Efficacy and safety of low-dose oral lenalidomide in refractory cutaneous lupus erythematosus: an open series of 19 cases

V Reymann 1, D Bessis 1, B Bergeret 2, D Lipsker 3, A Du-Thanh 1, N Terrail 4, M Dandurand 2, O Dereure 1

Sir,
Lenalidomide (LND), a synthetic thalidomide analog mainly used in haematological malignancies has proved efficient and well-tolerated in small case series of refractory Cutaneous Lupus Erythematosus (CLE). A retrospective survey of CLE patients treated with low-dose LND in three institutional Departments of Dermatology was conducted to further assess the benefit/risk ratio of this molecule in this setting (Institutional Review Board for ethical issues of University Hospital of Montpellier 2018_IRB-MTP_11-01). Primary endpoints were best overall response (BOR) obtained with initial dosage or after dose adjustment and time to achieve BOR.
Files of 19 white CLE patients (12 with chronic discoid lesions) were collected (4 M/15 F; median age at LND initiation 43 yrs). They had previously received a median of 6 systemic treatments (range 2-12) including thalidomide in 16/19 patients. Oral LND was initiated at 5mg/d associated with an antiagregant (acetylsalicylic acid or clopidogrel) and dosage was subsequently adjusted according to response and tolerance. Complete (CR: complete or almost complete resolution (>95%) of preexisting lesions and absence of new lesions)(Fig.1a and 1b) or Partial (PR: clearance of at least 50% of preexisting lesions with possible persistence of some active lesions and absence of new lesions) Responses were obtained in 12 (63%) and 5 (26.5%) patients respectively (overall response rate (ORR) 89.5%). Response could not be evaluated in 2 patients owing to early severe adverse events (SAE) with permanent discontinuation. Median time to BOR was 3 months (range 1-9) for both CR and PR. Median duration of CR was 14 months with 15/17 responding patients still treated at last news (10 sustained CR). Cutaneous lesions recurred in 4 responding patients including one patient after dose reduction for SAE. In 4 other patients LND was reduced or discontinued owing to SAE (1) or long-lasting response (3) with no relapse. No systemic relapse nor flare was observed in evaluable patients. Adverse events any grade and SAE occurred in 12 and 5/19 patients respectively including one early systemic LE flare, resulting in early or delayed permanent discontinuation in 3 patients or dosage reduction in 2 patients. No peripheral neuropathy either primary or relapse/exacerbation of previous thalidomide-induced neuropathy nor thrombosis were observed.
Despite limitations (retrospective design, relatively small number of patients, nonstandardized semi-qualitative evaluation method) this survey further supports a fair benefit/risk ratio of LND in refractory CLE. To date, 76 CLE patients (66 adults and 10 adolescents) have been treated with LND including the present survey with an ORR of 88% (53% CR and 35 % PR) (1-7), similar to thalidomide in a recent meta-analysis (ORR 90%) (8). Relapse rate during treatment was variable but relatively low overall in series of more than 5 patients (median 26.4 %; range 0-64%), usually occurring upon dosage reduction. 20% of responding patient relapsed after definitive discontinuation but corresponding data were scarce. These data also compare favorably with thalidomide (pooled rates of relapse with maintenance dose and after withdrawal 34% and 71% respectively). In the present study the frequency and severity of adverse events was comparable to most prior reports and SAE occurred overall in 13/76 patients (17%), with related permanent LND discontinuation in 9 cases (12%) vs 24% for thalidomide. Low occurrence of neuropathy even in high-risk patients with prior thalidomide-induced neuropathy must be particularly emphasized. Worsening of preexisting SLE with systemic flare is a crucial concern but occurred in only 4 patients overall. As for thalidomide, a high teratogenicity risk is present and requires strict precautions in women with child-bearing potential. LND appears as a valuable option in refractory CLE even after failure or limiting toxicity of thalidomide.

Key words: lenalidomide; cutaneous lupus erythematosus; refractory; neuropathy

REFERENCES

1. Shah A, Albrecht J, Bonilla-Martinez Z et al. Lenalidomide for the treatment of resistant discoid lupus erythematosus. Arch Dermatol 2009; 145:303–306.
2. Braunstein I, Goodman NG, Rosenbach M et al. Lenalidomide therapy in treatmentrefractory cutaneous lupus erythematosus: histologic and circulating leukocyte profile and potential risk of a systemic lupus flare. J Am Acad Dermatol 2012; 66:571–582.
3. Okon L, Rosenbach M, Krathen M et al. Lenalidomide in treatment-refractory cutaneous lupus erythematosus: Efficacy and safety in a 52-week trial. J Am Acad Dermatol 2014; 70:583–584.
4. Cortés-Hernández J, Ávila G, Vilardell-Tarrés M, Ordi-Ros J. Efficacy and safety of lenalidomide for refractory cutaneous lupus erythematosus. Arthritis Res Ther 2012; 14:R265.
5. Fennira F, Chasset F, Soubrier M, Cordel N, Petit A, Francès C. Lenalidomide for refractory chronic and subacute cutaneous lupus erythematosus: 16 patients. J Am Acad Dermatol 2016; 74:1248–1251.
6. Kindle SA, Wetter DA, Davis MDP, Pittelkow MR, Sciallis GF. Lenalidomide treatment of cutaneous lupus erythematosus: the Mayo Clinic experience. Int J Dermatol 2016; 55:e431–439.
7. Wu EY, Schanberg LE, Wershba EC, Rabinovich CE. Lenalidomide for refractory cutaneous manifestations of pediatric systemic lupus erythematosus.
8. Chasset F, Tounsi T, Cesbron E, Barbaud A, Francès C, Arnaud L. Efficacy and tolerance profile of thalidomide in cutaneous lupus erythematosus: A systematic review and metaanalysis. J Am Acad Dermatol. 2018;78:342-350