, MD 21287, USA.
E-mail: jacobda@jhmi.edu
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Adis International Limited. All rights reserved.
Drugs 2002; 62 (6)