Aggressive Lymphomas

ORLANDO – Rituximab conferred a significant progression-free survival benefit in reduced intensity conditioning regimens for patients with B-cell non-Hodgkin lymphoma who underwent allogeneic hematopoietic cell transplantation, based on data from the Center for International Blood & Marrow Transplant Research.

Further, higher cumulative rituximab doses appeared to confer a benefit in overall survival.

Rituximab is frequently a component of reduced intensity conditioning (RIC) regimens in allogeneic hematopoietic cell transplantation (HCT), but there has been a “paucity of comparative data” for rituximab-containing (R-RIC) versus non–R-RIC conditioning regimens for allogeneic transplant patients, Narendranath Epperla, MD, of the Medical College of Wisconsin, Milwaukee, said during the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society of Blood and Marrow Transplantation.

Using data from the Center for International Blood & Marrow Transplant Research, Dr. Epperla and his colleagues identified 1,022 patients who received rituximab and 379 patients who did not with diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, and marginal zone lymphoma. The patients received their first RIC or non-myeloablative allogeneic HCT between 2008 and 2014. The donors were matched, and either related or 8x8 allele-matched unrelated; the graft source could be bone marrow or peripheral blood. Graft versus host disease (GVHD) suppression was calcineurin inhibitor based.

Patients who had received myeloablative conditioning, or who had received radioimmunotherapy or alemtuzumab were excluded, as were those who received alternative donor allografts.

Dr. Epperla and his colleagues factored in patient and disease characteristics, as well as differences in transplant regimen, in determining the adjusted cumulative incidence of relapse or progression, as well as the incidence of nonrelapse mortality.

In the multivariable analysis, overall survival did not differ between the R-RIC and the non–R-RIC cohorts (relative risk [RR] of all-cause mortality, R-RIC = 0.83, 95% CI 0.67-1.03, P = .09).

Based on the cumulative dose of rituximab that patients had received, though, “we noted that patients who got higher doses of rituximab had lower risk of nonrelapse mortality,” Dr. Epperla said. “Higher cumulative doses of rituximab seem to confer overall survival benefit.” This was true even though the higher rituximab doses had no significant effect on the risk of therapy failure, nonrelapse mortality, or the risk of progression/relapse.

When the cumulative rituximab dose was 2,000 to 3,375 mg/m², the hazard ratio for all-cause mortality fell to 0.43 compared to a cumulative rituximab dose of less than 1,000 mg/m² (95% confidence interval [CI] 0.21-0.90, P = .02).

Among the R-RIC group, there was a nonsignificant trend toward reduced risk of progression or relapse (relative risk of progression/relapse, R-RIC = 0.79, 95% CI 0.63-1.01, P = .055). However, the R-RIC group fared significantly better in terms of progression-free survival (RR of PFS, R-RIC = 0.76, 95% CI 0.62-0.92, P = .006).

After transplant, patients in the R-RIC group were no more likely than those in the non–R-RIC group to experience chronic GVHD (RR of GVHD, R-RIC = 1.15, 95% CI 0.96-1.39, P = .13). There was no difference in the adjusted curves of nonrelapse mortality between the groups (RR of nonrelapse mortality, R-RIC = 0.90, 95% CI 0.67-1.22, P = .51).

Also, there were no fatal cytopenias in the R-RIC arm, although the literature warrants some concern for increased risk of infection with rituximab, Dr. Epperla said.

At baseline, there were no significant differences in demographic characteristics between the nonrituximab and rituximab arms of the study population. More than 90% of patients were white, and 65% were male; the median age was 57 years (range, 18-74).

Patients had been diagnosed about 3 years before receiving HCT; about 60% of patients had a baseline Karnofsky performance score greater than 90, and the HCT comorbidity index was 2. About 86% of patients were chemosensitive, and patients in both study arms had received a median of three prior lines of therapy.

There were some differences in conditioning regimens between the two groups. “There were a significantly higher number of patients in the nonrituximab group who received fludarabine/busulfan, while there were a significantly high number in the rituximab group who received a fludarabine/cyclophosphamide-based conditioning regimen,” Dr. Epperla said. Follicular lymphomas were more common in the R-RIC arm, while diffuse large B-cell lymphomas were seen more in the non–R-RIC arm.

Given the survival benefit and similar rates of chronic GVHD seen in the retrospective analysis, a prospective, randomized head-to-head trial of R-RIC versus non–R-RIC is warranted, Dr. Epperla concluded.

During the postpresentation discussion, Dr. Epperla acknowledged the variability of the lymphomas in the study, but that there was no significant statistical effect of specific histologies on the findings in a subgroup analysis. Dr. Epperla added that the chemosensitivity status at transplant was checked to account for patient exposure to rituximab before RIC, and that there was no effect of prior rituximab exposure on the outcomes examined.

Dr. Epperla reported no conflicts of interest.
 

[email protected]

On Twitter @karioakes

ORLANDO – Rituximab conferred a significant progression-free survival benefit in reduced intensity conditioning regimens for patients with B-cell non-Hodgkin lymphoma who underwent allogeneic hematopoietic cell transplantation, based on data from the Center for International Blood & Marrow Transplant Research.

Further, higher cumulative rituximab doses appeared to confer a benefit in overall survival.

Rituximab is frequently a component of reduced intensity conditioning (RIC) regimens in allogeneic hematopoietic cell transplantation (HCT), but there has been a “paucity of comparative data” for rituximab-containing (R-RIC) versus non–R-RIC conditioning regimens for allogeneic transplant patients, Narendranath Epperla, MD, of the Medical College of Wisconsin, Milwaukee, said during the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society of Blood and Marrow Transplantation.

Using data from the Center for International Blood & Marrow Transplant Research, Dr. Epperla and his colleagues identified 1,022 patients who received rituximab and 379 patients who did not with diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, and marginal zone lymphoma. The patients received their first RIC or non-myeloablative allogeneic HCT between 2008 and 2014. The donors were matched, and either related or 8x8 allele-matched unrelated; the graft source could be bone marrow or peripheral blood. Graft versus host disease (GVHD) suppression was calcineurin inhibitor based.

Patients who had received myeloablative conditioning, or who had received radioimmunotherapy or alemtuzumab were excluded, as were those who received alternative donor allografts.

Dr. Epperla and his colleagues factored in patient and disease characteristics, as well as differences in transplant regimen, in determining the adjusted cumulative incidence of relapse or progression, as well as the incidence of nonrelapse mortality.

In the multivariable analysis, overall survival did not differ between the R-RIC and the non–R-RIC cohorts (relative risk [RR] of all-cause mortality, R-RIC = 0.83, 95% CI 0.67-1.03, P = .09).

Based on the cumulative dose of rituximab that patients had received, though, “we noted that patients who got higher doses of rituximab had lower risk of nonrelapse mortality,” Dr. Epperla said. “Higher cumulative doses of rituximab seem to confer overall survival benefit.” This was true even though the higher rituximab doses had no significant effect on the risk of therapy failure, nonrelapse mortality, or the risk of progression/relapse.

When the cumulative rituximab dose was 2,000 to 3,375 mg/m², the hazard ratio for all-cause mortality fell to 0.43 compared to a cumulative rituximab dose of less than 1,000 mg/m² (95% confidence interval [CI] 0.21-0.90, P = .02).

Among the R-RIC group, there was a nonsignificant trend toward reduced risk of progression or relapse (relative risk of progression/relapse, R-RIC = 0.79, 95% CI 0.63-1.01, P = .055). However, the R-RIC group fared significantly better in terms of progression-free survival (RR of PFS, R-RIC = 0.76, 95% CI 0.62-0.92, P = .006).

After transplant, patients in the R-RIC group were no more likely than those in the non–R-RIC group to experience chronic GVHD (RR of GVHD, R-RIC = 1.15, 95% CI 0.96-1.39, P = .13). There was no difference in the adjusted curves of nonrelapse mortality between the groups (RR of nonrelapse mortality, R-RIC = 0.90, 95% CI 0.67-1.22, P = .51).

Also, there were no fatal cytopenias in the R-RIC arm, although the literature warrants some concern for increased risk of infection with rituximab, Dr. Epperla said.

At baseline, there were no significant differences in demographic characteristics between the nonrituximab and rituximab arms of the study population. More than 90% of patients were white, and 65% were male; the median age was 57 years (range, 18-74).

Patients had been diagnosed about 3 years before receiving HCT; about 60% of patients had a baseline Karnofsky performance score greater than 90, and the HCT comorbidity index was 2. About 86% of patients were chemosensitive, and patients in both study arms had received a median of three prior lines of therapy.

There were some differences in conditioning regimens between the two groups. “There were a significantly higher number of patients in the nonrituximab group who received fludarabine/busulfan, while there were a significantly high number in the rituximab group who received a fludarabine/cyclophosphamide-based conditioning regimen,” Dr. Epperla said. Follicular lymphomas were more common in the R-RIC arm, while diffuse large B-cell lymphomas were seen more in the non–R-RIC arm.

Given the survival benefit and similar rates of chronic GVHD seen in the retrospective analysis, a prospective, randomized head-to-head trial of R-RIC versus non–R-RIC is warranted, Dr. Epperla concluded.

During the postpresentation discussion, Dr. Epperla acknowledged the variability of the lymphomas in the study, but that there was no significant statistical effect of specific histologies on the findings in a subgroup analysis. Dr. Epperla added that the chemosensitivity status at transplant was checked to account for patient exposure to rituximab before RIC, and that there was no effect of prior rituximab exposure on the outcomes examined.

Dr. Epperla reported no conflicts of interest.
 

[email protected]

On Twitter @karioakes

ORLANDO – Rituximab conferred a significant progression-free survival benefit in reduced intensity conditioning regimens for patients with B-cell non-Hodgkin lymphoma who underwent allogeneic hematopoietic cell transplantation, based on data from the Center for International Blood & Marrow Transplant Research.

Further, higher cumulative rituximab doses appeared to confer a benefit in overall survival.

Rituximab is frequently a component of reduced intensity conditioning (RIC) regimens in allogeneic hematopoietic cell transplantation (HCT), but there has been a “paucity of comparative data” for rituximab-containing (R-RIC) versus non–R-RIC conditioning regimens for allogeneic transplant patients, Narendranath Epperla, MD, of the Medical College of Wisconsin, Milwaukee, said during the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society of Blood and Marrow Transplantation.

Using data from the Center for International Blood & Marrow Transplant Research, Dr. Epperla and his colleagues identified 1,022 patients who received rituximab and 379 patients who did not with diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, and marginal zone lymphoma. The patients received their first RIC or non-myeloablative allogeneic HCT between 2008 and 2014. The donors were matched, and either related or 8x8 allele-matched unrelated; the graft source could be bone marrow or peripheral blood. Graft versus host disease (GVHD) suppression was calcineurin inhibitor based.

Patients who had received myeloablative conditioning, or who had received radioimmunotherapy or alemtuzumab were excluded, as were those who received alternative donor allografts.

Dr. Epperla and his colleagues factored in patient and disease characteristics, as well as differences in transplant regimen, in determining the adjusted cumulative incidence of relapse or progression, as well as the incidence of nonrelapse mortality.

In the multivariable analysis, overall survival did not differ between the R-RIC and the non–R-RIC cohorts (relative risk [RR] of all-cause mortality, R-RIC = 0.83, 95% CI 0.67-1.03, P = .09).

Based on the cumulative dose of rituximab that patients had received, though, “we noted that patients who got higher doses of rituximab had lower risk of nonrelapse mortality,” Dr. Epperla said. “Higher cumulative doses of rituximab seem to confer overall survival benefit.” This was true even though the higher rituximab doses had no significant effect on the risk of therapy failure, nonrelapse mortality, or the risk of progression/relapse.

When the cumulative rituximab dose was 2,000 to 3,375 mg/m², the hazard ratio for all-cause mortality fell to 0.43 compared to a cumulative rituximab dose of less than 1,000 mg/m² (95% confidence interval [CI] 0.21-0.90, P = .02).

Among the R-RIC group, there was a nonsignificant trend toward reduced risk of progression or relapse (relative risk of progression/relapse, R-RIC = 0.79, 95% CI 0.63-1.01, P = .055). However, the R-RIC group fared significantly better in terms of progression-free survival (RR of PFS, R-RIC = 0.76, 95% CI 0.62-0.92, P = .006).

After transplant, patients in the R-RIC group were no more likely than those in the non–R-RIC group to experience chronic GVHD (RR of GVHD, R-RIC = 1.15, 95% CI 0.96-1.39, P = .13). There was no difference in the adjusted curves of nonrelapse mortality between the groups (RR of nonrelapse mortality, R-RIC = 0.90, 95% CI 0.67-1.22, P = .51).

Also, there were no fatal cytopenias in the R-RIC arm, although the literature warrants some concern for increased risk of infection with rituximab, Dr. Epperla said.

At baseline, there were no significant differences in demographic characteristics between the nonrituximab and rituximab arms of the study population. More than 90% of patients were white, and 65% were male; the median age was 57 years (range, 18-74).

Patients had been diagnosed about 3 years before receiving HCT; about 60% of patients had a baseline Karnofsky performance score greater than 90, and the HCT comorbidity index was 2. About 86% of patients were chemosensitive, and patients in both study arms had received a median of three prior lines of therapy.

There were some differences in conditioning regimens between the two groups. “There were a significantly higher number of patients in the nonrituximab group who received fludarabine/busulfan, while there were a significantly high number in the rituximab group who received a fludarabine/cyclophosphamide-based conditioning regimen,” Dr. Epperla said. Follicular lymphomas were more common in the R-RIC arm, while diffuse large B-cell lymphomas were seen more in the non–R-RIC arm.

Given the survival benefit and similar rates of chronic GVHD seen in the retrospective analysis, a prospective, randomized head-to-head trial of R-RIC versus non–R-RIC is warranted, Dr. Epperla concluded.

During the postpresentation discussion, Dr. Epperla acknowledged the variability of the lymphomas in the study, but that there was no significant statistical effect of specific histologies on the findings in a subgroup analysis. Dr. Epperla added that the chemosensitivity status at transplant was checked to account for patient exposure to rituximab before RIC, and that there was no effect of prior rituximab exposure on the outcomes examined.

Dr. Epperla reported no conflicts of interest.
 

[email protected]

On Twitter @karioakes

Image by Ed Uthman

Preclinical research has revealed a potential strategy for treating Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL).

Investigators discovered that miR-28 inhibits the growth of B-cell lymphomas, but this microRNA is often lost in these lymphomas.

Re-expressing miR-28 in mouse models of BL and DLBCL inhibited tumor growth, which supports the potential of synthetic miR-28 analogs for the treatment of these lymphomas.

In fact, the investigators believe their work could lead to the development of the first miRNA analog therapy for the treatment of B-cell lymphoma and provide the basis for clinical trials.

Almudena Ramiro, PhD, of Centro Nacional de Investigaciones Cardiovasculares in Madrid, Spain, and her colleagues described the work in Blood.

The team characterized the function of miR-28 in the biology of mature B lymphocytes and in the development of lymphomas associated with this cell type.

The investigators found that miR-28 regulates the terminal differentiation of B lymphocytes, a fundamental process in the biology of these cells that generates memory B lymphocytes and highly specific plasma cells.

But the team found that miR-28 expression is lost in several germinal center-derived lymphoma subtypes, including BL, DLBCL, follicular lymphoma, and chronic lymphocytic leukemia.

In vitro experiments showed that miR-28 expression dampens B-cell receptor signaling and diminishes the proliferation and survival of primary B cells and lymphoma cells.

And in vivo experiments showed that re-establishing miR-28 expression slows tumor growth in DLBCL and BL.

The investigators re-expressed miR-28 in xenograft models of BL and DLBCL via the use of viral vectors or synthetic molecules and found that both methods blocked tumor growth. The same effect was observed in mice with established BL tumors.

Dr Ramiro and her colleagues said these results reveal the therapeutic potential of miR-28 and provide ample justification for the initiation of clinical trials of miR-28-based therapies to treat B-cell lymphomas.

Image by Ed Uthman

Preclinical research has revealed a potential strategy for treating Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL).

Investigators discovered that miR-28 inhibits the growth of B-cell lymphomas, but this microRNA is often lost in these lymphomas.

Re-expressing miR-28 in mouse models of BL and DLBCL inhibited tumor growth, which supports the potential of synthetic miR-28 analogs for the treatment of these lymphomas.

In fact, the investigators believe their work could lead to the development of the first miRNA analog therapy for the treatment of B-cell lymphoma and provide the basis for clinical trials.

Almudena Ramiro, PhD, of Centro Nacional de Investigaciones Cardiovasculares in Madrid, Spain, and her colleagues described the work in Blood.

The team characterized the function of miR-28 in the biology of mature B lymphocytes and in the development of lymphomas associated with this cell type.

The investigators found that miR-28 regulates the terminal differentiation of B lymphocytes, a fundamental process in the biology of these cells that generates memory B lymphocytes and highly specific plasma cells.

But the team found that miR-28 expression is lost in several germinal center-derived lymphoma subtypes, including BL, DLBCL, follicular lymphoma, and chronic lymphocytic leukemia.

In vitro experiments showed that miR-28 expression dampens B-cell receptor signaling and diminishes the proliferation and survival of primary B cells and lymphoma cells.

And in vivo experiments showed that re-establishing miR-28 expression slows tumor growth in DLBCL and BL.

The investigators re-expressed miR-28 in xenograft models of BL and DLBCL via the use of viral vectors or synthetic molecules and found that both methods blocked tumor growth. The same effect was observed in mice with established BL tumors.

Dr Ramiro and her colleagues said these results reveal the therapeutic potential of miR-28 and provide ample justification for the initiation of clinical trials of miR-28-based therapies to treat B-cell lymphomas.

Image by Ed Uthman

Preclinical research has revealed a potential strategy for treating Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL).

Investigators discovered that miR-28 inhibits the growth of B-cell lymphomas, but this microRNA is often lost in these lymphomas.

Re-expressing miR-28 in mouse models of BL and DLBCL inhibited tumor growth, which supports the potential of synthetic miR-28 analogs for the treatment of these lymphomas.

In fact, the investigators believe their work could lead to the development of the first miRNA analog therapy for the treatment of B-cell lymphoma and provide the basis for clinical trials.

Almudena Ramiro, PhD, of Centro Nacional de Investigaciones Cardiovasculares in Madrid, Spain, and her colleagues described the work in Blood.

The team characterized the function of miR-28 in the biology of mature B lymphocytes and in the development of lymphomas associated with this cell type.

The investigators found that miR-28 regulates the terminal differentiation of B lymphocytes, a fundamental process in the biology of these cells that generates memory B lymphocytes and highly specific plasma cells.

But the team found that miR-28 expression is lost in several germinal center-derived lymphoma subtypes, including BL, DLBCL, follicular lymphoma, and chronic lymphocytic leukemia.

In vitro experiments showed that miR-28 expression dampens B-cell receptor signaling and diminishes the proliferation and survival of primary B cells and lymphoma cells.

And in vivo experiments showed that re-establishing miR-28 expression slows tumor growth in DLBCL and BL.

The investigators re-expressed miR-28 in xenograft models of BL and DLBCL via the use of viral vectors or synthetic molecules and found that both methods blocked tumor growth. The same effect was observed in mice with established BL tumors.

Dr Ramiro and her colleagues said these results reveal the therapeutic potential of miR-28 and provide ample justification for the initiation of clinical trials of miR-28-based therapies to treat B-cell lymphomas.

Photo by Bill Branson

Childhood cancer survivors (CCSs) who were diagnosed in the 1990s have a lower risk of subsequent malignancies than CCSs diagnosed in the 1970s, according to research published in JAMA.

The data suggest this outcome is associated with a reduction in the overall use and median dose of therapeutic radiation over time.

Past research has shown an association between therapeutic radiation and the development of subsequent neoplasms in CCSs. Studies have also linked specific chemotherapeutic agents to subsequent neoplasms.

This information has been used to modify childhood cancer treatment over time, with the hope of reducing the risk of subsequent neoplasms while maintaining or improving 5-year survival.

To assess the effects of these treatment modifications, Gregory Armstrong, MD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and his colleagues conducted a study of CCSs.

The researchers evaluated 23,603 five-year CCSs (mean age at diagnosis, 7.7 years) treated at pediatric hospitals in the US and Canada from 1970 through 1999, with follow-up through December 2015.

The most common initial diagnoses were acute lymphoblastic leukemia (35.1%), Hodgkin lymphoma (11.1%), and astrocytoma (9.6%).

Subsequent neoplasms, malignancies

At a mean follow-up of 20.5 years, 1639 CCSs had experienced 3115 subsequent neoplasms, including 1026 malignancies, 233 benign meningiomas, and 1856 non-melanoma skin cancers. The most common neoplasms were breast and thyroid cancers.

The 15-year cumulative incidence of subsequent neoplasms decreased by decade of diagnosis. The incidence was 2.9% for patients diagnosed in the 1970s, 2.4% for those diagnosed in the ’80s, and 1.5% for those diagnosed in the ’90s. For the 1970s vs 1980s, the P value was 0.02. For the 1970s vs 1990s and for the 1980s vs 1990s, the P value was <0.001.

The 15-year cumulative incidence of subsequent malignancies also decreased by decade of diagnosis—2.1% for the ’70s, 1.7% for the ’80s, and 1.3% for the ’90s. The P value was <0.001 for the ’70s vs the ’90s and the ’80s vs the ’90s.

Risk factors

In multivariable analyses, female CCSs had a higher rate of subsequent neoplasms (including malignancies) than males.

In addition, high doses of alkylating agents and platinum agents were associated with increased rates of subsequent malignancies.

The researchers noted that, although there was a decrease in the median cumulative dose of alkylating agents over time, the proportion of CCSs receiving these agents increased. And both the median cumulative dose of platinum agents and the proportion of CCSs receiving these agents increased from the ’70s to the ’90s.

Finally, therapeutic radiation was associated with increased rates of subsequent malignant neoplasms, meningiomas, and non-melanoma skin cancers.

This corresponded with the researchers’ findings that the proportion of individuals receiving radiation and the median dose of radiation both decreased over time.

The proportion of individuals receiving any radiation therapy was 77.7% in the ’70s, 56.7% in the ’80s, and 36.8% in the ’90s. The median dose of radiation was 30.0 Gy in the ’70s, 24.0 Gy in the ’80s, and 26.0 Gy in the ’90s.

“The most ominous late effect of pediatric cancer treatment is a second malignancy,” Dr Armstrong said. “This study shows efforts to reduce the late effects of treatment are paying off. The risk of second cancers for survivors increases with age, so it is good to see the reduction emerging early in survivorship while survivors are still young.”

Photo by Bill Branson

Childhood cancer survivors (CCSs) who were diagnosed in the 1990s have a lower risk of subsequent malignancies than CCSs diagnosed in the 1970s, according to research published in JAMA.

The data suggest this outcome is associated with a reduction in the overall use and median dose of therapeutic radiation over time.

Past research has shown an association between therapeutic radiation and the development of subsequent neoplasms in CCSs. Studies have also linked specific chemotherapeutic agents to subsequent neoplasms.

This information has been used to modify childhood cancer treatment over time, with the hope of reducing the risk of subsequent neoplasms while maintaining or improving 5-year survival.

To assess the effects of these treatment modifications, Gregory Armstrong, MD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and his colleagues conducted a study of CCSs.

The researchers evaluated 23,603 five-year CCSs (mean age at diagnosis, 7.7 years) treated at pediatric hospitals in the US and Canada from 1970 through 1999, with follow-up through December 2015.

The most common initial diagnoses were acute lymphoblastic leukemia (35.1%), Hodgkin lymphoma (11.1%), and astrocytoma (9.6%).

Subsequent neoplasms, malignancies

At a mean follow-up of 20.5 years, 1639 CCSs had experienced 3115 subsequent neoplasms, including 1026 malignancies, 233 benign meningiomas, and 1856 non-melanoma skin cancers. The most common neoplasms were breast and thyroid cancers.

The 15-year cumulative incidence of subsequent neoplasms decreased by decade of diagnosis. The incidence was 2.9% for patients diagnosed in the 1970s, 2.4% for those diagnosed in the ’80s, and 1.5% for those diagnosed in the ’90s. For the 1970s vs 1980s, the P value was 0.02. For the 1970s vs 1990s and for the 1980s vs 1990s, the P value was <0.001.

The 15-year cumulative incidence of subsequent malignancies also decreased by decade of diagnosis—2.1% for the ’70s, 1.7% for the ’80s, and 1.3% for the ’90s. The P value was <0.001 for the ’70s vs the ’90s and the ’80s vs the ’90s.

Risk factors

In multivariable analyses, female CCSs had a higher rate of subsequent neoplasms (including malignancies) than males.

In addition, high doses of alkylating agents and platinum agents were associated with increased rates of subsequent malignancies.

The researchers noted that, although there was a decrease in the median cumulative dose of alkylating agents over time, the proportion of CCSs receiving these agents increased. And both the median cumulative dose of platinum agents and the proportion of CCSs receiving these agents increased from the ’70s to the ’90s.

Finally, therapeutic radiation was associated with increased rates of subsequent malignant neoplasms, meningiomas, and non-melanoma skin cancers.

This corresponded with the researchers’ findings that the proportion of individuals receiving radiation and the median dose of radiation both decreased over time.

The proportion of individuals receiving any radiation therapy was 77.7% in the ’70s, 56.7% in the ’80s, and 36.8% in the ’90s. The median dose of radiation was 30.0 Gy in the ’70s, 24.0 Gy in the ’80s, and 26.0 Gy in the ’90s.

“The most ominous late effect of pediatric cancer treatment is a second malignancy,” Dr Armstrong said. “This study shows efforts to reduce the late effects of treatment are paying off. The risk of second cancers for survivors increases with age, so it is good to see the reduction emerging early in survivorship while survivors are still young.”

Photo by Bill Branson

Childhood cancer survivors (CCSs) who were diagnosed in the 1990s have a lower risk of subsequent malignancies than CCSs diagnosed in the 1970s, according to research published in JAMA.

The data suggest this outcome is associated with a reduction in the overall use and median dose of therapeutic radiation over time.

Past research has shown an association between therapeutic radiation and the development of subsequent neoplasms in CCSs. Studies have also linked specific chemotherapeutic agents to subsequent neoplasms.

This information has been used to modify childhood cancer treatment over time, with the hope of reducing the risk of subsequent neoplasms while maintaining or improving 5-year survival.

To assess the effects of these treatment modifications, Gregory Armstrong, MD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and his colleagues conducted a study of CCSs.

The researchers evaluated 23,603 five-year CCSs (mean age at diagnosis, 7.7 years) treated at pediatric hospitals in the US and Canada from 1970 through 1999, with follow-up through December 2015.

The most common initial diagnoses were acute lymphoblastic leukemia (35.1%), Hodgkin lymphoma (11.1%), and astrocytoma (9.6%).

Subsequent neoplasms, malignancies

At a mean follow-up of 20.5 years, 1639 CCSs had experienced 3115 subsequent neoplasms, including 1026 malignancies, 233 benign meningiomas, and 1856 non-melanoma skin cancers. The most common neoplasms were breast and thyroid cancers.

The 15-year cumulative incidence of subsequent neoplasms decreased by decade of diagnosis. The incidence was 2.9% for patients diagnosed in the 1970s, 2.4% for those diagnosed in the ’80s, and 1.5% for those diagnosed in the ’90s. For the 1970s vs 1980s, the P value was 0.02. For the 1970s vs 1990s and for the 1980s vs 1990s, the P value was <0.001.

The 15-year cumulative incidence of subsequent malignancies also decreased by decade of diagnosis—2.1% for the ’70s, 1.7% for the ’80s, and 1.3% for the ’90s. The P value was <0.001 for the ’70s vs the ’90s and the ’80s vs the ’90s.

Risk factors

In multivariable analyses, female CCSs had a higher rate of subsequent neoplasms (including malignancies) than males.

In addition, high doses of alkylating agents and platinum agents were associated with increased rates of subsequent malignancies.

The researchers noted that, although there was a decrease in the median cumulative dose of alkylating agents over time, the proportion of CCSs receiving these agents increased. And both the median cumulative dose of platinum agents and the proportion of CCSs receiving these agents increased from the ’70s to the ’90s.

Finally, therapeutic radiation was associated with increased rates of subsequent malignant neoplasms, meningiomas, and non-melanoma skin cancers.

This corresponded with the researchers’ findings that the proportion of individuals receiving radiation and the median dose of radiation both decreased over time.

The proportion of individuals receiving any radiation therapy was 77.7% in the ’70s, 56.7% in the ’80s, and 36.8% in the ’90s. The median dose of radiation was 30.0 Gy in the ’70s, 24.0 Gy in the ’80s, and 26.0 Gy in the ’90s.

“The most ominous late effect of pediatric cancer treatment is a second malignancy,” Dr Armstrong said. “This study shows efforts to reduce the late effects of treatment are paying off. The risk of second cancers for survivors increases with age, so it is good to see the reduction emerging early in survivorship while survivors are still young.”

ORLANDO – An inactivated varicella zoster virus vaccine currently in development for adult patients undergoing autologous hematopoietic stem cell transplantation is efficacious and well tolerated, according to findings from a randomized, placebo-controlled, phase III trial.

During the course of the 2 1/2-year pivotal multicenter trial, confirmed herpes zoster infections occurred in 42 of 560 patients who were randomized to receive inactivated varicella zoster virus vaccine (ZV_IN) consistency lot (overall incidence of 32.8 cases/1,000 patient-years), compared with 113 of 564 patients who received placebo (overall incidence of 91.8/1,000 patient-years). The estimated vaccine efficacy was 63.8% after adjusting for age and duration of antiviral prophylaxis, Drew J. Winston, MD, reported at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.

The vaccine also was effective for reducing moderate and severe herpes zoster pain (estimated vaccine efficacy, 69.5%), for preventing postherpetic neuralgia (estimated vaccine efficacy, 83.7%), and for prevention of herpes zoster–related complications (estimated vaccine efficacy, 73.5%), he noted.

Study subjects were adults aged 18 years or older who were undergoing autologous hematopoietic stem cell transplantation (auto-HCT) for a malignancy or other indication. The most common underlying diseases were lymphoma and multiple myeloma. All patients had a history of varicella infection or were seropositive for varicella zoster virus (VZV) antibody, and had no history of VZV vaccine or herpes zoster infection within the prior year.

They were randomized to receive a four-dose regimen of either ZV_IN consistency lot, ZV_IN high-antigen lot, or placebo. A group of 106 patients who received the ZV_IN high-antigen lot were included in the safety analysis only. The first ZV_IN dose was administered about a month before transplantation, and doses two through four were administered about 30, 60, and 90 days after transplantation. About 90% in each group received antiviral agents after transplantation, and the duration of the use of antivirals also was similar in the groups. All patients were followed for the duration of the study, and those who developed herpes zoster were followed for 6 months after onset.

Herpes zoster cases were confirmed by polymerase chain reaction or by blinded endpoint committee adjudication.

Serious adverse events and vaccine-related serious adverse events occurred in a similar proportion of patients in the treatment and placebo groups (32.9% and 32.7%, and 0.8% and 0.9%, respectively). Vaccine-related events were primarily injection-site reactions. Systemic adverse events that occurred up to 28 days after vaccination were mainly gastrointestinal side effects, such as diarrhea, nausea, and vomiting. Pyrexia, oral mucositis, thrombocytopenia, and febrile neutropenia also were reported.

The most common serious adverse events were infectious complications, such as febrile neutropenia and relapse of underlying disease.

The findings are notable, as patients undergoing auto-HCT have an increased risk of developing herpes zoster infection and its complications, including postherpetic neuralgia, secondary bacterial infections, and disseminated VZV infection, as well as an increased risk of hospitalization and mortality, Dr. Winston explained.

Herpes zoster infections are associated primarily with cell-mediated immunity, and in older studies done prior to the routine use of antiviral prophylaxis, the reported incidence in auto-HCT patients was between 16% and 25%. Because of this high risk, current guidelines call for antiviral prophylaxis during auto-HCT, but even in this current era of acyclovir or valacyclovir prophylaxis, infections occur at relatively high rates after auto-HCT, he noted.

“Now another approach to prevention of herpes zoster infection is vaccination,” he said.

The live attenuated vaccine currently on the market is generally contraindicated in immunocompromised patients – at least in early period after transplantation, but ZV_IN showed promise with respect to safety in earlier studies, which led to the current trial.

“This study demonstrated that the inactivated varicella vaccine is very effective for preventing herpes zoster after autologous stem cell transplantation,” Dr. Winston said, noting that efficacy was observed both in those younger than age 50 years and in those aged 50 and older, and also in those who received prophylaxis for less than 3 months and for 3-6 months.

“Finally!” said one audience member, who noted during a discussion of the findings that there has long been a need for a vaccine to prevent herpes zoster in auto-HCT patients.

Dr. Winston reported receiving research funding from Oxford, and serving as a consultant to Merck and Chimerix.

[email protected]

ORLANDO – An inactivated varicella zoster virus vaccine currently in development for adult patients undergoing autologous hematopoietic stem cell transplantation is efficacious and well tolerated, according to findings from a randomized, placebo-controlled, phase III trial.

During the course of the 2 1/2-year pivotal multicenter trial, confirmed herpes zoster infections occurred in 42 of 560 patients who were randomized to receive inactivated varicella zoster virus vaccine (ZV_IN) consistency lot (overall incidence of 32.8 cases/1,000 patient-years), compared with 113 of 564 patients who received placebo (overall incidence of 91.8/1,000 patient-years). The estimated vaccine efficacy was 63.8% after adjusting for age and duration of antiviral prophylaxis, Drew J. Winston, MD, reported at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.

The vaccine also was effective for reducing moderate and severe herpes zoster pain (estimated vaccine efficacy, 69.5%), for preventing postherpetic neuralgia (estimated vaccine efficacy, 83.7%), and for prevention of herpes zoster–related complications (estimated vaccine efficacy, 73.5%), he noted.

Study subjects were adults aged 18 years or older who were undergoing autologous hematopoietic stem cell transplantation (auto-HCT) for a malignancy or other indication. The most common underlying diseases were lymphoma and multiple myeloma. All patients had a history of varicella infection or were seropositive for varicella zoster virus (VZV) antibody, and had no history of VZV vaccine or herpes zoster infection within the prior year.

They were randomized to receive a four-dose regimen of either ZV_IN consistency lot, ZV_IN high-antigen lot, or placebo. A group of 106 patients who received the ZV_IN high-antigen lot were included in the safety analysis only. The first ZV_IN dose was administered about a month before transplantation, and doses two through four were administered about 30, 60, and 90 days after transplantation. About 90% in each group received antiviral agents after transplantation, and the duration of the use of antivirals also was similar in the groups. All patients were followed for the duration of the study, and those who developed herpes zoster were followed for 6 months after onset.

Herpes zoster cases were confirmed by polymerase chain reaction or by blinded endpoint committee adjudication.

Serious adverse events and vaccine-related serious adverse events occurred in a similar proportion of patients in the treatment and placebo groups (32.9% and 32.7%, and 0.8% and 0.9%, respectively). Vaccine-related events were primarily injection-site reactions. Systemic adverse events that occurred up to 28 days after vaccination were mainly gastrointestinal side effects, such as diarrhea, nausea, and vomiting. Pyrexia, oral mucositis, thrombocytopenia, and febrile neutropenia also were reported.

The most common serious adverse events were infectious complications, such as febrile neutropenia and relapse of underlying disease.

The findings are notable, as patients undergoing auto-HCT have an increased risk of developing herpes zoster infection and its complications, including postherpetic neuralgia, secondary bacterial infections, and disseminated VZV infection, as well as an increased risk of hospitalization and mortality, Dr. Winston explained.

Herpes zoster infections are associated primarily with cell-mediated immunity, and in older studies done prior to the routine use of antiviral prophylaxis, the reported incidence in auto-HCT patients was between 16% and 25%. Because of this high risk, current guidelines call for antiviral prophylaxis during auto-HCT, but even in this current era of acyclovir or valacyclovir prophylaxis, infections occur at relatively high rates after auto-HCT, he noted.

“Now another approach to prevention of herpes zoster infection is vaccination,” he said.

The live attenuated vaccine currently on the market is generally contraindicated in immunocompromised patients – at least in early period after transplantation, but ZV_IN showed promise with respect to safety in earlier studies, which led to the current trial.

“This study demonstrated that the inactivated varicella vaccine is very effective for preventing herpes zoster after autologous stem cell transplantation,” Dr. Winston said, noting that efficacy was observed both in those younger than age 50 years and in those aged 50 and older, and also in those who received prophylaxis for less than 3 months and for 3-6 months.

“Finally!” said one audience member, who noted during a discussion of the findings that there has long been a need for a vaccine to prevent herpes zoster in auto-HCT patients.

Dr. Winston reported receiving research funding from Oxford, and serving as a consultant to Merck and Chimerix.

[email protected]

ORLANDO – An inactivated varicella zoster virus vaccine currently in development for adult patients undergoing autologous hematopoietic stem cell transplantation is efficacious and well tolerated, according to findings from a randomized, placebo-controlled, phase III trial.

During the course of the 2 1/2-year pivotal multicenter trial, confirmed herpes zoster infections occurred in 42 of 560 patients who were randomized to receive inactivated varicella zoster virus vaccine (ZV_IN) consistency lot (overall incidence of 32.8 cases/1,000 patient-years), compared with 113 of 564 patients who received placebo (overall incidence of 91.8/1,000 patient-years). The estimated vaccine efficacy was 63.8% after adjusting for age and duration of antiviral prophylaxis, Drew J. Winston, MD, reported at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.

The vaccine also was effective for reducing moderate and severe herpes zoster pain (estimated vaccine efficacy, 69.5%), for preventing postherpetic neuralgia (estimated vaccine efficacy, 83.7%), and for prevention of herpes zoster–related complications (estimated vaccine efficacy, 73.5%), he noted.

Study subjects were adults aged 18 years or older who were undergoing autologous hematopoietic stem cell transplantation (auto-HCT) for a malignancy or other indication. The most common underlying diseases were lymphoma and multiple myeloma. All patients had a history of varicella infection or were seropositive for varicella zoster virus (VZV) antibody, and had no history of VZV vaccine or herpes zoster infection within the prior year.

They were randomized to receive a four-dose regimen of either ZV_IN consistency lot, ZV_IN high-antigen lot, or placebo. A group of 106 patients who received the ZV_IN high-antigen lot were included in the safety analysis only. The first ZV_IN dose was administered about a month before transplantation, and doses two through four were administered about 30, 60, and 90 days after transplantation. About 90% in each group received antiviral agents after transplantation, and the duration of the use of antivirals also was similar in the groups. All patients were followed for the duration of the study, and those who developed herpes zoster were followed for 6 months after onset.

Herpes zoster cases were confirmed by polymerase chain reaction or by blinded endpoint committee adjudication.

Serious adverse events and vaccine-related serious adverse events occurred in a similar proportion of patients in the treatment and placebo groups (32.9% and 32.7%, and 0.8% and 0.9%, respectively). Vaccine-related events were primarily injection-site reactions. Systemic adverse events that occurred up to 28 days after vaccination were mainly gastrointestinal side effects, such as diarrhea, nausea, and vomiting. Pyrexia, oral mucositis, thrombocytopenia, and febrile neutropenia also were reported.

The most common serious adverse events were infectious complications, such as febrile neutropenia and relapse of underlying disease.

The findings are notable, as patients undergoing auto-HCT have an increased risk of developing herpes zoster infection and its complications, including postherpetic neuralgia, secondary bacterial infections, and disseminated VZV infection, as well as an increased risk of hospitalization and mortality, Dr. Winston explained.

Herpes zoster infections are associated primarily with cell-mediated immunity, and in older studies done prior to the routine use of antiviral prophylaxis, the reported incidence in auto-HCT patients was between 16% and 25%. Because of this high risk, current guidelines call for antiviral prophylaxis during auto-HCT, but even in this current era of acyclovir or valacyclovir prophylaxis, infections occur at relatively high rates after auto-HCT, he noted.

“Now another approach to prevention of herpes zoster infection is vaccination,” he said.

The live attenuated vaccine currently on the market is generally contraindicated in immunocompromised patients – at least in early period after transplantation, but ZV_IN showed promise with respect to safety in earlier studies, which led to the current trial.

“This study demonstrated that the inactivated varicella vaccine is very effective for preventing herpes zoster after autologous stem cell transplantation,” Dr. Winston said, noting that efficacy was observed both in those younger than age 50 years and in those aged 50 and older, and also in those who received prophylaxis for less than 3 months and for 3-6 months.

“Finally!” said one audience member, who noted during a discussion of the findings that there has long been a need for a vaccine to prevent herpes zoster in auto-HCT patients.

Dr. Winston reported receiving research funding from Oxford, and serving as a consultant to Merck and Chimerix.

[email protected]

follicular lymphoma

The US Food and Drug Administration (FDA) has granted orphan designation to G100 for the treatment of follicular lymphoma.

G100 is a synthetic small-molecule toll-like receptor-4 agonist, glucopyranosyl lipid A, formulated in a stable emulsion.

The FDA grants orphan designation to drugs and biologics intended to treat, diagnose, or prevent rare diseases/disorders affecting fewer than 200,000 people in the US.

Orphan designation provides companies with certain incentives to develop products for rare diseases. This includes a 50% tax break on research and development, a fee waiver, access to federal grants, and 7 years of market exclusivity if the product is approved.

G100 is being developed by Immune Design. The company says G100 works by leveraging the activation of innate and adaptive immunity in the tumor microenvironment to create an immune response against the tumor’s pre-existing antigens.

According to Immune Design, clinical and preclinical data have demonstrated G100’s ability to activate tumor-infiltrating lymphocytes, macrophages, and dendritic cells, and promote antigen-presentation and the recruitment of T cells to the tumor.

The ensuing induction of local and systemic immune responses has been shown to result in local and abscopal tumor control in preclinical studies.

In fact, G100, when combined with local radiation, demonstrated efficacy against A20 lymphoma in mice. This research was presented in a poster at the 2016 ASH Annual Meeting (abstract 4166).

In this study, investigators evaluated the immune response and therapeutic effects of intratumoral G100 alone, local radiation alone, and concomitant G100 and local radiation in mice with A20 lymphoma.

The investigators said the combination therapy demonstrated:

• Synergistic antitumor effects in both injected as well as uninjected tumors (abscopal effects)
• Synergistic induction of pro-inflammatory cytokine and chemokine environment, as well as induction of genes governing antigen processing and presentation
• Increased infiltration of T cells, including CD4 and CD8 T cells, in treated tumors.

In contrast, tumors that received only radiation had significantly lower T-cell levels than untreated tumors.

“These findings highlight the potential beneficial effect that immunotherapy with G100 could provide when given with radiation by modulating the tumor microenvironment to generate a systemic, durable, T-cell anti-tumor response,” said study investigator Ramesh Rengan, MD, of the University of Washington in Seattle.

“As shown in this model, G100 may hold potential as a treatment for lymphoma patients.”

To test that theory, Immune Design is conducting a phase 1/2 trial of G100 given with local radiation or the anti-PD-1 agent pembrolizumab to patients with follicular lymphoma.

follicular lymphoma

The US Food and Drug Administration (FDA) has granted orphan designation to G100 for the treatment of follicular lymphoma.

G100 is a synthetic small-molecule toll-like receptor-4 agonist, glucopyranosyl lipid A, formulated in a stable emulsion.

The FDA grants orphan designation to drugs and biologics intended to treat, diagnose, or prevent rare diseases/disorders affecting fewer than 200,000 people in the US.

Orphan designation provides companies with certain incentives to develop products for rare diseases. This includes a 50% tax break on research and development, a fee waiver, access to federal grants, and 7 years of market exclusivity if the product is approved.

G100 is being developed by Immune Design. The company says G100 works by leveraging the activation of innate and adaptive immunity in the tumor microenvironment to create an immune response against the tumor’s pre-existing antigens.

According to Immune Design, clinical and preclinical data have demonstrated G100’s ability to activate tumor-infiltrating lymphocytes, macrophages, and dendritic cells, and promote antigen-presentation and the recruitment of T cells to the tumor.

The ensuing induction of local and systemic immune responses has been shown to result in local and abscopal tumor control in preclinical studies.

In fact, G100, when combined with local radiation, demonstrated efficacy against A20 lymphoma in mice. This research was presented in a poster at the 2016 ASH Annual Meeting (abstract 4166).

In this study, investigators evaluated the immune response and therapeutic effects of intratumoral G100 alone, local radiation alone, and concomitant G100 and local radiation in mice with A20 lymphoma.

The investigators said the combination therapy demonstrated:

• Synergistic antitumor effects in both injected as well as uninjected tumors (abscopal effects)
• Synergistic induction of pro-inflammatory cytokine and chemokine environment, as well as induction of genes governing antigen processing and presentation
• Increased infiltration of T cells, including CD4 and CD8 T cells, in treated tumors.

In contrast, tumors that received only radiation had significantly lower T-cell levels than untreated tumors.

“These findings highlight the potential beneficial effect that immunotherapy with G100 could provide when given with radiation by modulating the tumor microenvironment to generate a systemic, durable, T-cell anti-tumor response,” said study investigator Ramesh Rengan, MD, of the University of Washington in Seattle.

“As shown in this model, G100 may hold potential as a treatment for lymphoma patients.”

To test that theory, Immune Design is conducting a phase 1/2 trial of G100 given with local radiation or the anti-PD-1 agent pembrolizumab to patients with follicular lymphoma.

follicular lymphoma

The US Food and Drug Administration (FDA) has granted orphan designation to G100 for the treatment of follicular lymphoma.

G100 is a synthetic small-molecule toll-like receptor-4 agonist, glucopyranosyl lipid A, formulated in a stable emulsion.

The FDA grants orphan designation to drugs and biologics intended to treat, diagnose, or prevent rare diseases/disorders affecting fewer than 200,000 people in the US.

Orphan designation provides companies with certain incentives to develop products for rare diseases. This includes a 50% tax break on research and development, a fee waiver, access to federal grants, and 7 years of market exclusivity if the product is approved.

G100 is being developed by Immune Design. The company says G100 works by leveraging the activation of innate and adaptive immunity in the tumor microenvironment to create an immune response against the tumor’s pre-existing antigens.

According to Immune Design, clinical and preclinical data have demonstrated G100’s ability to activate tumor-infiltrating lymphocytes, macrophages, and dendritic cells, and promote antigen-presentation and the recruitment of T cells to the tumor.

The ensuing induction of local and systemic immune responses has been shown to result in local and abscopal tumor control in preclinical studies.

In fact, G100, when combined with local radiation, demonstrated efficacy against A20 lymphoma in mice. This research was presented in a poster at the 2016 ASH Annual Meeting (abstract 4166).

In this study, investigators evaluated the immune response and therapeutic effects of intratumoral G100 alone, local radiation alone, and concomitant G100 and local radiation in mice with A20 lymphoma.

The investigators said the combination therapy demonstrated:

• Synergistic antitumor effects in both injected as well as uninjected tumors (abscopal effects)
• Synergistic induction of pro-inflammatory cytokine and chemokine environment, as well as induction of genes governing antigen processing and presentation
• Increased infiltration of T cells, including CD4 and CD8 T cells, in treated tumors.

In contrast, tumors that received only radiation had significantly lower T-cell levels than untreated tumors.

“These findings highlight the potential beneficial effect that immunotherapy with G100 could provide when given with radiation by modulating the tumor microenvironment to generate a systemic, durable, T-cell anti-tumor response,” said study investigator Ramesh Rengan, MD, of the University of Washington in Seattle.

“As shown in this model, G100 may hold potential as a treatment for lymphoma patients.”

To test that theory, Immune Design is conducting a phase 1/2 trial of G100 given with local radiation or the anti-PD-1 agent pembrolizumab to patients with follicular lymphoma.

Photo by Etan J. Tal

New research has revealed factors that may increase the risk of B-cell non-Hodgkin lymphoma (B-NHL) in Israelis and Palestinians.

This large-scale, epidemiological study indicated that each group had its own unique risk factors.

However, in both groups, recreational sun exposure, black hair-dye use, a history of hospitalization for infection, and having a first-degree relative with a hematopoietic malignancy were all associated with B-NHL.

A team of Palestinian and Israeli researchers reported these findings in PLOS ONE.

The researchers noted that Israelis and Palestinians share the same ecosystem but differ in terms of lifestyle, health behaviors, and medical systems. Yet both populations report high incidences of NHL.

To gain some insight into this phenomenon, the team conducted a study examining risk factors for B-NHL and its subtypes in these two populations.

The researchers looked at medical history, environmental factors, and lifestyle factors in 823 B-NHL patients and 808 healthy controls.

There were 516 Israeli Jews with B-NHL and 307 Palestinian Arabs with B-NHL. The mean age at diagnosis was 60 and 51, respectively.

The proportion of patients with diffuse large B-cell lymphoma was 71% of Palestinian Arabs and 41% of Israeli Jews. The proportion of patients with follicular lymphoma was 14% and 28%, respectively. And the proportion of patients with marginal zone lymphoma was 2% and 14%, respectively.

Using data from questionnaires, pathology review, serology, and genotyping, the researchers uncovered potential risk factors for B-NHL common to both populations and other factors unique to each population.

Results

The data showed that, in both Palestinian Arabs and Israeli Jews, B-NHL was associated with:

• Recreational sun exposure (odds ratio [OR]=1.4)
• Black hair-dye use (OR=1.70)
• A history of hospitalization for infection (OR=1.68)
• Having a first-degree relative with a hematopoietic malignancy (OR=1.69).

Smoking was associated with follicular lymphoma in both populations (OR=1.46). And greater-than-monthly indoor pesticide use was associated with diffuse large B-cell lymphoma in both populations (OR=2.01).

There was an inverse association between alcohol use and B-NHL for both populations (OR=0.46).

Among Palestinian Arabs only, risk factors for B-NHL included gardening (OR=1.93) and a history of herpes (OR=3.73), mononucleosis (OR=6.34), rubella (OR=2.86), and blood transfusion (OR=2.53).

Risk factors that applied to Israeli Jews only included growing fruits and vegetables (OR=1.87) and self-reported autoimmune diseases (OR=1.99).

The researchers said differences in risk factors by ethnicity could reflect differences in lifestyle, medical systems, and reporting patterns, while variations by B-NHL subtypes suggest specific causal factors for different types of disease. However, these findings require further investigation to reveal their mechanisms.

“Apart from the scientific contribution that this research provides in terms of understanding risk factors for NHL, the study entails an important research cooperation among many institutions,” said study author Ora Paltiel, of Hadassah-Hebrew University Medical Organization in Jerusalem, Israel.

“The study provided opportunities for training Palestinian and Israeli researchers and will provide for intellectual interaction for years to come. The data collected will also provide a research platform for the future study of lymphoma. Epidemiologic research has the potential to improve and preserve human health, and it can also serve as a bridge to dialogue among nations.” 

Photo by Etan J. Tal

New research has revealed factors that may increase the risk of B-cell non-Hodgkin lymphoma (B-NHL) in Israelis and Palestinians.

This large-scale, epidemiological study indicated that each group had its own unique risk factors.

However, in both groups, recreational sun exposure, black hair-dye use, a history of hospitalization for infection, and having a first-degree relative with a hematopoietic malignancy were all associated with B-NHL.

A team of Palestinian and Israeli researchers reported these findings in PLOS ONE.

The researchers noted that Israelis and Palestinians share the same ecosystem but differ in terms of lifestyle, health behaviors, and medical systems. Yet both populations report high incidences of NHL.

To gain some insight into this phenomenon, the team conducted a study examining risk factors for B-NHL and its subtypes in these two populations.

The researchers looked at medical history, environmental factors, and lifestyle factors in 823 B-NHL patients and 808 healthy controls.

There were 516 Israeli Jews with B-NHL and 307 Palestinian Arabs with B-NHL. The mean age at diagnosis was 60 and 51, respectively.

The proportion of patients with diffuse large B-cell lymphoma was 71% of Palestinian Arabs and 41% of Israeli Jews. The proportion of patients with follicular lymphoma was 14% and 28%, respectively. And the proportion of patients with marginal zone lymphoma was 2% and 14%, respectively.

Using data from questionnaires, pathology review, serology, and genotyping, the researchers uncovered potential risk factors for B-NHL common to both populations and other factors unique to each population.

Results

The data showed that, in both Palestinian Arabs and Israeli Jews, B-NHL was associated with:

• Recreational sun exposure (odds ratio [OR]=1.4)
• Black hair-dye use (OR=1.70)
• A history of hospitalization for infection (OR=1.68)
• Having a first-degree relative with a hematopoietic malignancy (OR=1.69).

Smoking was associated with follicular lymphoma in both populations (OR=1.46). And greater-than-monthly indoor pesticide use was associated with diffuse large B-cell lymphoma in both populations (OR=2.01).

There was an inverse association between alcohol use and B-NHL for both populations (OR=0.46).

Among Palestinian Arabs only, risk factors for B-NHL included gardening (OR=1.93) and a history of herpes (OR=3.73), mononucleosis (OR=6.34), rubella (OR=2.86), and blood transfusion (OR=2.53).

Risk factors that applied to Israeli Jews only included growing fruits and vegetables (OR=1.87) and self-reported autoimmune diseases (OR=1.99).

The researchers said differences in risk factors by ethnicity could reflect differences in lifestyle, medical systems, and reporting patterns, while variations by B-NHL subtypes suggest specific causal factors for different types of disease. However, these findings require further investigation to reveal their mechanisms.

“Apart from the scientific contribution that this research provides in terms of understanding risk factors for NHL, the study entails an important research cooperation among many institutions,” said study author Ora Paltiel, of Hadassah-Hebrew University Medical Organization in Jerusalem, Israel.

“The study provided opportunities for training Palestinian and Israeli researchers and will provide for intellectual interaction for years to come. The data collected will also provide a research platform for the future study of lymphoma. Epidemiologic research has the potential to improve and preserve human health, and it can also serve as a bridge to dialogue among nations.” 

Photo by Etan J. Tal

New research has revealed factors that may increase the risk of B-cell non-Hodgkin lymphoma (B-NHL) in Israelis and Palestinians.

This large-scale, epidemiological study indicated that each group had its own unique risk factors.

However, in both groups, recreational sun exposure, black hair-dye use, a history of hospitalization for infection, and having a first-degree relative with a hematopoietic malignancy were all associated with B-NHL.

A team of Palestinian and Israeli researchers reported these findings in PLOS ONE.

The researchers noted that Israelis and Palestinians share the same ecosystem but differ in terms of lifestyle, health behaviors, and medical systems. Yet both populations report high incidences of NHL.

To gain some insight into this phenomenon, the team conducted a study examining risk factors for B-NHL and its subtypes in these two populations.

The researchers looked at medical history, environmental factors, and lifestyle factors in 823 B-NHL patients and 808 healthy controls.

There were 516 Israeli Jews with B-NHL and 307 Palestinian Arabs with B-NHL. The mean age at diagnosis was 60 and 51, respectively.

The proportion of patients with diffuse large B-cell lymphoma was 71% of Palestinian Arabs and 41% of Israeli Jews. The proportion of patients with follicular lymphoma was 14% and 28%, respectively. And the proportion of patients with marginal zone lymphoma was 2% and 14%, respectively.

Using data from questionnaires, pathology review, serology, and genotyping, the researchers uncovered potential risk factors for B-NHL common to both populations and other factors unique to each population.

Results

The data showed that, in both Palestinian Arabs and Israeli Jews, B-NHL was associated with:

• Recreational sun exposure (odds ratio [OR]=1.4)
• Black hair-dye use (OR=1.70)
• A history of hospitalization for infection (OR=1.68)
• Having a first-degree relative with a hematopoietic malignancy (OR=1.69).

Smoking was associated with follicular lymphoma in both populations (OR=1.46). And greater-than-monthly indoor pesticide use was associated with diffuse large B-cell lymphoma in both populations (OR=2.01).

There was an inverse association between alcohol use and B-NHL for both populations (OR=0.46).

Among Palestinian Arabs only, risk factors for B-NHL included gardening (OR=1.93) and a history of herpes (OR=3.73), mononucleosis (OR=6.34), rubella (OR=2.86), and blood transfusion (OR=2.53).

Risk factors that applied to Israeli Jews only included growing fruits and vegetables (OR=1.87) and self-reported autoimmune diseases (OR=1.99).

The researchers said differences in risk factors by ethnicity could reflect differences in lifestyle, medical systems, and reporting patterns, while variations by B-NHL subtypes suggest specific causal factors for different types of disease. However, these findings require further investigation to reveal their mechanisms.

“Apart from the scientific contribution that this research provides in terms of understanding risk factors for NHL, the study entails an important research cooperation among many institutions,” said study author Ora Paltiel, of Hadassah-Hebrew University Medical Organization in Jerusalem, Israel.

“The study provided opportunities for training Palestinian and Israeli researchers and will provide for intellectual interaction for years to come. The data collected will also provide a research platform for the future study of lymphoma. Epidemiologic research has the potential to improve and preserve human health, and it can also serve as a bridge to dialogue among nations.” 

Follicular lymphoma

The European Commission has approved a biosimilar rituximab product, Truxima™, for all the same indications as the reference product, MabThera.

This means Truxima (formerly called CT-P10) is approved for use in the European Union to treat patients with non-Hodgkin lymphoma, chronic lymphocytic leukemia, rheumatoid arthritis (RA), granulomatosis with polyangiitis (GPA), and microscopic polyangiitis (MPA).

Truxima, a product of Celltrion Healthcare Hungary Kft, is the first biosimilar monoclonal antibody approved in an oncology indication worldwide.

The approval is based on data submitted to the European Medicines Agency.

The agency’s Committee for Medicinal Products for Human Use (CHMP) said the evidence suggests Truxima and MabThera are similar in terms of efficacy, safety, immunogenicity, pharmacodynamics, and pharmacokinetics in patients with RA and advanced follicular lymphoma (FL).

Therefore, the European Commission approved Truxima for the following indications.

Non-Hodgkin lymphoma 

Truxima is indicated for use in combination with chemotherapy to treat previously untreated patients with stage III-IV FL.

Truxima maintenance therapy is indicated for the treatment of FL patients responding to induction therapy.

Truxima monotherapy is indicated for the treatment of patients with stage III-IV FL who are chemo-resistant or are in their second or subsequent relapse after chemotherapy.

Truxima is indicated for use in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) for the treatment of patients with CD20-positive diffuse large B-cell lymphoma.

Chronic lymphocytic leukemia

Truxima in combination with chemotherapy is indicated for the treatment of patients with previously untreated and relapsed/refractory chronic lymphocytic leukemia.

The CHMP noted that limited efficacy and safety data are available for patients previously treated with monoclonal antibodies, including rituximab, or patients who are refractory to previous rituximab plus chemotherapy.

RA, GPA, and MPA 

Truxima in combination with methotrexate is indicated for the treatment of adults with severe, active RA who have had an inadequate response to or cannot tolerate other disease-modifying anti-rheumatic drugs, including one or more tumor necrosis factor inhibitor therapies.

Truxima in combination with glucocorticoids is indicated for the induction of remission in adults with severe, active GPA or MPA.

Truxima studies

There are 3 ongoing, phase 3 trials of Truxima in patients with RA (NCT02149121), advanced FL (NCT02162771), and low-tumor-burden FL (NCT02260804).

Results from the phase 1/3 trial in patients with newly diagnosed, advanced FL suggest that Truxima and the reference rituximab are similar with regard to pharmacokinetics, immunogenicity, and safety (B Coiffier et al. ASH 2016, abstract 1807).

Results from the phase 3 study of RA patients indicate that Truxima is similar to reference products (EU and US-sourced rituximab) with regard to pharmacodynamics, safety, and efficacy for up to 24 weeks (DH Yoo et al. 2016 ACR/ARHP Annual Meeting, abstract 1635).  

Follicular lymphoma

The European Commission has approved a biosimilar rituximab product, Truxima™, for all the same indications as the reference product, MabThera.

This means Truxima (formerly called CT-P10) is approved for use in the European Union to treat patients with non-Hodgkin lymphoma, chronic lymphocytic leukemia, rheumatoid arthritis (RA), granulomatosis with polyangiitis (GPA), and microscopic polyangiitis (MPA).

Truxima, a product of Celltrion Healthcare Hungary Kft, is the first biosimilar monoclonal antibody approved in an oncology indication worldwide.

The approval is based on data submitted to the European Medicines Agency.

The agency’s Committee for Medicinal Products for Human Use (CHMP) said the evidence suggests Truxima and MabThera are similar in terms of efficacy, safety, immunogenicity, pharmacodynamics, and pharmacokinetics in patients with RA and advanced follicular lymphoma (FL).

Therefore, the European Commission approved Truxima for the following indications.

Non-Hodgkin lymphoma 

Truxima is indicated for use in combination with chemotherapy to treat previously untreated patients with stage III-IV FL.

Truxima maintenance therapy is indicated for the treatment of FL patients responding to induction therapy.

Truxima monotherapy is indicated for the treatment of patients with stage III-IV FL who are chemo-resistant or are in their second or subsequent relapse after chemotherapy.

Truxima is indicated for use in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) for the treatment of patients with CD20-positive diffuse large B-cell lymphoma.

Chronic lymphocytic leukemia

Truxima in combination with chemotherapy is indicated for the treatment of patients with previously untreated and relapsed/refractory chronic lymphocytic leukemia.

The CHMP noted that limited efficacy and safety data are available for patients previously treated with monoclonal antibodies, including rituximab, or patients who are refractory to previous rituximab plus chemotherapy.

RA, GPA, and MPA 

Truxima in combination with methotrexate is indicated for the treatment of adults with severe, active RA who have had an inadequate response to or cannot tolerate other disease-modifying anti-rheumatic drugs, including one or more tumor necrosis factor inhibitor therapies.

Truxima in combination with glucocorticoids is indicated for the induction of remission in adults with severe, active GPA or MPA.

Truxima studies

There are 3 ongoing, phase 3 trials of Truxima in patients with RA (NCT02149121), advanced FL (NCT02162771), and low-tumor-burden FL (NCT02260804).

Results from the phase 1/3 trial in patients with newly diagnosed, advanced FL suggest that Truxima and the reference rituximab are similar with regard to pharmacokinetics, immunogenicity, and safety (B Coiffier et al. ASH 2016, abstract 1807).

Results from the phase 3 study of RA patients indicate that Truxima is similar to reference products (EU and US-sourced rituximab) with regard to pharmacodynamics, safety, and efficacy for up to 24 weeks (DH Yoo et al. 2016 ACR/ARHP Annual Meeting, abstract 1635).  

Follicular lymphoma

The European Commission has approved a biosimilar rituximab product, Truxima™, for all the same indications as the reference product, MabThera.

This means Truxima (formerly called CT-P10) is approved for use in the European Union to treat patients with non-Hodgkin lymphoma, chronic lymphocytic leukemia, rheumatoid arthritis (RA), granulomatosis with polyangiitis (GPA), and microscopic polyangiitis (MPA).

Truxima, a product of Celltrion Healthcare Hungary Kft, is the first biosimilar monoclonal antibody approved in an oncology indication worldwide.

The approval is based on data submitted to the European Medicines Agency.

The agency’s Committee for Medicinal Products for Human Use (CHMP) said the evidence suggests Truxima and MabThera are similar in terms of efficacy, safety, immunogenicity, pharmacodynamics, and pharmacokinetics in patients with RA and advanced follicular lymphoma (FL).

Therefore, the European Commission approved Truxima for the following indications.

Non-Hodgkin lymphoma 

Truxima is indicated for use in combination with chemotherapy to treat previously untreated patients with stage III-IV FL.

Truxima maintenance therapy is indicated for the treatment of FL patients responding to induction therapy.

Truxima monotherapy is indicated for the treatment of patients with stage III-IV FL who are chemo-resistant or are in their second or subsequent relapse after chemotherapy.

Truxima is indicated for use in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) for the treatment of patients with CD20-positive diffuse large B-cell lymphoma.

Chronic lymphocytic leukemia

Truxima in combination with chemotherapy is indicated for the treatment of patients with previously untreated and relapsed/refractory chronic lymphocytic leukemia.

The CHMP noted that limited efficacy and safety data are available for patients previously treated with monoclonal antibodies, including rituximab, or patients who are refractory to previous rituximab plus chemotherapy.

RA, GPA, and MPA 

Truxima in combination with methotrexate is indicated for the treatment of adults with severe, active RA who have had an inadequate response to or cannot tolerate other disease-modifying anti-rheumatic drugs, including one or more tumor necrosis factor inhibitor therapies.

Truxima in combination with glucocorticoids is indicated for the induction of remission in adults with severe, active GPA or MPA.

Truxima studies

There are 3 ongoing, phase 3 trials of Truxima in patients with RA (NCT02149121), advanced FL (NCT02162771), and low-tumor-burden FL (NCT02260804).

Results from the phase 1/3 trial in patients with newly diagnosed, advanced FL suggest that Truxima and the reference rituximab are similar with regard to pharmacokinetics, immunogenicity, and safety (B Coiffier et al. ASH 2016, abstract 1807).

Results from the phase 3 study of RA patients indicate that Truxima is similar to reference products (EU and US-sourced rituximab) with regard to pharmacodynamics, safety, and efficacy for up to 24 weeks (DH Yoo et al. 2016 ACR/ARHP Annual Meeting, abstract 1635).  

Benjamin Chaigne-Delalande

The US Food and Drug Administration (FDA) has granted fast track designation to CMD-003 (baltaleucel-T) for patients with relapsed/refractory lymphoma and post-transplant lymphoproliferative disease associated with Epstein-Barr virus (EBV).

CMD-003 consists of patient-derived T cells that have been activated to kill malignant cells expressing antigens associated with EBV.

The T cells specifically target 4 EBV epitopes—LMP1, LMP2, EBNA, and BARF1.

CMD-003 is being developed by Cell Medica and the Baylor College of Medicine with funding provided, in part, by the Cancer Prevention and Research Institute of Texas.

About fast track designation

The FDA’s fast track program is designed to facilitate the development and expedite the review of products intended to treat or prevent serious or life-threatening conditions and address unmet medical need.

Through the FDA’s fast track program, a product may be eligible for priority review. In addition, the company developing the product may be allowed to submit sections of the biologic license application or new drug application on a rolling basis as data become available.

Fast track designation also provides the company with opportunities for more frequent meetings and written communications with the FDA.

CMD-003-related research

CMD-003 is currently under investigation in the phase 2 CITADEL trial for patients with extranodal natural killer T-cell lymphoma and the phase 2 CIVIC trial for patients with EBV-associated diffuse large B-cell lymphoma, Hodgkin lymphoma, and post-transplant lymphoproliferative disease.

Researchers have not published results from any trials of CMD-003, but they have published results with EBV-specific T-cell products related to CMD-003.

In one study, published in the Journal of Clinical Oncology in 2014, researchers administered cytotoxic T lymphocytes (CTLs) in 50 patients with EBV-associated Hodgkin or non-Hodgkin lymphoma.

Twenty-nine of the patients were in remission when they received CTL infusions, but they were at a high risk of relapse. The remaining 21 patients had relapsed or refractory disease at the time of CTL infusion.

Twenty-seven of the patients who received CTLs as an adjuvant treatment remained in remission at 3.1 years after treatment.

Their 2-year event-free survival rate was 82%. None of the patients died of lymphoma, but 9 died from complications associated with the chemotherapy and radiation they had received.

Of the 21 patients with relapsed or refractory disease, 13 responded to CTL infusions, and 11 patients achieved a complete response. In this group, the 2-year event-free survival rate was about 50%.

The researchers said there were no toxicities that were definitively related to CTL infusion.

One patient had central nervous system deterioration 2 weeks after infusion. This was attributed to disease progression but could possibly have been treatment-related.

Another patient developed respiratory complications about 4 weeks after a second CTL infusion that may have been treatment-related. However, the researchers attributed it to an intercurrent infection, and the patient made a complete recovery.

Benjamin Chaigne-Delalande

The US Food and Drug Administration (FDA) has granted fast track designation to CMD-003 (baltaleucel-T) for patients with relapsed/refractory lymphoma and post-transplant lymphoproliferative disease associated with Epstein-Barr virus (EBV).

CMD-003 consists of patient-derived T cells that have been activated to kill malignant cells expressing antigens associated with EBV.

The T cells specifically target 4 EBV epitopes—LMP1, LMP2, EBNA, and BARF1.

CMD-003 is being developed by Cell Medica and the Baylor College of Medicine with funding provided, in part, by the Cancer Prevention and Research Institute of Texas.

About fast track designation

The FDA’s fast track program is designed to facilitate the development and expedite the review of products intended to treat or prevent serious or life-threatening conditions and address unmet medical need.

Through the FDA’s fast track program, a product may be eligible for priority review. In addition, the company developing the product may be allowed to submit sections of the biologic license application or new drug application on a rolling basis as data become available.

Fast track designation also provides the company with opportunities for more frequent meetings and written communications with the FDA.

CMD-003-related research

CMD-003 is currently under investigation in the phase 2 CITADEL trial for patients with extranodal natural killer T-cell lymphoma and the phase 2 CIVIC trial for patients with EBV-associated diffuse large B-cell lymphoma, Hodgkin lymphoma, and post-transplant lymphoproliferative disease.

Researchers have not published results from any trials of CMD-003, but they have published results with EBV-specific T-cell products related to CMD-003.

In one study, published in the Journal of Clinical Oncology in 2014, researchers administered cytotoxic T lymphocytes (CTLs) in 50 patients with EBV-associated Hodgkin or non-Hodgkin lymphoma.

Twenty-nine of the patients were in remission when they received CTL infusions, but they were at a high risk of relapse. The remaining 21 patients had relapsed or refractory disease at the time of CTL infusion.

Twenty-seven of the patients who received CTLs as an adjuvant treatment remained in remission at 3.1 years after treatment.

Their 2-year event-free survival rate was 82%. None of the patients died of lymphoma, but 9 died from complications associated with the chemotherapy and radiation they had received.

Of the 21 patients with relapsed or refractory disease, 13 responded to CTL infusions, and 11 patients achieved a complete response. In this group, the 2-year event-free survival rate was about 50%.

The researchers said there were no toxicities that were definitively related to CTL infusion.

One patient had central nervous system deterioration 2 weeks after infusion. This was attributed to disease progression but could possibly have been treatment-related.

Another patient developed respiratory complications about 4 weeks after a second CTL infusion that may have been treatment-related. However, the researchers attributed it to an intercurrent infection, and the patient made a complete recovery.

Benjamin Chaigne-Delalande

The US Food and Drug Administration (FDA) has granted fast track designation to CMD-003 (baltaleucel-T) for patients with relapsed/refractory lymphoma and post-transplant lymphoproliferative disease associated with Epstein-Barr virus (EBV).

CMD-003 consists of patient-derived T cells that have been activated to kill malignant cells expressing antigens associated with EBV.

The T cells specifically target 4 EBV epitopes—LMP1, LMP2, EBNA, and BARF1.

CMD-003 is being developed by Cell Medica and the Baylor College of Medicine with funding provided, in part, by the Cancer Prevention and Research Institute of Texas.

About fast track designation

The FDA’s fast track program is designed to facilitate the development and expedite the review of products intended to treat or prevent serious or life-threatening conditions and address unmet medical need.

Through the FDA’s fast track program, a product may be eligible for priority review. In addition, the company developing the product may be allowed to submit sections of the biologic license application or new drug application on a rolling basis as data become available.

Fast track designation also provides the company with opportunities for more frequent meetings and written communications with the FDA.

CMD-003-related research

CMD-003 is currently under investigation in the phase 2 CITADEL trial for patients with extranodal natural killer T-cell lymphoma and the phase 2 CIVIC trial for patients with EBV-associated diffuse large B-cell lymphoma, Hodgkin lymphoma, and post-transplant lymphoproliferative disease.

Researchers have not published results from any trials of CMD-003, but they have published results with EBV-specific T-cell products related to CMD-003.

In one study, published in the Journal of Clinical Oncology in 2014, researchers administered cytotoxic T lymphocytes (CTLs) in 50 patients with EBV-associated Hodgkin or non-Hodgkin lymphoma.

Twenty-nine of the patients were in remission when they received CTL infusions, but they were at a high risk of relapse. The remaining 21 patients had relapsed or refractory disease at the time of CTL infusion.

Twenty-seven of the patients who received CTLs as an adjuvant treatment remained in remission at 3.1 years after treatment.

Their 2-year event-free survival rate was 82%. None of the patients died of lymphoma, but 9 died from complications associated with the chemotherapy and radiation they had received.

Of the 21 patients with relapsed or refractory disease, 13 responded to CTL infusions, and 11 patients achieved a complete response. In this group, the 2-year event-free survival rate was about 50%.

The researchers said there were no toxicities that were definitively related to CTL infusion.

One patient had central nervous system deterioration 2 weeks after infusion. This was attributed to disease progression but could possibly have been treatment-related.

Another patient developed respiratory complications about 4 weeks after a second CTL infusion that may have been treatment-related. However, the researchers attributed it to an intercurrent infection, and the patient made a complete recovery.

Wind turbines in Styria, Austria. Styrene is used in the manufacture of wind turbines.

A new study links styrene—a chemical used in the manufacture of plastics, rubber, and resins—to certain cancers.

The research showed that, contrary to previous suggestions, employees who have worked with styrene do not have an increased incidence of esophageal, pancreatic, lung, kidney, or bladder cancer.

On the other hand, they may have an increased risk of nasal and paranasal cancer, as well as myeloid leukemia and Hodgkin lymphoma (HL).

The research was published in Epidemiology.

“It is important to know for present and former workers exposed to styrene that they are unlikely to have become ill by doing their job if they have developed cancer of the esophagus, pancreas, lungs, kidneys, bladder, or a wide range of other types of cancer,” said study author Henrik A. Kolstad, MD, PhD, of Aarhus University in Denmark.

“This is also new and important knowledge in the USA, where styrene was added to the list of carcinogenic substances in 2011.”

In relation to the cancers for which the study shows a possible increased risk, Dr Kolstad emphasized that additional research is needed to determine if styrene is the actual cause of the employees’ disease.

For the current study, Dr Kolstad and his colleagues analyzed data on 72,292 employees who worked for 1 of 443 small and medium-sized companies in Denmark that used styrene for the production of wind turbines, pleasure boats, and other products from 1964 to 2007.

There were 8961 incident cases of cancer in this cohort from 1968 to 2012. The standardized incidence rate ratio (SIR) for all cancers was 1.04. When the researchers included a 10-year lag period, the SIR for all cancers was still 1.04.

As for hematologic malignancies, the researchers said they observed increased rate ratios associated with increased duration of employment for HL and myeloid leukemia.

For HL, the SIRs were 1.21 with no lag and 1.22 with a 10-year lag. For myeloid leukemia, the SIRs were 1.06 and 1.13, respectively.

The SIRs for non-Hodgkin lymphoma were 0.97 with no lag and 0.94 with a 10-year lag. The SIRs for multiple myeloma were 0.79 and 0.77, respectively.

For cancers of lymphatic and hematopoietic tissue, the SIRs were 0.97 with no lag and 0.96 with a 10-year lag. For lymphatic leukemia, the SIR was 0.96 for both time points.

The SIRs for monocytic leukemia were 0.77 with no lag and 0.56 with a 10-year lag. The SIRs for other and unspecified leukemias were 1.05 and 1.26, respectively.

The researchers noted that workers first employed in the 1960s had a higher risk of HL than workers first employed in subsequent years.

The SIRs were 2.12 for those first employed in 1964-1969, 0.82 for 1970-1979, 1.07 for 1980-1989, 1.52 for 1990-1999, and 1.10 for those first employed in 2000-2007.

There were no such associations for other cancer sites.

Wind turbines in Styria, Austria. Styrene is used in the manufacture of wind turbines.

A new study links styrene—a chemical used in the manufacture of plastics, rubber, and resins—to certain cancers.

The research showed that, contrary to previous suggestions, employees who have worked with styrene do not have an increased incidence of esophageal, pancreatic, lung, kidney, or bladder cancer.

On the other hand, they may have an increased risk of nasal and paranasal cancer, as well as myeloid leukemia and Hodgkin lymphoma (HL).

The research was published in Epidemiology.

“It is important to know for present and former workers exposed to styrene that they are unlikely to have become ill by doing their job if they have developed cancer of the esophagus, pancreas, lungs, kidneys, bladder, or a wide range of other types of cancer,” said study author Henrik A. Kolstad, MD, PhD, of Aarhus University in Denmark.

“This is also new and important knowledge in the USA, where styrene was added to the list of carcinogenic substances in 2011.”

In relation to the cancers for which the study shows a possible increased risk, Dr Kolstad emphasized that additional research is needed to determine if styrene is the actual cause of the employees’ disease.

For the current study, Dr Kolstad and his colleagues analyzed data on 72,292 employees who worked for 1 of 443 small and medium-sized companies in Denmark that used styrene for the production of wind turbines, pleasure boats, and other products from 1964 to 2007.

There were 8961 incident cases of cancer in this cohort from 1968 to 2012. The standardized incidence rate ratio (SIR) for all cancers was 1.04. When the researchers included a 10-year lag period, the SIR for all cancers was still 1.04.

As for hematologic malignancies, the researchers said they observed increased rate ratios associated with increased duration of employment for HL and myeloid leukemia.

For HL, the SIRs were 1.21 with no lag and 1.22 with a 10-year lag. For myeloid leukemia, the SIRs were 1.06 and 1.13, respectively.

The SIRs for non-Hodgkin lymphoma were 0.97 with no lag and 0.94 with a 10-year lag. The SIRs for multiple myeloma were 0.79 and 0.77, respectively.

For cancers of lymphatic and hematopoietic tissue, the SIRs were 0.97 with no lag and 0.96 with a 10-year lag. For lymphatic leukemia, the SIR was 0.96 for both time points.

The SIRs for monocytic leukemia were 0.77 with no lag and 0.56 with a 10-year lag. The SIRs for other and unspecified leukemias were 1.05 and 1.26, respectively.

The researchers noted that workers first employed in the 1960s had a higher risk of HL than workers first employed in subsequent years.

The SIRs were 2.12 for those first employed in 1964-1969, 0.82 for 1970-1979, 1.07 for 1980-1989, 1.52 for 1990-1999, and 1.10 for those first employed in 2000-2007.

There were no such associations for other cancer sites.

Wind turbines in Styria, Austria. Styrene is used in the manufacture of wind turbines.

A new study links styrene—a chemical used in the manufacture of plastics, rubber, and resins—to certain cancers.

The research showed that, contrary to previous suggestions, employees who have worked with styrene do not have an increased incidence of esophageal, pancreatic, lung, kidney, or bladder cancer.

On the other hand, they may have an increased risk of nasal and paranasal cancer, as well as myeloid leukemia and Hodgkin lymphoma (HL).

The research was published in Epidemiology.

“It is important to know for present and former workers exposed to styrene that they are unlikely to have become ill by doing their job if they have developed cancer of the esophagus, pancreas, lungs, kidneys, bladder, or a wide range of other types of cancer,” said study author Henrik A. Kolstad, MD, PhD, of Aarhus University in Denmark.

“This is also new and important knowledge in the USA, where styrene was added to the list of carcinogenic substances in 2011.”

In relation to the cancers for which the study shows a possible increased risk, Dr Kolstad emphasized that additional research is needed to determine if styrene is the actual cause of the employees’ disease.

For the current study, Dr Kolstad and his colleagues analyzed data on 72,292 employees who worked for 1 of 443 small and medium-sized companies in Denmark that used styrene for the production of wind turbines, pleasure boats, and other products from 1964 to 2007.

There were 8961 incident cases of cancer in this cohort from 1968 to 2012. The standardized incidence rate ratio (SIR) for all cancers was 1.04. When the researchers included a 10-year lag period, the SIR for all cancers was still 1.04.

As for hematologic malignancies, the researchers said they observed increased rate ratios associated with increased duration of employment for HL and myeloid leukemia.

For HL, the SIRs were 1.21 with no lag and 1.22 with a 10-year lag. For myeloid leukemia, the SIRs were 1.06 and 1.13, respectively.

The SIRs for non-Hodgkin lymphoma were 0.97 with no lag and 0.94 with a 10-year lag. The SIRs for multiple myeloma were 0.79 and 0.77, respectively.

For cancers of lymphatic and hematopoietic tissue, the SIRs were 0.97 with no lag and 0.96 with a 10-year lag. For lymphatic leukemia, the SIR was 0.96 for both time points.

The SIRs for monocytic leukemia were 0.77 with no lag and 0.56 with a 10-year lag. The SIRs for other and unspecified leukemias were 1.05 and 1.26, respectively.

The researchers noted that workers first employed in the 1960s had a higher risk of HL than workers first employed in subsequent years.

The SIRs were 2.12 for those first employed in 1964-1969, 0.82 for 1970-1979, 1.07 for 1980-1989, 1.52 for 1990-1999, and 1.10 for those first employed in 2000-2007.

There were no such associations for other cancer sites.

EBV-infected cell (green/red)

among uninfected cells (blue)

Image courtesy of

Benjamin Chaigne-Delalande

New research published in Nature Communications appears to explain how Epstein-Barr virus (EBV) reprograms cells into cancer cells.

Investigators said they discovered a mechanism by which EBV particles induce chromosomal instability without establishing a chronic infection, thereby conferring a risk for the development of tumors that do not necessarily carry the viral genome.

“The contribution of the viral infection to cancer development in patients with a weakened immune system is well understood,” said study author Henri-Jacques Delecluse, MD, PhD, of the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) in Heidelberg.

“But in the majority of cases, it remains unclear how an EBV infection leads to cancer development.”

With their research, Dr Delecluse and his colleagues found that BNRF1, a protein component of EBV, promotes the development of cancer. They said BNRF1 induces centrosome amplification, which is associated with chromosomal instability.

When a dividing cell comes in contact with EBV, BNRF1 frequently prompts the formation of an excessive number of centrosomes. As a result, chromosomes are no longer divided equally and accurately between daughter cells—a known cancer risk factor.

In contrast, when the investigators studied EBV deficient of BNRF1, they found the virus did not interfere with chromosome distribution to daughter cells.

The team noted that EBV normally remains silent in a few infected cells, but, occasionally, it reactivates to produce viral offspring that infects nearby cells. As a consequence, these cells come in close contact with BNRF1, thus increasing their risk of transforming into cancer cells.

“The novelty of our work is that we have uncovered a component of the viral particle as a cancer driver,” Dr Delecluse said. “All human-tumors viruses that have been studied so far cause cancer in a completely different manner.”

“Usually, the genetic material of the viruses needs to be permanently present in the infected cell, thus causing the activation of one or several viral genes that cause cancer development. However, these gene products are not present in the infectious particle itself.”

Dr Delecluse and his colleagues therefore suspect that EBV could cause cancers other than those that have already been linked to EBV. Certain cancers might not have been linked to the virus because they do not carry the viral genetic material.

“We must push forward with the development of a vaccine against EBV infection,” Dr Delecluse said. “This would be the most direct strategy to prevent an infection with the virus.”

“Our latest results show that the first infection could already be a cancer risk, and this fits with earlier work that showed an increase in the incidence of Hodgkin’s lymphoma in people who underwent an episode of infectious mononucleosis.”

EBV-infected cell (green/red)

among uninfected cells (blue)

Image courtesy of

Benjamin Chaigne-Delalande

New research published in Nature Communications appears to explain how Epstein-Barr virus (EBV) reprograms cells into cancer cells.

Investigators said they discovered a mechanism by which EBV particles induce chromosomal instability without establishing a chronic infection, thereby conferring a risk for the development of tumors that do not necessarily carry the viral genome.

“The contribution of the viral infection to cancer development in patients with a weakened immune system is well understood,” said study author Henri-Jacques Delecluse, MD, PhD, of the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) in Heidelberg.

“But in the majority of cases, it remains unclear how an EBV infection leads to cancer development.”

With their research, Dr Delecluse and his colleagues found that BNRF1, a protein component of EBV, promotes the development of cancer. They said BNRF1 induces centrosome amplification, which is associated with chromosomal instability.

When a dividing cell comes in contact with EBV, BNRF1 frequently prompts the formation of an excessive number of centrosomes. As a result, chromosomes are no longer divided equally and accurately between daughter cells—a known cancer risk factor.

In contrast, when the investigators studied EBV deficient of BNRF1, they found the virus did not interfere with chromosome distribution to daughter cells.

The team noted that EBV normally remains silent in a few infected cells, but, occasionally, it reactivates to produce viral offspring that infects nearby cells. As a consequence, these cells come in close contact with BNRF1, thus increasing their risk of transforming into cancer cells.

“The novelty of our work is that we have uncovered a component of the viral particle as a cancer driver,” Dr Delecluse said. “All human-tumors viruses that have been studied so far cause cancer in a completely different manner.”

“Usually, the genetic material of the viruses needs to be permanently present in the infected cell, thus causing the activation of one or several viral genes that cause cancer development. However, these gene products are not present in the infectious particle itself.”

Dr Delecluse and his colleagues therefore suspect that EBV could cause cancers other than those that have already been linked to EBV. Certain cancers might not have been linked to the virus because they do not carry the viral genetic material.

“We must push forward with the development of a vaccine against EBV infection,” Dr Delecluse said. “This would be the most direct strategy to prevent an infection with the virus.”

“Our latest results show that the first infection could already be a cancer risk, and this fits with earlier work that showed an increase in the incidence of Hodgkin’s lymphoma in people who underwent an episode of infectious mononucleosis.”

EBV-infected cell (green/red)

among uninfected cells (blue)

Image courtesy of

Benjamin Chaigne-Delalande

New research published in Nature Communications appears to explain how Epstein-Barr virus (EBV) reprograms cells into cancer cells.

Investigators said they discovered a mechanism by which EBV particles induce chromosomal instability without establishing a chronic infection, thereby conferring a risk for the development of tumors that do not necessarily carry the viral genome.

“The contribution of the viral infection to cancer development in patients with a weakened immune system is well understood,” said study author Henri-Jacques Delecluse, MD, PhD, of the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) in Heidelberg.

“But in the majority of cases, it remains unclear how an EBV infection leads to cancer development.”

With their research, Dr Delecluse and his colleagues found that BNRF1, a protein component of EBV, promotes the development of cancer. They said BNRF1 induces centrosome amplification, which is associated with chromosomal instability.

When a dividing cell comes in contact with EBV, BNRF1 frequently prompts the formation of an excessive number of centrosomes. As a result, chromosomes are no longer divided equally and accurately between daughter cells—a known cancer risk factor.

In contrast, when the investigators studied EBV deficient of BNRF1, they found the virus did not interfere with chromosome distribution to daughter cells.

The team noted that EBV normally remains silent in a few infected cells, but, occasionally, it reactivates to produce viral offspring that infects nearby cells. As a consequence, these cells come in close contact with BNRF1, thus increasing their risk of transforming into cancer cells.

“The novelty of our work is that we have uncovered a component of the viral particle as a cancer driver,” Dr Delecluse said. “All human-tumors viruses that have been studied so far cause cancer in a completely different manner.”

“Usually, the genetic material of the viruses needs to be permanently present in the infected cell, thus causing the activation of one or several viral genes that cause cancer development. However, these gene products are not present in the infectious particle itself.”

Dr Delecluse and his colleagues therefore suspect that EBV could cause cancers other than those that have already been linked to EBV. Certain cancers might not have been linked to the virus because they do not carry the viral genetic material.

“We must push forward with the development of a vaccine against EBV infection,” Dr Delecluse said. “This would be the most direct strategy to prevent an infection with the virus.”

“Our latest results show that the first infection could already be a cancer risk, and this fits with earlier work that showed an increase in the incidence of Hodgkin’s lymphoma in people who underwent an episode of infectious mononucleosis.”