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Bendamustine a safe alternative to fludarabine/cyclophosphamide lymphodepletion for axi-cel therapy in aggressive BCL

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Key clinical point: Bendamustine lymphodepletion (LD) relative to fludarabine/cyclophosphamide (Flu/Cy) LD prior to axicabtagene ciloleucel (axi-cel) therapy leads to comparable efficacy and lower rates of any-grade immune effector cell-associated neurotoxicity syndrome (ICANS) in patients with relapsed or refractory aggressive B-cell lymphoma (aBCL).

Major finding: The bendamustine and Flu/Cy cohorts had similar rates of best overall response (77.8%, 95% CI 57.7%-91.4%; and 81.0%, 95% CI 65.9%-91.4%, respectively) and complete response (48.1%, 95% CI 28.7%-68.1%; and 50.0%, 95% CI 34.2%-65.8%, respectively), 6-month progression-free survival (43.8%, 95% CI 24.7%-61.3%; and 55.6%, 95% CI 39.0%-69.3%, respectively), and 6-month overall survival (81.5%, 95% CI 61.1%-91.8%; and 90.4%, 95% CI 76.4%-96.3%, respectively). Bendamustine vs Flu/Cy was associated with decreased odds of any-grade ICANS (odds ratio 0.35; 95% CI 0.12-0.97).

Study details: This retrospective study included patients with relapsed or refractory aBCL who received bendamustine (n = 27) or Flu/Cy (n = 42) LD before axi-cel therapy.

Disclosures: This study did not receive any funding. Some authors declared serving as speaker's bureau members or consultants for or receiving research funding or honoraria from various organizations.

Source: Ong SY et al. Bendamustine lymphodepletion is a well-tolerated alternative to fludarabine and cyclophosphamide lymphodepletion for axicabtagene ciloleucel therapy for aggressive B-cell lymphoma. Am J Hematol. 2023 (Sep 5). doi: 10.1002/ajh.27069

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Key clinical point: Bendamustine lymphodepletion (LD) relative to fludarabine/cyclophosphamide (Flu/Cy) LD prior to axicabtagene ciloleucel (axi-cel) therapy leads to comparable efficacy and lower rates of any-grade immune effector cell-associated neurotoxicity syndrome (ICANS) in patients with relapsed or refractory aggressive B-cell lymphoma (aBCL).

Major finding: The bendamustine and Flu/Cy cohorts had similar rates of best overall response (77.8%, 95% CI 57.7%-91.4%; and 81.0%, 95% CI 65.9%-91.4%, respectively) and complete response (48.1%, 95% CI 28.7%-68.1%; and 50.0%, 95% CI 34.2%-65.8%, respectively), 6-month progression-free survival (43.8%, 95% CI 24.7%-61.3%; and 55.6%, 95% CI 39.0%-69.3%, respectively), and 6-month overall survival (81.5%, 95% CI 61.1%-91.8%; and 90.4%, 95% CI 76.4%-96.3%, respectively). Bendamustine vs Flu/Cy was associated with decreased odds of any-grade ICANS (odds ratio 0.35; 95% CI 0.12-0.97).

Study details: This retrospective study included patients with relapsed or refractory aBCL who received bendamustine (n = 27) or Flu/Cy (n = 42) LD before axi-cel therapy.

Disclosures: This study did not receive any funding. Some authors declared serving as speaker's bureau members or consultants for or receiving research funding or honoraria from various organizations.

Source: Ong SY et al. Bendamustine lymphodepletion is a well-tolerated alternative to fludarabine and cyclophosphamide lymphodepletion for axicabtagene ciloleucel therapy for aggressive B-cell lymphoma. Am J Hematol. 2023 (Sep 5). doi: 10.1002/ajh.27069

Key clinical point: Bendamustine lymphodepletion (LD) relative to fludarabine/cyclophosphamide (Flu/Cy) LD prior to axicabtagene ciloleucel (axi-cel) therapy leads to comparable efficacy and lower rates of any-grade immune effector cell-associated neurotoxicity syndrome (ICANS) in patients with relapsed or refractory aggressive B-cell lymphoma (aBCL).

Major finding: The bendamustine and Flu/Cy cohorts had similar rates of best overall response (77.8%, 95% CI 57.7%-91.4%; and 81.0%, 95% CI 65.9%-91.4%, respectively) and complete response (48.1%, 95% CI 28.7%-68.1%; and 50.0%, 95% CI 34.2%-65.8%, respectively), 6-month progression-free survival (43.8%, 95% CI 24.7%-61.3%; and 55.6%, 95% CI 39.0%-69.3%, respectively), and 6-month overall survival (81.5%, 95% CI 61.1%-91.8%; and 90.4%, 95% CI 76.4%-96.3%, respectively). Bendamustine vs Flu/Cy was associated with decreased odds of any-grade ICANS (odds ratio 0.35; 95% CI 0.12-0.97).

Study details: This retrospective study included patients with relapsed or refractory aBCL who received bendamustine (n = 27) or Flu/Cy (n = 42) LD before axi-cel therapy.

Disclosures: This study did not receive any funding. Some authors declared serving as speaker's bureau members or consultants for or receiving research funding or honoraria from various organizations.

Source: Ong SY et al. Bendamustine lymphodepletion is a well-tolerated alternative to fludarabine and cyclophosphamide lymphodepletion for axicabtagene ciloleucel therapy for aggressive B-cell lymphoma. Am J Hematol. 2023 (Sep 5). doi: 10.1002/ajh.27069

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Concurrent MYC overexpression and TP53/p53 alterations indicative of poor prognosis in MCL

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Concurrent MYC overexpression and TP53/p53 alterations indicative of poor prognosis in MCL

Key clinical point: Concurrent MYC overexpression and TP53/p53 alterations in tumors identifies a subset of patients with mantle cell lymphoma (MCL) having a poor prognosis with a median overall survival < 3 years.

Major finding: Patients with tumors comprising > 20% cells with MYC overexpression (MYChigh tumors) vs MYClow tumors had significantly higher risks for death (adjusted hazard ratio [aHR] 2.03; P = .007) and disease progression (aHR 2.20; P = .04). Patients with tumors with concomitant MYChigh expression and TP53/p53 alterations vs MYClow tumors had significantly increased risks for progression (HR 16.90) and death (HR 7.83) with a median overall survival of 0.9 years only (both P < .001).

Study details: The data come from a study including 252 patients with MCL, 14% of whom had MYChigh tumors, including 13 patients with concomitant MYChigh expression and TP53/p53 alterations.

 

Disclosures: This study was funded by the European Union’s Horizon 2020 Research and Innovation Programme. Some authors declared receiving research support or honoraria from or participating in educational sessions or advisory boards of various organizations.

 

Source: Rodrigues JM et al. MYC protein is a high-risk factor in mantle cell lymphoma and identifies cases beyond morphology, proliferation and TP53/p53 - A Nordic Lymphoma Group study. Haematologica. 2023 (Aug 31). doi: 10.3324/haematol.2023.283352

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Key clinical point: Concurrent MYC overexpression and TP53/p53 alterations in tumors identifies a subset of patients with mantle cell lymphoma (MCL) having a poor prognosis with a median overall survival < 3 years.

Major finding: Patients with tumors comprising > 20% cells with MYC overexpression (MYChigh tumors) vs MYClow tumors had significantly higher risks for death (adjusted hazard ratio [aHR] 2.03; P = .007) and disease progression (aHR 2.20; P = .04). Patients with tumors with concomitant MYChigh expression and TP53/p53 alterations vs MYClow tumors had significantly increased risks for progression (HR 16.90) and death (HR 7.83) with a median overall survival of 0.9 years only (both P < .001).

Study details: The data come from a study including 252 patients with MCL, 14% of whom had MYChigh tumors, including 13 patients with concomitant MYChigh expression and TP53/p53 alterations.

 

Disclosures: This study was funded by the European Union’s Horizon 2020 Research and Innovation Programme. Some authors declared receiving research support or honoraria from or participating in educational sessions or advisory boards of various organizations.

 

Source: Rodrigues JM et al. MYC protein is a high-risk factor in mantle cell lymphoma and identifies cases beyond morphology, proliferation and TP53/p53 - A Nordic Lymphoma Group study. Haematologica. 2023 (Aug 31). doi: 10.3324/haematol.2023.283352

Key clinical point: Concurrent MYC overexpression and TP53/p53 alterations in tumors identifies a subset of patients with mantle cell lymphoma (MCL) having a poor prognosis with a median overall survival < 3 years.

Major finding: Patients with tumors comprising > 20% cells with MYC overexpression (MYChigh tumors) vs MYClow tumors had significantly higher risks for death (adjusted hazard ratio [aHR] 2.03; P = .007) and disease progression (aHR 2.20; P = .04). Patients with tumors with concomitant MYChigh expression and TP53/p53 alterations vs MYClow tumors had significantly increased risks for progression (HR 16.90) and death (HR 7.83) with a median overall survival of 0.9 years only (both P < .001).

Study details: The data come from a study including 252 patients with MCL, 14% of whom had MYChigh tumors, including 13 patients with concomitant MYChigh expression and TP53/p53 alterations.

 

Disclosures: This study was funded by the European Union’s Horizon 2020 Research and Innovation Programme. Some authors declared receiving research support or honoraria from or participating in educational sessions or advisory boards of various organizations.

 

Source: Rodrigues JM et al. MYC protein is a high-risk factor in mantle cell lymphoma and identifies cases beyond morphology, proliferation and TP53/p53 - A Nordic Lymphoma Group study. Haematologica. 2023 (Aug 31). doi: 10.3324/haematol.2023.283352

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PI3Kδ inhibitor parsaclisib shows promise in relapsed or refractory follicular lymphoma

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Key clinical point: Parsaclisib provided rapid and durable responses and a manageable safety profile in patients with relapsed or refractory follicular lymphoma (FL).

Major finding: Among patients receiving parsaclisib daily, 77.7% (95% CI 68.4%-85.3%) achieved an objective response and 19.4% (95% CI 12.3%-28.4%) achieved a complete response. The median duration of response was 14.7 months (95% CI 10.4-not estimable) and the median time to response was 8.1 weeks. Most treatment-emergent adverse events were low-grade and manageable by dose interruptions or reductions.

 

Study details: This phase 2 CITADEL-203 study included 126 adult Bruton tyrosine kinase inhibitor-naive patients with relapsed or refractory FL previously treated with ≥2 systemic therapies who received 20 mg parsaclisib once daily for 8 weeks followed by either 20 mg parsaclisib once weekly (n = 23) or 2.5 mg parsaclisib once daily (n = 103).

 

Disclosures: This study was sponsored by Incyte Corporation, USA. Some authors declared serving as consultants or speakers for or receiving honoraria, research funding, or reimbursements for travel, accommodations, or expenses from Incyte and other sources. Four authors declared being employees and stockowners of Incyte.

 

Source: Trněný M et al. Parsaclisib, a PI3Kδ inhibitor, in relapsed and refractory follicular lymphoma (CITADEL-203): A phase 2 study. EClinicalMedicine. 2023;63:102130 (Aug 18). doi: 10.1016/j.eclinm.2023.102130

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Key clinical point: Parsaclisib provided rapid and durable responses and a manageable safety profile in patients with relapsed or refractory follicular lymphoma (FL).

Major finding: Among patients receiving parsaclisib daily, 77.7% (95% CI 68.4%-85.3%) achieved an objective response and 19.4% (95% CI 12.3%-28.4%) achieved a complete response. The median duration of response was 14.7 months (95% CI 10.4-not estimable) and the median time to response was 8.1 weeks. Most treatment-emergent adverse events were low-grade and manageable by dose interruptions or reductions.

 

Study details: This phase 2 CITADEL-203 study included 126 adult Bruton tyrosine kinase inhibitor-naive patients with relapsed or refractory FL previously treated with ≥2 systemic therapies who received 20 mg parsaclisib once daily for 8 weeks followed by either 20 mg parsaclisib once weekly (n = 23) or 2.5 mg parsaclisib once daily (n = 103).

 

Disclosures: This study was sponsored by Incyte Corporation, USA. Some authors declared serving as consultants or speakers for or receiving honoraria, research funding, or reimbursements for travel, accommodations, or expenses from Incyte and other sources. Four authors declared being employees and stockowners of Incyte.

 

Source: Trněný M et al. Parsaclisib, a PI3Kδ inhibitor, in relapsed and refractory follicular lymphoma (CITADEL-203): A phase 2 study. EClinicalMedicine. 2023;63:102130 (Aug 18). doi: 10.1016/j.eclinm.2023.102130

Key clinical point: Parsaclisib provided rapid and durable responses and a manageable safety profile in patients with relapsed or refractory follicular lymphoma (FL).

Major finding: Among patients receiving parsaclisib daily, 77.7% (95% CI 68.4%-85.3%) achieved an objective response and 19.4% (95% CI 12.3%-28.4%) achieved a complete response. The median duration of response was 14.7 months (95% CI 10.4-not estimable) and the median time to response was 8.1 weeks. Most treatment-emergent adverse events were low-grade and manageable by dose interruptions or reductions.

 

Study details: This phase 2 CITADEL-203 study included 126 adult Bruton tyrosine kinase inhibitor-naive patients with relapsed or refractory FL previously treated with ≥2 systemic therapies who received 20 mg parsaclisib once daily for 8 weeks followed by either 20 mg parsaclisib once weekly (n = 23) or 2.5 mg parsaclisib once daily (n = 103).

 

Disclosures: This study was sponsored by Incyte Corporation, USA. Some authors declared serving as consultants or speakers for or receiving honoraria, research funding, or reimbursements for travel, accommodations, or expenses from Incyte and other sources. Four authors declared being employees and stockowners of Incyte.

 

Source: Trněný M et al. Parsaclisib, a PI3Kδ inhibitor, in relapsed and refractory follicular lymphoma (CITADEL-203): A phase 2 study. EClinicalMedicine. 2023;63:102130 (Aug 18). doi: 10.1016/j.eclinm.2023.102130

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Tisagenlecleucel vs conventional treatment improves survival in DLBCL

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Key clinical point: Compared with the conventional third line or higher lines of chemotherapy, tisagenlecleucel led to a 41% reduction in the risk for death in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL).

Major finding: Patients receiving tisagenlecleucel vs conventional treatments had significantly longer median overall survival (11.7 vs 5.4 months; adjusted hazard ratio 0.59; P = .0035).

 

Study details: This study analyzed the published summary data of patients with relapsed or refractory DLBCL treated with tisagenlecleucel in the JULIET study (n = 111) and the real-world individual patient data of those treated with conventional therapies in the first and second Samsung Medical Center-Lymphoma Cohort studies (n = 53).

 

Disclosures: This study was supported by grants from the Ministry of Food and Drug Safety, South Korea. S Park and JY Shin declared receiving grants from various sources.

 

Source: Park S et al. Comparison of tisagenlecleucel with conventional treatments for relapsed/refractory diffuse large B-cell lymphomas: A retrospective external comparator study. Blood Cancer J. 2023;13:123 (Aug 18). doi: 10.1038/s41408-023-00889-5

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Key clinical point: Compared with the conventional third line or higher lines of chemotherapy, tisagenlecleucel led to a 41% reduction in the risk for death in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL).

Major finding: Patients receiving tisagenlecleucel vs conventional treatments had significantly longer median overall survival (11.7 vs 5.4 months; adjusted hazard ratio 0.59; P = .0035).

 

Study details: This study analyzed the published summary data of patients with relapsed or refractory DLBCL treated with tisagenlecleucel in the JULIET study (n = 111) and the real-world individual patient data of those treated with conventional therapies in the first and second Samsung Medical Center-Lymphoma Cohort studies (n = 53).

 

Disclosures: This study was supported by grants from the Ministry of Food and Drug Safety, South Korea. S Park and JY Shin declared receiving grants from various sources.

 

Source: Park S et al. Comparison of tisagenlecleucel with conventional treatments for relapsed/refractory diffuse large B-cell lymphomas: A retrospective external comparator study. Blood Cancer J. 2023;13:123 (Aug 18). doi: 10.1038/s41408-023-00889-5

Key clinical point: Compared with the conventional third line or higher lines of chemotherapy, tisagenlecleucel led to a 41% reduction in the risk for death in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL).

Major finding: Patients receiving tisagenlecleucel vs conventional treatments had significantly longer median overall survival (11.7 vs 5.4 months; adjusted hazard ratio 0.59; P = .0035).

 

Study details: This study analyzed the published summary data of patients with relapsed or refractory DLBCL treated with tisagenlecleucel in the JULIET study (n = 111) and the real-world individual patient data of those treated with conventional therapies in the first and second Samsung Medical Center-Lymphoma Cohort studies (n = 53).

 

Disclosures: This study was supported by grants from the Ministry of Food and Drug Safety, South Korea. S Park and JY Shin declared receiving grants from various sources.

 

Source: Park S et al. Comparison of tisagenlecleucel with conventional treatments for relapsed/refractory diffuse large B-cell lymphomas: A retrospective external comparator study. Blood Cancer J. 2023;13:123 (Aug 18). doi: 10.1038/s41408-023-00889-5

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CAR-HEMATOTOX score identifies patients at high risk for poor outcomes following brexu-cel infusion for MCL

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Key clinical point: The baseline CAR-HEMATOTOX (HT) score enables the early identification of patients at high risk for prolonged neutropenia, severe infections, and poor survival outcomes following brexucabtagene autoleucel (brexu-cel) infusion for relapsed or refractory mantle cell lymphoma (MCL).

Major finding: Patients with high (score 2-7) vs low (score 0-1) HT scores had significantly longer median duration of severe neutropenia (P < .0001), higher rates of severe infections (P = .001), and lower overall response rates (P = .003). The HT score represented an independent predictor of poor progression-free (adjusted hazard ratio [aHR] 3.7; P < .001) and overall (aHR 5.6; P = .002) survival.

 

Study details: This multicenter observational study included 103 patients with relapsed or refractory MCL receiving brexu-cel, of whom 47 patients had high and 56 patients had low HT scores.

 

Disclosures: This study was supported by the Gilead Research Scholar Program and other sources. Some authors declared serving as consultants or advisory board members for or receiving research funding, speakers’ honoraria, personal fees, or travel support from Gilead Sciences and other sources.

 

Source: Rejeski K et al. The CAR-HEMATOTOX score identifies patients at high risk for hematological toxicity, infectious complications, and poor treatment outcomes following brexucabtagene autoleucel for relapsed or refractory MCL. Am J Hematol. 2023 (Aug 16). doi: 10.1002/ajh.27056

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Key clinical point: The baseline CAR-HEMATOTOX (HT) score enables the early identification of patients at high risk for prolonged neutropenia, severe infections, and poor survival outcomes following brexucabtagene autoleucel (brexu-cel) infusion for relapsed or refractory mantle cell lymphoma (MCL).

Major finding: Patients with high (score 2-7) vs low (score 0-1) HT scores had significantly longer median duration of severe neutropenia (P < .0001), higher rates of severe infections (P = .001), and lower overall response rates (P = .003). The HT score represented an independent predictor of poor progression-free (adjusted hazard ratio [aHR] 3.7; P < .001) and overall (aHR 5.6; P = .002) survival.

 

Study details: This multicenter observational study included 103 patients with relapsed or refractory MCL receiving brexu-cel, of whom 47 patients had high and 56 patients had low HT scores.

 

Disclosures: This study was supported by the Gilead Research Scholar Program and other sources. Some authors declared serving as consultants or advisory board members for or receiving research funding, speakers’ honoraria, personal fees, or travel support from Gilead Sciences and other sources.

 

Source: Rejeski K et al. The CAR-HEMATOTOX score identifies patients at high risk for hematological toxicity, infectious complications, and poor treatment outcomes following brexucabtagene autoleucel for relapsed or refractory MCL. Am J Hematol. 2023 (Aug 16). doi: 10.1002/ajh.27056

Key clinical point: The baseline CAR-HEMATOTOX (HT) score enables the early identification of patients at high risk for prolonged neutropenia, severe infections, and poor survival outcomes following brexucabtagene autoleucel (brexu-cel) infusion for relapsed or refractory mantle cell lymphoma (MCL).

Major finding: Patients with high (score 2-7) vs low (score 0-1) HT scores had significantly longer median duration of severe neutropenia (P < .0001), higher rates of severe infections (P = .001), and lower overall response rates (P = .003). The HT score represented an independent predictor of poor progression-free (adjusted hazard ratio [aHR] 3.7; P < .001) and overall (aHR 5.6; P = .002) survival.

 

Study details: This multicenter observational study included 103 patients with relapsed or refractory MCL receiving brexu-cel, of whom 47 patients had high and 56 patients had low HT scores.

 

Disclosures: This study was supported by the Gilead Research Scholar Program and other sources. Some authors declared serving as consultants or advisory board members for or receiving research funding, speakers’ honoraria, personal fees, or travel support from Gilead Sciences and other sources.

 

Source: Rejeski K et al. The CAR-HEMATOTOX score identifies patients at high risk for hematological toxicity, infectious complications, and poor treatment outcomes following brexucabtagene autoleucel for relapsed or refractory MCL. Am J Hematol. 2023 (Aug 16). doi: 10.1002/ajh.27056

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Loncastuximab tesirine shows long-term efficacy in relapsed or refractory DLBCL

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Key clinical point: Loncastuximab tesirine (Lonca) shows long-term efficacy and a manageable safety profile in heavily pretreated patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL).

Major finding: At a median follow-up of 7.8 months, 48.3% of patients achieved an overall response, with a complete response being achieved by 24.8% of patients, 44% and 31% of whom remained event-free for ≥ 1 year and ≥ 2 years, respectively. The median overall and progression-free survival durations were 9.5 and 4.9 months, respectively. No new safety concerns were detected.

Study details: This long-term follow-up analysis of the phase 2 LOTIS-2 study included 145 heavily pretreated adult patients with relapsed or refractory DLBCL who received Lonca once every 3 weeks (0.15 mg/kg for 2 cycles; 0.075 mg/kg for subsequent cycles).

 

Disclosures: This study was funded by ADC Therapeutics SA. Some authors declared serving as consultants, advisors, or speakers for or receiving research funding or honoraria from various sources, including ADC Therapeutics. Four authors declared being employees of and holding equity and stock options in ADC Therapeutics.

 

Source: Caimi PF et al. Loncastuximab tesirine in relapsed/refractory diffuse large B-cell lymphoma: Long-term efficacy and safety from the phase 2 LOTIS-2 study. Haematologica. 2023 (Aug 31). doi: 10.3324/haematol.2023.283459

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Key clinical point: Loncastuximab tesirine (Lonca) shows long-term efficacy and a manageable safety profile in heavily pretreated patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL).

Major finding: At a median follow-up of 7.8 months, 48.3% of patients achieved an overall response, with a complete response being achieved by 24.8% of patients, 44% and 31% of whom remained event-free for ≥ 1 year and ≥ 2 years, respectively. The median overall and progression-free survival durations were 9.5 and 4.9 months, respectively. No new safety concerns were detected.

Study details: This long-term follow-up analysis of the phase 2 LOTIS-2 study included 145 heavily pretreated adult patients with relapsed or refractory DLBCL who received Lonca once every 3 weeks (0.15 mg/kg for 2 cycles; 0.075 mg/kg for subsequent cycles).

 

Disclosures: This study was funded by ADC Therapeutics SA. Some authors declared serving as consultants, advisors, or speakers for or receiving research funding or honoraria from various sources, including ADC Therapeutics. Four authors declared being employees of and holding equity and stock options in ADC Therapeutics.

 

Source: Caimi PF et al. Loncastuximab tesirine in relapsed/refractory diffuse large B-cell lymphoma: Long-term efficacy and safety from the phase 2 LOTIS-2 study. Haematologica. 2023 (Aug 31). doi: 10.3324/haematol.2023.283459

Key clinical point: Loncastuximab tesirine (Lonca) shows long-term efficacy and a manageable safety profile in heavily pretreated patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL).

Major finding: At a median follow-up of 7.8 months, 48.3% of patients achieved an overall response, with a complete response being achieved by 24.8% of patients, 44% and 31% of whom remained event-free for ≥ 1 year and ≥ 2 years, respectively. The median overall and progression-free survival durations were 9.5 and 4.9 months, respectively. No new safety concerns were detected.

Study details: This long-term follow-up analysis of the phase 2 LOTIS-2 study included 145 heavily pretreated adult patients with relapsed or refractory DLBCL who received Lonca once every 3 weeks (0.15 mg/kg for 2 cycles; 0.075 mg/kg for subsequent cycles).

 

Disclosures: This study was funded by ADC Therapeutics SA. Some authors declared serving as consultants, advisors, or speakers for or receiving research funding or honoraria from various sources, including ADC Therapeutics. Four authors declared being employees of and holding equity and stock options in ADC Therapeutics.

 

Source: Caimi PF et al. Loncastuximab tesirine in relapsed/refractory diffuse large B-cell lymphoma: Long-term efficacy and safety from the phase 2 LOTIS-2 study. Haematologica. 2023 (Aug 31). doi: 10.3324/haematol.2023.283459

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Parsaclisib a promising treatment option in BTKi-naive relapsed or refractory MCL

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Fri, 09/29/2023 - 18:56

Key clinical point: Parsaclisib led to clinically meaningful improvements and a manageable safety profile in Bruton tyrosine kinase inhibitor (BTKi)-naive patients with relapsed or refractory mantle cell lymphoma (MCL).

Major finding: Among BTKi-naive patients who received parsaclisib once daily, 70.1% (95% CI 58.6%-80.0%) and 15.6% (95% CI 8.3%-25.6%) of patients achieved an objective response and a complete response, respectively, with the median duration of response being 12.1 (95% CI 9.0-not evaluable) months. Most treatment-emergent adverse events were low grade and manageable by dose interruptions or reductions.

Study details: This phase 2 CITADEL-205 study included adult patients with relapsed or refractory MCL previously treated with 1-3 systemic therapies, with (n = 53) or without (n = 108) prior BTKi treatment, who received 20 mg parsaclisib once daily for 8 weeks followed by either 20 mg parsaclisib once weekly or 2.5 mg parsaclisib once daily.

 

Disclosures: This study was funded by Incyte Corporation. Some authors declared serving as consultants, advisors, or board members for or receiving research funding, honoraria, or travel and accommodation expenses from Incyte and others. Four authors declared being employees of and owning stocks in Incyte.

 

Source: Zinzani PL et al. Parsaclisib, a PI3Kδ inhibitor, in relapsed and refractory mantle cell lymphoma (CITADEL-205): A phase 2 study. EClinicalMedicine. 2023;62:102131 (Aug 10). doi: 10.1016/j.eclinm.2023.102131

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Key clinical point: Parsaclisib led to clinically meaningful improvements and a manageable safety profile in Bruton tyrosine kinase inhibitor (BTKi)-naive patients with relapsed or refractory mantle cell lymphoma (MCL).

Major finding: Among BTKi-naive patients who received parsaclisib once daily, 70.1% (95% CI 58.6%-80.0%) and 15.6% (95% CI 8.3%-25.6%) of patients achieved an objective response and a complete response, respectively, with the median duration of response being 12.1 (95% CI 9.0-not evaluable) months. Most treatment-emergent adverse events were low grade and manageable by dose interruptions or reductions.

Study details: This phase 2 CITADEL-205 study included adult patients with relapsed or refractory MCL previously treated with 1-3 systemic therapies, with (n = 53) or without (n = 108) prior BTKi treatment, who received 20 mg parsaclisib once daily for 8 weeks followed by either 20 mg parsaclisib once weekly or 2.5 mg parsaclisib once daily.

 

Disclosures: This study was funded by Incyte Corporation. Some authors declared serving as consultants, advisors, or board members for or receiving research funding, honoraria, or travel and accommodation expenses from Incyte and others. Four authors declared being employees of and owning stocks in Incyte.

 

Source: Zinzani PL et al. Parsaclisib, a PI3Kδ inhibitor, in relapsed and refractory mantle cell lymphoma (CITADEL-205): A phase 2 study. EClinicalMedicine. 2023;62:102131 (Aug 10). doi: 10.1016/j.eclinm.2023.102131

Key clinical point: Parsaclisib led to clinically meaningful improvements and a manageable safety profile in Bruton tyrosine kinase inhibitor (BTKi)-naive patients with relapsed or refractory mantle cell lymphoma (MCL).

Major finding: Among BTKi-naive patients who received parsaclisib once daily, 70.1% (95% CI 58.6%-80.0%) and 15.6% (95% CI 8.3%-25.6%) of patients achieved an objective response and a complete response, respectively, with the median duration of response being 12.1 (95% CI 9.0-not evaluable) months. Most treatment-emergent adverse events were low grade and manageable by dose interruptions or reductions.

Study details: This phase 2 CITADEL-205 study included adult patients with relapsed or refractory MCL previously treated with 1-3 systemic therapies, with (n = 53) or without (n = 108) prior BTKi treatment, who received 20 mg parsaclisib once daily for 8 weeks followed by either 20 mg parsaclisib once weekly or 2.5 mg parsaclisib once daily.

 

Disclosures: This study was funded by Incyte Corporation. Some authors declared serving as consultants, advisors, or board members for or receiving research funding, honoraria, or travel and accommodation expenses from Incyte and others. Four authors declared being employees of and owning stocks in Incyte.

 

Source: Zinzani PL et al. Parsaclisib, a PI3Kδ inhibitor, in relapsed and refractory mantle cell lymphoma (CITADEL-205): A phase 2 study. EClinicalMedicine. 2023;62:102131 (Aug 10). doi: 10.1016/j.eclinm.2023.102131

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‘Promising’ new txs for most common adult leukemia

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Fri, 09/08/2023 - 17:49

The rapid rise of chimeric antigen receptor T (CAR T-cell) therapy has allowed hematologists to make great strides in treating aggressive cases of multiple myeloma and several types of lymphoma and leukemia. But patients with chronic lymphocytic leukemia (CLL), the most common leukemia in adults, have been left out.

Now there are encouraging signs that CLL could join the list of blood cancers that can be effectively treated by CAR T therapy. On another front, bispecific antibodies – which just received FDA approval to treat B-cell lymphoma – are being tested as treatments for CLL.

“These are the two immunotherapies that have the most potential right now,” said Ohio State University, Columbus, hematologist Kerry A. Rogers, MD, in an interview. She went on to say that these treatments could be a boon for patients with CLL who don’t respond well to targeted therapy drugs or are so young that those medications may not retain effectiveness throughout the patients’ lifespans.

As the American Cancer Society explains, CAR T therapy is a way to get T cells “to fight cancer by changing them in the lab so they can find and destroy cancer cells.” The cells are then returned to the patient.

As the National Cancer Institute says, “If all goes as planned, the CAR T cells will continue to multiply in the patient’s body and, with guidance from their engineered receptor, recognize and kill any cancer cells that harbor the target antigen on their surfaces.”

According to Dr. Rogers, CAR T therapy is less toxic than stem cell transplantation, a related treatment. That means older people can better tolerate it, including many CLL patients in their late 60s and beyond, she said. (Side effects of CAR T therapy include cytokine release syndrome, nervous system impairment, and weakening of the immune system.)

Thus far, CAR T therapy has been approved by the U.S. Food and Drug Administration to treat lymphomas, some forms of leukemia, and multiple myeloma. “Despite the excitement around these therapies, they lead to long-term survival in fewer than half of the patients treated,” cautions the National Cancer Institute, which also notes their high cost: more than $450,000 in one case.

CAR T therapy is not FDA-approved for CLL. “There are many reasons why CAR T is less effective in patients with CLL versus other lymphomas,” said Lee Greenberger, PhD, chief scientific officer of the Leukemia & Lymphoma Society, in an interview. “For one, many patients with heavily pretreated CLL – prior to any use of CAR T – have mutations that are known to be difficult to treat. Dysfunctional T cells are also common in patients with CLL, and there’s often a lower number of available T-cells to manufacture.”

The results of a phase 1/2 trial released in August 2023 offered new insight about CAR T for CLL. In the open-label trial reported in The Lancet, 117 U.S. patients with CLL or small lymphocytic lymphoma underwent a form of CAR T therapy called lisocabtagene maraleucel after failing treatment with two lines of therapy, including a Bruton´s tyrosine kinase inhibitor. Among 49 patients at a specific dose, “the rate of complete response or remission (including with incomplete marrow recovery) was statistically significant at 18%,” the researchers reported. A total of 51 patients in the entire study died.

The rate of undetectable minimal residual disease blood was 64%. That rate is impressive, said University of Texas MD Anderson Cancer Center leukemia specialist Nitin Jain, MD, in an interview. It’s not nearly as high as researchers have seen in other disease settings, but it’s “a good, good thing for these patients. We’ll have to see in the longer follow-up how these patients fare 2, 3, or 4 years down the line.”

Dr. Rogers, the Ohio physician, said doctors had hoped durable benefit in the Lancet study would be more impressive. An important factor limiting its value may be the aggressiveness of the disease in patients who have already failed several treatments, she said. “The efficacy of CAR T might be improved by giving it as an earlier line of therapy before the CLL has become this aggressive. But it’s difficult to propose that you should use this before a Bruton´s tyrosine kinase inhibitor or venetoclax because it’s expensive and difficult.”

What’s next for CART T research in CLL? Understanding the best timing for treatment will be key, Dr. Rogers said.

The Leukemia & Lymphoma Society’s Dr. Greenberger predicted that “we will begin to see CAR T explored in CLL patients whose disease has a high risk of failing approved agents, such as Bruton´s tyrosine kinase and B cell lymphoma 2 inhibitors. However, CLL patients may still receive prior therapy with more effective Bruton’s tyrosine kinase or B cell lymphoma 2 inhibitors in the future before using CAR T. This will likely be heightened as more Bruton´s tyrosine kinase inhibitors become generic in the next 5 to 10 years and, hopefully, less expensive than CAR T therapy.”

In the big picture, he said, “treatment of CLL with CAR T is possible, but still needs significant improvements if it is to become a mainline therapy in the future.”

CAR T therapy remains available via clinical trials, and Dr. Rogers said it is “currently an important option for patients whose CLL has become resistant to standard targeted agents. We can certainly expect to extend someone’s expected survival by years if they have a favorable response.” She acknowledged that the cost is quite high, but noted that targeted therapies are also expensive, especially over the long term. They can run to $10,000-$20,000 a month. Bispecific antibodies are also being explored as potential therapy for CLL. “They’re really exciting,” Dr. Rogers said, with the potential to spur responses similar to those from CAR T therapy.

A 2022 review described these drugs as “molecules that combine antibody-directed therapies with cellular mediated immunotherapy.” The FDA explains that “by targeting two antigens or epitopes, they can cause multiple physiological or antitumor responses, which may be independent or connected.”

According to Dr. Greenberger, many bispecifics are in clinical trials now. However, “in the context of CLL, actually, the data is actually very, very limited. The development is just starting, and there are phase 1 and phase 2 trials ongoing.”

But data from lymphoma trials are encouraging, he said, and bispecifics “are actually looking as good as CAR T in some settings.”

Regimens can be a challenge for patients taking bispecifics, Dr. Greenberger said. “Repeat dosing with a step-up dosing approach to start is typically required when treating lymphoma.”

On the other hand, Dr. Rogers noted that antibody treatment can be easier for hematologists to arrange than CAR T therapy and stem cell transplants. “From an administrative side, there’s not as many things you need to have set up. So it’s able to be administered in a wider variety of settings,” she said,

Bispecific side effects include cytokine release syndrome and neurotoxicity as well as infusion reactions, Dr. Greenberger said, adding that “I would not exclude cost as a challenge.”

According to Formulary Watch, the bispecific Columvi (glofitamab-gxbm), which recently gained FDA approval to treat diffuse large B-cell lymphoma, is estimated to cost $350,000 for an 8.5-month round of treatment. Reuters reported that the bispecific Talvey (talquetamab-tgvs), which just received FDA approval to treat multiple myeloma, is estimated to cost $270,000-$360,000 for 6-8 months of treatment.

For now, bispecific trials “are mostly now reserved for patients with CLL who become resistant to our current standard targeted agents,” Dr. Rogers said. “It’s a little unclear if you can do CAR T therapy first and then bispecifics, or bispecifics and then CAR T therapy.”

What’s coming next for bispecifics? “On the horizon is better ease of administration, which is already being addressed by subcutaneous dosing for some bispecifics in lymphomas,” Dr. Greenberger said. “There’s also the possibility of combining bispecifics with conventional therapy.”

Dr. Rogers discloses ties with Genentech, AbbVie, Novartis, AstraZeneca, Janssen, Pharmacyclics, Beigene, and LOXO@Lilly. Dr. Greenberger discloses employment with the Leukemia & Lymphoma Society, which supports academic grants and a venture philanthropy via the Therapy Acceleration Program.

Dr. Jain reports ties with Pharmacyclics, AbbVie, Genentech, AstraZeneca, Pfizer, and numerous other disclosures.
 

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The rapid rise of chimeric antigen receptor T (CAR T-cell) therapy has allowed hematologists to make great strides in treating aggressive cases of multiple myeloma and several types of lymphoma and leukemia. But patients with chronic lymphocytic leukemia (CLL), the most common leukemia in adults, have been left out.

Now there are encouraging signs that CLL could join the list of blood cancers that can be effectively treated by CAR T therapy. On another front, bispecific antibodies – which just received FDA approval to treat B-cell lymphoma – are being tested as treatments for CLL.

“These are the two immunotherapies that have the most potential right now,” said Ohio State University, Columbus, hematologist Kerry A. Rogers, MD, in an interview. She went on to say that these treatments could be a boon for patients with CLL who don’t respond well to targeted therapy drugs or are so young that those medications may not retain effectiveness throughout the patients’ lifespans.

As the American Cancer Society explains, CAR T therapy is a way to get T cells “to fight cancer by changing them in the lab so they can find and destroy cancer cells.” The cells are then returned to the patient.

As the National Cancer Institute says, “If all goes as planned, the CAR T cells will continue to multiply in the patient’s body and, with guidance from their engineered receptor, recognize and kill any cancer cells that harbor the target antigen on their surfaces.”

According to Dr. Rogers, CAR T therapy is less toxic than stem cell transplantation, a related treatment. That means older people can better tolerate it, including many CLL patients in their late 60s and beyond, she said. (Side effects of CAR T therapy include cytokine release syndrome, nervous system impairment, and weakening of the immune system.)

Thus far, CAR T therapy has been approved by the U.S. Food and Drug Administration to treat lymphomas, some forms of leukemia, and multiple myeloma. “Despite the excitement around these therapies, they lead to long-term survival in fewer than half of the patients treated,” cautions the National Cancer Institute, which also notes their high cost: more than $450,000 in one case.

CAR T therapy is not FDA-approved for CLL. “There are many reasons why CAR T is less effective in patients with CLL versus other lymphomas,” said Lee Greenberger, PhD, chief scientific officer of the Leukemia & Lymphoma Society, in an interview. “For one, many patients with heavily pretreated CLL – prior to any use of CAR T – have mutations that are known to be difficult to treat. Dysfunctional T cells are also common in patients with CLL, and there’s often a lower number of available T-cells to manufacture.”

The results of a phase 1/2 trial released in August 2023 offered new insight about CAR T for CLL. In the open-label trial reported in The Lancet, 117 U.S. patients with CLL or small lymphocytic lymphoma underwent a form of CAR T therapy called lisocabtagene maraleucel after failing treatment with two lines of therapy, including a Bruton´s tyrosine kinase inhibitor. Among 49 patients at a specific dose, “the rate of complete response or remission (including with incomplete marrow recovery) was statistically significant at 18%,” the researchers reported. A total of 51 patients in the entire study died.

The rate of undetectable minimal residual disease blood was 64%. That rate is impressive, said University of Texas MD Anderson Cancer Center leukemia specialist Nitin Jain, MD, in an interview. It’s not nearly as high as researchers have seen in other disease settings, but it’s “a good, good thing for these patients. We’ll have to see in the longer follow-up how these patients fare 2, 3, or 4 years down the line.”

Dr. Rogers, the Ohio physician, said doctors had hoped durable benefit in the Lancet study would be more impressive. An important factor limiting its value may be the aggressiveness of the disease in patients who have already failed several treatments, she said. “The efficacy of CAR T might be improved by giving it as an earlier line of therapy before the CLL has become this aggressive. But it’s difficult to propose that you should use this before a Bruton´s tyrosine kinase inhibitor or venetoclax because it’s expensive and difficult.”

What’s next for CART T research in CLL? Understanding the best timing for treatment will be key, Dr. Rogers said.

The Leukemia & Lymphoma Society’s Dr. Greenberger predicted that “we will begin to see CAR T explored in CLL patients whose disease has a high risk of failing approved agents, such as Bruton´s tyrosine kinase and B cell lymphoma 2 inhibitors. However, CLL patients may still receive prior therapy with more effective Bruton’s tyrosine kinase or B cell lymphoma 2 inhibitors in the future before using CAR T. This will likely be heightened as more Bruton´s tyrosine kinase inhibitors become generic in the next 5 to 10 years and, hopefully, less expensive than CAR T therapy.”

In the big picture, he said, “treatment of CLL with CAR T is possible, but still needs significant improvements if it is to become a mainline therapy in the future.”

CAR T therapy remains available via clinical trials, and Dr. Rogers said it is “currently an important option for patients whose CLL has become resistant to standard targeted agents. We can certainly expect to extend someone’s expected survival by years if they have a favorable response.” She acknowledged that the cost is quite high, but noted that targeted therapies are also expensive, especially over the long term. They can run to $10,000-$20,000 a month. Bispecific antibodies are also being explored as potential therapy for CLL. “They’re really exciting,” Dr. Rogers said, with the potential to spur responses similar to those from CAR T therapy.

A 2022 review described these drugs as “molecules that combine antibody-directed therapies with cellular mediated immunotherapy.” The FDA explains that “by targeting two antigens or epitopes, they can cause multiple physiological or antitumor responses, which may be independent or connected.”

According to Dr. Greenberger, many bispecifics are in clinical trials now. However, “in the context of CLL, actually, the data is actually very, very limited. The development is just starting, and there are phase 1 and phase 2 trials ongoing.”

But data from lymphoma trials are encouraging, he said, and bispecifics “are actually looking as good as CAR T in some settings.”

Regimens can be a challenge for patients taking bispecifics, Dr. Greenberger said. “Repeat dosing with a step-up dosing approach to start is typically required when treating lymphoma.”

On the other hand, Dr. Rogers noted that antibody treatment can be easier for hematologists to arrange than CAR T therapy and stem cell transplants. “From an administrative side, there’s not as many things you need to have set up. So it’s able to be administered in a wider variety of settings,” she said,

Bispecific side effects include cytokine release syndrome and neurotoxicity as well as infusion reactions, Dr. Greenberger said, adding that “I would not exclude cost as a challenge.”

According to Formulary Watch, the bispecific Columvi (glofitamab-gxbm), which recently gained FDA approval to treat diffuse large B-cell lymphoma, is estimated to cost $350,000 for an 8.5-month round of treatment. Reuters reported that the bispecific Talvey (talquetamab-tgvs), which just received FDA approval to treat multiple myeloma, is estimated to cost $270,000-$360,000 for 6-8 months of treatment.

For now, bispecific trials “are mostly now reserved for patients with CLL who become resistant to our current standard targeted agents,” Dr. Rogers said. “It’s a little unclear if you can do CAR T therapy first and then bispecifics, or bispecifics and then CAR T therapy.”

What’s coming next for bispecifics? “On the horizon is better ease of administration, which is already being addressed by subcutaneous dosing for some bispecifics in lymphomas,” Dr. Greenberger said. “There’s also the possibility of combining bispecifics with conventional therapy.”

Dr. Rogers discloses ties with Genentech, AbbVie, Novartis, AstraZeneca, Janssen, Pharmacyclics, Beigene, and LOXO@Lilly. Dr. Greenberger discloses employment with the Leukemia & Lymphoma Society, which supports academic grants and a venture philanthropy via the Therapy Acceleration Program.

Dr. Jain reports ties with Pharmacyclics, AbbVie, Genentech, AstraZeneca, Pfizer, and numerous other disclosures.
 

The rapid rise of chimeric antigen receptor T (CAR T-cell) therapy has allowed hematologists to make great strides in treating aggressive cases of multiple myeloma and several types of lymphoma and leukemia. But patients with chronic lymphocytic leukemia (CLL), the most common leukemia in adults, have been left out.

Now there are encouraging signs that CLL could join the list of blood cancers that can be effectively treated by CAR T therapy. On another front, bispecific antibodies – which just received FDA approval to treat B-cell lymphoma – are being tested as treatments for CLL.

“These are the two immunotherapies that have the most potential right now,” said Ohio State University, Columbus, hematologist Kerry A. Rogers, MD, in an interview. She went on to say that these treatments could be a boon for patients with CLL who don’t respond well to targeted therapy drugs or are so young that those medications may not retain effectiveness throughout the patients’ lifespans.

As the American Cancer Society explains, CAR T therapy is a way to get T cells “to fight cancer by changing them in the lab so they can find and destroy cancer cells.” The cells are then returned to the patient.

As the National Cancer Institute says, “If all goes as planned, the CAR T cells will continue to multiply in the patient’s body and, with guidance from their engineered receptor, recognize and kill any cancer cells that harbor the target antigen on their surfaces.”

According to Dr. Rogers, CAR T therapy is less toxic than stem cell transplantation, a related treatment. That means older people can better tolerate it, including many CLL patients in their late 60s and beyond, she said. (Side effects of CAR T therapy include cytokine release syndrome, nervous system impairment, and weakening of the immune system.)

Thus far, CAR T therapy has been approved by the U.S. Food and Drug Administration to treat lymphomas, some forms of leukemia, and multiple myeloma. “Despite the excitement around these therapies, they lead to long-term survival in fewer than half of the patients treated,” cautions the National Cancer Institute, which also notes their high cost: more than $450,000 in one case.

CAR T therapy is not FDA-approved for CLL. “There are many reasons why CAR T is less effective in patients with CLL versus other lymphomas,” said Lee Greenberger, PhD, chief scientific officer of the Leukemia & Lymphoma Society, in an interview. “For one, many patients with heavily pretreated CLL – prior to any use of CAR T – have mutations that are known to be difficult to treat. Dysfunctional T cells are also common in patients with CLL, and there’s often a lower number of available T-cells to manufacture.”

The results of a phase 1/2 trial released in August 2023 offered new insight about CAR T for CLL. In the open-label trial reported in The Lancet, 117 U.S. patients with CLL or small lymphocytic lymphoma underwent a form of CAR T therapy called lisocabtagene maraleucel after failing treatment with two lines of therapy, including a Bruton´s tyrosine kinase inhibitor. Among 49 patients at a specific dose, “the rate of complete response or remission (including with incomplete marrow recovery) was statistically significant at 18%,” the researchers reported. A total of 51 patients in the entire study died.

The rate of undetectable minimal residual disease blood was 64%. That rate is impressive, said University of Texas MD Anderson Cancer Center leukemia specialist Nitin Jain, MD, in an interview. It’s not nearly as high as researchers have seen in other disease settings, but it’s “a good, good thing for these patients. We’ll have to see in the longer follow-up how these patients fare 2, 3, or 4 years down the line.”

Dr. Rogers, the Ohio physician, said doctors had hoped durable benefit in the Lancet study would be more impressive. An important factor limiting its value may be the aggressiveness of the disease in patients who have already failed several treatments, she said. “The efficacy of CAR T might be improved by giving it as an earlier line of therapy before the CLL has become this aggressive. But it’s difficult to propose that you should use this before a Bruton´s tyrosine kinase inhibitor or venetoclax because it’s expensive and difficult.”

What’s next for CART T research in CLL? Understanding the best timing for treatment will be key, Dr. Rogers said.

The Leukemia & Lymphoma Society’s Dr. Greenberger predicted that “we will begin to see CAR T explored in CLL patients whose disease has a high risk of failing approved agents, such as Bruton´s tyrosine kinase and B cell lymphoma 2 inhibitors. However, CLL patients may still receive prior therapy with more effective Bruton’s tyrosine kinase or B cell lymphoma 2 inhibitors in the future before using CAR T. This will likely be heightened as more Bruton´s tyrosine kinase inhibitors become generic in the next 5 to 10 years and, hopefully, less expensive than CAR T therapy.”

In the big picture, he said, “treatment of CLL with CAR T is possible, but still needs significant improvements if it is to become a mainline therapy in the future.”

CAR T therapy remains available via clinical trials, and Dr. Rogers said it is “currently an important option for patients whose CLL has become resistant to standard targeted agents. We can certainly expect to extend someone’s expected survival by years if they have a favorable response.” She acknowledged that the cost is quite high, but noted that targeted therapies are also expensive, especially over the long term. They can run to $10,000-$20,000 a month. Bispecific antibodies are also being explored as potential therapy for CLL. “They’re really exciting,” Dr. Rogers said, with the potential to spur responses similar to those from CAR T therapy.

A 2022 review described these drugs as “molecules that combine antibody-directed therapies with cellular mediated immunotherapy.” The FDA explains that “by targeting two antigens or epitopes, they can cause multiple physiological or antitumor responses, which may be independent or connected.”

According to Dr. Greenberger, many bispecifics are in clinical trials now. However, “in the context of CLL, actually, the data is actually very, very limited. The development is just starting, and there are phase 1 and phase 2 trials ongoing.”

But data from lymphoma trials are encouraging, he said, and bispecifics “are actually looking as good as CAR T in some settings.”

Regimens can be a challenge for patients taking bispecifics, Dr. Greenberger said. “Repeat dosing with a step-up dosing approach to start is typically required when treating lymphoma.”

On the other hand, Dr. Rogers noted that antibody treatment can be easier for hematologists to arrange than CAR T therapy and stem cell transplants. “From an administrative side, there’s not as many things you need to have set up. So it’s able to be administered in a wider variety of settings,” she said,

Bispecific side effects include cytokine release syndrome and neurotoxicity as well as infusion reactions, Dr. Greenberger said, adding that “I would not exclude cost as a challenge.”

According to Formulary Watch, the bispecific Columvi (glofitamab-gxbm), which recently gained FDA approval to treat diffuse large B-cell lymphoma, is estimated to cost $350,000 for an 8.5-month round of treatment. Reuters reported that the bispecific Talvey (talquetamab-tgvs), which just received FDA approval to treat multiple myeloma, is estimated to cost $270,000-$360,000 for 6-8 months of treatment.

For now, bispecific trials “are mostly now reserved for patients with CLL who become resistant to our current standard targeted agents,” Dr. Rogers said. “It’s a little unclear if you can do CAR T therapy first and then bispecifics, or bispecifics and then CAR T therapy.”

What’s coming next for bispecifics? “On the horizon is better ease of administration, which is already being addressed by subcutaneous dosing for some bispecifics in lymphomas,” Dr. Greenberger said. “There’s also the possibility of combining bispecifics with conventional therapy.”

Dr. Rogers discloses ties with Genentech, AbbVie, Novartis, AstraZeneca, Janssen, Pharmacyclics, Beigene, and LOXO@Lilly. Dr. Greenberger discloses employment with the Leukemia & Lymphoma Society, which supports academic grants and a venture philanthropy via the Therapy Acceleration Program.

Dr. Jain reports ties with Pharmacyclics, AbbVie, Genentech, AstraZeneca, Pfizer, and numerous other disclosures.
 

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Commentary: Updates in mantle cell lymphoma, September 2023

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Dr Crombie scans the journals so you don't have to!

Mantle cell lymphoma (MCL) is a rare subtype of non-Hodgkin lymphoma that is characterized by t(11;14) and cyclin D1 overexpression. It is also known to be clinically heterogenous, with disease presentations ranging from indolent to aggressive. Baseline risk can be determined on the basis of a combination of clinical and pathologic features. A key prognostic tool, for example, is the Mantle Cell Lymphoma International Prognostic Index-Combined (MIPI-c), which integrates the standard MIPI clinical factors (age, performance status, lactate dehydrogenase, and leukocyte count) with estimates of proliferation (Ki-67).1 Other features, including the presence of TP53 alterations, have also been associated with poor outcomes, even with intensive therapy.2

 

Recently, a study aimed to further refine prognostication in MCL in order to identify high-risk patients that may be more likely to benefit from novel treatment strategies (Scheubeck et al). This retrospective study included 684 patients with MCL from the MCL-Younger and MCL-Elderly trials with evaluable data for Ki-67 or p53 expression (a surrogate for TP53 alterations). Patients were classified as having high-risk disease on the basis of a high-risk MIPI-c or p53 expression > 50% or as having low-risk disease on the basis of low, low-intermediate, or high-intermediate MIPI-c and p53 expression ≤ 50%. Patients with high-risk disease had significantly shorter median failure-free survival (1.1 vs 5.6 years; P < .0001) and overall survival (2.2 vs 13.2 years; P < .0001) compared with those with low-risk disease. The differences were confirmed in two validation cohorts from the Italian MCL0208 and Nordic-MCL4 trials. These data highlight the poor outcomes of conventional therapy in patients with high-risk MCL. Evaluation of novel approaches should be considered in these patients.

 

Bruton tyrosine kinase (BTK) inhibitors have been promising options for patients with MCL, including those with high-risk features. Acalabrutinib is a second-generation covalent BTK inhibitor that is approved by the US Food and Drug Administration for patients who have received at least one prior line of therapy. The final results of the single-arm, phase 2 ACE-LY-004 study recently demonstrated long-term safety and efficacy in patients with relapsed/refractory MCL (Le Gouill et al). The overall and complete response rates were 81.5% (95% CI 73.5%-87.9%) and 47.6% (95% CI 38.5%-56.7%), respectively. After a 38.1-month median follow-up, the median duration of response and progression-free survival were 28.6 months (95% CI 17.5-39.1) and 22.0 months (95% CI 16.6-33.3), respectively. Responses were also seen in patients with high-risk features, including blastoid morphology, high-risk MIPI score, and high Ki-67. No new safety signals were observed. This study confirms the role of BTK inhibitors in MCL and providers longer-term estimates of response. Evaluation of BTK inhibitors in earlier lines of therapy and in combination with other agents are ongoing.

 

Although the majority of patients with MCL will have favorable responses to initial therapy, those with high-risk features, particularly TP53 aberrations, have poor outcomes with standard approaches. Despite a growing number of treatment options in the relapsed setting, such as targeted therapies and chimeric antigen receptor (CAR) T-cell therapy, relapses remain common. Allogenic stem cell transplantation can be associated with prolonged response for patients with relapsed MCL, though it has the potential for significant treatment-associated toxicity.

 

Recently, prolonged follow-up of a retrospective cohort of patients with MCL, including a subset with TP53 aberrations, was reported (Lew et al). Thirty-six patients with MCL were included, including 13 with TP53-mutated disease. A subset of patients (61%) received an allogeneic transplant in first remission. The estimated overall survival rates after allogenic transplant were 56% (95% CI 36%-72%) at 10 years for the overall cohort and 59% (95% CI 21%-75%) at 4 years for patients with TP53-mutated disease at median follow-ups of 10.8 and 4.2 years, respectively. No relapses were observed in the TP53-mutated subset beyond 6 months after transplantation. These data suggest a potentially curative option for patients with high-risk MCL. Given the availability of CAR T-cell therapy, the optimal timing of allogenic stem cell transplant has become less clear for patients with TP53-mutant disease. Although this study was small and retrospective, these data are encouraging for patients with high-risk disease.

 

Additional References

1.            Hoster E, Rosenwald A, Berger F, et al. Prognostic value of Ki-67 index, cytology, and growth pattern in mantle-cell lymphoma: Results from randomized trials of the European Mantle Cell Lymphoma Network. J Clin Oncol. 2016;34:1386-1394. doi: 10.1200/JCO.2015.63.8387

2.            Eskelund CW, Dahl C, Hansen JW, et al. TP53 mutations identify younger mantle cell lymphoma patients who do not benefit from intensive chemoimmunotherapy. Blood. 2017;130:1903-1910. doi: 10.1182/blood-2017-04-77973

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Dr Crombie scans the journals so you don't have to!
Dr Crombie scans the journals so you don't have to!

Mantle cell lymphoma (MCL) is a rare subtype of non-Hodgkin lymphoma that is characterized by t(11;14) and cyclin D1 overexpression. It is also known to be clinically heterogenous, with disease presentations ranging from indolent to aggressive. Baseline risk can be determined on the basis of a combination of clinical and pathologic features. A key prognostic tool, for example, is the Mantle Cell Lymphoma International Prognostic Index-Combined (MIPI-c), which integrates the standard MIPI clinical factors (age, performance status, lactate dehydrogenase, and leukocyte count) with estimates of proliferation (Ki-67).1 Other features, including the presence of TP53 alterations, have also been associated with poor outcomes, even with intensive therapy.2

 

Recently, a study aimed to further refine prognostication in MCL in order to identify high-risk patients that may be more likely to benefit from novel treatment strategies (Scheubeck et al). This retrospective study included 684 patients with MCL from the MCL-Younger and MCL-Elderly trials with evaluable data for Ki-67 or p53 expression (a surrogate for TP53 alterations). Patients were classified as having high-risk disease on the basis of a high-risk MIPI-c or p53 expression > 50% or as having low-risk disease on the basis of low, low-intermediate, or high-intermediate MIPI-c and p53 expression ≤ 50%. Patients with high-risk disease had significantly shorter median failure-free survival (1.1 vs 5.6 years; P < .0001) and overall survival (2.2 vs 13.2 years; P < .0001) compared with those with low-risk disease. The differences were confirmed in two validation cohorts from the Italian MCL0208 and Nordic-MCL4 trials. These data highlight the poor outcomes of conventional therapy in patients with high-risk MCL. Evaluation of novel approaches should be considered in these patients.

 

Bruton tyrosine kinase (BTK) inhibitors have been promising options for patients with MCL, including those with high-risk features. Acalabrutinib is a second-generation covalent BTK inhibitor that is approved by the US Food and Drug Administration for patients who have received at least one prior line of therapy. The final results of the single-arm, phase 2 ACE-LY-004 study recently demonstrated long-term safety and efficacy in patients with relapsed/refractory MCL (Le Gouill et al). The overall and complete response rates were 81.5% (95% CI 73.5%-87.9%) and 47.6% (95% CI 38.5%-56.7%), respectively. After a 38.1-month median follow-up, the median duration of response and progression-free survival were 28.6 months (95% CI 17.5-39.1) and 22.0 months (95% CI 16.6-33.3), respectively. Responses were also seen in patients with high-risk features, including blastoid morphology, high-risk MIPI score, and high Ki-67. No new safety signals were observed. This study confirms the role of BTK inhibitors in MCL and providers longer-term estimates of response. Evaluation of BTK inhibitors in earlier lines of therapy and in combination with other agents are ongoing.

 

Although the majority of patients with MCL will have favorable responses to initial therapy, those with high-risk features, particularly TP53 aberrations, have poor outcomes with standard approaches. Despite a growing number of treatment options in the relapsed setting, such as targeted therapies and chimeric antigen receptor (CAR) T-cell therapy, relapses remain common. Allogenic stem cell transplantation can be associated with prolonged response for patients with relapsed MCL, though it has the potential for significant treatment-associated toxicity.

 

Recently, prolonged follow-up of a retrospective cohort of patients with MCL, including a subset with TP53 aberrations, was reported (Lew et al). Thirty-six patients with MCL were included, including 13 with TP53-mutated disease. A subset of patients (61%) received an allogeneic transplant in first remission. The estimated overall survival rates after allogenic transplant were 56% (95% CI 36%-72%) at 10 years for the overall cohort and 59% (95% CI 21%-75%) at 4 years for patients with TP53-mutated disease at median follow-ups of 10.8 and 4.2 years, respectively. No relapses were observed in the TP53-mutated subset beyond 6 months after transplantation. These data suggest a potentially curative option for patients with high-risk MCL. Given the availability of CAR T-cell therapy, the optimal timing of allogenic stem cell transplant has become less clear for patients with TP53-mutant disease. Although this study was small and retrospective, these data are encouraging for patients with high-risk disease.

 

Additional References

1.            Hoster E, Rosenwald A, Berger F, et al. Prognostic value of Ki-67 index, cytology, and growth pattern in mantle-cell lymphoma: Results from randomized trials of the European Mantle Cell Lymphoma Network. J Clin Oncol. 2016;34:1386-1394. doi: 10.1200/JCO.2015.63.8387

2.            Eskelund CW, Dahl C, Hansen JW, et al. TP53 mutations identify younger mantle cell lymphoma patients who do not benefit from intensive chemoimmunotherapy. Blood. 2017;130:1903-1910. doi: 10.1182/blood-2017-04-77973

Mantle cell lymphoma (MCL) is a rare subtype of non-Hodgkin lymphoma that is characterized by t(11;14) and cyclin D1 overexpression. It is also known to be clinically heterogenous, with disease presentations ranging from indolent to aggressive. Baseline risk can be determined on the basis of a combination of clinical and pathologic features. A key prognostic tool, for example, is the Mantle Cell Lymphoma International Prognostic Index-Combined (MIPI-c), which integrates the standard MIPI clinical factors (age, performance status, lactate dehydrogenase, and leukocyte count) with estimates of proliferation (Ki-67).1 Other features, including the presence of TP53 alterations, have also been associated with poor outcomes, even with intensive therapy.2

 

Recently, a study aimed to further refine prognostication in MCL in order to identify high-risk patients that may be more likely to benefit from novel treatment strategies (Scheubeck et al). This retrospective study included 684 patients with MCL from the MCL-Younger and MCL-Elderly trials with evaluable data for Ki-67 or p53 expression (a surrogate for TP53 alterations). Patients were classified as having high-risk disease on the basis of a high-risk MIPI-c or p53 expression > 50% or as having low-risk disease on the basis of low, low-intermediate, or high-intermediate MIPI-c and p53 expression ≤ 50%. Patients with high-risk disease had significantly shorter median failure-free survival (1.1 vs 5.6 years; P < .0001) and overall survival (2.2 vs 13.2 years; P < .0001) compared with those with low-risk disease. The differences were confirmed in two validation cohorts from the Italian MCL0208 and Nordic-MCL4 trials. These data highlight the poor outcomes of conventional therapy in patients with high-risk MCL. Evaluation of novel approaches should be considered in these patients.

 

Bruton tyrosine kinase (BTK) inhibitors have been promising options for patients with MCL, including those with high-risk features. Acalabrutinib is a second-generation covalent BTK inhibitor that is approved by the US Food and Drug Administration for patients who have received at least one prior line of therapy. The final results of the single-arm, phase 2 ACE-LY-004 study recently demonstrated long-term safety and efficacy in patients with relapsed/refractory MCL (Le Gouill et al). The overall and complete response rates were 81.5% (95% CI 73.5%-87.9%) and 47.6% (95% CI 38.5%-56.7%), respectively. After a 38.1-month median follow-up, the median duration of response and progression-free survival were 28.6 months (95% CI 17.5-39.1) and 22.0 months (95% CI 16.6-33.3), respectively. Responses were also seen in patients with high-risk features, including blastoid morphology, high-risk MIPI score, and high Ki-67. No new safety signals were observed. This study confirms the role of BTK inhibitors in MCL and providers longer-term estimates of response. Evaluation of BTK inhibitors in earlier lines of therapy and in combination with other agents are ongoing.

 

Although the majority of patients with MCL will have favorable responses to initial therapy, those with high-risk features, particularly TP53 aberrations, have poor outcomes with standard approaches. Despite a growing number of treatment options in the relapsed setting, such as targeted therapies and chimeric antigen receptor (CAR) T-cell therapy, relapses remain common. Allogenic stem cell transplantation can be associated with prolonged response for patients with relapsed MCL, though it has the potential for significant treatment-associated toxicity.

 

Recently, prolonged follow-up of a retrospective cohort of patients with MCL, including a subset with TP53 aberrations, was reported (Lew et al). Thirty-six patients with MCL were included, including 13 with TP53-mutated disease. A subset of patients (61%) received an allogeneic transplant in first remission. The estimated overall survival rates after allogenic transplant were 56% (95% CI 36%-72%) at 10 years for the overall cohort and 59% (95% CI 21%-75%) at 4 years for patients with TP53-mutated disease at median follow-ups of 10.8 and 4.2 years, respectively. No relapses were observed in the TP53-mutated subset beyond 6 months after transplantation. These data suggest a potentially curative option for patients with high-risk MCL. Given the availability of CAR T-cell therapy, the optimal timing of allogenic stem cell transplant has become less clear for patients with TP53-mutant disease. Although this study was small and retrospective, these data are encouraging for patients with high-risk disease.

 

Additional References

1.            Hoster E, Rosenwald A, Berger F, et al. Prognostic value of Ki-67 index, cytology, and growth pattern in mantle-cell lymphoma: Results from randomized trials of the European Mantle Cell Lymphoma Network. J Clin Oncol. 2016;34:1386-1394. doi: 10.1200/JCO.2015.63.8387

2.            Eskelund CW, Dahl C, Hansen JW, et al. TP53 mutations identify younger mantle cell lymphoma patients who do not benefit from intensive chemoimmunotherapy. Blood. 2017;130:1903-1910. doi: 10.1182/blood-2017-04-77973

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What’s New in Diffuse Large B-cell Lymphoma?

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Diffuse large B-cell lymphoma (DLBCL) is the most diagnosed non-Hodgkin lymphoma (NHL), accounting for up to one-third of cases. For many decades, R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) has been the standard first-line treatment approach for eligible patients in the first-line setting, resulting in long-term remissions in about two-thirds of patients. However, as our understanding of the biologic heterogeneity of this disease has advanced with the ability to perform more sophisticated molecular testing at diagnosis, researchers have been able to identify high-risk patient subtypes with suboptimal outcomes. While survival outcomes among low-risk patient subgroups are favorable with first-line immunochemotherapy, the majority of high-risk patients will experience relapse and often succumb to their disease. 

Given the poor outcomes among patients with relapsed or refractory (R/R) DLBCL, there has been a massive research effort over the last decade to improve survival in this setting. Many experts agree that the approval of chimeric antigen receptor (CAR) T-cell therapy was the first major victory in this uphill battle. First approved in October of 2017, axicabtagene ciloleucel was the first of the 3 currently available commercial CAR T-cell therapy constructs to be approved in the third-line setting for DLBCL. Compared to historical controls, CAR T-cell therapy is associated with significant improvement in patient survival with complete response (CR) rates of 40%-50% compared to <20% with standard salvage immunochemotherapy

Following approval in the third-line setting, these agents were quickly expedited to second-line therapy with pivotal trials demonstrating superiority with CAR T-cell therapy in the second line compared to salvage immunochemotherapy followed by autologous stem cell transplant. In 2022 the ZUMA-7 study reported a 24-month event-free survival (EFS) of 41% with axicabtagene ciloleucel compared to 16% with standard of care, and the TRANSFORM study documented a median EFS not yet reached with lisocabtagene ciloleucel compared to 2.3 months with standard of care. Despite these drastic improvements in patient outcomes, more than half of patients will still fail CAR T-cell therapy and require further systemic therapy. 

Thankfully, this year has seen even more advancement in the treatment landscape of R/R DLBCL with two new commercially approved agents in yet another novel therapeutic category: bispecific antibodies. The following is a description of the newest data leading to the latest approvals by the US Food and Drug Administration.

Bispecific antibodies (BsAbs) are an off-the-shelf product that activate endogenous immune cells by cotargeting both tumor antigens as well as host T cells or natural killer cells. Several different experimental agents with varying constructs are under active observation in a wide variety of both hematologic and solid malignancies. Specifically within the realm of B-cell NHL, however, this class of agents is extremely promising and possibly represents the next significant milestone in the treatment of lymphoma. 

The toxicity profile of these agents has been reliably predictable in most early phase clinical studies and is related predominantly to T-cell overactivation. The most commonly reported adverse events consist of cytokine release syndrome (CRS) as well as neutropenia, anemia, and hypophosphatemia. While neurologic toxicity has been reported, the incidence is low, and the mechanism is thought to be different than that reported with CAR T-cell therapy given that BsAbs are not likely to cross the blood–brain barrier. 

Epcoritamab is a subcutaneously administered bispecific antibody that targets CD3 and CD20 in a 1:1 ratio and activates T cells to destroy CD20-expressing malignant cells. The recent EPCORE NHL-1 clinical trial investigated epcoritamab monotherapy in R/R mature B-cell lymphomas. This agent is administered with a step-up dosing strategy seen consistently across the BsAb drug class. Patients receive a first priming dose of 0.16 mg on cycle 1 day 1, followed by an intermediate dose of 0.8 mg on cycle 1 day 8, followed by the first full dose of 48 mg on cycle 1 day 15. Subsequent doses are administered once weekly for cycles 1-3 followed by every 2 weeks for cycles 4-9, and every 4 weeks starting with cycle 10.

The study enrolled 157 patients globally with median age of 64 and 3 median prior lines of antilymphoma therapy. Nearly 40% of patients had received at least 4 prior lines of therapy, and 83% of patients were refractory to last systemic therapy. Thirty-nine percent of patients had received prior CAR T-cell therapy; 75% of these patients developed progressive disease within 6 months of CAR T-cell therapy.

Among patients treated in the study, the results were as follows:

  • CR rate 39% with an overall response rate (ORR) of 63%

  • Duration of response 12 months; duration of objective response not reached in patients with CR

  • Duration of CR 12 months

  • Median PFS 4.4 months; median OS not reached

  • Time to CR of 2.7 months

Toxicity profile was notable for the following:

  • Any grade CRS in 50%, grade ≥3 in 2.5%

    • Most CRS occurs with first full dose on cycle 1 day 15 with median time to onset of 20 hours and median time to resolution of 48 hours

  • Any grade neutropenia in 22%, grade ≥3 in 15%, febrile neutropenia in 2.5%

  • Any grade anemia in 18%, grade ≥3 in 10%

  • Injection site reaction, any grade, in 20%

  • Any grade neurotoxicity in 6%, grade ≥3 in 1 patient (0.6%)

Epcoritamab was granted accelerated approval on May 19, 2023, for use in patients with R/R DLBCL who have received at least 2 prior lines of systemic therapy.

Glofitamab is the more recently approved BsAb for DLBCL. This agent is distinguished by its 2:1 binding configuration that confers bivalency for the CD20 binding site. Glofitamab is delivered intravenously and requires pretreatment with obinutuzumab 1000 mg 7 days before the first dose. With a similar step-up dosing strategy, patients receive a priming dose of 2.5mg on cycle 1 day 8, an intermediate dose of 10mg on cycle 1 day 15, and a first full dose of 30mg on cycle 2 day 1. Subsequent treatments are administered every 21 days for up to 12 cycles. 

The open-label phase 1-2 clinical trial of glofitamab monotherapy enrolled 155 patients with a median age of 66 and 3 median prior lines of therapy. Thirty-three percent of patients had received prior CAR T-cell therapy, and 86% were refractory to last line of therapy with 30% refractory to CAR T-cell therapy. 

Results were as follows:

  • CR rate of 39%, ORR 52%

  • Median duration of CR not reached, median duration of objective response 18.4 months

  • Median PFS 4.9 months, median OS not reached

Toxicity profile demonstrated the following:

  • Any grade CRS 66%, grade ≥ 2 in 18%

    • Median time to onset 13.5 hours from cycle 1 day 8, median duration 30.5 hours

  • Any grade neutropenia in 38%, grade ≥ 3 in 27%

  • Grade ≥ 2 neurologic event in 15%

Glofitamab received accelerated approval from the FDA on June 15, 2023, with an identical indication to epcoritamab. 

The introduction of BsAbs in DLBCL has highlighted some important issues. Will BsAbs supplant CAR T-cell therapy in DLBCL? Experts can be found on both sides of this debate. BsAbs circumvent the logistics surrounding the production of CAR T-cell therapy products and can, for the large part, be administered in the outpatient setting. However, CAR T-cell therapy has significantly longer follow-up times, which speaks to the curative potential of these agents even in the third-line setting. BsAbs, some may argue, seem to carry a more favorable toxicity profile with the CRS mitigation strategies. However, we still have much to learn about the downstream side effects with prolonged T-cell activation and the potential for T-cell exhaustion.

Finally, with the continued development of new agents in this arena, the art of sequencing therapies will become ever more important. What is the efficacy of CAR T-cell therapy after BsAb exposure? Can BsAbs be used as bridging therapy to a curative option with CAR T-cell therapy? With longer-term follow-up in several years, will we see late relapses after CR with BsAbs? Ongoing clinical trials investigating combination strategies and CAR T-cell therapy consolidation with BsAbs will hopefully eventually clarify some of these questions.

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Advisory board, ADC Therapeutics. Advisory board, Genentech.

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Diffuse large B-cell lymphoma (DLBCL) is the most diagnosed non-Hodgkin lymphoma (NHL), accounting for up to one-third of cases. For many decades, R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) has been the standard first-line treatment approach for eligible patients in the first-line setting, resulting in long-term remissions in about two-thirds of patients. However, as our understanding of the biologic heterogeneity of this disease has advanced with the ability to perform more sophisticated molecular testing at diagnosis, researchers have been able to identify high-risk patient subtypes with suboptimal outcomes. While survival outcomes among low-risk patient subgroups are favorable with first-line immunochemotherapy, the majority of high-risk patients will experience relapse and often succumb to their disease. 

Given the poor outcomes among patients with relapsed or refractory (R/R) DLBCL, there has been a massive research effort over the last decade to improve survival in this setting. Many experts agree that the approval of chimeric antigen receptor (CAR) T-cell therapy was the first major victory in this uphill battle. First approved in October of 2017, axicabtagene ciloleucel was the first of the 3 currently available commercial CAR T-cell therapy constructs to be approved in the third-line setting for DLBCL. Compared to historical controls, CAR T-cell therapy is associated with significant improvement in patient survival with complete response (CR) rates of 40%-50% compared to <20% with standard salvage immunochemotherapy

Following approval in the third-line setting, these agents were quickly expedited to second-line therapy with pivotal trials demonstrating superiority with CAR T-cell therapy in the second line compared to salvage immunochemotherapy followed by autologous stem cell transplant. In 2022 the ZUMA-7 study reported a 24-month event-free survival (EFS) of 41% with axicabtagene ciloleucel compared to 16% with standard of care, and the TRANSFORM study documented a median EFS not yet reached with lisocabtagene ciloleucel compared to 2.3 months with standard of care. Despite these drastic improvements in patient outcomes, more than half of patients will still fail CAR T-cell therapy and require further systemic therapy. 

Thankfully, this year has seen even more advancement in the treatment landscape of R/R DLBCL with two new commercially approved agents in yet another novel therapeutic category: bispecific antibodies. The following is a description of the newest data leading to the latest approvals by the US Food and Drug Administration.

Bispecific antibodies (BsAbs) are an off-the-shelf product that activate endogenous immune cells by cotargeting both tumor antigens as well as host T cells or natural killer cells. Several different experimental agents with varying constructs are under active observation in a wide variety of both hematologic and solid malignancies. Specifically within the realm of B-cell NHL, however, this class of agents is extremely promising and possibly represents the next significant milestone in the treatment of lymphoma. 

The toxicity profile of these agents has been reliably predictable in most early phase clinical studies and is related predominantly to T-cell overactivation. The most commonly reported adverse events consist of cytokine release syndrome (CRS) as well as neutropenia, anemia, and hypophosphatemia. While neurologic toxicity has been reported, the incidence is low, and the mechanism is thought to be different than that reported with CAR T-cell therapy given that BsAbs are not likely to cross the blood–brain barrier. 

Epcoritamab is a subcutaneously administered bispecific antibody that targets CD3 and CD20 in a 1:1 ratio and activates T cells to destroy CD20-expressing malignant cells. The recent EPCORE NHL-1 clinical trial investigated epcoritamab monotherapy in R/R mature B-cell lymphomas. This agent is administered with a step-up dosing strategy seen consistently across the BsAb drug class. Patients receive a first priming dose of 0.16 mg on cycle 1 day 1, followed by an intermediate dose of 0.8 mg on cycle 1 day 8, followed by the first full dose of 48 mg on cycle 1 day 15. Subsequent doses are administered once weekly for cycles 1-3 followed by every 2 weeks for cycles 4-9, and every 4 weeks starting with cycle 10.

The study enrolled 157 patients globally with median age of 64 and 3 median prior lines of antilymphoma therapy. Nearly 40% of patients had received at least 4 prior lines of therapy, and 83% of patients were refractory to last systemic therapy. Thirty-nine percent of patients had received prior CAR T-cell therapy; 75% of these patients developed progressive disease within 6 months of CAR T-cell therapy.

Among patients treated in the study, the results were as follows:

  • CR rate 39% with an overall response rate (ORR) of 63%

  • Duration of response 12 months; duration of objective response not reached in patients with CR

  • Duration of CR 12 months

  • Median PFS 4.4 months; median OS not reached

  • Time to CR of 2.7 months

Toxicity profile was notable for the following:

  • Any grade CRS in 50%, grade ≥3 in 2.5%

    • Most CRS occurs with first full dose on cycle 1 day 15 with median time to onset of 20 hours and median time to resolution of 48 hours

  • Any grade neutropenia in 22%, grade ≥3 in 15%, febrile neutropenia in 2.5%

  • Any grade anemia in 18%, grade ≥3 in 10%

  • Injection site reaction, any grade, in 20%

  • Any grade neurotoxicity in 6%, grade ≥3 in 1 patient (0.6%)

Epcoritamab was granted accelerated approval on May 19, 2023, for use in patients with R/R DLBCL who have received at least 2 prior lines of systemic therapy.

Glofitamab is the more recently approved BsAb for DLBCL. This agent is distinguished by its 2:1 binding configuration that confers bivalency for the CD20 binding site. Glofitamab is delivered intravenously and requires pretreatment with obinutuzumab 1000 mg 7 days before the first dose. With a similar step-up dosing strategy, patients receive a priming dose of 2.5mg on cycle 1 day 8, an intermediate dose of 10mg on cycle 1 day 15, and a first full dose of 30mg on cycle 2 day 1. Subsequent treatments are administered every 21 days for up to 12 cycles. 

The open-label phase 1-2 clinical trial of glofitamab monotherapy enrolled 155 patients with a median age of 66 and 3 median prior lines of therapy. Thirty-three percent of patients had received prior CAR T-cell therapy, and 86% were refractory to last line of therapy with 30% refractory to CAR T-cell therapy. 

Results were as follows:

  • CR rate of 39%, ORR 52%

  • Median duration of CR not reached, median duration of objective response 18.4 months

  • Median PFS 4.9 months, median OS not reached

Toxicity profile demonstrated the following:

  • Any grade CRS 66%, grade ≥ 2 in 18%

    • Median time to onset 13.5 hours from cycle 1 day 8, median duration 30.5 hours

  • Any grade neutropenia in 38%, grade ≥ 3 in 27%

  • Grade ≥ 2 neurologic event in 15%

Glofitamab received accelerated approval from the FDA on June 15, 2023, with an identical indication to epcoritamab. 

The introduction of BsAbs in DLBCL has highlighted some important issues. Will BsAbs supplant CAR T-cell therapy in DLBCL? Experts can be found on both sides of this debate. BsAbs circumvent the logistics surrounding the production of CAR T-cell therapy products and can, for the large part, be administered in the outpatient setting. However, CAR T-cell therapy has significantly longer follow-up times, which speaks to the curative potential of these agents even in the third-line setting. BsAbs, some may argue, seem to carry a more favorable toxicity profile with the CRS mitigation strategies. However, we still have much to learn about the downstream side effects with prolonged T-cell activation and the potential for T-cell exhaustion.

Finally, with the continued development of new agents in this arena, the art of sequencing therapies will become ever more important. What is the efficacy of CAR T-cell therapy after BsAb exposure? Can BsAbs be used as bridging therapy to a curative option with CAR T-cell therapy? With longer-term follow-up in several years, will we see late relapses after CR with BsAbs? Ongoing clinical trials investigating combination strategies and CAR T-cell therapy consolidation with BsAbs will hopefully eventually clarify some of these questions.

 

Diffuse large B-cell lymphoma (DLBCL) is the most diagnosed non-Hodgkin lymphoma (NHL), accounting for up to one-third of cases. For many decades, R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) has been the standard first-line treatment approach for eligible patients in the first-line setting, resulting in long-term remissions in about two-thirds of patients. However, as our understanding of the biologic heterogeneity of this disease has advanced with the ability to perform more sophisticated molecular testing at diagnosis, researchers have been able to identify high-risk patient subtypes with suboptimal outcomes. While survival outcomes among low-risk patient subgroups are favorable with first-line immunochemotherapy, the majority of high-risk patients will experience relapse and often succumb to their disease. 

Given the poor outcomes among patients with relapsed or refractory (R/R) DLBCL, there has been a massive research effort over the last decade to improve survival in this setting. Many experts agree that the approval of chimeric antigen receptor (CAR) T-cell therapy was the first major victory in this uphill battle. First approved in October of 2017, axicabtagene ciloleucel was the first of the 3 currently available commercial CAR T-cell therapy constructs to be approved in the third-line setting for DLBCL. Compared to historical controls, CAR T-cell therapy is associated with significant improvement in patient survival with complete response (CR) rates of 40%-50% compared to <20% with standard salvage immunochemotherapy

Following approval in the third-line setting, these agents were quickly expedited to second-line therapy with pivotal trials demonstrating superiority with CAR T-cell therapy in the second line compared to salvage immunochemotherapy followed by autologous stem cell transplant. In 2022 the ZUMA-7 study reported a 24-month event-free survival (EFS) of 41% with axicabtagene ciloleucel compared to 16% with standard of care, and the TRANSFORM study documented a median EFS not yet reached with lisocabtagene ciloleucel compared to 2.3 months with standard of care. Despite these drastic improvements in patient outcomes, more than half of patients will still fail CAR T-cell therapy and require further systemic therapy. 

Thankfully, this year has seen even more advancement in the treatment landscape of R/R DLBCL with two new commercially approved agents in yet another novel therapeutic category: bispecific antibodies. The following is a description of the newest data leading to the latest approvals by the US Food and Drug Administration.

Bispecific antibodies (BsAbs) are an off-the-shelf product that activate endogenous immune cells by cotargeting both tumor antigens as well as host T cells or natural killer cells. Several different experimental agents with varying constructs are under active observation in a wide variety of both hematologic and solid malignancies. Specifically within the realm of B-cell NHL, however, this class of agents is extremely promising and possibly represents the next significant milestone in the treatment of lymphoma. 

The toxicity profile of these agents has been reliably predictable in most early phase clinical studies and is related predominantly to T-cell overactivation. The most commonly reported adverse events consist of cytokine release syndrome (CRS) as well as neutropenia, anemia, and hypophosphatemia. While neurologic toxicity has been reported, the incidence is low, and the mechanism is thought to be different than that reported with CAR T-cell therapy given that BsAbs are not likely to cross the blood–brain barrier. 

Epcoritamab is a subcutaneously administered bispecific antibody that targets CD3 and CD20 in a 1:1 ratio and activates T cells to destroy CD20-expressing malignant cells. The recent EPCORE NHL-1 clinical trial investigated epcoritamab monotherapy in R/R mature B-cell lymphomas. This agent is administered with a step-up dosing strategy seen consistently across the BsAb drug class. Patients receive a first priming dose of 0.16 mg on cycle 1 day 1, followed by an intermediate dose of 0.8 mg on cycle 1 day 8, followed by the first full dose of 48 mg on cycle 1 day 15. Subsequent doses are administered once weekly for cycles 1-3 followed by every 2 weeks for cycles 4-9, and every 4 weeks starting with cycle 10.

The study enrolled 157 patients globally with median age of 64 and 3 median prior lines of antilymphoma therapy. Nearly 40% of patients had received at least 4 prior lines of therapy, and 83% of patients were refractory to last systemic therapy. Thirty-nine percent of patients had received prior CAR T-cell therapy; 75% of these patients developed progressive disease within 6 months of CAR T-cell therapy.

Among patients treated in the study, the results were as follows:

  • CR rate 39% with an overall response rate (ORR) of 63%

  • Duration of response 12 months; duration of objective response not reached in patients with CR

  • Duration of CR 12 months

  • Median PFS 4.4 months; median OS not reached

  • Time to CR of 2.7 months

Toxicity profile was notable for the following:

  • Any grade CRS in 50%, grade ≥3 in 2.5%

    • Most CRS occurs with first full dose on cycle 1 day 15 with median time to onset of 20 hours and median time to resolution of 48 hours

  • Any grade neutropenia in 22%, grade ≥3 in 15%, febrile neutropenia in 2.5%

  • Any grade anemia in 18%, grade ≥3 in 10%

  • Injection site reaction, any grade, in 20%

  • Any grade neurotoxicity in 6%, grade ≥3 in 1 patient (0.6%)

Epcoritamab was granted accelerated approval on May 19, 2023, for use in patients with R/R DLBCL who have received at least 2 prior lines of systemic therapy.

Glofitamab is the more recently approved BsAb for DLBCL. This agent is distinguished by its 2:1 binding configuration that confers bivalency for the CD20 binding site. Glofitamab is delivered intravenously and requires pretreatment with obinutuzumab 1000 mg 7 days before the first dose. With a similar step-up dosing strategy, patients receive a priming dose of 2.5mg on cycle 1 day 8, an intermediate dose of 10mg on cycle 1 day 15, and a first full dose of 30mg on cycle 2 day 1. Subsequent treatments are administered every 21 days for up to 12 cycles. 

The open-label phase 1-2 clinical trial of glofitamab monotherapy enrolled 155 patients with a median age of 66 and 3 median prior lines of therapy. Thirty-three percent of patients had received prior CAR T-cell therapy, and 86% were refractory to last line of therapy with 30% refractory to CAR T-cell therapy. 

Results were as follows:

  • CR rate of 39%, ORR 52%

  • Median duration of CR not reached, median duration of objective response 18.4 months

  • Median PFS 4.9 months, median OS not reached

Toxicity profile demonstrated the following:

  • Any grade CRS 66%, grade ≥ 2 in 18%

    • Median time to onset 13.5 hours from cycle 1 day 8, median duration 30.5 hours

  • Any grade neutropenia in 38%, grade ≥ 3 in 27%

  • Grade ≥ 2 neurologic event in 15%

Glofitamab received accelerated approval from the FDA on June 15, 2023, with an identical indication to epcoritamab. 

The introduction of BsAbs in DLBCL has highlighted some important issues. Will BsAbs supplant CAR T-cell therapy in DLBCL? Experts can be found on both sides of this debate. BsAbs circumvent the logistics surrounding the production of CAR T-cell therapy products and can, for the large part, be administered in the outpatient setting. However, CAR T-cell therapy has significantly longer follow-up times, which speaks to the curative potential of these agents even in the third-line setting. BsAbs, some may argue, seem to carry a more favorable toxicity profile with the CRS mitigation strategies. However, we still have much to learn about the downstream side effects with prolonged T-cell activation and the potential for T-cell exhaustion.

Finally, with the continued development of new agents in this arena, the art of sequencing therapies will become ever more important. What is the efficacy of CAR T-cell therapy after BsAb exposure? Can BsAbs be used as bridging therapy to a curative option with CAR T-cell therapy? With longer-term follow-up in several years, will we see late relapses after CR with BsAbs? Ongoing clinical trials investigating combination strategies and CAR T-cell therapy consolidation with BsAbs will hopefully eventually clarify some of these questions.

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