Emerging Treatment Options for Mantle Cell Lymphoma

Mantle cell lymphoma (MCL) is a rare, B-cell non-Hodgkin lymphoma whose biological heterogeneity has long challenged researchers and clinicians. There are no firmly-established therapies, and many individuals experience relapse even after successful treatment. There is a clear unmet need in MCL in the relapsed setting. In recent years, researchers have worked to address this need, demonstrating efficacy with covalent Bruton tyrosine kinase (BTK) inhibitors, led by ibrutinib, and anti-CD19 chimeric antigen receptor T-cell therapy. While these are helpful additions, relapse remains a challenge. 

Fortunately, progress continues. Owing to encouraging results in recent trials, individuals with relapsed/refractory MCL are now experiencing clinical benefit from the noncovalent BTK inhibitor pirtrobrutinib. Investigational bispecific antibody (bsAb) therapy awaits in the wings. 

Similarly, both younger and older patients with treatment naïve MCL could soon see improvement from the addition of BTK inhibitors to each age group’s standard treatment option. The following is a description of recent developments and their potential implications for practice.  

One of the most exciting developments is the US Food and Drug Administration’s accelerated approval of pirtrobrutinib. A noncovalent BTK inhibitor, pirtrobrutinib has been found to have activity in individuals with MCL who have failed on multiple therapies, including standard BTK inhibitors. Pirtrobrutinib targets certain mutations in the BTK protein that are associated with resistance to covalent BTK inhibitors. In addition to resistance, some patients discontinue treatment with non-reversible BTK inhibitors because of intolerable toxicity. 

Approval of pirtrobrutinib was based on an evaluation involving 120 individuals (median age 71) who were previously treated with a non-reversible BTK inhibitor. Two-thirds were previously treated with ibrutinib; 30% with acalabrutinib, and 8% zanubrutinib (some received more than one BTK inhibitor previously). The vast majority (83%) discontinued treatment due to refractory or progressive disease; 10% stopped due to toxicity; and the remainder halted treatment for other reasons. 

Six in every 10 of the participants were classified on the MCL International Prognostic Index as intermediate; one-fourth were classified as high; and the remainder low. Patients received 200 mg of pirtrobrutinib once a day until disease either progressed or they experienced intolerable toxicity. Among the results:

• Overall response rate was 50%; 13% responded completely

• Median duration of response was 8.3 months

• Duration of response rate at 6 months was 65%

• Grade 3 or 4 abnormalities experienced by 10% or more of participants included decreased neutrophil counts, lymphocyte counts, and platelet counts

Further, bsAb therapy targeting CD20-CD3 is not yet approved but is showing promise as a potential therapy following BTK inhibitor failure. The treatment consists of an antibody containing two prongs. One is a CD20 protein that attaches to the lymphoma cell. The other is an anti-CD3 antibody that attaches to the T cell to bring the patient’s own T cells closer to the lymphoma to increase the cell kill. 

Preliminary studies evaluating bsAbs in individuals with MCL, many of whom have failed on multiple other types of therapies, show a remarkably high response rate. In one such investigation, the bsAb glofitamab was given to 21 individuals as monotherapy following pretreatment with obinutuzumab. The regimen produced an overall response rate of 81% (n = 17) and a complete response rate of 68% (n = 14). Response was similar in participants who had and had not received prior BTK therapy. Among those who achieved a complete response, median duration was 2.4 months, and 12 of those who reached a complete response were still in remission at the study’s data cutoff point. 

For younger individuals with treatment-naïve MCL, the current standard is chemotherapy and autologous stem-cell transplant (ASCT). For older individuals the standard is chemoimmunotherapy. The replacement or addition of the BTK inhibitor ibrutinib to these regimens is showing the promise of added clinical benefit in both age contingents. 

Investigators presented results of the three-arm TRIANGLE trial at the 64th ASH Annual Meeting in December 2022. The study compared 1) chemotherapy followed by ASCT; 2) ibrutinib plus chemotherapy followed by ASCT and ibrutinib maintenance; and 3) ibrutinib plus chemotherapy followed by ibrutinib maintenance. Participants (n = 870) ≤ 65 years of age (median age 57) with previously untreated advanced-stage MCL were randomized to 1 of the 3 regimens. Investigators looked at overall response, complete response, and failure-free survival rates (FFS). Among the results: 

• Overall response rates were 98% in the 2 groups whose treatments included ibrutinib, versus 94% in the chemotherapy followed by ASCT group. 

• Complete response rates were 45% and 36%, respectively.

• The non-ibrutinib regimen did not attain FFS superiority over ibrutinib plus chemotherapy, with a 3-year FFS rate of 72% and 86%, respectively (p=0.9979, hazard ratio [HR]: 1.77).

• Ibrutinib plus chemotherapy was shown to be superior to chemotherapy/ASCT, with a 3-year FFS rate of 88% and 72%, respectively (p=0.0008, HR: 0.52).

• The only adverse event differences of note occurred during maintenance treatment; there were significantly more grade 3-5 adverse events in the ibrutinib/chemotherapy/ASCT group, compared with the other 2 contingents.

Researchers noted in materials accompanying their presentation that, “It has been clearly demonstrated that the current standard high-dose regimen is not superior to the new ibrutinib-containing regimen without ASCT. More follow-up is needed to clarify the role of ASCT in the context of ibrutinib-containing treatment. However, the current results already support the use of ibrutinib in the first-line treatment of younger MCL patients.”

It also appears that ibrutinib added to standard chemoimmunotherapy can improve outcomes in older individuals with treatment-naïve MCL. In 2022, researchers published results from the international, randomized, double-blind, phase 3 SHINE trial. Participants (n = 523) were ≥ 65 years of age with previously untreated MCL and were randomized to receive either ibrutinib 560 mg daily or placebo added to chemoimmunotherapy consisting of bendamustine and rituximab every 4 weeks for 6 cycles. Individuals with a partial or complete response continued treatment every 8 weeks for up to 12 more doses. Investigators looked primarily at progression-free survival (PFS), as well as complete response, undetectable minimal residual disease, and time to worsening. Among the results: 

• 116 participants (44%) in the ibrutinib group experienced disease progression or died, compared with 152 (58%) in the placebo contingent. 

• Median PFS was 80.6 months and 52.9 months, respectively.

• PFS benefit was seen across most subgroups (patients categorized as high risk, and those with TP53 mutations did not benefit).

• Complete response was seen in 66% and 58% of participants, respectively.

• Undetectable minimal residual disease was observed in 62% and 57%, respectively.

• Deaths attributed to disease progression or adverse events occurred in 22% and 28%, respectively.

• Grade 3 or 4 adverse event incident rates were 82% and 77%, respectively.

Researchers noted that, “Given the shorter progression-free survival with current standard-care chemoimmunotherapy options, a prolongation of progression-free survival in response to primary therapy may provide patients with an improved opportunity for durable disease control in order to prevent or delay relapse.”

Data on the use of other BTK inhibitors as first-line treatment for MCL are forthcoming, including: 

• ECHO, a phase 3 trial assessing the efficacy of acalabrutinib versus placebo added to bendamustine and rituximab.

• MANGROVE, a phase 3 study comparing zanubrutinib plus rituximab versus bendamustine plus rituximab.

• ENRICH, a phase 2 study evaluating a chemotherapy-free option–ibrutinib and rituximab in older individuals.

• OASIS, a randomized, phase 2 trial comparing ibrutinib/anti-CD20 antibodies (Ab) and Ibrutinib/anti-CD20 Ab/venetoclax given as fixed duration combinations. 

The evolution of BTK inhibitors for relapsed MCL has great potential; further benefits continue to be explored.

Mantle cell lymphoma (MCL) is a rare, B-cell non-Hodgkin lymphoma whose biological heterogeneity has long challenged researchers and clinicians. There are no firmly-established therapies, and many individuals experience relapse even after successful treatment. There is a clear unmet need in MCL in the relapsed setting. In recent years, researchers have worked to address this need, demonstrating efficacy with covalent Bruton tyrosine kinase (BTK) inhibitors, led by ibrutinib, and anti-CD19 chimeric antigen receptor T-cell therapy. While these are helpful additions, relapse remains a challenge. 

Fortunately, progress continues. Owing to encouraging results in recent trials, individuals with relapsed/refractory MCL are now experiencing clinical benefit from the noncovalent BTK inhibitor pirtrobrutinib. Investigational bispecific antibody (bsAb) therapy awaits in the wings. 

Similarly, both younger and older patients with treatment naïve MCL could soon see improvement from the addition of BTK inhibitors to each age group’s standard treatment option. The following is a description of recent developments and their potential implications for practice.  

One of the most exciting developments is the US Food and Drug Administration’s accelerated approval of pirtrobrutinib. A noncovalent BTK inhibitor, pirtrobrutinib has been found to have activity in individuals with MCL who have failed on multiple therapies, including standard BTK inhibitors. Pirtrobrutinib targets certain mutations in the BTK protein that are associated with resistance to covalent BTK inhibitors. In addition to resistance, some patients discontinue treatment with non-reversible BTK inhibitors because of intolerable toxicity. 

Approval of pirtrobrutinib was based on an evaluation involving 120 individuals (median age 71) who were previously treated with a non-reversible BTK inhibitor. Two-thirds were previously treated with ibrutinib; 30% with acalabrutinib, and 8% zanubrutinib (some received more than one BTK inhibitor previously). The vast majority (83%) discontinued treatment due to refractory or progressive disease; 10% stopped due to toxicity; and the remainder halted treatment for other reasons. 

Six in every 10 of the participants were classified on the MCL International Prognostic Index as intermediate; one-fourth were classified as high; and the remainder low. Patients received 200 mg of pirtrobrutinib once a day until disease either progressed or they experienced intolerable toxicity. Among the results:

• Overall response rate was 50%; 13% responded completely

• Median duration of response was 8.3 months

• Duration of response rate at 6 months was 65%

• Grade 3 or 4 abnormalities experienced by 10% or more of participants included decreased neutrophil counts, lymphocyte counts, and platelet counts

Further, bsAb therapy targeting CD20-CD3 is not yet approved but is showing promise as a potential therapy following BTK inhibitor failure. The treatment consists of an antibody containing two prongs. One is a CD20 protein that attaches to the lymphoma cell. The other is an anti-CD3 antibody that attaches to the T cell to bring the patient’s own T cells closer to the lymphoma to increase the cell kill. 

Preliminary studies evaluating bsAbs in individuals with MCL, many of whom have failed on multiple other types of therapies, show a remarkably high response rate. In one such investigation, the bsAb glofitamab was given to 21 individuals as monotherapy following pretreatment with obinutuzumab. The regimen produced an overall response rate of 81% (n = 17) and a complete response rate of 68% (n = 14). Response was similar in participants who had and had not received prior BTK therapy. Among those who achieved a complete response, median duration was 2.4 months, and 12 of those who reached a complete response were still in remission at the study’s data cutoff point. 

For younger individuals with treatment-naïve MCL, the current standard is chemotherapy and autologous stem-cell transplant (ASCT). For older individuals the standard is chemoimmunotherapy. The replacement or addition of the BTK inhibitor ibrutinib to these regimens is showing the promise of added clinical benefit in both age contingents. 

Investigators presented results of the three-arm TRIANGLE trial at the 64th ASH Annual Meeting in December 2022. The study compared 1) chemotherapy followed by ASCT; 2) ibrutinib plus chemotherapy followed by ASCT and ibrutinib maintenance; and 3) ibrutinib plus chemotherapy followed by ibrutinib maintenance. Participants (n = 870) ≤ 65 years of age (median age 57) with previously untreated advanced-stage MCL were randomized to 1 of the 3 regimens. Investigators looked at overall response, complete response, and failure-free survival rates (FFS). Among the results: 

• Overall response rates were 98% in the 2 groups whose treatments included ibrutinib, versus 94% in the chemotherapy followed by ASCT group. 

• Complete response rates were 45% and 36%, respectively.

• The non-ibrutinib regimen did not attain FFS superiority over ibrutinib plus chemotherapy, with a 3-year FFS rate of 72% and 86%, respectively (p=0.9979, hazard ratio [HR]: 1.77).

• Ibrutinib plus chemotherapy was shown to be superior to chemotherapy/ASCT, with a 3-year FFS rate of 88% and 72%, respectively (p=0.0008, HR: 0.52).

• The only adverse event differences of note occurred during maintenance treatment; there were significantly more grade 3-5 adverse events in the ibrutinib/chemotherapy/ASCT group, compared with the other 2 contingents.

Researchers noted in materials accompanying their presentation that, “It has been clearly demonstrated that the current standard high-dose regimen is not superior to the new ibrutinib-containing regimen without ASCT. More follow-up is needed to clarify the role of ASCT in the context of ibrutinib-containing treatment. However, the current results already support the use of ibrutinib in the first-line treatment of younger MCL patients.”

It also appears that ibrutinib added to standard chemoimmunotherapy can improve outcomes in older individuals with treatment-naïve MCL. In 2022, researchers published results from the international, randomized, double-blind, phase 3 SHINE trial. Participants (n = 523) were ≥ 65 years of age with previously untreated MCL and were randomized to receive either ibrutinib 560 mg daily or placebo added to chemoimmunotherapy consisting of bendamustine and rituximab every 4 weeks for 6 cycles. Individuals with a partial or complete response continued treatment every 8 weeks for up to 12 more doses. Investigators looked primarily at progression-free survival (PFS), as well as complete response, undetectable minimal residual disease, and time to worsening. Among the results: 

• 116 participants (44%) in the ibrutinib group experienced disease progression or died, compared with 152 (58%) in the placebo contingent. 

• Median PFS was 80.6 months and 52.9 months, respectively.

• PFS benefit was seen across most subgroups (patients categorized as high risk, and those with TP53 mutations did not benefit).

• Complete response was seen in 66% and 58% of participants, respectively.

• Undetectable minimal residual disease was observed in 62% and 57%, respectively.

• Deaths attributed to disease progression or adverse events occurred in 22% and 28%, respectively.

• Grade 3 or 4 adverse event incident rates were 82% and 77%, respectively.

Researchers noted that, “Given the shorter progression-free survival with current standard-care chemoimmunotherapy options, a prolongation of progression-free survival in response to primary therapy may provide patients with an improved opportunity for durable disease control in order to prevent or delay relapse.”

Data on the use of other BTK inhibitors as first-line treatment for MCL are forthcoming, including: 

• ECHO, a phase 3 trial assessing the efficacy of acalabrutinib versus placebo added to bendamustine and rituximab.

• MANGROVE, a phase 3 study comparing zanubrutinib plus rituximab versus bendamustine plus rituximab.

• ENRICH, a phase 2 study evaluating a chemotherapy-free option–ibrutinib and rituximab in older individuals.

• OASIS, a randomized, phase 2 trial comparing ibrutinib/anti-CD20 antibodies (Ab) and Ibrutinib/anti-CD20 Ab/venetoclax given as fixed duration combinations. 

The evolution of BTK inhibitors for relapsed MCL has great potential; further benefits continue to be explored.

Mantle cell lymphoma (MCL) is a rare, B-cell non-Hodgkin lymphoma whose biological heterogeneity has long challenged researchers and clinicians. There are no firmly-established therapies, and many individuals experience relapse even after successful treatment. There is a clear unmet need in MCL in the relapsed setting. In recent years, researchers have worked to address this need, demonstrating efficacy with covalent Bruton tyrosine kinase (BTK) inhibitors, led by ibrutinib, and anti-CD19 chimeric antigen receptor T-cell therapy. While these are helpful additions, relapse remains a challenge. 

Fortunately, progress continues. Owing to encouraging results in recent trials, individuals with relapsed/refractory MCL are now experiencing clinical benefit from the noncovalent BTK inhibitor pirtrobrutinib. Investigational bispecific antibody (bsAb) therapy awaits in the wings. 

Similarly, both younger and older patients with treatment naïve MCL could soon see improvement from the addition of BTK inhibitors to each age group’s standard treatment option. The following is a description of recent developments and their potential implications for practice.  

One of the most exciting developments is the US Food and Drug Administration’s accelerated approval of pirtrobrutinib. A noncovalent BTK inhibitor, pirtrobrutinib has been found to have activity in individuals with MCL who have failed on multiple therapies, including standard BTK inhibitors. Pirtrobrutinib targets certain mutations in the BTK protein that are associated with resistance to covalent BTK inhibitors. In addition to resistance, some patients discontinue treatment with non-reversible BTK inhibitors because of intolerable toxicity. 

Approval of pirtrobrutinib was based on an evaluation involving 120 individuals (median age 71) who were previously treated with a non-reversible BTK inhibitor. Two-thirds were previously treated with ibrutinib; 30% with acalabrutinib, and 8% zanubrutinib (some received more than one BTK inhibitor previously). The vast majority (83%) discontinued treatment due to refractory or progressive disease; 10% stopped due to toxicity; and the remainder halted treatment for other reasons. 

Six in every 10 of the participants were classified on the MCL International Prognostic Index as intermediate; one-fourth were classified as high; and the remainder low. Patients received 200 mg of pirtrobrutinib once a day until disease either progressed or they experienced intolerable toxicity. Among the results:

• Overall response rate was 50%; 13% responded completely

• Median duration of response was 8.3 months

• Duration of response rate at 6 months was 65%

• Grade 3 or 4 abnormalities experienced by 10% or more of participants included decreased neutrophil counts, lymphocyte counts, and platelet counts

Further, bsAb therapy targeting CD20-CD3 is not yet approved but is showing promise as a potential therapy following BTK inhibitor failure. The treatment consists of an antibody containing two prongs. One is a CD20 protein that attaches to the lymphoma cell. The other is an anti-CD3 antibody that attaches to the T cell to bring the patient’s own T cells closer to the lymphoma to increase the cell kill. 

Preliminary studies evaluating bsAbs in individuals with MCL, many of whom have failed on multiple other types of therapies, show a remarkably high response rate. In one such investigation, the bsAb glofitamab was given to 21 individuals as monotherapy following pretreatment with obinutuzumab. The regimen produced an overall response rate of 81% (n = 17) and a complete response rate of 68% (n = 14). Response was similar in participants who had and had not received prior BTK therapy. Among those who achieved a complete response, median duration was 2.4 months, and 12 of those who reached a complete response were still in remission at the study’s data cutoff point. 

For younger individuals with treatment-naïve MCL, the current standard is chemotherapy and autologous stem-cell transplant (ASCT). For older individuals the standard is chemoimmunotherapy. The replacement or addition of the BTK inhibitor ibrutinib to these regimens is showing the promise of added clinical benefit in both age contingents. 

Investigators presented results of the three-arm TRIANGLE trial at the 64th ASH Annual Meeting in December 2022. The study compared 1) chemotherapy followed by ASCT; 2) ibrutinib plus chemotherapy followed by ASCT and ibrutinib maintenance; and 3) ibrutinib plus chemotherapy followed by ibrutinib maintenance. Participants (n = 870) ≤ 65 years of age (median age 57) with previously untreated advanced-stage MCL were randomized to 1 of the 3 regimens. Investigators looked at overall response, complete response, and failure-free survival rates (FFS). Among the results: 

• Overall response rates were 98% in the 2 groups whose treatments included ibrutinib, versus 94% in the chemotherapy followed by ASCT group. 

• Complete response rates were 45% and 36%, respectively.

• The non-ibrutinib regimen did not attain FFS superiority over ibrutinib plus chemotherapy, with a 3-year FFS rate of 72% and 86%, respectively (p=0.9979, hazard ratio [HR]: 1.77).

• Ibrutinib plus chemotherapy was shown to be superior to chemotherapy/ASCT, with a 3-year FFS rate of 88% and 72%, respectively (p=0.0008, HR: 0.52).

• The only adverse event differences of note occurred during maintenance treatment; there were significantly more grade 3-5 adverse events in the ibrutinib/chemotherapy/ASCT group, compared with the other 2 contingents.

Researchers noted in materials accompanying their presentation that, “It has been clearly demonstrated that the current standard high-dose regimen is not superior to the new ibrutinib-containing regimen without ASCT. More follow-up is needed to clarify the role of ASCT in the context of ibrutinib-containing treatment. However, the current results already support the use of ibrutinib in the first-line treatment of younger MCL patients.”

It also appears that ibrutinib added to standard chemoimmunotherapy can improve outcomes in older individuals with treatment-naïve MCL. In 2022, researchers published results from the international, randomized, double-blind, phase 3 SHINE trial. Participants (n = 523) were ≥ 65 years of age with previously untreated MCL and were randomized to receive either ibrutinib 560 mg daily or placebo added to chemoimmunotherapy consisting of bendamustine and rituximab every 4 weeks for 6 cycles. Individuals with a partial or complete response continued treatment every 8 weeks for up to 12 more doses. Investigators looked primarily at progression-free survival (PFS), as well as complete response, undetectable minimal residual disease, and time to worsening. Among the results: 

• 116 participants (44%) in the ibrutinib group experienced disease progression or died, compared with 152 (58%) in the placebo contingent. 

• Median PFS was 80.6 months and 52.9 months, respectively.

• PFS benefit was seen across most subgroups (patients categorized as high risk, and those with TP53 mutations did not benefit).

• Complete response was seen in 66% and 58% of participants, respectively.

• Undetectable minimal residual disease was observed in 62% and 57%, respectively.

• Deaths attributed to disease progression or adverse events occurred in 22% and 28%, respectively.

• Grade 3 or 4 adverse event incident rates were 82% and 77%, respectively.

Researchers noted that, “Given the shorter progression-free survival with current standard-care chemoimmunotherapy options, a prolongation of progression-free survival in response to primary therapy may provide patients with an improved opportunity for durable disease control in order to prevent or delay relapse.”

Data on the use of other BTK inhibitors as first-line treatment for MCL are forthcoming, including: 

• ECHO, a phase 3 trial assessing the efficacy of acalabrutinib versus placebo added to bendamustine and rituximab.

• MANGROVE, a phase 3 study comparing zanubrutinib plus rituximab versus bendamustine plus rituximab.

• ENRICH, a phase 2 study evaluating a chemotherapy-free option–ibrutinib and rituximab in older individuals.

• OASIS, a randomized, phase 2 trial comparing ibrutinib/anti-CD20 antibodies (Ab) and Ibrutinib/anti-CD20 Ab/venetoclax given as fixed duration combinations. 

The evolution of BTK inhibitors for relapsed MCL has great potential; further benefits continue to be explored.