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Denileukin Diftitox for the Treatment of Panniculitic Lymphoma
Karen S. McGinnis, MD;
Michael Shapiro, MD;
Jacqueline M. Junkins-Hopkins, MD;
Mitchell Smith, MD, PhD;
Stuart R. Lessin, MD;
Carmela C. Vittorio, MD;
Alain H. Rook, MD
From the Department of Dermatology, University of Pennsylvania (Drs
McGinnis, Shapiro, Junkins-Hopkins, Vittorio, and Rook); and the Lymphoma
Service, Fox Chase Cancer Center (Drs Smith and Lessin), Philadelphia, Pa.
Arch Dermatol. 2002;138:740-742.
REPORT OF A CASE
A 24-year-old white woman presented with a 9-month history of proximal
extremity nodules, associated with fevers and arthralgias, that had only a
partial response to a combination of oral prednisone, topical betamethasone
ointment, and topical calcipotriene ointment.
Examination revealed a healthy-appearing woman with a low-grade fever.
There were annular and polycyclic eroded plaques and firm subcutaneous nodules
on her proximal arms and dusky red, atrophic plaques on her right thigh and
the middle of her back (Figure 1A).
Laboratory evaluation revealed a microcytic anemia (hemoglobin, 11.2 g/dL;
mean corpuscular volume, 77 fL) and normal liver function test results. Results
of several skin biopsies showed histological and immunophenotypic features
of subcutaneous panniculitic T-cell lymphoma (Figure 2A and B).
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Figure 1. A, Pretreatment clinical picture
showing skin lesions on right arm demonstrating a dusky red, annular eroded
plaque overlying a subcutaneous nodule. B, Posttreatment clinical picture
showing resolution of the erythema with residual subcutaneous tissue atrophy.
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Figure 2. A, Scanning-power view of a biopsy
specimen taken from a right thigh nodule prior to therapy demonstrating a
dense lobular atypical lymphoid infiltrate with areas of coagulation necrosis
(hematoxylin-eosin, original magnification x20). B, Intermediate-power
view of the lymphoid infiltrate showing a pleomorphic population of intermediate
to large lymphocytes. There is rimming of adipocytes by atypical lymphocytes,
enperipoesis, and karyorrhexis (hematoxylin-eosin, original magnification
x400).
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A positron emission tomographic scan showed multiple foci of intense
fludeoxyglucose F 18 uptake superficially within the upper extremities and
proximal right lower extremity consistent with the cutaneous T-cell malignancy,
without extracutaneous disease (Figure 3A).
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Figure 3. A, Pretreatment positron emission
tomographic scan (July 28, 2000) demonstrating multiple foci of intense fludeoxyglucose
F 18 uptake noted superficially within both upper extremities consistent with
the patient's known subcutaneous lymphoma. B, Positron emission tomographic
scan after 3 cycles of denileukin diftitox (February 1, 2001) showing resolution
of the initial findings of increased fludeoxyglucose F 18 uptake in the upper
extremities.
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She initially responded to bexarotene (Targretin; Ligand Pharmaceuticals
Inc, San Diego, Calif) (150 mg/d) and interferon alfa (1.8 x106 U, 3 times weekly). However, within 2 months of initiating these therapies,
her disease had progressed rapidly with an increase in size, number, and degree
of infiltration of the lesions and worsening of her constitutional symptoms
with increased fatigue and low-grade fevers. She was prescribed prednisone
(15 mg/d orally).
THERAPEUTIC CHALLENGE
The poor prognosis of rapidly progressive subcutaneous panniculitic
T-cell lymphoma as well as the proven therapeutic efficacy of denileukin diftitox
(Ontak; Ligand Pharmaceuticals Inc) for the treatment of cutaneous T-cell
lymphoma (CTCL)1 prompted us to evaluate its
potential benefit in subcutaneous panniculitic T-cell lymphoma.
SOLUTION
Five cycles of intravenous denileukin diftitox (9 µg/kg daily
for 5 days [1 cycle]) were administered. Clinical remission, with resolution
of all cutaneous disease and constitutional symptoms, was achieved 2 weeks
after the completion of the third cycle of denileukin diftitox (Figure 1B). A repeated positron emission tomographic scan confirmed
the resolution of cutaneous disease (Figure
3B). At that time, prednisone was tapered off prior to the fourth
cycle. Nine months after completion of denileukin diftitox therapy, the patient
remains in complete remission.
COMMENT
Subcutaneous panniculitic T-cell lymphoma is a rare form of T-cell lymphoma
characterized by primary involvement of the subcutaneous fat in a manner that
mimics panniculitis.2 It typically presents
with tan-to-red, deep-seated nodules, particularly on the extremities, with
systemic complaints of low-grade fever and weight loss.3-4
The behavior of subcutaneous panniculitic T-cell lymphoma is generally
considered to follow 1 of 2 clinical courses: aggressive disease associated
with a hemophagocytic syndrome or indolent disease with recurrent, self-healing
lesions.5 The hemophagocytic syndrome is characterized
by florid hemophagocytosis, thought to be triggered by a phagocytosis-inducing
factor secreted by the neoplastic T cells.4
Clinically, this is manifested as pancytopenia and hyperbilirubinemia, rapidly
terminating in death secondary to either bleeding or infection.6
Treatments that have been used in the past include systemic chemotherapy,5, 7-8 radiotherapy,5 high-dose chemoradiotherapy with stem cell support,9 and limb amputation.10
The results have ranged from a fulminant course with hemophagocytic syndrome
and death to complete and sustained remission. Unfortunately, there has been
no comprehensive study to determine clinicohistopathological features that
may predict progression to hemophagocytic syndrome. It is thought, however,
that the presence of fever, weight loss, cytopenia, involvement of multiple
sites, and hemophagocytosis at the time of diagnosis may portend a more aggressive
course and a poor clinical outcome.8
Denileukin diftitox is a recombinant fusion protein that combines human
interleukin 2 and diphtheria toxin.11 When
the gene is expressed in Escherichia coli, it results
in the production of a polypeptide chain with the capacity to bind to the
human interleukin 2 receptor (IL-2R) on T cells and to inhibit protein synthesis
upon internalization.12 The human IL-2R exists
in 3 forms: low, intermediate, and high affinity. Only the intermediate and
high-affinity forms will allow endocytosis of the bound ligand to occur. Cells
that exhibit the high-affinity IL-2R appear to be approximately 1 log more
sensitive to the cytotoxic effects of denileukin diftitox than are the cells
expressing the intermediate affinity receptor.13
Expression of the IL-2R in involved tissue has been observed in up to
75% of cases of CTCL using immunohistochemical techniques.14
Nevertheless, a great degree of variability has been observed from lesion
to lesion within individual patients and from patient to patient, depending
upon the particular reagents used. Furthermore, no clear correlation has been
observed between IL-2R expression and responsiveness of CTCL patients treated
with denileukin diftitox.
A recent phase 3 trial found that 30% of the 71 patients with CTCL treated
with denileukin diftitox had an objective response (20% partial reponse and
10% complete response).1 Some patients demonstrated
marked variability in IL-2R expression among different lesions, yet had significant
responses to treatment. The study concluded that denileukin diftitox is a
"useful and important" agent in the treatment of patients whose CTCL is "persistent
or recurrent despite other therapeutic interventions." Furthermore, it was
found to have a relatively benign side effect profile with less myelosuppression
compared with traditional chemotherapeutic regimens.1
In contrast to CTCL, expression of the IL-2R in panniculitic T-cell
lymphoma tumors has not been quantified. Since this is a disorder of malignant
T cells with an activated phenotype, we hypothesized that denileukin diftitox
would have the ability to kill the malignant T cells of subcutaneous panniculitic
T-cell lymphoma by a similar mechanism. Moreover, we believe that denileukin
diftitox may be able to exert its cytotoxic effect without activating the
cytokine storm that results from the secretion of the phagocytosis-inducing
factor that contributes to the hemophagocytic syndrome.
Since the report of our patient, we have become aware of 3 additional
patients with subcutaneous panniculitic T-cell lymphoma in whom other treatments
failed but who have responded to treatment with denileukin diftitox (A.H.R.,
unpublished data, 2001). These observations support our therapeutic concept
that denileukin diftitox is an effective, relatively nontoxic therapy for
panniculitic T-cell lymphoma that may not induce hemophagocytic syndrome and
should be considered as an acceptable first-line therapy for this disease.
AUTHOR INFORMATION
Accepted for publication January 15, 2002.
We thank William Witmer for his assistance with the photographic material
for this article.
Corresponding author: Alain H. Rook, MD, 2 Maloney, 3600 Spruce St,
Philadelphia, PA 19104-4283 (e-mail: arook{at}mail.med.upenn.edu).
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ABSTRACT
SECTION EDITOR: GEORGE J. HRUZA, MD; ASSISTANT SECTION EDITORS: DEE
ANNA GLASER, MD; ELAINE SIEGFRIED, MD
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