B-Cell Lymphoma ICYMI

In a sign of the power of combination therapy for high-risk chronic lymphocytic leukemia (CLL), a small new study showed that patients were more likely to reach undetectable measurable residual disease (U-MRD) when they added venetoclax to their drug regimen after a year or more of taking ibrutinib.

Of 45 patients, 57% reached U-MRD at 12 months, and 55% reached complete remission, according to the study, published in Leukemia.

By adding venetoclax, “you can get very deep remissions in high-risk patients with ibrutinib,” lead author Philip A. Thompson, MBBS, a hematologist-oncologist with the University of Melbourne and Peter MacCallum Cancer Center, also in Melbourne, said in an interview. “This is a significant advance for really high-risk patients.”

According to Dr. Thompson, Bruton’s tyrosine kinase inhibitors like ibrutinib have revolutionized the treatment of high-risk CLL by forcing the disease into remission for several years and allowing patients to avoid stem cell transplants. “But the drug doesn’t eradicate the disease,” he said, “so eventually these patients develop progression.”

The current hope, he said, is to use a combination therapy like ibrutinib and venetoclax to send CLL into remission with lower chance of drug resistance and then allow patients to stop taking the medications.

Previous research has supported the combination of ibrutinib and venetoclax in CLL in the frontline setting, and the European Commission approved it in 2022 for that use. But “ours is the first [study] that looked at patients who’ve been on ibrutinib for a long time and added venetoclax,” Dr. Thompson said. In some cases, he said, patients in the study had been on ibrutinib for several years.

For the new study, researchers at the University of Texas MD Anderson Cancer Center in Houston – where Dr. Thompson used to work – tracked 45 patients (average age, 68.5 years; 51-80 years) with CLL or small lymphocytic lymphoma who had MRD but no clinical disease progression. They all had at least 1 high-risk feature such as a mutated TP53. They’d been on ibrutinib for a median of 32 months (12-73 months), and two were in complete remission but with MRD.

An intention-to-treat analysis found that 71% reached U-MRD when they finished taking venetoclax. “We were actually pleasantly surprised by the high rate of undetectable MRD,” Dr. Thompson said.

At a median 41-month follow-up, 11% of patients had progressed, but none had died of CLL or Richter transformation, a deadly complication of CLL. “The main side effects were neutropenia and diarrhea, which we were manageable,” Dr. Thompson said.

It’s not clear why the drug combination is especially effective, he said, but it may be because the medications are synergistic. According to the National Cancer Institute, synergy in medicine refers to “the interaction of two or more drugs when their combined effect is greater than the sum of the effects seen when each drug is given alone.”

The findings suggest that “you can get deep remissions in high-risk patients with ibrutinib and venetoclax with very with good tolerability and very low risk of on-treatment progression,” Dr. Thompson said. “We don’t yet have enough progression events to talk about retreatment data, but we do feel that retreatment with Bruton’s tyrosine kinase inhibitors – plus or minus venetoclax – will be successful in the vast majority of patients.”

The combination can be given off label in the United States, Dr. Thompson added. As for expense, adding venetoclax will double the cost of ibrutinib. The two drugs are some of the most expensive medications in the world. But patients will save money if they can stop therapy when they reach remission.

In an interview, hematologist-oncologist Kerry A. Rogers, MD, of Ohio State University, Columbus, who is not involved with the study, praised the research: “While small, this study does say quite a bit about this as a strategy to help people discontinue ibrutinib prior to resistance developing.”

She noted that Bruton’s tyrosine kinase inhibitors “are generally given as a continuous monotherapy, and venetoclax is usually given for a fixed duration in combination with an anti-CD20 antibody.”

Going forward, she said, “the fact that the study was in high-risk patients who have the most to gain from such a combination suggests that similar or better rates of undetectable minimal residual disease might be seen in non–high-risk groups. Additional follow-up should be reported as well as use of this strategy in a larger group of patients before this should be considered a standard approach.”

AbbVie funding the study and provided study drugs. MD Anderson Cancer Center conducted the study and discloses funding from the National Cancer Institute. Dr. Thompson reported ties with AbbVie, Pharmacyclics, Lilly, Adaptive Biotechnologies, Janssen, BeiGene, and Genentech. The other study authors reported multiple disclosures. Dr. Rogers disclosed relationships with Genentech, AbbVie, Novartis, Janssen, Pharmacyclics, BeiGene, Lilly, and AstraZeneca.

In a sign of the power of combination therapy for high-risk chronic lymphocytic leukemia (CLL), a small new study showed that patients were more likely to reach undetectable measurable residual disease (U-MRD) when they added venetoclax to their drug regimen after a year or more of taking ibrutinib.

Of 45 patients, 57% reached U-MRD at 12 months, and 55% reached complete remission, according to the study, published in Leukemia.

By adding venetoclax, “you can get very deep remissions in high-risk patients with ibrutinib,” lead author Philip A. Thompson, MBBS, a hematologist-oncologist with the University of Melbourne and Peter MacCallum Cancer Center, also in Melbourne, said in an interview. “This is a significant advance for really high-risk patients.”

According to Dr. Thompson, Bruton’s tyrosine kinase inhibitors like ibrutinib have revolutionized the treatment of high-risk CLL by forcing the disease into remission for several years and allowing patients to avoid stem cell transplants. “But the drug doesn’t eradicate the disease,” he said, “so eventually these patients develop progression.”

The current hope, he said, is to use a combination therapy like ibrutinib and venetoclax to send CLL into remission with lower chance of drug resistance and then allow patients to stop taking the medications.

Previous research has supported the combination of ibrutinib and venetoclax in CLL in the frontline setting, and the European Commission approved it in 2022 for that use. But “ours is the first [study] that looked at patients who’ve been on ibrutinib for a long time and added venetoclax,” Dr. Thompson said. In some cases, he said, patients in the study had been on ibrutinib for several years.

For the new study, researchers at the University of Texas MD Anderson Cancer Center in Houston – where Dr. Thompson used to work – tracked 45 patients (average age, 68.5 years; 51-80 years) with CLL or small lymphocytic lymphoma who had MRD but no clinical disease progression. They all had at least 1 high-risk feature such as a mutated TP53. They’d been on ibrutinib for a median of 32 months (12-73 months), and two were in complete remission but with MRD.

An intention-to-treat analysis found that 71% reached U-MRD when they finished taking venetoclax. “We were actually pleasantly surprised by the high rate of undetectable MRD,” Dr. Thompson said.

At a median 41-month follow-up, 11% of patients had progressed, but none had died of CLL or Richter transformation, a deadly complication of CLL. “The main side effects were neutropenia and diarrhea, which we were manageable,” Dr. Thompson said.

It’s not clear why the drug combination is especially effective, he said, but it may be because the medications are synergistic. According to the National Cancer Institute, synergy in medicine refers to “the interaction of two or more drugs when their combined effect is greater than the sum of the effects seen when each drug is given alone.”

The findings suggest that “you can get deep remissions in high-risk patients with ibrutinib and venetoclax with very with good tolerability and very low risk of on-treatment progression,” Dr. Thompson said. “We don’t yet have enough progression events to talk about retreatment data, but we do feel that retreatment with Bruton’s tyrosine kinase inhibitors – plus or minus venetoclax – will be successful in the vast majority of patients.”

The combination can be given off label in the United States, Dr. Thompson added. As for expense, adding venetoclax will double the cost of ibrutinib. The two drugs are some of the most expensive medications in the world. But patients will save money if they can stop therapy when they reach remission.

In an interview, hematologist-oncologist Kerry A. Rogers, MD, of Ohio State University, Columbus, who is not involved with the study, praised the research: “While small, this study does say quite a bit about this as a strategy to help people discontinue ibrutinib prior to resistance developing.”

She noted that Bruton’s tyrosine kinase inhibitors “are generally given as a continuous monotherapy, and venetoclax is usually given for a fixed duration in combination with an anti-CD20 antibody.”

Going forward, she said, “the fact that the study was in high-risk patients who have the most to gain from such a combination suggests that similar or better rates of undetectable minimal residual disease might be seen in non–high-risk groups. Additional follow-up should be reported as well as use of this strategy in a larger group of patients before this should be considered a standard approach.”

AbbVie funding the study and provided study drugs. MD Anderson Cancer Center conducted the study and discloses funding from the National Cancer Institute. Dr. Thompson reported ties with AbbVie, Pharmacyclics, Lilly, Adaptive Biotechnologies, Janssen, BeiGene, and Genentech. The other study authors reported multiple disclosures. Dr. Rogers disclosed relationships with Genentech, AbbVie, Novartis, Janssen, Pharmacyclics, BeiGene, Lilly, and AstraZeneca.

In a sign of the power of combination therapy for high-risk chronic lymphocytic leukemia (CLL), a small new study showed that patients were more likely to reach undetectable measurable residual disease (U-MRD) when they added venetoclax to their drug regimen after a year or more of taking ibrutinib.

Of 45 patients, 57% reached U-MRD at 12 months, and 55% reached complete remission, according to the study, published in Leukemia.

By adding venetoclax, “you can get very deep remissions in high-risk patients with ibrutinib,” lead author Philip A. Thompson, MBBS, a hematologist-oncologist with the University of Melbourne and Peter MacCallum Cancer Center, also in Melbourne, said in an interview. “This is a significant advance for really high-risk patients.”

According to Dr. Thompson, Bruton’s tyrosine kinase inhibitors like ibrutinib have revolutionized the treatment of high-risk CLL by forcing the disease into remission for several years and allowing patients to avoid stem cell transplants. “But the drug doesn’t eradicate the disease,” he said, “so eventually these patients develop progression.”

The current hope, he said, is to use a combination therapy like ibrutinib and venetoclax to send CLL into remission with lower chance of drug resistance and then allow patients to stop taking the medications.

Previous research has supported the combination of ibrutinib and venetoclax in CLL in the frontline setting, and the European Commission approved it in 2022 for that use. But “ours is the first [study] that looked at patients who’ve been on ibrutinib for a long time and added venetoclax,” Dr. Thompson said. In some cases, he said, patients in the study had been on ibrutinib for several years.

For the new study, researchers at the University of Texas MD Anderson Cancer Center in Houston – where Dr. Thompson used to work – tracked 45 patients (average age, 68.5 years; 51-80 years) with CLL or small lymphocytic lymphoma who had MRD but no clinical disease progression. They all had at least 1 high-risk feature such as a mutated TP53. They’d been on ibrutinib for a median of 32 months (12-73 months), and two were in complete remission but with MRD.

An intention-to-treat analysis found that 71% reached U-MRD when they finished taking venetoclax. “We were actually pleasantly surprised by the high rate of undetectable MRD,” Dr. Thompson said.

At a median 41-month follow-up, 11% of patients had progressed, but none had died of CLL or Richter transformation, a deadly complication of CLL. “The main side effects were neutropenia and diarrhea, which we were manageable,” Dr. Thompson said.

It’s not clear why the drug combination is especially effective, he said, but it may be because the medications are synergistic. According to the National Cancer Institute, synergy in medicine refers to “the interaction of two or more drugs when their combined effect is greater than the sum of the effects seen when each drug is given alone.”

The findings suggest that “you can get deep remissions in high-risk patients with ibrutinib and venetoclax with very with good tolerability and very low risk of on-treatment progression,” Dr. Thompson said. “We don’t yet have enough progression events to talk about retreatment data, but we do feel that retreatment with Bruton’s tyrosine kinase inhibitors – plus or minus venetoclax – will be successful in the vast majority of patients.”

The combination can be given off label in the United States, Dr. Thompson added. As for expense, adding venetoclax will double the cost of ibrutinib. The two drugs are some of the most expensive medications in the world. But patients will save money if they can stop therapy when they reach remission.

In an interview, hematologist-oncologist Kerry A. Rogers, MD, of Ohio State University, Columbus, who is not involved with the study, praised the research: “While small, this study does say quite a bit about this as a strategy to help people discontinue ibrutinib prior to resistance developing.”

She noted that Bruton’s tyrosine kinase inhibitors “are generally given as a continuous monotherapy, and venetoclax is usually given for a fixed duration in combination with an anti-CD20 antibody.”

Going forward, she said, “the fact that the study was in high-risk patients who have the most to gain from such a combination suggests that similar or better rates of undetectable minimal residual disease might be seen in non–high-risk groups. Additional follow-up should be reported as well as use of this strategy in a larger group of patients before this should be considered a standard approach.”

AbbVie funding the study and provided study drugs. MD Anderson Cancer Center conducted the study and discloses funding from the National Cancer Institute. Dr. Thompson reported ties with AbbVie, Pharmacyclics, Lilly, Adaptive Biotechnologies, Janssen, BeiGene, and Genentech. The other study authors reported multiple disclosures. Dr. Rogers disclosed relationships with Genentech, AbbVie, Novartis, Janssen, Pharmacyclics, BeiGene, Lilly, and AstraZeneca.

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.

Key clinical point: Pembrolizumab offers potent and sustained efficacy with an acceptable safety profile in heavily pretreated patients with relapsed or refractory primary mediastinal B-cell lymphoma (PMBCL).

Major finding: After a median follow-up of 48.7 months, the median progression-free survival and overall survival were 4.3 (95% CI 2.8-13.8) months and 22.3 (95% CI 7.3-not reached) months, respectively. The objective response rate was 41.5%. Grade 3 or 4 treatment-related adverse events occurred in 22.6% of patients.

Study details: Findings are from the final analysis of the phase 2 KEYNOTE-170 trial including 53 adult patients with relapsed or refractory PMBCL whose disease progressed after or who were ineligible for (after ≥2 prior lines of therapy) autologous stem cell transplantation and received pembrolizumab every 3 weeks for up to 2 years.

Disclosures: The KEYNOTE-170 trial was funded by Merck Sharp & Dohme (MSD). Some authors reported ties with various organizations, including MSD. Three authors declared being employees of and holding stock or stock options in MSD.

Source: Zinzani PL et al. Pembrolizumab in relapsed or refractory primary mediastinal large B-cell lymphoma: Final analysis of KEYNOTE-170. Blood. 2023 (May 2). Doi: 10.1182/blood.2022019340

Key clinical point: Pembrolizumab offers potent and sustained efficacy with an acceptable safety profile in heavily pretreated patients with relapsed or refractory primary mediastinal B-cell lymphoma (PMBCL).

Major finding: After a median follow-up of 48.7 months, the median progression-free survival and overall survival were 4.3 (95% CI 2.8-13.8) months and 22.3 (95% CI 7.3-not reached) months, respectively. The objective response rate was 41.5%. Grade 3 or 4 treatment-related adverse events occurred in 22.6% of patients.

Study details: Findings are from the final analysis of the phase 2 KEYNOTE-170 trial including 53 adult patients with relapsed or refractory PMBCL whose disease progressed after or who were ineligible for (after ≥2 prior lines of therapy) autologous stem cell transplantation and received pembrolizumab every 3 weeks for up to 2 years.

Disclosures: The KEYNOTE-170 trial was funded by Merck Sharp & Dohme (MSD). Some authors reported ties with various organizations, including MSD. Three authors declared being employees of and holding stock or stock options in MSD.

Source: Zinzani PL et al. Pembrolizumab in relapsed or refractory primary mediastinal large B-cell lymphoma: Final analysis of KEYNOTE-170. Blood. 2023 (May 2). Doi: 10.1182/blood.2022019340

Key clinical point: Pembrolizumab offers potent and sustained efficacy with an acceptable safety profile in heavily pretreated patients with relapsed or refractory primary mediastinal B-cell lymphoma (PMBCL).

Major finding: After a median follow-up of 48.7 months, the median progression-free survival and overall survival were 4.3 (95% CI 2.8-13.8) months and 22.3 (95% CI 7.3-not reached) months, respectively. The objective response rate was 41.5%. Grade 3 or 4 treatment-related adverse events occurred in 22.6% of patients.

Study details: Findings are from the final analysis of the phase 2 KEYNOTE-170 trial including 53 adult patients with relapsed or refractory PMBCL whose disease progressed after or who were ineligible for (after ≥2 prior lines of therapy) autologous stem cell transplantation and received pembrolizumab every 3 weeks for up to 2 years.

Disclosures: The KEYNOTE-170 trial was funded by Merck Sharp & Dohme (MSD). Some authors reported ties with various organizations, including MSD. Three authors declared being employees of and holding stock or stock options in MSD.

Source: Zinzani PL et al. Pembrolizumab in relapsed or refractory primary mediastinal large B-cell lymphoma: Final analysis of KEYNOTE-170. Blood. 2023 (May 2). Doi: 10.1182/blood.2022019340

Key clinical point: Among patients with diffuse large B-cell lymphoma (DLBCL) who do not complete the recommended six cycles of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) combination chemotherapy, those who do vs do not achieve primary response or complete ≥3 chemotherapy cycles have better survival.

Major finding: The 5-year overall survival rate was significantly higher in patients who did vs did not complete ≥3 cycles of R-CHOP (58.5% vs 24.2%; P < .001) and in those who did vs did not achieve complete or partial response after R-CHOP (56.9% vs 14.1%; P < .001).

Study details: Findings are from a single-center real-world retrospective study including 165 patients with DLBCL who did not receive the planned 6 cycles of R-CHOP.

Disclosures: No information on the source of funding was provided. SS Yoon declared serving as an advisor for and receiving research grants from various organizations.

Source: Yoon J et al. Clinical outcomes after incomplete cycles of R-CHOP for diffuse large B-cell lymphoma: 10 years' real-world experience in a single institute. Ann Hematol. 2023;102:1467-1476 (Apr 26). Doi: 10.1007/s00277-023-05179-5

Key clinical point: Among patients with diffuse large B-cell lymphoma (DLBCL) who do not complete the recommended six cycles of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) combination chemotherapy, those who do vs do not achieve primary response or complete ≥3 chemotherapy cycles have better survival.

Major finding: The 5-year overall survival rate was significantly higher in patients who did vs did not complete ≥3 cycles of R-CHOP (58.5% vs 24.2%; P < .001) and in those who did vs did not achieve complete or partial response after R-CHOP (56.9% vs 14.1%; P < .001).

Study details: Findings are from a single-center real-world retrospective study including 165 patients with DLBCL who did not receive the planned 6 cycles of R-CHOP.

Disclosures: No information on the source of funding was provided. SS Yoon declared serving as an advisor for and receiving research grants from various organizations.

Source: Yoon J et al. Clinical outcomes after incomplete cycles of R-CHOP for diffuse large B-cell lymphoma: 10 years' real-world experience in a single institute. Ann Hematol. 2023;102:1467-1476 (Apr 26). Doi: 10.1007/s00277-023-05179-5

Key clinical point: Among patients with diffuse large B-cell lymphoma (DLBCL) who do not complete the recommended six cycles of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) combination chemotherapy, those who do vs do not achieve primary response or complete ≥3 chemotherapy cycles have better survival.

Major finding: The 5-year overall survival rate was significantly higher in patients who did vs did not complete ≥3 cycles of R-CHOP (58.5% vs 24.2%; P < .001) and in those who did vs did not achieve complete or partial response after R-CHOP (56.9% vs 14.1%; P < .001).

Study details: Findings are from a single-center real-world retrospective study including 165 patients with DLBCL who did not receive the planned 6 cycles of R-CHOP.

Disclosures: No information on the source of funding was provided. SS Yoon declared serving as an advisor for and receiving research grants from various organizations.

Source: Yoon J et al. Clinical outcomes after incomplete cycles of R-CHOP for diffuse large B-cell lymphoma: 10 years' real-world experience in a single institute. Ann Hematol. 2023;102:1467-1476 (Apr 26). Doi: 10.1007/s00277-023-05179-5

Key clinical point: Orelabrutinib showed considerable efficacy and a favorable safety profile in patients with relapsed or refractory mantle cell lymphoma (MCL).

Major finding: After a median follow-up of 23.8 months, the overall response rate was 81.1%, with 27.4% and 53.8% of patients achieving complete and partial responses, respectively. The median duration of response and progression-free survival were 22.9 (95% CI 16.4-not reached) and 22.0 (95% CI 13.8-not reached) months, respectively. The median overall survival was not reached. Most adverse events (AE) were grade 1 or 2. Grade ≥3 AE were infrequent, with thrombocytopenia (13.2%), neutropenia (8.5%), and anemia (7.5%) being the most common.

Study details: This multicenter phase 1/2 study included adult patients with MCL who had relapsed after or were refractory to ≥1 and ≤4 prior therapies and received 150 mg oral orelabrutinib once daily (n = 86) or 100 mg twice daily (n = 20).

Disclosures: This study was sponsored by InnoCare Pharma Limited, China. Four authors declared being employees of InnoCare. The other authors declared no financial conflicts of interest.

Source: Deng LJ et al. Orelabrutinib for the treatment of relapsed or refractory MCL: A phase 1/2, open-label, multicenter, single-arm study. Blood Adv. 2023 (Apr 20). Doi: 10.1182/bloodadvances.2022009168

Key clinical point: Orelabrutinib showed considerable efficacy and a favorable safety profile in patients with relapsed or refractory mantle cell lymphoma (MCL).

Major finding: After a median follow-up of 23.8 months, the overall response rate was 81.1%, with 27.4% and 53.8% of patients achieving complete and partial responses, respectively. The median duration of response and progression-free survival were 22.9 (95% CI 16.4-not reached) and 22.0 (95% CI 13.8-not reached) months, respectively. The median overall survival was not reached. Most adverse events (AE) were grade 1 or 2. Grade ≥3 AE were infrequent, with thrombocytopenia (13.2%), neutropenia (8.5%), and anemia (7.5%) being the most common.

Study details: This multicenter phase 1/2 study included adult patients with MCL who had relapsed after or were refractory to ≥1 and ≤4 prior therapies and received 150 mg oral orelabrutinib once daily (n = 86) or 100 mg twice daily (n = 20).

Disclosures: This study was sponsored by InnoCare Pharma Limited, China. Four authors declared being employees of InnoCare. The other authors declared no financial conflicts of interest.

Source: Deng LJ et al. Orelabrutinib for the treatment of relapsed or refractory MCL: A phase 1/2, open-label, multicenter, single-arm study. Blood Adv. 2023 (Apr 20). Doi: 10.1182/bloodadvances.2022009168

Key clinical point: Orelabrutinib showed considerable efficacy and a favorable safety profile in patients with relapsed or refractory mantle cell lymphoma (MCL).

Major finding: After a median follow-up of 23.8 months, the overall response rate was 81.1%, with 27.4% and 53.8% of patients achieving complete and partial responses, respectively. The median duration of response and progression-free survival were 22.9 (95% CI 16.4-not reached) and 22.0 (95% CI 13.8-not reached) months, respectively. The median overall survival was not reached. Most adverse events (AE) were grade 1 or 2. Grade ≥3 AE were infrequent, with thrombocytopenia (13.2%), neutropenia (8.5%), and anemia (7.5%) being the most common.

Study details: This multicenter phase 1/2 study included adult patients with MCL who had relapsed after or were refractory to ≥1 and ≤4 prior therapies and received 150 mg oral orelabrutinib once daily (n = 86) or 100 mg twice daily (n = 20).

Disclosures: This study was sponsored by InnoCare Pharma Limited, China. Four authors declared being employees of InnoCare. The other authors declared no financial conflicts of interest.

Source: Deng LJ et al. Orelabrutinib for the treatment of relapsed or refractory MCL: A phase 1/2, open-label, multicenter, single-arm study. Blood Adv. 2023 (Apr 20). Doi: 10.1182/bloodadvances.2022009168

Key clinical point: First-line autologous stem cell transplantation (ASCT) resulted in long-term clinical and molecular remissions in patients with disseminated mantle cell lymphoma (MCL).

Major finding: The 10-year overall survival, progression-free survival, and freedom from progression rates for the first-line vs second-line cohort were 64%, 52%, and 59% vs 50%, 20%, and 20%, respectively. Overall, 27 patients experienced sustained clinical remissions between 5 and 19 years, of which 26 were continuously minimal residual disease (MRD) negative based on all samples collected after ASCT.

Study details: The data come from a partly prospective and partly retrospective study including 65 patients with disseminated MCL who received high-dose therapy with ASCT as first- (n = 54), second- (n = 10), or third-line (n = 1) treatment.

Disclosures: The MRD analysis was partly funded by BMBF (The Federal Ministry of Education and Research, Germany). M Dreyling declared serving on the scientific advisory boards of and receiving research support and speaker honoraria from various organizations. Other authors declared no conflicts of interest.

Source: Metzner B et al. Long-term outcome in patients with mantle cell lymphoma following high-dose therapy and autologous stem cell transplantation. Eur J Haematol. 2023 (Apr 24). Doi: 10.1111/ejh.13985

Key clinical point: First-line autologous stem cell transplantation (ASCT) resulted in long-term clinical and molecular remissions in patients with disseminated mantle cell lymphoma (MCL).

Major finding: The 10-year overall survival, progression-free survival, and freedom from progression rates for the first-line vs second-line cohort were 64%, 52%, and 59% vs 50%, 20%, and 20%, respectively. Overall, 27 patients experienced sustained clinical remissions between 5 and 19 years, of which 26 were continuously minimal residual disease (MRD) negative based on all samples collected after ASCT.

Study details: The data come from a partly prospective and partly retrospective study including 65 patients with disseminated MCL who received high-dose therapy with ASCT as first- (n = 54), second- (n = 10), or third-line (n = 1) treatment.

Disclosures: The MRD analysis was partly funded by BMBF (The Federal Ministry of Education and Research, Germany). M Dreyling declared serving on the scientific advisory boards of and receiving research support and speaker honoraria from various organizations. Other authors declared no conflicts of interest.

Source: Metzner B et al. Long-term outcome in patients with mantle cell lymphoma following high-dose therapy and autologous stem cell transplantation. Eur J Haematol. 2023 (Apr 24). Doi: 10.1111/ejh.13985

Key clinical point: First-line autologous stem cell transplantation (ASCT) resulted in long-term clinical and molecular remissions in patients with disseminated mantle cell lymphoma (MCL).

Major finding: The 10-year overall survival, progression-free survival, and freedom from progression rates for the first-line vs second-line cohort were 64%, 52%, and 59% vs 50%, 20%, and 20%, respectively. Overall, 27 patients experienced sustained clinical remissions between 5 and 19 years, of which 26 were continuously minimal residual disease (MRD) negative based on all samples collected after ASCT.

Study details: The data come from a partly prospective and partly retrospective study including 65 patients with disseminated MCL who received high-dose therapy with ASCT as first- (n = 54), second- (n = 10), or third-line (n = 1) treatment.

Disclosures: The MRD analysis was partly funded by BMBF (The Federal Ministry of Education and Research, Germany). M Dreyling declared serving on the scientific advisory boards of and receiving research support and speaker honoraria from various organizations. Other authors declared no conflicts of interest.

Source: Metzner B et al. Long-term outcome in patients with mantle cell lymphoma following high-dose therapy and autologous stem cell transplantation. Eur J Haematol. 2023 (Apr 24). Doi: 10.1111/ejh.13985

Key clinical point: Single nucleotide polymorphisms (SNP) of genes encoding specific cellular proteins may be associated with clinical outcomes and represent predictive biomarkers of poor response to lenalidomide maintenance after autologous stem cell transplantation (ASCT) in mantle cell lymphoma (MCL).

Major finding: Patients with ABCB1 or VEGF polymorphisms vs homozygous wild type (WT) in the lenalidomide arm had significantly higher 3-year progression-free survival (PFS) rates (85% vs 70%; P  =  .047 and 85% vs 60%; P  =  .0021, respectively). Lenalidomide vs observation did not improve 3-year PFS rates in patients carrying both ABCB1 and VEGF WT (P  =  .632).

Study details: This pharmacogenetic study included 278 adult patients with previously untreated MCL and adequate biological samples from the phase 3 MCL0208 study, 197 of whom were genotyped after ASCT and randomly assigned to the lenalidomide maintenance or observation arm.

Disclosures: This study was funded by Cancer Research UK and others. Some authors reported ties with various organizations.

Source: Ferrero S et al. Candidate germline biomarkers of lenalidomide efficacy in mantle cell lymphoma: The FIL MCL0208 trial. Blood Adv. 2023 (Apr 14). Doi: 10.1182/bloodadvances.2022009504

Key clinical point: Single nucleotide polymorphisms (SNP) of genes encoding specific cellular proteins may be associated with clinical outcomes and represent predictive biomarkers of poor response to lenalidomide maintenance after autologous stem cell transplantation (ASCT) in mantle cell lymphoma (MCL).

Major finding: Patients with ABCB1 or VEGF polymorphisms vs homozygous wild type (WT) in the lenalidomide arm had significantly higher 3-year progression-free survival (PFS) rates (85% vs 70%; P  =  .047 and 85% vs 60%; P  =  .0021, respectively). Lenalidomide vs observation did not improve 3-year PFS rates in patients carrying both ABCB1 and VEGF WT (P  =  .632).

Study details: This pharmacogenetic study included 278 adult patients with previously untreated MCL and adequate biological samples from the phase 3 MCL0208 study, 197 of whom were genotyped after ASCT and randomly assigned to the lenalidomide maintenance or observation arm.

Disclosures: This study was funded by Cancer Research UK and others. Some authors reported ties with various organizations.

Source: Ferrero S et al. Candidate germline biomarkers of lenalidomide efficacy in mantle cell lymphoma: The FIL MCL0208 trial. Blood Adv. 2023 (Apr 14). Doi: 10.1182/bloodadvances.2022009504

Key clinical point: Single nucleotide polymorphisms (SNP) of genes encoding specific cellular proteins may be associated with clinical outcomes and represent predictive biomarkers of poor response to lenalidomide maintenance after autologous stem cell transplantation (ASCT) in mantle cell lymphoma (MCL).

Major finding: Patients with ABCB1 or VEGF polymorphisms vs homozygous wild type (WT) in the lenalidomide arm had significantly higher 3-year progression-free survival (PFS) rates (85% vs 70%; P  =  .047 and 85% vs 60%; P  =  .0021, respectively). Lenalidomide vs observation did not improve 3-year PFS rates in patients carrying both ABCB1 and VEGF WT (P  =  .632).

Study details: This pharmacogenetic study included 278 adult patients with previously untreated MCL and adequate biological samples from the phase 3 MCL0208 study, 197 of whom were genotyped after ASCT and randomly assigned to the lenalidomide maintenance or observation arm.

Disclosures: This study was funded by Cancer Research UK and others. Some authors reported ties with various organizations.

Source: Ferrero S et al. Candidate germline biomarkers of lenalidomide efficacy in mantle cell lymphoma: The FIL MCL0208 trial. Blood Adv. 2023 (Apr 14). Doi: 10.1182/bloodadvances.2022009504

Key clinical point: The addition of venetoclax to ibrutinib treatment led to a high rate of undetectable measurable residual disease with 10^–4 sensitivity (U-MRD4) in the bone marrow (BM) in high-risk patients with chronic lymphocytic leukemia (CLL).

Major finding: Adding venetoclax to ibrutinib therapy led to a cumulative BM U-MRD4 rate of 73%. BM U-MRD4 was achieved by 71% of patients after venetoclax therapy completion and by 38% and 57% of patients after 6 and 12 cycles, respectively.

Study details: This phase 2 study included 45 patients with CLL and detectable disease (≥0.01% measurable residual disease in BM) treated with ibrutinib for ≥12 months who had ≥1 high-risk feature for disease progression and received combined treatment with ibrutinib (previously tolerated dose) and venetoclax (escalated to 400 mg once daily) for ≤24 cycles.

Disclosures: This study was funded by AbbVie. Some authors declared serving as consultants or on speaker’s bureaus for or receiving advisory board or consulting honoraria or research support from AbbVie and others.

Source: Thompson PA et al. Venetoclax consolidation in high-risk CLL treated with ibrutinib for ≥1 year achieves a high rate of undetectable MRD. Leukemia. 2023 (May 3). Doi: 10.1038/s41375-023-01901-4

Key clinical point: The addition of venetoclax to ibrutinib treatment led to a high rate of undetectable measurable residual disease with 10^–4 sensitivity (U-MRD4) in the bone marrow (BM) in high-risk patients with chronic lymphocytic leukemia (CLL).

Major finding: Adding venetoclax to ibrutinib therapy led to a cumulative BM U-MRD4 rate of 73%. BM U-MRD4 was achieved by 71% of patients after venetoclax therapy completion and by 38% and 57% of patients after 6 and 12 cycles, respectively.

Study details: This phase 2 study included 45 patients with CLL and detectable disease (≥0.01% measurable residual disease in BM) treated with ibrutinib for ≥12 months who had ≥1 high-risk feature for disease progression and received combined treatment with ibrutinib (previously tolerated dose) and venetoclax (escalated to 400 mg once daily) for ≤24 cycles.

Disclosures: This study was funded by AbbVie. Some authors declared serving as consultants or on speaker’s bureaus for or receiving advisory board or consulting honoraria or research support from AbbVie and others.

Source: Thompson PA et al. Venetoclax consolidation in high-risk CLL treated with ibrutinib for ≥1 year achieves a high rate of undetectable MRD. Leukemia. 2023 (May 3). Doi: 10.1038/s41375-023-01901-4

Key clinical point: The addition of venetoclax to ibrutinib treatment led to a high rate of undetectable measurable residual disease with 10^–4 sensitivity (U-MRD4) in the bone marrow (BM) in high-risk patients with chronic lymphocytic leukemia (CLL).

Major finding: Adding venetoclax to ibrutinib therapy led to a cumulative BM U-MRD4 rate of 73%. BM U-MRD4 was achieved by 71% of patients after venetoclax therapy completion and by 38% and 57% of patients after 6 and 12 cycles, respectively.

Study details: This phase 2 study included 45 patients with CLL and detectable disease (≥0.01% measurable residual disease in BM) treated with ibrutinib for ≥12 months who had ≥1 high-risk feature for disease progression and received combined treatment with ibrutinib (previously tolerated dose) and venetoclax (escalated to 400 mg once daily) for ≤24 cycles.

Disclosures: This study was funded by AbbVie. Some authors declared serving as consultants or on speaker’s bureaus for or receiving advisory board or consulting honoraria or research support from AbbVie and others.

Source: Thompson PA et al. Venetoclax consolidation in high-risk CLL treated with ibrutinib for ≥1 year achieves a high rate of undetectable MRD. Leukemia. 2023 (May 3). Doi: 10.1038/s41375-023-01901-4

Key clinical point: The addition of rituximab to chemotherapy increased the risk for prolonged hypogammaglobulinemia in children with high-risk mature B-cell non-Hodgkin lymphoma (B-NHL); however, severe infections after therapy completion were rare.

Major finding: At 1 year after therapy commencement, the chemotherapy+rituximab vs chemotherapy arm had a significantly higher proportion of children with low immunoglobulin G levels (55% vs 25%; odds ratio 3.64; P  =  .0003). The occurrence of grade ≥3 nonhematologic adverse events after 1 month of therapy completion was rare.

Study details: This secondary analysis of the Inter-B-NHL-Ritux 2010 trial included children (6 months-18 years) with high-risk mature B-NHL who were randomly (n = 289) or nonrandomly (n = 132) assigned to receive either chemotherapy alone or chemotherapy+rituximab.

Disclosures: The Inter-B-NHL-Ritux 2010 trial was supported by F Hoffmann-La Roche and others, and this study was funded by the National Cancer Institute of the US National Institutes of Health. Some authors reported ties with F Hoffmann-La Roche or other sources.

Source: Alexander S et al for the Children's Oncology Group and the European Intergroup for Childhood Non-Hodgkin's Lymphoma. Effect of rituximab on immune status in children with mature B-cell non-Hodgkin lymphoma: A prespecified secondary analysis of the Inter-B-NHL Ritux 2010 trial. Lancet Haematol. 2023 (Apr 21). Doi: 10.1016/S2352-3026(23)00062-5

Key clinical point: The addition of rituximab to chemotherapy increased the risk for prolonged hypogammaglobulinemia in children with high-risk mature B-cell non-Hodgkin lymphoma (B-NHL); however, severe infections after therapy completion were rare.

Major finding: At 1 year after therapy commencement, the chemotherapy+rituximab vs chemotherapy arm had a significantly higher proportion of children with low immunoglobulin G levels (55% vs 25%; odds ratio 3.64; P  =  .0003). The occurrence of grade ≥3 nonhematologic adverse events after 1 month of therapy completion was rare.

Study details: This secondary analysis of the Inter-B-NHL-Ritux 2010 trial included children (6 months-18 years) with high-risk mature B-NHL who were randomly (n = 289) or nonrandomly (n = 132) assigned to receive either chemotherapy alone or chemotherapy+rituximab.

Disclosures: The Inter-B-NHL-Ritux 2010 trial was supported by F Hoffmann-La Roche and others, and this study was funded by the National Cancer Institute of the US National Institutes of Health. Some authors reported ties with F Hoffmann-La Roche or other sources.

Source: Alexander S et al for the Children's Oncology Group and the European Intergroup for Childhood Non-Hodgkin's Lymphoma. Effect of rituximab on immune status in children with mature B-cell non-Hodgkin lymphoma: A prespecified secondary analysis of the Inter-B-NHL Ritux 2010 trial. Lancet Haematol. 2023 (Apr 21). Doi: 10.1016/S2352-3026(23)00062-5

Key clinical point: The addition of rituximab to chemotherapy increased the risk for prolonged hypogammaglobulinemia in children with high-risk mature B-cell non-Hodgkin lymphoma (B-NHL); however, severe infections after therapy completion were rare.

Major finding: At 1 year after therapy commencement, the chemotherapy+rituximab vs chemotherapy arm had a significantly higher proportion of children with low immunoglobulin G levels (55% vs 25%; odds ratio 3.64; P  =  .0003). The occurrence of grade ≥3 nonhematologic adverse events after 1 month of therapy completion was rare.

Study details: This secondary analysis of the Inter-B-NHL-Ritux 2010 trial included children (6 months-18 years) with high-risk mature B-NHL who were randomly (n = 289) or nonrandomly (n = 132) assigned to receive either chemotherapy alone or chemotherapy+rituximab.

Disclosures: The Inter-B-NHL-Ritux 2010 trial was supported by F Hoffmann-La Roche and others, and this study was funded by the National Cancer Institute of the US National Institutes of Health. Some authors reported ties with F Hoffmann-La Roche or other sources.

Source: Alexander S et al for the Children's Oncology Group and the European Intergroup for Childhood Non-Hodgkin's Lymphoma. Effect of rituximab on immune status in children with mature B-cell non-Hodgkin lymphoma: A prespecified secondary analysis of the Inter-B-NHL Ritux 2010 trial. Lancet Haematol. 2023 (Apr 21). Doi: 10.1016/S2352-3026(23)00062-5

Key clinical point: Compared with the standard intravenous (IV) rituximab induction therapy, a short subcutaneous rituximab maintenance therapy after subcutaneous rituximab induction therapy improves complete response (CR) and progression-free survival (PFS) in patients with CD20⁺ low-tumor burden follicular lymphoma (FL).

Major finding: Patients receiving rituximab induction (first IV and then subcutaneous) followed by a short subcutaneous rituximab maintenance therapy (four infusions; experimental arm) vs four weekly IV rituximab infusions (control arm) had significantly higher 4-year PFS (58.1% vs 41.2%; hazard ratio 0.585; P  =  .008) and CR (59.0% vs 36.3%; P  =  .001) rates.

Study details: Findings are from a phase 3 study, FLIRT, that included 202 patients with CD20⁺ low-tumor burden FL who were randomly assigned to the control or experimental arm.

Disclosures: This study was supported by the Lymphoma Academic Research Organization (LYSARC), France. Some authors declared serving as consultants or advisors for or receiving honoraria, research funding, or travel and accommodation expenses from various sources.

Source: Cartron G et al. Randomized phase III trial evaluating subcutaneous rituximab for the first-line treatment of low–tumor burden follicular lymphoma: Results of a LYSA study. J Clin Oncol. 2023 (Apr 18). Doi: 10.1200/JCO.22.02327

Key clinical point: Compared with the standard intravenous (IV) rituximab induction therapy, a short subcutaneous rituximab maintenance therapy after subcutaneous rituximab induction therapy improves complete response (CR) and progression-free survival (PFS) in patients with CD20⁺ low-tumor burden follicular lymphoma (FL).

Major finding: Patients receiving rituximab induction (first IV and then subcutaneous) followed by a short subcutaneous rituximab maintenance therapy (four infusions; experimental arm) vs four weekly IV rituximab infusions (control arm) had significantly higher 4-year PFS (58.1% vs 41.2%; hazard ratio 0.585; P  =  .008) and CR (59.0% vs 36.3%; P  =  .001) rates.

Study details: Findings are from a phase 3 study, FLIRT, that included 202 patients with CD20⁺ low-tumor burden FL who were randomly assigned to the control or experimental arm.

Disclosures: This study was supported by the Lymphoma Academic Research Organization (LYSARC), France. Some authors declared serving as consultants or advisors for or receiving honoraria, research funding, or travel and accommodation expenses from various sources.

Source: Cartron G et al. Randomized phase III trial evaluating subcutaneous rituximab for the first-line treatment of low–tumor burden follicular lymphoma: Results of a LYSA study. J Clin Oncol. 2023 (Apr 18). Doi: 10.1200/JCO.22.02327

Key clinical point: Compared with the standard intravenous (IV) rituximab induction therapy, a short subcutaneous rituximab maintenance therapy after subcutaneous rituximab induction therapy improves complete response (CR) and progression-free survival (PFS) in patients with CD20⁺ low-tumor burden follicular lymphoma (FL).

Major finding: Patients receiving rituximab induction (first IV and then subcutaneous) followed by a short subcutaneous rituximab maintenance therapy (four infusions; experimental arm) vs four weekly IV rituximab infusions (control arm) had significantly higher 4-year PFS (58.1% vs 41.2%; hazard ratio 0.585; P  =  .008) and CR (59.0% vs 36.3%; P  =  .001) rates.

Study details: Findings are from a phase 3 study, FLIRT, that included 202 patients with CD20⁺ low-tumor burden FL who were randomly assigned to the control or experimental arm.

Disclosures: This study was supported by the Lymphoma Academic Research Organization (LYSARC), France. Some authors declared serving as consultants or advisors for or receiving honoraria, research funding, or travel and accommodation expenses from various sources.

Source: Cartron G et al. Randomized phase III trial evaluating subcutaneous rituximab for the first-line treatment of low–tumor burden follicular lymphoma: Results of a LYSA study. J Clin Oncol. 2023 (Apr 18). Doi: 10.1200/JCO.22.02327