B Cell Lymphoma

While the use of Bruton tyrosine kinase inhibitors has significantly enhanced treatment of patients with B-cell malignancies, BTKi resistance is the “Achilles’ heel” of this otherwise effective therapeutic option, Deborah M. Stephens, DO, and John C. Byrd, MD, stated in a review article published in Blood.

Among patients with B-cell malignancies – including chronic lymphocytic leukemia (CLL), Waldenström’s macroglobulinemia (WM), mantle cell lymphoma (MCL), and marginal zone lymphoma (MZL) – BTKis have substantial efficacy. The review article focuses mainly on extremely rare primary or more common acquired BTKi resistance, particularly among patients with acquired resistance to ibrutinib (11%-38% in large studies).

Primary resistance suggests an alternative diagnosis or transformation to a more aggressive lymphoma. Acquired ibrutinib resistance manifests either as progressive CLL (typically after 2 years of therapy) or as early transformation (within the first 2 years of therapy) to more aggressive entities such as diffuse large B-cell lymphoma, Hodgkin lymphoma, or prolymphocytic leukemia. Less studied than ibrutinib, acquired resistance to acalabrutinib and zanubrutinib has been in the 12%-15% range.

Acquired resistance has meant a reduction in expected overall survival, and while the introduction of new therapies like venetoclax has extended OS, short progression-free survival (PFS) provides a rationale for research into mechanisms of resistance and alternative treatments.

Acquired resistance

Most often acquired, resistance to ibrutinib monotherapy in CLL patients has been associated with high-risk genomic features: complex karyotype, TP53 mutation, del(17)p13.1, and heavy pretreatment. In the phase 3 RESONATE trial, patients with both TP53 mutation and del(17)p13.1 had shorter PFS than those with only one or the other genomic feature. This feature may have explained the fairly good ibrutinib monotherapy outcomes in treatment-naive patients with del(17p)13.1.

Through univariable and multivariable analysis, a machine-learning program consistently identified TP53 mutation, prior CLL therapy, beta-2 microglobulin of at least5 mg/L, and lactate dehydrogenase greater than250 U/L as four risk factors associated with impaired survival. A second survival factor program comparing ibrutinib with chemoimmunotherapy identified beta-2 microglobulin levels of at least5 mg/L, lactate dehydrogenase greater than ULN, hemoglobin less than 110 g/L for women or less than120 g/L for men, and time from initiation of last therapy less than 24 months as risk factors.

While the mechanisms leading to ibrutinib resistance are not clearly known for patients with these risk factors, some research suggests that survival of TP53-mutated CLL cells is less dependent on the BCR pathway, making this CLL type more prone to ibrutinib resistance. TP53-mutated CLL cells, compared with T53–wild-type CLL cells, demonstrate a down-regulation of BCR-related genes and an up-regulation of prosurvival and antiapototic genes.
 

BTK mutations

Mutation of the active kinase domain on the BTK enzyme (C481) is the most common BTKi resistance mechanism described in CLL. A thymidine to adenine mutation (nucleotide 1634) leads to a 25-fold decrease in drug potency. Other known gene or chromosome regions affected in BTKi resistance include PLCy2, Del(8p), CARD11, TRAF2&3, BIRC3, MAP3k14, ARID2, SMARCA2, SMARCA4, MYD88, KLH14, and TNFAIP3.

Multiple mutations of PLCy2, the next most common BTKi resistance mechanism, include mutations of arginine to tryptophan, leucine to phenylalanine, serine to tyrosine, and others. When activated, these gain-of-function mutations prolong BCR signaling.

Ibrutinib resistance has also been associated with deletion of the short arm of chromosome 8 (del[8p]), with CLL cells harboring del(8p) insensitive to TRAIL-induced apoptosis, leading to continuous cell growth. Ibrutinib resistance in patients with WM has also been associated with del(8p).

CARD11 mutations, which allow for BTK-independent activation of NFkB, have been documented in ibrutinib-resistant patients with CLL and other lymphoid malignancies, as detailed in this review.
 

Novel therapies suggest promise

Survival in CLL after BTKi resistance develops is quite short, according to the authors, and they expressed hope that continued research into novel agents would prolong this population’s survival.

Venetoclax, an oral inhibitor of the antiapoptotic protein BCL2, is approved for all patients with CLL, both as monotherapy and in combination with an anti-CD20 monoclonal antibody. Data support its use after BTKi resistance has been detected. Some evidence in CLL cell lines supports use of the oral phosphoinositide 3-kinases inhibitors idelalisib and duvelisib in relapsed CLL and the BTK C481S mutation. Early response data with third-generation BTKis, such as ARQ-531 and LOXO-305, suggest promise in this setting. Also, for young and healthy patients who have progressed on both BTKi and venetoclax therapy, allogeneic hematopoietic stem cell transplantation could be considered.

In patients with heavily pretreated CLL, early clinical data support chimeric antigen receptor T-cell therapy (CAR T), a novel therapy where patients’ own T cells are extracted, engineered, and reinfused. A related immunotherapy, using a similar process of retroviral vector insertion of an anti-CD19 CAR into donor NK cells before infusion into the patient, is termed CAR-NK cell therapy. It shows promise in early data from patients with CLL who all had previously been heavily treated with ibrutinib.

More research, more hope

Despite the significant advance that BTKis represent, BTKi resistance, with shortened survival, remains a clinical problem for patients with B-cell malignancies. BTKi resistance has been associated with several genetic and clinical risk factors, with mutations in BTK and PLCy2 the most common and most thoroughly researched. “Ongoing clinical trials of third-generation noncovalent BTKis and cellular therapies, such as CAR T, provide much hope for these patients. ... Continued additional research is needed to further prolong the survival of patients with BTKi-resistant B-cell malignancies.”

Dr. Stephens has received research funding and has served on advisory boards for a variety of pharmaceutical and biotechnology companies. Dr. Byrd has received research funding and has consulted for a variety of pharmaceutical and biotechnology companies.

While the use of Bruton tyrosine kinase inhibitors has significantly enhanced treatment of patients with B-cell malignancies, BTKi resistance is the “Achilles’ heel” of this otherwise effective therapeutic option, Deborah M. Stephens, DO, and John C. Byrd, MD, stated in a review article published in Blood.

Among patients with B-cell malignancies – including chronic lymphocytic leukemia (CLL), Waldenström’s macroglobulinemia (WM), mantle cell lymphoma (MCL), and marginal zone lymphoma (MZL) – BTKis have substantial efficacy. The review article focuses mainly on extremely rare primary or more common acquired BTKi resistance, particularly among patients with acquired resistance to ibrutinib (11%-38% in large studies).

Primary resistance suggests an alternative diagnosis or transformation to a more aggressive lymphoma. Acquired ibrutinib resistance manifests either as progressive CLL (typically after 2 years of therapy) or as early transformation (within the first 2 years of therapy) to more aggressive entities such as diffuse large B-cell lymphoma, Hodgkin lymphoma, or prolymphocytic leukemia. Less studied than ibrutinib, acquired resistance to acalabrutinib and zanubrutinib has been in the 12%-15% range.

Acquired resistance has meant a reduction in expected overall survival, and while the introduction of new therapies like venetoclax has extended OS, short progression-free survival (PFS) provides a rationale for research into mechanisms of resistance and alternative treatments.

Acquired resistance

Most often acquired, resistance to ibrutinib monotherapy in CLL patients has been associated with high-risk genomic features: complex karyotype, TP53 mutation, del(17)p13.1, and heavy pretreatment. In the phase 3 RESONATE trial, patients with both TP53 mutation and del(17)p13.1 had shorter PFS than those with only one or the other genomic feature. This feature may have explained the fairly good ibrutinib monotherapy outcomes in treatment-naive patients with del(17p)13.1.

Through univariable and multivariable analysis, a machine-learning program consistently identified TP53 mutation, prior CLL therapy, beta-2 microglobulin of at least5 mg/L, and lactate dehydrogenase greater than250 U/L as four risk factors associated with impaired survival. A second survival factor program comparing ibrutinib with chemoimmunotherapy identified beta-2 microglobulin levels of at least5 mg/L, lactate dehydrogenase greater than ULN, hemoglobin less than 110 g/L for women or less than120 g/L for men, and time from initiation of last therapy less than 24 months as risk factors.

While the mechanisms leading to ibrutinib resistance are not clearly known for patients with these risk factors, some research suggests that survival of TP53-mutated CLL cells is less dependent on the BCR pathway, making this CLL type more prone to ibrutinib resistance. TP53-mutated CLL cells, compared with T53–wild-type CLL cells, demonstrate a down-regulation of BCR-related genes and an up-regulation of prosurvival and antiapototic genes.
 

BTK mutations

Mutation of the active kinase domain on the BTK enzyme (C481) is the most common BTKi resistance mechanism described in CLL. A thymidine to adenine mutation (nucleotide 1634) leads to a 25-fold decrease in drug potency. Other known gene or chromosome regions affected in BTKi resistance include PLCy2, Del(8p), CARD11, TRAF2&3, BIRC3, MAP3k14, ARID2, SMARCA2, SMARCA4, MYD88, KLH14, and TNFAIP3.

Multiple mutations of PLCy2, the next most common BTKi resistance mechanism, include mutations of arginine to tryptophan, leucine to phenylalanine, serine to tyrosine, and others. When activated, these gain-of-function mutations prolong BCR signaling.

Ibrutinib resistance has also been associated with deletion of the short arm of chromosome 8 (del[8p]), with CLL cells harboring del(8p) insensitive to TRAIL-induced apoptosis, leading to continuous cell growth. Ibrutinib resistance in patients with WM has also been associated with del(8p).

CARD11 mutations, which allow for BTK-independent activation of NFkB, have been documented in ibrutinib-resistant patients with CLL and other lymphoid malignancies, as detailed in this review.
 

Novel therapies suggest promise

Survival in CLL after BTKi resistance develops is quite short, according to the authors, and they expressed hope that continued research into novel agents would prolong this population’s survival.

Venetoclax, an oral inhibitor of the antiapoptotic protein BCL2, is approved for all patients with CLL, both as monotherapy and in combination with an anti-CD20 monoclonal antibody. Data support its use after BTKi resistance has been detected. Some evidence in CLL cell lines supports use of the oral phosphoinositide 3-kinases inhibitors idelalisib and duvelisib in relapsed CLL and the BTK C481S mutation. Early response data with third-generation BTKis, such as ARQ-531 and LOXO-305, suggest promise in this setting. Also, for young and healthy patients who have progressed on both BTKi and venetoclax therapy, allogeneic hematopoietic stem cell transplantation could be considered.

In patients with heavily pretreated CLL, early clinical data support chimeric antigen receptor T-cell therapy (CAR T), a novel therapy where patients’ own T cells are extracted, engineered, and reinfused. A related immunotherapy, using a similar process of retroviral vector insertion of an anti-CD19 CAR into donor NK cells before infusion into the patient, is termed CAR-NK cell therapy. It shows promise in early data from patients with CLL who all had previously been heavily treated with ibrutinib.

More research, more hope

Despite the significant advance that BTKis represent, BTKi resistance, with shortened survival, remains a clinical problem for patients with B-cell malignancies. BTKi resistance has been associated with several genetic and clinical risk factors, with mutations in BTK and PLCy2 the most common and most thoroughly researched. “Ongoing clinical trials of third-generation noncovalent BTKis and cellular therapies, such as CAR T, provide much hope for these patients. ... Continued additional research is needed to further prolong the survival of patients with BTKi-resistant B-cell malignancies.”

Dr. Stephens has received research funding and has served on advisory boards for a variety of pharmaceutical and biotechnology companies. Dr. Byrd has received research funding and has consulted for a variety of pharmaceutical and biotechnology companies.

While the use of Bruton tyrosine kinase inhibitors has significantly enhanced treatment of patients with B-cell malignancies, BTKi resistance is the “Achilles’ heel” of this otherwise effective therapeutic option, Deborah M. Stephens, DO, and John C. Byrd, MD, stated in a review article published in Blood.

Among patients with B-cell malignancies – including chronic lymphocytic leukemia (CLL), Waldenström’s macroglobulinemia (WM), mantle cell lymphoma (MCL), and marginal zone lymphoma (MZL) – BTKis have substantial efficacy. The review article focuses mainly on extremely rare primary or more common acquired BTKi resistance, particularly among patients with acquired resistance to ibrutinib (11%-38% in large studies).

Primary resistance suggests an alternative diagnosis or transformation to a more aggressive lymphoma. Acquired ibrutinib resistance manifests either as progressive CLL (typically after 2 years of therapy) or as early transformation (within the first 2 years of therapy) to more aggressive entities such as diffuse large B-cell lymphoma, Hodgkin lymphoma, or prolymphocytic leukemia. Less studied than ibrutinib, acquired resistance to acalabrutinib and zanubrutinib has been in the 12%-15% range.

Acquired resistance has meant a reduction in expected overall survival, and while the introduction of new therapies like venetoclax has extended OS, short progression-free survival (PFS) provides a rationale for research into mechanisms of resistance and alternative treatments.

Acquired resistance

Most often acquired, resistance to ibrutinib monotherapy in CLL patients has been associated with high-risk genomic features: complex karyotype, TP53 mutation, del(17)p13.1, and heavy pretreatment. In the phase 3 RESONATE trial, patients with both TP53 mutation and del(17)p13.1 had shorter PFS than those with only one or the other genomic feature. This feature may have explained the fairly good ibrutinib monotherapy outcomes in treatment-naive patients with del(17p)13.1.

Through univariable and multivariable analysis, a machine-learning program consistently identified TP53 mutation, prior CLL therapy, beta-2 microglobulin of at least5 mg/L, and lactate dehydrogenase greater than250 U/L as four risk factors associated with impaired survival. A second survival factor program comparing ibrutinib with chemoimmunotherapy identified beta-2 microglobulin levels of at least5 mg/L, lactate dehydrogenase greater than ULN, hemoglobin less than 110 g/L for women or less than120 g/L for men, and time from initiation of last therapy less than 24 months as risk factors.

While the mechanisms leading to ibrutinib resistance are not clearly known for patients with these risk factors, some research suggests that survival of TP53-mutated CLL cells is less dependent on the BCR pathway, making this CLL type more prone to ibrutinib resistance. TP53-mutated CLL cells, compared with T53–wild-type CLL cells, demonstrate a down-regulation of BCR-related genes and an up-regulation of prosurvival and antiapototic genes.
 

BTK mutations

Mutation of the active kinase domain on the BTK enzyme (C481) is the most common BTKi resistance mechanism described in CLL. A thymidine to adenine mutation (nucleotide 1634) leads to a 25-fold decrease in drug potency. Other known gene or chromosome regions affected in BTKi resistance include PLCy2, Del(8p), CARD11, TRAF2&3, BIRC3, MAP3k14, ARID2, SMARCA2, SMARCA4, MYD88, KLH14, and TNFAIP3.

Multiple mutations of PLCy2, the next most common BTKi resistance mechanism, include mutations of arginine to tryptophan, leucine to phenylalanine, serine to tyrosine, and others. When activated, these gain-of-function mutations prolong BCR signaling.

Ibrutinib resistance has also been associated with deletion of the short arm of chromosome 8 (del[8p]), with CLL cells harboring del(8p) insensitive to TRAIL-induced apoptosis, leading to continuous cell growth. Ibrutinib resistance in patients with WM has also been associated with del(8p).

CARD11 mutations, which allow for BTK-independent activation of NFkB, have been documented in ibrutinib-resistant patients with CLL and other lymphoid malignancies, as detailed in this review.
 

Novel therapies suggest promise

Survival in CLL after BTKi resistance develops is quite short, according to the authors, and they expressed hope that continued research into novel agents would prolong this population’s survival.

Venetoclax, an oral inhibitor of the antiapoptotic protein BCL2, is approved for all patients with CLL, both as monotherapy and in combination with an anti-CD20 monoclonal antibody. Data support its use after BTKi resistance has been detected. Some evidence in CLL cell lines supports use of the oral phosphoinositide 3-kinases inhibitors idelalisib and duvelisib in relapsed CLL and the BTK C481S mutation. Early response data with third-generation BTKis, such as ARQ-531 and LOXO-305, suggest promise in this setting. Also, for young and healthy patients who have progressed on both BTKi and venetoclax therapy, allogeneic hematopoietic stem cell transplantation could be considered.

In patients with heavily pretreated CLL, early clinical data support chimeric antigen receptor T-cell therapy (CAR T), a novel therapy where patients’ own T cells are extracted, engineered, and reinfused. A related immunotherapy, using a similar process of retroviral vector insertion of an anti-CD19 CAR into donor NK cells before infusion into the patient, is termed CAR-NK cell therapy. It shows promise in early data from patients with CLL who all had previously been heavily treated with ibrutinib.

More research, more hope

Despite the significant advance that BTKis represent, BTKi resistance, with shortened survival, remains a clinical problem for patients with B-cell malignancies. BTKi resistance has been associated with several genetic and clinical risk factors, with mutations in BTK and PLCy2 the most common and most thoroughly researched. “Ongoing clinical trials of third-generation noncovalent BTKis and cellular therapies, such as CAR T, provide much hope for these patients. ... Continued additional research is needed to further prolong the survival of patients with BTKi-resistant B-cell malignancies.”

Dr. Stephens has received research funding and has served on advisory boards for a variety of pharmaceutical and biotechnology companies. Dr. Byrd has received research funding and has consulted for a variety of pharmaceutical and biotechnology companies.

The U.S. Food and Drug Administration has granted an accelerated approval to zanubrutinib (Brukinsa) for the treatment of adult patients with relapsed or refractory (R/R) marginal zone lymphoma (MZL) who have received at least one anti-CD20–based regimen, the drug’s maker BeiGene announced in a press statement.  

The drug works as an inhibitor of Bruton’s tyrosine kinase (BTK), which plays a critical role in B-cell–receptor signaling, a driver in the development of marginal zone lymphoma, according to the company.

The new approval comes just 2 weeks after the oral drug received an accelerated approval for the treatment of adult patients with Waldenström’s macroglobulinemia, a rare non-Hodgkin lymphoma. The drug also has an accelerated approval for treating mantle cell lymphoma in patients who have received at least one prior therapy and is being studied in the treatment of chronic lymphocytic leukemia.

The latest indication is based on results from two single-arm clinical trials, with overall response rate (ORR) as the primary endpoint.

In the multicenter, phase 2 MAGNOLIA trial, zanubrutinib “demonstrated impressive overall response and complete remission rates, with responses observed in all MZL subtypes,” said Stephen Opat, MBBS, of Monash University in Melbourne, lead principal investigator of the study. “In addition, this next-generation BTK inhibitor was well-tolerated in these patients, with low rate of discontinuation due to adverse reactions.”

In the MAGNOLIA trial, 66 patients with R/R MZL who had received at least one anti-CD20–based regimen were treated with zanubrutinib. Among the patients were 26 with extranodal subtype, 26 with nodal subtype, 12 with splenic subtype, and 4 with unknown subtype.

The ORR was 56% with a complete response rate of 20%, based on CT scan assessment.

In addition, the ORR was 67% with a complete response rate of 26%, based on PET-CT scan assessment.

The median duration of response (DoR) was not reached at the median follow-up time of 8.3 months, with 85% of responders still in remission at 12 months. Responses were observed in all MZL subtypes.

In an earlier, phase 1/2 trial of the agent, 20 patients were evaluated, including 9 with extranodal subtype, 5 with nodal subtype, and 6 with splenic subtype. Based on CT scan assessment, the ORR was 80% with a complete remission rate of 20%. The median DoR was not reached at the median follow-up time of 31.4 months, with 72% of responders still in remission at 12 months.

The most common (≥30%) adverse reactions, including laboratory abnormalities, in the pooled safety population of 847 patients were decreased neutrophil count, upper respiratory tract infection, decreased platelet count, hemorrhage, decreased lymphocyte count, rash, and musculoskeletal pain, said the company.

A version of this article first appeared on Medscape.com.

The U.S. Food and Drug Administration has granted an accelerated approval to zanubrutinib (Brukinsa) for the treatment of adult patients with relapsed or refractory (R/R) marginal zone lymphoma (MZL) who have received at least one anti-CD20–based regimen, the drug’s maker BeiGene announced in a press statement.  

The drug works as an inhibitor of Bruton’s tyrosine kinase (BTK), which plays a critical role in B-cell–receptor signaling, a driver in the development of marginal zone lymphoma, according to the company.

The new approval comes just 2 weeks after the oral drug received an accelerated approval for the treatment of adult patients with Waldenström’s macroglobulinemia, a rare non-Hodgkin lymphoma. The drug also has an accelerated approval for treating mantle cell lymphoma in patients who have received at least one prior therapy and is being studied in the treatment of chronic lymphocytic leukemia.

The latest indication is based on results from two single-arm clinical trials, with overall response rate (ORR) as the primary endpoint.

In the multicenter, phase 2 MAGNOLIA trial, zanubrutinib “demonstrated impressive overall response and complete remission rates, with responses observed in all MZL subtypes,” said Stephen Opat, MBBS, of Monash University in Melbourne, lead principal investigator of the study. “In addition, this next-generation BTK inhibitor was well-tolerated in these patients, with low rate of discontinuation due to adverse reactions.”

In the MAGNOLIA trial, 66 patients with R/R MZL who had received at least one anti-CD20–based regimen were treated with zanubrutinib. Among the patients were 26 with extranodal subtype, 26 with nodal subtype, 12 with splenic subtype, and 4 with unknown subtype.

The ORR was 56% with a complete response rate of 20%, based on CT scan assessment.

In addition, the ORR was 67% with a complete response rate of 26%, based on PET-CT scan assessment.

The median duration of response (DoR) was not reached at the median follow-up time of 8.3 months, with 85% of responders still in remission at 12 months. Responses were observed in all MZL subtypes.

In an earlier, phase 1/2 trial of the agent, 20 patients were evaluated, including 9 with extranodal subtype, 5 with nodal subtype, and 6 with splenic subtype. Based on CT scan assessment, the ORR was 80% with a complete remission rate of 20%. The median DoR was not reached at the median follow-up time of 31.4 months, with 72% of responders still in remission at 12 months.

The most common (≥30%) adverse reactions, including laboratory abnormalities, in the pooled safety population of 847 patients were decreased neutrophil count, upper respiratory tract infection, decreased platelet count, hemorrhage, decreased lymphocyte count, rash, and musculoskeletal pain, said the company.

A version of this article first appeared on Medscape.com.

The U.S. Food and Drug Administration has granted an accelerated approval to zanubrutinib (Brukinsa) for the treatment of adult patients with relapsed or refractory (R/R) marginal zone lymphoma (MZL) who have received at least one anti-CD20–based regimen, the drug’s maker BeiGene announced in a press statement.  

The drug works as an inhibitor of Bruton’s tyrosine kinase (BTK), which plays a critical role in B-cell–receptor signaling, a driver in the development of marginal zone lymphoma, according to the company.

The new approval comes just 2 weeks after the oral drug received an accelerated approval for the treatment of adult patients with Waldenström’s macroglobulinemia, a rare non-Hodgkin lymphoma. The drug also has an accelerated approval for treating mantle cell lymphoma in patients who have received at least one prior therapy and is being studied in the treatment of chronic lymphocytic leukemia.

The latest indication is based on results from two single-arm clinical trials, with overall response rate (ORR) as the primary endpoint.

In the multicenter, phase 2 MAGNOLIA trial, zanubrutinib “demonstrated impressive overall response and complete remission rates, with responses observed in all MZL subtypes,” said Stephen Opat, MBBS, of Monash University in Melbourne, lead principal investigator of the study. “In addition, this next-generation BTK inhibitor was well-tolerated in these patients, with low rate of discontinuation due to adverse reactions.”

In the MAGNOLIA trial, 66 patients with R/R MZL who had received at least one anti-CD20–based regimen were treated with zanubrutinib. Among the patients were 26 with extranodal subtype, 26 with nodal subtype, 12 with splenic subtype, and 4 with unknown subtype.

The ORR was 56% with a complete response rate of 20%, based on CT scan assessment.

In addition, the ORR was 67% with a complete response rate of 26%, based on PET-CT scan assessment.

The median duration of response (DoR) was not reached at the median follow-up time of 8.3 months, with 85% of responders still in remission at 12 months. Responses were observed in all MZL subtypes.

In an earlier, phase 1/2 trial of the agent, 20 patients were evaluated, including 9 with extranodal subtype, 5 with nodal subtype, and 6 with splenic subtype. Based on CT scan assessment, the ORR was 80% with a complete remission rate of 20%. The median DoR was not reached at the median follow-up time of 31.4 months, with 72% of responders still in remission at 12 months.

The most common (≥30%) adverse reactions, including laboratory abnormalities, in the pooled safety population of 847 patients were decreased neutrophil count, upper respiratory tract infection, decreased platelet count, hemorrhage, decreased lymphocyte count, rash, and musculoskeletal pain, said the company.

A version of this article first appeared on Medscape.com.

Durable remissions have been obtained in around 30%-40% of relapsed/refractory large B-cell lymphomas (BCL) through the use of CD19-directed chimeric antigen receptor-modified T-cell (CAR T-cell) therapy. However, T cell exhaustion and/or an immunosuppressive tumor environment may contribute to CAR T cell failure and BCL relapse.

To counter this failure, researchers assessed the use PD1 blockade with pembrolizumab after CD19-directed CAR T-cell therapy. Such treatment appeared safe and was able to achieve clinical responses in some patients with B-cell lymphomas refractory to or relapsed after CAR T-cell therapy, according to the results of a small study (NCT02650999) reported in Blood.

Success for some

Twelve patients with BCL who were either refractory to (nine patients) or relapsed after (three patients) CD19-directed CAR T-cell therapy were treated with pembrolizumab at 200 mg IV every 3 weeks, according to Elise A. Chong, MD, of the University of Pennsylvania, Philadelphia, and colleagues.

Overall, 3 of the 12 patients showed a response after pembrolizumab: One complete response; two partial responses. In addition, 1 patient had stable disease; thus, 4 of the 12 patients showed clinical benefit, according to the researchers. After pembrolizumab, these four patients with clinical benefit showed an increase in the percentage of CAR T cells as assessed by mass cytometry, and three out of the four also showed increases in CAR19 transgene levels as determined by qPCR. In addition, immune profiling using mass cytometry revealed increased CAR T-cell activation and proliferation and less T-cell exhaustion in these clinical responders.

In terms of safety, pembrolizumab appeared to be well tolerated and the only ≥ grade 3 adverse events related to pembrolizumab were neutropenia in three patients, the researchers added.
 

Looking forward

“Although patient numbers are small, these data suggest potential differences in the biology of CAR T cells or in the overall immune landscape of responders and nonresponders that influence the clinical efficacy of PD-1 blockade administered in this setting. Future work aimed at improving immune health after CAR T-cell infusion, as well as work aimed at decreasing CD8+ CAR T-cell exhaustion in CAR T-cell products, may serve as potential platforms for enhancing the efficacy of immune checkpoint blockade in patients treated with CAR T cells,” the researchers concluded.

The study was sponsored by the Abramson Cancer Center of the University of Pennsylvania. The authors reported serving on advisory boards and receiving research funding from a variety of pharmaceutical and biotechnology companies.

[email protected]

Durable remissions have been obtained in around 30%-40% of relapsed/refractory large B-cell lymphomas (BCL) through the use of CD19-directed chimeric antigen receptor-modified T-cell (CAR T-cell) therapy. However, T cell exhaustion and/or an immunosuppressive tumor environment may contribute to CAR T cell failure and BCL relapse.

To counter this failure, researchers assessed the use PD1 blockade with pembrolizumab after CD19-directed CAR T-cell therapy. Such treatment appeared safe and was able to achieve clinical responses in some patients with B-cell lymphomas refractory to or relapsed after CAR T-cell therapy, according to the results of a small study (NCT02650999) reported in Blood.

Success for some

Twelve patients with BCL who were either refractory to (nine patients) or relapsed after (three patients) CD19-directed CAR T-cell therapy were treated with pembrolizumab at 200 mg IV every 3 weeks, according to Elise A. Chong, MD, of the University of Pennsylvania, Philadelphia, and colleagues.

Overall, 3 of the 12 patients showed a response after pembrolizumab: One complete response; two partial responses. In addition, 1 patient had stable disease; thus, 4 of the 12 patients showed clinical benefit, according to the researchers. After pembrolizumab, these four patients with clinical benefit showed an increase in the percentage of CAR T cells as assessed by mass cytometry, and three out of the four also showed increases in CAR19 transgene levels as determined by qPCR. In addition, immune profiling using mass cytometry revealed increased CAR T-cell activation and proliferation and less T-cell exhaustion in these clinical responders.

In terms of safety, pembrolizumab appeared to be well tolerated and the only ≥ grade 3 adverse events related to pembrolizumab were neutropenia in three patients, the researchers added.
 

Looking forward

“Although patient numbers are small, these data suggest potential differences in the biology of CAR T cells or in the overall immune landscape of responders and nonresponders that influence the clinical efficacy of PD-1 blockade administered in this setting. Future work aimed at improving immune health after CAR T-cell infusion, as well as work aimed at decreasing CD8+ CAR T-cell exhaustion in CAR T-cell products, may serve as potential platforms for enhancing the efficacy of immune checkpoint blockade in patients treated with CAR T cells,” the researchers concluded.

The study was sponsored by the Abramson Cancer Center of the University of Pennsylvania. The authors reported serving on advisory boards and receiving research funding from a variety of pharmaceutical and biotechnology companies.

[email protected]

Durable remissions have been obtained in around 30%-40% of relapsed/refractory large B-cell lymphomas (BCL) through the use of CD19-directed chimeric antigen receptor-modified T-cell (CAR T-cell) therapy. However, T cell exhaustion and/or an immunosuppressive tumor environment may contribute to CAR T cell failure and BCL relapse.

To counter this failure, researchers assessed the use PD1 blockade with pembrolizumab after CD19-directed CAR T-cell therapy. Such treatment appeared safe and was able to achieve clinical responses in some patients with B-cell lymphomas refractory to or relapsed after CAR T-cell therapy, according to the results of a small study (NCT02650999) reported in Blood.

Success for some

Twelve patients with BCL who were either refractory to (nine patients) or relapsed after (three patients) CD19-directed CAR T-cell therapy were treated with pembrolizumab at 200 mg IV every 3 weeks, according to Elise A. Chong, MD, of the University of Pennsylvania, Philadelphia, and colleagues.

Overall, 3 of the 12 patients showed a response after pembrolizumab: One complete response; two partial responses. In addition, 1 patient had stable disease; thus, 4 of the 12 patients showed clinical benefit, according to the researchers. After pembrolizumab, these four patients with clinical benefit showed an increase in the percentage of CAR T cells as assessed by mass cytometry, and three out of the four also showed increases in CAR19 transgene levels as determined by qPCR. In addition, immune profiling using mass cytometry revealed increased CAR T-cell activation and proliferation and less T-cell exhaustion in these clinical responders.

In terms of safety, pembrolizumab appeared to be well tolerated and the only ≥ grade 3 adverse events related to pembrolizumab were neutropenia in three patients, the researchers added.
 

Looking forward

“Although patient numbers are small, these data suggest potential differences in the biology of CAR T cells or in the overall immune landscape of responders and nonresponders that influence the clinical efficacy of PD-1 blockade administered in this setting. Future work aimed at improving immune health after CAR T-cell infusion, as well as work aimed at decreasing CD8+ CAR T-cell exhaustion in CAR T-cell products, may serve as potential platforms for enhancing the efficacy of immune checkpoint blockade in patients treated with CAR T cells,” the researchers concluded.

The study was sponsored by the Abramson Cancer Center of the University of Pennsylvania. The authors reported serving on advisory boards and receiving research funding from a variety of pharmaceutical and biotechnology companies.

[email protected]

The Food and Drug Administration has approved zanubrutinib (Brukinsa) capsules for use in the treatment of adult patients with Waldenström’s macroglobulinemia (WM), a rare non-Hodgkin lymphoma, according to an approval letter from the agency to BeiGene, the drug’s maker.

The FDA stipulated that the company conduct an additional clinical trial (rather than an observational study) to assess the “known serious risk of second primary malignancies” associated with use of zanubrutinib. The study should further characterize the clinical benefit and safety of zanubrutinib for the treatment of patients with newly diagnosed WM with MYD88 mutation, the agency said.

The drug, which is a small-molecule inhibitor of Bruton’s tyrosine kinase (BTK), previously received accelerated approval for use in patients with mantle cell lymphoma who have received one prior therapy. It is also being studied for the treatment of chronic lymphocytic leukemia.

The new approval is primarily based on results from ASPEN, a randomized, active control, open-label trial that compared zanubrutinib and ibrutinib.

The ASPEN trial provided “compelling evidence” that zanubrutinib is a highly active BTK inhibitor in WM and that it showed improved tolerability across a number of clinically important side effects in comparison with the first-generation BTK inhibitor ibrutinib, said study investigator Steven Treon, MD, PhD, director of the Bing Center for Waldenström’s Macroglobulinemia Research at the Dana-Farber Cancer Institute, Boston. “The approval of [zanubrutinib] provides an important new option for targeted therapy in Waldenström’s macroglobulinemia,” he added in a company press statement.

The recommended dosage is 160 mg orally twice daily or 320 mg orally once; the drug should be swallowed whole with water with or without food.

In ASPEN, all patients had MYD88 mutation WM. Patients in cohort 1 (n = 201) were randomly assigned in a 1:1 ratio to receive zanubrutinib 160 mg twice daily or ibrutinib 420 mg once daily until disease progression or unacceptable toxicity. A total of 82% of patients had relapsed/refractory disease.

The major efficacy outcome was the response rate, defined as partial response or better (i.e., partial response, very good partial response, and complete response), as determined on the basis of standard consensus response criteria from the International Workshop on Waldenström’s Macroglobulinemia (IWWM-6) criteria.

The drugs had nearly identical response rates (roughly 77%). There were no complete responses with either drug. However, zanubrutinib had twice the rate of very good partial responses compared with ibrutinib (15.7% vs. 7.1%). In addition, on the basis of modified IWWM-6 criteria, the very good partial response rate was 28% with zanubrutinib, compared to 19% with ibrutinib.

An additional efficacy outcome measure was duration of response, which was measured by the percentage of patients who were event free at 12 months. Zanubrutinib bested ibrutinib in this measure (94.4% vs. 87.9%).

The safety of zanubrutinib was also investigated in the ASPEN trial. Among patients who received zanubrutinib, 93% were exposed for 6 months or longer, and 89% were exposed for longer than 1 year. In cohort 1, serious adverse reactions occurred in 44% of patients who received zanubrutinib. Serious adverse reactions that occurred in > 2% of patients included influenza (3%), pneumonia (4%), neutropenia and decreased neutrophil count (3%), hemorrhage (4%), pyrexia (3%), and febrile neutropenia (3%).

In the FDA’s prescribing information for the drug, which includes approved indications and pooled safety data, the most common adverse reactions for zanubrutinib (≥ 20%) are listed as decreased neutrophil count, upper respiratory tract infection, decreased platelet count, rash, hemorrhage, musculoskeletal pain, decreased hemoglobin, bruising, diarrhea, pneumonia, and cough.
 

A version of this article first appeared on Medscape.com.

The Food and Drug Administration has approved zanubrutinib (Brukinsa) capsules for use in the treatment of adult patients with Waldenström’s macroglobulinemia (WM), a rare non-Hodgkin lymphoma, according to an approval letter from the agency to BeiGene, the drug’s maker.

The FDA stipulated that the company conduct an additional clinical trial (rather than an observational study) to assess the “known serious risk of second primary malignancies” associated with use of zanubrutinib. The study should further characterize the clinical benefit and safety of zanubrutinib for the treatment of patients with newly diagnosed WM with MYD88 mutation, the agency said.

The drug, which is a small-molecule inhibitor of Bruton’s tyrosine kinase (BTK), previously received accelerated approval for use in patients with mantle cell lymphoma who have received one prior therapy. It is also being studied for the treatment of chronic lymphocytic leukemia.

The new approval is primarily based on results from ASPEN, a randomized, active control, open-label trial that compared zanubrutinib and ibrutinib.

The ASPEN trial provided “compelling evidence” that zanubrutinib is a highly active BTK inhibitor in WM and that it showed improved tolerability across a number of clinically important side effects in comparison with the first-generation BTK inhibitor ibrutinib, said study investigator Steven Treon, MD, PhD, director of the Bing Center for Waldenström’s Macroglobulinemia Research at the Dana-Farber Cancer Institute, Boston. “The approval of [zanubrutinib] provides an important new option for targeted therapy in Waldenström’s macroglobulinemia,” he added in a company press statement.

The recommended dosage is 160 mg orally twice daily or 320 mg orally once; the drug should be swallowed whole with water with or without food.

In ASPEN, all patients had MYD88 mutation WM. Patients in cohort 1 (n = 201) were randomly assigned in a 1:1 ratio to receive zanubrutinib 160 mg twice daily or ibrutinib 420 mg once daily until disease progression or unacceptable toxicity. A total of 82% of patients had relapsed/refractory disease.

The major efficacy outcome was the response rate, defined as partial response or better (i.e., partial response, very good partial response, and complete response), as determined on the basis of standard consensus response criteria from the International Workshop on Waldenström’s Macroglobulinemia (IWWM-6) criteria.

The drugs had nearly identical response rates (roughly 77%). There were no complete responses with either drug. However, zanubrutinib had twice the rate of very good partial responses compared with ibrutinib (15.7% vs. 7.1%). In addition, on the basis of modified IWWM-6 criteria, the very good partial response rate was 28% with zanubrutinib, compared to 19% with ibrutinib.

An additional efficacy outcome measure was duration of response, which was measured by the percentage of patients who were event free at 12 months. Zanubrutinib bested ibrutinib in this measure (94.4% vs. 87.9%).

The safety of zanubrutinib was also investigated in the ASPEN trial. Among patients who received zanubrutinib, 93% were exposed for 6 months or longer, and 89% were exposed for longer than 1 year. In cohort 1, serious adverse reactions occurred in 44% of patients who received zanubrutinib. Serious adverse reactions that occurred in > 2% of patients included influenza (3%), pneumonia (4%), neutropenia and decreased neutrophil count (3%), hemorrhage (4%), pyrexia (3%), and febrile neutropenia (3%).

In the FDA’s prescribing information for the drug, which includes approved indications and pooled safety data, the most common adverse reactions for zanubrutinib (≥ 20%) are listed as decreased neutrophil count, upper respiratory tract infection, decreased platelet count, rash, hemorrhage, musculoskeletal pain, decreased hemoglobin, bruising, diarrhea, pneumonia, and cough.
 

A version of this article first appeared on Medscape.com.

The Food and Drug Administration has approved zanubrutinib (Brukinsa) capsules for use in the treatment of adult patients with Waldenström’s macroglobulinemia (WM), a rare non-Hodgkin lymphoma, according to an approval letter from the agency to BeiGene, the drug’s maker.

The FDA stipulated that the company conduct an additional clinical trial (rather than an observational study) to assess the “known serious risk of second primary malignancies” associated with use of zanubrutinib. The study should further characterize the clinical benefit and safety of zanubrutinib for the treatment of patients with newly diagnosed WM with MYD88 mutation, the agency said.

The drug, which is a small-molecule inhibitor of Bruton’s tyrosine kinase (BTK), previously received accelerated approval for use in patients with mantle cell lymphoma who have received one prior therapy. It is also being studied for the treatment of chronic lymphocytic leukemia.

The new approval is primarily based on results from ASPEN, a randomized, active control, open-label trial that compared zanubrutinib and ibrutinib.

The ASPEN trial provided “compelling evidence” that zanubrutinib is a highly active BTK inhibitor in WM and that it showed improved tolerability across a number of clinically important side effects in comparison with the first-generation BTK inhibitor ibrutinib, said study investigator Steven Treon, MD, PhD, director of the Bing Center for Waldenström’s Macroglobulinemia Research at the Dana-Farber Cancer Institute, Boston. “The approval of [zanubrutinib] provides an important new option for targeted therapy in Waldenström’s macroglobulinemia,” he added in a company press statement.

The recommended dosage is 160 mg orally twice daily or 320 mg orally once; the drug should be swallowed whole with water with or without food.

In ASPEN, all patients had MYD88 mutation WM. Patients in cohort 1 (n = 201) were randomly assigned in a 1:1 ratio to receive zanubrutinib 160 mg twice daily or ibrutinib 420 mg once daily until disease progression or unacceptable toxicity. A total of 82% of patients had relapsed/refractory disease.

The major efficacy outcome was the response rate, defined as partial response or better (i.e., partial response, very good partial response, and complete response), as determined on the basis of standard consensus response criteria from the International Workshop on Waldenström’s Macroglobulinemia (IWWM-6) criteria.

The drugs had nearly identical response rates (roughly 77%). There were no complete responses with either drug. However, zanubrutinib had twice the rate of very good partial responses compared with ibrutinib (15.7% vs. 7.1%). In addition, on the basis of modified IWWM-6 criteria, the very good partial response rate was 28% with zanubrutinib, compared to 19% with ibrutinib.

An additional efficacy outcome measure was duration of response, which was measured by the percentage of patients who were event free at 12 months. Zanubrutinib bested ibrutinib in this measure (94.4% vs. 87.9%).

The safety of zanubrutinib was also investigated in the ASPEN trial. Among patients who received zanubrutinib, 93% were exposed for 6 months or longer, and 89% were exposed for longer than 1 year. In cohort 1, serious adverse reactions occurred in 44% of patients who received zanubrutinib. Serious adverse reactions that occurred in > 2% of patients included influenza (3%), pneumonia (4%), neutropenia and decreased neutrophil count (3%), hemorrhage (4%), pyrexia (3%), and febrile neutropenia (3%).

In the FDA’s prescribing information for the drug, which includes approved indications and pooled safety data, the most common adverse reactions for zanubrutinib (≥ 20%) are listed as decreased neutrophil count, upper respiratory tract infection, decreased platelet count, rash, hemorrhage, musculoskeletal pain, decreased hemoglobin, bruising, diarrhea, pneumonia, and cough.
 

A version of this article first appeared on Medscape.com.

The risk of in-hospital complications and poor birth outcomes were greater in pregnant women with current or historical cancer diagnoses, new research suggests.

The study, published in Mayo Clinic Proceedings, found that women with current and historical cancer diagnoses had an increased risk of death, kidney injury, and stroke during delivery hospitalizations, compared with those with no cancer. When it came to delivery outcomes, this group also had a higher risk for preterm birth and postpartum hemorrhage. Those with a current cancer diagnoses had a 1.7-fold increase in odds for a preterm birth, compared with women without cancer.

“Our study found that metastases increased the odds of mortality, cesarean delivery, preterm birth, and stillbirth,” the researchers noted. “Coupled with previous research reporting that pregnant women are more likely to be diagnosed with advanced disease, this implies that pregnant women with newly diagnosed cancer have poor prognoses.”

However, although women with prior cancer had increased odds of mortality, the researchers said it was not statistically significant.

“The study really did not show an increase of mortality [for women with prior cancer diagnosis],” said Justin Chura, MD, a specialist in gynecologic oncology who was not involved in the study. “And the reason might be because there is not or the reason might be because it’s such a rare event. You would need 100 million births to assess that. So I would actually use caution in that interpretation.”

Researchers analyzed more than 43 million delivery hospitalizations of women with or without current or historical cancer diagnoses between January 2004 and December 2014. They found that the most common cancer diagnoses were hematologic, thyroid, cervical, skin, and breast.

Of the five most common cancers, the prevalence of all maternal complications and negative delivery outcomes was the highest among women with hematologic cancers. They were more likely to experience peripartum cardiomyopathy, acute kidney injury, and arrhythmia, compared with other cancers. Postpartum hemorrhage, maternal mortality, and placental abruption was also more likely to occur in those with this type of cancer.

“I was surprised that it was the hematologic cancers that were worse when they did it by cancer type,” said Dr. Chura, who is the chief of surgery and the director of gynecologic oncology and robotic surgery at the Cancer Treatment Centers of America’s Eastern Regional Medical Center in Philadelphia. “I think this is a useful bit of information for counseling our patients and also to identify the cohort with the highest risk.”

The findings also suggested that those with skin cancer had the highest odds for stroke, while women with cervical and breast cancers were more likely to experience acute kidney injury and preterm birth.

Dr. Chura said cancer treatments can have an impact on a woman’s health when she’s giving birth. For example, if a woman is diagnosed with cervical cancer, doctors may perform a cone biopsy on her where they remove a large portion of the cervix and still leave them with the ability to conceive and become pregnant. However, those patients are left with a higher risk of a preterm delivery.

For women with a hematologic cancer like non-Hodgkin’s lymphoma, chest radiation may cause some subsequent damage to their heart muscles “and now the stress of pregnancy puts more demand on the heart that can lead to cardiac complications for that patient,” Dr. Chura said.

“There are potential long-term effects from radiation and chemotherapy,” Dr. Chura said.

Previous studies have shown that chemotherapy may affect pregnancy and delivery. A 2019 study published in the Journal of Cancer also found that 59 pregnant women with cancer had increased mortality compared with those without the long-term illness. Meanwhile, another 2018 study published in Cancer found that women who conceived less than a year after starting chemotherapy had higher risks of preterm birth in comparison with those who conceived more than a year after starting chemotherapy. The study also found that cancer survivors who conceived more than a year after finishing chemotherapy with or without radiation had no higher risk of a preterm birth than those without cancer.

Dr. Chura said the new study could force doctors to think about the long-term effects of their cancer therapies and make them more apt to think about how to make cancer therapy less toxic with less long-term health consequences, while still curing patients.

“Most oncologists, when dealing with younger patients, are very focused on curing the cancer at hand, but not necessarily thinking 5 or 10 years down the road,” Dr. Chura said. “[This study] could help inform or at least make us aware of the long-term consequences of our cancer therapies.”

Dr. Chura had no relevant financial disclosures.

The risk of in-hospital complications and poor birth outcomes were greater in pregnant women with current or historical cancer diagnoses, new research suggests.

The study, published in Mayo Clinic Proceedings, found that women with current and historical cancer diagnoses had an increased risk of death, kidney injury, and stroke during delivery hospitalizations, compared with those with no cancer. When it came to delivery outcomes, this group also had a higher risk for preterm birth and postpartum hemorrhage. Those with a current cancer diagnoses had a 1.7-fold increase in odds for a preterm birth, compared with women without cancer.

“Our study found that metastases increased the odds of mortality, cesarean delivery, preterm birth, and stillbirth,” the researchers noted. “Coupled with previous research reporting that pregnant women are more likely to be diagnosed with advanced disease, this implies that pregnant women with newly diagnosed cancer have poor prognoses.”

However, although women with prior cancer had increased odds of mortality, the researchers said it was not statistically significant.

“The study really did not show an increase of mortality [for women with prior cancer diagnosis],” said Justin Chura, MD, a specialist in gynecologic oncology who was not involved in the study. “And the reason might be because there is not or the reason might be because it’s such a rare event. You would need 100 million births to assess that. So I would actually use caution in that interpretation.”

Researchers analyzed more than 43 million delivery hospitalizations of women with or without current or historical cancer diagnoses between January 2004 and December 2014. They found that the most common cancer diagnoses were hematologic, thyroid, cervical, skin, and breast.

Of the five most common cancers, the prevalence of all maternal complications and negative delivery outcomes was the highest among women with hematologic cancers. They were more likely to experience peripartum cardiomyopathy, acute kidney injury, and arrhythmia, compared with other cancers. Postpartum hemorrhage, maternal mortality, and placental abruption was also more likely to occur in those with this type of cancer.

“I was surprised that it was the hematologic cancers that were worse when they did it by cancer type,” said Dr. Chura, who is the chief of surgery and the director of gynecologic oncology and robotic surgery at the Cancer Treatment Centers of America’s Eastern Regional Medical Center in Philadelphia. “I think this is a useful bit of information for counseling our patients and also to identify the cohort with the highest risk.”

The findings also suggested that those with skin cancer had the highest odds for stroke, while women with cervical and breast cancers were more likely to experience acute kidney injury and preterm birth.

Dr. Chura said cancer treatments can have an impact on a woman’s health when she’s giving birth. For example, if a woman is diagnosed with cervical cancer, doctors may perform a cone biopsy on her where they remove a large portion of the cervix and still leave them with the ability to conceive and become pregnant. However, those patients are left with a higher risk of a preterm delivery.

For women with a hematologic cancer like non-Hodgkin’s lymphoma, chest radiation may cause some subsequent damage to their heart muscles “and now the stress of pregnancy puts more demand on the heart that can lead to cardiac complications for that patient,” Dr. Chura said.

“There are potential long-term effects from radiation and chemotherapy,” Dr. Chura said.

Previous studies have shown that chemotherapy may affect pregnancy and delivery. A 2019 study published in the Journal of Cancer also found that 59 pregnant women with cancer had increased mortality compared with those without the long-term illness. Meanwhile, another 2018 study published in Cancer found that women who conceived less than a year after starting chemotherapy had higher risks of preterm birth in comparison with those who conceived more than a year after starting chemotherapy. The study also found that cancer survivors who conceived more than a year after finishing chemotherapy with or without radiation had no higher risk of a preterm birth than those without cancer.

Dr. Chura said the new study could force doctors to think about the long-term effects of their cancer therapies and make them more apt to think about how to make cancer therapy less toxic with less long-term health consequences, while still curing patients.

“Most oncologists, when dealing with younger patients, are very focused on curing the cancer at hand, but not necessarily thinking 5 or 10 years down the road,” Dr. Chura said. “[This study] could help inform or at least make us aware of the long-term consequences of our cancer therapies.”

Dr. Chura had no relevant financial disclosures.

The risk of in-hospital complications and poor birth outcomes were greater in pregnant women with current or historical cancer diagnoses, new research suggests.

The study, published in Mayo Clinic Proceedings, found that women with current and historical cancer diagnoses had an increased risk of death, kidney injury, and stroke during delivery hospitalizations, compared with those with no cancer. When it came to delivery outcomes, this group also had a higher risk for preterm birth and postpartum hemorrhage. Those with a current cancer diagnoses had a 1.7-fold increase in odds for a preterm birth, compared with women without cancer.

“Our study found that metastases increased the odds of mortality, cesarean delivery, preterm birth, and stillbirth,” the researchers noted. “Coupled with previous research reporting that pregnant women are more likely to be diagnosed with advanced disease, this implies that pregnant women with newly diagnosed cancer have poor prognoses.”

However, although women with prior cancer had increased odds of mortality, the researchers said it was not statistically significant.

“The study really did not show an increase of mortality [for women with prior cancer diagnosis],” said Justin Chura, MD, a specialist in gynecologic oncology who was not involved in the study. “And the reason might be because there is not or the reason might be because it’s such a rare event. You would need 100 million births to assess that. So I would actually use caution in that interpretation.”

Researchers analyzed more than 43 million delivery hospitalizations of women with or without current or historical cancer diagnoses between January 2004 and December 2014. They found that the most common cancer diagnoses were hematologic, thyroid, cervical, skin, and breast.

Of the five most common cancers, the prevalence of all maternal complications and negative delivery outcomes was the highest among women with hematologic cancers. They were more likely to experience peripartum cardiomyopathy, acute kidney injury, and arrhythmia, compared with other cancers. Postpartum hemorrhage, maternal mortality, and placental abruption was also more likely to occur in those with this type of cancer.

“I was surprised that it was the hematologic cancers that were worse when they did it by cancer type,” said Dr. Chura, who is the chief of surgery and the director of gynecologic oncology and robotic surgery at the Cancer Treatment Centers of America’s Eastern Regional Medical Center in Philadelphia. “I think this is a useful bit of information for counseling our patients and also to identify the cohort with the highest risk.”

The findings also suggested that those with skin cancer had the highest odds for stroke, while women with cervical and breast cancers were more likely to experience acute kidney injury and preterm birth.

Dr. Chura said cancer treatments can have an impact on a woman’s health when she’s giving birth. For example, if a woman is diagnosed with cervical cancer, doctors may perform a cone biopsy on her where they remove a large portion of the cervix and still leave them with the ability to conceive and become pregnant. However, those patients are left with a higher risk of a preterm delivery.

For women with a hematologic cancer like non-Hodgkin’s lymphoma, chest radiation may cause some subsequent damage to their heart muscles “and now the stress of pregnancy puts more demand on the heart that can lead to cardiac complications for that patient,” Dr. Chura said.

“There are potential long-term effects from radiation and chemotherapy,” Dr. Chura said.

Previous studies have shown that chemotherapy may affect pregnancy and delivery. A 2019 study published in the Journal of Cancer also found that 59 pregnant women with cancer had increased mortality compared with those without the long-term illness. Meanwhile, another 2018 study published in Cancer found that women who conceived less than a year after starting chemotherapy had higher risks of preterm birth in comparison with those who conceived more than a year after starting chemotherapy. The study also found that cancer survivors who conceived more than a year after finishing chemotherapy with or without radiation had no higher risk of a preterm birth than those without cancer.

Dr. Chura said the new study could force doctors to think about the long-term effects of their cancer therapies and make them more apt to think about how to make cancer therapy less toxic with less long-term health consequences, while still curing patients.

“Most oncologists, when dealing with younger patients, are very focused on curing the cancer at hand, but not necessarily thinking 5 or 10 years down the road,” Dr. Chura said. “[This study] could help inform or at least make us aware of the long-term consequences of our cancer therapies.”

Dr. Chura had no relevant financial disclosures.

Data from a large French registry on a multicenter experience with chimeric antigen receptor T-cell (CAR T) therapy for aggressive lymphoma suggests that the favorable outcomes seen in clinical trials can be replicated in the real world.

Among 481 patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) treated with either of two commercially available CAR T products – tisagenlecleucel (Kymriah) or axicabtagene ciloleucel (Yescarta) – the duration of responses, progression-free survival (PFS), and overall survival (OS) rates at 6 months mirror those seen in clinical trials, reported Steven LeGouill, MD, PhD, from the University of Nantes (France), on behalf of colleagues in the DESCAR-T (Dispositive d’Evaluation et de Suivi des CAR-T) registry.

“CAR T has now become a standard of care in a lot of French centers, with more than 640 patients treated with CAR T in less than 2 years. The DESCAR-T real-life experience mimics the experience that had been previously by other real-life registries but also in clinical trials. We didn’t see new emerging toxicity signals in real life,” he said in an oral abstract session during the European Hematology Association annual congress (Abstract S216).

“I am convinced that a population registry about CAR T–treated patients is needed,” commented Pieter Sonneveld, MD, from Erasmus Medical Center in Rotterdam, the Netherlands, who was not involved in the study.

“Selection criteria for CAR T trials have been incredibly restrictive, and academic trials have not gained ground yet. It is important to collect and analyze more data, include non-trial patients and analyze long-term follow-up in order to determine the real effects of this innovative treatment in lymphoma and other diseases,” he said.

Dr. Sonneveld, EHA past president, was the moderator a briefing where Dr. LeGouill presented the DESCAR-T study findings.

Natalie Sophia Grover, MD, a leukemia and lymphoma specialist at the University of North Carolina at Chapel Hill, noted in an interview that “there have been several publications recently that have shown that these promising outcomes for these really refractory, high-risk patients with diffuse large B-cell lymphoma seem to be similar with what we’ve seen in trials, which is definitely exciting.”

She noted that the median time from CAR T order to treatment in the study, 50 days, was longer than in her experience.

“Generally, from collection to treatment is less than a month. Looking at that, I would have expected more patients not to make it CAR T, but nearly 90% of patients who had collections got treatment, which is pretty good. Those patients that didn’t make it to treatment had really poor outcomes,” she said.

Dr. Grover was not involved in the study.
 

More data, s’il vous plait

The DESCAR-T registry was created in response to a request from French health authorities for data beyond that provided in the EBMT patient registry. The health authorities asked for characterization of the CAR T–eligible population in an intention to treat, 15-year follow-up of both CAR T recipients and candidates who were not treated for whatever reasons, and a full accounting of previous lines of therapy.

Dr. LeGouill presented the first analysis of data from the registry involving 19 enrolling site and 647 patients with DLBCL for whom CAR T cells were ordered from January 2018 to March 2021.

Of the 647 candidates, 10 did not have CAR T ordered for reasons that included patient deaths or disease progression, infection, and patient refusal. An additional 30 patients either had leukapheresis performed or pending, and 607 had CAR T ordered.

Of the 607 patients, 53 did not receive CAR T infusions because of disease progression, death before product administration, manufacturing or leukapheresis failures, uncontrolled infections, patient choice, or progression of other malignancies.

That left 550 patients (85%) who received a CAR T product, either tisagenlecleucel (200 patients) or axicabtagene ciloleucel (350 patients).

Among all patients, the median age at CAR T order was 63 for patients who received tisagenlecleucel, and 65 for patients receiving axicabtagene ciloleucel. Patients 65 and older comprised 44% and 51% of the population, respectively.

Patients treated with each CAR T product had a median of three prior lines of therapy.
 

Manageable toxicities

Toxicities within 10 days of CAR T infusion included 418 cases among 515 patients (81.2%) of cytokine release syndrome, with most being grade 1 or 2 in severity; 44 patients had grade 3 or 4 CRS.

Any-grade neurotoxicity was seen in 184 patients (35.7%), primarily grade 1 or 2 in severity; 50 patients had grade 3 or greater neurotoxicity.

Of 427 patients with at least one CAR T–specific toxicity within 10 days, 139 (32.8%) required ICU admission, 325 (76,1%) were treated for CAR T–specific toxicities, 278 (65.1%) received tocilizumab, 13 (3%) received siltuximab, and 176 (41.2%) received corticosteroids.
 

Favorable outcomes

Overall response rates, at 1, 3, and 6 months post infusions were 70.6%, 56.3%, and 60%, respectively, with the majority of response at each time point being complete responses (CR).

The 6-month overall survival (OS) rate among all patients who were treated was 83.7%, compared with 5.5% for patients who did not receive CAR T infusions.

Progression-free survival (PFS) at 6 months was 44.5%, and 57.7% of patients had an ongoing response at the same time point.

Among patients who received bridging therapy between leukapheresis and CAR T infusion, the 6-month PFS was 58.4% for patients with either a CR, partial response, or stable disease, compared with 63.3% for patients who did not receive bridging therapy, and 29.8% for those with disease progression.

The respective 6 months OS rates were 87.4%, 82.3%, and 65.5%.

The results showed that patients who do not have at least stable disease at the time of CAR T infusion are at risk for early relapse, but approximately 30% of these patients still had long-term disease control, Dr. LeGouill said.

He acknowledged that longer follow-up will be need to see whether the plateaus in the PFS and OS curves the investigators observed can be maintained over time. Questions that still need to be answered include the impact of bridging therapy or disease status at the start of treatment on outcomes, and how to improve CAR T efficacy based on individual patient characteristics.

The registry will be extended to include data on patients treated with CAR T for mantle cell lymphoma and multiple myeloma, investigators announced.

The study is supported by participating centers and Gilead/Kite and Novartis. Dr. LeGouill disclosed advisory board activity and honoraria from the companies and others. Dr. Grover disclosed advisory board participating for Kite and others. Dr. Sonneveld has disclosed research grants and honoraria from several companies, not including Kite or Novartis.

Data from a large French registry on a multicenter experience with chimeric antigen receptor T-cell (CAR T) therapy for aggressive lymphoma suggests that the favorable outcomes seen in clinical trials can be replicated in the real world.

Among 481 patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) treated with either of two commercially available CAR T products – tisagenlecleucel (Kymriah) or axicabtagene ciloleucel (Yescarta) – the duration of responses, progression-free survival (PFS), and overall survival (OS) rates at 6 months mirror those seen in clinical trials, reported Steven LeGouill, MD, PhD, from the University of Nantes (France), on behalf of colleagues in the DESCAR-T (Dispositive d’Evaluation et de Suivi des CAR-T) registry.

“CAR T has now become a standard of care in a lot of French centers, with more than 640 patients treated with CAR T in less than 2 years. The DESCAR-T real-life experience mimics the experience that had been previously by other real-life registries but also in clinical trials. We didn’t see new emerging toxicity signals in real life,” he said in an oral abstract session during the European Hematology Association annual congress (Abstract S216).

“I am convinced that a population registry about CAR T–treated patients is needed,” commented Pieter Sonneveld, MD, from Erasmus Medical Center in Rotterdam, the Netherlands, who was not involved in the study.

“Selection criteria for CAR T trials have been incredibly restrictive, and academic trials have not gained ground yet. It is important to collect and analyze more data, include non-trial patients and analyze long-term follow-up in order to determine the real effects of this innovative treatment in lymphoma and other diseases,” he said.

Dr. Sonneveld, EHA past president, was the moderator a briefing where Dr. LeGouill presented the DESCAR-T study findings.

Natalie Sophia Grover, MD, a leukemia and lymphoma specialist at the University of North Carolina at Chapel Hill, noted in an interview that “there have been several publications recently that have shown that these promising outcomes for these really refractory, high-risk patients with diffuse large B-cell lymphoma seem to be similar with what we’ve seen in trials, which is definitely exciting.”

She noted that the median time from CAR T order to treatment in the study, 50 days, was longer than in her experience.

“Generally, from collection to treatment is less than a month. Looking at that, I would have expected more patients not to make it CAR T, but nearly 90% of patients who had collections got treatment, which is pretty good. Those patients that didn’t make it to treatment had really poor outcomes,” she said.

Dr. Grover was not involved in the study.
 

More data, s’il vous plait

The DESCAR-T registry was created in response to a request from French health authorities for data beyond that provided in the EBMT patient registry. The health authorities asked for characterization of the CAR T–eligible population in an intention to treat, 15-year follow-up of both CAR T recipients and candidates who were not treated for whatever reasons, and a full accounting of previous lines of therapy.

Dr. LeGouill presented the first analysis of data from the registry involving 19 enrolling site and 647 patients with DLBCL for whom CAR T cells were ordered from January 2018 to March 2021.

Of the 647 candidates, 10 did not have CAR T ordered for reasons that included patient deaths or disease progression, infection, and patient refusal. An additional 30 patients either had leukapheresis performed or pending, and 607 had CAR T ordered.

Of the 607 patients, 53 did not receive CAR T infusions because of disease progression, death before product administration, manufacturing or leukapheresis failures, uncontrolled infections, patient choice, or progression of other malignancies.

That left 550 patients (85%) who received a CAR T product, either tisagenlecleucel (200 patients) or axicabtagene ciloleucel (350 patients).

Among all patients, the median age at CAR T order was 63 for patients who received tisagenlecleucel, and 65 for patients receiving axicabtagene ciloleucel. Patients 65 and older comprised 44% and 51% of the population, respectively.

Patients treated with each CAR T product had a median of three prior lines of therapy.
 

Manageable toxicities

Toxicities within 10 days of CAR T infusion included 418 cases among 515 patients (81.2%) of cytokine release syndrome, with most being grade 1 or 2 in severity; 44 patients had grade 3 or 4 CRS.

Any-grade neurotoxicity was seen in 184 patients (35.7%), primarily grade 1 or 2 in severity; 50 patients had grade 3 or greater neurotoxicity.

Of 427 patients with at least one CAR T–specific toxicity within 10 days, 139 (32.8%) required ICU admission, 325 (76,1%) were treated for CAR T–specific toxicities, 278 (65.1%) received tocilizumab, 13 (3%) received siltuximab, and 176 (41.2%) received corticosteroids.
 

Favorable outcomes

Overall response rates, at 1, 3, and 6 months post infusions were 70.6%, 56.3%, and 60%, respectively, with the majority of response at each time point being complete responses (CR).

The 6-month overall survival (OS) rate among all patients who were treated was 83.7%, compared with 5.5% for patients who did not receive CAR T infusions.

Progression-free survival (PFS) at 6 months was 44.5%, and 57.7% of patients had an ongoing response at the same time point.

Among patients who received bridging therapy between leukapheresis and CAR T infusion, the 6-month PFS was 58.4% for patients with either a CR, partial response, or stable disease, compared with 63.3% for patients who did not receive bridging therapy, and 29.8% for those with disease progression.

The respective 6 months OS rates were 87.4%, 82.3%, and 65.5%.

The results showed that patients who do not have at least stable disease at the time of CAR T infusion are at risk for early relapse, but approximately 30% of these patients still had long-term disease control, Dr. LeGouill said.

He acknowledged that longer follow-up will be need to see whether the plateaus in the PFS and OS curves the investigators observed can be maintained over time. Questions that still need to be answered include the impact of bridging therapy or disease status at the start of treatment on outcomes, and how to improve CAR T efficacy based on individual patient characteristics.

The registry will be extended to include data on patients treated with CAR T for mantle cell lymphoma and multiple myeloma, investigators announced.

The study is supported by participating centers and Gilead/Kite and Novartis. Dr. LeGouill disclosed advisory board activity and honoraria from the companies and others. Dr. Grover disclosed advisory board participating for Kite and others. Dr. Sonneveld has disclosed research grants and honoraria from several companies, not including Kite or Novartis.

Data from a large French registry on a multicenter experience with chimeric antigen receptor T-cell (CAR T) therapy for aggressive lymphoma suggests that the favorable outcomes seen in clinical trials can be replicated in the real world.

Among 481 patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) treated with either of two commercially available CAR T products – tisagenlecleucel (Kymriah) or axicabtagene ciloleucel (Yescarta) – the duration of responses, progression-free survival (PFS), and overall survival (OS) rates at 6 months mirror those seen in clinical trials, reported Steven LeGouill, MD, PhD, from the University of Nantes (France), on behalf of colleagues in the DESCAR-T (Dispositive d’Evaluation et de Suivi des CAR-T) registry.

“CAR T has now become a standard of care in a lot of French centers, with more than 640 patients treated with CAR T in less than 2 years. The DESCAR-T real-life experience mimics the experience that had been previously by other real-life registries but also in clinical trials. We didn’t see new emerging toxicity signals in real life,” he said in an oral abstract session during the European Hematology Association annual congress (Abstract S216).

“I am convinced that a population registry about CAR T–treated patients is needed,” commented Pieter Sonneveld, MD, from Erasmus Medical Center in Rotterdam, the Netherlands, who was not involved in the study.

“Selection criteria for CAR T trials have been incredibly restrictive, and academic trials have not gained ground yet. It is important to collect and analyze more data, include non-trial patients and analyze long-term follow-up in order to determine the real effects of this innovative treatment in lymphoma and other diseases,” he said.

Dr. Sonneveld, EHA past president, was the moderator a briefing where Dr. LeGouill presented the DESCAR-T study findings.

Natalie Sophia Grover, MD, a leukemia and lymphoma specialist at the University of North Carolina at Chapel Hill, noted in an interview that “there have been several publications recently that have shown that these promising outcomes for these really refractory, high-risk patients with diffuse large B-cell lymphoma seem to be similar with what we’ve seen in trials, which is definitely exciting.”

She noted that the median time from CAR T order to treatment in the study, 50 days, was longer than in her experience.

“Generally, from collection to treatment is less than a month. Looking at that, I would have expected more patients not to make it CAR T, but nearly 90% of patients who had collections got treatment, which is pretty good. Those patients that didn’t make it to treatment had really poor outcomes,” she said.

Dr. Grover was not involved in the study.
 

More data, s’il vous plait

The DESCAR-T registry was created in response to a request from French health authorities for data beyond that provided in the EBMT patient registry. The health authorities asked for characterization of the CAR T–eligible population in an intention to treat, 15-year follow-up of both CAR T recipients and candidates who were not treated for whatever reasons, and a full accounting of previous lines of therapy.

Dr. LeGouill presented the first analysis of data from the registry involving 19 enrolling site and 647 patients with DLBCL for whom CAR T cells were ordered from January 2018 to March 2021.

Of the 647 candidates, 10 did not have CAR T ordered for reasons that included patient deaths or disease progression, infection, and patient refusal. An additional 30 patients either had leukapheresis performed or pending, and 607 had CAR T ordered.

Of the 607 patients, 53 did not receive CAR T infusions because of disease progression, death before product administration, manufacturing or leukapheresis failures, uncontrolled infections, patient choice, or progression of other malignancies.

That left 550 patients (85%) who received a CAR T product, either tisagenlecleucel (200 patients) or axicabtagene ciloleucel (350 patients).

Among all patients, the median age at CAR T order was 63 for patients who received tisagenlecleucel, and 65 for patients receiving axicabtagene ciloleucel. Patients 65 and older comprised 44% and 51% of the population, respectively.

Patients treated with each CAR T product had a median of three prior lines of therapy.
 

Manageable toxicities

Toxicities within 10 days of CAR T infusion included 418 cases among 515 patients (81.2%) of cytokine release syndrome, with most being grade 1 or 2 in severity; 44 patients had grade 3 or 4 CRS.

Any-grade neurotoxicity was seen in 184 patients (35.7%), primarily grade 1 or 2 in severity; 50 patients had grade 3 or greater neurotoxicity.

Of 427 patients with at least one CAR T–specific toxicity within 10 days, 139 (32.8%) required ICU admission, 325 (76,1%) were treated for CAR T–specific toxicities, 278 (65.1%) received tocilizumab, 13 (3%) received siltuximab, and 176 (41.2%) received corticosteroids.
 

Favorable outcomes

Overall response rates, at 1, 3, and 6 months post infusions were 70.6%, 56.3%, and 60%, respectively, with the majority of response at each time point being complete responses (CR).

The 6-month overall survival (OS) rate among all patients who were treated was 83.7%, compared with 5.5% for patients who did not receive CAR T infusions.

Progression-free survival (PFS) at 6 months was 44.5%, and 57.7% of patients had an ongoing response at the same time point.

Among patients who received bridging therapy between leukapheresis and CAR T infusion, the 6-month PFS was 58.4% for patients with either a CR, partial response, or stable disease, compared with 63.3% for patients who did not receive bridging therapy, and 29.8% for those with disease progression.

The respective 6 months OS rates were 87.4%, 82.3%, and 65.5%.

The results showed that patients who do not have at least stable disease at the time of CAR T infusion are at risk for early relapse, but approximately 30% of these patients still had long-term disease control, Dr. LeGouill said.

He acknowledged that longer follow-up will be need to see whether the plateaus in the PFS and OS curves the investigators observed can be maintained over time. Questions that still need to be answered include the impact of bridging therapy or disease status at the start of treatment on outcomes, and how to improve CAR T efficacy based on individual patient characteristics.

The registry will be extended to include data on patients treated with CAR T for mantle cell lymphoma and multiple myeloma, investigators announced.

The study is supported by participating centers and Gilead/Kite and Novartis. Dr. LeGouill disclosed advisory board activity and honoraria from the companies and others. Dr. Grover disclosed advisory board participating for Kite and others. Dr. Sonneveld has disclosed research grants and honoraria from several companies, not including Kite or Novartis.

Patients with relapsed or refractory B-cell non-Hodgkin lymphomas who are not candidates for hematopoietic stem cell transplant have a generally poor prognosis and few treatment options, but an experimental combination of the antibody-drug conjugate naratuximab with rituximab showed promising efficacy and acceptable safety in these patients in a phase 2 trial.

Among patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) the combination was associated with a 44.7% overall response rate, including 31.6% complete responses, and two-thirds of patients had responses lasting more than 12 months, reported Moshe Yair Levy, MD, from Texas Oncology–Baylor Charles A Sammons Cancer Center in Dallas.

“This is, in my viewpoint, very exciting therapy,” he said in a question-and-answer session following his presentation of the data in a late-breaking abstract session during the European Hematology Association annual congress. (Abstract LB1903).

Naratuximab emtansine is an investigational antibody-drug conjugate (ADC) consisting of a humanized monoclonal antibody against CD37, a surface marker on B lymphocytes that is highly expressed in non-Hodgkin lymphoma (NHL), conjugated to a cytotoxic derivative of maitansine.

CD37 is also an internalizable cell-surface antigen, making it an attractive candidate for an ADC approach.

In a phase 1 trial, naratuximab monotherapy showed a good safety profile and a 22% overall response rate, Dr. Levy noted.

“What they found is that, if you coadminister this ADC with rituximab, you’re actually going to get more internalization of the CD37 monoclonal, therefore more payload delivered to your target cells,” he said.

He reported results of a multicenter, adaptive phase 2 study of the combination in patients with DLBCL and other relapsed/refractory NHL.
 

DLBCL and others

The trial was divided into two parts, with the first consisting of a safety run-in phase with expansion in patients with confirmed diagnoses of relapsed/refractory NHL, including DLBCL, follicular lymphoma, mantle cell lymphoma, and marginal zone lymphoma.

Patients with double- or triple-hit disease (with translocations in MYC plus either BCL2 and/or BCL6), bulky disease, or transformed lymphoma were eligible.

The second part consisted of two cohorts of patients with DLBCL treated with naratuximab and rituximab either weekly or every 3 weeks.

All patients in the study had received one to six prior lines of therapy, and had Eastern Cooperative Oncology Group performance status of 0-2. Patients with CNS lymphomas or prior anti-CD37 targeting therapy were excluded.

The safety population included 50 patients with DLBCL assigned to therapy every 3 weeks, 30 assigned to weekly therapy, and 20 patients with other NHL.
 

DLBCL efficacy

A total of 76 patients with DLBCL were evaluable for efficacy.

The ORR was 44% for patients in both the weekly and every 3 week cohorts, with 31.6% having complete responses.

Among 61 patients with nonbulky disease (longest diameter 7.5 cm or less), the ORR was 50.8%, and among 28 patients who had three or more prior lines of therapy the ORR was 46.4%, with 32.1% having a complete response.

Among responders followed for a median of 15 months, the median duration of response was not reached, and 66% had responses lasting beyond 12 months.

In the weekly dosing DLBCL cohort, 53.3% of patients discontinued treatment of both study drugs because of disease progression, as did 58% of those in the every 3 week cohort, and 30% of patients with other lymphomas. Only eight patients discontinued the combination because of treatment-emergent adverse events. Six patients had treatment-emergent adverse events leading to naratuximab dose reduction.

The most common grade 3 or 4 adverse events were neutropenia, leukopenia, lymphopenia and thrombocytopenias. Dr. Levy commented that the use of granulocyte colony-stimulating factor, which was not mandatory in the study, would likely have lowered the incidence of cytopenias.

There were 10 deaths during the study, 2 of which were considered to be treatment related, occurring in 1 patient each in the DLBCL dosing cohorts; 1 of the patients died from pneumonitis, and the other from left ventricular heart failure.

Other patients deaths were attributed to non–treatment-related cardiac arrest, acute renal failure, exacerbation of chronic heart failure, respiratory failure, multiorgan failure, lung infection, or colon adenocarcinoma.
 

Q 3 weeks suffices

In the question-and-answer session following the presentation, Kenny Lei, MD, from the Chinese University of Hong Kong asked Dr. Levy what the half-life of naratuximab is, and what was the investigator’s rationale for testing a weekly dosing schedule.

“I think the reason they checked the two different regimens, the Q week and the Q 3-week group, is that they noted that [naratuximab] was cleared relatively quickly, and they wanted to see whether or not, by giving Q weekly, when you get a continuous CD37 site occupancy if they would have a better outcome. But as you saw, in the groups there was really no clinically relevant difference in outcome,” Dr. Levy said.

Andrew Davies, MD, PhD, from the University of Southampton (England), asked whether the neutropenia seen in the study was related to myeloid expression of the target of from the off-target deconjugated payload.

“I don’t know that I necessarily have the answer to that,” Dr. Levy replied. “Remember there is the CD20 monoclonal rituximab which we know can cause neutropenia, as well as the CD37 and the target payload. I don’t know if we have enough information to attribute it to one specific component of the therapy,” he said.

The study was funded by Debiopharm International. Dr. Levy disclosed speaker activities for multiple companies, not including Debiopharm. Dr. Lei and Dr. Davies had no disclosures relevant to the study.

Patients with relapsed or refractory B-cell non-Hodgkin lymphomas who are not candidates for hematopoietic stem cell transplant have a generally poor prognosis and few treatment options, but an experimental combination of the antibody-drug conjugate naratuximab with rituximab showed promising efficacy and acceptable safety in these patients in a phase 2 trial.

Among patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) the combination was associated with a 44.7% overall response rate, including 31.6% complete responses, and two-thirds of patients had responses lasting more than 12 months, reported Moshe Yair Levy, MD, from Texas Oncology–Baylor Charles A Sammons Cancer Center in Dallas.

“This is, in my viewpoint, very exciting therapy,” he said in a question-and-answer session following his presentation of the data in a late-breaking abstract session during the European Hematology Association annual congress. (Abstract LB1903).

Naratuximab emtansine is an investigational antibody-drug conjugate (ADC) consisting of a humanized monoclonal antibody against CD37, a surface marker on B lymphocytes that is highly expressed in non-Hodgkin lymphoma (NHL), conjugated to a cytotoxic derivative of maitansine.

CD37 is also an internalizable cell-surface antigen, making it an attractive candidate for an ADC approach.

In a phase 1 trial, naratuximab monotherapy showed a good safety profile and a 22% overall response rate, Dr. Levy noted.

“What they found is that, if you coadminister this ADC with rituximab, you’re actually going to get more internalization of the CD37 monoclonal, therefore more payload delivered to your target cells,” he said.

He reported results of a multicenter, adaptive phase 2 study of the combination in patients with DLBCL and other relapsed/refractory NHL.
 

DLBCL and others

The trial was divided into two parts, with the first consisting of a safety run-in phase with expansion in patients with confirmed diagnoses of relapsed/refractory NHL, including DLBCL, follicular lymphoma, mantle cell lymphoma, and marginal zone lymphoma.

Patients with double- or triple-hit disease (with translocations in MYC plus either BCL2 and/or BCL6), bulky disease, or transformed lymphoma were eligible.

The second part consisted of two cohorts of patients with DLBCL treated with naratuximab and rituximab either weekly or every 3 weeks.

All patients in the study had received one to six prior lines of therapy, and had Eastern Cooperative Oncology Group performance status of 0-2. Patients with CNS lymphomas or prior anti-CD37 targeting therapy were excluded.

The safety population included 50 patients with DLBCL assigned to therapy every 3 weeks, 30 assigned to weekly therapy, and 20 patients with other NHL.
 

DLBCL efficacy

A total of 76 patients with DLBCL were evaluable for efficacy.

The ORR was 44% for patients in both the weekly and every 3 week cohorts, with 31.6% having complete responses.

Among 61 patients with nonbulky disease (longest diameter 7.5 cm or less), the ORR was 50.8%, and among 28 patients who had three or more prior lines of therapy the ORR was 46.4%, with 32.1% having a complete response.

Among responders followed for a median of 15 months, the median duration of response was not reached, and 66% had responses lasting beyond 12 months.

In the weekly dosing DLBCL cohort, 53.3% of patients discontinued treatment of both study drugs because of disease progression, as did 58% of those in the every 3 week cohort, and 30% of patients with other lymphomas. Only eight patients discontinued the combination because of treatment-emergent adverse events. Six patients had treatment-emergent adverse events leading to naratuximab dose reduction.

The most common grade 3 or 4 adverse events were neutropenia, leukopenia, lymphopenia and thrombocytopenias. Dr. Levy commented that the use of granulocyte colony-stimulating factor, which was not mandatory in the study, would likely have lowered the incidence of cytopenias.

There were 10 deaths during the study, 2 of which were considered to be treatment related, occurring in 1 patient each in the DLBCL dosing cohorts; 1 of the patients died from pneumonitis, and the other from left ventricular heart failure.

Other patients deaths were attributed to non–treatment-related cardiac arrest, acute renal failure, exacerbation of chronic heart failure, respiratory failure, multiorgan failure, lung infection, or colon adenocarcinoma.
 

Q 3 weeks suffices

In the question-and-answer session following the presentation, Kenny Lei, MD, from the Chinese University of Hong Kong asked Dr. Levy what the half-life of naratuximab is, and what was the investigator’s rationale for testing a weekly dosing schedule.

“I think the reason they checked the two different regimens, the Q week and the Q 3-week group, is that they noted that [naratuximab] was cleared relatively quickly, and they wanted to see whether or not, by giving Q weekly, when you get a continuous CD37 site occupancy if they would have a better outcome. But as you saw, in the groups there was really no clinically relevant difference in outcome,” Dr. Levy said.

Andrew Davies, MD, PhD, from the University of Southampton (England), asked whether the neutropenia seen in the study was related to myeloid expression of the target of from the off-target deconjugated payload.

“I don’t know that I necessarily have the answer to that,” Dr. Levy replied. “Remember there is the CD20 monoclonal rituximab which we know can cause neutropenia, as well as the CD37 and the target payload. I don’t know if we have enough information to attribute it to one specific component of the therapy,” he said.

The study was funded by Debiopharm International. Dr. Levy disclosed speaker activities for multiple companies, not including Debiopharm. Dr. Lei and Dr. Davies had no disclosures relevant to the study.

Patients with relapsed or refractory B-cell non-Hodgkin lymphomas who are not candidates for hematopoietic stem cell transplant have a generally poor prognosis and few treatment options, but an experimental combination of the antibody-drug conjugate naratuximab with rituximab showed promising efficacy and acceptable safety in these patients in a phase 2 trial.

Among patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) the combination was associated with a 44.7% overall response rate, including 31.6% complete responses, and two-thirds of patients had responses lasting more than 12 months, reported Moshe Yair Levy, MD, from Texas Oncology–Baylor Charles A Sammons Cancer Center in Dallas.

“This is, in my viewpoint, very exciting therapy,” he said in a question-and-answer session following his presentation of the data in a late-breaking abstract session during the European Hematology Association annual congress. (Abstract LB1903).

Naratuximab emtansine is an investigational antibody-drug conjugate (ADC) consisting of a humanized monoclonal antibody against CD37, a surface marker on B lymphocytes that is highly expressed in non-Hodgkin lymphoma (NHL), conjugated to a cytotoxic derivative of maitansine.

CD37 is also an internalizable cell-surface antigen, making it an attractive candidate for an ADC approach.

In a phase 1 trial, naratuximab monotherapy showed a good safety profile and a 22% overall response rate, Dr. Levy noted.

“What they found is that, if you coadminister this ADC with rituximab, you’re actually going to get more internalization of the CD37 monoclonal, therefore more payload delivered to your target cells,” he said.

He reported results of a multicenter, adaptive phase 2 study of the combination in patients with DLBCL and other relapsed/refractory NHL.
 

DLBCL and others

The trial was divided into two parts, with the first consisting of a safety run-in phase with expansion in patients with confirmed diagnoses of relapsed/refractory NHL, including DLBCL, follicular lymphoma, mantle cell lymphoma, and marginal zone lymphoma.

Patients with double- or triple-hit disease (with translocations in MYC plus either BCL2 and/or BCL6), bulky disease, or transformed lymphoma were eligible.

The second part consisted of two cohorts of patients with DLBCL treated with naratuximab and rituximab either weekly or every 3 weeks.

All patients in the study had received one to six prior lines of therapy, and had Eastern Cooperative Oncology Group performance status of 0-2. Patients with CNS lymphomas or prior anti-CD37 targeting therapy were excluded.

The safety population included 50 patients with DLBCL assigned to therapy every 3 weeks, 30 assigned to weekly therapy, and 20 patients with other NHL.
 

DLBCL efficacy

A total of 76 patients with DLBCL were evaluable for efficacy.

The ORR was 44% for patients in both the weekly and every 3 week cohorts, with 31.6% having complete responses.

Among 61 patients with nonbulky disease (longest diameter 7.5 cm or less), the ORR was 50.8%, and among 28 patients who had three or more prior lines of therapy the ORR was 46.4%, with 32.1% having a complete response.

Among responders followed for a median of 15 months, the median duration of response was not reached, and 66% had responses lasting beyond 12 months.

In the weekly dosing DLBCL cohort, 53.3% of patients discontinued treatment of both study drugs because of disease progression, as did 58% of those in the every 3 week cohort, and 30% of patients with other lymphomas. Only eight patients discontinued the combination because of treatment-emergent adverse events. Six patients had treatment-emergent adverse events leading to naratuximab dose reduction.

The most common grade 3 or 4 adverse events were neutropenia, leukopenia, lymphopenia and thrombocytopenias. Dr. Levy commented that the use of granulocyte colony-stimulating factor, which was not mandatory in the study, would likely have lowered the incidence of cytopenias.

There were 10 deaths during the study, 2 of which were considered to be treatment related, occurring in 1 patient each in the DLBCL dosing cohorts; 1 of the patients died from pneumonitis, and the other from left ventricular heart failure.

Other patients deaths were attributed to non–treatment-related cardiac arrest, acute renal failure, exacerbation of chronic heart failure, respiratory failure, multiorgan failure, lung infection, or colon adenocarcinoma.
 

Q 3 weeks suffices

In the question-and-answer session following the presentation, Kenny Lei, MD, from the Chinese University of Hong Kong asked Dr. Levy what the half-life of naratuximab is, and what was the investigator’s rationale for testing a weekly dosing schedule.

“I think the reason they checked the two different regimens, the Q week and the Q 3-week group, is that they noted that [naratuximab] was cleared relatively quickly, and they wanted to see whether or not, by giving Q weekly, when you get a continuous CD37 site occupancy if they would have a better outcome. But as you saw, in the groups there was really no clinically relevant difference in outcome,” Dr. Levy said.

Andrew Davies, MD, PhD, from the University of Southampton (England), asked whether the neutropenia seen in the study was related to myeloid expression of the target of from the off-target deconjugated payload.

“I don’t know that I necessarily have the answer to that,” Dr. Levy replied. “Remember there is the CD20 monoclonal rituximab which we know can cause neutropenia, as well as the CD37 and the target payload. I don’t know if we have enough information to attribute it to one specific component of the therapy,” he said.

The study was funded by Debiopharm International. Dr. Levy disclosed speaker activities for multiple companies, not including Debiopharm. Dr. Lei and Dr. Davies had no disclosures relevant to the study.

Physicians often face the choice of whether to treat elderly patients with diffuse large B-cell lymphoma (DLBCL) with a full or reduced dose intensity (DI) of R-CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone + rituximab), according to Edward J. Bataillard of the Imperial College Healthcare National Health Service Trust, London, and colleagues.

To address this issue, the researchers conducted a systematic review assessing the impact of R-CHOP DI on DLBCL survival outcomes, according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Protocols (PRISMA-P) guidelines. They found that greater than 80 years of age is an important cutoff for treating patients with a reduced R-CHOP dosage, according to their results, published in Blood Advances (2021;5[9]:2426-37).

Cutoff at 80 years of age

Their final review comprised 13 studies including 5,188 patients. Overall, the lower DI (intended or relative) was associated with inferior survival in seven of nine studies reporting crude survival analyses. In addition, most studies and those larger studies of higher quality showed poorer outcomes associated with reduced R-CHOP DI.

However, in subgroups of patients aged 80 years or more, survival was not consistently affected by the use of lower dosage R-CHOP, according to the researchers.

“We found evidence of improved survival with higher RDIs (up to R-CHOP-21) in those aged < 80 years, but the literature to date does not support full-dose intensity in those 80 years [or older],” they stated.

However, the researchers concluded that: “In the absence of improved options beyond R-CHOP in DLBCL over the past 20 years, prospective studies of DI are warranted, despite the recognized challenges involved.”

Two of the authors reported being previously employed by Roche. A third served as a consultant and adviser and received honoraria from Roche and other pharmaceutical companies. Several authors reported disclosures related to multiple other pharmaceutical companies.

[email protected]

Physicians often face the choice of whether to treat elderly patients with diffuse large B-cell lymphoma (DLBCL) with a full or reduced dose intensity (DI) of R-CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone + rituximab), according to Edward J. Bataillard of the Imperial College Healthcare National Health Service Trust, London, and colleagues.

To address this issue, the researchers conducted a systematic review assessing the impact of R-CHOP DI on DLBCL survival outcomes, according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Protocols (PRISMA-P) guidelines. They found that greater than 80 years of age is an important cutoff for treating patients with a reduced R-CHOP dosage, according to their results, published in Blood Advances (2021;5[9]:2426-37).

Cutoff at 80 years of age

Their final review comprised 13 studies including 5,188 patients. Overall, the lower DI (intended or relative) was associated with inferior survival in seven of nine studies reporting crude survival analyses. In addition, most studies and those larger studies of higher quality showed poorer outcomes associated with reduced R-CHOP DI.

However, in subgroups of patients aged 80 years or more, survival was not consistently affected by the use of lower dosage R-CHOP, according to the researchers.

“We found evidence of improved survival with higher RDIs (up to R-CHOP-21) in those aged < 80 years, but the literature to date does not support full-dose intensity in those 80 years [or older],” they stated.

However, the researchers concluded that: “In the absence of improved options beyond R-CHOP in DLBCL over the past 20 years, prospective studies of DI are warranted, despite the recognized challenges involved.”

Two of the authors reported being previously employed by Roche. A third served as a consultant and adviser and received honoraria from Roche and other pharmaceutical companies. Several authors reported disclosures related to multiple other pharmaceutical companies.

[email protected]

Physicians often face the choice of whether to treat elderly patients with diffuse large B-cell lymphoma (DLBCL) with a full or reduced dose intensity (DI) of R-CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone + rituximab), according to Edward J. Bataillard of the Imperial College Healthcare National Health Service Trust, London, and colleagues.

To address this issue, the researchers conducted a systematic review assessing the impact of R-CHOP DI on DLBCL survival outcomes, according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Protocols (PRISMA-P) guidelines. They found that greater than 80 years of age is an important cutoff for treating patients with a reduced R-CHOP dosage, according to their results, published in Blood Advances (2021;5[9]:2426-37).

Cutoff at 80 years of age

Their final review comprised 13 studies including 5,188 patients. Overall, the lower DI (intended or relative) was associated with inferior survival in seven of nine studies reporting crude survival analyses. In addition, most studies and those larger studies of higher quality showed poorer outcomes associated with reduced R-CHOP DI.

However, in subgroups of patients aged 80 years or more, survival was not consistently affected by the use of lower dosage R-CHOP, according to the researchers.

“We found evidence of improved survival with higher RDIs (up to R-CHOP-21) in those aged < 80 years, but the literature to date does not support full-dose intensity in those 80 years [or older],” they stated.

However, the researchers concluded that: “In the absence of improved options beyond R-CHOP in DLBCL over the past 20 years, prospective studies of DI are warranted, despite the recognized challenges involved.”

Two of the authors reported being previously employed by Roche. A third served as a consultant and adviser and received honoraria from Roche and other pharmaceutical companies. Several authors reported disclosures related to multiple other pharmaceutical companies.

[email protected]

Patients with high-risk diffuse large B-cell lymphoma (DLBCL) have a greater than 10% risk of central nervous system (CNS) relapse, and the use of prophylactic high-dose methotrexate (HD-MTX) has been proposed as a preventative measure.

Nephron/Wikimedia Commons/CC BY-SA 3.0

However, the use of prophylactic HD-MTX did not improve CNS or survival outcomes of patients with high-risk DLBCL, but instead was associated with increased toxicities, according to the results of a retrospective study by Hyehyun Jeong, MD, of University of Ulsan College of Medicine, Seoul, Republic of Korea, and colleagues.

The researchers evaluated the effects of prophylactic HD-MTX on CNS relapse and survival outcomes in newly diagnosed R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone)–treated patients with high-risk DLBCL. The assessment was based on the initial treatment intent (ITT) of the physician on the use of prophylactic HD-MTX.

A total of 5,130 patients were classified into an ITT HD-MTX group and an equal number into a non-ITT HD-MTX group, according to the report, published online in Blood Advances.

Equivalent results

The study showed that the CNS relapse rate was not significantly different between the two groups, with 2-year CNS relapse rates of 12.4% and 13.9%, respectively (P = .96). Three-year progression-free survival and overall survival rates in the ITT HD-MTX and non-ITT HD-MTX groups were 62.4% vs. 64.5% (P = .94) and 71.7% vs. 71.4% (P = .7), respectively. In addition, the propensity score–matched analyses showed no significant differences in the time-to-CNS relapse, progression-free survival, or overall survival, according to the researchers.

One key concern, however, was the increase in toxicity seen in the HD-MTX group. In this study, the ITT HD-MTX group had a statistically higher incidence of grade 3/4 oral mucositis and elevated alanine aminotransferase (ALT) levels, a marker for liver damage. In addition, the ITT HD-MTX group tended to have a higher incidence of elevated creatinine levels during treatment compared with the non-ITT HD-MTX group.

The HD-MTX group also showed a more common treatment delay or a dose reduction in R-CHOP, which might be attributable to toxicities related to intercalated HD-MTX treatments between R-CHOP cycles, the researchers suggested, potentially resulting in a reduced dose intensity of R-CHOP that could play a role in the lack of an observed survival benefit with additional HD-MTX.

“Another vital issue to consider is that HD-MTX treatment requires hospitalization because intensive hydration and leucovorin rescue is needed, which increases the medical costs,” the authors added.

“This real-world experience, which is unique in its scope and analytical methods, should provide insightful information on the role of HD-MTX prophylaxis to help guide current practice, given the lack of prospective clinical evidence in this patient population,” the researchers concluded.

The authors reported that they had no competing financial interests.

[email protected]

Patients with high-risk diffuse large B-cell lymphoma (DLBCL) have a greater than 10% risk of central nervous system (CNS) relapse, and the use of prophylactic high-dose methotrexate (HD-MTX) has been proposed as a preventative measure.

Nephron/Wikimedia Commons/CC BY-SA 3.0

However, the use of prophylactic HD-MTX did not improve CNS or survival outcomes of patients with high-risk DLBCL, but instead was associated with increased toxicities, according to the results of a retrospective study by Hyehyun Jeong, MD, of University of Ulsan College of Medicine, Seoul, Republic of Korea, and colleagues.

The researchers evaluated the effects of prophylactic HD-MTX on CNS relapse and survival outcomes in newly diagnosed R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone)–treated patients with high-risk DLBCL. The assessment was based on the initial treatment intent (ITT) of the physician on the use of prophylactic HD-MTX.

A total of 5,130 patients were classified into an ITT HD-MTX group and an equal number into a non-ITT HD-MTX group, according to the report, published online in Blood Advances.

Equivalent results

The study showed that the CNS relapse rate was not significantly different between the two groups, with 2-year CNS relapse rates of 12.4% and 13.9%, respectively (P = .96). Three-year progression-free survival and overall survival rates in the ITT HD-MTX and non-ITT HD-MTX groups were 62.4% vs. 64.5% (P = .94) and 71.7% vs. 71.4% (P = .7), respectively. In addition, the propensity score–matched analyses showed no significant differences in the time-to-CNS relapse, progression-free survival, or overall survival, according to the researchers.

One key concern, however, was the increase in toxicity seen in the HD-MTX group. In this study, the ITT HD-MTX group had a statistically higher incidence of grade 3/4 oral mucositis and elevated alanine aminotransferase (ALT) levels, a marker for liver damage. In addition, the ITT HD-MTX group tended to have a higher incidence of elevated creatinine levels during treatment compared with the non-ITT HD-MTX group.

The HD-MTX group also showed a more common treatment delay or a dose reduction in R-CHOP, which might be attributable to toxicities related to intercalated HD-MTX treatments between R-CHOP cycles, the researchers suggested, potentially resulting in a reduced dose intensity of R-CHOP that could play a role in the lack of an observed survival benefit with additional HD-MTX.

“Another vital issue to consider is that HD-MTX treatment requires hospitalization because intensive hydration and leucovorin rescue is needed, which increases the medical costs,” the authors added.

“This real-world experience, which is unique in its scope and analytical methods, should provide insightful information on the role of HD-MTX prophylaxis to help guide current practice, given the lack of prospective clinical evidence in this patient population,” the researchers concluded.

The authors reported that they had no competing financial interests.

[email protected]

Patients with high-risk diffuse large B-cell lymphoma (DLBCL) have a greater than 10% risk of central nervous system (CNS) relapse, and the use of prophylactic high-dose methotrexate (HD-MTX) has been proposed as a preventative measure.

Nephron/Wikimedia Commons/CC BY-SA 3.0

However, the use of prophylactic HD-MTX did not improve CNS or survival outcomes of patients with high-risk DLBCL, but instead was associated with increased toxicities, according to the results of a retrospective study by Hyehyun Jeong, MD, of University of Ulsan College of Medicine, Seoul, Republic of Korea, and colleagues.

The researchers evaluated the effects of prophylactic HD-MTX on CNS relapse and survival outcomes in newly diagnosed R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone)–treated patients with high-risk DLBCL. The assessment was based on the initial treatment intent (ITT) of the physician on the use of prophylactic HD-MTX.

A total of 5,130 patients were classified into an ITT HD-MTX group and an equal number into a non-ITT HD-MTX group, according to the report, published online in Blood Advances.

Equivalent results

The study showed that the CNS relapse rate was not significantly different between the two groups, with 2-year CNS relapse rates of 12.4% and 13.9%, respectively (P = .96). Three-year progression-free survival and overall survival rates in the ITT HD-MTX and non-ITT HD-MTX groups were 62.4% vs. 64.5% (P = .94) and 71.7% vs. 71.4% (P = .7), respectively. In addition, the propensity score–matched analyses showed no significant differences in the time-to-CNS relapse, progression-free survival, or overall survival, according to the researchers.

One key concern, however, was the increase in toxicity seen in the HD-MTX group. In this study, the ITT HD-MTX group had a statistically higher incidence of grade 3/4 oral mucositis and elevated alanine aminotransferase (ALT) levels, a marker for liver damage. In addition, the ITT HD-MTX group tended to have a higher incidence of elevated creatinine levels during treatment compared with the non-ITT HD-MTX group.

The HD-MTX group also showed a more common treatment delay or a dose reduction in R-CHOP, which might be attributable to toxicities related to intercalated HD-MTX treatments between R-CHOP cycles, the researchers suggested, potentially resulting in a reduced dose intensity of R-CHOP that could play a role in the lack of an observed survival benefit with additional HD-MTX.

“Another vital issue to consider is that HD-MTX treatment requires hospitalization because intensive hydration and leucovorin rescue is needed, which increases the medical costs,” the authors added.

“This real-world experience, which is unique in its scope and analytical methods, should provide insightful information on the role of HD-MTX prophylaxis to help guide current practice, given the lack of prospective clinical evidence in this patient population,” the researchers concluded.

The authors reported that they had no competing financial interests.

[email protected]

Survivors of childhood cancers are at increased risk for prescription opioid misuse compared with their peers, a review of a claims database revealed.

Among more than 8,000 patients age 21 or younger who had completed treatment for hematologic, central nervous system, bone, or gonadal cancers, survivors were significantly more likely than were their peers to have an opioid prescription, longer duration of prescription, and higher daily doses of opioids, and to have opioid prescriptions overlapping for a week or more, reported Xu Ji, PhD, of Emory University in Atlanta.

Teenage and young adult patients were at higher risk than were patients younger than 12, and the risk was highest among patients who had been treated for bone malignancies, as well as those who had undergone any hematopoietic stem cell transplant.

“These findings suggest that health care providers who regularly see survivors should explore nonopioid options to help prevent opioid misuse, and screen for potential misuse in those who actually receive opioids,” she said in an oral abstract presented during the annual meeting of the American Society of Pediatric Hematology/Oncology.

“This is a really important topic, and something that’s probably been underinvestigated and underexplored in our patient population,” said session comoderator Sheri Spunt, MD, Endowed Professor of Pediatric Cancer at Stanford (Calif.) University.
 

Database review

Dr. Ji and colleagues used the IBM MarketScan Commercial Claims and Encounters database from 2009 to 2018 to examine prescription opioid use, potential misuse, and substance use disorders in pediatric cancer survivors in the first year after completion of therapy, and to identify factors associated with risk for misuse or substance use disorders. Specifically, the period of interest was the first year after completion of all treatments, including surgery, chemotherapy, radiation, and stem cell transplant (Abstract 2015).

They looked at deidentified records on any opioid prescription and for treatment of any opioid use or substance use disorder (alcohol, psychotherapeutic drugs, marijuana, or illicit drug use disorders).

They defined indicators of potential misuse as either prescriptions for long-acting or extended-release opioids for acute pain conditions; opioid and benzodiazepine prescriptions overlapping by a week or more; opioid prescriptions overlapping by a week or more; high daily opioid dosage (prescribed daily dose of 100 or greater morphine milligram equivalent [MME]; and/or opioid dose escalation (an increase of at least 50% in mean MMEs per month twice consecutively within 1 year).

They compared outcomes between a total of 8,635 survivors and 44,175 controls, matched on a 1:5 basis with survivors by age, sex, and region, and continuous enrollment during the 1-year posttherapy period.

In each of three age categories – 0 to 11 years, 12 to 17 years, and 18 years and older – survivors were significantly more likely to have received an opioid prescription, at 15% for the youngest survivors vs. 2% of controls, 25% vs. 8% for 12- to 17-year-olds, and 28% vs. 12% for those 18 and older (P < .01 for all three comparisons).

Survivors were also significantly more likely to have any indicator of potential misuse (1.6% vs. 0.1%, 4.6% vs. 0.5%, and 7.4% vs. 1.2%, respectively, P < .001 for all) and both the youngest and oldest groups (but not 12- to 17-year-olds) were significantly more like to have opioid or substance use disorder (0.4% vs. 0% for 0-11 years, 5.76% vs. 4.2% for 18 years and older, P < .001 for both).

Among patients with any opioid prescription, survivors were significantly more likely than were controls of any age to have indicators for potential misuse. For example, 13% of survivors aged 18 years and older had prescriptions for high opioid doses, compared with 5% of controls, and 12% had prescription overlap, vs. 2%.

Compared with patients with leukemia, patients treated for bone malignancies had a 6% greater risk for having any indicator of misuse, while patients with other malignancies were at slightly lower risk for misuse than those who completed leukemia therapy.

Patients who received any stem cell transplant had an 8.4% greater risk for misuse compared with patients who had surgery only.
 

Opioids pre- and posttreatment?

“Being someone who takes care of a lot of bone cancer patients, I do see patients with these issues,” Dr. Spunt said.

Audience member Jack H. Staddon, MD, PhD, of the Billings (Montana) Clinic, noted the possibility that opioid use during treatment may have been carried on into the posttreatment period, and asked whether use of narcotics during treatment was an independent risk factor for posttreatment narcotic use or misuse.

The researchers plan to investigate this question in future studies, Dr. Ji replied.

They did not report a study funding source. Dr. Ji and coauthors and Dr. Staddon reported no relevant disclosures.

Survivors of childhood cancers are at increased risk for prescription opioid misuse compared with their peers, a review of a claims database revealed.

Among more than 8,000 patients age 21 or younger who had completed treatment for hematologic, central nervous system, bone, or gonadal cancers, survivors were significantly more likely than were their peers to have an opioid prescription, longer duration of prescription, and higher daily doses of opioids, and to have opioid prescriptions overlapping for a week or more, reported Xu Ji, PhD, of Emory University in Atlanta.

Teenage and young adult patients were at higher risk than were patients younger than 12, and the risk was highest among patients who had been treated for bone malignancies, as well as those who had undergone any hematopoietic stem cell transplant.

“These findings suggest that health care providers who regularly see survivors should explore nonopioid options to help prevent opioid misuse, and screen for potential misuse in those who actually receive opioids,” she said in an oral abstract presented during the annual meeting of the American Society of Pediatric Hematology/Oncology.

“This is a really important topic, and something that’s probably been underinvestigated and underexplored in our patient population,” said session comoderator Sheri Spunt, MD, Endowed Professor of Pediatric Cancer at Stanford (Calif.) University.
 

Database review

Dr. Ji and colleagues used the IBM MarketScan Commercial Claims and Encounters database from 2009 to 2018 to examine prescription opioid use, potential misuse, and substance use disorders in pediatric cancer survivors in the first year after completion of therapy, and to identify factors associated with risk for misuse or substance use disorders. Specifically, the period of interest was the first year after completion of all treatments, including surgery, chemotherapy, radiation, and stem cell transplant (Abstract 2015).

They looked at deidentified records on any opioid prescription and for treatment of any opioid use or substance use disorder (alcohol, psychotherapeutic drugs, marijuana, or illicit drug use disorders).

They defined indicators of potential misuse as either prescriptions for long-acting or extended-release opioids for acute pain conditions; opioid and benzodiazepine prescriptions overlapping by a week or more; opioid prescriptions overlapping by a week or more; high daily opioid dosage (prescribed daily dose of 100 or greater morphine milligram equivalent [MME]; and/or opioid dose escalation (an increase of at least 50% in mean MMEs per month twice consecutively within 1 year).

They compared outcomes between a total of 8,635 survivors and 44,175 controls, matched on a 1:5 basis with survivors by age, sex, and region, and continuous enrollment during the 1-year posttherapy period.

In each of three age categories – 0 to 11 years, 12 to 17 years, and 18 years and older – survivors were significantly more likely to have received an opioid prescription, at 15% for the youngest survivors vs. 2% of controls, 25% vs. 8% for 12- to 17-year-olds, and 28% vs. 12% for those 18 and older (P < .01 for all three comparisons).

Survivors were also significantly more likely to have any indicator of potential misuse (1.6% vs. 0.1%, 4.6% vs. 0.5%, and 7.4% vs. 1.2%, respectively, P < .001 for all) and both the youngest and oldest groups (but not 12- to 17-year-olds) were significantly more like to have opioid or substance use disorder (0.4% vs. 0% for 0-11 years, 5.76% vs. 4.2% for 18 years and older, P < .001 for both).

Among patients with any opioid prescription, survivors were significantly more likely than were controls of any age to have indicators for potential misuse. For example, 13% of survivors aged 18 years and older had prescriptions for high opioid doses, compared with 5% of controls, and 12% had prescription overlap, vs. 2%.

Compared with patients with leukemia, patients treated for bone malignancies had a 6% greater risk for having any indicator of misuse, while patients with other malignancies were at slightly lower risk for misuse than those who completed leukemia therapy.

Patients who received any stem cell transplant had an 8.4% greater risk for misuse compared with patients who had surgery only.
 

Opioids pre- and posttreatment?

“Being someone who takes care of a lot of bone cancer patients, I do see patients with these issues,” Dr. Spunt said.

Audience member Jack H. Staddon, MD, PhD, of the Billings (Montana) Clinic, noted the possibility that opioid use during treatment may have been carried on into the posttreatment period, and asked whether use of narcotics during treatment was an independent risk factor for posttreatment narcotic use or misuse.

The researchers plan to investigate this question in future studies, Dr. Ji replied.

They did not report a study funding source. Dr. Ji and coauthors and Dr. Staddon reported no relevant disclosures.

Survivors of childhood cancers are at increased risk for prescription opioid misuse compared with their peers, a review of a claims database revealed.

Among more than 8,000 patients age 21 or younger who had completed treatment for hematologic, central nervous system, bone, or gonadal cancers, survivors were significantly more likely than were their peers to have an opioid prescription, longer duration of prescription, and higher daily doses of opioids, and to have opioid prescriptions overlapping for a week or more, reported Xu Ji, PhD, of Emory University in Atlanta.

Teenage and young adult patients were at higher risk than were patients younger than 12, and the risk was highest among patients who had been treated for bone malignancies, as well as those who had undergone any hematopoietic stem cell transplant.

“These findings suggest that health care providers who regularly see survivors should explore nonopioid options to help prevent opioid misuse, and screen for potential misuse in those who actually receive opioids,” she said in an oral abstract presented during the annual meeting of the American Society of Pediatric Hematology/Oncology.

“This is a really important topic, and something that’s probably been underinvestigated and underexplored in our patient population,” said session comoderator Sheri Spunt, MD, Endowed Professor of Pediatric Cancer at Stanford (Calif.) University.
 

Database review

Dr. Ji and colleagues used the IBM MarketScan Commercial Claims and Encounters database from 2009 to 2018 to examine prescription opioid use, potential misuse, and substance use disorders in pediatric cancer survivors in the first year after completion of therapy, and to identify factors associated with risk for misuse or substance use disorders. Specifically, the period of interest was the first year after completion of all treatments, including surgery, chemotherapy, radiation, and stem cell transplant (Abstract 2015).

They looked at deidentified records on any opioid prescription and for treatment of any opioid use or substance use disorder (alcohol, psychotherapeutic drugs, marijuana, or illicit drug use disorders).

They defined indicators of potential misuse as either prescriptions for long-acting or extended-release opioids for acute pain conditions; opioid and benzodiazepine prescriptions overlapping by a week or more; opioid prescriptions overlapping by a week or more; high daily opioid dosage (prescribed daily dose of 100 or greater morphine milligram equivalent [MME]; and/or opioid dose escalation (an increase of at least 50% in mean MMEs per month twice consecutively within 1 year).

They compared outcomes between a total of 8,635 survivors and 44,175 controls, matched on a 1:5 basis with survivors by age, sex, and region, and continuous enrollment during the 1-year posttherapy period.

In each of three age categories – 0 to 11 years, 12 to 17 years, and 18 years and older – survivors were significantly more likely to have received an opioid prescription, at 15% for the youngest survivors vs. 2% of controls, 25% vs. 8% for 12- to 17-year-olds, and 28% vs. 12% for those 18 and older (P < .01 for all three comparisons).

Survivors were also significantly more likely to have any indicator of potential misuse (1.6% vs. 0.1%, 4.6% vs. 0.5%, and 7.4% vs. 1.2%, respectively, P < .001 for all) and both the youngest and oldest groups (but not 12- to 17-year-olds) were significantly more like to have opioid or substance use disorder (0.4% vs. 0% for 0-11 years, 5.76% vs. 4.2% for 18 years and older, P < .001 for both).

Among patients with any opioid prescription, survivors were significantly more likely than were controls of any age to have indicators for potential misuse. For example, 13% of survivors aged 18 years and older had prescriptions for high opioid doses, compared with 5% of controls, and 12% had prescription overlap, vs. 2%.

Compared with patients with leukemia, patients treated for bone malignancies had a 6% greater risk for having any indicator of misuse, while patients with other malignancies were at slightly lower risk for misuse than those who completed leukemia therapy.

Patients who received any stem cell transplant had an 8.4% greater risk for misuse compared with patients who had surgery only.
 

Opioids pre- and posttreatment?

“Being someone who takes care of a lot of bone cancer patients, I do see patients with these issues,” Dr. Spunt said.

Audience member Jack H. Staddon, MD, PhD, of the Billings (Montana) Clinic, noted the possibility that opioid use during treatment may have been carried on into the posttreatment period, and asked whether use of narcotics during treatment was an independent risk factor for posttreatment narcotic use or misuse.

The researchers plan to investigate this question in future studies, Dr. Ji replied.

They did not report a study funding source. Dr. Ji and coauthors and Dr. Staddon reported no relevant disclosures.