Breast Implant Associated-Anaplastic Large-Cell Lymphoma (BIA-ALCL): Data Based on the Lymphoma Study Association (LYSA) Registry. Promising Results of Brentuximab Vedotin Combined with Cyclophosphamide, Doxorubicin and Prednisone (BV-CHP) As First Line Treatment for Patient Requiring Chemotherapy
Authors: Le Bras Fabien , Schiano De Colella Jean Marc , Oberic Lucie , Itti Emmanuel , Dao Thua-Ha , Laurent Camille , Xerri Luc , Bachy Emmanuel , Traverse-Glehen Alexandra , Bonnet Christophe , André Marc , Fornecker Luc Mathieu , Bannier Marie , Slama Bohrane , Kirova Youlia , Nicolas-Virelizier Emmanuelle , Croix Manon , Fogarty Patrick , Amara Nadia , Fataccioli Virginie , Ricci Romain , Tilly Hervé , Tortolano Lionel , Bosc Romain , Gaulard Philippe , Haioun Corinne 
Published: November 2021

Abstract
Background: Breast implant-associated anaplastic large-cell lymphoma (BI-ALCL) is a rare form of T-cell lymphoma arising adjacent to a breast implant, recently recognized as a provisional entity in the 2017 revised World Health Organization (WHO) lymphoma classification. The pathogenesis of this entity remains elusive even if gene alterations in epigenetic modifiers and JAK-STAT signaling are frequent. ECHELON 2 trial (Horwitz S et al. The Lancet 2019) has set BV-CHP as a new standard of treatment for CD30-positive peripheral T-cell lymphoma, mainly in systemic ALCL patients (pts) but not in BIA-ALCL. Our objective is to describe a series of pts with BIA-ALCL included in the LYSA registry focusing on the use of BV CHP as front-line chemotherapy for patient requiring chemotherapy.
Methods: since 2016, a national multidisciplinary meeting has been implemented by the French Cancer Agency to better define therapeutic strategies for newly diagnosed cases after histologic confirmation. Meanwhile, BIA-ALCL registry was funded by the LYSA to collect ambispectively, in France and more recently in Belgium, patient clinical data including reasons for breast implantation, implant manufacturer, treatment and outcome.
Results: from 2009 to 2021 , 85 pts (73 in France and 12 in Belgium) gave their informed consent to participate to the registry. Median age was 57 years (range 29-82) at diagnosis. In 39 out of 85 pts (45.9%) the first implant followed a mastectomy for breast cancer. In this analysis, only implants in the breast(s) where the lymphoma occurred have been considered. Five pts (5.9%) had bilateral lymphoma and 80 pts had unilateral lymphoma (35 left side and 45 right side), 35 pts were implanted once (41.2%), 35 twice (41.2%) and 15 pts (17.6%) 3 times or more. The median period between first implant and BIA-ALCL diagnosis was 12.2 years (range 4.1-40.5), and 7 years (range 0.2-25.4) from last implant to diagnosis. The clinical presentation was seroma in 64 pts (75.3%), breast tumor mass with or without seroma in 18 pts (21.1%) and 3 pts were diagnosed without any mass or seroma (1 contiguous lymph node involvement, 2 in the context of systematic implant removal). The two main clinical presentation (i.e. seroma and tumor mass) were most often correlated with the two distinct histological subtypes (in "situ/mixed" (n=62) or "infiltrative" (n=21)). For 2 pts, histological subtype was not available. The majority of pts were Ann Arbor stage I-II (n=65, 76.5%), and 18 (21.2%) pts were stage IV. Stage was unknown in 2 pts. Considering available information, almost all patients had at least one silicone-filled (n=76) and at least one textured implant (n=85) with Biocell texturation (n=61, 71.8%). No patient had only smooth implant.
Implant removal with total capsulectomy was performed in 66 patients and 25 underwent chemotherapy based on CHOP or CHOP-like (4 to 6 cycles) chemotherapy regimens (n=13), BV-CHP (6 cycles) (n=10) and others (n=2). Among the patients receiving chemotherapy, CR was obtained in 21 pts (84%) and in 2 pts failed to respond (8%). Among the patients treated with BV-CHP, 8 pts achieved CR (80%) and 2 pts were not yet evaluated at the time of analysis. No limiting toxicity was noted.
After a median follow-up of 28.6 months, 78 pts are alive and free of evolutive disease and 8 are lost to follow up. Seven pts died, either from lymphoma progression alone (n=2) or associated with concomitant active breast cancer (n=2), one from breast cancer alone, one from lung epidermoid cancer and one due to myocardial infarction.
Patients with an "infiltrative" histological subtype have a significantly worse outcome with a 2y-PFS of 73.8% vs 96.7% for other subtypes ("in situ/mixed subtypes") (p=0.0039, HR=5.3) and a 2y-OS of 78.7% vs 100% (p=0.0022, HR=8.5). With a median follow-up of one year, the 10 patients treated with BV-CHP are alive and free of evolutive disease at the time of analysis.
Conclusions: We report on the basis of a limited series of patients that 6 cycles of BV-CHP provide an excellent disease control in patients with BIA-ALCL requiring chemotherapy. Confirmation of these results on a larger series of patients with a longer follow-up is needed. Such observation provides basis for a prospective trial in order to determine if treatment with BV-CHP could be installed as a standard of care for higher risk patients with BIA-ALCL, as those presenting with tumor mass and /or infiltrative subtype.

Disclosures
Le Bras: Novartis: Honoraria; Celgene BMS: Research Funding; Takeda: Honoraria, Research Funding; Kite Gilead: Honoraria. Bachy: Kite, a Gilead Company: Honoraria; Novartis: Honoraria; Daiishi: Research Funding; Roche: Consultancy; Takeda: Consultancy; Incyte: Consultancy. Bonnet: Roche: Consultancy. André: AbbVie: Other: Travel/accomodation/expenses; Roche: Other: Travel/accomodation/expenses, Research Funding; Johnson & Johnson: Research Funding; Celgene: Other: Travel/accomodation/expenses; Bristol-Myers-Squibb: Consultancy, Other: Travel/Accommodations/Expenses; Karyopharm: Consultancy; Gilead: Consultancy, Other: Travel/Accommodations/Expenses; Incyte: Consultancy; Takeda: Consultancy, Research Funding. Haioun: Amgen: Honoraria, Research Funding; Servier: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Miltenyi: Honoraria, Research Funding.