Commentary: Updates on the Treatment of Mantle Cell Lymphoma, April 2023

Mantle cell lymphoma (MCL) is an uncommon subtype of non-Hodgkin lymphoma (NHL) that is clinically heterogeneous, ranging from indolent to aggressive in nature. As with other subtypes of NHL, the treatment landscape is rapidly evolving.

Chemoimmunotherapy remains the standard first-line therapy for younger, fit patients. Although multiple induction regimens are used in this setting, it is typical to use a cytarabine-containing approach. Recently, the long-term analysis of the MCL Younger trial continued to demonstrate improved outcomes with this strategy.¹ This phase 3 study included 497 patients aged ≥ 18 to < 66 years with previously untreated MCL who were randomly assigned to R-CHOP (cyclophosphamide, doxorubicin, prednisone, rituximab, and vincristine; n = 249) or R-DHAP (rituximab, dexamethasone, cytarabine, cisplatin; n = 248). After a median follow-up of 10.6 years, the R-DHAP vs R-CHOP arm continued to have a significantly longer time to treatment failure (hazard ratio [HR] 0.59; P = .038) and overall survival (Mantle Cell Lymphoma International Prognostic Index + Ki-67–adjusted HR 0.60; P = .0066).

Following chemoimmunotherapy, treatment for this patient population typically consists of consolidation with autologous stem cell transplantation (ASCT) and maintenance rituximab.² Recently, the role of ASCT has been called into question.³ Preliminary data from the phase 3 TRIANGLE study demonstrated improvement in outcomes when the Bruton tyrosine kinase (BTK) inhibitor ibrutinib was added to chemoimmunotherapy, regardless of whether patients received ASCT.⁴ Additional studies evaluating the role of transplantation, particularly among patients who are minimal residual disease negative after chemoimmunotherapy, are ongoing (NCT03267433).

Options continue to expand in the relapsed/refractory setting. The chimeric antigen receptor (CAR) T-cell therapy, brexucabtagene autoleucel (brexu-cel), was approved by the US Food and Drug Administration for relapsed/refractory MCL on the basis of the results of the ZUMA-2 study.⁵ Recently, a multicenter, retrospective study demonstrated promising efficacy in the real world as well (Wang et al). This study was performed across 16 medical centers and included 189 patients with relapsed/refractory MCL who underwent leukapheresis for commercial manufacturing of brexu-cel, of which 168 received brexu-cel infusion. Of all patients receiving leukapheresis, 149 (79%) would not have met the eligibility criteria for ZUMA-2. At a median follow-up of 14.3 months after infusion, the best overall and complete response rates were 90% and 82%, respectively. The 6- and 12-month progression-free survival (PFS) rates were 69% (95% CI 61%-75%) and 59% (95% CI 51%-66%), respectively. This approach, however, was associated with significant toxicity, with a nonrelapse mortality rate of 9.1% at 1 year, primarily because of infections. The grade ≥ 3 cytokine release syndrome and neurotoxicity rates were 8% and 32%, respectively. Despite risks, this study confirms the role of CAR T-cell therapy for patients with relapsed/refractory MCL.

Other options in the relapsed setting include BTK and anti-apoptotic protein B-cell lymphoma (BCL-2) inhibitors. Although venetoclax, a BCL-2 inhibitor, has demonstrated activity in MCL in early-phase clinical trials, the role of this drug in clinical practice remains unclear.^6,7 A recent multicenter, retrospective study evaluated the use of venetoclax in 81 adult patients with relapsed/refractory MCL, most of whom were heavily pretreated (median of three prior treatments) and had high-risk features, including high Ki-67 and TP53 alterations, who received venetoclax without (n = 50) or with (n = 31) other agents (Sawalha et al). In this study, venetoclax resulted in a good overall response rate (ORR) but short PFS. At a median follow-up of 16.4 months, patients had a median PFS and overall survival of 3.7 months (95% CI 2.3-5.6) and 12.5 months (95% CI 6.2-28.2), respectively, and an ORR of 40%. Studies of venetoclax in earlier lines of therapy and in combination with other agents are ongoing. There may also be a role for this treatment as a bridge to more definitive therapies, including CAR T-cell therapy or allogeneic stem cell transplantation. Other studies that are evaluating the role of bispecific antibodies and antibody drug conjugates are also underway, suggesting the potential for additional options in this patient population.

Additional References

1.         Hermine O, Jiang L, Walewski J, et al. High-dose cytarabine and autologous stem-cell transplantation in mantle cell lymphoma: Long-term follow-up of the randomized Mantle Cell Lymphoma Younger Trial of the European Mantle Cell Lymphoma Network. J Clin Oncol. 2023;41:479-484. doi: 10.1200/JCO.22.01780

2.         Le Gouill S, Thieblemont C, Oberic L, et al. Rituximab after autologous stem-cell transplantation in mantle-cell lymphoma. N Engl J Med. 2017;377:1250-1260. doi: 10.1056/NEJMoa1701769

3.         Martin P, Cohen JB, Wang M, et al. Treatment outcomes and roles of transplantation and maintenance rituximab in patients with previously untreated mantle cell lymphoma: Results from large real-world cohorts. J Clin Oncol. 2023;41:541-554. doi: 10.1200/JCO.21.02698

4.         Dreyling M, Doorduijn JK, Gine E, et al. Efficacy and safety of ibrutinib combined with standard first-line treatment or as substitute for autologous stem cell transplantation in younger patients with mantle cell lymphoma: Results from the randomized Triangle Trial by the European MCL Network. Blood. 2022;140(Suppl 1):1-3. doi: 10.1182/blood-2022-163018

5.         Wang M, Munoz J, Goy A, et al. KTE-X19 CAR T-Cell therapy in relapsed or refractory mantle-cell lymphoma. N Engl J Med. 2020;382:1331-1342. doi: 10.1056/NEJMoa1914347

6.         Davids MS, Roberts AW, Seymour JF, et al. Phase I first-in-human study of venetoclax in patients with relapsed or refractory non-Hodgkin lymphoma. J Clin Oncol. 2017;35:826-833. doi: 10.1200/JCO.2016.70.4320

7.         Tam CS, Anderson MA, Pott C, et al. Ibrutinib plus venetoclax for the treatment of mantle-cell lymphoma. N Engl J Med. 2018;378:1211-1223. doi: 10.1056/NEJMoa1715519

Mantle cell lymphoma (MCL) is an uncommon subtype of non-Hodgkin lymphoma (NHL) that is clinically heterogeneous, ranging from indolent to aggressive in nature. As with other subtypes of NHL, the treatment landscape is rapidly evolving.

Chemoimmunotherapy remains the standard first-line therapy for younger, fit patients. Although multiple induction regimens are used in this setting, it is typical to use a cytarabine-containing approach. Recently, the long-term analysis of the MCL Younger trial continued to demonstrate improved outcomes with this strategy.¹ This phase 3 study included 497 patients aged ≥ 18 to < 66 years with previously untreated MCL who were randomly assigned to R-CHOP (cyclophosphamide, doxorubicin, prednisone, rituximab, and vincristine; n = 249) or R-DHAP (rituximab, dexamethasone, cytarabine, cisplatin; n = 248). After a median follow-up of 10.6 years, the R-DHAP vs R-CHOP arm continued to have a significantly longer time to treatment failure (hazard ratio [HR] 0.59; P = .038) and overall survival (Mantle Cell Lymphoma International Prognostic Index + Ki-67–adjusted HR 0.60; P = .0066).

Following chemoimmunotherapy, treatment for this patient population typically consists of consolidation with autologous stem cell transplantation (ASCT) and maintenance rituximab.² Recently, the role of ASCT has been called into question.³ Preliminary data from the phase 3 TRIANGLE study demonstrated improvement in outcomes when the Bruton tyrosine kinase (BTK) inhibitor ibrutinib was added to chemoimmunotherapy, regardless of whether patients received ASCT.⁴ Additional studies evaluating the role of transplantation, particularly among patients who are minimal residual disease negative after chemoimmunotherapy, are ongoing (NCT03267433).

Options continue to expand in the relapsed/refractory setting. The chimeric antigen receptor (CAR) T-cell therapy, brexucabtagene autoleucel (brexu-cel), was approved by the US Food and Drug Administration for relapsed/refractory MCL on the basis of the results of the ZUMA-2 study.⁵ Recently, a multicenter, retrospective study demonstrated promising efficacy in the real world as well (Wang et al). This study was performed across 16 medical centers and included 189 patients with relapsed/refractory MCL who underwent leukapheresis for commercial manufacturing of brexu-cel, of which 168 received brexu-cel infusion. Of all patients receiving leukapheresis, 149 (79%) would not have met the eligibility criteria for ZUMA-2. At a median follow-up of 14.3 months after infusion, the best overall and complete response rates were 90% and 82%, respectively. The 6- and 12-month progression-free survival (PFS) rates were 69% (95% CI 61%-75%) and 59% (95% CI 51%-66%), respectively. This approach, however, was associated with significant toxicity, with a nonrelapse mortality rate of 9.1% at 1 year, primarily because of infections. The grade ≥ 3 cytokine release syndrome and neurotoxicity rates were 8% and 32%, respectively. Despite risks, this study confirms the role of CAR T-cell therapy for patients with relapsed/refractory MCL.

Other options in the relapsed setting include BTK and anti-apoptotic protein B-cell lymphoma (BCL-2) inhibitors. Although venetoclax, a BCL-2 inhibitor, has demonstrated activity in MCL in early-phase clinical trials, the role of this drug in clinical practice remains unclear.^6,7 A recent multicenter, retrospective study evaluated the use of venetoclax in 81 adult patients with relapsed/refractory MCL, most of whom were heavily pretreated (median of three prior treatments) and had high-risk features, including high Ki-67 and TP53 alterations, who received venetoclax without (n = 50) or with (n = 31) other agents (Sawalha et al). In this study, venetoclax resulted in a good overall response rate (ORR) but short PFS. At a median follow-up of 16.4 months, patients had a median PFS and overall survival of 3.7 months (95% CI 2.3-5.6) and 12.5 months (95% CI 6.2-28.2), respectively, and an ORR of 40%. Studies of venetoclax in earlier lines of therapy and in combination with other agents are ongoing. There may also be a role for this treatment as a bridge to more definitive therapies, including CAR T-cell therapy or allogeneic stem cell transplantation. Other studies that are evaluating the role of bispecific antibodies and antibody drug conjugates are also underway, suggesting the potential for additional options in this patient population.

Additional References

1.         Hermine O, Jiang L, Walewski J, et al. High-dose cytarabine and autologous stem-cell transplantation in mantle cell lymphoma: Long-term follow-up of the randomized Mantle Cell Lymphoma Younger Trial of the European Mantle Cell Lymphoma Network. J Clin Oncol. 2023;41:479-484. doi: 10.1200/JCO.22.01780

2.         Le Gouill S, Thieblemont C, Oberic L, et al. Rituximab after autologous stem-cell transplantation in mantle-cell lymphoma. N Engl J Med. 2017;377:1250-1260. doi: 10.1056/NEJMoa1701769

3.         Martin P, Cohen JB, Wang M, et al. Treatment outcomes and roles of transplantation and maintenance rituximab in patients with previously untreated mantle cell lymphoma: Results from large real-world cohorts. J Clin Oncol. 2023;41:541-554. doi: 10.1200/JCO.21.02698

4.         Dreyling M, Doorduijn JK, Gine E, et al. Efficacy and safety of ibrutinib combined with standard first-line treatment or as substitute for autologous stem cell transplantation in younger patients with mantle cell lymphoma: Results from the randomized Triangle Trial by the European MCL Network. Blood. 2022;140(Suppl 1):1-3. doi: 10.1182/blood-2022-163018

5.         Wang M, Munoz J, Goy A, et al. KTE-X19 CAR T-Cell therapy in relapsed or refractory mantle-cell lymphoma. N Engl J Med. 2020;382:1331-1342. doi: 10.1056/NEJMoa1914347

6.         Davids MS, Roberts AW, Seymour JF, et al. Phase I first-in-human study of venetoclax in patients with relapsed or refractory non-Hodgkin lymphoma. J Clin Oncol. 2017;35:826-833. doi: 10.1200/JCO.2016.70.4320

7.         Tam CS, Anderson MA, Pott C, et al. Ibrutinib plus venetoclax for the treatment of mantle-cell lymphoma. N Engl J Med. 2018;378:1211-1223. doi: 10.1056/NEJMoa1715519

Mantle cell lymphoma (MCL) is an uncommon subtype of non-Hodgkin lymphoma (NHL) that is clinically heterogeneous, ranging from indolent to aggressive in nature. As with other subtypes of NHL, the treatment landscape is rapidly evolving.

Chemoimmunotherapy remains the standard first-line therapy for younger, fit patients. Although multiple induction regimens are used in this setting, it is typical to use a cytarabine-containing approach. Recently, the long-term analysis of the MCL Younger trial continued to demonstrate improved outcomes with this strategy.¹ This phase 3 study included 497 patients aged ≥ 18 to < 66 years with previously untreated MCL who were randomly assigned to R-CHOP (cyclophosphamide, doxorubicin, prednisone, rituximab, and vincristine; n = 249) or R-DHAP (rituximab, dexamethasone, cytarabine, cisplatin; n = 248). After a median follow-up of 10.6 years, the R-DHAP vs R-CHOP arm continued to have a significantly longer time to treatment failure (hazard ratio [HR] 0.59; P = .038) and overall survival (Mantle Cell Lymphoma International Prognostic Index + Ki-67–adjusted HR 0.60; P = .0066).

Following chemoimmunotherapy, treatment for this patient population typically consists of consolidation with autologous stem cell transplantation (ASCT) and maintenance rituximab.² Recently, the role of ASCT has been called into question.³ Preliminary data from the phase 3 TRIANGLE study demonstrated improvement in outcomes when the Bruton tyrosine kinase (BTK) inhibitor ibrutinib was added to chemoimmunotherapy, regardless of whether patients received ASCT.⁴ Additional studies evaluating the role of transplantation, particularly among patients who are minimal residual disease negative after chemoimmunotherapy, are ongoing (NCT03267433).

Options continue to expand in the relapsed/refractory setting. The chimeric antigen receptor (CAR) T-cell therapy, brexucabtagene autoleucel (brexu-cel), was approved by the US Food and Drug Administration for relapsed/refractory MCL on the basis of the results of the ZUMA-2 study.⁵ Recently, a multicenter, retrospective study demonstrated promising efficacy in the real world as well (Wang et al). This study was performed across 16 medical centers and included 189 patients with relapsed/refractory MCL who underwent leukapheresis for commercial manufacturing of brexu-cel, of which 168 received brexu-cel infusion. Of all patients receiving leukapheresis, 149 (79%) would not have met the eligibility criteria for ZUMA-2. At a median follow-up of 14.3 months after infusion, the best overall and complete response rates were 90% and 82%, respectively. The 6- and 12-month progression-free survival (PFS) rates were 69% (95% CI 61%-75%) and 59% (95% CI 51%-66%), respectively. This approach, however, was associated with significant toxicity, with a nonrelapse mortality rate of 9.1% at 1 year, primarily because of infections. The grade ≥ 3 cytokine release syndrome and neurotoxicity rates were 8% and 32%, respectively. Despite risks, this study confirms the role of CAR T-cell therapy for patients with relapsed/refractory MCL.

Other options in the relapsed setting include BTK and anti-apoptotic protein B-cell lymphoma (BCL-2) inhibitors. Although venetoclax, a BCL-2 inhibitor, has demonstrated activity in MCL in early-phase clinical trials, the role of this drug in clinical practice remains unclear.^6,7 A recent multicenter, retrospective study evaluated the use of venetoclax in 81 adult patients with relapsed/refractory MCL, most of whom were heavily pretreated (median of three prior treatments) and had high-risk features, including high Ki-67 and TP53 alterations, who received venetoclax without (n = 50) or with (n = 31) other agents (Sawalha et al). In this study, venetoclax resulted in a good overall response rate (ORR) but short PFS. At a median follow-up of 16.4 months, patients had a median PFS and overall survival of 3.7 months (95% CI 2.3-5.6) and 12.5 months (95% CI 6.2-28.2), respectively, and an ORR of 40%. Studies of venetoclax in earlier lines of therapy and in combination with other agents are ongoing. There may also be a role for this treatment as a bridge to more definitive therapies, including CAR T-cell therapy or allogeneic stem cell transplantation. Other studies that are evaluating the role of bispecific antibodies and antibody drug conjugates are also underway, suggesting the potential for additional options in this patient population.

Additional References

1.         Hermine O, Jiang L, Walewski J, et al. High-dose cytarabine and autologous stem-cell transplantation in mantle cell lymphoma: Long-term follow-up of the randomized Mantle Cell Lymphoma Younger Trial of the European Mantle Cell Lymphoma Network. J Clin Oncol. 2023;41:479-484. doi: 10.1200/JCO.22.01780

2.         Le Gouill S, Thieblemont C, Oberic L, et al. Rituximab after autologous stem-cell transplantation in mantle-cell lymphoma. N Engl J Med. 2017;377:1250-1260. doi: 10.1056/NEJMoa1701769

3.         Martin P, Cohen JB, Wang M, et al. Treatment outcomes and roles of transplantation and maintenance rituximab in patients with previously untreated mantle cell lymphoma: Results from large real-world cohorts. J Clin Oncol. 2023;41:541-554. doi: 10.1200/JCO.21.02698

4.         Dreyling M, Doorduijn JK, Gine E, et al. Efficacy and safety of ibrutinib combined with standard first-line treatment or as substitute for autologous stem cell transplantation in younger patients with mantle cell lymphoma: Results from the randomized Triangle Trial by the European MCL Network. Blood. 2022;140(Suppl 1):1-3. doi: 10.1182/blood-2022-163018

5.         Wang M, Munoz J, Goy A, et al. KTE-X19 CAR T-Cell therapy in relapsed or refractory mantle-cell lymphoma. N Engl J Med. 2020;382:1331-1342. doi: 10.1056/NEJMoa1914347

6.         Davids MS, Roberts AW, Seymour JF, et al. Phase I first-in-human study of venetoclax in patients with relapsed or refractory non-Hodgkin lymphoma. J Clin Oncol. 2017;35:826-833. doi: 10.1200/JCO.2016.70.4320

7.         Tam CS, Anderson MA, Pott C, et al. Ibrutinib plus venetoclax for the treatment of mantle-cell lymphoma. N Engl J Med. 2018;378:1211-1223. doi: 10.1056/NEJMoa1715519