B Cell Lymphoma

Key clinical point: The combination of tisagenlecleucel and time-limited ibrutinib improved outcomes and could be safely administered to patients with relapsed or refractory mantle cell lymphoma (r/r MCL), irrespective of prior covalent Bruton tyrosine kinase inhibitor (BTKi) exposure.

Major finding: At 4 months post infusion, the overall and complete response rates were 80% each. Patients with and without prior BTKi exposure had complete response rates of 90% and 70%, respectively. Grades 1-2 and grade 3 cytokine release syndrome rates were 55% and 20%, respectively.

Study details: This phase 2 study, TARMAC, included 20 patients having r/r MCL after ≥1 prior lines of therapy with (n = 10) or without (n = 10) a BTKi who were infused with tisagenlecleucel and commenced ibrutinib before leukapheresis and continued it for ≥6 months post infusion.

Disclosures: The study was sponsored by Peter MacCallum Cancer Centre, Australia. Several authors declared being members of the advisory committee, board of directors, or speakers’ bureau of or receiving honoraria or research funding from various sources.

Source: Minson AG et al. CAR T-cells and time-limited ibrutinib as treatment for relapsed/refractory mantle cell lymphoma: Phase II TARMAC study. Blood. 2023 (Oct 26). doi: 10.1182/blood.2023021306

Key clinical point: The combination of tisagenlecleucel and time-limited ibrutinib improved outcomes and could be safely administered to patients with relapsed or refractory mantle cell lymphoma (r/r MCL), irrespective of prior covalent Bruton tyrosine kinase inhibitor (BTKi) exposure.

Major finding: At 4 months post infusion, the overall and complete response rates were 80% each. Patients with and without prior BTKi exposure had complete response rates of 90% and 70%, respectively. Grades 1-2 and grade 3 cytokine release syndrome rates were 55% and 20%, respectively.

Study details: This phase 2 study, TARMAC, included 20 patients having r/r MCL after ≥1 prior lines of therapy with (n = 10) or without (n = 10) a BTKi who were infused with tisagenlecleucel and commenced ibrutinib before leukapheresis and continued it for ≥6 months post infusion.

Disclosures: The study was sponsored by Peter MacCallum Cancer Centre, Australia. Several authors declared being members of the advisory committee, board of directors, or speakers’ bureau of or receiving honoraria or research funding from various sources.

Source: Minson AG et al. CAR T-cells and time-limited ibrutinib as treatment for relapsed/refractory mantle cell lymphoma: Phase II TARMAC study. Blood. 2023 (Oct 26). doi: 10.1182/blood.2023021306

Key clinical point: The combination of tisagenlecleucel and time-limited ibrutinib improved outcomes and could be safely administered to patients with relapsed or refractory mantle cell lymphoma (r/r MCL), irrespective of prior covalent Bruton tyrosine kinase inhibitor (BTKi) exposure.

Major finding: At 4 months post infusion, the overall and complete response rates were 80% each. Patients with and without prior BTKi exposure had complete response rates of 90% and 70%, respectively. Grades 1-2 and grade 3 cytokine release syndrome rates were 55% and 20%, respectively.

Study details: This phase 2 study, TARMAC, included 20 patients having r/r MCL after ≥1 prior lines of therapy with (n = 10) or without (n = 10) a BTKi who were infused with tisagenlecleucel and commenced ibrutinib before leukapheresis and continued it for ≥6 months post infusion.

Disclosures: The study was sponsored by Peter MacCallum Cancer Centre, Australia. Several authors declared being members of the advisory committee, board of directors, or speakers’ bureau of or receiving honoraria or research funding from various sources.

Source: Minson AG et al. CAR T-cells and time-limited ibrutinib as treatment for relapsed/refractory mantle cell lymphoma: Phase II TARMAC study. Blood. 2023 (Oct 26). doi: 10.1182/blood.2023021306

Key clinical point: Compared with tisagenlecleucel, axicabtagene ciloleucel (axi-cel) was associated with improved treatment outcomes but increased the risk for grade ≥ 3 neurologic events in patients with relapsed or refractory large B-cell lymphoma (LBCL) in real-world settings.

Major finding: Axi-cel vs tisagenlecleucel improved the overall survival (adjusted hazard ratio [aHR] 0.60; 95% CI 0.47-0.77), progression-free survival (aHR 0.67; 95% CI 0.57-0.78), and overall response rate (odds ratio 2.05; 95% CI 1.76-2.40). However, it was associated with a higher incidence of grade ≥ 3 immune effector cell-associated neurotoxicity syndrome (odds ratio 3.95; 95% CI 3.05-5.11).

Study details: This comparative meta-analysis of 14 real-world cohorts included patients with relapsed or refractory LBCL who received axi-cel (n = 2432) or tisagenlecleucel (n = 1514) chimeric antigen receptor T-cell therapy.

Disclosures: This study was funded by Kite, a Gilead Company. Six authors declared being employees of or holding leadership positions and stocks in Kite or Gilead. Several authors reported receiving honoraria, travel fees, research funding, etc., from various sources, including Kite.

Source: Jacobson CA et al. Real-world outcomes with CAR T-cell therapies in large B-cell lymphoma: A systematic review and meta-analysis. Transplant Cell Ther. 2023 (Oct 25). doi: 10.1016/j.jtct.2023.10.017

Key clinical point: Compared with tisagenlecleucel, axicabtagene ciloleucel (axi-cel) was associated with improved treatment outcomes but increased the risk for grade ≥ 3 neurologic events in patients with relapsed or refractory large B-cell lymphoma (LBCL) in real-world settings.

Major finding: Axi-cel vs tisagenlecleucel improved the overall survival (adjusted hazard ratio [aHR] 0.60; 95% CI 0.47-0.77), progression-free survival (aHR 0.67; 95% CI 0.57-0.78), and overall response rate (odds ratio 2.05; 95% CI 1.76-2.40). However, it was associated with a higher incidence of grade ≥ 3 immune effector cell-associated neurotoxicity syndrome (odds ratio 3.95; 95% CI 3.05-5.11).

Study details: This comparative meta-analysis of 14 real-world cohorts included patients with relapsed or refractory LBCL who received axi-cel (n = 2432) or tisagenlecleucel (n = 1514) chimeric antigen receptor T-cell therapy.

Disclosures: This study was funded by Kite, a Gilead Company. Six authors declared being employees of or holding leadership positions and stocks in Kite or Gilead. Several authors reported receiving honoraria, travel fees, research funding, etc., from various sources, including Kite.

Source: Jacobson CA et al. Real-world outcomes with CAR T-cell therapies in large B-cell lymphoma: A systematic review and meta-analysis. Transplant Cell Ther. 2023 (Oct 25). doi: 10.1016/j.jtct.2023.10.017

Key clinical point: Compared with tisagenlecleucel, axicabtagene ciloleucel (axi-cel) was associated with improved treatment outcomes but increased the risk for grade ≥ 3 neurologic events in patients with relapsed or refractory large B-cell lymphoma (LBCL) in real-world settings.

Major finding: Axi-cel vs tisagenlecleucel improved the overall survival (adjusted hazard ratio [aHR] 0.60; 95% CI 0.47-0.77), progression-free survival (aHR 0.67; 95% CI 0.57-0.78), and overall response rate (odds ratio 2.05; 95% CI 1.76-2.40). However, it was associated with a higher incidence of grade ≥ 3 immune effector cell-associated neurotoxicity syndrome (odds ratio 3.95; 95% CI 3.05-5.11).

Study details: This comparative meta-analysis of 14 real-world cohorts included patients with relapsed or refractory LBCL who received axi-cel (n = 2432) or tisagenlecleucel (n = 1514) chimeric antigen receptor T-cell therapy.

Disclosures: This study was funded by Kite, a Gilead Company. Six authors declared being employees of or holding leadership positions and stocks in Kite or Gilead. Several authors reported receiving honoraria, travel fees, research funding, etc., from various sources, including Kite.

Source: Jacobson CA et al. Real-world outcomes with CAR T-cell therapies in large B-cell lymphoma: A systematic review and meta-analysis. Transplant Cell Ther. 2023 (Oct 25). doi: 10.1016/j.jtct.2023.10.017

Key clinical point: Total metabolic tumor volume (MTV) is an independent prognostic factor for treatment response and survival in patients receiving loncastuximab tesirine for relapsed or refractory diffuse large B-cell lymphoma (DLBCL) treated with ≥2 prior systemic therapy lines.

Major finding: An MTV ≥ 96 mL was significantly associated with failure to achieve a complete metabolic response (adjusted odds ratio 5.42; P  =  .002). Patients with an MTV ≥ 96 mL vs < 96 mL had shorter progression-free survival (adjusted hazard ratio [aHR] 2.68; P  =  .002) and overall survival (aHR 3.09; P < .0001).L

Study details: This post hoc analysis reviewed the screening PET/CT scans of 138 patients with relapsed or refractory DLBCL treated with ≥2 prior systemic therapy lines who received loncastuximab tesirine in LOTIS-2.

Disclosures: This study was supported by ADC Therapeutics, SA, and the Sylvester Comprehensive Cancer Center, Miami. Some authors declared serving as consultants, advisors, etc., for or receiving research funding or honoraria from ADC Therapeutics and others. J Radford declared owing stocks in ADC Therapeutics.

Source: Alderuccio JP et al. PET/CT-biomarkers enable risk stratification of patients with relapsed/refractory diffuse large B-cell lymphoma enrolled in the LOTIS-2 clinical trial. Clin Cancer Res. 2023 (Oct 19). doi: 10.1158/1078-0432.CCR-23-1561

Key clinical point: Total metabolic tumor volume (MTV) is an independent prognostic factor for treatment response and survival in patients receiving loncastuximab tesirine for relapsed or refractory diffuse large B-cell lymphoma (DLBCL) treated with ≥2 prior systemic therapy lines.

Major finding: An MTV ≥ 96 mL was significantly associated with failure to achieve a complete metabolic response (adjusted odds ratio 5.42; P  =  .002). Patients with an MTV ≥ 96 mL vs < 96 mL had shorter progression-free survival (adjusted hazard ratio [aHR] 2.68; P  =  .002) and overall survival (aHR 3.09; P < .0001).L

Study details: This post hoc analysis reviewed the screening PET/CT scans of 138 patients with relapsed or refractory DLBCL treated with ≥2 prior systemic therapy lines who received loncastuximab tesirine in LOTIS-2.

Disclosures: This study was supported by ADC Therapeutics, SA, and the Sylvester Comprehensive Cancer Center, Miami. Some authors declared serving as consultants, advisors, etc., for or receiving research funding or honoraria from ADC Therapeutics and others. J Radford declared owing stocks in ADC Therapeutics.

Source: Alderuccio JP et al. PET/CT-biomarkers enable risk stratification of patients with relapsed/refractory diffuse large B-cell lymphoma enrolled in the LOTIS-2 clinical trial. Clin Cancer Res. 2023 (Oct 19). doi: 10.1158/1078-0432.CCR-23-1561

Key clinical point: Total metabolic tumor volume (MTV) is an independent prognostic factor for treatment response and survival in patients receiving loncastuximab tesirine for relapsed or refractory diffuse large B-cell lymphoma (DLBCL) treated with ≥2 prior systemic therapy lines.

Major finding: An MTV ≥ 96 mL was significantly associated with failure to achieve a complete metabolic response (adjusted odds ratio 5.42; P  =  .002). Patients with an MTV ≥ 96 mL vs < 96 mL had shorter progression-free survival (adjusted hazard ratio [aHR] 2.68; P  =  .002) and overall survival (aHR 3.09; P < .0001).L

Study details: This post hoc analysis reviewed the screening PET/CT scans of 138 patients with relapsed or refractory DLBCL treated with ≥2 prior systemic therapy lines who received loncastuximab tesirine in LOTIS-2.

Disclosures: This study was supported by ADC Therapeutics, SA, and the Sylvester Comprehensive Cancer Center, Miami. Some authors declared serving as consultants, advisors, etc., for or receiving research funding or honoraria from ADC Therapeutics and others. J Radford declared owing stocks in ADC Therapeutics.

Source: Alderuccio JP et al. PET/CT-biomarkers enable risk stratification of patients with relapsed/refractory diffuse large B-cell lymphoma enrolled in the LOTIS-2 clinical trial. Clin Cancer Res. 2023 (Oct 19). doi: 10.1158/1078-0432.CCR-23-1561

Key clinical point: The outcomes of autologous stem cell transplantation (ASCT) are not superior to those of anti-CD20 radioimmunotherapy, which offers a less toxic consolidation approach, in patients with relapsed or refractory (R/R) follicular lymphoma (FL) receiving rituximab-based induction and maintenance.

Major finding: At a 77-month median follow-up, both treatment groups had estimated 3-year progression-free survival rates of 62% (hazard ratio [HR] 1.11; P  =  .6662) and similar 3-year overall survival (HR 0.94; P  =  .8588). ASCT vs radioimmunotherapy led to higher rates of grade ≥ 3 hematological toxicity and grade ≥ 3 neutropenia (both P < .001).

Study details: This phase 3 FLAZ12 trial included 159 patients with R/R FL after ≤2 chemotherapy lines (≥1 lines containing rituximab) who received rituximab-based induction chemoimmunotherapy, with those showing a partial or complete response being randomized 1:1 to receive ASCT or radioimmunotherapy, both followed by rituximab maintenance.

Disclosures: This study was funded by the Agenzia Italiana del Farmaco (AIFA) and Fondazione Italiana Linfomi. Some authors declared receiving honoraria or research funding from AIFA and others.

Source: Ladetto M, Tavarozzi  R, et al. Radioimmunotherapy versus autologous hematopoietic stem cell transplantation in relapse/refractory follicular lymphoma: A Fondazione Italiana Linfomi multicenter, randomized, phase 3 trial. Ann Oncol. 2023 (Nov 1). doi: 10.1016/j.annonc.2023.10.095

Key clinical point: The outcomes of autologous stem cell transplantation (ASCT) are not superior to those of anti-CD20 radioimmunotherapy, which offers a less toxic consolidation approach, in patients with relapsed or refractory (R/R) follicular lymphoma (FL) receiving rituximab-based induction and maintenance.

Major finding: At a 77-month median follow-up, both treatment groups had estimated 3-year progression-free survival rates of 62% (hazard ratio [HR] 1.11; P  =  .6662) and similar 3-year overall survival (HR 0.94; P  =  .8588). ASCT vs radioimmunotherapy led to higher rates of grade ≥ 3 hematological toxicity and grade ≥ 3 neutropenia (both P < .001).

Study details: This phase 3 FLAZ12 trial included 159 patients with R/R FL after ≤2 chemotherapy lines (≥1 lines containing rituximab) who received rituximab-based induction chemoimmunotherapy, with those showing a partial or complete response being randomized 1:1 to receive ASCT or radioimmunotherapy, both followed by rituximab maintenance.

Disclosures: This study was funded by the Agenzia Italiana del Farmaco (AIFA) and Fondazione Italiana Linfomi. Some authors declared receiving honoraria or research funding from AIFA and others.

Source: Ladetto M, Tavarozzi  R, et al. Radioimmunotherapy versus autologous hematopoietic stem cell transplantation in relapse/refractory follicular lymphoma: A Fondazione Italiana Linfomi multicenter, randomized, phase 3 trial. Ann Oncol. 2023 (Nov 1). doi: 10.1016/j.annonc.2023.10.095

Key clinical point: The outcomes of autologous stem cell transplantation (ASCT) are not superior to those of anti-CD20 radioimmunotherapy, which offers a less toxic consolidation approach, in patients with relapsed or refractory (R/R) follicular lymphoma (FL) receiving rituximab-based induction and maintenance.

Major finding: At a 77-month median follow-up, both treatment groups had estimated 3-year progression-free survival rates of 62% (hazard ratio [HR] 1.11; P  =  .6662) and similar 3-year overall survival (HR 0.94; P  =  .8588). ASCT vs radioimmunotherapy led to higher rates of grade ≥ 3 hematological toxicity and grade ≥ 3 neutropenia (both P < .001).

Study details: This phase 3 FLAZ12 trial included 159 patients with R/R FL after ≤2 chemotherapy lines (≥1 lines containing rituximab) who received rituximab-based induction chemoimmunotherapy, with those showing a partial or complete response being randomized 1:1 to receive ASCT or radioimmunotherapy, both followed by rituximab maintenance.

Disclosures: This study was funded by the Agenzia Italiana del Farmaco (AIFA) and Fondazione Italiana Linfomi. Some authors declared receiving honoraria or research funding from AIFA and others.

Source: Ladetto M, Tavarozzi  R, et al. Radioimmunotherapy versus autologous hematopoietic stem cell transplantation in relapse/refractory follicular lymphoma: A Fondazione Italiana Linfomi multicenter, randomized, phase 3 trial. Ann Oncol. 2023 (Nov 1). doi: 10.1016/j.annonc.2023.10.095

Key clinical point: TP53 mutations detected by clinical laboratory mutation analysis (CLMA) can independently predict poor outcomes in patients with newly diagnosed diffuse large B cell lymphoma (DLBCL) or high-grade B cell lymphoma (HGBL) treated with first-line immunochemotherapy.

Major finding: TP53 mutations significantly predicted disease progression at 2 years (adjusted hazard ratio 2.3; P  =  .03). Patients with vs without TP53 mutations had significantly lower overall response (71% vs 90%; P  =  .009), complete response (55% vs 77%, P  =  .01), estimated 2-year progression-free survival (57% vs 77%; P  =  .006), and estimated 2-year overall survival (70% vs 91%; P  =  .001) rates.

Study details: This study included 122 patients with newly diagnosed DLBCL or HGBL receiving first-line immunochemotherapy whose diagnostic biopsies underwent CLMA, of whom 42 patients had TP53 mutations.

Disclosures: This study did not disclose any funding source. All authors, except A Bagg, declared receiving honoraria, travel grants, or research funding from or having other ties with various sources.

Source: Landsburg DJ et al. TP53 mutations predict for poor outcomes in patients with newly-diagnosed aggressive B cell lymphomas in the current era. Blood Adv. 2023 (Oct 18). doi: 10.1182/bloodadvances.2023011384

Key clinical point: TP53 mutations detected by clinical laboratory mutation analysis (CLMA) can independently predict poor outcomes in patients with newly diagnosed diffuse large B cell lymphoma (DLBCL) or high-grade B cell lymphoma (HGBL) treated with first-line immunochemotherapy.

Major finding: TP53 mutations significantly predicted disease progression at 2 years (adjusted hazard ratio 2.3; P  =  .03). Patients with vs without TP53 mutations had significantly lower overall response (71% vs 90%; P  =  .009), complete response (55% vs 77%, P  =  .01), estimated 2-year progression-free survival (57% vs 77%; P  =  .006), and estimated 2-year overall survival (70% vs 91%; P  =  .001) rates.

Study details: This study included 122 patients with newly diagnosed DLBCL or HGBL receiving first-line immunochemotherapy whose diagnostic biopsies underwent CLMA, of whom 42 patients had TP53 mutations.

Disclosures: This study did not disclose any funding source. All authors, except A Bagg, declared receiving honoraria, travel grants, or research funding from or having other ties with various sources.

Source: Landsburg DJ et al. TP53 mutations predict for poor outcomes in patients with newly-diagnosed aggressive B cell lymphomas in the current era. Blood Adv. 2023 (Oct 18). doi: 10.1182/bloodadvances.2023011384

Key clinical point: TP53 mutations detected by clinical laboratory mutation analysis (CLMA) can independently predict poor outcomes in patients with newly diagnosed diffuse large B cell lymphoma (DLBCL) or high-grade B cell lymphoma (HGBL) treated with first-line immunochemotherapy.

Major finding: TP53 mutations significantly predicted disease progression at 2 years (adjusted hazard ratio 2.3; P  =  .03). Patients with vs without TP53 mutations had significantly lower overall response (71% vs 90%; P  =  .009), complete response (55% vs 77%, P  =  .01), estimated 2-year progression-free survival (57% vs 77%; P  =  .006), and estimated 2-year overall survival (70% vs 91%; P  =  .001) rates.

Study details: This study included 122 patients with newly diagnosed DLBCL or HGBL receiving first-line immunochemotherapy whose diagnostic biopsies underwent CLMA, of whom 42 patients had TP53 mutations.

Disclosures: This study did not disclose any funding source. All authors, except A Bagg, declared receiving honoraria, travel grants, or research funding from or having other ties with various sources.

Source: Landsburg DJ et al. TP53 mutations predict for poor outcomes in patients with newly-diagnosed aggressive B cell lymphomas in the current era. Blood Adv. 2023 (Oct 18). doi: 10.1182/bloodadvances.2023011384

Key clinical point: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) led to acceptable survival outcomes in patients with relapsed or refractory diffuse large B cell lymphoma (DLBCL), particularly in those achieving a partial or complete response to chemotherapy before allo-HSCT.

Major finding: At a median follow-up of 38.3 months, the estimated 5-year overall survival and event-free survival rates were 38.4% (95% CI 24.7%-51.8%) and 30.6% (95% CI 18.8%-43.3%), respectively, with patients who achieved a partial or complete response before allo-HSCT having overall survival and event-free survival rates of 54.1% (95% CI 34.2%-70.3%) and 46.4% (95% CI 28.1%-62.9%), respectively.

Study details: This retrospective study included 52 adult patients with relapsed or refractory DLBCL who either had an active disease status or achieved a partial or complete response before transplantation and underwent allo-HSCT.

Disclosures: This study did not disclose any funding source. The authors declared no conflicts of interest.

Source: Min GJ et al. The salvage role of allogeneic hematopoietic stem-cell transplantation in relapsed/refractory diffuse large B cell lymphoma. Sci Rep. 2023;13:17496 (Oct 15). doi: 10.1038/s41598-023-44241-0

Key clinical point: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) led to acceptable survival outcomes in patients with relapsed or refractory diffuse large B cell lymphoma (DLBCL), particularly in those achieving a partial or complete response to chemotherapy before allo-HSCT.

Major finding: At a median follow-up of 38.3 months, the estimated 5-year overall survival and event-free survival rates were 38.4% (95% CI 24.7%-51.8%) and 30.6% (95% CI 18.8%-43.3%), respectively, with patients who achieved a partial or complete response before allo-HSCT having overall survival and event-free survival rates of 54.1% (95% CI 34.2%-70.3%) and 46.4% (95% CI 28.1%-62.9%), respectively.

Study details: This retrospective study included 52 adult patients with relapsed or refractory DLBCL who either had an active disease status or achieved a partial or complete response before transplantation and underwent allo-HSCT.

Disclosures: This study did not disclose any funding source. The authors declared no conflicts of interest.

Source: Min GJ et al. The salvage role of allogeneic hematopoietic stem-cell transplantation in relapsed/refractory diffuse large B cell lymphoma. Sci Rep. 2023;13:17496 (Oct 15). doi: 10.1038/s41598-023-44241-0

Key clinical point: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) led to acceptable survival outcomes in patients with relapsed or refractory diffuse large B cell lymphoma (DLBCL), particularly in those achieving a partial or complete response to chemotherapy before allo-HSCT.

Major finding: At a median follow-up of 38.3 months, the estimated 5-year overall survival and event-free survival rates were 38.4% (95% CI 24.7%-51.8%) and 30.6% (95% CI 18.8%-43.3%), respectively, with patients who achieved a partial or complete response before allo-HSCT having overall survival and event-free survival rates of 54.1% (95% CI 34.2%-70.3%) and 46.4% (95% CI 28.1%-62.9%), respectively.

Study details: This retrospective study included 52 adult patients with relapsed or refractory DLBCL who either had an active disease status or achieved a partial or complete response before transplantation and underwent allo-HSCT.

Disclosures: This study did not disclose any funding source. The authors declared no conflicts of interest.

Source: Min GJ et al. The salvage role of allogeneic hematopoietic stem-cell transplantation in relapsed/refractory diffuse large B cell lymphoma. Sci Rep. 2023;13:17496 (Oct 15). doi: 10.1038/s41598-023-44241-0

Key clinical point: Fixed-duration ibrutinib-venetoclax vs chlorambucil-obinutuzumab continues to extend progression-free survival and leads to overall survival advantage at a 4-year follow-up in patients with previously untreated chronic lymphocytic leukemia (CLL).

Major finding: At a median follow-up of 46 months, the ibrutinib-venetoclax vs chlorambucil-obinutuzumab group continued to show better progression-free survival (hazard ratio [HR] 0.214; P < .0001) while also demonstrating overall survival benefit (HR 0.487; P  =  .021). One treatment-related death was reported in each group.

Study details: Findings are from a 4-year follow-up of the phase 3 GLOW trial including 211 patients with previously untreated CLL who were randomly assigned to receive ibrutinib-venetoclax or chlorambucil-obinutuzumab.

Disclosures: This study was funded by Janssen Research & Development and Pharmacyclics. Several authors declared serving on the boards of directors or advisory committees of or receiving consultancy fees, research funding, or honoraria from various sources, including Janssen. Nine authors declared being employees or equity holders of Janssen.

Source: Niemann CU et al. Fixed-duration ibrutinib–venetoclax versus chlorambucil–obinutuzumab in previously untreated chronic lymphocytic leukaemia (GLOW): 4-Year follow-up from a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2023 (Nov 6). doi: 10.1016/S1470-2045(23)00452-7

Key clinical point: Fixed-duration ibrutinib-venetoclax vs chlorambucil-obinutuzumab continues to extend progression-free survival and leads to overall survival advantage at a 4-year follow-up in patients with previously untreated chronic lymphocytic leukemia (CLL).

Major finding: At a median follow-up of 46 months, the ibrutinib-venetoclax vs chlorambucil-obinutuzumab group continued to show better progression-free survival (hazard ratio [HR] 0.214; P < .0001) while also demonstrating overall survival benefit (HR 0.487; P  =  .021). One treatment-related death was reported in each group.

Study details: Findings are from a 4-year follow-up of the phase 3 GLOW trial including 211 patients with previously untreated CLL who were randomly assigned to receive ibrutinib-venetoclax or chlorambucil-obinutuzumab.

Disclosures: This study was funded by Janssen Research & Development and Pharmacyclics. Several authors declared serving on the boards of directors or advisory committees of or receiving consultancy fees, research funding, or honoraria from various sources, including Janssen. Nine authors declared being employees or equity holders of Janssen.

Source: Niemann CU et al. Fixed-duration ibrutinib–venetoclax versus chlorambucil–obinutuzumab in previously untreated chronic lymphocytic leukaemia (GLOW): 4-Year follow-up from a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2023 (Nov 6). doi: 10.1016/S1470-2045(23)00452-7

Key clinical point: Fixed-duration ibrutinib-venetoclax vs chlorambucil-obinutuzumab continues to extend progression-free survival and leads to overall survival advantage at a 4-year follow-up in patients with previously untreated chronic lymphocytic leukemia (CLL).

Major finding: At a median follow-up of 46 months, the ibrutinib-venetoclax vs chlorambucil-obinutuzumab group continued to show better progression-free survival (hazard ratio [HR] 0.214; P < .0001) while also demonstrating overall survival benefit (HR 0.487; P  =  .021). One treatment-related death was reported in each group.

Study details: Findings are from a 4-year follow-up of the phase 3 GLOW trial including 211 patients with previously untreated CLL who were randomly assigned to receive ibrutinib-venetoclax or chlorambucil-obinutuzumab.

Disclosures: This study was funded by Janssen Research & Development and Pharmacyclics. Several authors declared serving on the boards of directors or advisory committees of or receiving consultancy fees, research funding, or honoraria from various sources, including Janssen. Nine authors declared being employees or equity holders of Janssen.

Source: Niemann CU et al. Fixed-duration ibrutinib–venetoclax versus chlorambucil–obinutuzumab in previously untreated chronic lymphocytic leukaemia (GLOW): 4-Year follow-up from a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2023 (Nov 6). doi: 10.1016/S1470-2045(23)00452-7

Key clinical point: Brexucabtagene autoleucel (brexu-cel) provides survival benefit over non-chimeric antigen receptor (CAR) T-cell standard of care (SOC) in patients with relapsed or refractory mantle cell lymphoma (MCL) treated with covalent Bruton tyrosine kinase inhibitors (BTKi).

Major finding: Inverse probability weighting showed that brexu-cel vs SOC led to a significantly reduced risk for death (adjusted hazard ratio 0.38; P < .001), with the findings being similar for other adjusted comparisons.

Study details: This indirect comparison study analyzed the individual patient data of BTKi-treated patients with relapsed or refractory MCL who received brexu-cel in ZUMA-2 (n = 68) and non-CAR T-cell SOC in SCHOLAR-2 (n = 149).

Disclosures: This study was sponsored by Kite, a Gilead Company. Some authors declared participating in the data safety monitoring or advisory boards of or receiving grants, consulting fees, travel support, or honoraria for lectures, etc., from Kite, Gilead, and others. Five authors declared being employees or stockowners of Kite, Gilead, or PRECISIONheor.

Source: Hess G et al. Indirect treatment comparison of brexucabtagene autoleucel (ZUMA-2) versus standard of care (SCHOLAR-2) in relapsed/refractory mantle cell lymphoma. Leuk Lymphoma. 2023 (Oct 16). doi: 10.1080/10428194.2023.2268228

Key clinical point: Brexucabtagene autoleucel (brexu-cel) provides survival benefit over non-chimeric antigen receptor (CAR) T-cell standard of care (SOC) in patients with relapsed or refractory mantle cell lymphoma (MCL) treated with covalent Bruton tyrosine kinase inhibitors (BTKi).

Major finding: Inverse probability weighting showed that brexu-cel vs SOC led to a significantly reduced risk for death (adjusted hazard ratio 0.38; P < .001), with the findings being similar for other adjusted comparisons.

Study details: This indirect comparison study analyzed the individual patient data of BTKi-treated patients with relapsed or refractory MCL who received brexu-cel in ZUMA-2 (n = 68) and non-CAR T-cell SOC in SCHOLAR-2 (n = 149).

Disclosures: This study was sponsored by Kite, a Gilead Company. Some authors declared participating in the data safety monitoring or advisory boards of or receiving grants, consulting fees, travel support, or honoraria for lectures, etc., from Kite, Gilead, and others. Five authors declared being employees or stockowners of Kite, Gilead, or PRECISIONheor.

Source: Hess G et al. Indirect treatment comparison of brexucabtagene autoleucel (ZUMA-2) versus standard of care (SCHOLAR-2) in relapsed/refractory mantle cell lymphoma. Leuk Lymphoma. 2023 (Oct 16). doi: 10.1080/10428194.2023.2268228

Key clinical point: Brexucabtagene autoleucel (brexu-cel) provides survival benefit over non-chimeric antigen receptor (CAR) T-cell standard of care (SOC) in patients with relapsed or refractory mantle cell lymphoma (MCL) treated with covalent Bruton tyrosine kinase inhibitors (BTKi).

Major finding: Inverse probability weighting showed that brexu-cel vs SOC led to a significantly reduced risk for death (adjusted hazard ratio 0.38; P < .001), with the findings being similar for other adjusted comparisons.

Study details: This indirect comparison study analyzed the individual patient data of BTKi-treated patients with relapsed or refractory MCL who received brexu-cel in ZUMA-2 (n = 68) and non-CAR T-cell SOC in SCHOLAR-2 (n = 149).

Disclosures: This study was sponsored by Kite, a Gilead Company. Some authors declared participating in the data safety monitoring or advisory boards of or receiving grants, consulting fees, travel support, or honoraria for lectures, etc., from Kite, Gilead, and others. Five authors declared being employees or stockowners of Kite, Gilead, or PRECISIONheor.

Source: Hess G et al. Indirect treatment comparison of brexucabtagene autoleucel (ZUMA-2) versus standard of care (SCHOLAR-2) in relapsed/refractory mantle cell lymphoma. Leuk Lymphoma. 2023 (Oct 16). doi: 10.1080/10428194.2023.2268228

Key clinical point: Patients with relapsed or refractory large B-cell lymphoma (LBCL) who were recently exposed to preapheresis bendamustine showed negative treatment outcomes, hematologic toxicity, and severe infections after CD19-targeted chimeric antigen receptor (CAR) T-cell therapy.

Major finding: Patients recently exposed to bendamustine (<9 months) vs those naive to it before apheresis had a significantly lower overall response rate (40% vs 66%; P  =  .01) and shorter overall survival (adjusted hazard ratio [aHR] 2.11; P < .01) and progression-free survival (aHR 1.82; P < .01) after CAR T-cell infusion.

Study details: This retrospective multicenter study included 439 patients with relapsed or refractory LBCL who received CD19-targeted commercial CAR T-cell therapy after ≥2 prior treatment lines, of whom 80 patients had received bendamustine before apheresis.

Disclosures: This study was supported by the Carlos III Health Institute, Spain, and others. Some authors declared serving in consulting or advisory roles for or as members of speakers’ bureaus of or receiving honoraria, research funding, or travel or accommodation expenses from various sources.

Source: Iacoboni G et al. Recent bendamustine treatment before apheresis has a negative impact on outcomes in patients with large B-cell lymphoma receiving chimeric antigen receptor T-cell therapy. J Clin Oncol. 2023 (Oct 24). doi: 10.1200/JCO.23.01097

Key clinical point: Patients with relapsed or refractory large B-cell lymphoma (LBCL) who were recently exposed to preapheresis bendamustine showed negative treatment outcomes, hematologic toxicity, and severe infections after CD19-targeted chimeric antigen receptor (CAR) T-cell therapy.

Major finding: Patients recently exposed to bendamustine (<9 months) vs those naive to it before apheresis had a significantly lower overall response rate (40% vs 66%; P  =  .01) and shorter overall survival (adjusted hazard ratio [aHR] 2.11; P < .01) and progression-free survival (aHR 1.82; P < .01) after CAR T-cell infusion.

Study details: This retrospective multicenter study included 439 patients with relapsed or refractory LBCL who received CD19-targeted commercial CAR T-cell therapy after ≥2 prior treatment lines, of whom 80 patients had received bendamustine before apheresis.

Disclosures: This study was supported by the Carlos III Health Institute, Spain, and others. Some authors declared serving in consulting or advisory roles for or as members of speakers’ bureaus of or receiving honoraria, research funding, or travel or accommodation expenses from various sources.

Source: Iacoboni G et al. Recent bendamustine treatment before apheresis has a negative impact on outcomes in patients with large B-cell lymphoma receiving chimeric antigen receptor T-cell therapy. J Clin Oncol. 2023 (Oct 24). doi: 10.1200/JCO.23.01097

Key clinical point: Patients with relapsed or refractory large B-cell lymphoma (LBCL) who were recently exposed to preapheresis bendamustine showed negative treatment outcomes, hematologic toxicity, and severe infections after CD19-targeted chimeric antigen receptor (CAR) T-cell therapy.

Major finding: Patients recently exposed to bendamustine (<9 months) vs those naive to it before apheresis had a significantly lower overall response rate (40% vs 66%; P  =  .01) and shorter overall survival (adjusted hazard ratio [aHR] 2.11; P < .01) and progression-free survival (aHR 1.82; P < .01) after CAR T-cell infusion.

Study details: This retrospective multicenter study included 439 patients with relapsed or refractory LBCL who received CD19-targeted commercial CAR T-cell therapy after ≥2 prior treatment lines, of whom 80 patients had received bendamustine before apheresis.

Disclosures: This study was supported by the Carlos III Health Institute, Spain, and others. Some authors declared serving in consulting or advisory roles for or as members of speakers’ bureaus of or receiving honoraria, research funding, or travel or accommodation expenses from various sources.

Source: Iacoboni G et al. Recent bendamustine treatment before apheresis has a negative impact on outcomes in patients with large B-cell lymphoma receiving chimeric antigen receptor T-cell therapy. J Clin Oncol. 2023 (Oct 24). doi: 10.1200/JCO.23.01097

The ZUMA-7 and TRANSFORM studies have been practice-changing for the treatment of relapsed/refractory (R/R) large B-cell lymphoma (LBCL). These studies demonstrated an improvement in outcomes with axicabtagene ciloleucel (axi-cel) and lisocabtagene maraleucel (liso-cel), respectively, as compared with standard-of-care treatment (chemotherapy and autologous stem cell transplantation).^1,2 Patients included in these studies were refractory to their initial therapy or experienced relapse within 12 months and were considered fit for autologous stem cell transplant. It has remained unclear, however, whether patients who are not transplant candidates may also derive benefit and tolerate treatment with chimeric antigen receptor (CAR) T-cell therapy. The PILOT study was a single-arm phase 2 study that demonstrated favorable outcomes with liso-cel in this patient population, thus resulting in the approval of liso-cel by the US Food and Drug Administration for this population.³ Recently, the ALYCATE study similarly examined outcomes in transplant-ineligible patients treated with axi-cel (Houot et al). This phase 2 study included 62 patients with high-risk R/R LBCL who underwent leukapheresis and subsequently received second-line axi-cel. The complete metabolic response rate 3 months after axi-cel infusion was 71.0% (95% CI 58.1%-81.8%). At a median 12-month follow-up, the median progression-free survival was 11.8 months (95% CI 8.4-not reached) whereas median overall survival was not reached. Grade ≥ 3 cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 8.1% and 14.5% of patients, respectively. Also of note, patients age ≥ 70 years did not show increased toxicity compared with those age < 70 years, with similar rates of CRS, ICANS, and intensive care unit transfer. This study supports the role of axi-cel in the second-line setting, regardless of transplant eligibility.

Another important study recently published for patients with LBCL examined the role of central nervous system (CNS) prophylaxis (Lewis et al). We know that certain patients with LBCL, including those with a high CNS international prognostic index (IPI) score, double-hit lymphoma, or disease involvement of multiple or certain extranodal sites (ie, breast, testes, adrenals, kidney) can be at increased risk for lymphoma spread to the CNS.⁴ Strategies to reduce this risk have subsequently been developed for these high-risk patients, though consensus regarding who should be treated and how best to treat patients has been consistent. Recently, retrospective data have also called into question whether our current approaches meaningfully reduce this risk. One such study was a multicenter, international, retrospective observational study that included 2418 adults with aggressive LBCL and a high risk for CNS progression who were treated with curative-intent anti-CD20–based chemoimmunotherapy and who did or did not receive high-dose methotrexate (HD-MTX). Patients who did vs did not receive HD-MTX had a significantly lower risk for CNS progression (adjusted 5-year risk difference 1.6%; adjusted hazard ratio [aHR] 0.59; P = .014), but the significance was lost when considering only those patients who achieved a complete response at chemoimmunotherapy completion (adjusted 5-year risk difference 1.4%; aHR 0.74; P = .30). The study was not sufficiently powered to make definitive conclusions for individual risk groups, though there was no obvious reduction in CNS involvement risk in any high-risk subgroup. With an absolute risk reduction of 1.6% with the use of HD-MTX, 63 patients would require treatment to prevent one CNS progression event over 5 years (Lewis et al). Given the absence of prospective, randomized data, these results, though retrospective in nature, call into question the benefit of CNS prophylaxis. The authors suggest that studies evaluating alternative strategies for prophylaxis and tools for early detection of relapse, such as circulating tumor DNA, may be helpful.

Another study worth noting was one exploring Bruton tyrosine kinase (BTK) inhibition in mantle cell lymphoma (MCL). BTK inhibitors, including zanubrutinib, have emerged as effective therapies for patients with R/R disease. A recent pooled analysis included 112 patients from the BGB-3111-AU-003 and BGB-3111-206 clinical trials who had R/R MCL and received second-line (n = 41) or later-line (n = 71) zanubrutinib (Song et al). At a median follow-up of 35.2 months, patients receiving second-line vs later-line zanubrutinib had significantly improved median overall survival (aHR 0.459; P = .044) and numerically longer median progression-free survival (27.8 vs 22.1 months). Adverse events observed in both groups were consistent with the known safety profile of zanubrutinib. These findings were in line with a prior similar pooled study that demonstrated improved outcomes with second-line ibrutinib for patients with MCL as compared with later-line ibrutinib therapy.⁵ This study, however, did not evaluate the impact on CAR T–cell therapy in MCL, which is also an effective treatment option for patients with R/R disease, and how best to sequence with BTK inhibitors.

Additional References

1.       Locke FL, Miklos DB, Jacobson CA, et al, for All ZUMA-7 Investigators and Contributing Kite Members. Axicabtagene ciloleucel as second-line therapy for large B-cell lymphoma. N Engl J Med. 2022;386:640-654. doi: 10.1056/NEJMoa2116133

2.       Kamdar M, Solomon SR, Arnason J, et al, for theTRANSFORM Investigators. Lisocabtagene maraleucel versus standard of care with salvage chemotherapy followed by autologous stem cell transplantation as second-line treatment in patients with relapsed or refractory large B-cell lymphoma (TRANSFORM): Results from an interim analysis of an open-label, randomised, phase 3 trial. Lancet. 2022;399:2294-2308. doi: 10.1016/S0140-6736(22)00662-6

3.       Gordon LI, Liu FF, Braverman J, et al. Lisocabtagene maraleucel for second-line relapsed or refractory large B-cell lymphoma: Patient-reported outcomes from the PILOT study. Haematologica. 2023 (Aug 31). doi: 10.3324/haematol.2023.283162

4.       Schmitz N, Zeynalova S, Nickelsen M, et al. CNS International Prognostic Index: A risk model for CNS relapse in patients with diffuse large B-cell lymphoma treated with R-CHOP. J Clin Oncol. 2016;34:3150-3156. doi: 10.1200/JCO.2015.65.6520

5.       Dreyling M, Goy A, Hess G, et al. Long-term outcomes with ibrutinib treatment for patients with relapsed/refractory mantle cell lymphoma: A pooled analysis of 3 clinical trials with nearly 10 years of follow-up. Hemasphere. 2022;6:e712. doi: 10.1097/HS9.0000000000000712

The ZUMA-7 and TRANSFORM studies have been practice-changing for the treatment of relapsed/refractory (R/R) large B-cell lymphoma (LBCL). These studies demonstrated an improvement in outcomes with axicabtagene ciloleucel (axi-cel) and lisocabtagene maraleucel (liso-cel), respectively, as compared with standard-of-care treatment (chemotherapy and autologous stem cell transplantation).^1,2 Patients included in these studies were refractory to their initial therapy or experienced relapse within 12 months and were considered fit for autologous stem cell transplant. It has remained unclear, however, whether patients who are not transplant candidates may also derive benefit and tolerate treatment with chimeric antigen receptor (CAR) T-cell therapy. The PILOT study was a single-arm phase 2 study that demonstrated favorable outcomes with liso-cel in this patient population, thus resulting in the approval of liso-cel by the US Food and Drug Administration for this population.³ Recently, the ALYCATE study similarly examined outcomes in transplant-ineligible patients treated with axi-cel (Houot et al). This phase 2 study included 62 patients with high-risk R/R LBCL who underwent leukapheresis and subsequently received second-line axi-cel. The complete metabolic response rate 3 months after axi-cel infusion was 71.0% (95% CI 58.1%-81.8%). At a median 12-month follow-up, the median progression-free survival was 11.8 months (95% CI 8.4-not reached) whereas median overall survival was not reached. Grade ≥ 3 cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 8.1% and 14.5% of patients, respectively. Also of note, patients age ≥ 70 years did not show increased toxicity compared with those age < 70 years, with similar rates of CRS, ICANS, and intensive care unit transfer. This study supports the role of axi-cel in the second-line setting, regardless of transplant eligibility.

Another important study recently published for patients with LBCL examined the role of central nervous system (CNS) prophylaxis (Lewis et al). We know that certain patients with LBCL, including those with a high CNS international prognostic index (IPI) score, double-hit lymphoma, or disease involvement of multiple or certain extranodal sites (ie, breast, testes, adrenals, kidney) can be at increased risk for lymphoma spread to the CNS.⁴ Strategies to reduce this risk have subsequently been developed for these high-risk patients, though consensus regarding who should be treated and how best to treat patients has been consistent. Recently, retrospective data have also called into question whether our current approaches meaningfully reduce this risk. One such study was a multicenter, international, retrospective observational study that included 2418 adults with aggressive LBCL and a high risk for CNS progression who were treated with curative-intent anti-CD20–based chemoimmunotherapy and who did or did not receive high-dose methotrexate (HD-MTX). Patients who did vs did not receive HD-MTX had a significantly lower risk for CNS progression (adjusted 5-year risk difference 1.6%; adjusted hazard ratio [aHR] 0.59; P = .014), but the significance was lost when considering only those patients who achieved a complete response at chemoimmunotherapy completion (adjusted 5-year risk difference 1.4%; aHR 0.74; P = .30). The study was not sufficiently powered to make definitive conclusions for individual risk groups, though there was no obvious reduction in CNS involvement risk in any high-risk subgroup. With an absolute risk reduction of 1.6% with the use of HD-MTX, 63 patients would require treatment to prevent one CNS progression event over 5 years (Lewis et al). Given the absence of prospective, randomized data, these results, though retrospective in nature, call into question the benefit of CNS prophylaxis. The authors suggest that studies evaluating alternative strategies for prophylaxis and tools for early detection of relapse, such as circulating tumor DNA, may be helpful.

Another study worth noting was one exploring Bruton tyrosine kinase (BTK) inhibition in mantle cell lymphoma (MCL). BTK inhibitors, including zanubrutinib, have emerged as effective therapies for patients with R/R disease. A recent pooled analysis included 112 patients from the BGB-3111-AU-003 and BGB-3111-206 clinical trials who had R/R MCL and received second-line (n = 41) or later-line (n = 71) zanubrutinib (Song et al). At a median follow-up of 35.2 months, patients receiving second-line vs later-line zanubrutinib had significantly improved median overall survival (aHR 0.459; P = .044) and numerically longer median progression-free survival (27.8 vs 22.1 months). Adverse events observed in both groups were consistent with the known safety profile of zanubrutinib. These findings were in line with a prior similar pooled study that demonstrated improved outcomes with second-line ibrutinib for patients with MCL as compared with later-line ibrutinib therapy.⁵ This study, however, did not evaluate the impact on CAR T–cell therapy in MCL, which is also an effective treatment option for patients with R/R disease, and how best to sequence with BTK inhibitors.

Additional References

1.       Locke FL, Miklos DB, Jacobson CA, et al, for All ZUMA-7 Investigators and Contributing Kite Members. Axicabtagene ciloleucel as second-line therapy for large B-cell lymphoma. N Engl J Med. 2022;386:640-654. doi: 10.1056/NEJMoa2116133

2.       Kamdar M, Solomon SR, Arnason J, et al, for theTRANSFORM Investigators. Lisocabtagene maraleucel versus standard of care with salvage chemotherapy followed by autologous stem cell transplantation as second-line treatment in patients with relapsed or refractory large B-cell lymphoma (TRANSFORM): Results from an interim analysis of an open-label, randomised, phase 3 trial. Lancet. 2022;399:2294-2308. doi: 10.1016/S0140-6736(22)00662-6

3.       Gordon LI, Liu FF, Braverman J, et al. Lisocabtagene maraleucel for second-line relapsed or refractory large B-cell lymphoma: Patient-reported outcomes from the PILOT study. Haematologica. 2023 (Aug 31). doi: 10.3324/haematol.2023.283162

4.       Schmitz N, Zeynalova S, Nickelsen M, et al. CNS International Prognostic Index: A risk model for CNS relapse in patients with diffuse large B-cell lymphoma treated with R-CHOP. J Clin Oncol. 2016;34:3150-3156. doi: 10.1200/JCO.2015.65.6520

5.       Dreyling M, Goy A, Hess G, et al. Long-term outcomes with ibrutinib treatment for patients with relapsed/refractory mantle cell lymphoma: A pooled analysis of 3 clinical trials with nearly 10 years of follow-up. Hemasphere. 2022;6:e712. doi: 10.1097/HS9.0000000000000712

The ZUMA-7 and TRANSFORM studies have been practice-changing for the treatment of relapsed/refractory (R/R) large B-cell lymphoma (LBCL). These studies demonstrated an improvement in outcomes with axicabtagene ciloleucel (axi-cel) and lisocabtagene maraleucel (liso-cel), respectively, as compared with standard-of-care treatment (chemotherapy and autologous stem cell transplantation).^1,2 Patients included in these studies were refractory to their initial therapy or experienced relapse within 12 months and were considered fit for autologous stem cell transplant. It has remained unclear, however, whether patients who are not transplant candidates may also derive benefit and tolerate treatment with chimeric antigen receptor (CAR) T-cell therapy. The PILOT study was a single-arm phase 2 study that demonstrated favorable outcomes with liso-cel in this patient population, thus resulting in the approval of liso-cel by the US Food and Drug Administration for this population.³ Recently, the ALYCATE study similarly examined outcomes in transplant-ineligible patients treated with axi-cel (Houot et al). This phase 2 study included 62 patients with high-risk R/R LBCL who underwent leukapheresis and subsequently received second-line axi-cel. The complete metabolic response rate 3 months after axi-cel infusion was 71.0% (95% CI 58.1%-81.8%). At a median 12-month follow-up, the median progression-free survival was 11.8 months (95% CI 8.4-not reached) whereas median overall survival was not reached. Grade ≥ 3 cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 8.1% and 14.5% of patients, respectively. Also of note, patients age ≥ 70 years did not show increased toxicity compared with those age < 70 years, with similar rates of CRS, ICANS, and intensive care unit transfer. This study supports the role of axi-cel in the second-line setting, regardless of transplant eligibility.

Another important study recently published for patients with LBCL examined the role of central nervous system (CNS) prophylaxis (Lewis et al). We know that certain patients with LBCL, including those with a high CNS international prognostic index (IPI) score, double-hit lymphoma, or disease involvement of multiple or certain extranodal sites (ie, breast, testes, adrenals, kidney) can be at increased risk for lymphoma spread to the CNS.⁴ Strategies to reduce this risk have subsequently been developed for these high-risk patients, though consensus regarding who should be treated and how best to treat patients has been consistent. Recently, retrospective data have also called into question whether our current approaches meaningfully reduce this risk. One such study was a multicenter, international, retrospective observational study that included 2418 adults with aggressive LBCL and a high risk for CNS progression who were treated with curative-intent anti-CD20–based chemoimmunotherapy and who did or did not receive high-dose methotrexate (HD-MTX). Patients who did vs did not receive HD-MTX had a significantly lower risk for CNS progression (adjusted 5-year risk difference 1.6%; adjusted hazard ratio [aHR] 0.59; P = .014), but the significance was lost when considering only those patients who achieved a complete response at chemoimmunotherapy completion (adjusted 5-year risk difference 1.4%; aHR 0.74; P = .30). The study was not sufficiently powered to make definitive conclusions for individual risk groups, though there was no obvious reduction in CNS involvement risk in any high-risk subgroup. With an absolute risk reduction of 1.6% with the use of HD-MTX, 63 patients would require treatment to prevent one CNS progression event over 5 years (Lewis et al). Given the absence of prospective, randomized data, these results, though retrospective in nature, call into question the benefit of CNS prophylaxis. The authors suggest that studies evaluating alternative strategies for prophylaxis and tools for early detection of relapse, such as circulating tumor DNA, may be helpful.

Another study worth noting was one exploring Bruton tyrosine kinase (BTK) inhibition in mantle cell lymphoma (MCL). BTK inhibitors, including zanubrutinib, have emerged as effective therapies for patients with R/R disease. A recent pooled analysis included 112 patients from the BGB-3111-AU-003 and BGB-3111-206 clinical trials who had R/R MCL and received second-line (n = 41) or later-line (n = 71) zanubrutinib (Song et al). At a median follow-up of 35.2 months, patients receiving second-line vs later-line zanubrutinib had significantly improved median overall survival (aHR 0.459; P = .044) and numerically longer median progression-free survival (27.8 vs 22.1 months). Adverse events observed in both groups were consistent with the known safety profile of zanubrutinib. These findings were in line with a prior similar pooled study that demonstrated improved outcomes with second-line ibrutinib for patients with MCL as compared with later-line ibrutinib therapy.⁵ This study, however, did not evaluate the impact on CAR T–cell therapy in MCL, which is also an effective treatment option for patients with R/R disease, and how best to sequence with BTK inhibitors.

Additional References

1.       Locke FL, Miklos DB, Jacobson CA, et al, for All ZUMA-7 Investigators and Contributing Kite Members. Axicabtagene ciloleucel as second-line therapy for large B-cell lymphoma. N Engl J Med. 2022;386:640-654. doi: 10.1056/NEJMoa2116133

2.       Kamdar M, Solomon SR, Arnason J, et al, for theTRANSFORM Investigators. Lisocabtagene maraleucel versus standard of care with salvage chemotherapy followed by autologous stem cell transplantation as second-line treatment in patients with relapsed or refractory large B-cell lymphoma (TRANSFORM): Results from an interim analysis of an open-label, randomised, phase 3 trial. Lancet. 2022;399:2294-2308. doi: 10.1016/S0140-6736(22)00662-6

3.       Gordon LI, Liu FF, Braverman J, et al. Lisocabtagene maraleucel for second-line relapsed or refractory large B-cell lymphoma: Patient-reported outcomes from the PILOT study. Haematologica. 2023 (Aug 31). doi: 10.3324/haematol.2023.283162

4.       Schmitz N, Zeynalova S, Nickelsen M, et al. CNS International Prognostic Index: A risk model for CNS relapse in patients with diffuse large B-cell lymphoma treated with R-CHOP. J Clin Oncol. 2016;34:3150-3156. doi: 10.1200/JCO.2015.65.6520

5.       Dreyling M, Goy A, Hess G, et al. Long-term outcomes with ibrutinib treatment for patients with relapsed/refractory mantle cell lymphoma: A pooled analysis of 3 clinical trials with nearly 10 years of follow-up. Hemasphere. 2022;6:e712. doi: 10.1097/HS9.0000000000000712