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A complete and durable response to denileukin diftitox in a patient with mycosis fungoides
CASE
REPORTS
A complete and durable response to denileukin diftitox in a patient with mycosis fungoides Catherine D. Carretero-Margolis, MD, and David P. Fivenson, MD Detroit, Michigan We describe a patient with stage IA mycosis fungoides treated with denileukin diftitox as part of a randomized phase III trial. The patient had a rapid and complete response and has remained in remission for more than 5 years without maintenance therapy. Although denileukin diftitox is not usually considered for patients with early-stage mycosis fungoides, our experience provides anecdotal evidence that fusion toxin therapy may be worth considering as a treatment for patients with stage I disease. (J Am Acad Dermatol 2003;48:275-6.)
T
raditional therapies for mycosis fungoides (MF) include topical nitrogen mustard (NM), total skin electron beam radiotherapy, psoralen followed by ultraviolet A (PUVA), interferon, and systemic chemotherapy.1-3 More recent therapies have begun to focus on immune modulation.4 The interleukin 2 receptor (IL-2R) is expressed on activated T cells, B cells, and monocytes as well as 50% of abnormal lymphocytes in cutaneous T-cell lymphoma.2,5 Denileukin diftitox is a recombinant DNA-derived cytotoxic protein that combines the cytotoxic and translocation components of diphtheria toxin with IL-2.1 Cells that express IL-2R bind denileukin diftitox, which is then internalized via receptor-mediated endocytosis. Once internalized, protein synthesis is inhibited by adenosine diphosphate ribosylation of elongation factor 2 by the diphtheria toxin, resulting in cell apoptosis.3,6 We report the case of a patient with stage IA MF treated with denileukin diftitox as part of a randomized doubleblind, placebo-controlled phase III trial.
CASE REPORT In January 1996, a 71-year-old white woman presented with a chief complaint of gradually expanding nonpruritic scaly patches over her abdomen, From the Department of Dermatology, Henry Ford Health System. Funding sources: There was no funding received for this work. Seragen, Inc (now part of Ligand Pharmaceuticals, Inc) funded the clinical trial referred to in this report. Conflict of interest: None. Reprints not available from authors. Correspondence: David P. Fivenson, MD, Department of Dermatology, Henry Ford Hospital, 2799 W Grand Blvd, Detroit, MI 482022689. E-mail: [email protected]. Published online December 20, 2002. Copyright © 2002 by the American Academy of Dermatology, Inc. 0190-9622/2002/$30.00 ⫹ 0 doi:10.1067/mjd.2002.227
back, pubic area, and chest wall, which had been present for 3 years. One year earlier, she had noticed that these lesions were spreading, and she was told by her primary physician that she had ringworm. Treatment with topical steroids had yielded only mild improvement. Two recent biopsy specimens had been read as parapsoriasis en plaque and poikiloderma atrophicans vasculare versus early MF. On clinical examination, the patient had multiple erythematous macules and patches with slight crinkling atrophy on her chest, back, and abdomen extending down to the mons pubis. These patches were minimally scaly and measured 1 to 3 cm in diameter. The back lesions were situated within an area of poikiloderma and telangiectasia. In all, 9 discrete patches were identified, involving less than 10% of her body surface area. She had no abnormal cervical, inguinal, or axillary lymphadenopathy, and no hepatosplenomegaly. A biopsy specimen from the left upper abdomen showed an atypical lymphocytic infiltrate in the superficial dermis, focal epidermotropism, and sclerosis of the papillary dermis consistent with MF. Immunophenotypic analysis of the biopsy specimen showed lymphocytes that were strongly CD4 positive with loss of CD7 (35% positive for CD7 antigen; normal range, 53%-93%) consistent with MF. Atypical lymphocytes were 20% to 30% CD25 positive. The remainder of her staging examinations, including computed tomographic scanning of the chest, abdomen, and pelvis, were negative. A diagnosis of MF stage IA was made, and treatment options including PUVA alone, PUVA plus interferon, a clinical trial of denileukin diftitox, and topical NM were discussed. After informed consent had been obtained, the patient was entered into a 3-arm, randomized, double-blind phase III trial of denileukin diftitox in May 1996. Eight cycles of treatment with minimal side 275
276 Carretero-Margolis and Fivenson
effects yielded no response. She was then entered into the open-label, single-arm, high-dose denileukin diftitox treatment protocol, beginning treatment on October 21, 1996. After completing the first cycle of denileukin diftitox (18 g/kg per day for 5 days), the patient reported breaking out in generalized hives, which responded to antihistamines. Three weeks later, when she reported for cycle 2 of the treatment, she was noted to have generalized erythema over the trunk, most prominent on the chest and abdomen. The previously identified MF patches were completely obscured by this eruption. A skin biopsy specimen showed lymphocytic vasculitis that was believed to be secondary to either drug eruption or viral exanthem. Cycle 2 was delayed for 1 week, during which the eruption was symptomatically treated with low-potency topical steroids, wet compresses, and antihistamines. After the second day of cycle 2, she was removed from the study because of exacerbation of the eruption. She was then treated with antihistamines and 0.1% triamcinolone ointment. Two months later the eruption had completely resolved and all of her MF lesions had disappeared. She has now been in complete remission for more than 5 years.
DISCUSSION The pivotal phase III trial of denileukin diftitox reported by Olsen et al7 demonstrates an overall response rate of 30%, with a complete response rate of 10% in patients with recalcitrant MF. In actuality, their response rate may have been even higher because patients were excluded from analysis when side effects prevented them from completing the protocol. Patients like ours, who completed fewer than 2 of 6 cycles of treatment and currently has had documented durable complete response for 5 years and more, were not included in the final calculation of overall response rate secondary to exclusion criteria. Our patient was part of a phase III trial for early-stage disease that included a placebo control arm. This study has not yet been published. In patients with MF who have achieved complete response, denileukin diftitox has taken less time to achieve complete response than standard therapies, and maintenance therapy does not appear to be necessary. Our patient stopped treatment after day 2 of cycle 2 of denileukin diftitox and still remains in remission. In total, she received only 6 doses of the fusion toxin and was documented to have achieved complete response within 3 months of beginning treatment. Complete response may have been evident even sooner, but any positive findings were obscured by the generalized rash. In both phase I and phase II trials of denileukin diftitox, tumor regression began to occur after the first or second
J AM ACAD DERMATOL FEBRUARY 2003
course of treatment, with median time to response cited as 1.2 months.1,3 In comparison, NM therapy takes 6 to 8 months to produce complete response in stage IA MF and must then be followed by 6 months of maintenance therapy. PUVA takes 2 to 6 months to clear the patient with typical stage IA MF, but when maintenance therapy is discontinued, most patients experience relapse.8 Similarly, total skin electron beam therapy takes 3 to 4 months to complete and relapse is common, with 50% of patients with stage I disease experiencing relapse within 10 years.4 Like other current treatments, denileukin diftitox is not without side effects. In our case, the main side effect was a morbilliform, urticarial reaction that was sufficiently severe to cause her to drop out of the clinical trial. Rash is seen in 25% of people taking denileukin diftitox2 and has been attributed to a drug eruption. It could also be that the “rash” is caused by an anti-tumor immune reaction that is stimulated by denileukin diftitox or a serum-sickness type reaction to the drug itself. Further studies are needed to ascertain whether an immune reaction takes place in response to denileukin diftitox and whether this may be part of its mechanism of action or a positive prognostic sign of long-term complete response. Protocol guidelines prohibited the use of systemic steroids during phase III trials of denileukin diftitox. Most clinicians now regularly premedicate patients receiving denileukin diftitox with intravenous corticosteroids to prevent side effects. This practice has not changed the postmarketing efficacy of denileukin diftitox, but has been noted to decrease the incidence and severity of “rash,” vascular leakage, and other common side effects. REFERENCES 1. Saleh MN, LeMaistre CF, Kuzel TM, Foss F, Platanias LC, Schwartz G, et al. Antitumor activity of DAB389IL-2 fusion toxin in mycosis fungoides. J Am Acad Dermatol 1998;39:63-73. 2. Bunn PA. Rational therapy for cutaneous T cell lymphomas in the 1990s. Arch Dermatol 1995;131:603-5. 3. Duvic M, Cather J, Maize J, Frankel AE. DAB389IL2 diphtheria fusion toxin produces clinical responses in tumor stage cutaneous T cell lymphoma. Am J Hematol 1998;58:87-90. 4. Duvic M, Cather JC. Emerging therapies in CTCL. Clin Dermatol 2000;18:147-56. 5. Railan D, Fivenson D, Wittenberg G. Capillary leak syndrome in a patient treated with interleukin 2 fusion toxin for cutaneous T cell lymphoma. J Am Acad Dermatol 2000;43:323-4. 6. LeMaistre CF, Saleh MN, Kuzel TM, Foss F, Platanias LC, Schwartz G, et al. Phase I trial of a ligand fusion-protein (DAB389IL-2) in lymphomas expressing the receptor for interleukin-2. Blood 1998;91:399-405. 7. Olsen EA, Duvic M, Frankel A, Kim Y, Martin A, Vonderheid E, et al. Pivotal phase III trial of two dose levels of denileukin diftitox for the treatment of cutaneous t-cell lymphoma. J Clin Oncol 2001; 19:376-88. 8. Kim YH, Hoppe T. Mycosis fungoides and the Se´zary syndrome. Semin Oncol 1999;26:276-89.
REPORTS
A complete and durable response to denileukin diftitox in a patient with mycosis fungoides Catherine D. Carretero-Margolis, MD, and David P. Fivenson, MD Detroit, Michigan We describe a patient with stage IA mycosis fungoides treated with denileukin diftitox as part of a randomized phase III trial. The patient had a rapid and complete response and has remained in remission for more than 5 years without maintenance therapy. Although denileukin diftitox is not usually considered for patients with early-stage mycosis fungoides, our experience provides anecdotal evidence that fusion toxin therapy may be worth considering as a treatment for patients with stage I disease. (J Am Acad Dermatol 2003;48:275-6.)
T
raditional therapies for mycosis fungoides (MF) include topical nitrogen mustard (NM), total skin electron beam radiotherapy, psoralen followed by ultraviolet A (PUVA), interferon, and systemic chemotherapy.1-3 More recent therapies have begun to focus on immune modulation.4 The interleukin 2 receptor (IL-2R) is expressed on activated T cells, B cells, and monocytes as well as 50% of abnormal lymphocytes in cutaneous T-cell lymphoma.2,5 Denileukin diftitox is a recombinant DNA-derived cytotoxic protein that combines the cytotoxic and translocation components of diphtheria toxin with IL-2.1 Cells that express IL-2R bind denileukin diftitox, which is then internalized via receptor-mediated endocytosis. Once internalized, protein synthesis is inhibited by adenosine diphosphate ribosylation of elongation factor 2 by the diphtheria toxin, resulting in cell apoptosis.3,6 We report the case of a patient with stage IA MF treated with denileukin diftitox as part of a randomized doubleblind, placebo-controlled phase III trial.
CASE REPORT In January 1996, a 71-year-old white woman presented with a chief complaint of gradually expanding nonpruritic scaly patches over her abdomen, From the Department of Dermatology, Henry Ford Health System. Funding sources: There was no funding received for this work. Seragen, Inc (now part of Ligand Pharmaceuticals, Inc) funded the clinical trial referred to in this report. Conflict of interest: None. Reprints not available from authors. Correspondence: David P. Fivenson, MD, Department of Dermatology, Henry Ford Hospital, 2799 W Grand Blvd, Detroit, MI 482022689. E-mail: [email protected]. Published online December 20, 2002. Copyright © 2002 by the American Academy of Dermatology, Inc. 0190-9622/2002/$30.00 ⫹ 0 doi:10.1067/mjd.2002.227
back, pubic area, and chest wall, which had been present for 3 years. One year earlier, she had noticed that these lesions were spreading, and she was told by her primary physician that she had ringworm. Treatment with topical steroids had yielded only mild improvement. Two recent biopsy specimens had been read as parapsoriasis en plaque and poikiloderma atrophicans vasculare versus early MF. On clinical examination, the patient had multiple erythematous macules and patches with slight crinkling atrophy on her chest, back, and abdomen extending down to the mons pubis. These patches were minimally scaly and measured 1 to 3 cm in diameter. The back lesions were situated within an area of poikiloderma and telangiectasia. In all, 9 discrete patches were identified, involving less than 10% of her body surface area. She had no abnormal cervical, inguinal, or axillary lymphadenopathy, and no hepatosplenomegaly. A biopsy specimen from the left upper abdomen showed an atypical lymphocytic infiltrate in the superficial dermis, focal epidermotropism, and sclerosis of the papillary dermis consistent with MF. Immunophenotypic analysis of the biopsy specimen showed lymphocytes that were strongly CD4 positive with loss of CD7 (35% positive for CD7 antigen; normal range, 53%-93%) consistent with MF. Atypical lymphocytes were 20% to 30% CD25 positive. The remainder of her staging examinations, including computed tomographic scanning of the chest, abdomen, and pelvis, were negative. A diagnosis of MF stage IA was made, and treatment options including PUVA alone, PUVA plus interferon, a clinical trial of denileukin diftitox, and topical NM were discussed. After informed consent had been obtained, the patient was entered into a 3-arm, randomized, double-blind phase III trial of denileukin diftitox in May 1996. Eight cycles of treatment with minimal side 275
276 Carretero-Margolis and Fivenson
effects yielded no response. She was then entered into the open-label, single-arm, high-dose denileukin diftitox treatment protocol, beginning treatment on October 21, 1996. After completing the first cycle of denileukin diftitox (18 g/kg per day for 5 days), the patient reported breaking out in generalized hives, which responded to antihistamines. Three weeks later, when she reported for cycle 2 of the treatment, she was noted to have generalized erythema over the trunk, most prominent on the chest and abdomen. The previously identified MF patches were completely obscured by this eruption. A skin biopsy specimen showed lymphocytic vasculitis that was believed to be secondary to either drug eruption or viral exanthem. Cycle 2 was delayed for 1 week, during which the eruption was symptomatically treated with low-potency topical steroids, wet compresses, and antihistamines. After the second day of cycle 2, she was removed from the study because of exacerbation of the eruption. She was then treated with antihistamines and 0.1% triamcinolone ointment. Two months later the eruption had completely resolved and all of her MF lesions had disappeared. She has now been in complete remission for more than 5 years.
DISCUSSION The pivotal phase III trial of denileukin diftitox reported by Olsen et al7 demonstrates an overall response rate of 30%, with a complete response rate of 10% in patients with recalcitrant MF. In actuality, their response rate may have been even higher because patients were excluded from analysis when side effects prevented them from completing the protocol. Patients like ours, who completed fewer than 2 of 6 cycles of treatment and currently has had documented durable complete response for 5 years and more, were not included in the final calculation of overall response rate secondary to exclusion criteria. Our patient was part of a phase III trial for early-stage disease that included a placebo control arm. This study has not yet been published. In patients with MF who have achieved complete response, denileukin diftitox has taken less time to achieve complete response than standard therapies, and maintenance therapy does not appear to be necessary. Our patient stopped treatment after day 2 of cycle 2 of denileukin diftitox and still remains in remission. In total, she received only 6 doses of the fusion toxin and was documented to have achieved complete response within 3 months of beginning treatment. Complete response may have been evident even sooner, but any positive findings were obscured by the generalized rash. In both phase I and phase II trials of denileukin diftitox, tumor regression began to occur after the first or second
J AM ACAD DERMATOL FEBRUARY 2003
course of treatment, with median time to response cited as 1.2 months.1,3 In comparison, NM therapy takes 6 to 8 months to produce complete response in stage IA MF and must then be followed by 6 months of maintenance therapy. PUVA takes 2 to 6 months to clear the patient with typical stage IA MF, but when maintenance therapy is discontinued, most patients experience relapse.8 Similarly, total skin electron beam therapy takes 3 to 4 months to complete and relapse is common, with 50% of patients with stage I disease experiencing relapse within 10 years.4 Like other current treatments, denileukin diftitox is not without side effects. In our case, the main side effect was a morbilliform, urticarial reaction that was sufficiently severe to cause her to drop out of the clinical trial. Rash is seen in 25% of people taking denileukin diftitox2 and has been attributed to a drug eruption. It could also be that the “rash” is caused by an anti-tumor immune reaction that is stimulated by denileukin diftitox or a serum-sickness type reaction to the drug itself. Further studies are needed to ascertain whether an immune reaction takes place in response to denileukin diftitox and whether this may be part of its mechanism of action or a positive prognostic sign of long-term complete response. Protocol guidelines prohibited the use of systemic steroids during phase III trials of denileukin diftitox. Most clinicians now regularly premedicate patients receiving denileukin diftitox with intravenous corticosteroids to prevent side effects. This practice has not changed the postmarketing efficacy of denileukin diftitox, but has been noted to decrease the incidence and severity of “rash,” vascular leakage, and other common side effects. REFERENCES 1. Saleh MN, LeMaistre CF, Kuzel TM, Foss F, Platanias LC, Schwartz G, et al. Antitumor activity of DAB389IL-2 fusion toxin in mycosis fungoides. J Am Acad Dermatol 1998;39:63-73. 2. Bunn PA. Rational therapy for cutaneous T cell lymphomas in the 1990s. Arch Dermatol 1995;131:603-5. 3. Duvic M, Cather J, Maize J, Frankel AE. DAB389IL2 diphtheria fusion toxin produces clinical responses in tumor stage cutaneous T cell lymphoma. Am J Hematol 1998;58:87-90. 4. Duvic M, Cather JC. Emerging therapies in CTCL. Clin Dermatol 2000;18:147-56. 5. Railan D, Fivenson D, Wittenberg G. Capillary leak syndrome in a patient treated with interleukin 2 fusion toxin for cutaneous T cell lymphoma. J Am Acad Dermatol 2000;43:323-4. 6. LeMaistre CF, Saleh MN, Kuzel TM, Foss F, Platanias LC, Schwartz G, et al. Phase I trial of a ligand fusion-protein (DAB389IL-2) in lymphomas expressing the receptor for interleukin-2. Blood 1998;91:399-405. 7. Olsen EA, Duvic M, Frankel A, Kim Y, Martin A, Vonderheid E, et al. Pivotal phase III trial of two dose levels of denileukin diftitox for the treatment of cutaneous t-cell lymphoma. J Clin Oncol 2001; 19:376-88. 8. Kim YH, Hoppe T. Mycosis fungoides and the Se´zary syndrome. Semin Oncol 1999;26:276-89.