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4299 Central Nervous System Relapse in Patients with Primary Mediastinal Large B-Cell Lymphoma: Incidence and Risk Factors in the Rituximab Era

Program: Oral and Poster Abstracts
Session: 627. Aggressive Lymphomas: Clinical and Epidemiological: Poster III
Hematology Disease Topics & Pathways:
Clinical Practice (Health Services and Quality), Lymphomas, non-Hodgkin lymphoma, B Cell lymphoma, Diseases, aggressive lymphoma, Lymphoid Malignancies
Monday, December 12, 2022, 6:00 PM-8:00 PM

Theodoros P. Vassilakopoulos1*, Fotios Panitsas1*, Zois Mellios, MD2*, John Apostolidis, MD MSc M.D.(res)3*, Alexia Piperidou1*, Michalis D Michael, MD, PhD4*, Ronit Gurion, MD5*, Meltem Akay6*, Eleftheria Hatzimichael7, Stamatis J. Karakatsanis, MD, MSc8*, Maria Dimou9, Christina Kalpadakis10*, Eirini Katodritou, MD11*, Theoni Leonidopoulou, MD12*, Ioannis Kotsianidis, MD, PhD13, Chara Giatra, MD2*, Nikolaos Kanellias, MD14*, Ayman Sayyed, BMBS, MRCP15*, Tamar Tadmor, MD16*, Leylagul Kaynar, MD17, Miri Zektser18*, Argiris Symeonidis, MD, PhD19, SC Atalar6*, Evgenia Verrou, MD11*, Odit Gutwein20*, Chezi Ganzel21*, Giorgos Karianakis22*, Jonathan Isenberg, MD23*, Gabriela Gainaru22*, Theodora Triantafyllou11*, Efimia Vrakidou, MD24, Maria Palassopoulou25*, Mehmet Ozgur26*, Semra Paydas, MD27*, Panagiotis Tsirigotis, MD, PhD28*, Maria Tsirogianni29*, Tulin Tuglular, MD30*, Chrysovalantou Chatzidimitriou1*, Maria Kotsopoulou31*, Evangelos Terpos, MD, PhD32, Panagiotis Zikos33*, Argyro Koumarianou34*, Christos Poziopoulos, MD34*, Dimitrios Boutsis35*, Anat Gafter-Gvili, MD5*, Themistoklis Karmiris, MD2*, Maria K. Angelopoulou, MD1*, Maria Bakiri Papaioannou2*, Gerassimos Pangalis1,36*, Panayiotis Panayiotidis, MD1, Burhan Ferhanoglu, MD6, Netanel A. Horowitz23* and Sotirios Papageorgiou, MD, PhD37*

1Department of Haematology and Bone Marrow Transplantation, National and Kapodistrian University of Athens, Laikon General Hospital, Athens, Greece
2Department of Haematology and Lymphoma, Evangelismos General Hospital, Athens, Greece
3Lymphoma Program, Department of Adult Hematology & Stem Cell Transplantation, King Fahad Specialist Hospital, Dammam, Saudi Arabia
4Department of Haematology, Nicosia General Hospital, NICOSIA, Cyprus
5Rabin Medical Center, PetachTikva, Tel Aviv University, Tel Aviv, Israel
6Hematology Department, Koç University, School of Medicine, Istanbul, Turkey
7Department of Haematology, Faculty of Medicine, School of Health Sciences, University of Ioannina, Ioannina, Greece
8Third Department of Internal Medicine, National and Kapodistrian University of Athens, Sotiria Hospital, Athens, Greece
91st Internal Medicine Department, Propaedeutic, Hematology Clinical Trial Unit, National and Kapodistrian University of Athens, Athens, Greece
10Department of Haematology, University of Crete, Heraklion, Crete, GRC
11Department of Haematology, Theagenion Anticancer General Hospital, Thessaloniki, Greece
12Department of Haematology, Sismanoglion General Hospital, Athens, Greece
13Department of Hematology, Democritus University of Thrace Medical School, University Hospital of Alexandroupolis, Alexandroupolis, Greece
14Department of Therapeutics, National and Kapodistrian University of Athens, Alexandra Hospital, Athens, Greece
15Lymphoma Program, Department of Adult Hematology & Stem Cell Transplantation, King Fahad Specialist Hospital, Riyadh, Saudi Arabia
16Bnai Zion Medical Center, Haifa, Israel
17Erciyes University, Kayseri, Turkey
18Soroka Medical Center, Beer Sheva, Israel
19Hematology Division, Department of Internal Medicine, University of Patras, Patras, Greece
20Department of Hematology, Shamir Medical Center, Zerifin, Israel
21Shaare Zedek Medical Center, Jerusalem, Israel
22HYGEIA Hospital, Athens, Greece
23Rambam Medical Center, Haifa, Israel
24HYGEIA Hospital, Athens, ATTICA, Greece
25Department of Hematology, University Hospital, University of Thessaly, Larissa, Greece
26Kocaeli University, Kocaeli, Turkey
27Cukurova University, Adana, Turkey
28Second Propaedeutic Department of Internal Medicine, National and Kapodistrian University of Athens, Attikon Hospital, Athens, Greece
29Department of Hematology and Bone Marrow Transplantation, Saint Savvas Regional Cancer Hospita, Athens, Greece
30Marmara University, İstanbul, Turkey
31Department of Hematology, METAXA Cancer Hospital, Peireas, Greece
32Department of Therapeutics, National and Kapodistrian University of Athens, Alexandra Hospital, Drosia, Attiki, Greece
33Hematology Department, General Hospitalof Patras “Agios Andreas”, Patra, Greece
34Department of Hematology, METROPOLITAN Hospital, Athens, Greece
35Department of Hematology, Athens Navy Hospital, Athens, Greece
36Department of Haematology, Athens Medical Center, Psychikon Branch, Athens, Greece
37Second Department of Internal Medicine and Research Institute, Attikon University General Hospital, Athens, Greece

Background: Central nervous system relapses (CNSR) are uncommon in primary mediastinal large B-cell lymphoma (PMLBCL) with a reported incidence of 2.3-3.8% in the Rituximab era. Clinical risk factors for CNSR have been recognized in diffuse large B-cell lymphoma (DLBCL), but may not be applicable in PMLBCL, a pathobiologically distinct entity with constitutive activation of NFκB and JAK-STAT pathways and Programmed Death (PD) Ligand 1 and 2 overexpression.

Aim: To evaluate the incidence of first CNSR events without prior systemic progression and explore prognostic associations with baseline characteristics, CNS-IPI, and induction immunochemotherapy.

Methods: This is a retrospective study of a multinational cohort of 596 adult PMLBCL patients treated with R-CHOP or DA-EPOCH-R immunochemotherapy with or without radiotherapy between 2000 and early 2022. The cumulative incidence of first CNSR (CI-CNSR) was estimated considering the competing risks of death from any cause or prior systemic disease relapse/progression.

Results: Baseline characteristics are shown in Table 1. Only 17 patients (2.9%) received CNS prophylaxis [high-dose methotrexate (HD-MTX) 9, intrathecal MTX±other 7, both 1]. Kidney and/ or adrenal involvement at diagnosis was highly correlated with advanced stage, ≥2extranodal sites and high CNS-IPI (4-6) (p<0.001), with the vast majority of the latter also having kidney and/or adrenal involvement. With a 55-month median follow-up [interquartile range (IQR) 32-97 months], all 10 first CNSR events(9 isolated and 1 associated with systemic relapse) were recorded within 2 years of diagnosis [median time7.5 months, IQR 6-8, range 5-13 months], for a 2-year CI-CNSR of 1.78% (95% CI 0.9-3.2%). Two of 10 CNSR cases had received CNS prophylaxis with HD-MTX. All CNSR were parenchymal and only 2/8 were successfully salvaged (2 still under treatment). Four patients with CNSR had kidney involvement (plus adrenal in 2/4). Two of seven patients with both kidney and adrenal involvement and 2/ 17 with kidney infiltration only relapsed in the CNS. Kidney [subhazard ratio (SHR) 15.4, p<0.001], adrenal (SHR 13.6, p=0.001), any kidney or adrenal involvement (SHR 12.5, p<0.001), and high CNS-IPI (4-6, SHR 13.0, p<0.001) were associated with CNSR in univariate analysis. All 4 patients with high CNS-IPI who experienced CNSR (out of 35), had also kidney and/or adrenal involvement. Looser but significant associations were observed with high IPI (2-5; SHR 6.3, p=0.009), advanced stage (III/IV; SHR 5.5, p=0.007), impaired performance status (≥2; SHR 6.6, p=0.005), and ≥2 extranodal sites (SHR 5.4, p=0.009) but not chemotherapy backbone (R-CHOP or DA-EPOCH-R), CNS prophylactic therapy, age, gender, B-symptoms, LDH elevations or other baseline labs, serositis or PMLBCL-specific prognostic indices (stage IV/ extranodal plus bulky or high LDH≥2x).

Conclusion: In PMLBCL, CNSR is rare and appears to be primarily associated with kidney and/or adrenal involvement. CNS-IPI is also strongly prognostic but highly correlated with kidney and/or adrenal involvement. No late (>2 years) occurrences were seen and 9/10 relapses were isolated in the CNS. No inferences regarding the value of primary CNS prophylaxis can be made. Even in this very large series multivariate is not reliable due to the small number of events. A larger multinational effort is warranted.

Disclosures: Gurion: Takeda: Honoraria; Medison Ltd: Honoraria; Gilead: Honoraria; Roche: Honoraria; Novartis: Honoraria. Katodritou: JANSSEN: Other: travel expenses, Research Funding; AMGEN: Honoraria, Research Funding; GSK: Honoraria, Other: travel expenses, Research Funding; Takeda: Honoraria, Other: research expenses, Research Funding; Sanofi: Research Funding; Integris Pharma: Honoraria; Karyopharm: Research Funding; Abbvie: Honoraria, Other: travel expenses, Research Funding. Tadmor: Janssen: Research Funding; AbbVie, Roche, Novartis, Sanofi, Takeda, Janssen, Pfizer: Consultancy, Honoraria, Speakers Bureau. Symeonidis: Servier SOBI: Membership on an entity's Board of Directors or advisory committees; Rafarm: Honoraria; Demo/Apopharma: Research Funding; WinMedica: Research Funding; Roche: Research Funding; Vianex: Research Funding; Abbvie, Amgen, Astra-Zeneca, BMS, GenesisPharma, Gilead, Glaxo, Integris, Janssen, Novartis, Pfizer, Sanofi, Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Research Funding. Terpos: Genesis: Honoraria, Research Funding; BMS: Honoraria; EUSA Pharma: Honoraria, Other: Travel expenses; Janssen: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Novartis: Honoraria; Takeda: Honoraria, Other: Travel expenses, Research Funding; GSK: Honoraria, Research Funding; Amgen: Honoraria, Other: Travel expenses, Research Funding. Gafter-Gvili: Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Medison: Honoraria, Membership on an entity's Board of Directors or advisory committees. Panayiotidis: ABBVIE, NOVARTIS, GENESISPHARMA, BMS,Gilead, Glaxo, Integris, Janssen, Novartis, Pfizer: Honoraria, Research Funding.

*signifies non-member of ASH