Originally published as JCO Early Release 10.1200/JCO.2008.20.3737 on December 1 2008

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Erythema Multiforme/Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis in Lenalidomide-Treated Patients

Carmen P. Castaneda, Nancy A. Brandenburg, Robert Bwire, Graham H. Burton, Jerome B. Zeldis

Celgene Corporation, Summit, NJ

To the Editor:

Stevens-Johnson syndrome (SJS) is a rare but life-threatening cutaneous adverse reaction. While SJS may sometimes be admixed with diagnoses of erythema multiforme (EM) minor or major,¹ SJS and toxic epidermal necrolysis (TEN) are considered to be severity variants of the same disease with drug exposure the primary etiologic factor.² The incidence of SJS has been estimated at 1.1 to 7.1 cases per million person-years, and that of TEN at 0.4 to 1.2 per million person-years.¹ Mortality among patients with SJS or TEN has been reported to be between 1% to 3% and 10% to 70%, respectively.¹

Risk factors for SJS include infection, vaccination, drugs, systemic diseases, physical agents, and food.¹ SJS has been associated with more than 100 drugs through case reports and studies, including drugs such as allopurinol,³ quinolones,³ corticosteroids (including dexamethasone),^3,4 rituximab,⁵ imatinib,⁶ and bortezomib.⁷ Risk was greatest in the first 2 months of treatment.

Celgene Corporation has received 12 reports of SJS, three reports of EM and one report of TEN among approximately 57,000 patients who received lenalidomide from market launch on December 27, 2005, through June 26, 2008. The majority (83%; 10 of 12) of the SJS cases were spontaneous reports from US health care professionals. Two reports were received from US investigator-initiated trials. The 12 cases occurred in seven women and five men with a median age of 63.5 years (range, 50 to 83 years). Lenalidomide was prescribed for the approved indication of multiple myeloma (MM; 10), as well as for myelofibrosis (1) and amyloidosis (1).

One SJS case was confirmed by a skin biopsy in a patient with amyloidosis on lenalidomide, cyclophosphamide, and dexamethasone treatment who received levofloxacin one week before the onset of a localized rash that became generalized. The patient developed pneumonia and sepsis and died from septicemia 11 days following hospitalization.

Clinical information quality was variable. In four cases, it was too limited for further interpretation of the diagnoses provided by the reporters. Generalized rash was noted in five patients of which one was characterized as maculopapular and the others as erythematous. Some patients had urticaria, pruritus, swelling of the face or lips, weeping blisters, sores in the mouth, and dysphagia. One patient had a history of rash with thalidomide. The median time to onset of event from start of lenalidomide was 24 days with a range of 3 to 45 days (n = 9). Medications implicated in SJS received concomitantly by these patients included dexamethasone (eight), allopurinol (two), moxifloxacin (one), levofloxacin (one), and bortezomib (two). In one report of SJS, the prescriber attributed the event to bortezomib, which was discontinued while lenalidomide was continued. Seven patients were hospitalized. At the time of the report, six patients recovered from the event, one had not recovered, and two were unknown. Two patients later died, one from disease progression and the other of unknown cause.

Three cases of EM were reported in the United States among patients who received lenalidomide with dexamethasone for MM. There were two women and one man age 85, 74, and 70 years, respectively. The times to onset of EM from start of lenalidomide were 7, 24, and 112 days. The patients presented with lesions or rash associated with blistering, sores, mucosal involvement, crusting, fever, and erythema of the skin. In one patient, herpes simplex of the mouth preceded the EM. Two patients were hospitalized. The patients recovered from EM but one eventually died due to disease progression 59 days following hospitalization and 62 days after discontinuing lenalidomide. Concomitant medications included allopurinol and sulfamethozaxole/trimethoprim.

TEN was reported in an 85-year-old woman hospitalized 18 days after initiating lenalidomide with dexamethasone for MM. Concomitant medications were tamoxifen and alendronate. She developed a florid, patchy, erythematous, pruritic rash that was confluent in many areas and with mild exfoliation and somewhat weepy appearance. The patient recovered.

Most cases were postmarketing reports and as such had inadequate information, making confirmation of the reporters’ diagnoses difficult and hampering causality assessment. The temporal relationship between the events and lenalidomide initiation in many reports cannot exclude a causal relationship. The company is updating the prescribing information for lenalidomide to include guidance on these rare events.

A study of the dermatologic effects of lenalidomide alone or in combination with dexamethasone reported an incidence of skin eruptions of 29% in MM patients, which in most cases were mild.⁸ Physicians prescribing lenalidomide should monitor their patients for possible dermatologic adverse effects, and particular care should be given to patients with a history of thalidomide rash. In most instances, complete discontinuation of the therapy is not necessary, but may require temporary interruption of therapy or drug dosage reduction and close scrutiny.⁸

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment or Leadership Position: Carmen P. Castaneda, Celgene (C); Nancy A. Brandenburg, Celgene (C); Robert Bwire, Celgene (C); Graham H. Burton, Celgene (C); Jerome B. Zeldis, Celgene (C) Consultant or Advisory Role: None Stock Ownership: Carmen P. Castaneda, Celgene; Nancy A. Brandenburg, Celgene; Robert Bwire, Celgene; Graham H. Burton, Celgene; Jerome B. Zeldis, Celgene Honoraria: None Research Funding: None Expert Testimony: None Other Remuneration: None

NOTES

published online ahead of print at www.jco.org on December 1, 2008

REFERENCES

1. Letko GN, Papaliodis DN, Papaliodis GN, et al: Stevens-Johnson syndrome and toxic epidermal necrolysis: A review of the literature. Annals Allergy Asthma Immunol 94:419-436, 2007

2. Roujeau JC: Stevens-Johnson syndrome and toxic epidermal necrolysis are severity variants of the same disease which differs from erythema multiforme. J Dermatol 24(11):726-729, 1997[Medline]

3. Roujeau JC, Kelly JP, Naldi L, et al: Medication use and the risk of Stevens-Johnson syndrome or toxic epidermal necrolysis. N Engl J Med 333:1600-1606, 1995[Abstract/Free Full Text]

4. Mockenhaupt M, Viboud C, Dunant A, et al: Stevens-Johnson syndrome and toxic epidermal necrolysis: Assessment of medication risks with emphasis on recently marketed drugs—The EuroSCAR study. J Invest Dermatol 128:35-44, 2008[CrossRef][Medline]

5. Lowndes S, Darby A, Mead G, et al: Stevens-Johnson syndrome after treatment with rituximab. Ann Oncol 13:1948-1950, 2002[Abstract/Free Full Text]

6. Sanchez-Gonzalez B, Pascual-Ramirez, Fernandez-Abellan P, et al: Severe skin reaction to imatinib in a case of Philadelphia-positive lymphoblastic leukemia. Blood 101:2446, 2003[Free Full Text]

7. Fang B, Song Y, Ma J, et al: Severe epidermal necrolysis after bortezomib treatment for multiple myeloma. Acta Haematol 118:65-67, 2007[CrossRef][Medline]

8. Svigguni H, Davis M, Rajkumar V, et al: Dermatologic adverse effects of lenalidomide therapy for amyloidosis and multiple myeloma. Arch Dermatol 142:1298-1302, 2006[Abstract/Free Full Text]

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