Introduction: Despite significant advances in characterizing aggressive B-cell non-Hodgkin lymphomas (aNHL) based on molecular and genetic signatures, the Hans algorithm, determined by immunohistochemistry, remains the most commonly used approach to differentiate aNHLs based on the cell-of-origin (COO) into germinal center B-cell (GCB) and non-GCB types. Although the Hans algorithm has demonstrated reliability as a predictor of better outcomes in newly diagnosed GCB cases, conflicting evidence has emerged, particularly in the relapsed/refractory (R/R) setting, and there are no definitive data about the impact of COO in patients (pts) receiving CAR-T cells. Thus, we conducted a retrospective analysis to evaluate the impact of COO extended to R/R aNHLs who underwent treatment with axicabtagene-ciloleucel (axi-cel).
Methods: We retrospectively collected data from pts with R/R aNHLs treated with axi-cel at Fred Hutchinson Cancer Center between February 2018 and August 2022. The Hans algorithm, using CD10, BCL6 and MUM1 markers, was employed to stratify the pts into two cohorts: GCB and non-GCB. Paired biopsies of diagnosis and relapse before CAR-T eligibility were reviewed at our institution. Response to CAR-T was assessed at one month per Lugano PET/CT criteria.
Univariate cox proportional hazard regression was used to estimate associations between baseline factors and outcomes. Statistically significant factors ( p<.05) in univariate analysis were further evaluated by multivariate analysis. Continuous variables were compared by Mann-Whitney U test and categorical variables by Fischer's exact test. Progression-free survival (PFS) was calculated from the date of CAR-T cell infusion to the date of death from any cause, disease progression or relapse. Overall survival (OS) was calculated from the date of CAR-T cell infusion to the date of death from any cause.
Results: Sixty-four pts were included in this analysis, with an equal distribution of pts in the two cohorts: 32 with GCB subtype and 32 with non-GCB subtype. Baseline pts' characteristics and histology subtypes are listed in Table 1. Transformed follicular lymphoma and primary mediastinal B-cell lymphoma were not included in this analysis. The presence of bulky disease (defined as >5cm diameter) was higher in the GCB subtype (56% vs 22%, p<.001). Although primary refractory cases were more frequent in the GCB cohort (87.5 vs 66%), statistical significance was not reached (NR)( p=.07). The same proportion of pts received bridging therapy in the two groups (53% vs 53%, p=.99). Pts evaluable for response assessment were 62. Median time to best response was 29 days (range, 21-186) for GCB pts and 31 days (range, 22-182) for non-GCB pts ( p=.91). The overall response rate was 70% for GCBs (34.5% complete response [CR], 34.5% partial response [PR]) and 75% for non-GCBs (44% CR, 31% PR). After a median follow-up of 24.5 months (range, 9-121), comparable outcomes were observed for both the COO groups: despite the estimated median OS of 14 months (95% CI, 4.73-NR) for GCB vs 40 months (95% CI, 12.55-67.46) for non-GCB, we did not find any significant differences ( p=.73) (Figure 1A). Estimated median PFS was 10 months (95% confidence interval [CI], 3.5-16) for GCB and 11 months (95% CI, 0-24) for non-GCB ( p=.57) (Figure 1B). The 2-year OS and PFS were: GCB, 45% (95% CI, 30-69) and 44% (95% CI, 29-67) respectively; non-GCB, 55% (95% CI, 38-79) and 29% (95% CI, 16-55), respectively.
Treatment-related toxicities did not differ between GCB and non-GCB, with cytokine-release syndrome rates of 97% vs 94% ( p=.99) and neurotoxicity rates of 53% vs 62.5% ( p=.61), respectively. The incidence of infectious complications was 25% vs 19% ( p=.76).
On univariate analysis, the impact of COO on OS (HR=0.82, 95% CI 0.39-1.73, p=.60) and PFS (HR=1.18, 95% CI 0.61-2.28, p=.62) was undetermined. After adjusting for bulky disease, elevated LDH, absolute lymphocyte count≤1000/uL, performance status≥2, >2 lines of therapy and response status before axi-cel infusion, the impact of COO on OS (adjusted HR [aHR]=1.73, 95% CI 0.71-4.22, p=.23) and PFS (aHR=2.01, 95% CI 0.93-4.35, p=.08), remained undetermined.
Conclusion: We could not confirm an association between COO, as determined by Hans algorithm, and outcomes in R/R aNHLs who received axi-cel at our center. Prospective analyses on larger datasets and other types of CAR-T products are needed.
Disclosures
Gauthier:Kite Pharma: Consultancy, Honoraria; Century Therapeutics: Other: Independent data review committee; Angiocrine Bioscience: Research Funding; MorphoSys: Consultancy, Research Funding; Legend Biotech: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celgene (a Bristol Myers Squibb company): Research Funding; Juno Therapeutics (a Bristol Myers Squibb company): Research Funding; Sobi: Consultancy, Honoraria, Research Funding. Lynch:TG Therapeutics: Research Funding; Incyte: Research Funding; Bayer: Research Funding; Cyteir: Research Funding; Genentech: Research Funding; Seagen Inc.: Research Funding; Rapt: Research Funding; Cancer Study Group: Consultancy; SeaGen: Consultancy; Foresight Diagnostics: Consultancy; Abbvie: Consultancy; Merck: Research Funding. Gopal:Compliment Corporation: Current holder of stock options in a privately-held company; Incyte, Kite, Morphosys/Incyte, ADCT, Acrotech, Merck, Karyopharm, Servier, Beigene, Cellectar, Janssen, SeaGen, Epizyme, I-Mab bio, Gilead, Genentech, Lilly, Caribou, Fresenius-Kabi: Consultancy; Merck, I-Mab bio, IgM Bio, Takeda, Gilead, Astra-Zeneca, Agios, Janssen, BMS, SeaGen, Teva, Genmab: Research Funding. Hirayama:Juno Therapeutics, a Bristol Myers Squibb Company: Research Funding; Nektar Therapeutics: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria. Smith:ADC Therapeutics, AstraZeneca, BeiGene, Epizyme, Karyopharm, KITE pharma, Incyte, Numab Therapeutics AG, Abbvie, Coherus Biosciences, advisory board (spouse) Genentech, Inc.: Consultancy; ADC Therapeutics, AstraZeneca, Ayala (spouse), Bayer, BeiGene, Bristol Myers Squibb (spouse), De Novo Biopharma, Enterome, Genentech, Inc., Ignyta (spouse), Incyte Corporation, Kymera Therapeutics, Merck Sharp and Dohme Corp., MorphoSys, Nanjing Pharmaceu: Research Funding; BeiGene: Membership on an entity's Board of Directors or advisory committees. Till:BMS/Juno Therapeutics: Research Funding; Proteios Technology: Consultancy, Current holder of stock options in a privately-held company; Mustang Bio: Consultancy, Patents & Royalties, Research Funding. Maloney:A2 Biotherapeutics: Consultancy, Current holder of stock options in a privately-held company, Honoraria, Other: Member of the Scientific Advisory Board; Genentech: Consultancy, Honoraria, Other: Chair and Member of the Lymphoma Steering Committee; Amgen: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria, Other: Member of the JCAR017 EAP-001 Safety Review Committee and Member, CLL Strategic Council, Member of the JCAR017-BCM-03 Scientific Steering Committee under BMS, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Participation on a Data Safety Monitory Board , Research Funding; Gilead Sciences: Consultancy, Honoraria, Other: Member, Scientific Review Committee, Research Scholars Program in Hematologic Malignancies; Incyte: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Juno Therapeutics: Consultancy, Honoraria, Patents & Royalties: Rights to royalties from Fred Hutch for patents licensed to Juno Therapeutics/BMS, Research Funding; Kite, a Gilead Sciences: Consultancy, Honoraria, Research Funding; Legend Biotech: Consultancy, Honoraria, Research Funding; MorphoSys: Consultancy, Honoraria; Mustang Bio: Consultancy, Honoraria; Navan Technologies: Consultancy, Honoraria, Other: Member of the Scientific Advisory Board; Novartis: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria; Umoja: Consultancy, Honoraria; Bioline Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participation on a Data Safety Monitory Board ; Fred Hutch: Other: rights to royalties for patents licensed to Juno; Navan Technologies: Current holder of stock options in a privately-held company; Chimeric Therapeutics: Other: Member of the Scientific Advisory Board; ImmPACT Bio: Other: Member, Clinical Advisory Board, CD19/CD20 bi-specific CAR-T Cell Therapy Program; Interius: Other: Member, Clinical Advisory Board; Lyell Immunopharma: Other: Member, CAR T Steering Committee. Ujjani:Genentech: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Research Funding; Beigene: Consultancy, Honoraria; Atara: Consultancy; Pharmacyclics: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Lilly: Consultancy, Honoraria, Research Funding; Epizyme: Consultancy; Astrazeneca: Consultancy, Honoraria, Research Funding; Kite, a Gilead Company: Consultancy, Other: Travel expenses , Research Funding; PCYC: Research Funding. Poh:BeiGene: Consultancy; Seattle Genetics: Consultancy; Incyte: Research Funding; Acrotech: Consultancy. Milano:ExCellThera Inc.: Research Funding. Chapuis:Juno Therapeutics: Research Funding. Shadman:BeiGene: Consultancy, Research Funding; Vincerx: Research Funding; Eli Lilly: Consultancy; Janssen: Consultancy; AbbVie: Consultancy, Research Funding; TG Therapeutics: Research Funding; Genentech: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Fate Therapeutics: Consultancy; MorphoSys/Incyte: Consultancy, Research Funding; Mustang Bio: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; MEI Pharma: Consultancy; ADC therapeutics: Consultancy; Regeneron: Consultancy; Kite, a Gilead Company: Consultancy; Genmab: Consultancy, Research Funding. Iovino:Mustang Bio: Current equity holder in publicly-traded company.
