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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 93 No. 1 (January 1), 1999:
pp. 66-70
Etretinate Therapy for Refractory Sclerodermatous Chronic
Graft-Versus-Host Disease
By
D.C. Marcellus,
V.L. Altomonte,
E.R. Farmer,
T.D. Horn,
C.S. Freemer,
J. Grant, and
G.B. Vogelsang
From the Departments of Oncology, of Dermatology and Pathology, and
of Rehabilitation Medicine, Johns Hopkins University, Baltimore, MD;
the Department of Dermatology, Indiana University, Indianapolis; and
the Department of Dermatology, University of Arkansas, Little Rock.
 |
ABSTRACT |
Chronic graft-versus-host disease (GVHD) is the most common late
complication of allogeneic bone marrow transplantation (BMT). The
sclerodermatous form of the disease is often refractory to standard
treatment modalities. Based on reports of response to etretinate, a
synthetic retinoid, among patients with scleroderma, we have added
etretinate to the treatment regimen of 32 patients with refractory
sclerodermatous chronic GVHD. This case series is comprised mainly of
patients who had chronic GVHD of long duration (median of 30 months
before the initiation of etretinate). Most had failed to respond to
three or more agents before etretinate treatment was started. Clinical
response was assessed after 3 months of therapy. Five patients did not
complete a 3-month trial. Among the 27 patients evaluable for response,
20 showed improvement including softening of the skin, flattening of
cutaneous lesions, increased range of motion, and improved
performance status. Four showed no response after 3 months of
therapy and 3 had progression of their sclerosis. Overall, etretinate
has been fairly well tolerated in our patients, with skin breakdown
and/or ulceration leading to its discontinuation in 6 patients.
We believe the results in our patients are encouraging and suggest that
further evaluation of etretinate in the treatment of sclerodermatous
chronic GVHD is warranted.
© 1999 by The American Society of Hematology.
| |
INTRODUCTION |
AS THE MOST COMMON late complication of
allogeneic bone marrow transplantation (BMT), chronic graft-versus-host
disease (GVHD) presents many clinical and therapeutic challenges. With the increasing number of allogeneic, mismatched, and unrelated BMTs
being performed, the number of patients with chronic GVHD continues to
grow. When chronic GVHD takes on sclerodermatous features, the
patient's mobility, independence in activities of daily living, and
overall quality of life may be severely affected. Many patients with
sclerodermatous chronic GVHD are refractory to standard
immunosuppressing medications, such as steroids and cyclosporine-A
(CSA). In this report, we present results of a case series of 32 patients with refractory sclerodermatous chronic GVHD who, after
failing to show improvement in the cutaneous manifestations of this
condition, had etretinate added to their regimen.
Etretinate is a synthetic vitamin A derivative belonging to the class
of drugs known as retinoids. Because of their role in the normal
maintenance and differentiation of epithelial tissue, retinoids have
been used in the treatment of several dermatologic conditions.1-8 Isotretinoin (Accutane) is used in the
treatment of severe acne and has also been administered to patients
with systemic sclerosis.8 Etretinate (Tegison), too, has
been used for the treatment of scleroderma, although its primary use
has been in other dermatologic conditions, such as psoriasis, mycosis fungoides, and Sezary syndrome.6,7 Our interest in using etretinate in the treatment of sclerodermatous chronic GVHD grew out of
the observed benefit in other dermatologic conditions.
| |
MATERIALS AND METHODS |
Between July 1989 and September 1995, we used etretinate to treat 32 patients with refractory sclerodermatous chronic GVHD. Potential
patients were identified from among those transplanted at the Johns
Hopkins Oncology Center and those referred to our Chronic GVHD
Consultation Clinic. The diagnosis of sclerodermatous chronic GVHD was
made clinically in patients who had previous histologic documentation
of cutaneous GVHD. All patients had received a therapeutic trial of
standard therapy for their chronic GVHD, such as steroids
and/or CSA for a minimum of 3 months, before the initiation of
etretinate therapy. All patients were felt to have either progressive
or persistent disease despite treatment with such agents. Patients were
maintained on therapeutic doses of immunosuppressive therapy, to which
etretinate was then added. All patients received standard supportive
measures, including prophylaxis against infections, as well as a
thorough evaluation and recommendations by physical therapy.
Patients in this case series were treated over a 6-year period, and the
method of administration of etretinate changed as our experience with
this agent in this population grew. Initially, the agent was
administered in the same dose and dosing schedule used for other
dermatologic conditions, with the full desired dose (1.0 mg/kg/d) being
administered from the initiation of therapy. Over time, we found that
patients tolerated the drug best when it was started at a lower initial
dose and gradually increased according to patient tolerance. The
initial dose ranged between 0.25 and 1.0 mg/kg/d administered orally in
two to four divided doses. Our current approach is to start at 0.25 mg/kg/d in two divided doses and increase over 2 weeks towards the full
desired dose of 1 mg/kg/d. Serum cholesterol, triglycerides, and liver enzymes were measured and adjustments in therapy were made based on
these results.
All patients were observed by the multidisciplinary team in our Chronic
GVHD Clinic. The clinical response to therapy and development of side
effects were recorded. Initial response was assessed at a minimum of 3 months of therapy. In addition to the subjective reporting of the
patient, improvement was documented when we had evidence of softening
of the skin, flattening of cutaneous lesions, objective increases in
range of motion, and/or objective increases in muscle strength
as measured by the physical therapist on the team.
| |
RESULTS |
These 32 patients, transplanted at a number of different institutions,
represent a heterogeneous group, with the common feature being the
development of refractory sclerodermatous chronic GVHD. The age of
these patients, at the time of BMT, ranged from 5 to 49 years (median,
29 years). Fifteen patients were male. The transplants were performed
for a variety of hematologic conditions: chronic myelogenous leukemia
(11 patients), acute myelogenous leukemia (7 patients),
acute lymphoblastic leukemia (5 patients), aplastic anemia (3 patients), myelodysplastic syndrome (2 patients), Hodgkin's disease (1 patient), non-Hodgkin's lymphoma (1 patient), chronic lymphocytic
leukemia (1 patient), and multiple myeloma (1 patient).
Nineteen of the 32 patients underwent an allogeneic BMT from an
HLA-identical sibling donor. Three patients received marrow from
related donors who were not a complete HLA match: either one-antigen (n = 2) or two-antigen (n = 1) mismatches. Two patients have undergone two
transplants. In both cases, the second transplant was performed using
marrow from the same matched sibling donor. Eight patients had
transplants from unrelated donors. Most transplants (20/34) were
performed using total body irradiation as part of the conditioning
regimen. With respect to the first or only transplant for the 32 patients, 30 are known to have received CSA as prophylaxis against
acute GVHD; 16 received CSA in combination with other agents, including
steroids, methotrexate, and azathioprine. Twenty-four of these patients
developed acute GVHD requiring therapy; 10 had involvement of the skin
alone, 1 is reported to have had acute GVHD limited to the liver, and
the remainder were felt to have had multiorgan acute GVHD.
Chronic GVHD developed 1 to 24 months post-BMT (median, 7 months) and
involved the skin and/or fascia in all patients. Other sites or
organs were also involved in all but 4 patients. Before initiating
etretinate, all but 1 patient had received systemic steroids for their
chronic GVHD. All but 2 patients had received additional agents,
including CSA (N = 24), thalidomide (N = 14), psoralen-ultraviolet A
irradiation (PUVA) (N = 12), azathioprine (N = 10), FK506 (N = 1),
colchicine (N = 1), and photopheresis (N = 1), before starting
etretinate. Fourteen of the patients had received three
drugs/modalities and 9 patients had received four before etretinate
therapy was started. The time from the onset of chronic GVHD to the
initiation of etretinate therapy ranged from 3 to 84 months (median, 30 months).
As shown in Table 1, the
main indication to start etretinate was progression of sclerodermatous
skin changes despite treatment (21/32). Less commonly, etretinate was
started for failure to improve (N = 8). Two patients received
etretinate for the development of sclerodermatous changes while on
full-dose therapy for lichenoid chronic GVHD and 1 patient received
etretinate for a flare of previously controlled sclerodermatous GVHD.
The intention was to assess response after 3 months of therapy. Five
patients received less than 3 months of therapy and are considered
nonevaluable for response. The course was shorter than 3 months in
these 5 patients because of skin breakdown (N = 1), patient choice to
stop the drug after 1 day (N = 1), and early death not considered
directly attributable to etretinate (N = 3). All patients were
considered evaluable for toxicity.
Among the 27 patients evaluable for response, 20 have shown improvement
while receiving etretinate. Two of these patients have continued to
improve after the withdrawal of the drug. In the majority of these
patients, response has been evidenced by improved functional status and
objective increase in range of motion. Likely as a result of the
duration, extent, and severity of disease, most patients have not had
complete reversal of their sclerodermatous chronic GVHD. However, 2 patients have had nearly complete resolution of the sclerodermatous
GVHD. Of the remaining 7 evaluable patients, 3 had progressive disease
and 4 had equivocal or no response but did not progress while on
therapy.
The duration of therapy in the evaluable patients has ranged from 3 months to 3 years, with 14 patients continuing to receive etretinate at
the time that these data were complied. The drug was discontinued after
3 months in the remaining evaluable patients for the following reasons:
maximal improvement (N = 4), skin breakdown and/or ulceration
(N = 5), progressive sclerosis (N = 3), and death due to bacterial
pneumonia and liver failure (N = 1).
All 32 patients were evaluable for toxicity, as shown in
Table 2. Previously reported side effects
with this agent have been observed among our
patients.9 All patients have noted cracking of
their nails. Many patients have had scaling and/or ulceration of the skin. This required discontinuation of the etretinate in 6 of 32 patients: 1 before a full 3-month trial could be completed, 1 in whom a
response to the therapy was observed, and 4 in whom no response was
seen despite a 3- to 10-month trial. Xerosis, cheilitis, pruritus,
transient hypertriglyceridemia, transient hypercholesterolemia, and eye
irritation have occurred but have not necessitated stopping
administration of the drug. Some patients have also noted thinning of
the hair. No serious organ toxicity attributable to the etretinate has
been documented. Four patients died during this period. Three patients
died of, or with, infections. In one case, the cause of death was
unknown.
| |
DISCUSSION |
As reported in this case series, the systemic administration of the
vitamin A derivative, etretinate, has produced encouraging results
among patients with refractory sclerodermatous chronic GVHD. Whereas
Gryn and Crilley10 have reported on the use of topical
retinoic acid (tretinoin) in 1 patient with cutaneous GVHD, our
interest in this class of agents stems from their use in a
variety of dermatologic conditions, including
scleroderma.1-8 The skin manifestations of the autoimmune
disease, systemic sclerosis (scleroderma), are clinically and
histologically similar to the cutaneous manifestations of
sclerodermatous chronic GVHD. Both conditions are characterized by
excess collagen production. Although the exact mechanism of action of
etretinate is not clearly understood, it is likely that inhibition of
fibroblast growth and decreased collagen production in dermal
fibroblasts is of importance.11-15 Patients with
sclerodermatous chronic GVHD may fail to improve either because of
progressive chronic GVHD or when there is no improvement of their
fibrosis, despite stable or improved GVHD.
Because GVHD is felt to be immune mediated, standard approaches to
chronic GVHD have, to date, been aimed at immunosuppression. Retinoids
have been shown to affect the production of various cytokines in
vitro.16-22 It is of interest that immunomodulatory effects
of retinoids are being recognized. We do not know if etretinate works
predominantly as an immunosuppressant in this setting, because as our
patients were failing to respond or, more commonly, progressing despite
immunosuppressive therapy when etretinate was added. We do not know how
the immune process connects to the resolution of fibrosis, but it seems
reasonable to administer a therapy with a unique mechanism of action to
patients who have significant sclerodermatous involvement. The probable
effects on fibroblasts make etretinate an attractive consideration in
such patients.
Although etretinate has been relatively well-tolerated in our patients,
there are important potential toxicities that must be closely
monitored. Of particular concern is the fact that etretinate is
teratogenic and must not be administered to women who are pregnant or
who intend to become pregnant. Although many BMT patients
are rendered sterile by the procedure, not all patients will be
permanently infertile. The period of time during which pregnancy should
be avoided after discontinuation of etretinate therapy has not been established. The drug is stored in adipose tissue and has been detected
in the blood of some patients even 2.9 years after therapy was stopped.
Acetretin, a less lipophilic formulation of etretinate, has now
replaced Tegison and will be used in subsequent studies. Other less
common but serious side effects include hepatotoxicity. Although
relatively uncommon and usually reversible, there have been at least
four reports of hepatitis-related deaths worldwide. Our patient who
died of bacterial pneumonia developed liver failure during this septic
event and not during the previous 12 months of etretinate therapy.
Etretinate and other retinoids have been associated with pseudo-tumor
cerebri in less than 1% of patients treated but was not seen in any of
our patients.
We believe that the preliminary results in this series of patients are
encouraging and suggest that further evaluation of etretinate in the
treatment of sclerodermatous chronic GVHD is warranted. Etretinate may
offer a new therapeutic option in this setting; however, where it might
fit into the treatment schema remains to be determined. The activity of
the sclerotic process and, therefore, the determination of response
presents unique challenges in this setting. In addition, given the
potential toxicities of etretinate, we believe that further study in
the form of a clinical trial using a systematic approach to determine
duration of therapy, response rate, and toxicity is needed.
| |
FOOTNOTES |
Submitted January 21, 1998;
accepted September 1, 1998.
The publication costs of this
article were defrayed in part by
page charge payment. This article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. section
1734 solely to indicate this fact.
Address reprint requests to D.C. Marcellus, MD, Room 171, Johns Hopkins Oncology Center, 600 N Wolfe St, Baltimore, MD
21287-8985.
| |
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Abstract
Introduction