Evaluation of treatment results in multifocal primary cutaneous anaplastic large cell lymphoma: Report of the Dutch Cutaneous Lymphoma Group Melchers RC1, Willemze R1, Bekkenk MW2, de Haas ERM3, Horvath B4, van Rossum MM5, Sanders CJG6, Veraart JCJM7, Vermeer MH1, Quint KD1. 1 Department of Dermatology, Leiden University Medical Center, The Netherlands. 2 Department of Dermatology, Academic Medical Center and Vrije University Medical Center, Amsterdam, The Netherlands. 3 Department of Dermatology, Erasmus Medical Center, Rotterdam, The Netherlands. 4 Department of Dermatology, University Medical Center of Groningen, The Netherlands. 5 Department of Dermatology, Radboud University Medical Center, Nijmegen, The Netherlands. 6 Department of Dermatology, University Medical Center Utrecht, The Netherlands. 7 Department of Dermatology, Maastricht University Medical Center, The Netherlands. British Journal of Dermatology. DOI: 10.111/bjd.16501

Rutger Melchers, Lead author

Introduction What’s already known? There is no consensus on the treatment of multifocal primary cutaneous anaplastic large cell lymphoma (C-ALCL). New targeted therapies are evaluated without knowledge of the efficacy of conventional therapies. Few published reports about treatment of multifocal C-ALCL

Objective To assess the efficacy of conventional treatment strategies for patients with multifocal C-ALCL, and to define which patients may require novel targeted therapies.

283 28 24 Methods Design: Multicenter study C-ALCL patients in the Dutch registry of cutaneous lymphomas between 1985-2017 Multifocal C-ALCL patients Final study group after exclusion of: ALK+ (n=1), insufficient follow-up (n=1), underlying immunodeficiency (n=1) and death before initial therapy (n=1)

Methods Treatment was evaluated in patients initially presenting (n=24) and relapsing with multifocal C-ALCL (n=17; 23 relapses). Endpoints: Complete response rate (CR) and overall response rate (ORR), (extracutaneous)relapse rate, 5-year disease specific (DSS) and overall survival (OS) Distinction was made between cases with 2-5 (n=36) and cases with >5 lesions (n=11).

Extracutaneous relapse Results Patients initially presenting (n=24) with multifocal C-ALCL 19 male, 5 female Median age 56 (range, 25-88) 2-5 lesions (n=15) vs >5 lesions (n=9) Treatment . Therapy No CR Relapse only skin Extracutaneous relapse Total relapse CHOP 5 5/5 (100%) 2/5 3/5 MTX 4 1/4 (25%) 1/4 2/4 3/4 (75%) RT (+ excision) 7 7/7 (100%) 5/7 0/7 5/7 (71%) Spontaneous remission 4/4 (100%) 0/4

Results (follow-up) 16/24 patients (67%) developed a relapse (8 (33%) extracutaneous) Median time to relapse: 12.5 months (range, 4-20 months) 5-year DSS: 78%, 5-year OS: 66% Compared to patients presenting with 2-5 skin lesions, patients presenting with >5 lesions had a higher chance of developing extracutaneous relapse (56% vs 20%) and more often died of lymphoma (44% vs 7%).

Cumulative results of treatment 47 clinical presentations of multifocal C-ALCL Therapy No >5 lesions CR ORR CHOP 9 3/9 (33%) 7/9 (78%) 9/9 (100%) MTX 7 4/7 (57%) 3/7 (43%) RT 21 0/21 (0%) 21/21 (100%) Spontaneous remission 4 2/4 (50%) 4/4 (100%) Other 6 2/6 (33%) 4/6 (66%) 6/6 (100%) Total 47 11/47 (23%) 39/47 (83%) 44/47 (94%) Most patients with 2-5 lesions were treated with RT Most patients with >5 lesions were treated with CHOP or MTX

Conclusion (I) Multifocal C-ALCL is rare  10% of all C-ALCL  3% had >5 lesions High relapse rate (67%); 33% developed extracutaneous disease No role for CHOP

Conclusion (II) Patients with ≤5 lesions should be treated with low-dose RT (2x4 Gy). Maintenance low-dose MTX (20 mg/week) is a suitable option in patients with >5 lesions. In patients showing signs of spontaneous remission, an expectant policy should be considered. Targeted therapies may be considered in rare patients refractory to MTX or patients developing extracutaneous disease.

Solitary/localized (90%) Treatment flow-chart C-ALCL Solitary/localized (90%) RT Multifocal (10%) ≤5 lesions (7%) >5 lesions (3%) MTX Targeted Therapies

What does this study add? This study evaluated the efficacy of conventional therapies for multifocal C-ALCL. Radiotherapy and low-dose methotrexate are suitable options in patients with ≤5 and >5 lesions, respectively. Targeted therapies may be considered in rare patients refractory to methotrexate or developing extracutaneous disease.

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