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455 High-Grade B-Cell Lymphoma, Not Otherwise Specified (HGBL, NOS): Characteristics, Treatment, and Outcomes from 17 Academic US Centers

Program: Oral and Poster Abstracts
Type: Oral
Session: 627. Aggressive Lymphomas: Clinical and Epidemiological: Clinical Management of Aggressive B cell NHL
Hematology Disease Topics & Pathways:
Biological, Antibody Therapy, Adults, Epidemiology, Lymphomas, Non-Hodgkin Lymphoma, Non-Biological, Clinical Research, B Cell Lymphoma, Chemotherapy, Chimeric Antigen Receptor (CAR)-T Cell Therapies, Clinically Relevant, Diseases, Real World Evidence, Aggressive Lymphoma, Therapies, Lymphoid Malignancies, Monoclonal Antibody Therapy, Study Population, Clinical Practice (e.g. Guidelines, Health Outcomes and Services, and Survivorship, Value; etc.)
Sunday, December 12, 2021: 1:00 PM

Adam Zayac, MD1, Daniel J Landsburg, MD2, Mitchell Hughes, PharmD2*, Emily C. Ayers, MD3, Mark Girton, MD4*, Marie Hu, MD5, Amy Beckman, MD6*, Shaoying Li7*, L. Jeffrey Medeiros, MD8, Habibe Kurt, MD9*, Jose Sandoval-Sus, MD10, M. Ali Ansari-Lari, MD11*, Shalin K. Kothari, MD12, Anna Kress, MD12, Mina L. Xu, MD13*, Pallawi Torka, MD14, Suchitra Sundaram, MD15*, Stephen D. Smith, MD16,17, Kikkeri N Naresh, MD, MBBS18, Yasmin Karimi, MD19*, Narendranath Epperla, MD, MS20, David A. Bond, MD, BS21, Andrew M. Evens, DO, MMSc22, Karan Pandya, MD22*, Seema G Naik, MD23*, Manali Kamdar, MD24, Brad Haverkos, MD, MPH, MS25, Reem Karmali, MD, MSc26, Timothy Seijung Oh, MD26*, Julie M. Vose, MD, MBA27, Heather Nutsch27*, Paul Rubinstein, MD28*, Amina Chaudhry, MD28 and Adam J. Olszewski, MD1,29

1Lifespan Cancer Institute, Alpert Medical School of Brown University, Providence, RI
2Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA
3Division of Hematology/Oncology, University of Virginia, Charlottesville, VA
4Department of Pathology, University of Virginia School of Medicine, Charlottesville, VA
5Department of Medicine, Division of Hematology, Oncology, and Transplantation, University of Minnesota, Minneapolis, MN
6University of Minnesota, Minneapolis, MN
7Department of Hematopathology, Division of Pathology and Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX
8Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX
9Department of Pathology and Laboratory Medicine, Rhode Island Hospital, Providence, RI
10Department of Malignant Hematology and Cellular Therapy at Memorial Healthcare System, Moffitt Cancer Center, Pembroke Pines, FL
11Department of Pathology, Hematopathology, Memorial Health System-Moffitt Cancer Center, Hollywood, FL
12Yale University School of Medicine, New Haven, CT
13Department of Pathology and Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT
14Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY
15Roswell Park Comprehensive Cancer Center, Buffalo, NY
16Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA
17Division of Medical Oncology, University of Washington/Fred Hutchinson Cancer Research Center, Seattle, WA
18Department of Pathology, University of Washington, Seattle, WA
19Division of Hematology-Oncology, University of Michigan Health, Ann Arbor, MI
20The Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, OH, USA, Columbus, OH
21The Ohio State University Comprehensive Cancer Center, Columbus, OH
22Rutgers Cancer Institute of New Jersey, New Brunswick, NJ
23Penn State Cancer Institute, Penn State Hershey Medical Center, Hershey, PA
24Division of Hematology, Hematologic Malignancies and Stem Cell Transplantation, University of Colorado Cancer Center, Denver, CO
25Division of Hematology, Hematologic Malignancies and Stem Cell Transplantation, University of Colorado, Denver, CO
26Division of Hematology and Oncology, Northwestern University, Chicago, IL
27University of Nebraska Medical Center, Omaha, NE
28Department of Hematology-Oncology, University of Illinois-Chicago, Chicago, IL
29Rhode Island Hospital, Providence, RI

Background: The term HGBL, NOS was introduced by the World Health Organization (WHO) in 2016 for aggressive B-cell lymphomas with Burkitt lymphoma-like (BLL) or blastoid cytomorphology that lack double-hit genetics and do not meet criteria for other entities. Diagnostic patterns and prognosis of these rare tumors are not well understood. We examined the characteristics and outcomes of patients (pts) with HGBL, NOS diagnosed in 17 academic centers across the United States.

Methods: We collected retrospective data on HGBL, NOS cases diagnosed by academic hematopathologists in 2017-2021; 8 centers performed a local review by lymphoma pathology experts to confirm fulfillment of the WHO criteria; pathology reports were reviewed centrally. We excluded pts not tested for MYC rearrangement (MYC-R), any double/triple-hit, diffuse large B-cell, or lymphoblastic lymphomas. Immunohistochemistry (IHC) and cytogenetic tests were done locally. Outcomes included rates of complete response (CR), progression-free (PFS) and overall survival (OS) estimated with 95% confidence intervals (CI).

Results: Among 126 pts with HGBL, NOS, median age was 64 years (range 18-91), 67% were male, and 3 were HIV+. Advanced stage was present in 68%, poor performance status (PS, ECOG ≥2) in 21%, high serum lactate dehydrogenase (LDH) in 68%, extranodal (EN) sites in 79%, central nervous system (CNS) involvement in 6%, and International Prognostic Index (IPI) ≥ 3 in 55%.

Cytomorphology was reported as BLL in 59 (47%) cases, blastoid in 28 (22%), and unspecified in 39 (31%). By IHC, 83% had germinal center B-cell (GCB) phenotype. Using cases with available data, CD10 was expressed in 79%, BCL6 in 81%, MUM1/IRF4 in 48%, MYC in 73%, BCL2 in 55% (dual MYC/BCL2 expressor [DEL]: 37%), CD5 in 13%, and median Ki-67 was 95%. MYC-R (single-hit) was detected in 27% (Fig A), MYC extra copies (EC) in 9%, BCL2-R in 13%, and BCL6­-R in 10%. MYC­-EC were present in 16% of cases with BCL2-R or BCL6-R, and BCL2/BCL6-EC in 12% of those with MYC-R. Blastoid tumors were more likely than BLL to involve >1 EN site or to have BCL2-R (Fig B). 9 cases were assessed by next generation sequencing and 5 (56%) had a TP53 mutation. Cases which underwent confirmatory pathology review (N=74) did not differ from others clinically but more often had a well-defined HGBL morphology (77% vs 58%, P=.031) and less often MYC-R (20% vs. 37%, P=.004).

The most common first-line regimens (among treated pts, N=121) were DA-EPOCH-R (50%) and RCHOP (35%), with few pts receiving HyperCVAD/MA (5%) or CODOX-M±IVAC (2%); 97% received rituximab, and 44% CNS prophylaxis. Pts selected for DA-EPOCH-R vs. RCHOP were younger (median 61 vs. 68 years, P=.006), more often had stage 3/4 (P=.04), BLL morphology (56% vs. 29%, P=.009) or MYC-R (31% vs. 14%, P=.06). CR was attained in 62% of pts, whereas 20% had progressive disease. The most frequent salvage regimens (± rituximab) included ICE (N=12), DHAP (N=6), and GemOx (N=5). 3 pts underwent autologous, and 3 allogeneic transplant (2/3 subsequently relapsed). 13 received chimeric antigen receptor (CAR) T-cells, with response noted in 7 (54%) and CR in 4 (31%); HGBL relapsed in 3/7 (43%) responders.

With median follow-up of 2.7 years, 39% of pts relapsed, and 33% died. Of 49 observed relapses, 13 (27%) involved the CNS. PFS estimate at 2 years was 51% (95% CI, 42-60%) and OS was 68% (95% CI, 58-76%; Fig C). PFS and OS were not significantly associated with age or PS, but stage and LDH were prognostic (Fig D-G). Furthermore, PFS did not differ by BLL/blastoid morphology, MYC-R status or DEL status, but non-GCB tumors had somewhat worse PFS (Fig H-J). We observed no significant PFS (or OS) difference between pts selected for RCHOP vs. DA-EPOCH-R (P=.83 for PFS, Fig K; P=.55 for OS) in aggregate or in any subset, except for de novo tumors with BLL morphology (N=41), where DA-EPOCH-R showed a superior 2-year PFS (73% vs 38% for RCHOP, P=.027; stratified by IPI: P=.040, Fig L).

Conclusions: HGBL, NOS, as diagnosed in current academic practice, is highly heterogeneous, highlighting the need to classify high-grade lymphomas using molecular rather than morphologic features. Considering poor survival in all age groups (except for few pts with early stage and normal LDH), lack of prognostic significance of MYC-R, DEL status, or cytomorphology, HGBL, NOS needs prospective trials to delineate prognostic biomarkers, the role of intensified chemotherapy, and novel therapeutic approaches.

Disclosures: Landsburg: Triphase: Research Funding; Takeda: Research Funding; Curis: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Other: DSMB member; ADCT: Membership on an entity's Board of Directors or advisory committees; Morphosys: Membership on an entity's Board of Directors or advisory committees. Hughes: Acerta Pharma: Research Funding; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genzyme: Consultancy; Janssen: Consultancy; Karyopharm: Membership on an entity's Board of Directors or advisory committees. Sandoval-Sus: SeaGen, Janssen, MassiveBio, TG: Other: Advisory Board; BMS: Other: Advisory Board, Speakers Bureau. Kothari: Incyte pharmaceuticals: Consultancy, Honoraria; Karyopharm pharmaceuticals: Consultancy, Honoraria. Torka: TG Therapeutics: Membership on an entity's Board of Directors or advisory committees. Smith: ADC Therapeutics: Consultancy; Portola Pharmaceuticals: Research Funding; Ayala (spouse): Research Funding; Genentech: Research Funding; Bristol Myers Squibb (spouse): Research Funding; Merck Sharp & Dohme Corp: Research Funding; Incyte: Consultancy; KITE pharm: Consultancy; Incyte Corporation: Research Funding; De Novo Biopharma: Research Funding; Karyopharm: Consultancy; Ignyta (spouse): Research Funding; Millenium/Takeda: Consultancy; Acerta Pharma BV: Research Funding; AstraZeneca: Consultancy, Research Funding; Beigene: Consultancy, Research Funding; Bayer: Research Funding. Epperla: Verastem: Speakers Bureau; Beigene: Speakers Bureau; Karyopharm: Other: Ad Board; Genzyme: Honoraria. Bond: Kite/Gilead: Honoraria. Naik: Sanofi: Other: Virtual Advisory Board Member ; Takeda: Other: Virtual Advisory Board Member ; Kite: Other: Virtual Advisory Board Member. Kamdar: ADC Therapeutics: Consultancy; AbbVie: Consultancy; KaryoPharm: Consultancy; Kite: Consultancy; Adaptive Biotechnologies: Consultancy; AstraZeneca: Consultancy; Celgene (BMS): Consultancy; TG Therapeutics: Research Funding; Genentech: Research Funding; Genetech: Other; Celgene: Other; SeaGen: Speakers Bureau. Haverkos: Viracta Therapeutics: Consultancy. Karmali: EUSA: Consultancy; Janssen/Pharmacyclics: Consultancy; Morphosys: Consultancy, Speakers Bureau; BeiGene: Consultancy, Speakers Bureau; Takeda: Research Funding; BMS/Celgene/Juno: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding, Speakers Bureau; AstraZeneca: Speakers Bureau; Karyopharm: Consultancy; Genentech: Consultancy; Epizyme: Consultancy; Roche: Consultancy. Vose: Kite, a Gilead Company: Honoraria, Research Funding. Olszewski: PrecisionBio: Research Funding; Celldex Therapeutics: Research Funding; TG Therapeutics: Research Funding; Acrotech Pharma: Research Funding; Genentech, Inc.: Research Funding; Genmab: Research Funding.

*signifies non-member of ASH