Clinical Outcomes and CNS Relapse Risk in Patients with Primary Cutaneous DLBCL, Leg Type Treated in the Rituximab Era: Long-Term Follow-up of a Single-Center Experience
Authors: Falchi Lorenzo , Qiu Annie , Ewalt Mark D. , Batlevi Connie Lee , Caron Philip C , Hamlin Paul A. , Hamilton Audrey , Horwitz Steven M. , Joffe Erel , Khan Niloufer , Kumar Anita , Moskowitz Alison J. , Noy Ariela , Owens Colette , Palomba Maria Lia , Straus David J. , von Keudell Gottfried , Zelenetz Andrew D. , Dogan Ahmet , Busam Klaus , Myskowski Patricia , Yahalom Joachim , Salles Gilles , Matasar Matthew J. 
Published: November 2021

Abstract
Introduction:
Primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL,LT) is a rare subtype of lymphoma that has been reported to have aggressive clinical behavior and carry a poor prognosis. However, due to the extreme scarcity of data, optimal management of this entity remains poorly defined, particularly with respect to optimal induction therapy and the role for central nervous system (CNS) prophylaxis. We therefore reviewed our institutional experience with patients with PCDLBCL,LT to better delineate their clinical course and risk of CNS relapse.
Methods:
We searched our electronic database and individual electronic medical records for cases of skin-only PCDLBCL,LT and analyzed the presenting characteristics, treatment approaches, use of CNS prophylaxis, and clinical outcomes, including skin, systemic, and CNS relapse. Primary cutaneous follicle center lymphoma, primary cutaneous marginal zone lymphoma, and skin-only DLBCL arising in patients with a concurrent or antecedent indolent B-cell lymphoma were excluded. Additionally, cases with DLBCL involving both skin and nodal and/or extranodal sites at diagnosis were excluded. All patients underwent staging with positron emission tomography-computerized tomography (PET-CT). Diagnostic specimens were independently reviewed by hematopathologists with expertise in cutaneous lymphoma.
Results:
We identified 38 patients with PCDLBCL,LT followed at Memorial Sloan Kettering Cancer Center between July 2002 and October 2020. Fifteen (39%) were female and the median age was 76 years (range, 40-96). The disease was localized to the lower extremity in 15 cases (39%) and consisted of multiple lesions in 11 cases (29%). All but one patient had IPI 0-2. By Hans algorithm 79% of the samples had a non-GCB phenotype, 79% expressed MUM-1, 3% expressed CD10, and 82% exhibited Bcl2 expression. The median Ki-67 was 85% (range, 20%-100%). According to the CNS-IPI score, 25 out of 36 evaluable patients (69%) had low-risk disease and 11 (31%) intermediate-risk disease; no patient had high-risk disease.
Induction therapy consisted of R-CHOP immunochemotherapy in 13 patients (33%), R-CHOP followed by radiation therapy (RT), at doses of 30-40 Gy, in 12 (31%), and RT alone, at doses of 30-45 Gy, in 10 (26%). One patient underwent excision alone, one received rituximab after excisional biopsy, and one best supportive care. Three patients (2 treated with chemotherapy + RT and one with chemotherapy only) received CNS prophylaxis with intrathecal methotrexate.
Among 35 patients evaluable for response, the objective response rate was 86%, all of which were complete responses. One patient treated with rituximab had stable disease and 4 (2 treated with chemotherapy only, one RT, and one best supportive care) progressed. At a median follow-up of 8.9 years [range, 2.9-14.7], the 5-year progression-free survival for the cohort is 42% (Figure panel A). CNS relapse occurred in 5 patients (13%) involving leptomeninges in 1 case, parenchyma in 2, and both in 2. None of these patients received CNS prophylaxis. Of note, none of the three who did receive prophylaxis experienced CNS relapse. The 2-year and 5-year cumulative risk of CNS relapse are 7% and 19%, respectively (Figure panel B).
At the time of this analysis, the 5-year overall survival rate is 66% (Figure Panel A), and in all, 16 patients (42%) have died. Among the 7 patients with known cause of death, 5 succumbed to progressive disease (including 3 with CNS disease), one to sepsis, and one to secondary acute myelogenous leukemia.
Conclusions:
To the best of our knowledge, this is the largest study analyzing the risk of CNS relapse in PCLBCL,LT patients treated with rituximab-containing immunochemotherapy. Our findings indicate that PCLBCL,LT is a highly aggressive disease associated with poor prognosis and high risk of CNS relapse. The 13% rate of CNS relapse in a population of patients with limited-stage disease, none of whom had high-risk CNS-IPI, suggests that alternate models of risk prediction are needed for patients with PCLBCL,LT and that clinical trials aimed at improving rates of cure and reducing the risk of CNS relapse for patients with PCLBCL,LT are needed.
Figure 1 Figure 1.

Disclosures
Falchi: Abbvie: Consultancy, Research Funding; Genmab: Consultancy, Research Funding; Roche: Research Funding; Genetech: Research Funding. Ewalt: Loxo Oncology at Lilly: Membership on an entity's Board of Directors or advisory committees; Acceleron Pharma: Membership on an entity's Board of Directors or advisory committees. Batlevi: Memorial Sloan Kettering Cancer Center: Current Employment; Pfizer: Current holder of individual stocks in a privately-held company; Viatris: Current holder of individual stocks in a privately-held company; Life Sciences: Consultancy; Bayer: Research Funding; BMS: Current holder of individual stocks in a privately-held company; Seattle Genetics: Consultancy; Kite Pharma: Consultancy; Karyopharm: Consultancy; ADC Therapeutics: Consultancy; Dava Oncology: Honoraria; TouchIME: Honoraria; Moderna: Current holder of individual stocks in a privately-held company; TG Therapeutics: Consultancy; Medscape: Honoraria; Regeneron: Current holder of individual stocks in a privately-held company; Juno/Celgene: Consultancy; GLG Pharma: Consultancy; Xynomic: Research Funding; Roche/Genentech: Research Funding; Novartis: Research Funding; Epizyme: Research Funding; Janssen: Research Funding; Autolus: Research Funding. Caron: Astra-Zeneca: Current holder of individual stocks in a privately-held company; bristol myers: Current holder of individual stocks in a privately-held company; GlaxoSmithKlein: Current holder of individual stocks in a privately-held company; Johnson and Johnson: Current holder of individual stocks in a privately-held company; Novartis: Current holder of individual stocks in a privately-held company; pfizer: Current holder of individual stocks in a privately-held company; Teva: Current holder of individual stocks in a privately-held company. Hamlin: Alexion, AstraZeneca Rare Disease (formerly Portola Pharmaceuticals): Other: Study investigator, Research Funding; Incyte, Janssen, Molecular Templates: Research Funding; Kite, Karyopharm, Celgene: Membership on an entity's Board of Directors or advisory committees. Horwitz: ADC Therapeutics: Consultancy, Research Funding; Kyowa Hakko Kirin: Consultancy, Research Funding; Myeloid Therapeutics: Consultancy; Affimed: Research Funding; Vividion Therapeutics: Consultancy; Aileron: Research Funding; Verastem: Research Funding; C4 Therapeutics: Consultancy; Janssen: Consultancy; Seattle Genetics: Consultancy, Research Funding; Millennium /Takeda: Consultancy, Research Funding; Daiichi Sankyo: Research Funding; Forty Seven, Inc.: Research Funding; Trillium Therapeutics: Consultancy, Research Funding; Acrotech Biopharma: Consultancy; ONO Pharmaceuticals: Consultancy; Shoreline Biosciences, Inc.: Consultancy; Celgene: Research Funding; Tubulis: Consultancy; SecuraBio: Consultancy, Research Funding; Kura Oncology: Consultancy. Joffe: Epizyme: Consultancy; AstraZeneca: Consultancy. Khan: Seattle Genetics: Research Funding. Kumar: Seattle Genetics: Research Funding; Kite Pharmaceuticals: Other: advisory board , Research Funding; Pharmacyclics: Research Funding; Astra Zeneca: Honoraria, Other: Advisory Board, Research Funding; Celgene: Honoraria, Other: advisory board, Research Funding; Adaptive Biotechnologies, Celgene, Abbvie Pharmaceticals, Pharmacyclics, Seattle Genetics: Research Funding; Abbvie Pharmaceuticals: Research Funding. Moskowitz: Merck: Consultancy, Research Funding; Miragen: Research Funding; Janpix Ltd.: Consultancy; Bristol-Myers Squibb: Research Funding; Incyte: Research Funding; Beigene: Research Funding; ADC Therapeutics: Research Funding; Imbrium Therapeutics L.P./Purdue: Consultancy; Takeda: Consultancy; Seattle Genetics: Consultancy, Research Funding. Noy: Pharmacyclics: Consultancy, Research Funding; Medscape: Consultancy; Targeted Oncology: Consultancy; Morphosys: Consultancy; Rafael Parhma: Research Funding; Epizyme: Consultancy; Janssen: Consultancy, Honoraria. Palomba: Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Kite Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. von Keudell: Pharmacyclics: Consultancy, Honoraria; Merck: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; AbbVie: Research Funding; Merck: Research Funding; BMS: Research Funding; Janssen: Research Funding. Zelenetz: MEI Pharma: Honoraria, Research Funding; Pharmacyclics: Honoraria; BMS/Celgene/JUNO: Honoraria, Other; Gilead: Honoraria, Research Funding; Gilead: Honoraria; Novartis: Honoraria; Verastem: Honoraria; AstraZeneca: Honoraria; MethylGene: Research Funding; MorphoSys: Honoraria; Genentech/Roche: Honoraria, Research Funding; NCCN: Other; SecuraBio: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Beigene: Honoraria, Other, Research Funding; Abbvie: Honoraria, Research Funding; LFR: Other. Dogan: Takeda: Consultancy, Research Funding; Peer View: Honoraria; Physicians' Education Resource: Honoraria; Seattle Genetics: Consultancy; Roche: Consultancy, Research Funding; EUSA Pharma: Consultancy. Salles: Allogene: Consultancy; Miltneiy: Consultancy; Loxo: Consultancy; Velosbio: Consultancy; Takeda: Consultancy; Novartis: Consultancy; Rapt: Consultancy; Regeneron: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; Genmab: Consultancy; Incyte: Consultancy; Genentech/Roche: Consultancy; Ipsen: Consultancy; Janssen: Consultancy; Kite/Gilead: Consultancy; Debiopharm: Consultancy; BMS/Celgene: Consultancy; Beigene: Consultancy; Abbvie: Consultancy, Honoraria; Bayer: Honoraria. Matasar: Janssen: Honoraria, Research Funding; TG Therapeutics: Consultancy, Honoraria; Teva: Consultancy; Daiichi Sankyo: Consultancy; Merck Sharp & Dohme: Current holder of individual stocks in a privately-held company; Genentech, Inc.: Consultancy, Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; IGM Biosciences: Research Funding; Rocket Medical: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; ImmunoVaccine Technologies: Consultancy, Honoraria, Research Funding; Juno Therapeutics: Consultancy; Memorial Sloan Kettering Cancer Center: Current Employment; Pharmacyclics: Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Merck: Consultancy.