HT Staff

Photo from Georgia Tech

Although many scientific journals try to provide details about authors’ contributions to a publication by requiring explicit statements, contribution statements get much less attention than authorship order, according to research published in Science Advances.

Researchers surveyed more than 6000 corresponding authors of studies published in recent years and found they consider contribution statements helpful for understanding the specific skills individual authors bring to a study.

However, the respondents said they still use author order for deciphering which authors did how much of the work and deserve most of the credit.

“The lack of uniformity and detail in contribution statements leaves open the door for varied interpretations, which could be why only a minority of respondents found them more useful than author order,” said Henry Sauermann, PhD, of ESMT Berlin in Germany.

Dr Sauermann and his colleagues also examined the relationship between author order and contribution statements on more than 12,000 published articles.

The contribution statements studied did include information about the types of work contributed by each author. However, multiple authors could be listed under the same contributions, and the statements had little information about the level of effort for each author.

The statements also said little about how important a particular contribution was for project success.

Still, Dr Sauermann and his colleagues noted that author order has its own problems.

“When we talked to scientists, many think that there are certain norms, and they know how to interpret author order,” Dr Sauermann said. “But when you really push, it’s not clear at all, at least not at the level of detail we need.”

That’s further complicated by the fact that conventions of author order vary depending on the research field.

This work also revealed a difference of opinion between junior and senior researchers, with the former caring more strongly about contribution statements and how they are discussed and crafted.

“When we read open-ended responses to our survey questions, we got the impression of a really divided community,” Dr Sauermann said. “Some believe that forcing more detail in contribution statements is great, and some are concerned that it could really hurt teamwork and collaboration. It’s not that everyone is lukewarm; many really care.”

That level of interest could pave the way for more discussion, which is something Dr Sauermann said is ultimately needed for the scientific and research community to move forward and add more clarity to the process.

“This is not going to get any easier,” Dr Sauermann said. “It’s going to get harder as how we perform research changes and as teams get bigger and more diverse.”

Photo from Georgia Tech

Although many scientific journals try to provide details about authors’ contributions to a publication by requiring explicit statements, contribution statements get much less attention than authorship order, according to research published in Science Advances.

Researchers surveyed more than 6000 corresponding authors of studies published in recent years and found they consider contribution statements helpful for understanding the specific skills individual authors bring to a study.

However, the respondents said they still use author order for deciphering which authors did how much of the work and deserve most of the credit.

“The lack of uniformity and detail in contribution statements leaves open the door for varied interpretations, which could be why only a minority of respondents found them more useful than author order,” said Henry Sauermann, PhD, of ESMT Berlin in Germany.

Dr Sauermann and his colleagues also examined the relationship between author order and contribution statements on more than 12,000 published articles.

The contribution statements studied did include information about the types of work contributed by each author. However, multiple authors could be listed under the same contributions, and the statements had little information about the level of effort for each author.

The statements also said little about how important a particular contribution was for project success.

Still, Dr Sauermann and his colleagues noted that author order has its own problems.

“When we talked to scientists, many think that there are certain norms, and they know how to interpret author order,” Dr Sauermann said. “But when you really push, it’s not clear at all, at least not at the level of detail we need.”

That’s further complicated by the fact that conventions of author order vary depending on the research field.

This work also revealed a difference of opinion between junior and senior researchers, with the former caring more strongly about contribution statements and how they are discussed and crafted.

“When we read open-ended responses to our survey questions, we got the impression of a really divided community,” Dr Sauermann said. “Some believe that forcing more detail in contribution statements is great, and some are concerned that it could really hurt teamwork and collaboration. It’s not that everyone is lukewarm; many really care.”

That level of interest could pave the way for more discussion, which is something Dr Sauermann said is ultimately needed for the scientific and research community to move forward and add more clarity to the process.

“This is not going to get any easier,” Dr Sauermann said. “It’s going to get harder as how we perform research changes and as teams get bigger and more diverse.”

Photo from Georgia Tech

Although many scientific journals try to provide details about authors’ contributions to a publication by requiring explicit statements, contribution statements get much less attention than authorship order, according to research published in Science Advances.

Researchers surveyed more than 6000 corresponding authors of studies published in recent years and found they consider contribution statements helpful for understanding the specific skills individual authors bring to a study.

However, the respondents said they still use author order for deciphering which authors did how much of the work and deserve most of the credit.

“The lack of uniformity and detail in contribution statements leaves open the door for varied interpretations, which could be why only a minority of respondents found them more useful than author order,” said Henry Sauermann, PhD, of ESMT Berlin in Germany.

Dr Sauermann and his colleagues also examined the relationship between author order and contribution statements on more than 12,000 published articles.

The contribution statements studied did include information about the types of work contributed by each author. However, multiple authors could be listed under the same contributions, and the statements had little information about the level of effort for each author.

The statements also said little about how important a particular contribution was for project success.

Still, Dr Sauermann and his colleagues noted that author order has its own problems.

“When we talked to scientists, many think that there are certain norms, and they know how to interpret author order,” Dr Sauermann said. “But when you really push, it’s not clear at all, at least not at the level of detail we need.”

That’s further complicated by the fact that conventions of author order vary depending on the research field.

This work also revealed a difference of opinion between junior and senior researchers, with the former caring more strongly about contribution statements and how they are discussed and crafted.

“When we read open-ended responses to our survey questions, we got the impression of a really divided community,” Dr Sauermann said. “Some believe that forcing more detail in contribution statements is great, and some are concerned that it could really hurt teamwork and collaboration. It’s not that everyone is lukewarm; many really care.”

That level of interest could pave the way for more discussion, which is something Dr Sauermann said is ultimately needed for the scientific and research community to move forward and add more clarity to the process.

“This is not going to get any easier,” Dr Sauermann said. “It’s going to get harder as how we perform research changes and as teams get bigger and more diverse.”

Image by Spencer Phillips

Researchers say they have identified significant genetic differences between African-American patients with multiple myeloma (MM) and Caucasian patients with the disease.

For example, the researchers found that African Americans were more likely to have mutations in BCL7A, BRWD3, and AUTS2, but Caucasians were more likely to have mutations in IRF4 and TP53.

“A cancer therapy that targets TP53 would not be as effective for African Americans with multiple myeloma as it would be for a white population because doctors would be trying to fix the wrong mutated gene,” said Zarko Manojlovic, PhD, of the University of Southern California in Los Angeles.

Dr Manojlovic and his colleagues conducted this research and detailed the results in PLOS Genetics.

The researchers analyzed genetic sequencing data and clinical data from 718 MM patients participating in the MMRF CoMMpass Study.

Race was reported by the patients, but the researchers also used the genetic data to determine that 127 patients were of African descent and 591 were of European descent. The researchers noted that the mean European admixture among self-reported African Americans was 31% (range; 11%-67.8%). And the mean west-African admixture among self-reported Caucasians was 0.1% (range; 0-34.3).

The African-American patients were significantly more likely than the Caucasians to have early onset MM (at ages 40-49)—11% and 4.6%, respectively (P=0.004). And Caucasians were significantly more likely than African Americans to have late-onset MM (at ages 70-79)—22% and 14%, respectively (P=0.04).

There was no significant difference in overall survival based on race, age of onset, or MM karyotype in this population.

Mutations in the following genes occurred at significantly higher frequencies in African-American patients than in Caucasians: RYR1, RPL10, PTCHD3, BCL7A, SPEF2, MYH13, ABI3BP, BRWD3, GRM7, AUTS2, PARP4, PLD1, ANKRD26, DDX17, and STXBP4.

On the other hand, Caucasians had a significantly higher frequency of mutations in IRF4 and TP53. In fact, there was a TP53 somatic mutation frequency of 6.3% in Caucasians and 1.6% in African Americans (P=0.035).

“One of the most surprising discoveries from this large cohort is that cancers from patients of European descent were 6 times more likely than their African-descent counterparts to have mutations in TP53, a known tumor suppressor gene,” Dr Manojlovic said.

“Biologically speaking, higher mutation rates in this gene should lead to overall lower survival rates among patients of European descent, but that does not correlate with what we see in clinical outcomes. Going forward, we hope to functionally validate these results for more insight into the underlying biology.”

“We in the cancer genomics community have a responsibility to ensure that our studies represent true population diversity so we can understand the role of ancestry and biology in health outcomes,” added study author John D. Carpten, PhD, of the University of Southern California.

“The new candidate myeloma genes we identified in the African-American population may have been overlooked because of the lack of diversity in previous genomic efforts. There are clearly molecular differences between African-American and Caucasian multiple myeloma cases, and it will be critical to pursue these observations to better improve clinical management of the disease for all patients.”

Image by Spencer Phillips

Researchers say they have identified significant genetic differences between African-American patients with multiple myeloma (MM) and Caucasian patients with the disease.

For example, the researchers found that African Americans were more likely to have mutations in BCL7A, BRWD3, and AUTS2, but Caucasians were more likely to have mutations in IRF4 and TP53.

“A cancer therapy that targets TP53 would not be as effective for African Americans with multiple myeloma as it would be for a white population because doctors would be trying to fix the wrong mutated gene,” said Zarko Manojlovic, PhD, of the University of Southern California in Los Angeles.

Dr Manojlovic and his colleagues conducted this research and detailed the results in PLOS Genetics.

The researchers analyzed genetic sequencing data and clinical data from 718 MM patients participating in the MMRF CoMMpass Study.

Race was reported by the patients, but the researchers also used the genetic data to determine that 127 patients were of African descent and 591 were of European descent. The researchers noted that the mean European admixture among self-reported African Americans was 31% (range; 11%-67.8%). And the mean west-African admixture among self-reported Caucasians was 0.1% (range; 0-34.3).

The African-American patients were significantly more likely than the Caucasians to have early onset MM (at ages 40-49)—11% and 4.6%, respectively (P=0.004). And Caucasians were significantly more likely than African Americans to have late-onset MM (at ages 70-79)—22% and 14%, respectively (P=0.04).

There was no significant difference in overall survival based on race, age of onset, or MM karyotype in this population.

Mutations in the following genes occurred at significantly higher frequencies in African-American patients than in Caucasians: RYR1, RPL10, PTCHD3, BCL7A, SPEF2, MYH13, ABI3BP, BRWD3, GRM7, AUTS2, PARP4, PLD1, ANKRD26, DDX17, and STXBP4.

On the other hand, Caucasians had a significantly higher frequency of mutations in IRF4 and TP53. In fact, there was a TP53 somatic mutation frequency of 6.3% in Caucasians and 1.6% in African Americans (P=0.035).

“One of the most surprising discoveries from this large cohort is that cancers from patients of European descent were 6 times more likely than their African-descent counterparts to have mutations in TP53, a known tumor suppressor gene,” Dr Manojlovic said.

“Biologically speaking, higher mutation rates in this gene should lead to overall lower survival rates among patients of European descent, but that does not correlate with what we see in clinical outcomes. Going forward, we hope to functionally validate these results for more insight into the underlying biology.”

“We in the cancer genomics community have a responsibility to ensure that our studies represent true population diversity so we can understand the role of ancestry and biology in health outcomes,” added study author John D. Carpten, PhD, of the University of Southern California.

“The new candidate myeloma genes we identified in the African-American population may have been overlooked because of the lack of diversity in previous genomic efforts. There are clearly molecular differences between African-American and Caucasian multiple myeloma cases, and it will be critical to pursue these observations to better improve clinical management of the disease for all patients.”

Image by Spencer Phillips

Researchers say they have identified significant genetic differences between African-American patients with multiple myeloma (MM) and Caucasian patients with the disease.

For example, the researchers found that African Americans were more likely to have mutations in BCL7A, BRWD3, and AUTS2, but Caucasians were more likely to have mutations in IRF4 and TP53.

“A cancer therapy that targets TP53 would not be as effective for African Americans with multiple myeloma as it would be for a white population because doctors would be trying to fix the wrong mutated gene,” said Zarko Manojlovic, PhD, of the University of Southern California in Los Angeles.

Dr Manojlovic and his colleagues conducted this research and detailed the results in PLOS Genetics.

The researchers analyzed genetic sequencing data and clinical data from 718 MM patients participating in the MMRF CoMMpass Study.

Race was reported by the patients, but the researchers also used the genetic data to determine that 127 patients were of African descent and 591 were of European descent. The researchers noted that the mean European admixture among self-reported African Americans was 31% (range; 11%-67.8%). And the mean west-African admixture among self-reported Caucasians was 0.1% (range; 0-34.3).

The African-American patients were significantly more likely than the Caucasians to have early onset MM (at ages 40-49)—11% and 4.6%, respectively (P=0.004). And Caucasians were significantly more likely than African Americans to have late-onset MM (at ages 70-79)—22% and 14%, respectively (P=0.04).

There was no significant difference in overall survival based on race, age of onset, or MM karyotype in this population.

Mutations in the following genes occurred at significantly higher frequencies in African-American patients than in Caucasians: RYR1, RPL10, PTCHD3, BCL7A, SPEF2, MYH13, ABI3BP, BRWD3, GRM7, AUTS2, PARP4, PLD1, ANKRD26, DDX17, and STXBP4.

On the other hand, Caucasians had a significantly higher frequency of mutations in IRF4 and TP53. In fact, there was a TP53 somatic mutation frequency of 6.3% in Caucasians and 1.6% in African Americans (P=0.035).

“One of the most surprising discoveries from this large cohort is that cancers from patients of European descent were 6 times more likely than their African-descent counterparts to have mutations in TP53, a known tumor suppressor gene,” Dr Manojlovic said.

“Biologically speaking, higher mutation rates in this gene should lead to overall lower survival rates among patients of European descent, but that does not correlate with what we see in clinical outcomes. Going forward, we hope to functionally validate these results for more insight into the underlying biology.”

“We in the cancer genomics community have a responsibility to ensure that our studies represent true population diversity so we can understand the role of ancestry and biology in health outcomes,” added study author John D. Carpten, PhD, of the University of Southern California.

“The new candidate myeloma genes we identified in the African-American population may have been overlooked because of the lack of diversity in previous genomic efforts. There are clearly molecular differences between African-American and Caucasian multiple myeloma cases, and it will be critical to pursue these observations to better improve clinical management of the disease for all patients.”

Micrograph showing CLL

New research suggests patients with chronic lymphocytic leukemia (CLL) are willing to trade treatment efficacy for a reduced risk of side effects, but the cost of treatment may trump other factors.

The patients studied placed the highest value on treatments that deliver the longest progression-free survival (PFS), but the patients were also willing to swap some efficacy for a reduced risk of serious adverse events (AEs).

Study results also indicated that factoring out-of-pocket costs into the decision-making process can significantly influence a patient’s choice of treatment.

Carol Mansfield, PhD, of RTI Health Solutions in Research Triangle Park, North Carolina, and her colleagues conducted this study and reported the results in Blood Advances. The study was supported by funding from Genentech, Inc., to RTI Health Solutions.

The researchers surveyed 384 patients with CLL. Patients were asked to choose between hypothetical treatment options, each of which was defined by 5 variable attributes—PFS, mode of administration, typical severity of diarrhea, chance of serious infection, and chance of organ damage.

The attribute patients ranked highest was a change in PFS from 10 months to 60 months. This was followed by a change in infection risk from 30% to 0%, a change in the risk of organ damage from 8% to 0%, a change in diarrhea from severe to none, and a change in the mode of administration from intravenous to oral.

On average, a gain in PFS of 35.9 months was needed for patients to accept a 30% risk of serious infection. A gain in PFS of 26.3 months was needed for patients to accept an 8% risk of organ damage.

A gain in PFS of 21.6 months was needed for patients to accept severe diarrhea. And a gain in PFS of 3.5 months was needed for patients to accept the change from a daily pill to intravenous administration for 6 months.

There were no significant differences in preferences among treatment-naïve patients, first-line patients, and relapsed/refractory patients.

Impact of cost

When the researchers conducted a supplemental cost analysis, they found that out-of-pocket cost had a substantial impact on treatment choice.

The cost analysis included 2 treatments—medicines A and B. Based on the prior analysis, the researchers predicted that 91% of patients would choose medicine B if cost were not a concern because B offered longer PFS than A.

“We used the results from the discrete-choice experiment to forecast the probability that a respondent would pick each hypothetical drug without any mention of cost and then compared that to the choices people made when out-of-pocket costs for these medicines were included,” Dr Mansfield explained.

Patients were asked to choose between medicines A and B under 2 circumstances in which B cost more than A.

When medicine B had a monthly out-of-pocket cost that was $75 more than medicine A, 50% of patients chose medicine A.

When medicine B had a monthly out-of-pocket cost that was $400 more than medicine A, 74% of patients chose medicine A.

“Cost is clearly something that has an impact,” Dr Mansfield said. “When patients get prescribed something they can’t afford, they have to make very difficult choices.”

Dr Mansfield and her colleagues believe their findings will help doctors and patients focus on treatments that account for a patient’s unique circumstances and goals.

“Patients don’t always know that they could be making these tradeoffs,” Dr Mansfield said. “We hope that our findings can help doctors to have frank discussions with their patients about the differences between treatments and how these might affect their lives.”

Micrograph showing CLL

New research suggests patients with chronic lymphocytic leukemia (CLL) are willing to trade treatment efficacy for a reduced risk of side effects, but the cost of treatment may trump other factors.

The patients studied placed the highest value on treatments that deliver the longest progression-free survival (PFS), but the patients were also willing to swap some efficacy for a reduced risk of serious adverse events (AEs).

Study results also indicated that factoring out-of-pocket costs into the decision-making process can significantly influence a patient’s choice of treatment.

Carol Mansfield, PhD, of RTI Health Solutions in Research Triangle Park, North Carolina, and her colleagues conducted this study and reported the results in Blood Advances. The study was supported by funding from Genentech, Inc., to RTI Health Solutions.

The researchers surveyed 384 patients with CLL. Patients were asked to choose between hypothetical treatment options, each of which was defined by 5 variable attributes—PFS, mode of administration, typical severity of diarrhea, chance of serious infection, and chance of organ damage.

The attribute patients ranked highest was a change in PFS from 10 months to 60 months. This was followed by a change in infection risk from 30% to 0%, a change in the risk of organ damage from 8% to 0%, a change in diarrhea from severe to none, and a change in the mode of administration from intravenous to oral.

On average, a gain in PFS of 35.9 months was needed for patients to accept a 30% risk of serious infection. A gain in PFS of 26.3 months was needed for patients to accept an 8% risk of organ damage.

A gain in PFS of 21.6 months was needed for patients to accept severe diarrhea. And a gain in PFS of 3.5 months was needed for patients to accept the change from a daily pill to intravenous administration for 6 months.

There were no significant differences in preferences among treatment-naïve patients, first-line patients, and relapsed/refractory patients.

Impact of cost

When the researchers conducted a supplemental cost analysis, they found that out-of-pocket cost had a substantial impact on treatment choice.

The cost analysis included 2 treatments—medicines A and B. Based on the prior analysis, the researchers predicted that 91% of patients would choose medicine B if cost were not a concern because B offered longer PFS than A.

“We used the results from the discrete-choice experiment to forecast the probability that a respondent would pick each hypothetical drug without any mention of cost and then compared that to the choices people made when out-of-pocket costs for these medicines were included,” Dr Mansfield explained.

Patients were asked to choose between medicines A and B under 2 circumstances in which B cost more than A.

When medicine B had a monthly out-of-pocket cost that was $75 more than medicine A, 50% of patients chose medicine A.

When medicine B had a monthly out-of-pocket cost that was $400 more than medicine A, 74% of patients chose medicine A.

“Cost is clearly something that has an impact,” Dr Mansfield said. “When patients get prescribed something they can’t afford, they have to make very difficult choices.”

Dr Mansfield and her colleagues believe their findings will help doctors and patients focus on treatments that account for a patient’s unique circumstances and goals.

“Patients don’t always know that they could be making these tradeoffs,” Dr Mansfield said. “We hope that our findings can help doctors to have frank discussions with their patients about the differences between treatments and how these might affect their lives.”

Micrograph showing CLL

New research suggests patients with chronic lymphocytic leukemia (CLL) are willing to trade treatment efficacy for a reduced risk of side effects, but the cost of treatment may trump other factors.

The patients studied placed the highest value on treatments that deliver the longest progression-free survival (PFS), but the patients were also willing to swap some efficacy for a reduced risk of serious adverse events (AEs).

Study results also indicated that factoring out-of-pocket costs into the decision-making process can significantly influence a patient’s choice of treatment.

Carol Mansfield, PhD, of RTI Health Solutions in Research Triangle Park, North Carolina, and her colleagues conducted this study and reported the results in Blood Advances. The study was supported by funding from Genentech, Inc., to RTI Health Solutions.

The researchers surveyed 384 patients with CLL. Patients were asked to choose between hypothetical treatment options, each of which was defined by 5 variable attributes—PFS, mode of administration, typical severity of diarrhea, chance of serious infection, and chance of organ damage.

The attribute patients ranked highest was a change in PFS from 10 months to 60 months. This was followed by a change in infection risk from 30% to 0%, a change in the risk of organ damage from 8% to 0%, a change in diarrhea from severe to none, and a change in the mode of administration from intravenous to oral.

On average, a gain in PFS of 35.9 months was needed for patients to accept a 30% risk of serious infection. A gain in PFS of 26.3 months was needed for patients to accept an 8% risk of organ damage.

A gain in PFS of 21.6 months was needed for patients to accept severe diarrhea. And a gain in PFS of 3.5 months was needed for patients to accept the change from a daily pill to intravenous administration for 6 months.

There were no significant differences in preferences among treatment-naïve patients, first-line patients, and relapsed/refractory patients.

Impact of cost

When the researchers conducted a supplemental cost analysis, they found that out-of-pocket cost had a substantial impact on treatment choice.

The cost analysis included 2 treatments—medicines A and B. Based on the prior analysis, the researchers predicted that 91% of patients would choose medicine B if cost were not a concern because B offered longer PFS than A.

“We used the results from the discrete-choice experiment to forecast the probability that a respondent would pick each hypothetical drug without any mention of cost and then compared that to the choices people made when out-of-pocket costs for these medicines were included,” Dr Mansfield explained.

Patients were asked to choose between medicines A and B under 2 circumstances in which B cost more than A.

When medicine B had a monthly out-of-pocket cost that was $75 more than medicine A, 50% of patients chose medicine A.

When medicine B had a monthly out-of-pocket cost that was $400 more than medicine A, 74% of patients chose medicine A.

“Cost is clearly something that has an impact,” Dr Mansfield said. “When patients get prescribed something they can’t afford, they have to make very difficult choices.”

Dr Mansfield and her colleagues believe their findings will help doctors and patients focus on treatments that account for a patient’s unique circumstances and goals.

“Patients don’t always know that they could be making these tradeoffs,” Dr Mansfield said. “We hope that our findings can help doctors to have frank discussions with their patients about the differences between treatments and how these might affect their lives.”

and Drug Administration

Results of a safety review suggest there is a low incidence of breast implant-associated anaplastic large-cell lymphoma (BIA-ALCL) in Canada.

Health Canada undertook the review because of an increase in reporting of BIA-ALCL internationally.

The review showed that 5 confirmed cases of BIA-ALCL have been reported by Canadian manufacturers in the last 10 years.

This is equal to 1 case of BIA-ALCL per 77,190 implants sold, or 0.0013%.

However, Health Canada acknowledges that some cases may not have been reported to the manufacturers or Health Canada.

Available data suggest that BIA-ALCL is more frequently reported with textured surface implants than smooth surface implants. Textured surface implants account for a quarter of all breast implants sold in Canada.

Four of the 5 reported Canadian cases of BIA-ALCL involved textured implants. The surface type was not reported in the remaining case.

The rate of occurrence of BIA‑ALCL per textured implant sold in Canada is 1 case per 24,177 or 0.0041%.

As a result of its safety review, Health Canada is working with manufacturers to update the safety information on the product labeling for all breast implants.

The agency is also communicating this safety information to Canadians through the Recalls and Safety Alerts database on the Healthy Canadians website.

Health Canada continues to monitor the safety profile of breast implants through its post-market surveillance program.

The agency will also monitor cases of BIA-ALCL through an annual follow-up with manufacturers of breast implants.

Health Canada is recommending that healthcare professionals learn about the signs, symptoms, and testing steps to recognize and diagnose BIA‑ALCL.

In addition, healthcare professionals in Canada should report incidents of BIA-ALCL to Health Canada. These reports should include specific details, such as symptoms, how BIA-ALCL was discovered, the age of the patient at implantation, prior implant history, the age of the patient at discovery, tests conducted to diagnose BIA-ALCL, staging information, the course of therapy, and clinical outcomes.

Reports can be made by calling Health Canada at 1-866-234-2345. Alternatively, visit Health Canada’s webpage on Adverse Reaction Reporting for information on how to report online, by mail, or by fax.

and Drug Administration

Results of a safety review suggest there is a low incidence of breast implant-associated anaplastic large-cell lymphoma (BIA-ALCL) in Canada.

Health Canada undertook the review because of an increase in reporting of BIA-ALCL internationally.

The review showed that 5 confirmed cases of BIA-ALCL have been reported by Canadian manufacturers in the last 10 years.

This is equal to 1 case of BIA-ALCL per 77,190 implants sold, or 0.0013%.

However, Health Canada acknowledges that some cases may not have been reported to the manufacturers or Health Canada.

Available data suggest that BIA-ALCL is more frequently reported with textured surface implants than smooth surface implants. Textured surface implants account for a quarter of all breast implants sold in Canada.

Four of the 5 reported Canadian cases of BIA-ALCL involved textured implants. The surface type was not reported in the remaining case.

The rate of occurrence of BIA‑ALCL per textured implant sold in Canada is 1 case per 24,177 or 0.0041%.

As a result of its safety review, Health Canada is working with manufacturers to update the safety information on the product labeling for all breast implants.

The agency is also communicating this safety information to Canadians through the Recalls and Safety Alerts database on the Healthy Canadians website.

Health Canada continues to monitor the safety profile of breast implants through its post-market surveillance program.

The agency will also monitor cases of BIA-ALCL through an annual follow-up with manufacturers of breast implants.

Health Canada is recommending that healthcare professionals learn about the signs, symptoms, and testing steps to recognize and diagnose BIA‑ALCL.

In addition, healthcare professionals in Canada should report incidents of BIA-ALCL to Health Canada. These reports should include specific details, such as symptoms, how BIA-ALCL was discovered, the age of the patient at implantation, prior implant history, the age of the patient at discovery, tests conducted to diagnose BIA-ALCL, staging information, the course of therapy, and clinical outcomes.

Reports can be made by calling Health Canada at 1-866-234-2345. Alternatively, visit Health Canada’s webpage on Adverse Reaction Reporting for information on how to report online, by mail, or by fax.

and Drug Administration

Results of a safety review suggest there is a low incidence of breast implant-associated anaplastic large-cell lymphoma (BIA-ALCL) in Canada.

Health Canada undertook the review because of an increase in reporting of BIA-ALCL internationally.

The review showed that 5 confirmed cases of BIA-ALCL have been reported by Canadian manufacturers in the last 10 years.

This is equal to 1 case of BIA-ALCL per 77,190 implants sold, or 0.0013%.

However, Health Canada acknowledges that some cases may not have been reported to the manufacturers or Health Canada.

Available data suggest that BIA-ALCL is more frequently reported with textured surface implants than smooth surface implants. Textured surface implants account for a quarter of all breast implants sold in Canada.

Four of the 5 reported Canadian cases of BIA-ALCL involved textured implants. The surface type was not reported in the remaining case.

The rate of occurrence of BIA‑ALCL per textured implant sold in Canada is 1 case per 24,177 or 0.0041%.

As a result of its safety review, Health Canada is working with manufacturers to update the safety information on the product labeling for all breast implants.

The agency is also communicating this safety information to Canadians through the Recalls and Safety Alerts database on the Healthy Canadians website.

Health Canada continues to monitor the safety profile of breast implants through its post-market surveillance program.

The agency will also monitor cases of BIA-ALCL through an annual follow-up with manufacturers of breast implants.

Health Canada is recommending that healthcare professionals learn about the signs, symptoms, and testing steps to recognize and diagnose BIA‑ALCL.

In addition, healthcare professionals in Canada should report incidents of BIA-ALCL to Health Canada. These reports should include specific details, such as symptoms, how BIA-ALCL was discovered, the age of the patient at implantation, prior implant history, the age of the patient at discovery, tests conducted to diagnose BIA-ALCL, staging information, the course of therapy, and clinical outcomes.

Reports can be made by calling Health Canada at 1-866-234-2345. Alternatively, visit Health Canada’s webpage on Adverse Reaction Reporting for information on how to report online, by mail, or by fax.

Photo from NIH

A study of childhood cancer survivors (CCSs) suggests these individuals have an increased risk of developing hypertension as adults.

The CCSs studied had more than double the rate of hypertension observed in the matched general population.

Sex, age, race, and weight were all significantly associated with hypertension among CCSs, but most treatment types were not.

The exception was nephrectomy, which was associated with an increased risk of hypertension.

Todd M. Gibson, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and his colleagues conducted this research and reported the results in Cancer Epidemiology, Biomarkers & Prevention.

“High blood pressure is an important modifiable risk factor that increases the risk of heart problems in everyone,” Dr Gibson said. “Research has shown that high blood pressure can have an even greater negative impact on survivors of childhood cancer who were treated with cardiotoxic therapies such as anthracyclines or chest radiation.”

To assess the prevalence of hypertension among CCSs, Dr Gibson and his colleagues examined 3016 adults who were 10-year survivors of childhood cancers. The subjects were enrolled in the St. Jude Lifetime Cohort Study, which provides ongoing medical assessments of CCSs to advance knowledge of their long-term health outcomes.

The subjects’ mean age at the initial study assessment was 32, and 52% were male. Most (83%) were non-Hispanic white, 14% were non-Hispanic black, 2% were Hispanic, and 1% were “other.”

Thirty-seven percent of subjects had leukemia, 12% had Hodgkin lymphoma, and 7% had non-Hodgkin lymphoma.

Eighty-six percent of subjects had received chemotherapy, and 59% received radiation.

Results

Subjects were considered to have hypertension if their systolic blood pressure was 140 or greater, their diastolic blood pressure was 90 or greater, or if they had been previously diagnosed with hypertension and were taking antihypertensive medication.

The prevalence of hypertension was 2.6 times higher among CCSs than expected, based on age-, sex-, race- and body mass index-specific rates in the general population.

In addition, the incidence of hypertension increased for CCSs over time. Thirteen percent of CCSs had hypertension at age 30, 37% had it at age 40, and more than 70% had it at age 50.

Dr Gibson said rates of hypertension in CCSs matched rates in the general population of people about a decade older.

The researchers identified several factors that were significantly associated with hypertension among CCSs, including:

• Male sex (odd ratio [OR], 1.38; 95% CI, 1.14–1.67)
• Non-Hispanic black race (OR, 1.66; 95% CI, 1.28–2.16)
• Older age at assessment (OR per 1 year of age, 1.10; 95% CI, 1.08–1.11)
• Being overweight (OR, 1.58; 95% CI, 1.21–2.07)
• Obesity (OR, 3.02; 95% CI, 2.34–3.88).

Exposure to any type of radiation or chemotherapy was not significantly associated with hypertension, but nephrectomy was (OR, 1.68; 95% CI, 1.11–2.53).

Dr Gibson said the lack of an association between hypertension and radiation/chemotherapy was surprising. It suggests the connection between childhood cancer survival and adult hypertension is multifactorial and worthy of future research.

In the meantime, he said, clinicians should be mindful that CCSs are more likely than the general public to develop hypertension.

“The good news is that, unlike prior cancer therapy, high blood pressure is a modifiable risk factor,” Dr Gibson noted. “Research is needed to identify effective interventions to prevent hypertension in survivors, but our results emphasize the importance of blood pressure surveillance and management.”

Dr Gibson said a limitation of this study is that it was based on blood pressure measurements taken at a single study visit. A clinical diagnosis of hypertension typically requires measurements taken at multiple intervals.

In addition, the St. Jude Lifetime Cohort is a group of CCSs who undergo frequent clinical follow-up, so its participants may have benefited from being monitored and may therefore be in better health than CCSs who have less comprehensive follow-up.

Photo from NIH

A study of childhood cancer survivors (CCSs) suggests these individuals have an increased risk of developing hypertension as adults.

The CCSs studied had more than double the rate of hypertension observed in the matched general population.

Sex, age, race, and weight were all significantly associated with hypertension among CCSs, but most treatment types were not.

The exception was nephrectomy, which was associated with an increased risk of hypertension.

Todd M. Gibson, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and his colleagues conducted this research and reported the results in Cancer Epidemiology, Biomarkers & Prevention.

“High blood pressure is an important modifiable risk factor that increases the risk of heart problems in everyone,” Dr Gibson said. “Research has shown that high blood pressure can have an even greater negative impact on survivors of childhood cancer who were treated with cardiotoxic therapies such as anthracyclines or chest radiation.”

To assess the prevalence of hypertension among CCSs, Dr Gibson and his colleagues examined 3016 adults who were 10-year survivors of childhood cancers. The subjects were enrolled in the St. Jude Lifetime Cohort Study, which provides ongoing medical assessments of CCSs to advance knowledge of their long-term health outcomes.

The subjects’ mean age at the initial study assessment was 32, and 52% were male. Most (83%) were non-Hispanic white, 14% were non-Hispanic black, 2% were Hispanic, and 1% were “other.”

Thirty-seven percent of subjects had leukemia, 12% had Hodgkin lymphoma, and 7% had non-Hodgkin lymphoma.

Eighty-six percent of subjects had received chemotherapy, and 59% received radiation.

Results

Subjects were considered to have hypertension if their systolic blood pressure was 140 or greater, their diastolic blood pressure was 90 or greater, or if they had been previously diagnosed with hypertension and were taking antihypertensive medication.

The prevalence of hypertension was 2.6 times higher among CCSs than expected, based on age-, sex-, race- and body mass index-specific rates in the general population.

In addition, the incidence of hypertension increased for CCSs over time. Thirteen percent of CCSs had hypertension at age 30, 37% had it at age 40, and more than 70% had it at age 50.

Dr Gibson said rates of hypertension in CCSs matched rates in the general population of people about a decade older.

The researchers identified several factors that were significantly associated with hypertension among CCSs, including:

• Male sex (odd ratio [OR], 1.38; 95% CI, 1.14–1.67)
• Non-Hispanic black race (OR, 1.66; 95% CI, 1.28–2.16)
• Older age at assessment (OR per 1 year of age, 1.10; 95% CI, 1.08–1.11)
• Being overweight (OR, 1.58; 95% CI, 1.21–2.07)
• Obesity (OR, 3.02; 95% CI, 2.34–3.88).

Exposure to any type of radiation or chemotherapy was not significantly associated with hypertension, but nephrectomy was (OR, 1.68; 95% CI, 1.11–2.53).

Dr Gibson said the lack of an association between hypertension and radiation/chemotherapy was surprising. It suggests the connection between childhood cancer survival and adult hypertension is multifactorial and worthy of future research.

In the meantime, he said, clinicians should be mindful that CCSs are more likely than the general public to develop hypertension.

“The good news is that, unlike prior cancer therapy, high blood pressure is a modifiable risk factor,” Dr Gibson noted. “Research is needed to identify effective interventions to prevent hypertension in survivors, but our results emphasize the importance of blood pressure surveillance and management.”

Dr Gibson said a limitation of this study is that it was based on blood pressure measurements taken at a single study visit. A clinical diagnosis of hypertension typically requires measurements taken at multiple intervals.

In addition, the St. Jude Lifetime Cohort is a group of CCSs who undergo frequent clinical follow-up, so its participants may have benefited from being monitored and may therefore be in better health than CCSs who have less comprehensive follow-up.

Photo from NIH

A study of childhood cancer survivors (CCSs) suggests these individuals have an increased risk of developing hypertension as adults.

The CCSs studied had more than double the rate of hypertension observed in the matched general population.

Sex, age, race, and weight were all significantly associated with hypertension among CCSs, but most treatment types were not.

The exception was nephrectomy, which was associated with an increased risk of hypertension.

Todd M. Gibson, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and his colleagues conducted this research and reported the results in Cancer Epidemiology, Biomarkers & Prevention.

“High blood pressure is an important modifiable risk factor that increases the risk of heart problems in everyone,” Dr Gibson said. “Research has shown that high blood pressure can have an even greater negative impact on survivors of childhood cancer who were treated with cardiotoxic therapies such as anthracyclines or chest radiation.”

To assess the prevalence of hypertension among CCSs, Dr Gibson and his colleagues examined 3016 adults who were 10-year survivors of childhood cancers. The subjects were enrolled in the St. Jude Lifetime Cohort Study, which provides ongoing medical assessments of CCSs to advance knowledge of their long-term health outcomes.

The subjects’ mean age at the initial study assessment was 32, and 52% were male. Most (83%) were non-Hispanic white, 14% were non-Hispanic black, 2% were Hispanic, and 1% were “other.”

Thirty-seven percent of subjects had leukemia, 12% had Hodgkin lymphoma, and 7% had non-Hodgkin lymphoma.

Eighty-six percent of subjects had received chemotherapy, and 59% received radiation.

Results

Subjects were considered to have hypertension if their systolic blood pressure was 140 or greater, their diastolic blood pressure was 90 or greater, or if they had been previously diagnosed with hypertension and were taking antihypertensive medication.

The prevalence of hypertension was 2.6 times higher among CCSs than expected, based on age-, sex-, race- and body mass index-specific rates in the general population.

In addition, the incidence of hypertension increased for CCSs over time. Thirteen percent of CCSs had hypertension at age 30, 37% had it at age 40, and more than 70% had it at age 50.

Dr Gibson said rates of hypertension in CCSs matched rates in the general population of people about a decade older.

The researchers identified several factors that were significantly associated with hypertension among CCSs, including:

• Male sex (odd ratio [OR], 1.38; 95% CI, 1.14–1.67)
• Non-Hispanic black race (OR, 1.66; 95% CI, 1.28–2.16)
• Older age at assessment (OR per 1 year of age, 1.10; 95% CI, 1.08–1.11)
• Being overweight (OR, 1.58; 95% CI, 1.21–2.07)
• Obesity (OR, 3.02; 95% CI, 2.34–3.88).

Exposure to any type of radiation or chemotherapy was not significantly associated with hypertension, but nephrectomy was (OR, 1.68; 95% CI, 1.11–2.53).

Dr Gibson said the lack of an association between hypertension and radiation/chemotherapy was surprising. It suggests the connection between childhood cancer survival and adult hypertension is multifactorial and worthy of future research.

In the meantime, he said, clinicians should be mindful that CCSs are more likely than the general public to develop hypertension.

“The good news is that, unlike prior cancer therapy, high blood pressure is a modifiable risk factor,” Dr Gibson noted. “Research is needed to identify effective interventions to prevent hypertension in survivors, but our results emphasize the importance of blood pressure surveillance and management.”

Dr Gibson said a limitation of this study is that it was based on blood pressure measurements taken at a single study visit. A clinical diagnosis of hypertension typically requires measurements taken at multiple intervals.

In addition, the St. Jude Lifetime Cohort is a group of CCSs who undergo frequent clinical follow-up, so its participants may have benefited from being monitored and may therefore be in better health than CCSs who have less comprehensive follow-up.

Wolfgang Däuble

An ex vivo drug screening method can reveal optimal therapies for patients with hematologic malignancies, according to research published in The Lancet Haematology.

Researchers used a method called pharmacoscopy to measure single-cell responses to possible treatments in samples from patients with leukemias and lymphomas.

The team then used these results to guide treatment decisions and found that pharmacoscopy-guided treatment greatly improved response rates and progression-free survival (PFS).

“Having a robust, fast, and reliable predictive test at our disposal during the patient treatment process, especially at the time of relapse where a new intervention must be selected quickly, will change how medical doctors prioritize drugs to use for late-stage patients,” said study author Philipp Staber, MD, of Medical University of Vienna in Austria.

With pharmacoscopy, hundreds of drug options can be pre-tested ex vivo in small liquid biopsy samples collected from individual patients. The effects of each drug on the individual cells are quantified using high-throughput and high-content automated confocal microscopy.

In combination with specially developed analysis methods, machine learning, and other algorithms, pharmacoscopy allows quantification of never-before visualized phenotypes. The method was first described last April in Nature Chemical Biology.

Now, Dr Staber and his colleagues have reported, in The Lancet Haematology, an interim analysis of the first clinical trial testing pharmacoscopy-guided treatment.

There were 17 evaluable patients, all of whom had aggressive hematologic malignancies. This included diffuse large B-cell lymphoma (n=6), acute myeloid leukemia (n=3), B-cell acute lymphoblastic leukemia (n=2), precursor B-cell lymphoblastic lymphoma (n=1), peripheral T-cell lymphoma (n=1), primary mediastinal B-cell lymphoma (n=1), T-cell lymphoblastic lymphoma (n=1), follicular lymphoma (n=1), and T-cell prolymphocytic leukemia (n=1).

The researchers compared outcomes with pharmacoscopy-guided treatment to outcomes with the most recent regimen on which the patient had progressed.

The overall response rate was 88% with pharmacoscopy-guided treatment and 24% with the patients’ most recent previous treatment regimen (odds ratio=24.38; 95%, CI 3.99–125.4; P=0.0013).

None of the patients had progressive disease as their best overall response when they received pharmacoscopy-guided treatment. However, 7 patients had progressive disease in response to their most recent prior regimen.

At the time of analysis, 8 patients (47%) still had ongoing responses after pharmacoscopy-guided treatment.

In addition, pharmacoscopy-guided treatment significantly improved PFS. The median PFS was 22.6 weeks with pharmacoscopy-guided treatment and 5.7 weeks with the most recent prior regimen (hazard ratio=3.14; 95%, CI 1.37–7.22; P=0.0075).

“Evidence that the pharmacoscopy approach is helpful for clinical evaluation of therapy is wonderful,” said study author Giulio Superti-Furga, PhD, of CeMM Research Center for Molecular Medicine in Vienna, Austria.

“Single-cell functional analysis of primary material gives unprecedented resolution and precision that we are sure to further develop in the future to address yet more diseases.”

Wolfgang Däuble

An ex vivo drug screening method can reveal optimal therapies for patients with hematologic malignancies, according to research published in The Lancet Haematology.

Researchers used a method called pharmacoscopy to measure single-cell responses to possible treatments in samples from patients with leukemias and lymphomas.

The team then used these results to guide treatment decisions and found that pharmacoscopy-guided treatment greatly improved response rates and progression-free survival (PFS).

“Having a robust, fast, and reliable predictive test at our disposal during the patient treatment process, especially at the time of relapse where a new intervention must be selected quickly, will change how medical doctors prioritize drugs to use for late-stage patients,” said study author Philipp Staber, MD, of Medical University of Vienna in Austria.

With pharmacoscopy, hundreds of drug options can be pre-tested ex vivo in small liquid biopsy samples collected from individual patients. The effects of each drug on the individual cells are quantified using high-throughput and high-content automated confocal microscopy.

In combination with specially developed analysis methods, machine learning, and other algorithms, pharmacoscopy allows quantification of never-before visualized phenotypes. The method was first described last April in Nature Chemical Biology.

Now, Dr Staber and his colleagues have reported, in The Lancet Haematology, an interim analysis of the first clinical trial testing pharmacoscopy-guided treatment.

There were 17 evaluable patients, all of whom had aggressive hematologic malignancies. This included diffuse large B-cell lymphoma (n=6), acute myeloid leukemia (n=3), B-cell acute lymphoblastic leukemia (n=2), precursor B-cell lymphoblastic lymphoma (n=1), peripheral T-cell lymphoma (n=1), primary mediastinal B-cell lymphoma (n=1), T-cell lymphoblastic lymphoma (n=1), follicular lymphoma (n=1), and T-cell prolymphocytic leukemia (n=1).

The researchers compared outcomes with pharmacoscopy-guided treatment to outcomes with the most recent regimen on which the patient had progressed.

The overall response rate was 88% with pharmacoscopy-guided treatment and 24% with the patients’ most recent previous treatment regimen (odds ratio=24.38; 95%, CI 3.99–125.4; P=0.0013).

None of the patients had progressive disease as their best overall response when they received pharmacoscopy-guided treatment. However, 7 patients had progressive disease in response to their most recent prior regimen.

At the time of analysis, 8 patients (47%) still had ongoing responses after pharmacoscopy-guided treatment.

In addition, pharmacoscopy-guided treatment significantly improved PFS. The median PFS was 22.6 weeks with pharmacoscopy-guided treatment and 5.7 weeks with the most recent prior regimen (hazard ratio=3.14; 95%, CI 1.37–7.22; P=0.0075).

“Evidence that the pharmacoscopy approach is helpful for clinical evaluation of therapy is wonderful,” said study author Giulio Superti-Furga, PhD, of CeMM Research Center for Molecular Medicine in Vienna, Austria.

“Single-cell functional analysis of primary material gives unprecedented resolution and precision that we are sure to further develop in the future to address yet more diseases.”

Wolfgang Däuble

An ex vivo drug screening method can reveal optimal therapies for patients with hematologic malignancies, according to research published in The Lancet Haematology.

Researchers used a method called pharmacoscopy to measure single-cell responses to possible treatments in samples from patients with leukemias and lymphomas.

The team then used these results to guide treatment decisions and found that pharmacoscopy-guided treatment greatly improved response rates and progression-free survival (PFS).

“Having a robust, fast, and reliable predictive test at our disposal during the patient treatment process, especially at the time of relapse where a new intervention must be selected quickly, will change how medical doctors prioritize drugs to use for late-stage patients,” said study author Philipp Staber, MD, of Medical University of Vienna in Austria.

With pharmacoscopy, hundreds of drug options can be pre-tested ex vivo in small liquid biopsy samples collected from individual patients. The effects of each drug on the individual cells are quantified using high-throughput and high-content automated confocal microscopy.

In combination with specially developed analysis methods, machine learning, and other algorithms, pharmacoscopy allows quantification of never-before visualized phenotypes. The method was first described last April in Nature Chemical Biology.

Now, Dr Staber and his colleagues have reported, in The Lancet Haematology, an interim analysis of the first clinical trial testing pharmacoscopy-guided treatment.

There were 17 evaluable patients, all of whom had aggressive hematologic malignancies. This included diffuse large B-cell lymphoma (n=6), acute myeloid leukemia (n=3), B-cell acute lymphoblastic leukemia (n=2), precursor B-cell lymphoblastic lymphoma (n=1), peripheral T-cell lymphoma (n=1), primary mediastinal B-cell lymphoma (n=1), T-cell lymphoblastic lymphoma (n=1), follicular lymphoma (n=1), and T-cell prolymphocytic leukemia (n=1).

The researchers compared outcomes with pharmacoscopy-guided treatment to outcomes with the most recent regimen on which the patient had progressed.

The overall response rate was 88% with pharmacoscopy-guided treatment and 24% with the patients’ most recent previous treatment regimen (odds ratio=24.38; 95%, CI 3.99–125.4; P=0.0013).

None of the patients had progressive disease as their best overall response when they received pharmacoscopy-guided treatment. However, 7 patients had progressive disease in response to their most recent prior regimen.

At the time of analysis, 8 patients (47%) still had ongoing responses after pharmacoscopy-guided treatment.

In addition, pharmacoscopy-guided treatment significantly improved PFS. The median PFS was 22.6 weeks with pharmacoscopy-guided treatment and 5.7 weeks with the most recent prior regimen (hazard ratio=3.14; 95%, CI 1.37–7.22; P=0.0075).

“Evidence that the pharmacoscopy approach is helpful for clinical evaluation of therapy is wonderful,” said study author Giulio Superti-Furga, PhD, of CeMM Research Center for Molecular Medicine in Vienna, Austria.

“Single-cell functional analysis of primary material gives unprecedented resolution and precision that we are sure to further develop in the future to address yet more diseases.”

Photo by Rhoda Baer

Cancer patients may experience lasting post-traumatic stress disorder (PTSD), according to a study published in the journal Cancer.

Approximately one-fifth of patients involved in the study experienced PTSD several months after their cancer diagnosis, and roughly a third of these patients continued to live with PTSD 4 years later.

Researchers say these findings highlight the need for early identification, careful monitoring, and treatment of PTSD in cancer survivors.

Caryn Mei Hsien Chan, PhD, of the National University of Malaysia in Kuala Lumpur, and her colleagues conducted this research.

The study included 469 adults with various cancers who were within 1 month of cancer diagnosis at enrollment.

Patients who had significant psychological distress (defined as a Hospital Anxiety and Depression Scale total cutoff score of 16 or higher) underwent

testing for PTSD at 6 months of follow-up. All patients were tested for PTSD at 4 years of follow-up (regardless of their Hospital Anxiety and Depression Scale score).

The incidence of PTSD was 21.7% at 6 months and 6.1% at 4 years. Although overall rates of PTSD decreased with time, roughly one-third of patients initially diagnosed with PTSD were found to have persistent or worsening symptoms 4 years later.

“Many cancer patients believe they need to adopt a ‘warrior mentality’ and remain positive and optimistic from diagnosis through treatment to stand a better chance of beating their cancer,” Dr Chan said.

“To these patients, seeking help for the emotional issues they face is akin to admitting weakness. There needs to be greater awareness that there is nothing wrong with getting help to manage the emotional upheaval—particularly depression, anxiety, and PTSD—post-cancer.”

Dr Chan also stressed that many patients live in fear that their cancer may come back, and they may think the cancer has returned with every lump or bump, pain or ache, fatigue or fever.

In addition, cancer survivors might skip visits to their oncologists or other physicians to avoid triggering memories of their past cancer experience. This can lead to delays in seeking help for new symptoms or even refusal of treatment for unrelated conditions.

“We need psychological evaluation and support services for patients with cancer at an initial stage and at continued follows-up because psychological well-being and mental health—and by extension, quality of life—are just as important as physical health,” Dr Chan noted.

Photo by Rhoda Baer

Cancer patients may experience lasting post-traumatic stress disorder (PTSD), according to a study published in the journal Cancer.

Approximately one-fifth of patients involved in the study experienced PTSD several months after their cancer diagnosis, and roughly a third of these patients continued to live with PTSD 4 years later.

Researchers say these findings highlight the need for early identification, careful monitoring, and treatment of PTSD in cancer survivors.

Caryn Mei Hsien Chan, PhD, of the National University of Malaysia in Kuala Lumpur, and her colleagues conducted this research.

The study included 469 adults with various cancers who were within 1 month of cancer diagnosis at enrollment.

Patients who had significant psychological distress (defined as a Hospital Anxiety and Depression Scale total cutoff score of 16 or higher) underwent

testing for PTSD at 6 months of follow-up. All patients were tested for PTSD at 4 years of follow-up (regardless of their Hospital Anxiety and Depression Scale score).

The incidence of PTSD was 21.7% at 6 months and 6.1% at 4 years. Although overall rates of PTSD decreased with time, roughly one-third of patients initially diagnosed with PTSD were found to have persistent or worsening symptoms 4 years later.

“Many cancer patients believe they need to adopt a ‘warrior mentality’ and remain positive and optimistic from diagnosis through treatment to stand a better chance of beating their cancer,” Dr Chan said.

“To these patients, seeking help for the emotional issues they face is akin to admitting weakness. There needs to be greater awareness that there is nothing wrong with getting help to manage the emotional upheaval—particularly depression, anxiety, and PTSD—post-cancer.”

Dr Chan also stressed that many patients live in fear that their cancer may come back, and they may think the cancer has returned with every lump or bump, pain or ache, fatigue or fever.

In addition, cancer survivors might skip visits to their oncologists or other physicians to avoid triggering memories of their past cancer experience. This can lead to delays in seeking help for new symptoms or even refusal of treatment for unrelated conditions.

“We need psychological evaluation and support services for patients with cancer at an initial stage and at continued follows-up because psychological well-being and mental health—and by extension, quality of life—are just as important as physical health,” Dr Chan noted.

Photo by Rhoda Baer

Cancer patients may experience lasting post-traumatic stress disorder (PTSD), according to a study published in the journal Cancer.

Approximately one-fifth of patients involved in the study experienced PTSD several months after their cancer diagnosis, and roughly a third of these patients continued to live with PTSD 4 years later.

Researchers say these findings highlight the need for early identification, careful monitoring, and treatment of PTSD in cancer survivors.

Caryn Mei Hsien Chan, PhD, of the National University of Malaysia in Kuala Lumpur, and her colleagues conducted this research.

The study included 469 adults with various cancers who were within 1 month of cancer diagnosis at enrollment.

Patients who had significant psychological distress (defined as a Hospital Anxiety and Depression Scale total cutoff score of 16 or higher) underwent

testing for PTSD at 6 months of follow-up. All patients were tested for PTSD at 4 years of follow-up (regardless of their Hospital Anxiety and Depression Scale score).

The incidence of PTSD was 21.7% at 6 months and 6.1% at 4 years. Although overall rates of PTSD decreased with time, roughly one-third of patients initially diagnosed with PTSD were found to have persistent or worsening symptoms 4 years later.

“Many cancer patients believe they need to adopt a ‘warrior mentality’ and remain positive and optimistic from diagnosis through treatment to stand a better chance of beating their cancer,” Dr Chan said.

“To these patients, seeking help for the emotional issues they face is akin to admitting weakness. There needs to be greater awareness that there is nothing wrong with getting help to manage the emotional upheaval—particularly depression, anxiety, and PTSD—post-cancer.”

Dr Chan also stressed that many patients live in fear that their cancer may come back, and they may think the cancer has returned with every lump or bump, pain or ache, fatigue or fever.

In addition, cancer survivors might skip visits to their oncologists or other physicians to avoid triggering memories of their past cancer experience. This can lead to delays in seeking help for new symptoms or even refusal of treatment for unrelated conditions.

“We need psychological evaluation and support services for patients with cancer at an initial stage and at continued follows-up because psychological well-being and mental health—and by extension, quality of life—are just as important as physical health,” Dr Chan noted.

Photo by Steven Harbour

The US Food and Drug Administration (FDA) has granted orphan drug designation to rofecoxib (TRM-201) as a potential treatment for degenerative joint disease in hemophilia, also known as hemophilic arthropathy (HA).

Rofecoxib is a COX-2 selective non-steroidal anti-inflammatory drug (NSAID) that was previously sold in the US under the name Vioxx.

Vioxx was FDA-approved to relieve the signs and symptoms of osteoarthritis, manage acute pain in adults, and treat primary dysmenorrhea.

Merck & Co. pulled Vioxx from the US market in 2004 due to safety concerns. The drug was shown to increase a person’s risk of cardiovascular events, including heart attack and stroke.

Now, Tremeau Pharmaceuticals, Inc., is working to bring rofecoxib back to market to treat patients with HA.

HA patients should not receive traditional NSAIDs due to their effects on platelet aggregation and the risk of gastrointestinal ulcers associated with these drugs. Therefore, high potency opioids are the current standard of care in HA.

“Being granted an orphan drug designation for rofecoxib by FDA is an important regulatory milestone for Tremeau and affirms our strategy of providing non-opioid pain treatments for rare diseases like hemophilic arthropathy,” said Bradford C. Sippy, chief executive officer of Tremeau.

Sippy is a former Merck employee who helped with the recall of Vioxx and knew the final patent protecting the drug’s monopoly was expiring this fall.

When it stopped making Vioxx, Merck was facing thousands of lawsuits from people claiming the drug caused their heart attacks or strokes.

Merck’s own research showed the drug doubled those risks, but lawyers for patients claimed the company downplayed or concealed that. Merck initially fought the lawsuits but, in 2007, agreed to a $4.85 billion settlement.

If approved to treat HA, rofecoxib would carry a warning about the increased risk of heart attack and stroke associated with the drug.

Although the orphan designation for rofecoxib is a step toward FDA approval, Sippy said Tremeau must still raise $25 million or more to fund trials of the drug in hemophilia patients.

About orphan designation

The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

Photo by Steven Harbour

The US Food and Drug Administration (FDA) has granted orphan drug designation to rofecoxib (TRM-201) as a potential treatment for degenerative joint disease in hemophilia, also known as hemophilic arthropathy (HA).

Rofecoxib is a COX-2 selective non-steroidal anti-inflammatory drug (NSAID) that was previously sold in the US under the name Vioxx.

Vioxx was FDA-approved to relieve the signs and symptoms of osteoarthritis, manage acute pain in adults, and treat primary dysmenorrhea.

Merck & Co. pulled Vioxx from the US market in 2004 due to safety concerns. The drug was shown to increase a person’s risk of cardiovascular events, including heart attack and stroke.

Now, Tremeau Pharmaceuticals, Inc., is working to bring rofecoxib back to market to treat patients with HA.

HA patients should not receive traditional NSAIDs due to their effects on platelet aggregation and the risk of gastrointestinal ulcers associated with these drugs. Therefore, high potency opioids are the current standard of care in HA.

“Being granted an orphan drug designation for rofecoxib by FDA is an important regulatory milestone for Tremeau and affirms our strategy of providing non-opioid pain treatments for rare diseases like hemophilic arthropathy,” said Bradford C. Sippy, chief executive officer of Tremeau.

Sippy is a former Merck employee who helped with the recall of Vioxx and knew the final patent protecting the drug’s monopoly was expiring this fall.

When it stopped making Vioxx, Merck was facing thousands of lawsuits from people claiming the drug caused their heart attacks or strokes.

Merck’s own research showed the drug doubled those risks, but lawyers for patients claimed the company downplayed or concealed that. Merck initially fought the lawsuits but, in 2007, agreed to a $4.85 billion settlement.

If approved to treat HA, rofecoxib would carry a warning about the increased risk of heart attack and stroke associated with the drug.

Although the orphan designation for rofecoxib is a step toward FDA approval, Sippy said Tremeau must still raise $25 million or more to fund trials of the drug in hemophilia patients.

About orphan designation

The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

Photo by Steven Harbour

The US Food and Drug Administration (FDA) has granted orphan drug designation to rofecoxib (TRM-201) as a potential treatment for degenerative joint disease in hemophilia, also known as hemophilic arthropathy (HA).

Rofecoxib is a COX-2 selective non-steroidal anti-inflammatory drug (NSAID) that was previously sold in the US under the name Vioxx.

Vioxx was FDA-approved to relieve the signs and symptoms of osteoarthritis, manage acute pain in adults, and treat primary dysmenorrhea.

Merck & Co. pulled Vioxx from the US market in 2004 due to safety concerns. The drug was shown to increase a person’s risk of cardiovascular events, including heart attack and stroke.

Now, Tremeau Pharmaceuticals, Inc., is working to bring rofecoxib back to market to treat patients with HA.

HA patients should not receive traditional NSAIDs due to their effects on platelet aggregation and the risk of gastrointestinal ulcers associated with these drugs. Therefore, high potency opioids are the current standard of care in HA.

“Being granted an orphan drug designation for rofecoxib by FDA is an important regulatory milestone for Tremeau and affirms our strategy of providing non-opioid pain treatments for rare diseases like hemophilic arthropathy,” said Bradford C. Sippy, chief executive officer of Tremeau.

Sippy is a former Merck employee who helped with the recall of Vioxx and knew the final patent protecting the drug’s monopoly was expiring this fall.

When it stopped making Vioxx, Merck was facing thousands of lawsuits from people claiming the drug caused their heart attacks or strokes.

Merck’s own research showed the drug doubled those risks, but lawyers for patients claimed the company downplayed or concealed that. Merck initially fought the lawsuits but, in 2007, agreed to a $4.85 billion settlement.

If approved to treat HA, rofecoxib would carry a warning about the increased risk of heart attack and stroke associated with the drug.

Although the orphan designation for rofecoxib is a step toward FDA approval, Sippy said Tremeau must still raise $25 million or more to fund trials of the drug in hemophilia patients.

About orphan designation

The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

Photo from Novartis

The European Commission has approved nilotinib (Tasigna®) for the treatment of pediatric patients.

The drug is now approved to treat children age 2 and older with newly diagnosed, Philadelphia chromosome-positive (Ph+), chronic phase (CP) chronic myeloid leukemia (CML) or Ph+ CP-CML with resistance or intolerance to prior therapy, including imatinib.

Nilotinib is the only second-generation tyrosine kinase inhibitor currently approved in the European Union (EU) for the treatment of Ph+ CP-CML in children. The approval applies to all EU member states.

According to Novartis, the expanded indication for nilotinib is based on 2 prospective studies of the drug in children with Ph+ CP-CML, which were part of a formal “pediatric investigation plan” agreed upon with the European Medicines Agency.

The company said 69 patients received nilotinib in these studies. The patients ranged in age from 2 to 18. They had either newly diagnosed Ph+ CP-CML or Ph+ CP-CML with resistance or intolerance to prior therapy, including imatinib.

In the newly diagnosed patients, the major molecular response (MMR) rate was 60.0% (95% CI: 38.7, 78.9) at 12 cycles, with 15 patients achieving MMR.

In patients with resistance or intolerance to prior therapy, the MMR rate was 40.9% (95% CI: 26.3, 56.8) at 12 cycles, with 18 patients being in MMR.

In newly diagnosed patients, the cumulative MMR rate was 64.0% by cycle 12. In patients with resistance or intolerance to prior therapy, the cumulative MMR rate was 47.7% by cycle 12.

Adverse events were generally consistent with those observed in adults, with the exception of hyperbilirubinemia and transaminase elevation, which were reported at a higher frequency than in adults.

The rate of grade 3/4 hyperbilirubinemia was 13.0%, the rate of grade 3/4 AST elevation was 1.4%, and the rate of grade 3/4 ALT elevation was 8.7%.

There were no deaths on treatment or after treatment discontinuation.

Photo from Novartis

The European Commission has approved nilotinib (Tasigna®) for the treatment of pediatric patients.

The drug is now approved to treat children age 2 and older with newly diagnosed, Philadelphia chromosome-positive (Ph+), chronic phase (CP) chronic myeloid leukemia (CML) or Ph+ CP-CML with resistance or intolerance to prior therapy, including imatinib.

Nilotinib is the only second-generation tyrosine kinase inhibitor currently approved in the European Union (EU) for the treatment of Ph+ CP-CML in children. The approval applies to all EU member states.

According to Novartis, the expanded indication for nilotinib is based on 2 prospective studies of the drug in children with Ph+ CP-CML, which were part of a formal “pediatric investigation plan” agreed upon with the European Medicines Agency.

The company said 69 patients received nilotinib in these studies. The patients ranged in age from 2 to 18. They had either newly diagnosed Ph+ CP-CML or Ph+ CP-CML with resistance or intolerance to prior therapy, including imatinib.

In the newly diagnosed patients, the major molecular response (MMR) rate was 60.0% (95% CI: 38.7, 78.9) at 12 cycles, with 15 patients achieving MMR.

In patients with resistance or intolerance to prior therapy, the MMR rate was 40.9% (95% CI: 26.3, 56.8) at 12 cycles, with 18 patients being in MMR.

In newly diagnosed patients, the cumulative MMR rate was 64.0% by cycle 12. In patients with resistance or intolerance to prior therapy, the cumulative MMR rate was 47.7% by cycle 12.

Adverse events were generally consistent with those observed in adults, with the exception of hyperbilirubinemia and transaminase elevation, which were reported at a higher frequency than in adults.

The rate of grade 3/4 hyperbilirubinemia was 13.0%, the rate of grade 3/4 AST elevation was 1.4%, and the rate of grade 3/4 ALT elevation was 8.7%.

There were no deaths on treatment or after treatment discontinuation.

Photo from Novartis

The European Commission has approved nilotinib (Tasigna®) for the treatment of pediatric patients.

The drug is now approved to treat children age 2 and older with newly diagnosed, Philadelphia chromosome-positive (Ph+), chronic phase (CP) chronic myeloid leukemia (CML) or Ph+ CP-CML with resistance or intolerance to prior therapy, including imatinib.

Nilotinib is the only second-generation tyrosine kinase inhibitor currently approved in the European Union (EU) for the treatment of Ph+ CP-CML in children. The approval applies to all EU member states.

According to Novartis, the expanded indication for nilotinib is based on 2 prospective studies of the drug in children with Ph+ CP-CML, which were part of a formal “pediatric investigation plan” agreed upon with the European Medicines Agency.

The company said 69 patients received nilotinib in these studies. The patients ranged in age from 2 to 18. They had either newly diagnosed Ph+ CP-CML or Ph+ CP-CML with resistance or intolerance to prior therapy, including imatinib.

In the newly diagnosed patients, the major molecular response (MMR) rate was 60.0% (95% CI: 38.7, 78.9) at 12 cycles, with 15 patients achieving MMR.

In patients with resistance or intolerance to prior therapy, the MMR rate was 40.9% (95% CI: 26.3, 56.8) at 12 cycles, with 18 patients being in MMR.

In newly diagnosed patients, the cumulative MMR rate was 64.0% by cycle 12. In patients with resistance or intolerance to prior therapy, the cumulative MMR rate was 47.7% by cycle 12.

Adverse events were generally consistent with those observed in adults, with the exception of hyperbilirubinemia and transaminase elevation, which were reported at a higher frequency than in adults.

The rate of grade 3/4 hyperbilirubinemia was 13.0%, the rate of grade 3/4 AST elevation was 1.4%, and the rate of grade 3/4 ALT elevation was 8.7%.

There were no deaths on treatment or after treatment discontinuation.

Micrograph showing B-ALL

Researchers say they have reported the first results demonstrating clinical activity of a CD22-directed chimeric antigen receptor (CAR) T-cell therapy in B-cell acute lymphoblastic leukemia (B-ALL).

The team conducted a phase 1 study of the therapy in 21 children and adults with relapsed/refractory B-ALL.

Twelve patients achieved a complete response (CR) to the treatment, with 3 patients still in CR at last follow-up.

Sixteen patients developed cytokine release syndrome (CRS), all grade 1 or 2.

Crystal Mackall, MD, of Stanford University in California, and her colleagues reported these results in Nature Medicine.*

“This is the first time that we’ve seen response rates anything like we achieved when we were first testing the CD19 CAR T therapy,” Dr Mackall said.

“We were all a little worried that we wouldn’t find anything comparable, but this study gives hope to the idea that there may be another similar, very potent treatment.”

Patients

Dr Mackall and her colleagues studied the CD22-CAR T-cell therapy in 21 patients with relapsed/refractory B-ALL. They had a median age of 19 (range, 7 to 30).

All of the patients had received a hematopoietic stem cell transplant at least once, and 2 patients had 2 prior transplants each. Seventeen patients had received prior CD19-directed immunotherapy. Fifteen had received CD19-directed CAR T-cell therapy, and 2 had received blinatumomab.

Lymphoblasts were CD19⁻ or CD19^dim in 10 patients (9 who had received a CD19-CAR and 1 treated with blinatumomab).

The median CD22 site density was 2839 molecules per cell (range, 613 to 13,452).

Dosing and DLTs

Patients received the CD22-CAR T-cell therapy at 1 of 3 dose levels:

• 0.3 × 10⁶ CD22-CAR T cells per kg body weight (n=6)
• 1 × 10⁶ cells per kg (n=13)
• 3 × 10⁶ cells per kg (n=2).

There was 1 dose-limiting toxicity (DLT) at the first dose level. It was grade 3, self-limited, noninfectious diarrhea that occurred during CRS and resolved with supportive care.

The other DLT occurred in a patient who received treatment at the third dose level. This patient had grade 4 hypoxia that was associated with rapid disease progression. The patient required brief intubation, and the hypoxia was resolved within 24 hours of starting steroid treatment.

Based on these results, the second dose level became the recommended phase 2 dose.

Other adverse events

The researchers said the primary toxicity was CRS, which occurred in 16 patients. Nine patients had grade 1 CRS, and 7 had grade 2.

There were no cases of irreversible neurotoxicity or seizure reported. Among the first 16 patients with complete assessments, there were cases of transient visual hallucinations (n=2), mild unresponsiveness (n=1), mild disorientation (n=1), and mild to moderate pain (n=2). However, these incidents resolved by day 28.

One patient died from gram-negative rod sepsis that developed after the resolution of CRS and neutrophil count recovery to >1000 cells/μL blood. The patient had a history of multi-organ failure due to sepsis.

Response

Twelve patients (57%) had a CR, and 9 of them were minimal residual disease negative.

One CR occurred at the lowest dose of therapy, 1 occurred at the highest dose, and the remaining 10 CRs occurred in patients who received dose level 2.

The researchers said there was no evidence to suggest that previous CD19-directed immunotherapy or diminished surface expression of CD19 impacted response to the CD22-CAR T-cell therapy.

Of the 9 patients who did not respond, 4 progressed and 5 had stable disease.

The researchers said 4 non-responders had “very high disease burden with rapid disease progression.” And 2 non-responders expressed diminished or partial CD22 on leukemic blasts at the time of enrollment.

The median duration of response was 6 months (range, 1.5 to 21+ months). Three patients are still in CR at 6, 9, and 21 months of follow-up.

“The take-home message is that we’ve found another CAR T-cell therapy that displays high-level activity in this phase 1 trial,” Dr Mackall said. “But the relapse rate was also high. So this forces the field to get even more sophisticated. How much of a target is needed for successful, long-lasting treatment? What happens if we target both CD19 and CD22 simultaneously?”

The researchers are already tackling the last question by testing a CAR T-cell therapy that recognizes both CD19 and CD22. They’ve confirmed this therapy can kill cancer cells in vitro and in vivo. Now, they’re testing it in a clinical trial that has opened at Stanford University and will open soon at the National Cancer Institute.

*This research was supported, in part, by the Intramural Research Program, National Cancer Institute and NIH Clinical Center, National Institutes of Health; by a Stand Up to Cancer–St. Baldrick’s Pediatric Dream Team translational research grant; and by a St. Baldrick’s Foundation Scholar Award.

Micrograph showing B-ALL

Researchers say they have reported the first results demonstrating clinical activity of a CD22-directed chimeric antigen receptor (CAR) T-cell therapy in B-cell acute lymphoblastic leukemia (B-ALL).

The team conducted a phase 1 study of the therapy in 21 children and adults with relapsed/refractory B-ALL.

Twelve patients achieved a complete response (CR) to the treatment, with 3 patients still in CR at last follow-up.

Sixteen patients developed cytokine release syndrome (CRS), all grade 1 or 2.

Crystal Mackall, MD, of Stanford University in California, and her colleagues reported these results in Nature Medicine.*

“This is the first time that we’ve seen response rates anything like we achieved when we were first testing the CD19 CAR T therapy,” Dr Mackall said.

“We were all a little worried that we wouldn’t find anything comparable, but this study gives hope to the idea that there may be another similar, very potent treatment.”

Patients

Dr Mackall and her colleagues studied the CD22-CAR T-cell therapy in 21 patients with relapsed/refractory B-ALL. They had a median age of 19 (range, 7 to 30).

All of the patients had received a hematopoietic stem cell transplant at least once, and 2 patients had 2 prior transplants each. Seventeen patients had received prior CD19-directed immunotherapy. Fifteen had received CD19-directed CAR T-cell therapy, and 2 had received blinatumomab.

Lymphoblasts were CD19⁻ or CD19^dim in 10 patients (9 who had received a CD19-CAR and 1 treated with blinatumomab).

The median CD22 site density was 2839 molecules per cell (range, 613 to 13,452).

Dosing and DLTs

Patients received the CD22-CAR T-cell therapy at 1 of 3 dose levels:

• 0.3 × 10⁶ CD22-CAR T cells per kg body weight (n=6)
• 1 × 10⁶ cells per kg (n=13)
• 3 × 10⁶ cells per kg (n=2).

There was 1 dose-limiting toxicity (DLT) at the first dose level. It was grade 3, self-limited, noninfectious diarrhea that occurred during CRS and resolved with supportive care.

The other DLT occurred in a patient who received treatment at the third dose level. This patient had grade 4 hypoxia that was associated with rapid disease progression. The patient required brief intubation, and the hypoxia was resolved within 24 hours of starting steroid treatment.

Based on these results, the second dose level became the recommended phase 2 dose.

Other adverse events

The researchers said the primary toxicity was CRS, which occurred in 16 patients. Nine patients had grade 1 CRS, and 7 had grade 2.

There were no cases of irreversible neurotoxicity or seizure reported. Among the first 16 patients with complete assessments, there were cases of transient visual hallucinations (n=2), mild unresponsiveness (n=1), mild disorientation (n=1), and mild to moderate pain (n=2). However, these incidents resolved by day 28.

One patient died from gram-negative rod sepsis that developed after the resolution of CRS and neutrophil count recovery to >1000 cells/μL blood. The patient had a history of multi-organ failure due to sepsis.

Response

Twelve patients (57%) had a CR, and 9 of them were minimal residual disease negative.

One CR occurred at the lowest dose of therapy, 1 occurred at the highest dose, and the remaining 10 CRs occurred in patients who received dose level 2.

The researchers said there was no evidence to suggest that previous CD19-directed immunotherapy or diminished surface expression of CD19 impacted response to the CD22-CAR T-cell therapy.

Of the 9 patients who did not respond, 4 progressed and 5 had stable disease.

The researchers said 4 non-responders had “very high disease burden with rapid disease progression.” And 2 non-responders expressed diminished or partial CD22 on leukemic blasts at the time of enrollment.

The median duration of response was 6 months (range, 1.5 to 21+ months). Three patients are still in CR at 6, 9, and 21 months of follow-up.

“The take-home message is that we’ve found another CAR T-cell therapy that displays high-level activity in this phase 1 trial,” Dr Mackall said. “But the relapse rate was also high. So this forces the field to get even more sophisticated. How much of a target is needed for successful, long-lasting treatment? What happens if we target both CD19 and CD22 simultaneously?”

The researchers are already tackling the last question by testing a CAR T-cell therapy that recognizes both CD19 and CD22. They’ve confirmed this therapy can kill cancer cells in vitro and in vivo. Now, they’re testing it in a clinical trial that has opened at Stanford University and will open soon at the National Cancer Institute.

*This research was supported, in part, by the Intramural Research Program, National Cancer Institute and NIH Clinical Center, National Institutes of Health; by a Stand Up to Cancer–St. Baldrick’s Pediatric Dream Team translational research grant; and by a St. Baldrick’s Foundation Scholar Award.

Micrograph showing B-ALL

Researchers say they have reported the first results demonstrating clinical activity of a CD22-directed chimeric antigen receptor (CAR) T-cell therapy in B-cell acute lymphoblastic leukemia (B-ALL).

The team conducted a phase 1 study of the therapy in 21 children and adults with relapsed/refractory B-ALL.

Twelve patients achieved a complete response (CR) to the treatment, with 3 patients still in CR at last follow-up.

Sixteen patients developed cytokine release syndrome (CRS), all grade 1 or 2.

Crystal Mackall, MD, of Stanford University in California, and her colleagues reported these results in Nature Medicine.*

“This is the first time that we’ve seen response rates anything like we achieved when we were first testing the CD19 CAR T therapy,” Dr Mackall said.

“We were all a little worried that we wouldn’t find anything comparable, but this study gives hope to the idea that there may be another similar, very potent treatment.”

Patients

Dr Mackall and her colleagues studied the CD22-CAR T-cell therapy in 21 patients with relapsed/refractory B-ALL. They had a median age of 19 (range, 7 to 30).

All of the patients had received a hematopoietic stem cell transplant at least once, and 2 patients had 2 prior transplants each. Seventeen patients had received prior CD19-directed immunotherapy. Fifteen had received CD19-directed CAR T-cell therapy, and 2 had received blinatumomab.

Lymphoblasts were CD19⁻ or CD19^dim in 10 patients (9 who had received a CD19-CAR and 1 treated with blinatumomab).

The median CD22 site density was 2839 molecules per cell (range, 613 to 13,452).

Dosing and DLTs

Patients received the CD22-CAR T-cell therapy at 1 of 3 dose levels:

• 0.3 × 10⁶ CD22-CAR T cells per kg body weight (n=6)
• 1 × 10⁶ cells per kg (n=13)
• 3 × 10⁶ cells per kg (n=2).

There was 1 dose-limiting toxicity (DLT) at the first dose level. It was grade 3, self-limited, noninfectious diarrhea that occurred during CRS and resolved with supportive care.

The other DLT occurred in a patient who received treatment at the third dose level. This patient had grade 4 hypoxia that was associated with rapid disease progression. The patient required brief intubation, and the hypoxia was resolved within 24 hours of starting steroid treatment.

Based on these results, the second dose level became the recommended phase 2 dose.

Other adverse events

The researchers said the primary toxicity was CRS, which occurred in 16 patients. Nine patients had grade 1 CRS, and 7 had grade 2.

There were no cases of irreversible neurotoxicity or seizure reported. Among the first 16 patients with complete assessments, there were cases of transient visual hallucinations (n=2), mild unresponsiveness (n=1), mild disorientation (n=1), and mild to moderate pain (n=2). However, these incidents resolved by day 28.

One patient died from gram-negative rod sepsis that developed after the resolution of CRS and neutrophil count recovery to >1000 cells/μL blood. The patient had a history of multi-organ failure due to sepsis.

Response

Twelve patients (57%) had a CR, and 9 of them were minimal residual disease negative.

One CR occurred at the lowest dose of therapy, 1 occurred at the highest dose, and the remaining 10 CRs occurred in patients who received dose level 2.

The researchers said there was no evidence to suggest that previous CD19-directed immunotherapy or diminished surface expression of CD19 impacted response to the CD22-CAR T-cell therapy.

Of the 9 patients who did not respond, 4 progressed and 5 had stable disease.

The researchers said 4 non-responders had “very high disease burden with rapid disease progression.” And 2 non-responders expressed diminished or partial CD22 on leukemic blasts at the time of enrollment.

The median duration of response was 6 months (range, 1.5 to 21+ months). Three patients are still in CR at 6, 9, and 21 months of follow-up.

“The take-home message is that we’ve found another CAR T-cell therapy that displays high-level activity in this phase 1 trial,” Dr Mackall said. “But the relapse rate was also high. So this forces the field to get even more sophisticated. How much of a target is needed for successful, long-lasting treatment? What happens if we target both CD19 and CD22 simultaneously?”

The researchers are already tackling the last question by testing a CAR T-cell therapy that recognizes both CD19 and CD22. They’ve confirmed this therapy can kill cancer cells in vitro and in vivo. Now, they’re testing it in a clinical trial that has opened at Stanford University and will open soon at the National Cancer Institute.

*This research was supported, in part, by the Intramural Research Program, National Cancer Institute and NIH Clinical Center, National Institutes of Health; by a Stand Up to Cancer–St. Baldrick’s Pediatric Dream Team translational research grant; and by a St. Baldrick’s Foundation Scholar Award.