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Blood, 1 December 2000, Vol. 96, No. 12, pp. 3995-3996
BRIEF REPORT
Thalidomide for treatment of patients with chronic
graft-versus-host disease
Sibel Koc,
Wendy Leisenring,
Mary E. D. Flowers,
Claudio Anasetti,
H. Joachim Deeg,
Richard A. Nash,
Jean E. Sanders,
Robert P. Witherspoon,
Frederick R. Appelbaum,
Rainer Storb, and
Paul J. Martin
From the Division of Clinical Research, Fred Hutchinson
Cancer Research Center, Seattle, WA, and Department of Medicine,
University of Washington, Seattle, WA.
 |
Abstract |
In a randomized, placebo-controlled, double-blind trial,
thalidomide or placebo together with glucocorticoids and either
cyclosporine or tacrolimus was administered as initial therapy for
clinical extensive chronic graft-versus-host disease (cGVHD). All
patients had thrombocytopenia or cGVHD that evolved directly from acute GVHD as an indicator of a poor prognosis. The study drug (thalidomide or placebo) was administered initially at a dose of 200 mg orally per
day, followed by a gradual increase to 800 mg/d if side effects were
tolerable. Treatment with the study drug was discontinued before
resolution of cGVHD in 23 (92%) of the 25 patients who received
thalidomide and in 17 (65%) of the 26 patients who received placebo
(P = .02). Neutropenia and neurologic symptoms were the most frequent reasons for early discontinuation of treatment with thalidomide. The duration of treatment with thalidomide was too short
to assess its efficacy in controlling cGVHD.
(Blood. 2000;96:3995-3996)
© 2000 by The American Society of Hematology.
| |
Introduction |
Case reports have described the use of thalidomide
for treatment of chronic graft-versus-host disease
(cGVHD),1-4 and preclinical studies demonstrated activity
in a rat model of cGVHD.5 In a subsequent phase II
clinical trial, 8 (38%) of 21 patients with high-risk cGVHD improved
after primary treatment with thalidomide.6 In the same
study, improvement was also observed after treatment with thalidomide
in 18 (78%) of 23 patients with cGVHD who had not responded previously
to other treatment. In a confirmatory study, 16 (20%) of 80 patients
with refractory cGVHD showed improvement after treatment with
thalidomide.7 To evaluate the efficacy of thalidomide as
primary treatment for patients with high-risk cGVHD, we conducted a
phase III, randomized trial comparing thalidomide versus placebo, given
in combination with cyclosporine (or tacrolimus) and prednisone.
| |
Study design |
Fifty-two patients with clinical extensive cGVHD consented to
participate. Twenty-six were assigned to receive thalidomide and 26 were assigned to receive placebo. One patient assigned to receive
thalidomide withdrew from the study before beginning treatment and was
excluded from further evaluation.
Prednisone was administered orally at a dose of 1.0 mg/kg per day
for the first 2 weeks, followed by gradual reduction to 0.5 mg/kg every
other day by week 22. Cyclosporine was administered orally at a dose of
12 mg/kg per day, if tolerated, and then gradually decreased after 22 weeks to 6 mg/kg per day. Alternatively, tacrolimus was administered
orally at a dose of 0.12 mg/kg per day, if tolerated, and then
gradually decreased after 22 weeks to 0.06 mg/kg per day.
The study drug (thalidomide or placebo with identical appearance) was
supplied by Grünenthal GmbH (Stolberg, Germany), dispensed under
IND 40758 and administered initially at 200 mg orally once daily (3 mg/kg once daily for children less than 12 years of age and less than
67 kg of body weight). The dose was gradually increased to reach a
target dose of 200 mg 4 times daily (3 mg/kg 4 times daily for
children), if sedation was tolerable. If sedation was intolerable, the
dose of study drug was decreased by 25% to 50%. After sedation
resolved, the dose was re-escalated by 25% to 50% increments as
tolerated. A monthly patient self-assessment for symptoms of weakness,
dysesthesias, or clumsiness was used for interim neurologic
evaluations, and administration of the study drug was discontinued if
neuropathy was documented at any time after starting treatment.
Treatment with the study drug was suspended if the absolute neutrophil
count was 500 to 1000/µL on 2 consecutive occasions or less than
500/µL on a single occasion. Treatment was resumed with a 50%
reduction in dose when the absolute neutrophil count surpassed
1500/µL, and the dose was gradually increased as allowed by toxicity.
If neutropenia recurred, treatment with study drug was discontinued permanently.
The original study design specified that the primary end point was
death from any cause other than recurrent malignancy. Enrollment of 66 patients in each arm was projected to have 90% power and 95%
confidence for detecting a decrease from 35% transplant-related mortality at 2 years among patients treated with placebo to 10% among
patients treated with thalidomide. An interim analysis by an
independent data and safety monitoring committee was planned after the
first 15 transplant-related deaths had occurred, and the study was to
be terminated if the P value for the difference between the
2 arms was less than .0051. Results of the interim analysis did not
show a significant transplant-related mortality difference between the
2 arms. Moreover, the results indicated less than 42% probability of
reaching statistical significance for this end point if the study was
continued to its originally planned enrollment, assuming that the
original hypothesis was correct for the remaining patients. Because it
had taken nearly 5 years to enroll the first 51 patients, and because
there was little chance of a positive result, the study was closed
prematurely. In the analysis summarized below, survival was evaluated
with the use of Kaplan-Meier estimates, and all other time-to-event end
points were evaluated with the use of cumulative incidence estimates to
account for competing risk events.8 Time-to-event data
were compared by log-rank tests, and other outcomes were compared by
Mann-Whitney tests,  2 tests, or Fisher exact tests.
| |
Results and discussion |
The maximum administered dose of the study drug was significantly
lower for patients who received thalidomide as compared to those who
received placebo (P = .005) (Table
1). Only 4 (16%) of 25 patients were
able to tolerate thalidomide at the prescribed daily target dose,
whereas 14 (54%) of 26 patients were able to tolerate placebo at the
prescribed daily target dose. Thirteen patients (52%) in the
thalidomide group and 2 (8%) in the placebo group received only 25%
of the prescribed daily target dose. Neutropenia occurred in 64% of
the patients treated with thalidomide and in 23% of those who received
placebo (P = .003). Numbness occurred in 48% of the
patients treated with thalidomide and in 23% of those who received
placebo (P = .08). After treatment with thalidomide, 17 patients reported sedation, and 10 had constipation. After treatment
with placebo, 5 patients reported sedation, and 2 had constipation
(P = .001 and .009, respectively).
The median duration of treatment with thalidomide was 53 days
(range, 1-411) compared to 245 days (range, 9-654) for placebo (Figure
1). Administration of study drug was
discontinued before resolution of cGVHD in 23 (92%) of the patients
assigned to receive thalidomide and in 17 (65%) of those assigned to
receive placebo (P = .02). Treatment with study drug was
discontinued before resolution of cGVHD because of neutropenia in 14 patients who received thalidomide and in 4 patients who received
placebo (P = .002). Treatment with study drug was
discontinued because of neurologic symptoms in 11 patients who received
thalidomide and in 3 patients who received placebo
(P = .01). We suspect that patients who enrolled in
previously published studies6,7 required considerable
encouragement and support to sustain compliance with a regimen of
thalidomide at doses of 200 mg or greater per day.
View larger version (14K):
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| Figure 1.
Duration of treatment.
The time to discontinuation of study drug was shorter for patients who
received thalidomide than for those who received placebo. One patient
who received thalidomide and 5 patients who received placebo continued
treatment with study drug until the onset of their terminal illness.
These patients were categorized as not having discontinued treatment
with the study drug before death.
|
|
The cumulative incidence of secondary therapy for cGVHD is projected to
reach 28% at 4 years for patients treated with thalidomide and 47%
for those who received placebo (P = .35). The cumulative incidence of discontinuation of all immunosuppressive medications after
resolution of cGVHD is projected to reach 39% at 4 years for patients
who received thalidomide and 23% for those who received placebo
(P = .12). These trends support previous
results6,7 suggesting that thalidomide might have limited
efficacy for treatment of cGVHD. At 3 years after enrollment in the
study, the product limit estimate of survival was 49% for patients
treated with thalidomide and 47% for those who received placebo
(P = .87). The most frequent causes of death were
infection, cGVHD, and recurrent malignancy.
The duration of treatment with thalidomide in our study was quite
short. Treatment with thalidomide might promote the development of
tolerance, thereby explaining how such a limited intervention might
improve the longer-term prospects of resolving cGVHD during continued
immunosuppressive treatment. Our results suggest that a regimen of 100 mg/d might be well tolerated, especially if given as a single dose at
night. With this regimen, it would be possible to determine whether
administration of thalidomide for 9 to 12 months has any benefit for
patients with cGVHD.
| |
Acknowledgments |
We thank the physicians and nurses who cared for patients, Aurora
Brandvold and Terese Ajer for help with data collection and data
management, Alison Sell and Jennifer Brackensick for editorial assistance.
| |
Footnotes |
Submitted April 17, 2000; accepted August 1, 2000.
Supported by grants HL36444 and CA18221 from the National Institutes of
Health, Department of Health and Human Services, and Grünenthal
GmbH, Stolberg, Germany.
The publication costs of this
article were defrayed in part by
page charge payment. Therefore,
and solely to indicate this fact,
this article is hereby marked
"advertisement"
in accordance with 18 U.S.C.
section 1734.
Reprints: Paul J. Martin, Fred Hutchinson Cancer Research
Center, 1100 Fairview Ave North, D2-100, PO Box 19024, Seattle, WA
98109-1024; e-mail: pmartin{at}fhcrc.org.
| |
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Abstract
Introduction