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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2005-2839
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The Journal of Clinical Endocrinology & Metabolism Vol. 91, No. 6 2205-2208
Copyright © 2006 by The Endocrine Society

BRIEF REPORT

Thyrotoxicosis after Denileukin Diftitox Therapy in Patients with Mycosis Fungoides

Farah Ghori, Kristel D. Polder, Lauren C. Pinter-Brown, Ana O. Hoff, Robert F. Gagel, Steven I. Sherman1 and Madeleine Duvic1

Departments of Endocrine Neoplasia and Hormonal Disorders (F.G., A.O.H., R.F.G., S.I.S.) and Dermatology (K.D.P., M.D.), University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030; and Division of Hematology and Oncology (L.C.P.-B.), University of California Los Angeles Medical Center, Los Angeles, California 90095

Address all correspondence and requests for reprints to: Madeleine Duvic, M.D., Department of Dermatology, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Box 434, Houston, Texas 77030. E-mail: mduvic{at}mdanderson.org.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Context: Denileukin diftitox is a recombinant novel fusion protein of diphtheria toxin and the ligand-binding domain of human IL-2. Denileukin diftitox binds to the high-affinity IL-2 receptor on the cell surface, and it is internalized by endocytosis and enzymatically cleaved. The cytotoxic A-fragment of the toxin inhibits protein synthesis and causes cell death.

Objective: The objective of this study was to recognize thyrotoxicosis in association with denileukin diftitox therapy.

Design: This study was a retrospective case series.

Setting: The setting of this study was a comprehensive cancer center.

Patients: Eight mycosis fungoides patients who were receiving 9 or 18 µg/kg·d iv denileukin diftitox for 5 d every 3 wk were identified with thyrotoxicosis.

Intervention(s): Thyroid testing was performed. Hypothyroidism after thyrotoxicosis was treated.

Results: In eight mycosis fungoides patients who developed transient thyrotoxicosis during therapy, thyroid function tests were normal before onset of therapy. Clinical thyrotoxicosis developed within days of the first cycle of denileukin diftitox therapy in four patients and after the second cycle in the other four patients. Symptoms included tremors, nervousness, tachycardia, diarrhea, and weight loss. After cessation of denileukin diftitox, thyrotoxicosis resolved in all patients; two became euthyroid, and five became hypothyroid, requiring levothyroxine therapy. One patient was lost to follow-up.

Conclusions: Monitoring thyroid function before and during treatment with denileukin diftitox is recommended. Symptomatic thyrotoxicosis may be missed due to other acute reactions to the drug, and subsequent hypothyroidism may develop.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
SELECTIVE TARGETING OF malignant cells while preserving normal cells underlies the development of newer therapeutic agents including immunomodulatory agents and immunotoxins. Denileukin diftitox (DAB389IL-2, ONTAK, Ligand Pharmaceuticals Inc., San Diego, CA) is a novel fusion toxin consisting of the enzymatic and translocating domain of diphtheria toxin (amino acids 1–389) and the ligand-binding domain of recombinant human IL-2 (1). The potential for denileukin diftitox to bind selectively to high-affinity (CD25/CD122/CD132) IL-2 receptors, generally expressed only on activated T and B lymphocytes and macrophages (2, 3), provided the rationale for its use in cutaneous T cell lymphomas (CTCLs) (4, 5, 6) and non-Hodgkin’s lymphomas (7, 8). Denileukin diftitox has also been used in psoriasis (9), graft-vs.-host disease (10, 11), chronic lymphocytic leukemia (12), and for targeting T-regulatory cells in solid tumors (7, 8, 13).

The IL-2 receptor is a heterodimer of two to three chains with different affinities. Although denileukin diftitox can bind to the intermediate or high-affinity IL-2 receptors, only binding to the high-affinity chain will result in receptor endocytosis. Upon acidification of the formed vesicle, the cytotoxic A fragment of diphtheria toxin inhibits protein synthesis by ADP ribosylation of elongation factor 2, resulting in cell death (1).

Acute side effects to denileukin diftitox include flu-like symptoms (fever, chills, hypotension), chest pain, hypertension, and anaphylaxis. Delayed side effects include vascular leak syndrome (hypotension, hypoalbuminemia, edema), elevated hepatic transaminases with nausea and vomiting, fatigue, anemia, and, less commonly leukopenia, thrombocytopenia, and deep vein thrombosis (5, 6). We report eight patients with mycosis fungoides (MF) variant of CTCL who developed clinical or laboratory evidence of thyrotoxicosis while receiving denileukin diftitox therapy.


   Patients and Methods
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 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
Seven MF patients treated with denileukin diftitox at M.D. Anderson Cancer Center and one treated at University of California Los Angeles (UCLA) Medical Center developed evidence of thyrotoxicosis during therapy and were further evaluated. The retrospective study was approved by the institutional review board and was conducted according to the Helsinki recommendations.

Previous treatments in this cohort are summarized in Table 1Go. The patients had been premedicated with 25–50 mg oral diphenhydramine and 625 mg acetaminophen before each infusion. Denileukin diftitox was infused at either 9 or 18 µg/kg·d by iv infusion for 5 consecutive d and was repeated every 3 wk for up to eight cycles according to the pivotal trial recommendations (6).


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  		TABLE 1. Demographics and treatment parameters in MF patients with thyrotoxicosis

 
Serum free T4 was measured by direct chemiluminescence immunoassay (Chiron Diagnostics, Norwood, MA) in which the normal range was 0.9–1.8 ng/dl (11.6–23.2 pmol/liter). Serum TSH was measured by a chemiluminescence immunoassay (Chiron Diagnostics) in which the normal range was 0.5–5.0 mU/liter. The interassay coefficients of variation were 7% for serum free T4 and 3% for TSH. Antithyroid peroxidase (TPO) antibodies and antithyroglobulin (Tg) antibodies were assayed by ELISA (Kronus, Boise, ID) with limit sensitivities of 1 and 2 U/ml, respectively. The intraassay coefficients of variation were 5% for anti-TPO and 8% for anti-Tg antibodies. Serum thyroid-stimulating Ig was assayed in one patient by recombinant bioassay through Mayo Medical Laboratories (Rochester, MN).


   Results
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 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
The index patient was a 63-yr-old man with a 10-yr history of MF skin tumors (stage IIB). He had previously achieved a complete remission on combined modality therapy [interferon-{alpha} (IFN{alpha}), isotretinoin, nitrogen mustard, electron beam radiotherapy, with topical nitrogen mustard maintenance] (9) but relapsed in skin and nodes. His past history was significant for paroxysmal atrial fibrillation and IFN{alpha}-induced positive antinuclear antibody. Amiodarone and flecainide for paroxysmal atrial fibrillation were discontinued 2 months before the initiation of denileukin diftitox.

Before starting denileukin diftitox, he did not have a goiter or dysthyroid ophthalmopathy. Thyroid function tests were normal, but his serum anti-TPO antibody titer was elevated, 80 U/ml (normal < 1.0 U/ml). Two weeks after his second course of denileukin diftitox at 18 µg/kg, he developed decreased energy, nausea, vomiting, insomnia, and problems with concentration and memory. Physical exam revealed weight loss. TSH was 0.16, and total T4 was 17.9 µg/dl. Serum obtained during his thyrotoxic episode was subsequently found to contain an elevated level of thyroid-stimulating Ig (270%; reference range, <130% of basal activity). No specific treatment was initiated for his thyrotoxicosis. He became permanently hypothyroid during cycle 7 of denileukin diftitox therapy and was treated with levothyroxine.

The clinical characteristics of the eight patients who developed thyrotoxicosis are presented in Table 1Go. All of these patients had been diagnosed with MF within the previous 10 yr. None had clinical evidence of Graves’ disease or concomitant treatment with medications known to induce thyroiditis, except amiodarone, which had been discontinued in patient 1. Six patients had been treated with IFN{alpha} in the past, but it had been discontinued well in advance of treatment with denileukin diftitox. Clinical thyrotoxicosis developed within days of the first cycle of denileukin diftitox in four patients and after the second cycle in the other four patients. Only one patient who developed thyrotoxicosis was able to complete the full, prescribed course of denileukin diftitox therapy.

The most common symptoms of thyrotoxicosis in the eight patients were tremors, tachycardia, nausea, diarrhea, and weight loss. One patient (patient 5) developed dyspnea due to capillary leak syndrome and required termination of therapy without overt symptoms of thyrotoxicosis. However, the thyroid function test results were consistent with thyrotoxicosis. Patient 6 also developed severe capillary leak syndrome after the first cycle and was hospitalized. She developed palpitations, chest pain, nausea, and vomiting with subsequent normal EKG and cardiac enzymes. However, her free T4 and TSH values were consistent with thyrotoxicosis (Table 2Go).


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  		TABLE 2. Thyroid laboratory studies during and after thyrotoxicosis

 
Patient 7, who was treated with denileukin diftitox at UCLA Medical Center, developed a rapidly enlarging neck mass and a fine tremor 10 d after d 1 of cycle 2. On physical examination, she was mildly tachycardic to 108 beats per minute and demonstrated a diffusely enlarged thyroid gland. Thyroid function tests were drawn. Three days later, she developed recumbent light-headedness, weakness, tremors, and was in atrial fibrillation with a heart rate of 160. MRI showed diffuse thyroid enlargement. She was admitted and treated with oral ß-blockers and Oragrafin.

The results of baseline, thyrotoxic, and recovery thyroid function tests are presented in Table 2Go. Three patients had elevated anti-TPO antibody titers at baseline (patients 1, 2, and 5). Three patients did not have antithyroid antibody titers measured at baseline but were found to have elevated anti-TPO and anti-Tg antibodies during the thyrotoxic phase (patients 3, 4, and 6). Patients 7 and 8 did not demonstrate anti-TPO or anti-Tg antibodies during the thyrotoxic phase. Two patients (patients 4 and 8) had low radioactive iodine uptake documented during the episode of thyrotoxicosis (24-h value, 0.5%), a finding consistent with subacute thyroiditis. Both patients became permanently hypothyroid. Radioactive iodine uptake was not determined in the other patients.

Although acute thyrotoxicosis clinically resolved in all patients, five became hypothyroid, requiring long-term hormone replacement. Two became euthyroid, and one patient did not have her thyroid status evaluated after clinical resolution of thyrotoxicosis.


   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
This is the first report of thyrotoxicosis related to denileukin diftitox therapy. The onset of thyrotoxicosis was sudden and was masked by other expected side effects of the drug including acute infusion reactions and vascular leak syndrome. Complicating thyroid function assessment in these patients can be the effects of acute illness to lower free T4 and TSH levels, particularly the patients who also developed vascular leak. The transient nature of thyrotoxicosis, elevation of thyroid autoantibody titers, and subsequent development of hypothyroidism in five of the eight affected patients is suggestive of thyroiditis induced by denileukin diftitox therapy. However, the absence of complete baseline and follow-up data on all patients and the documentation of low radioiodine uptakes in only two patients provide important caveats to this conclusion.

The mechanism of acute thyrotoxicosis accompanying denileukin diftitox is not known. It is likely to be similar to thyroid dysfunction (goiter, hypothyroidism, biphasic thyroiditis, and hyperthyroidism) reported with IL-2 alone or in combination with IFN{alpha} and other cytokines (15, 16, 17, 18, 19). Cytokine-induced thyroid injury is thought to arise from activation or dysregulation of the immune system (15, 16, 17). Against a direct effect is that denileukin diftitox has an inactive IL-2 ligand binding domain that targets IL-2-positive cells for death without triggering T cell activation. Instead, cytokines released after fusion toxin-induced T cell death may stimulate other mediators of thyroid inflammation and clinical thyroiditis.

Denileukin diftitox may induce transient autoimmune thyroiditis in MF patients who are already predisposed to develop autoimmune thyroiditis. Of note, three patients had elevated anti-TPO antibodies before receiving denileukin diftitox therapy. Three more developed TPO antibodies and Tg antibodies during thyrotoxicosis. The index case had preexisting antiperoxidase antibodies. Thus, denileukin diftitox may have exacerbated preexisting subclinical thyroiditis. In previous studies reporting antithyroid antibodies in patients with cytokine-induced thyroiditis, a relationship between elevated autoantibody titers with thyroid damage was not consistently demonstrated. However, mice generated to have a T cell response to TPO spontaneously develop autoimmune thyroiditis (20). Sera from patients with Hashimoto’s thyroiditis have increased levels of soluble IL-2 receptors, supporting a relationship (21). MF patients may have a genetic predisposition and increased risk for developing Hashimoto’s thyroiditis because both diseases are associated with an increased frequency of HLA-DR5 alleles (22).

Of note, thyroid dysfunction occurred rapidly after 1–35 d in MF patients after denileukin diftitox, in contrast to longer onset (14 d to 12 months) after IL-2 therapy (15, 16, 17). Rapid onset suggests acute injury of thyrocytes with release of hormone; however, thyrocytes did not stain for high-affinity IL-2 receptors (Prieto, V., unpublished data). A potential bystander effect could be rapidly induced if infiltrating T cells were present in the thyroid gland, killed by denileukin diftitox, and released cytokines such as IL-2 (16).

Subsequent development of permanent hypothyroidism in five of the patients also supports an inflammatory mechanism. Given the high frequency of antithyroid antibodies detectable in serum obtained before exposure to denileukin diftitox, transient Graves’ disease cannot be excluded in those patients who did not undergo measurement of radioactive iodine uptake, particularly patient 1. The measurement of radioactive iodine uptake would distinguish between a drug-induced Graves’ disease, wherein the uptake would be elevated, and a drug-induced inflammatory thyroiditis, in which a low uptake would be expected (23, 24). Thyroid function has been reported to normalize after the discontinuation of cytokine therapy with IL-2 or IFN{alpha}; however, patients remain at risk for the development of autoimmune thyroid dysfunction when treated with these cytokines (23, 24).

Denileukin diftitox-induced thyrotoxicosis, reported for the first time in eight MF patients, appears to occur more rapidly than IL-2-induced thyroiditis and may arise in patients who are especially susceptible based on HLA alleles or due to release of cytokines with triggered T cell death. Denileukin diftitox also results in acute infusion symptoms mimicking thyrotoxicosis, and the latter could be easily missed. Symptomatic treatment including ß-blockers, corticosteroids, and nonsteroidal antiinflammatory medications should be instituted in patients with overt thyrotoxicosis. Five of the patients subsequently developed long-standing hypothyroidism, requiring replacement with levothyroxine. Because thyrotoxicosis may increase morbidity to these patients, we recommend monitoring of thyroid function before and during denileukin diftitox therapy and call attention to this possible previously unknown side effect of therapy.


   Footnotes
 
This work was supported in part by National Cancer Institute Grants CA16672 and K24 CA86815 (to M.D.) and by the Sherry L. Anderson CTCL Research Fund.

First Published Online April 4, 2006

1 S.I.S. and M.D. are cosenior authors. Back

Abbreviations: CTCL, Cutaneous T cell lymphoma; IFN, interferon; MF, mycosis fungoides; Tg, thyroglobulin; TPO, thyroid peroxidase.

Received December 29, 2005.

Accepted March 24, 2006.


   References
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 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

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