Commentary: Genetics, prognosis score, and PI3K in MCL, October 2023

The treatment of mantle cell lymphoma (MCL) continues to evolve. In the front-line setting, studies are evaluating the role of novel therapies as well as consolidation with autologous stem cell transplantation. In the relapsed/refractory setting, patients can be considered for treatment with Bruton tyrosine kinase (BTK) inhibitors, other targeted therapies, or chimeric antigen receptor (CAR) T-cell therapy. Other novel therapies, including bispecific antibodies and novel antibody drug conjugates, are being studied as well.

Despite the availability of novel agents, a subset of patients continues to have difficult-to-treat disease and a poor prognosis. Established prognostic tools that aid in identifying high-risk patients include alternations in TP53, high proliferation rates, nonclassic morphology, and the Mantle Cell Lymphoma International Prognostic Index (MIPI) score, which incorporates age, performance status, lactate dehydrogenase levels, and white blood cell count. The Nordic study group recently published a paper which provides additional prognostic information beyond these known variables (Rodrigues et al). They examined MYC expression in a cohort of 251 patients with MCL and structural aberrations in MYC and MYC mRNA levels in a smaller cohort. They found that patients with tumors comprising 20% or more cells with MYC overexpression (MYC^high tumors) vs MYC^low tumors had significantly higher risks for death (adjusted hazard ratio [aHR] 2.03; P = .007) and disease progression (aHR 2.20; P = .04), when adjusted for additional high-risk features. Patients with tumors with concomitant MYC^high expression and TP53/p53 alterations vs MYC^low tumors had a particularly poor prognosis, with significantly increased risks for progression (HR 16.90) and death (HR 7.83) with a median overall survival of only 0.9 years (both P < .001). Though MYC overexpression was rare, this study identified a high-risk group of patients, especially those harboring concurrent TP53 aberrations, that may benefit from novel treatment approaches.

Another study recently aimed to identify patients who are at risk for poor outcomes after treatment with brexucabtagene autoleucel (brexu-cel) infusion. Though brexu-cel is an active therapy for patients with relapsed/refractory MCL, there are known toxicities, including cytokine release syndrome, neurologic toxicity, and hematologic toxicity. Given the potential for prolonged cytopenias and immune suppression, patients are also at risk for severe infections, which currently represent the driving determinant of nonrelapse mortality.¹ The CAR-HEMATOTOX (HT) score was previously found to identify patients who are at increased risk for hematologic toxicity after CAR T-cell therapy in diffuse large B-cell lymphoma.² In the current multicenter observational study, which included 103 patients receiving brexu-cel, the authors reported an association between baseline HT score and outcome in MCL as well. Patients with high (2-7) vs low (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 (aHR 3.7; P < .001) and overall (aHR 5.6; P = .002) survival. This tool may provide a helpful guide when counseling patients on treatment options and allow for more personalized toxicity management.

Despite availability of BTK inhibitors and CAR T-cell therapy for patients with MCL, relapses remain common. As upregulation of phosphoinositide 3-kinase (PI3K) is known to play a critical role in lymphomagenesis, there has been interest in targeting this pathway across lymphoma subtypes. Though PI3K inhibitors have been found to be active agents, they have also been associated with poor tolerability and safety concerns. Parsaclisib is a selective PI3K delta inhibitor that showed encouraging data in the phase 1/2 study in patients with non-Hodgkin lymphoma.³ More recently, the phase 2 CITADEL-205 study, which included adult patients with relapsed or refractory MCL previously treated with one to three systemic therapies, with (n = 53) or without (n = 108) prior BTK inhibitor treatment, was published (Zinazni et al). Patients received 20 mg parsaclisib once daily for 8 weeks followed by either 20 mg parsaclisib once weekly or 2.5 mg parsaclisib once daily. Among BTK inhibitor–naive patients who received parsaclisib once daily, 70.1% (95% CI 58.6%-80.0%) and 15.6% (95% CI 8.3%-25.6%) achieved an objective response and a complete response, respectively, with the median duration of response being 12.1 months (95% CI 9.0 to not evaluable). Responses were not thought to be clinically meaningful in the patients treated with prior BTK inhibitors. Most treatment-emergent adverse events were low grade and manageable by dose interruptions or reductions. A total of 30% of patients required drug discontinuation due to adverse events. Though parsaclisib demonstrated activity in patients with relapsed/refractory MCL, the role of this drug in clinical practice is not clear given the increased use of BTK inhibitors as a preferred second-line therapy and ongoing concerns regarding PI3K inhibitor-related toxicity.

Additional References

1.      Wang Y, Jain P, Locke FL, et al. Brexucabtagene autoleucel for relapsed or refractory mantle cell lymphoma in standard-of-care practice: Results from the US Lymphoma CAR T Consortium. J Clin Oncol. 2023;41:2594-2606. doi: 10.1200/JCO.22.01797

2.      Rejeski K, Perez A, Sesques P, et al. CAR-HEMATOTOX: A model for CAR T-cell-related hematologic toxicity in relapsed/refractory large B-cell lymphoma. Blood. 2021;138:2499-2513. doi: 10.1182/blood.2020010543

3.      Forero-Torres A, Ramchandren R, Yacoub A, et al. Parsaclisib, a potent and highly selective PI3Kδ inhibitor, in patients with relapsed or refractory B-cell malignancies. Blood. 2019;133:1742-1752. doi: 10.1182/blood-2018-08-867499

The treatment of mantle cell lymphoma (MCL) continues to evolve. In the front-line setting, studies are evaluating the role of novel therapies as well as consolidation with autologous stem cell transplantation. In the relapsed/refractory setting, patients can be considered for treatment with Bruton tyrosine kinase (BTK) inhibitors, other targeted therapies, or chimeric antigen receptor (CAR) T-cell therapy. Other novel therapies, including bispecific antibodies and novel antibody drug conjugates, are being studied as well.

Despite the availability of novel agents, a subset of patients continues to have difficult-to-treat disease and a poor prognosis. Established prognostic tools that aid in identifying high-risk patients include alternations in TP53, high proliferation rates, nonclassic morphology, and the Mantle Cell Lymphoma International Prognostic Index (MIPI) score, which incorporates age, performance status, lactate dehydrogenase levels, and white blood cell count. The Nordic study group recently published a paper which provides additional prognostic information beyond these known variables (Rodrigues et al). They examined MYC expression in a cohort of 251 patients with MCL and structural aberrations in MYC and MYC mRNA levels in a smaller cohort. They found that patients with tumors comprising 20% or more cells with MYC overexpression (MYC^high tumors) vs MYC^low tumors had significantly higher risks for death (adjusted hazard ratio [aHR] 2.03; P = .007) and disease progression (aHR 2.20; P = .04), when adjusted for additional high-risk features. Patients with tumors with concomitant MYC^high expression and TP53/p53 alterations vs MYC^low tumors had a particularly poor prognosis, with significantly increased risks for progression (HR 16.90) and death (HR 7.83) with a median overall survival of only 0.9 years (both P < .001). Though MYC overexpression was rare, this study identified a high-risk group of patients, especially those harboring concurrent TP53 aberrations, that may benefit from novel treatment approaches.

Another study recently aimed to identify patients who are at risk for poor outcomes after treatment with brexucabtagene autoleucel (brexu-cel) infusion. Though brexu-cel is an active therapy for patients with relapsed/refractory MCL, there are known toxicities, including cytokine release syndrome, neurologic toxicity, and hematologic toxicity. Given the potential for prolonged cytopenias and immune suppression, patients are also at risk for severe infections, which currently represent the driving determinant of nonrelapse mortality.¹ The CAR-HEMATOTOX (HT) score was previously found to identify patients who are at increased risk for hematologic toxicity after CAR T-cell therapy in diffuse large B-cell lymphoma.² In the current multicenter observational study, which included 103 patients receiving brexu-cel, the authors reported an association between baseline HT score and outcome in MCL as well. Patients with high (2-7) vs low (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 (aHR 3.7; P < .001) and overall (aHR 5.6; P = .002) survival. This tool may provide a helpful guide when counseling patients on treatment options and allow for more personalized toxicity management.

Despite availability of BTK inhibitors and CAR T-cell therapy for patients with MCL, relapses remain common. As upregulation of phosphoinositide 3-kinase (PI3K) is known to play a critical role in lymphomagenesis, there has been interest in targeting this pathway across lymphoma subtypes. Though PI3K inhibitors have been found to be active agents, they have also been associated with poor tolerability and safety concerns. Parsaclisib is a selective PI3K delta inhibitor that showed encouraging data in the phase 1/2 study in patients with non-Hodgkin lymphoma.³ More recently, the phase 2 CITADEL-205 study, which included adult patients with relapsed or refractory MCL previously treated with one to three systemic therapies, with (n = 53) or without (n = 108) prior BTK inhibitor treatment, was published (Zinazni et al). Patients received 20 mg parsaclisib once daily for 8 weeks followed by either 20 mg parsaclisib once weekly or 2.5 mg parsaclisib once daily. Among BTK inhibitor–naive patients who received parsaclisib once daily, 70.1% (95% CI 58.6%-80.0%) and 15.6% (95% CI 8.3%-25.6%) achieved an objective response and a complete response, respectively, with the median duration of response being 12.1 months (95% CI 9.0 to not evaluable). Responses were not thought to be clinically meaningful in the patients treated with prior BTK inhibitors. Most treatment-emergent adverse events were low grade and manageable by dose interruptions or reductions. A total of 30% of patients required drug discontinuation due to adverse events. Though parsaclisib demonstrated activity in patients with relapsed/refractory MCL, the role of this drug in clinical practice is not clear given the increased use of BTK inhibitors as a preferred second-line therapy and ongoing concerns regarding PI3K inhibitor-related toxicity.

Additional References

1.      Wang Y, Jain P, Locke FL, et al. Brexucabtagene autoleucel for relapsed or refractory mantle cell lymphoma in standard-of-care practice: Results from the US Lymphoma CAR T Consortium. J Clin Oncol. 2023;41:2594-2606. doi: 10.1200/JCO.22.01797

2.      Rejeski K, Perez A, Sesques P, et al. CAR-HEMATOTOX: A model for CAR T-cell-related hematologic toxicity in relapsed/refractory large B-cell lymphoma. Blood. 2021;138:2499-2513. doi: 10.1182/blood.2020010543

3.      Forero-Torres A, Ramchandren R, Yacoub A, et al. Parsaclisib, a potent and highly selective PI3Kδ inhibitor, in patients with relapsed or refractory B-cell malignancies. Blood. 2019;133:1742-1752. doi: 10.1182/blood-2018-08-867499

The treatment of mantle cell lymphoma (MCL) continues to evolve. In the front-line setting, studies are evaluating the role of novel therapies as well as consolidation with autologous stem cell transplantation. In the relapsed/refractory setting, patients can be considered for treatment with Bruton tyrosine kinase (BTK) inhibitors, other targeted therapies, or chimeric antigen receptor (CAR) T-cell therapy. Other novel therapies, including bispecific antibodies and novel antibody drug conjugates, are being studied as well.

Despite the availability of novel agents, a subset of patients continues to have difficult-to-treat disease and a poor prognosis. Established prognostic tools that aid in identifying high-risk patients include alternations in TP53, high proliferation rates, nonclassic morphology, and the Mantle Cell Lymphoma International Prognostic Index (MIPI) score, which incorporates age, performance status, lactate dehydrogenase levels, and white blood cell count. The Nordic study group recently published a paper which provides additional prognostic information beyond these known variables (Rodrigues et al). They examined MYC expression in a cohort of 251 patients with MCL and structural aberrations in MYC and MYC mRNA levels in a smaller cohort. They found that patients with tumors comprising 20% or more cells with MYC overexpression (MYC^high tumors) vs MYC^low tumors had significantly higher risks for death (adjusted hazard ratio [aHR] 2.03; P = .007) and disease progression (aHR 2.20; P = .04), when adjusted for additional high-risk features. Patients with tumors with concomitant MYC^high expression and TP53/p53 alterations vs MYC^low tumors had a particularly poor prognosis, with significantly increased risks for progression (HR 16.90) and death (HR 7.83) with a median overall survival of only 0.9 years (both P < .001). Though MYC overexpression was rare, this study identified a high-risk group of patients, especially those harboring concurrent TP53 aberrations, that may benefit from novel treatment approaches.

Another study recently aimed to identify patients who are at risk for poor outcomes after treatment with brexucabtagene autoleucel (brexu-cel) infusion. Though brexu-cel is an active therapy for patients with relapsed/refractory MCL, there are known toxicities, including cytokine release syndrome, neurologic toxicity, and hematologic toxicity. Given the potential for prolonged cytopenias and immune suppression, patients are also at risk for severe infections, which currently represent the driving determinant of nonrelapse mortality.¹ The CAR-HEMATOTOX (HT) score was previously found to identify patients who are at increased risk for hematologic toxicity after CAR T-cell therapy in diffuse large B-cell lymphoma.² In the current multicenter observational study, which included 103 patients receiving brexu-cel, the authors reported an association between baseline HT score and outcome in MCL as well. Patients with high (2-7) vs low (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 (aHR 3.7; P < .001) and overall (aHR 5.6; P = .002) survival. This tool may provide a helpful guide when counseling patients on treatment options and allow for more personalized toxicity management.

Despite availability of BTK inhibitors and CAR T-cell therapy for patients with MCL, relapses remain common. As upregulation of phosphoinositide 3-kinase (PI3K) is known to play a critical role in lymphomagenesis, there has been interest in targeting this pathway across lymphoma subtypes. Though PI3K inhibitors have been found to be active agents, they have also been associated with poor tolerability and safety concerns. Parsaclisib is a selective PI3K delta inhibitor that showed encouraging data in the phase 1/2 study in patients with non-Hodgkin lymphoma.³ More recently, the phase 2 CITADEL-205 study, which included adult patients with relapsed or refractory MCL previously treated with one to three systemic therapies, with (n = 53) or without (n = 108) prior BTK inhibitor treatment, was published (Zinazni et al). Patients received 20 mg parsaclisib once daily for 8 weeks followed by either 20 mg parsaclisib once weekly or 2.5 mg parsaclisib once daily. Among BTK inhibitor–naive patients who received parsaclisib once daily, 70.1% (95% CI 58.6%-80.0%) and 15.6% (95% CI 8.3%-25.6%) achieved an objective response and a complete response, respectively, with the median duration of response being 12.1 months (95% CI 9.0 to not evaluable). Responses were not thought to be clinically meaningful in the patients treated with prior BTK inhibitors. Most treatment-emergent adverse events were low grade and manageable by dose interruptions or reductions. A total of 30% of patients required drug discontinuation due to adverse events. Though parsaclisib demonstrated activity in patients with relapsed/refractory MCL, the role of this drug in clinical practice is not clear given the increased use of BTK inhibitors as a preferred second-line therapy and ongoing concerns regarding PI3K inhibitor-related toxicity.

Additional References

1.      Wang Y, Jain P, Locke FL, et al. Brexucabtagene autoleucel for relapsed or refractory mantle cell lymphoma in standard-of-care practice: Results from the US Lymphoma CAR T Consortium. J Clin Oncol. 2023;41:2594-2606. doi: 10.1200/JCO.22.01797

2.      Rejeski K, Perez A, Sesques P, et al. CAR-HEMATOTOX: A model for CAR T-cell-related hematologic toxicity in relapsed/refractory large B-cell lymphoma. Blood. 2021;138:2499-2513. doi: 10.1182/blood.2020010543

3.      Forero-Torres A, Ramchandren R, Yacoub A, et al. Parsaclisib, a potent and highly selective PI3Kδ inhibitor, in patients with relapsed or refractory B-cell malignancies. Blood. 2019;133:1742-1752. doi: 10.1182/blood-2018-08-867499