Hematology Times

Photo courtesy of CDC

MUNICH—Extended thromboprophylaxis with rivaroxaban does not significantly reduce the risk of fatal venous thromboembolism (VTE) in patients hospitalized for medical illness, according to new research.

In the MARINER trial, the combined rate of symptomatic VTE and VTE-related death was similar in patients who received placebo and those who received rivaroxaban for 45 days after hospital discharge.

Rates of VTE-related death were similar between the treatment groups, but the rate of nonfatal VTE was lower with rivaroxaban.

The researchers therefore concluded that some medically ill patients may benefit from extended thromboprophylaxis with rivaroxaban, although more research is needed.

Alex C. Spyropoulos, MD, of Northwell Health at Lenox Hill Hospital in New York, New York, presented these results at ESC Congress 2018.

The research was also published in NEJM. The study was funded by Janssen Research and Development.

The MARINER trial included 12,019 medically ill patients who had an increased risk of VTE and had been hospitalized for 3 to 10 days.

The patients were randomized to receive rivaroxaban (n=6007) at 10 mg daily (7.5 mg in patients with renal impairment) or daily placebo (n=6012) for 45 days after hospital discharge. In all, 11,962 patients (99.5%) received at least one dose of assigned treatment.

Results

The study’s primary endpoint was a composite of symptomatic VTE and VTE-related death. This endpoint was met in 0.83% (n=50) of patients in the rivaroxaban arm and 1.10% (n=66) of patients in the placebo arm (hazard ratio [HR]=0.76; P=0.136).

The incidence of VTE-related death was 0.72% (n=43) in the rivaroxaban arm and 0.77% (n=46) in the placebo arm (HR=0.93, P=0.751).

The incidence of symptomatic VTE was 0.18% (n=11) in the rivaroxaban arm and 0.42% (n=25) in the placebo arm (HR=0.44, P=0.023).

“We were able to reduce instances of non-fatal blood clots and pulmonary embolism by more than half, which shows that the use of direct oral anticoagulants . . . after the hospitalization of medically ill patients could help prevent clots from forming,” Dr. Spyropoulos said.

He and his colleagues also examined an exploratory secondary composite endpoint of symptomatic VTE and all-cause mortality and found that 1.30% (n=78) of patients in the rivaroxaban arm experienced an event, compared to 1.78% (n=107) of patients in the placebo arm (HR=0.73, P=0.033).

The study’s principal safety outcome was major bleeding. It occurred in 0.28% (n=17) of patients in the rivaroxaban arm and 0.15% (n=9) of those in the placebo arm (HR=1.88, P=0.124).

The difference in risk of major bleeding with rivaroxaban compared to placebo was 0.28 percentage points, and the difference in risk of symptomatic VTE with rivaroxaban vs placebo was -0.24 percentage points.

This suggests the number of patients needed to prevent one symptomatic VTE event is 430, and the number needed to cause one major bleed is 856.

Dr. Spyropoulos therefore concluded that thromboprophylaxis, when used in appropriate medically ill patients, might reduce the population health burden of symptomatic VTE with little serious bleeding.

“Our next course of research is to further identify and refine a post-discharge treatment program which would maximize the net clinical benefit across a defined spectrum of medically ill patients,” he said.

Photo courtesy of CDC

MUNICH—Extended thromboprophylaxis with rivaroxaban does not significantly reduce the risk of fatal venous thromboembolism (VTE) in patients hospitalized for medical illness, according to new research.

In the MARINER trial, the combined rate of symptomatic VTE and VTE-related death was similar in patients who received placebo and those who received rivaroxaban for 45 days after hospital discharge.

Rates of VTE-related death were similar between the treatment groups, but the rate of nonfatal VTE was lower with rivaroxaban.

The researchers therefore concluded that some medically ill patients may benefit from extended thromboprophylaxis with rivaroxaban, although more research is needed.

Alex C. Spyropoulos, MD, of Northwell Health at Lenox Hill Hospital in New York, New York, presented these results at ESC Congress 2018.

The research was also published in NEJM. The study was funded by Janssen Research and Development.

The MARINER trial included 12,019 medically ill patients who had an increased risk of VTE and had been hospitalized for 3 to 10 days.

The patients were randomized to receive rivaroxaban (n=6007) at 10 mg daily (7.5 mg in patients with renal impairment) or daily placebo (n=6012) for 45 days after hospital discharge. In all, 11,962 patients (99.5%) received at least one dose of assigned treatment.

Results

The study’s primary endpoint was a composite of symptomatic VTE and VTE-related death. This endpoint was met in 0.83% (n=50) of patients in the rivaroxaban arm and 1.10% (n=66) of patients in the placebo arm (hazard ratio [HR]=0.76; P=0.136).

The incidence of VTE-related death was 0.72% (n=43) in the rivaroxaban arm and 0.77% (n=46) in the placebo arm (HR=0.93, P=0.751).

The incidence of symptomatic VTE was 0.18% (n=11) in the rivaroxaban arm and 0.42% (n=25) in the placebo arm (HR=0.44, P=0.023).

“We were able to reduce instances of non-fatal blood clots and pulmonary embolism by more than half, which shows that the use of direct oral anticoagulants . . . after the hospitalization of medically ill patients could help prevent clots from forming,” Dr. Spyropoulos said.

He and his colleagues also examined an exploratory secondary composite endpoint of symptomatic VTE and all-cause mortality and found that 1.30% (n=78) of patients in the rivaroxaban arm experienced an event, compared to 1.78% (n=107) of patients in the placebo arm (HR=0.73, P=0.033).

The study’s principal safety outcome was major bleeding. It occurred in 0.28% (n=17) of patients in the rivaroxaban arm and 0.15% (n=9) of those in the placebo arm (HR=1.88, P=0.124).

The difference in risk of major bleeding with rivaroxaban compared to placebo was 0.28 percentage points, and the difference in risk of symptomatic VTE with rivaroxaban vs placebo was -0.24 percentage points.

This suggests the number of patients needed to prevent one symptomatic VTE event is 430, and the number needed to cause one major bleed is 856.

Dr. Spyropoulos therefore concluded that thromboprophylaxis, when used in appropriate medically ill patients, might reduce the population health burden of symptomatic VTE with little serious bleeding.

“Our next course of research is to further identify and refine a post-discharge treatment program which would maximize the net clinical benefit across a defined spectrum of medically ill patients,” he said.

Photo courtesy of CDC

MUNICH—Extended thromboprophylaxis with rivaroxaban does not significantly reduce the risk of fatal venous thromboembolism (VTE) in patients hospitalized for medical illness, according to new research.

In the MARINER trial, the combined rate of symptomatic VTE and VTE-related death was similar in patients who received placebo and those who received rivaroxaban for 45 days after hospital discharge.

Rates of VTE-related death were similar between the treatment groups, but the rate of nonfatal VTE was lower with rivaroxaban.

The researchers therefore concluded that some medically ill patients may benefit from extended thromboprophylaxis with rivaroxaban, although more research is needed.

Alex C. Spyropoulos, MD, of Northwell Health at Lenox Hill Hospital in New York, New York, presented these results at ESC Congress 2018.

The research was also published in NEJM. The study was funded by Janssen Research and Development.

The MARINER trial included 12,019 medically ill patients who had an increased risk of VTE and had been hospitalized for 3 to 10 days.

The patients were randomized to receive rivaroxaban (n=6007) at 10 mg daily (7.5 mg in patients with renal impairment) or daily placebo (n=6012) for 45 days after hospital discharge. In all, 11,962 patients (99.5%) received at least one dose of assigned treatment.

Results

The study’s primary endpoint was a composite of symptomatic VTE and VTE-related death. This endpoint was met in 0.83% (n=50) of patients in the rivaroxaban arm and 1.10% (n=66) of patients in the placebo arm (hazard ratio [HR]=0.76; P=0.136).

The incidence of VTE-related death was 0.72% (n=43) in the rivaroxaban arm and 0.77% (n=46) in the placebo arm (HR=0.93, P=0.751).

The incidence of symptomatic VTE was 0.18% (n=11) in the rivaroxaban arm and 0.42% (n=25) in the placebo arm (HR=0.44, P=0.023).

“We were able to reduce instances of non-fatal blood clots and pulmonary embolism by more than half, which shows that the use of direct oral anticoagulants . . . after the hospitalization of medically ill patients could help prevent clots from forming,” Dr. Spyropoulos said.

He and his colleagues also examined an exploratory secondary composite endpoint of symptomatic VTE and all-cause mortality and found that 1.30% (n=78) of patients in the rivaroxaban arm experienced an event, compared to 1.78% (n=107) of patients in the placebo arm (HR=0.73, P=0.033).

The study’s principal safety outcome was major bleeding. It occurred in 0.28% (n=17) of patients in the rivaroxaban arm and 0.15% (n=9) of those in the placebo arm (HR=1.88, P=0.124).

The difference in risk of major bleeding with rivaroxaban compared to placebo was 0.28 percentage points, and the difference in risk of symptomatic VTE with rivaroxaban vs placebo was -0.24 percentage points.

This suggests the number of patients needed to prevent one symptomatic VTE event is 430, and the number needed to cause one major bleed is 856.

Dr. Spyropoulos therefore concluded that thromboprophylaxis, when used in appropriate medically ill patients, might reduce the population health burden of symptomatic VTE with little serious bleeding.

“Our next course of research is to further identify and refine a post-discharge treatment program which would maximize the net clinical benefit across a defined spectrum of medically ill patients,” he said.

Photo by Bill Branson

A low-intensity regimen could be an effective treatment option for elderly or unfit patients with newly diagnosed acute myeloid leukemia (AML) or high-risk myelodysplastic syndromes (MDS), according to researchers.

The regimen—cladribine plus low-dose cytarabine alternating with decitabine—produced a response rate of 68%.

The median disease-free survival (DFS) was 10.8 months, and the median overall survival (OS) was 13.8 months.

The regimen was considered well tolerated, although all patients experienced myelosuppression, and three-quarters developed infections that may have been treatment-related.

Tapan M. Kadia, MD, of the University of Texas MD Anderson Cancer Center in Houston, and his colleagues reported these results in The Lancet Haematology.

This phase 2 trial enrolled 118 patients with previously untreated AML or high-risk MDS. Seventeen percent of patients had therapy-related AML, 25% had secondary AML (prior MDS or myeloproliferative neoplasm [MPN]), and 15% had treated secondary AML (received treatment for MDS/MPN).

Forty-one percent of patients had an adverse risk karyotype, and 27% had a complex karyotype. Patients had a range of mutations, but the most common were in RAS, TP53, DNMT3a, NPM1, and FLT3-ITD.

Most patients (n=116) were age 60 or older, with a median age of 69. However, there were 2 patients younger than age 60. Both had “extensive” exposure to anthracycline, and one had a prior myocardial infarction.

Treatment

Patients received cladribine plus low-dose cytarabine for two cycles, alternating with decitabine for two cycles, for up to 18 cycles (28 days each).

For cycle 1, patients received cladribine at 5 mg/m² (given intravenously over 1 to 2 hours) on days 1 to 5 and cytarabine at 20 mg (given subcutaneously) twice daily on days 1 to 10.

Patients who achieved remission went on to receive consolidation with cladribine at 5 mg/m² (given intravenously over 1 to 2 hours) on days 1 to 3 and cytarabine at 20 mg twice daily on days 1 to 10, alternating with decitabine at 20 mg/m² (intravenously) on days 1 to 5.

Efficacy

The objective response rate was 68%, the rate of complete response was 58%, and the rate of complete response with incomplete count recovery was 9%.

The median DFS was 10.8 months, and the median OS was 13.8 months. The 1-year OS rate was 64%, and the 2-year OS rate was 28%.

Outcomes were better in patients with a diploid karyotype than in those with adverse karyotypes or TP53 mutation. Among patients with a diploid karyotype (n=38), the response rate was 84%, and the median OS was 19.9 months.

Among patients with adverse karyotypes (n=48), the response rate was 50%, and the median OS was 10.5 months. In patients with TP53 mutation (n=20), the response rate was 40%, and the median OS was 8.9 months.

Of all responders (n=80), 23% went on to allogeneic stem cell transplant. There was no significant difference in OS between patients who received a transplant and those who did not. The median OS was 16.4 months and 15.9 months, respectively (P=0.18).

Safety

The researchers said this regimen was generally well tolerated, but all patients experienced myelosuppression.

The most common non-hematologic adverse events (AEs) considered at least possibly related to treatment included infection (n=88), elevated total bilirubin (n=26), rash (n=13), nausea (n=13), diarrhea (n=9), ALT/AST elevation (n=7), elevated creatinine (n=7), mucositis (n=7), and constipation (n=6).

Overall, grade 3/4 non-hematologic AEs tended to occur in few patients. The exception was infections. There were 77 grade 3 infections, and two grade 4 infections.

There were 9 grade 5 infections but no other fatal AEs considered at least possibly related to treatment.

One patient (1%) died within the first 4 weeks of treatment, and 8 (7%) died within the first 8 weeks. None of these patients had responded.

“Our findings suggest that the combination of cladribine and low-dose cytarabine alternating with decitabine is a highly active and well tolerated regimen for older patients with AML,” the researchers wrote.

The team also called for a phase 3 trial comparing this regimen to hypomethylating agents.

This study was sponsored by MD Anderson and supported, in part, by the National Institutes of Health.

Photo by Bill Branson

A low-intensity regimen could be an effective treatment option for elderly or unfit patients with newly diagnosed acute myeloid leukemia (AML) or high-risk myelodysplastic syndromes (MDS), according to researchers.

The regimen—cladribine plus low-dose cytarabine alternating with decitabine—produced a response rate of 68%.

The median disease-free survival (DFS) was 10.8 months, and the median overall survival (OS) was 13.8 months.

The regimen was considered well tolerated, although all patients experienced myelosuppression, and three-quarters developed infections that may have been treatment-related.

Tapan M. Kadia, MD, of the University of Texas MD Anderson Cancer Center in Houston, and his colleagues reported these results in The Lancet Haematology.

This phase 2 trial enrolled 118 patients with previously untreated AML or high-risk MDS. Seventeen percent of patients had therapy-related AML, 25% had secondary AML (prior MDS or myeloproliferative neoplasm [MPN]), and 15% had treated secondary AML (received treatment for MDS/MPN).

Forty-one percent of patients had an adverse risk karyotype, and 27% had a complex karyotype. Patients had a range of mutations, but the most common were in RAS, TP53, DNMT3a, NPM1, and FLT3-ITD.

Most patients (n=116) were age 60 or older, with a median age of 69. However, there were 2 patients younger than age 60. Both had “extensive” exposure to anthracycline, and one had a prior myocardial infarction.

Treatment

Patients received cladribine plus low-dose cytarabine for two cycles, alternating with decitabine for two cycles, for up to 18 cycles (28 days each).

For cycle 1, patients received cladribine at 5 mg/m² (given intravenously over 1 to 2 hours) on days 1 to 5 and cytarabine at 20 mg (given subcutaneously) twice daily on days 1 to 10.

Patients who achieved remission went on to receive consolidation with cladribine at 5 mg/m² (given intravenously over 1 to 2 hours) on days 1 to 3 and cytarabine at 20 mg twice daily on days 1 to 10, alternating with decitabine at 20 mg/m² (intravenously) on days 1 to 5.

Efficacy

The objective response rate was 68%, the rate of complete response was 58%, and the rate of complete response with incomplete count recovery was 9%.

The median DFS was 10.8 months, and the median OS was 13.8 months. The 1-year OS rate was 64%, and the 2-year OS rate was 28%.

Outcomes were better in patients with a diploid karyotype than in those with adverse karyotypes or TP53 mutation. Among patients with a diploid karyotype (n=38), the response rate was 84%, and the median OS was 19.9 months.

Among patients with adverse karyotypes (n=48), the response rate was 50%, and the median OS was 10.5 months. In patients with TP53 mutation (n=20), the response rate was 40%, and the median OS was 8.9 months.

Of all responders (n=80), 23% went on to allogeneic stem cell transplant. There was no significant difference in OS between patients who received a transplant and those who did not. The median OS was 16.4 months and 15.9 months, respectively (P=0.18).

Safety

The researchers said this regimen was generally well tolerated, but all patients experienced myelosuppression.

The most common non-hematologic adverse events (AEs) considered at least possibly related to treatment included infection (n=88), elevated total bilirubin (n=26), rash (n=13), nausea (n=13), diarrhea (n=9), ALT/AST elevation (n=7), elevated creatinine (n=7), mucositis (n=7), and constipation (n=6).

Overall, grade 3/4 non-hematologic AEs tended to occur in few patients. The exception was infections. There were 77 grade 3 infections, and two grade 4 infections.

There were 9 grade 5 infections but no other fatal AEs considered at least possibly related to treatment.

One patient (1%) died within the first 4 weeks of treatment, and 8 (7%) died within the first 8 weeks. None of these patients had responded.

“Our findings suggest that the combination of cladribine and low-dose cytarabine alternating with decitabine is a highly active and well tolerated regimen for older patients with AML,” the researchers wrote.

The team also called for a phase 3 trial comparing this regimen to hypomethylating agents.

This study was sponsored by MD Anderson and supported, in part, by the National Institutes of Health.

Photo by Bill Branson

A low-intensity regimen could be an effective treatment option for elderly or unfit patients with newly diagnosed acute myeloid leukemia (AML) or high-risk myelodysplastic syndromes (MDS), according to researchers.

The regimen—cladribine plus low-dose cytarabine alternating with decitabine—produced a response rate of 68%.

The median disease-free survival (DFS) was 10.8 months, and the median overall survival (OS) was 13.8 months.

The regimen was considered well tolerated, although all patients experienced myelosuppression, and three-quarters developed infections that may have been treatment-related.

Tapan M. Kadia, MD, of the University of Texas MD Anderson Cancer Center in Houston, and his colleagues reported these results in The Lancet Haematology.

This phase 2 trial enrolled 118 patients with previously untreated AML or high-risk MDS. Seventeen percent of patients had therapy-related AML, 25% had secondary AML (prior MDS or myeloproliferative neoplasm [MPN]), and 15% had treated secondary AML (received treatment for MDS/MPN).

Forty-one percent of patients had an adverse risk karyotype, and 27% had a complex karyotype. Patients had a range of mutations, but the most common were in RAS, TP53, DNMT3a, NPM1, and FLT3-ITD.

Most patients (n=116) were age 60 or older, with a median age of 69. However, there were 2 patients younger than age 60. Both had “extensive” exposure to anthracycline, and one had a prior myocardial infarction.

Treatment

Patients received cladribine plus low-dose cytarabine for two cycles, alternating with decitabine for two cycles, for up to 18 cycles (28 days each).

For cycle 1, patients received cladribine at 5 mg/m² (given intravenously over 1 to 2 hours) on days 1 to 5 and cytarabine at 20 mg (given subcutaneously) twice daily on days 1 to 10.

Patients who achieved remission went on to receive consolidation with cladribine at 5 mg/m² (given intravenously over 1 to 2 hours) on days 1 to 3 and cytarabine at 20 mg twice daily on days 1 to 10, alternating with decitabine at 20 mg/m² (intravenously) on days 1 to 5.

Efficacy

The objective response rate was 68%, the rate of complete response was 58%, and the rate of complete response with incomplete count recovery was 9%.

The median DFS was 10.8 months, and the median OS was 13.8 months. The 1-year OS rate was 64%, and the 2-year OS rate was 28%.

Outcomes were better in patients with a diploid karyotype than in those with adverse karyotypes or TP53 mutation. Among patients with a diploid karyotype (n=38), the response rate was 84%, and the median OS was 19.9 months.

Among patients with adverse karyotypes (n=48), the response rate was 50%, and the median OS was 10.5 months. In patients with TP53 mutation (n=20), the response rate was 40%, and the median OS was 8.9 months.

Of all responders (n=80), 23% went on to allogeneic stem cell transplant. There was no significant difference in OS between patients who received a transplant and those who did not. The median OS was 16.4 months and 15.9 months, respectively (P=0.18).

Safety

The researchers said this regimen was generally well tolerated, but all patients experienced myelosuppression.

The most common non-hematologic adverse events (AEs) considered at least possibly related to treatment included infection (n=88), elevated total bilirubin (n=26), rash (n=13), nausea (n=13), diarrhea (n=9), ALT/AST elevation (n=7), elevated creatinine (n=7), mucositis (n=7), and constipation (n=6).

Overall, grade 3/4 non-hematologic AEs tended to occur in few patients. The exception was infections. There were 77 grade 3 infections, and two grade 4 infections.

There were 9 grade 5 infections but no other fatal AEs considered at least possibly related to treatment.

One patient (1%) died within the first 4 weeks of treatment, and 8 (7%) died within the first 8 weeks. None of these patients had responded.

“Our findings suggest that the combination of cladribine and low-dose cytarabine alternating with decitabine is a highly active and well tolerated regimen for older patients with AML,” the researchers wrote.

The team also called for a phase 3 trial comparing this regimen to hypomethylating agents.

This study was sponsored by MD Anderson and supported, in part, by the National Institutes of Health.

Photo by Rhoda Baer

New research suggests cancer survivors are just as likely as people without a history of cancer to have complete mental health (CMH), which is defined as “optimal functioning” and the “absence of psychopathology.”

In a study of nearly 11,000 Canadians, 77.5% of cancer survivors and 76.8% of people with no cancer history had CMH.

As for patients who were battling cancer at the time of the study, 66.1% had CMH.

Esme Fuller-Thomson, PhD, and Keri West, both of the University of Toronto in Canada, conducted this research and reported the findings in Aging & Mental Health.

“Cancer patients were doing much better than we had expected,” Dr. Fuller-Thomson said. “Two-thirds met our very stringent criteria for complete mental health . . . . The news for cancer survivors was even better, with three-quarters living in complete mental health, which is a prevalence comparable to that of individuals with no cancer history.”

This study included a nationally representative sample of Canadian community dwellers age 50 and older. Subjects had current cancer (n=438), previous cancer (n=1174), or no cancer history (n=9279).

Data were obtained from Statistics Canada’s 2012 Canadian Community Health Survey-Mental Health.

To meet criteria for CMH, subjects had to have all of the following:

• Absence of mental illness, addictions, and suicidal thoughts in the past year
• Almost daily happiness or life satisfaction in the past month
• Psychosocial well-being.

The prevalence of CMH was 77.5% in cancer survivors and 76.8% in subjects who had never had cancer. Both were significantly higher than the 66.1% prevalence of CMH in current cancer patients (P<0.001).

In a multivariable model adjusted for demographics, current cancer patients had 45% lower odds of CMH compared to subjects with no cancer history (odds ratio [OR]=0.55). The odds of CMH were comparable for cancer survivors and those without a history of cancer (OR=0.98).

The researchers also conducted a multivariable analysis in which they adjusted for “all relevant factors,” which included demographics as well as adverse childhood events, socioeconomic status, health variables, lifetime mental illness, etc.

In this analysis, current cancer patients had 37% lower odds of CMH than subjects with no cancer history (OR=0.63). And cancer survivors had comparable odds of CMH as those with no cancer history (OR=1.06).

The researchers identified several factors that were associated with CMH in the population affected by cancer.

“Among those with former or current cancer, the odds of complete mental health were higher for women, white, married, and older respondents, as well as those with higher income and those who did not have disabling pain nor functional limitations,” West said.

“We found that earlier difficulties cast a long shadow. Those who had been physically abused during their childhood and those who had ever had depression or anxiety disorders were less likely to be in complete mental health.”

West and Dr Fuller-Thomson emphasized that these results are only correlational, and it is impossible to determine causality due to the cross-sectional and observational nature of the study.

The pair also said future longitudinal research is needed to improve understanding of what pathways improve resilience and recovery among cancer patients.

Photo by Rhoda Baer

New research suggests cancer survivors are just as likely as people without a history of cancer to have complete mental health (CMH), which is defined as “optimal functioning” and the “absence of psychopathology.”

In a study of nearly 11,000 Canadians, 77.5% of cancer survivors and 76.8% of people with no cancer history had CMH.

As for patients who were battling cancer at the time of the study, 66.1% had CMH.

Esme Fuller-Thomson, PhD, and Keri West, both of the University of Toronto in Canada, conducted this research and reported the findings in Aging & Mental Health.

“Cancer patients were doing much better than we had expected,” Dr. Fuller-Thomson said. “Two-thirds met our very stringent criteria for complete mental health . . . . The news for cancer survivors was even better, with three-quarters living in complete mental health, which is a prevalence comparable to that of individuals with no cancer history.”

This study included a nationally representative sample of Canadian community dwellers age 50 and older. Subjects had current cancer (n=438), previous cancer (n=1174), or no cancer history (n=9279).

Data were obtained from Statistics Canada’s 2012 Canadian Community Health Survey-Mental Health.

To meet criteria for CMH, subjects had to have all of the following:

• Absence of mental illness, addictions, and suicidal thoughts in the past year
• Almost daily happiness or life satisfaction in the past month
• Psychosocial well-being.

The prevalence of CMH was 77.5% in cancer survivors and 76.8% in subjects who had never had cancer. Both were significantly higher than the 66.1% prevalence of CMH in current cancer patients (P<0.001).

In a multivariable model adjusted for demographics, current cancer patients had 45% lower odds of CMH compared to subjects with no cancer history (odds ratio [OR]=0.55). The odds of CMH were comparable for cancer survivors and those without a history of cancer (OR=0.98).

The researchers also conducted a multivariable analysis in which they adjusted for “all relevant factors,” which included demographics as well as adverse childhood events, socioeconomic status, health variables, lifetime mental illness, etc.

In this analysis, current cancer patients had 37% lower odds of CMH than subjects with no cancer history (OR=0.63). And cancer survivors had comparable odds of CMH as those with no cancer history (OR=1.06).

The researchers identified several factors that were associated with CMH in the population affected by cancer.

“Among those with former or current cancer, the odds of complete mental health were higher for women, white, married, and older respondents, as well as those with higher income and those who did not have disabling pain nor functional limitations,” West said.

“We found that earlier difficulties cast a long shadow. Those who had been physically abused during their childhood and those who had ever had depression or anxiety disorders were less likely to be in complete mental health.”

West and Dr Fuller-Thomson emphasized that these results are only correlational, and it is impossible to determine causality due to the cross-sectional and observational nature of the study.

The pair also said future longitudinal research is needed to improve understanding of what pathways improve resilience and recovery among cancer patients.

Photo by Rhoda Baer

New research suggests cancer survivors are just as likely as people without a history of cancer to have complete mental health (CMH), which is defined as “optimal functioning” and the “absence of psychopathology.”

In a study of nearly 11,000 Canadians, 77.5% of cancer survivors and 76.8% of people with no cancer history had CMH.

As for patients who were battling cancer at the time of the study, 66.1% had CMH.

Esme Fuller-Thomson, PhD, and Keri West, both of the University of Toronto in Canada, conducted this research and reported the findings in Aging & Mental Health.

“Cancer patients were doing much better than we had expected,” Dr. Fuller-Thomson said. “Two-thirds met our very stringent criteria for complete mental health . . . . The news for cancer survivors was even better, with three-quarters living in complete mental health, which is a prevalence comparable to that of individuals with no cancer history.”

This study included a nationally representative sample of Canadian community dwellers age 50 and older. Subjects had current cancer (n=438), previous cancer (n=1174), or no cancer history (n=9279).

Data were obtained from Statistics Canada’s 2012 Canadian Community Health Survey-Mental Health.

To meet criteria for CMH, subjects had to have all of the following:

• Absence of mental illness, addictions, and suicidal thoughts in the past year
• Almost daily happiness or life satisfaction in the past month
• Psychosocial well-being.

The prevalence of CMH was 77.5% in cancer survivors and 76.8% in subjects who had never had cancer. Both were significantly higher than the 66.1% prevalence of CMH in current cancer patients (P<0.001).

In a multivariable model adjusted for demographics, current cancer patients had 45% lower odds of CMH compared to subjects with no cancer history (odds ratio [OR]=0.55). The odds of CMH were comparable for cancer survivors and those without a history of cancer (OR=0.98).

The researchers also conducted a multivariable analysis in which they adjusted for “all relevant factors,” which included demographics as well as adverse childhood events, socioeconomic status, health variables, lifetime mental illness, etc.

In this analysis, current cancer patients had 37% lower odds of CMH than subjects with no cancer history (OR=0.63). And cancer survivors had comparable odds of CMH as those with no cancer history (OR=1.06).

The researchers identified several factors that were associated with CMH in the population affected by cancer.

“Among those with former or current cancer, the odds of complete mental health were higher for women, white, married, and older respondents, as well as those with higher income and those who did not have disabling pain nor functional limitations,” West said.

“We found that earlier difficulties cast a long shadow. Those who had been physically abused during their childhood and those who had ever had depression or anxiety disorders were less likely to be in complete mental health.”

West and Dr Fuller-Thomson emphasized that these results are only correlational, and it is impossible to determine causality due to the cross-sectional and observational nature of the study.

The pair also said future longitudinal research is needed to improve understanding of what pathways improve resilience and recovery among cancer patients.

Micrograph showing CLL

Bendamustine followed by obinutuzumab and venetoclax produces a high overall response rate in chronic lymphocytic leukemia (CLL), according to research published in The Lancet Oncology.

In an ongoing, phase 2 study, researchers examined the outcomes of this treatment in 66 patients with CLL.

Patients underwent initial debulking with two cycles of bendamustine, received six cycles of obinutuzumab and venetoclax for induction, and could receive up to 24 months of maintenance with obinutuzumab and venetoclax.

Efficacy

Of the 63 patients included in the efficacy analysis, 34 (54%) were treatment-naïve, and 29 (46%) had relapsed or refractory disease.

At the end of induction, the overall response rate was 95% (60/63), with responses observed in 100% (34/34) of treatment-naive patients and 90% (26/29) of relapsed/refractory patients.

Five patients (8%) achieved complete remission (CR)—3 who were treatment-naïve and 2 with relapsed/refractory disease.

Twenty patients (32%) had a clinical CR or CR with incomplete bone marrow recovery—14 who were treatment-naïve and 6 with relapsed/refractory disease.

Thirty-five patients (56%) had a partial response—17 who were treatment-naïve and 18 with relapsed/refractory disease.

By 15 months, both progression-free and overall survival were 100% among treatment-naive patients.

In the relapsed/refractory patients, progression-free survival was 83%, and overall survival was 90%.

Researchers observed minimal residual disease negativity in the peripheral blood of 91% (31/34) of treatment-naive patients and 83% (24/29) of relapsed/refractory patients. (Most patients did not have data for MRD in the bone marrow.)

Study author Paula Cramer, MD, from the German CLL Study Group at University Hospital, Cologne, and her colleagues described the efficacy of the combination as “encouraging.”

Safety

Safety data were available for all 66 patients. Of the 677 AEs, 427 (63%) were deemed related to study treatment, and 69 of these were serious AEs. Twelve patients had related, serious AEs during debulking, and 23 patients had related, serious AEs during induction.

The most common serious AEs were infections and cytopenias. There were four infections during debulking and 18 infections in 11 patients during induction. The most common infections were pneumonia and sepsis.

There were two cases of neutropenia during debulking and six cases in five patients during induction. There were four cases of thrombocytopenia in three patients during induction.

Other common treatment-related, serious AEs were:

• Infusion-related reactions—six cases during induction
• Coronary artery disorder—one case during debulking and three during induction
• Tumor lysis syndrome —one case during debulking and two during induction
• Neoplasms—two squamous cell carcinomas and one malignant melanoma during induction
• Increased creatinine—two cases during debulking.

Five patients in the relapsed/refractory group died—three of sepsis related to study treatment and two from unrelated Richter’s transformation.

“With three deaths from sepsis in 66 enrolled patients, the treatment-related mortality seems high; however, in cases of low patient numbers, a few patients can have a substantial effect on the overall results,” the researchers wrote.

The study was funded by F Hoffmann-La Roche and AbbVie. Several authors reported research funding, grants, honoraria, and other support from the pharmaceutical industry, including from the study sponsors.

Micrograph showing CLL

Bendamustine followed by obinutuzumab and venetoclax produces a high overall response rate in chronic lymphocytic leukemia (CLL), according to research published in The Lancet Oncology.

In an ongoing, phase 2 study, researchers examined the outcomes of this treatment in 66 patients with CLL.

Patients underwent initial debulking with two cycles of bendamustine, received six cycles of obinutuzumab and venetoclax for induction, and could receive up to 24 months of maintenance with obinutuzumab and venetoclax.

Efficacy

Of the 63 patients included in the efficacy analysis, 34 (54%) were treatment-naïve, and 29 (46%) had relapsed or refractory disease.

At the end of induction, the overall response rate was 95% (60/63), with responses observed in 100% (34/34) of treatment-naive patients and 90% (26/29) of relapsed/refractory patients.

Five patients (8%) achieved complete remission (CR)—3 who were treatment-naïve and 2 with relapsed/refractory disease.

Twenty patients (32%) had a clinical CR or CR with incomplete bone marrow recovery—14 who were treatment-naïve and 6 with relapsed/refractory disease.

Thirty-five patients (56%) had a partial response—17 who were treatment-naïve and 18 with relapsed/refractory disease.

By 15 months, both progression-free and overall survival were 100% among treatment-naive patients.

In the relapsed/refractory patients, progression-free survival was 83%, and overall survival was 90%.

Researchers observed minimal residual disease negativity in the peripheral blood of 91% (31/34) of treatment-naive patients and 83% (24/29) of relapsed/refractory patients. (Most patients did not have data for MRD in the bone marrow.)

Study author Paula Cramer, MD, from the German CLL Study Group at University Hospital, Cologne, and her colleagues described the efficacy of the combination as “encouraging.”

Safety

Safety data were available for all 66 patients. Of the 677 AEs, 427 (63%) were deemed related to study treatment, and 69 of these were serious AEs. Twelve patients had related, serious AEs during debulking, and 23 patients had related, serious AEs during induction.

The most common serious AEs were infections and cytopenias. There were four infections during debulking and 18 infections in 11 patients during induction. The most common infections were pneumonia and sepsis.

There were two cases of neutropenia during debulking and six cases in five patients during induction. There were four cases of thrombocytopenia in three patients during induction.

Other common treatment-related, serious AEs were:

• Infusion-related reactions—six cases during induction
• Coronary artery disorder—one case during debulking and three during induction
• Tumor lysis syndrome —one case during debulking and two during induction
• Neoplasms—two squamous cell carcinomas and one malignant melanoma during induction
• Increased creatinine—two cases during debulking.

Five patients in the relapsed/refractory group died—three of sepsis related to study treatment and two from unrelated Richter’s transformation.

“With three deaths from sepsis in 66 enrolled patients, the treatment-related mortality seems high; however, in cases of low patient numbers, a few patients can have a substantial effect on the overall results,” the researchers wrote.

The study was funded by F Hoffmann-La Roche and AbbVie. Several authors reported research funding, grants, honoraria, and other support from the pharmaceutical industry, including from the study sponsors.

Micrograph showing CLL

Bendamustine followed by obinutuzumab and venetoclax produces a high overall response rate in chronic lymphocytic leukemia (CLL), according to research published in The Lancet Oncology.

In an ongoing, phase 2 study, researchers examined the outcomes of this treatment in 66 patients with CLL.

Patients underwent initial debulking with two cycles of bendamustine, received six cycles of obinutuzumab and venetoclax for induction, and could receive up to 24 months of maintenance with obinutuzumab and venetoclax.

Efficacy

Of the 63 patients included in the efficacy analysis, 34 (54%) were treatment-naïve, and 29 (46%) had relapsed or refractory disease.

At the end of induction, the overall response rate was 95% (60/63), with responses observed in 100% (34/34) of treatment-naive patients and 90% (26/29) of relapsed/refractory patients.

Five patients (8%) achieved complete remission (CR)—3 who were treatment-naïve and 2 with relapsed/refractory disease.

Twenty patients (32%) had a clinical CR or CR with incomplete bone marrow recovery—14 who were treatment-naïve and 6 with relapsed/refractory disease.

Thirty-five patients (56%) had a partial response—17 who were treatment-naïve and 18 with relapsed/refractory disease.

By 15 months, both progression-free and overall survival were 100% among treatment-naive patients.

In the relapsed/refractory patients, progression-free survival was 83%, and overall survival was 90%.

Researchers observed minimal residual disease negativity in the peripheral blood of 91% (31/34) of treatment-naive patients and 83% (24/29) of relapsed/refractory patients. (Most patients did not have data for MRD in the bone marrow.)

Study author Paula Cramer, MD, from the German CLL Study Group at University Hospital, Cologne, and her colleagues described the efficacy of the combination as “encouraging.”

Safety

Safety data were available for all 66 patients. Of the 677 AEs, 427 (63%) were deemed related to study treatment, and 69 of these were serious AEs. Twelve patients had related, serious AEs during debulking, and 23 patients had related, serious AEs during induction.

The most common serious AEs were infections and cytopenias. There were four infections during debulking and 18 infections in 11 patients during induction. The most common infections were pneumonia and sepsis.

There were two cases of neutropenia during debulking and six cases in five patients during induction. There were four cases of thrombocytopenia in three patients during induction.

Other common treatment-related, serious AEs were:

• Infusion-related reactions—six cases during induction
• Coronary artery disorder—one case during debulking and three during induction
• Tumor lysis syndrome —one case during debulking and two during induction
• Neoplasms—two squamous cell carcinomas and one malignant melanoma during induction
• Increased creatinine—two cases during debulking.

Five patients in the relapsed/refractory group died—three of sepsis related to study treatment and two from unrelated Richter’s transformation.

“With three deaths from sepsis in 66 enrolled patients, the treatment-related mortality seems high; however, in cases of low patient numbers, a few patients can have a substantial effect on the overall results,” the researchers wrote.

The study was funded by F Hoffmann-La Roche and AbbVie. Several authors reported research funding, grants, honoraria, and other support from the pharmaceutical industry, including from the study sponsors.

Bristol-Myers Squibb

The US Food and Drug Administration (FDA) has accepted for priority review a supplemental biologics license application (sBLA) for elotuzumab (Empliciti).

With this sBLA, Bristol-Myers Squibb Company is seeking approval for elotuzumab in combination with pomalidomide and low-dose dexamethasone to treat patients with relapsed/refractory multiple myeloma (MM) who have received at least two prior therapies, including lenalidomide and a proteasome inhibitor.

The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions. The agency intends to take action on a priority review application within 6 months of receiving it rather than the standard 10 months.

The FDA expects to make a decision on the sBLA for elotuzumab by December 27, 2018.

Elotuzumab is already FDA-approved for use in combination with lenalidomide and dexamethasone to treat MM patients who have received one to three prior therapies.

Bristol-Myers Squibb and AbbVie are co-developing elotuzumab, with Bristol-Myers Squibb solely responsible for commercial activities.

Supporting trial

The sBLA for elotuzumab is supported by data from ELOQUENT-3, a randomized, phase 2 study in which researchers evaluated the addition of elotuzumab to pomalidomide and low-dose dexamethasone in patients with relapsed/refractory MM.

Data from this study were presented at the 23rd Congress of the European Hematology Association in June.

The trial randomized 117 MM patients who received two or more prior therapies and were either refractory or relapsed and refractory to lenalidomide and a proteasome inhibitor.

The patients were randomized to receive either elotuzumab, pomalidomide, and low-dose dexamethasone (EPd; n=60) or pomalidomide and low-dose dexamethasone (Pd; n=57) in 28-day cycles until disease progression or unacceptable toxicity.

The overall response rate was 53% in the EPd arm and 26% in the Pd arm (odds ratio=3.25; P=0.0029).

The median progression-free survival was 10.3 months in the EPd arm and 4.7 months in the Pd arm (hazard ratio=0.54, P=0.0078).

Overall survival data were not mature at last follow-up, but there was a trend favoring EPd over Pd (hazard ratio=0.62).

The researchers said adverse events (AEs) in the EPd arm were consistent with expectations based on previous results with elotuzumab and pomalidomide regimens.

Grade 3-4 nonhematologic AEs (in the EPd and Pd arms, respectively) included constipation (2% and 0%), hyperglycemia (8% and 7%), bone pain (3% and 0%), dyspnea (3% and 2%), fatigue (0% and 4%), respiratory tract infection (0% and 2%), and upper respiratory tract infection (0% and 2%).

Grade 3-4 hematologic AEs (in the EPd and Pd arms, respectively) included anemia (10% and 20%), neutropenia (13% and 27%), thrombocytopenia (8% and 5%), and lymphopenia (8% and 2%).

Grade 3-4 AEs of special interest (in the EPd and Pd arms, respectively) included infections (13% and 22%), vascular disorders (3% and 0%), cardiac disorders (7% and 4%), and neoplasms (2% and 11%).

In the EPd arm, grade 5 AEs included infection (n=3), cardiac failure (n=1), and general physical health deterioration (n=1).

In the Pd arm, grade 5 AEs included malignant neoplasm progression (n=4), infection (n=1), multiple organ failure and infection (n=1), myocardial infarction (n=1), and plasma cell myeloma (n=1).

Bristol-Myers Squibb

The US Food and Drug Administration (FDA) has accepted for priority review a supplemental biologics license application (sBLA) for elotuzumab (Empliciti).

With this sBLA, Bristol-Myers Squibb Company is seeking approval for elotuzumab in combination with pomalidomide and low-dose dexamethasone to treat patients with relapsed/refractory multiple myeloma (MM) who have received at least two prior therapies, including lenalidomide and a proteasome inhibitor.

The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions. The agency intends to take action on a priority review application within 6 months of receiving it rather than the standard 10 months.

The FDA expects to make a decision on the sBLA for elotuzumab by December 27, 2018.

Elotuzumab is already FDA-approved for use in combination with lenalidomide and dexamethasone to treat MM patients who have received one to three prior therapies.

Bristol-Myers Squibb and AbbVie are co-developing elotuzumab, with Bristol-Myers Squibb solely responsible for commercial activities.

Supporting trial

The sBLA for elotuzumab is supported by data from ELOQUENT-3, a randomized, phase 2 study in which researchers evaluated the addition of elotuzumab to pomalidomide and low-dose dexamethasone in patients with relapsed/refractory MM.

Data from this study were presented at the 23rd Congress of the European Hematology Association in June.

The trial randomized 117 MM patients who received two or more prior therapies and were either refractory or relapsed and refractory to lenalidomide and a proteasome inhibitor.

The patients were randomized to receive either elotuzumab, pomalidomide, and low-dose dexamethasone (EPd; n=60) or pomalidomide and low-dose dexamethasone (Pd; n=57) in 28-day cycles until disease progression or unacceptable toxicity.

The overall response rate was 53% in the EPd arm and 26% in the Pd arm (odds ratio=3.25; P=0.0029).

The median progression-free survival was 10.3 months in the EPd arm and 4.7 months in the Pd arm (hazard ratio=0.54, P=0.0078).

Overall survival data were not mature at last follow-up, but there was a trend favoring EPd over Pd (hazard ratio=0.62).

The researchers said adverse events (AEs) in the EPd arm were consistent with expectations based on previous results with elotuzumab and pomalidomide regimens.

Grade 3-4 nonhematologic AEs (in the EPd and Pd arms, respectively) included constipation (2% and 0%), hyperglycemia (8% and 7%), bone pain (3% and 0%), dyspnea (3% and 2%), fatigue (0% and 4%), respiratory tract infection (0% and 2%), and upper respiratory tract infection (0% and 2%).

Grade 3-4 hematologic AEs (in the EPd and Pd arms, respectively) included anemia (10% and 20%), neutropenia (13% and 27%), thrombocytopenia (8% and 5%), and lymphopenia (8% and 2%).

Grade 3-4 AEs of special interest (in the EPd and Pd arms, respectively) included infections (13% and 22%), vascular disorders (3% and 0%), cardiac disorders (7% and 4%), and neoplasms (2% and 11%).

In the EPd arm, grade 5 AEs included infection (n=3), cardiac failure (n=1), and general physical health deterioration (n=1).

In the Pd arm, grade 5 AEs included malignant neoplasm progression (n=4), infection (n=1), multiple organ failure and infection (n=1), myocardial infarction (n=1), and plasma cell myeloma (n=1).

Bristol-Myers Squibb

The US Food and Drug Administration (FDA) has accepted for priority review a supplemental biologics license application (sBLA) for elotuzumab (Empliciti).

With this sBLA, Bristol-Myers Squibb Company is seeking approval for elotuzumab in combination with pomalidomide and low-dose dexamethasone to treat patients with relapsed/refractory multiple myeloma (MM) who have received at least two prior therapies, including lenalidomide and a proteasome inhibitor.

The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions. The agency intends to take action on a priority review application within 6 months of receiving it rather than the standard 10 months.

The FDA expects to make a decision on the sBLA for elotuzumab by December 27, 2018.

Elotuzumab is already FDA-approved for use in combination with lenalidomide and dexamethasone to treat MM patients who have received one to three prior therapies.

Bristol-Myers Squibb and AbbVie are co-developing elotuzumab, with Bristol-Myers Squibb solely responsible for commercial activities.

Supporting trial

The sBLA for elotuzumab is supported by data from ELOQUENT-3, a randomized, phase 2 study in which researchers evaluated the addition of elotuzumab to pomalidomide and low-dose dexamethasone in patients with relapsed/refractory MM.

Data from this study were presented at the 23rd Congress of the European Hematology Association in June.

The trial randomized 117 MM patients who received two or more prior therapies and were either refractory or relapsed and refractory to lenalidomide and a proteasome inhibitor.

The patients were randomized to receive either elotuzumab, pomalidomide, and low-dose dexamethasone (EPd; n=60) or pomalidomide and low-dose dexamethasone (Pd; n=57) in 28-day cycles until disease progression or unacceptable toxicity.

The overall response rate was 53% in the EPd arm and 26% in the Pd arm (odds ratio=3.25; P=0.0029).

The median progression-free survival was 10.3 months in the EPd arm and 4.7 months in the Pd arm (hazard ratio=0.54, P=0.0078).

Overall survival data were not mature at last follow-up, but there was a trend favoring EPd over Pd (hazard ratio=0.62).

The researchers said adverse events (AEs) in the EPd arm were consistent with expectations based on previous results with elotuzumab and pomalidomide regimens.

Grade 3-4 nonhematologic AEs (in the EPd and Pd arms, respectively) included constipation (2% and 0%), hyperglycemia (8% and 7%), bone pain (3% and 0%), dyspnea (3% and 2%), fatigue (0% and 4%), respiratory tract infection (0% and 2%), and upper respiratory tract infection (0% and 2%).

Grade 3-4 hematologic AEs (in the EPd and Pd arms, respectively) included anemia (10% and 20%), neutropenia (13% and 27%), thrombocytopenia (8% and 5%), and lymphopenia (8% and 2%).

Grade 3-4 AEs of special interest (in the EPd and Pd arms, respectively) included infections (13% and 22%), vascular disorders (3% and 0%), cardiac disorders (7% and 4%), and neoplasms (2% and 11%).

In the EPd arm, grade 5 AEs included infection (n=3), cardiac failure (n=1), and general physical health deterioration (n=1).

In the Pd arm, grade 5 AEs included malignant neoplasm progression (n=4), infection (n=1), multiple organ failure and infection (n=1), myocardial infarction (n=1), and plasma cell myeloma (n=1).

West Virginia University

Venous duplex ultrasounds (VDUs) may be over-utilized in patients suspected of having deep vein thrombosis (DVT), according to research published in Annals of Vascular Surgery.

The retrospective study indicated that D-dimer tests and the pretest Wells criteria probability (WCP) score could safely exclude DVT.

The researchers therefore believe that consistent use of D-dimer and WCP could reduce the number of unnecessary immediate VDUs, cut costs, and save time.

“Usually, waiting for a venous ultrasound would be a matter of three, four, five hours,” said study author Albeir Mousa, MD, of West Virginia University in Charleston, West Virginia.

“With the D-dimer test, it’s a few minutes, and you’re done.”

For this study, Dr. Mousa and his colleagues reviewed data on 1670 patients who presented to a high-volume tertiary care center with suspected DVT and were referred for VDU. Their average age was 62.1, and 55.7% were female.

The researchers calculated WCP scores for all 1670 patients and divided them into DVT risk groups accordingly—low- (<1), moderate- (1-2), and high-risk (≥3).

The team also divided patients according to D-dimer values—low (0.1-0.59), moderate (0.60-1.2), and high (≥1.3 mg/L FEU).

Results

The researchers found that D-dimer (with an abnormal threshold of ≥0.60 mg/L FEU) identified all patients with DVT (n=183, 11%).

The sensitivity and negative predictive values of D-dimer were both 100%, while specificity was 14.9% and the positive predictive value was 15.9%.

When the researchers used an age-adjusted D-dimer threshold (age x 0.01), the specificity increased from 14.9% to 21.3%, and the positive predictive value increased from 15.9% to 17%.

There were no DVTs among patients with low D-dimer values, but the rate of DVT significantly increased in the moderate (5.9%) and high groups (20.0%; P=0.007).

The rate of DVT increased with increasing WCP as well. The DVT rate was 6.6% in the low WCP group, 14% in the moderate group, and 29.1% in the high group (P<0.001).

The researchers also noted an increase in the rate of DVT across all levels of WCP as D-dimer levels increased.

Based on these findings, the researchers said there were 762 patients who were sent for unnecessary immediate VDUs. This included 685 patients in the low WCP group (<1) who did not undergo D-dimer testing, 51 patients who had moderate D-dimer values, and 26 who had low D-dimer values.

The researchers calculated the potential savings of using D-dimer instead of VDU in these patients, based on US 2016 dollar estimates.

A VDU cost of $1557 per person would mean a total cost of $1,186,434 for 762 patients. A D-dimer cost of $182 per person would mean a total cost of $138,684. So the total potential savings would be $1,047,750.

Dr. Mousa also noted that D-dimer testing is quicker than VDU and requires fewer resources.

“It’s a very simple sample of blood, which is sent to the lab,” he said. “And, usually in 15 or 20 minutes, you have significant information that can help you take good care of the patients. And you can send patients home quicker, with less demand on the hospital staff and the institution, yet increase patient satisfaction.”

West Virginia University

Venous duplex ultrasounds (VDUs) may be over-utilized in patients suspected of having deep vein thrombosis (DVT), according to research published in Annals of Vascular Surgery.

The retrospective study indicated that D-dimer tests and the pretest Wells criteria probability (WCP) score could safely exclude DVT.

The researchers therefore believe that consistent use of D-dimer and WCP could reduce the number of unnecessary immediate VDUs, cut costs, and save time.

“Usually, waiting for a venous ultrasound would be a matter of three, four, five hours,” said study author Albeir Mousa, MD, of West Virginia University in Charleston, West Virginia.

“With the D-dimer test, it’s a few minutes, and you’re done.”

For this study, Dr. Mousa and his colleagues reviewed data on 1670 patients who presented to a high-volume tertiary care center with suspected DVT and were referred for VDU. Their average age was 62.1, and 55.7% were female.

The researchers calculated WCP scores for all 1670 patients and divided them into DVT risk groups accordingly—low- (<1), moderate- (1-2), and high-risk (≥3).

The team also divided patients according to D-dimer values—low (0.1-0.59), moderate (0.60-1.2), and high (≥1.3 mg/L FEU).

Results

The researchers found that D-dimer (with an abnormal threshold of ≥0.60 mg/L FEU) identified all patients with DVT (n=183, 11%).

The sensitivity and negative predictive values of D-dimer were both 100%, while specificity was 14.9% and the positive predictive value was 15.9%.

When the researchers used an age-adjusted D-dimer threshold (age x 0.01), the specificity increased from 14.9% to 21.3%, and the positive predictive value increased from 15.9% to 17%.

There were no DVTs among patients with low D-dimer values, but the rate of DVT significantly increased in the moderate (5.9%) and high groups (20.0%; P=0.007).

The rate of DVT increased with increasing WCP as well. The DVT rate was 6.6% in the low WCP group, 14% in the moderate group, and 29.1% in the high group (P<0.001).

The researchers also noted an increase in the rate of DVT across all levels of WCP as D-dimer levels increased.

Based on these findings, the researchers said there were 762 patients who were sent for unnecessary immediate VDUs. This included 685 patients in the low WCP group (<1) who did not undergo D-dimer testing, 51 patients who had moderate D-dimer values, and 26 who had low D-dimer values.

The researchers calculated the potential savings of using D-dimer instead of VDU in these patients, based on US 2016 dollar estimates.

A VDU cost of $1557 per person would mean a total cost of $1,186,434 for 762 patients. A D-dimer cost of $182 per person would mean a total cost of $138,684. So the total potential savings would be $1,047,750.

Dr. Mousa also noted that D-dimer testing is quicker than VDU and requires fewer resources.

“It’s a very simple sample of blood, which is sent to the lab,” he said. “And, usually in 15 or 20 minutes, you have significant information that can help you take good care of the patients. And you can send patients home quicker, with less demand on the hospital staff and the institution, yet increase patient satisfaction.”

West Virginia University

Venous duplex ultrasounds (VDUs) may be over-utilized in patients suspected of having deep vein thrombosis (DVT), according to research published in Annals of Vascular Surgery.

The retrospective study indicated that D-dimer tests and the pretest Wells criteria probability (WCP) score could safely exclude DVT.

The researchers therefore believe that consistent use of D-dimer and WCP could reduce the number of unnecessary immediate VDUs, cut costs, and save time.

“Usually, waiting for a venous ultrasound would be a matter of three, four, five hours,” said study author Albeir Mousa, MD, of West Virginia University in Charleston, West Virginia.

“With the D-dimer test, it’s a few minutes, and you’re done.”

For this study, Dr. Mousa and his colleagues reviewed data on 1670 patients who presented to a high-volume tertiary care center with suspected DVT and were referred for VDU. Their average age was 62.1, and 55.7% were female.

The researchers calculated WCP scores for all 1670 patients and divided them into DVT risk groups accordingly—low- (<1), moderate- (1-2), and high-risk (≥3).

The team also divided patients according to D-dimer values—low (0.1-0.59), moderate (0.60-1.2), and high (≥1.3 mg/L FEU).

Results

The researchers found that D-dimer (with an abnormal threshold of ≥0.60 mg/L FEU) identified all patients with DVT (n=183, 11%).

The sensitivity and negative predictive values of D-dimer were both 100%, while specificity was 14.9% and the positive predictive value was 15.9%.

When the researchers used an age-adjusted D-dimer threshold (age x 0.01), the specificity increased from 14.9% to 21.3%, and the positive predictive value increased from 15.9% to 17%.

There were no DVTs among patients with low D-dimer values, but the rate of DVT significantly increased in the moderate (5.9%) and high groups (20.0%; P=0.007).

The rate of DVT increased with increasing WCP as well. The DVT rate was 6.6% in the low WCP group, 14% in the moderate group, and 29.1% in the high group (P<0.001).

The researchers also noted an increase in the rate of DVT across all levels of WCP as D-dimer levels increased.

Based on these findings, the researchers said there were 762 patients who were sent for unnecessary immediate VDUs. This included 685 patients in the low WCP group (<1) who did not undergo D-dimer testing, 51 patients who had moderate D-dimer values, and 26 who had low D-dimer values.

The researchers calculated the potential savings of using D-dimer instead of VDU in these patients, based on US 2016 dollar estimates.

A VDU cost of $1557 per person would mean a total cost of $1,186,434 for 762 patients. A D-dimer cost of $182 per person would mean a total cost of $138,684. So the total potential savings would be $1,047,750.

Dr. Mousa also noted that D-dimer testing is quicker than VDU and requires fewer resources.

“It’s a very simple sample of blood, which is sent to the lab,” he said. “And, usually in 15 or 20 minutes, you have significant information that can help you take good care of the patients. And you can send patients home quicker, with less demand on the hospital staff and the institution, yet increase patient satisfaction.”

Photo by Elise Amendola

BOSTON—New research suggests enzymes from the human gut can turn type A blood into type O more efficiently than previously studied enzymes.

Researchers found this new family of enzymes—whose name has not been made public—can remove the A antigens from red blood cells (RBCs), thereby converting type A blood to O.

Stephen Withers, PhD, of the University of British Columbia in Vancouver, Canada, presented details on the enzymes at the 256th National Meeting & Exposition of the American Chemical Society (abstract CARB105).

A metagenomics approach

Dr. Withers said researchers have been studying the use of enzymes to modify blood as far back as 1982. However, it has been difficult to identify efficient, selective enzymes that are also safe and economical.

To assess potential enzyme candidates quickly, Dr. Withers and his colleagues used metagenomics.

“With metagenomics, you take all of the organisms from an environment and extract the sum total DNA of those organisms all mixed up together,” Dr. Withers explained.

Casting such a wide net allowed the researchers to sample the genes of millions of microorganisms without the need for individual cultures. The researchers then used E. coli to select for genes that code for enzymes that can cleave sugar residues.

“This is a way of getting that genetic information out of the environment and into the laboratory setting and then screening for the activity we are interested in,” Dr. Withers said.

Focusing on the gut

Dr. Withers and his colleagues had considered sampling DNA from mosquitoes and leeches, the types of organisms that degrade blood, but the researchers ultimately found successful candidate enzymes in the human gut microbiome.

Glycosylated proteins called mucins line the gut wall, providing sugars that serve as attachment points for gut bacteria while also feeding them as they assist in digestion. Some of the mucin sugars are similar in structure to the antigens on RBCs in type A and B blood.

Dr. Withers and his colleagues studied the enzymes the bacteria use to pluck the sugars off mucin and identified a family of enzymes that could convert type A blood to type O.

The name of this enzyme family has not been released to the public, as the patent for the enzymes has not been submitted.

“By homing in on the bacteria feeding on those sugars, we isolated the enzymes the bacteria use to pluck off the sugar molecules,” Dr. Withers explained. “We then produced quantities of those enzymes through cloning and found that they were capable of performing a similar action on blood antigens.”

The enzymes could convert type A blood to type O by removing N-Acetyl galactosamine from the surface of RBCs.

In fact, the new enzymes were 30 times more effective for converting A to O than the alpha-N-acetylgalactosaminidase from Elizabethkingia meningospeticum that was described in a 2007 Nature Biotechnology paper.

Dr. Withers said he and his colleagues needed to use 30 times less of the new enzymes. This means the new enzymes are more economical, and it is easier to remove all traces of the added enzymes, which would need to be done before transfusion.

Looking ahead

Dr. Withers noted that the new enzymes work in whole blood. So if they prove safe for use in humans, the enzymes could potentially be introduced to whole blood donations and left to make the conversion from A to O. Then, the enzymes could be removed by washing RBCs before transfusion.

Dr. Withers and his colleagues are now working to validate these enzymes and test them on a larger scale for potential clinical testing. He also plans to carry out directed evolution, a protein engineering technique that simulates natural evolution, with the goal of creating the most efficient sugar-removing enzyme.

“I am optimistic that we have a very interesting candidate to adjust donated blood to a common type,” Dr. Withers said. “Of course, it will have to go through lots of clinical trials to make sure that it doesn’t have any adverse consequences, but it is looking very promising.”

The researchers acknowledged support and funding from the Canadian Institutes of Health Research.

Photo by Elise Amendola

BOSTON—New research suggests enzymes from the human gut can turn type A blood into type O more efficiently than previously studied enzymes.

Researchers found this new family of enzymes—whose name has not been made public—can remove the A antigens from red blood cells (RBCs), thereby converting type A blood to O.

Stephen Withers, PhD, of the University of British Columbia in Vancouver, Canada, presented details on the enzymes at the 256th National Meeting & Exposition of the American Chemical Society (abstract CARB105).

A metagenomics approach

Dr. Withers said researchers have been studying the use of enzymes to modify blood as far back as 1982. However, it has been difficult to identify efficient, selective enzymes that are also safe and economical.

To assess potential enzyme candidates quickly, Dr. Withers and his colleagues used metagenomics.

“With metagenomics, you take all of the organisms from an environment and extract the sum total DNA of those organisms all mixed up together,” Dr. Withers explained.

Casting such a wide net allowed the researchers to sample the genes of millions of microorganisms without the need for individual cultures. The researchers then used E. coli to select for genes that code for enzymes that can cleave sugar residues.

“This is a way of getting that genetic information out of the environment and into the laboratory setting and then screening for the activity we are interested in,” Dr. Withers said.

Focusing on the gut

Dr. Withers and his colleagues had considered sampling DNA from mosquitoes and leeches, the types of organisms that degrade blood, but the researchers ultimately found successful candidate enzymes in the human gut microbiome.

Glycosylated proteins called mucins line the gut wall, providing sugars that serve as attachment points for gut bacteria while also feeding them as they assist in digestion. Some of the mucin sugars are similar in structure to the antigens on RBCs in type A and B blood.

Dr. Withers and his colleagues studied the enzymes the bacteria use to pluck the sugars off mucin and identified a family of enzymes that could convert type A blood to type O.

The name of this enzyme family has not been released to the public, as the patent for the enzymes has not been submitted.

“By homing in on the bacteria feeding on those sugars, we isolated the enzymes the bacteria use to pluck off the sugar molecules,” Dr. Withers explained. “We then produced quantities of those enzymes through cloning and found that they were capable of performing a similar action on blood antigens.”

The enzymes could convert type A blood to type O by removing N-Acetyl galactosamine from the surface of RBCs.

In fact, the new enzymes were 30 times more effective for converting A to O than the alpha-N-acetylgalactosaminidase from Elizabethkingia meningospeticum that was described in a 2007 Nature Biotechnology paper.

Dr. Withers said he and his colleagues needed to use 30 times less of the new enzymes. This means the new enzymes are more economical, and it is easier to remove all traces of the added enzymes, which would need to be done before transfusion.

Looking ahead

Dr. Withers noted that the new enzymes work in whole blood. So if they prove safe for use in humans, the enzymes could potentially be introduced to whole blood donations and left to make the conversion from A to O. Then, the enzymes could be removed by washing RBCs before transfusion.

Dr. Withers and his colleagues are now working to validate these enzymes and test them on a larger scale for potential clinical testing. He also plans to carry out directed evolution, a protein engineering technique that simulates natural evolution, with the goal of creating the most efficient sugar-removing enzyme.

“I am optimistic that we have a very interesting candidate to adjust donated blood to a common type,” Dr. Withers said. “Of course, it will have to go through lots of clinical trials to make sure that it doesn’t have any adverse consequences, but it is looking very promising.”

The researchers acknowledged support and funding from the Canadian Institutes of Health Research.

Photo by Elise Amendola

BOSTON—New research suggests enzymes from the human gut can turn type A blood into type O more efficiently than previously studied enzymes.

Researchers found this new family of enzymes—whose name has not been made public—can remove the A antigens from red blood cells (RBCs), thereby converting type A blood to O.

Stephen Withers, PhD, of the University of British Columbia in Vancouver, Canada, presented details on the enzymes at the 256th National Meeting & Exposition of the American Chemical Society (abstract CARB105).

A metagenomics approach

Dr. Withers said researchers have been studying the use of enzymes to modify blood as far back as 1982. However, it has been difficult to identify efficient, selective enzymes that are also safe and economical.

To assess potential enzyme candidates quickly, Dr. Withers and his colleagues used metagenomics.

“With metagenomics, you take all of the organisms from an environment and extract the sum total DNA of those organisms all mixed up together,” Dr. Withers explained.

Casting such a wide net allowed the researchers to sample the genes of millions of microorganisms without the need for individual cultures. The researchers then used E. coli to select for genes that code for enzymes that can cleave sugar residues.

“This is a way of getting that genetic information out of the environment and into the laboratory setting and then screening for the activity we are interested in,” Dr. Withers said.

Focusing on the gut

Dr. Withers and his colleagues had considered sampling DNA from mosquitoes and leeches, the types of organisms that degrade blood, but the researchers ultimately found successful candidate enzymes in the human gut microbiome.

Glycosylated proteins called mucins line the gut wall, providing sugars that serve as attachment points for gut bacteria while also feeding them as they assist in digestion. Some of the mucin sugars are similar in structure to the antigens on RBCs in type A and B blood.

Dr. Withers and his colleagues studied the enzymes the bacteria use to pluck the sugars off mucin and identified a family of enzymes that could convert type A blood to type O.

The name of this enzyme family has not been released to the public, as the patent for the enzymes has not been submitted.

“By homing in on the bacteria feeding on those sugars, we isolated the enzymes the bacteria use to pluck off the sugar molecules,” Dr. Withers explained. “We then produced quantities of those enzymes through cloning and found that they were capable of performing a similar action on blood antigens.”

The enzymes could convert type A blood to type O by removing N-Acetyl galactosamine from the surface of RBCs.

In fact, the new enzymes were 30 times more effective for converting A to O than the alpha-N-acetylgalactosaminidase from Elizabethkingia meningospeticum that was described in a 2007 Nature Biotechnology paper.

Dr. Withers said he and his colleagues needed to use 30 times less of the new enzymes. This means the new enzymes are more economical, and it is easier to remove all traces of the added enzymes, which would need to be done before transfusion.

Looking ahead

Dr. Withers noted that the new enzymes work in whole blood. So if they prove safe for use in humans, the enzymes could potentially be introduced to whole blood donations and left to make the conversion from A to O. Then, the enzymes could be removed by washing RBCs before transfusion.

Dr. Withers and his colleagues are now working to validate these enzymes and test them on a larger scale for potential clinical testing. He also plans to carry out directed evolution, a protein engineering technique that simulates natural evolution, with the goal of creating the most efficient sugar-removing enzyme.

“I am optimistic that we have a very interesting candidate to adjust donated blood to a common type,” Dr. Withers said. “Of course, it will have to go through lots of clinical trials to make sure that it doesn’t have any adverse consequences, but it is looking very promising.”

The researchers acknowledged support and funding from the Canadian Institutes of Health Research.

Image courtesy of AFIP

A new report addresses the clinical relevance of DNA variants in chronic myeloid neoplasms (CMNs).

The report is intended to aid clinical laboratory professionals with the management of most CMNs and the development of high-throughput pan-myeloid sequencing testing panels.

The authors list 34 genes they consider “critical” for sequencing tests to help standardize clinical practice and improve care of patients with CMNs.

The Association for Molecular Pathology (AMP) established a CMN Working Group to generate the report, which was published in The Journal of Molecular Diagnostics.

“The molecular pathology community has witnessed a recent explosion of scientific literature highlighting the clinical significance of small DNA variants in CMNs,” said Rebecca F. McClure, MD, a member of the AMP CMN Working Group and an associate professor at Health Sciences North/Horizon Santé-Nord in Sudbury, Ontario, Canada.

“AMP’s working group recognized a clear, unmet need for evidence-based recommendations to assist in the development of the high-quality pan-myeloid gene panels that provide relevant diagnostic and prognostic information and enable monitoring of clonal architecture.”

The increasing availability of targeted, high-throughput, next-generation sequencing panels has enabled scientists to explore the genetic heterogeneity and clinical relevance of the small DNA variants in CMNs.

However, the biological complexity and multiple forms of CMNs have led to variability in the genes included on the available panels that are used to make an accurate diagnosis, provide reliable prognostic information, and select an appropriate therapy based on DNA variant profiles present at various time points.

AMP established its CMN Working Group to review the published literature on CMNs, summarize key findings that support clinical utility, and define a set of critical gene inclusions for all high-throughput pan-myeloid sequencing testing panels.

The group proposed the following 34 genes as a minimum recommended testing list: ASXL1, BCOR, BCORL1, CALR, CBL, CEBPA, CSF3R, DNMT3A, ETV6, EZH2, FLT3, IDH1, IDH2, JAK2, KIT, KRAS, MPL, NF1, NPM1, NRAS, PHF6, PPM1D, PTPN11, RAD21, RUNX1, SETBP1, SF3B1, SMC3, SRSF2, STAG2, TET2, TP53, U2AF1, and ZRSR2.

“While the goal of the study was to distill the literature for molecular pathologists, in doing so, we also revealed recurrent mutational patterns of clonal evolution that will [help] hematologist/oncologists, researchers, and pathologists understand how to interpret the results of these panels as they reveal critical biology of the neoplasms,” said Annette S. Kim, MD, PhD, CMN Working Group Chair and an associate professor at Harvard Medical School and Brigham and Women’s Hospital in Boston, Massachusetts.

Image courtesy of AFIP

A new report addresses the clinical relevance of DNA variants in chronic myeloid neoplasms (CMNs).

The report is intended to aid clinical laboratory professionals with the management of most CMNs and the development of high-throughput pan-myeloid sequencing testing panels.

The authors list 34 genes they consider “critical” for sequencing tests to help standardize clinical practice and improve care of patients with CMNs.

The Association for Molecular Pathology (AMP) established a CMN Working Group to generate the report, which was published in The Journal of Molecular Diagnostics.

“The molecular pathology community has witnessed a recent explosion of scientific literature highlighting the clinical significance of small DNA variants in CMNs,” said Rebecca F. McClure, MD, a member of the AMP CMN Working Group and an associate professor at Health Sciences North/Horizon Santé-Nord in Sudbury, Ontario, Canada.

“AMP’s working group recognized a clear, unmet need for evidence-based recommendations to assist in the development of the high-quality pan-myeloid gene panels that provide relevant diagnostic and prognostic information and enable monitoring of clonal architecture.”

The increasing availability of targeted, high-throughput, next-generation sequencing panels has enabled scientists to explore the genetic heterogeneity and clinical relevance of the small DNA variants in CMNs.

However, the biological complexity and multiple forms of CMNs have led to variability in the genes included on the available panels that are used to make an accurate diagnosis, provide reliable prognostic information, and select an appropriate therapy based on DNA variant profiles present at various time points.

AMP established its CMN Working Group to review the published literature on CMNs, summarize key findings that support clinical utility, and define a set of critical gene inclusions for all high-throughput pan-myeloid sequencing testing panels.

The group proposed the following 34 genes as a minimum recommended testing list: ASXL1, BCOR, BCORL1, CALR, CBL, CEBPA, CSF3R, DNMT3A, ETV6, EZH2, FLT3, IDH1, IDH2, JAK2, KIT, KRAS, MPL, NF1, NPM1, NRAS, PHF6, PPM1D, PTPN11, RAD21, RUNX1, SETBP1, SF3B1, SMC3, SRSF2, STAG2, TET2, TP53, U2AF1, and ZRSR2.

“While the goal of the study was to distill the literature for molecular pathologists, in doing so, we also revealed recurrent mutational patterns of clonal evolution that will [help] hematologist/oncologists, researchers, and pathologists understand how to interpret the results of these panels as they reveal critical biology of the neoplasms,” said Annette S. Kim, MD, PhD, CMN Working Group Chair and an associate professor at Harvard Medical School and Brigham and Women’s Hospital in Boston, Massachusetts.

Image courtesy of AFIP

A new report addresses the clinical relevance of DNA variants in chronic myeloid neoplasms (CMNs).

The report is intended to aid clinical laboratory professionals with the management of most CMNs and the development of high-throughput pan-myeloid sequencing testing panels.

The authors list 34 genes they consider “critical” for sequencing tests to help standardize clinical practice and improve care of patients with CMNs.

The Association for Molecular Pathology (AMP) established a CMN Working Group to generate the report, which was published in The Journal of Molecular Diagnostics.

“The molecular pathology community has witnessed a recent explosion of scientific literature highlighting the clinical significance of small DNA variants in CMNs,” said Rebecca F. McClure, MD, a member of the AMP CMN Working Group and an associate professor at Health Sciences North/Horizon Santé-Nord in Sudbury, Ontario, Canada.

“AMP’s working group recognized a clear, unmet need for evidence-based recommendations to assist in the development of the high-quality pan-myeloid gene panels that provide relevant diagnostic and prognostic information and enable monitoring of clonal architecture.”

The increasing availability of targeted, high-throughput, next-generation sequencing panels has enabled scientists to explore the genetic heterogeneity and clinical relevance of the small DNA variants in CMNs.

However, the biological complexity and multiple forms of CMNs have led to variability in the genes included on the available panels that are used to make an accurate diagnosis, provide reliable prognostic information, and select an appropriate therapy based on DNA variant profiles present at various time points.

AMP established its CMN Working Group to review the published literature on CMNs, summarize key findings that support clinical utility, and define a set of critical gene inclusions for all high-throughput pan-myeloid sequencing testing panels.

The group proposed the following 34 genes as a minimum recommended testing list: ASXL1, BCOR, BCORL1, CALR, CBL, CEBPA, CSF3R, DNMT3A, ETV6, EZH2, FLT3, IDH1, IDH2, JAK2, KIT, KRAS, MPL, NF1, NPM1, NRAS, PHF6, PPM1D, PTPN11, RAD21, RUNX1, SETBP1, SF3B1, SMC3, SRSF2, STAG2, TET2, TP53, U2AF1, and ZRSR2.

“While the goal of the study was to distill the literature for molecular pathologists, in doing so, we also revealed recurrent mutational patterns of clonal evolution that will [help] hematologist/oncologists, researchers, and pathologists understand how to interpret the results of these panels as they reveal critical biology of the neoplasms,” said Annette S. Kim, MD, PhD, CMN Working Group Chair and an associate professor at Harvard Medical School and Brigham and Women’s Hospital in Boston, Massachusetts.

Photo by Daniel Sone

Investigators found that chimeric antigen receptor (CAR) T cells with stronger signaling capabilities were less effective against lymphoma cells in a mouse model.

Intracellular signaling strength was a key determinant of T-cell fate in the study, which was published in Science Signaling.

By contrast, CAR signaling pathways could not be predicted solely by the costimulatory domains used to construct the receptor, investigators said.

These findings suggest tailoring CAR design based on signal strength might improve the efficacy and reduce the toxicity of CAR T-cell therapy, according to Alexander Salter, an MD/PhD student at Fred Hutchinson Cancer Research Center in Seattle, Wash.

For this study, Salter and his colleagues used mass spectrometry to evaluate CARs encoding CD28 or 4-1BB costimulatory domains in primary human T cells.

While CARs with CD28 domains elicited more robust intracellular signaling than those with 4-1BB domains, there was considerable overlap in activation of T-cell signaling pathways, Salter said.

That overlap was somewhat surprising, according to Salter, since researchers have generally assumed that CARs with CD28 and 4-1BB costimulatory domains will primarily signal through those respective pathways.

“No matter what costimulatory domain was encoded by the receptor, both CARs… activated both CD28 and 41BB signaling pathways,” Salter said.

The major determinant of efficacy in the study turned out to be not the domain used to construct the receptor but the speed and strength of signaling, he added.

In particular, the CARs that evoked stronger signals also had increased T-cell dysfunction, decreasing their potency in the mouse model of lymphoma.

The T cells with a CD28 CAR had very strong initial antitumor function that quickly waned in the mouse model.

By contrast, the “slower burning” 4-1BB CAR signal led to T cells that better retained their function in vivo and were associated with longer median survival in the model, Salter said.

These findings suggest tailoring CAR design based on signal strength may improve clinical efficacy and reduce toxicity.

As part of the study, Salter and his co-investigators were able to modify the CAR CD28 domain to make the signaling of the CD28 CARs less intense.

“This is a modification that we think should be considered in future CAR design,” Salter said.

While the alterations in the CD28 signaling domain were able to reduce levels of cytokines produced by T cells, the study was primarily designed to look at efficacy, noted Stanley Riddell, MD, of Fred Hutchinson Cancer Research Center.

“Our models were not set up to address the question of toxicity, so we can’t directly say this would translate to what we would see in patients,” Dr. Riddell said.

“But I think we gleaned a lot of insights as to why cytokines are produced at greater or lesser levels with various CAR designs, and insights as to how to redesign these receptors to lower the levels of cytokines they make without compromising their ability to kill.”

Dr. Riddell is a founder, shareholder, and scientific advisor of Juno Therapeutics. He and Salter have filed a patent application on the use of mutant CD28 CARs for cellular therapy. Co-author Raphael Gottardo, PhD, also with Fred Hutchinson Cancer Research Center, is a consultant for Juno Therapeutics. No other competing interests were reported.

Photo by Daniel Sone

Investigators found that chimeric antigen receptor (CAR) T cells with stronger signaling capabilities were less effective against lymphoma cells in a mouse model.

Intracellular signaling strength was a key determinant of T-cell fate in the study, which was published in Science Signaling.

By contrast, CAR signaling pathways could not be predicted solely by the costimulatory domains used to construct the receptor, investigators said.

These findings suggest tailoring CAR design based on signal strength might improve the efficacy and reduce the toxicity of CAR T-cell therapy, according to Alexander Salter, an MD/PhD student at Fred Hutchinson Cancer Research Center in Seattle, Wash.

For this study, Salter and his colleagues used mass spectrometry to evaluate CARs encoding CD28 or 4-1BB costimulatory domains in primary human T cells.

While CARs with CD28 domains elicited more robust intracellular signaling than those with 4-1BB domains, there was considerable overlap in activation of T-cell signaling pathways, Salter said.

That overlap was somewhat surprising, according to Salter, since researchers have generally assumed that CARs with CD28 and 4-1BB costimulatory domains will primarily signal through those respective pathways.

“No matter what costimulatory domain was encoded by the receptor, both CARs… activated both CD28 and 41BB signaling pathways,” Salter said.

The major determinant of efficacy in the study turned out to be not the domain used to construct the receptor but the speed and strength of signaling, he added.

In particular, the CARs that evoked stronger signals also had increased T-cell dysfunction, decreasing their potency in the mouse model of lymphoma.

The T cells with a CD28 CAR had very strong initial antitumor function that quickly waned in the mouse model.

By contrast, the “slower burning” 4-1BB CAR signal led to T cells that better retained their function in vivo and were associated with longer median survival in the model, Salter said.

These findings suggest tailoring CAR design based on signal strength may improve clinical efficacy and reduce toxicity.

As part of the study, Salter and his co-investigators were able to modify the CAR CD28 domain to make the signaling of the CD28 CARs less intense.

“This is a modification that we think should be considered in future CAR design,” Salter said.

While the alterations in the CD28 signaling domain were able to reduce levels of cytokines produced by T cells, the study was primarily designed to look at efficacy, noted Stanley Riddell, MD, of Fred Hutchinson Cancer Research Center.

“Our models were not set up to address the question of toxicity, so we can’t directly say this would translate to what we would see in patients,” Dr. Riddell said.

“But I think we gleaned a lot of insights as to why cytokines are produced at greater or lesser levels with various CAR designs, and insights as to how to redesign these receptors to lower the levels of cytokines they make without compromising their ability to kill.”

Dr. Riddell is a founder, shareholder, and scientific advisor of Juno Therapeutics. He and Salter have filed a patent application on the use of mutant CD28 CARs for cellular therapy. Co-author Raphael Gottardo, PhD, also with Fred Hutchinson Cancer Research Center, is a consultant for Juno Therapeutics. No other competing interests were reported.

Photo by Daniel Sone

Investigators found that chimeric antigen receptor (CAR) T cells with stronger signaling capabilities were less effective against lymphoma cells in a mouse model.

Intracellular signaling strength was a key determinant of T-cell fate in the study, which was published in Science Signaling.

By contrast, CAR signaling pathways could not be predicted solely by the costimulatory domains used to construct the receptor, investigators said.

These findings suggest tailoring CAR design based on signal strength might improve the efficacy and reduce the toxicity of CAR T-cell therapy, according to Alexander Salter, an MD/PhD student at Fred Hutchinson Cancer Research Center in Seattle, Wash.

For this study, Salter and his colleagues used mass spectrometry to evaluate CARs encoding CD28 or 4-1BB costimulatory domains in primary human T cells.

While CARs with CD28 domains elicited more robust intracellular signaling than those with 4-1BB domains, there was considerable overlap in activation of T-cell signaling pathways, Salter said.

That overlap was somewhat surprising, according to Salter, since researchers have generally assumed that CARs with CD28 and 4-1BB costimulatory domains will primarily signal through those respective pathways.

“No matter what costimulatory domain was encoded by the receptor, both CARs… activated both CD28 and 41BB signaling pathways,” Salter said.

The major determinant of efficacy in the study turned out to be not the domain used to construct the receptor but the speed and strength of signaling, he added.

In particular, the CARs that evoked stronger signals also had increased T-cell dysfunction, decreasing their potency in the mouse model of lymphoma.

The T cells with a CD28 CAR had very strong initial antitumor function that quickly waned in the mouse model.

By contrast, the “slower burning” 4-1BB CAR signal led to T cells that better retained their function in vivo and were associated with longer median survival in the model, Salter said.

These findings suggest tailoring CAR design based on signal strength may improve clinical efficacy and reduce toxicity.

As part of the study, Salter and his co-investigators were able to modify the CAR CD28 domain to make the signaling of the CD28 CARs less intense.

“This is a modification that we think should be considered in future CAR design,” Salter said.

While the alterations in the CD28 signaling domain were able to reduce levels of cytokines produced by T cells, the study was primarily designed to look at efficacy, noted Stanley Riddell, MD, of Fred Hutchinson Cancer Research Center.

“Our models were not set up to address the question of toxicity, so we can’t directly say this would translate to what we would see in patients,” Dr. Riddell said.

“But I think we gleaned a lot of insights as to why cytokines are produced at greater or lesser levels with various CAR designs, and insights as to how to redesign these receptors to lower the levels of cytokines they make without compromising their ability to kill.”

Dr. Riddell is a founder, shareholder, and scientific advisor of Juno Therapeutics. He and Salter have filed a patent application on the use of mutant CD28 CARs for cellular therapy. Co-author Raphael Gottardo, PhD, also with Fred Hutchinson Cancer Research Center, is a consultant for Juno Therapeutics. No other competing interests were reported.

Red blood cells

The US Food and Drug Administration (FDA) has accepted for priority review the biologics license application (BLA) for ALXN1210, a long-acting C5 complement inhibitor.

With this BLA, Alexion Pharmaceuticals, Inc., is seeking approval for ALXN1210 for the treatment of patients with paroxysmal nocturnal hemoglobinuria (PNH).

The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.

The agency intends to take action on a priority review application within 6 months of receiving it rather than the standard 10 months.

The FDA expects to make a decision on the BLA for ALXN1210 by February 18, 2019.

The application is supported by data from a pair of phase 3 trials—PNH-301 and the Switch trial. Alexion released topline results from the PNH-301 trial in March and the Switch trial in April.

PNH-301 trial

This study enrolled 246 adults (age 18+) with PNH who were naïve to treatment with a complement inhibitor. Patients received ALXN1210 (n=125) or eculizumab (n=121).

Patients in the ALXN1210 arm received a single loading dose of ALXN1210, followed by regular maintenance weight-based dosing every 8 weeks. Patients in the eculizumab arm received 4 weekly induction doses, followed by regular maintenance dosing every 2 weeks.

Both arms were treated for 26 weeks. All patients enrolled in an extension study of up to 2 years, during which they will receive ALXN1210 every 8 weeks.

The study’s co-primary endpoints are:

• Transfusion avoidance, which was defined as the proportion of patients who remain transfusion-free and do not require a transfusion per protocol-specified guidelines through day 183
• Normalization of lactate dehydrogenase (LDH) levels as directly measured every 2 weeks by LDH levels ≤ 1 times the upper limit of normal from day 29 through day 183.

ALXN1210 proved non-inferior to eculizumab for both primary endpoints. Specifically, 73.6% of patients in the ALXN1210 arm and 66.1% in the eculizumab arm were able to avoid transfusion. LDH normalization occurred in 53.6% and 49.4%, respectively.

ALXN1210 also demonstrated non-inferiority to eculizumab on all 4 key secondary endpoints:

• Percentage change from baseline in LDH levels (-76.8% and -76.0%, respectively)
• Change from baseline in quality of life as assessed by the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scale (7.1 and 6.4, respectively)
• Proportion of patients with breakthrough hemolysis (4.0% and 10.7%, respectively)
• Proportion of patients with stabilized hemoglobin levels (68.0% and 64.5%, respectively).

Alexion said there were no notable differences in the safety profiles for ALXN1210 and eculizumab. The most frequently observed adverse event (AE) was headache, and the most frequently observed serious AE was pyrexia.

One anti-drug antibody (ADA) was observed in the ALXN1210 arm and 1 in the eculizumab arm. There were no neutralizing antibodies detected and no cases of meningococcal infection.

Switch study

This study is a comparison of ALXN1210 and eculizumab in 195 adults (18+). At baseline, patients had a confirmed diagnosis of PNH, had LDH levels ≤ 1.5 times the upper limit of normal, and had been treated with eculizumab for at least the past 6 months.

ALXN1210 was administered every 8 weeks, and eculizumab was administered every 2 weeks. The 26-week treatment period is followed by an extension period, in which all patients will receive ALXN1210 every 8 weeks for up to 2 years.

Alexion did not provide any efficacy data in its announcement of results. However, the company said ALXN1210 proved non-inferior to eculizumab based on the primary endpoint of change in LDH levels.

Alexion also said ALXN1210 demonstrated non-inferiority on all 4 key secondary endpoints:

• The proportion of patients with breakthrough hemolysis
• The change from baseline in quality of life as assessed via the FACIT-Fatigue Scale
• The proportion of patients avoiding transfusion
• The proportion of patients with stabilized hemoglobin levels.

ALXN1210 had a safety profile that is consistent with that seen for eculizumab, according to Alexion. The most frequently observed AEs were headache and upper respiratory infection. The most frequently observed serious AEs were pyrexia and hemolysis.

There were no treatment-emergent ADAs in the ALXN1210 arm, but one patient in the eculizumab arm did have ADAs. There were no neutralizing antibodies and no cases of meningococcal infection in either arm.

Red blood cells

The US Food and Drug Administration (FDA) has accepted for priority review the biologics license application (BLA) for ALXN1210, a long-acting C5 complement inhibitor.

With this BLA, Alexion Pharmaceuticals, Inc., is seeking approval for ALXN1210 for the treatment of patients with paroxysmal nocturnal hemoglobinuria (PNH).

The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.

The agency intends to take action on a priority review application within 6 months of receiving it rather than the standard 10 months.

The FDA expects to make a decision on the BLA for ALXN1210 by February 18, 2019.

The application is supported by data from a pair of phase 3 trials—PNH-301 and the Switch trial. Alexion released topline results from the PNH-301 trial in March and the Switch trial in April.

PNH-301 trial

This study enrolled 246 adults (age 18+) with PNH who were naïve to treatment with a complement inhibitor. Patients received ALXN1210 (n=125) or eculizumab (n=121).

Patients in the ALXN1210 arm received a single loading dose of ALXN1210, followed by regular maintenance weight-based dosing every 8 weeks. Patients in the eculizumab arm received 4 weekly induction doses, followed by regular maintenance dosing every 2 weeks.

Both arms were treated for 26 weeks. All patients enrolled in an extension study of up to 2 years, during which they will receive ALXN1210 every 8 weeks.

The study’s co-primary endpoints are:

• Transfusion avoidance, which was defined as the proportion of patients who remain transfusion-free and do not require a transfusion per protocol-specified guidelines through day 183
• Normalization of lactate dehydrogenase (LDH) levels as directly measured every 2 weeks by LDH levels ≤ 1 times the upper limit of normal from day 29 through day 183.

ALXN1210 proved non-inferior to eculizumab for both primary endpoints. Specifically, 73.6% of patients in the ALXN1210 arm and 66.1% in the eculizumab arm were able to avoid transfusion. LDH normalization occurred in 53.6% and 49.4%, respectively.

ALXN1210 also demonstrated non-inferiority to eculizumab on all 4 key secondary endpoints:

• Percentage change from baseline in LDH levels (-76.8% and -76.0%, respectively)
• Change from baseline in quality of life as assessed by the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scale (7.1 and 6.4, respectively)
• Proportion of patients with breakthrough hemolysis (4.0% and 10.7%, respectively)
• Proportion of patients with stabilized hemoglobin levels (68.0% and 64.5%, respectively).

Alexion said there were no notable differences in the safety profiles for ALXN1210 and eculizumab. The most frequently observed adverse event (AE) was headache, and the most frequently observed serious AE was pyrexia.

One anti-drug antibody (ADA) was observed in the ALXN1210 arm and 1 in the eculizumab arm. There were no neutralizing antibodies detected and no cases of meningococcal infection.

Switch study

This study is a comparison of ALXN1210 and eculizumab in 195 adults (18+). At baseline, patients had a confirmed diagnosis of PNH, had LDH levels ≤ 1.5 times the upper limit of normal, and had been treated with eculizumab for at least the past 6 months.

ALXN1210 was administered every 8 weeks, and eculizumab was administered every 2 weeks. The 26-week treatment period is followed by an extension period, in which all patients will receive ALXN1210 every 8 weeks for up to 2 years.

Alexion did not provide any efficacy data in its announcement of results. However, the company said ALXN1210 proved non-inferior to eculizumab based on the primary endpoint of change in LDH levels.

Alexion also said ALXN1210 demonstrated non-inferiority on all 4 key secondary endpoints:

• The proportion of patients with breakthrough hemolysis
• The change from baseline in quality of life as assessed via the FACIT-Fatigue Scale
• The proportion of patients avoiding transfusion
• The proportion of patients with stabilized hemoglobin levels.

ALXN1210 had a safety profile that is consistent with that seen for eculizumab, according to Alexion. The most frequently observed AEs were headache and upper respiratory infection. The most frequently observed serious AEs were pyrexia and hemolysis.

There were no treatment-emergent ADAs in the ALXN1210 arm, but one patient in the eculizumab arm did have ADAs. There were no neutralizing antibodies and no cases of meningococcal infection in either arm.

Red blood cells

The US Food and Drug Administration (FDA) has accepted for priority review the biologics license application (BLA) for ALXN1210, a long-acting C5 complement inhibitor.

With this BLA, Alexion Pharmaceuticals, Inc., is seeking approval for ALXN1210 for the treatment of patients with paroxysmal nocturnal hemoglobinuria (PNH).

The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.

The agency intends to take action on a priority review application within 6 months of receiving it rather than the standard 10 months.

The FDA expects to make a decision on the BLA for ALXN1210 by February 18, 2019.

The application is supported by data from a pair of phase 3 trials—PNH-301 and the Switch trial. Alexion released topline results from the PNH-301 trial in March and the Switch trial in April.

PNH-301 trial

This study enrolled 246 adults (age 18+) with PNH who were naïve to treatment with a complement inhibitor. Patients received ALXN1210 (n=125) or eculizumab (n=121).

Patients in the ALXN1210 arm received a single loading dose of ALXN1210, followed by regular maintenance weight-based dosing every 8 weeks. Patients in the eculizumab arm received 4 weekly induction doses, followed by regular maintenance dosing every 2 weeks.

Both arms were treated for 26 weeks. All patients enrolled in an extension study of up to 2 years, during which they will receive ALXN1210 every 8 weeks.

The study’s co-primary endpoints are:

• Transfusion avoidance, which was defined as the proportion of patients who remain transfusion-free and do not require a transfusion per protocol-specified guidelines through day 183
• Normalization of lactate dehydrogenase (LDH) levels as directly measured every 2 weeks by LDH levels ≤ 1 times the upper limit of normal from day 29 through day 183.

ALXN1210 proved non-inferior to eculizumab for both primary endpoints. Specifically, 73.6% of patients in the ALXN1210 arm and 66.1% in the eculizumab arm were able to avoid transfusion. LDH normalization occurred in 53.6% and 49.4%, respectively.

ALXN1210 also demonstrated non-inferiority to eculizumab on all 4 key secondary endpoints:

• Percentage change from baseline in LDH levels (-76.8% and -76.0%, respectively)
• Change from baseline in quality of life as assessed by the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scale (7.1 and 6.4, respectively)
• Proportion of patients with breakthrough hemolysis (4.0% and 10.7%, respectively)
• Proportion of patients with stabilized hemoglobin levels (68.0% and 64.5%, respectively).

Alexion said there were no notable differences in the safety profiles for ALXN1210 and eculizumab. The most frequently observed adverse event (AE) was headache, and the most frequently observed serious AE was pyrexia.

One anti-drug antibody (ADA) was observed in the ALXN1210 arm and 1 in the eculizumab arm. There were no neutralizing antibodies detected and no cases of meningococcal infection.

Switch study

This study is a comparison of ALXN1210 and eculizumab in 195 adults (18+). At baseline, patients had a confirmed diagnosis of PNH, had LDH levels ≤ 1.5 times the upper limit of normal, and had been treated with eculizumab for at least the past 6 months.

ALXN1210 was administered every 8 weeks, and eculizumab was administered every 2 weeks. The 26-week treatment period is followed by an extension period, in which all patients will receive ALXN1210 every 8 weeks for up to 2 years.

Alexion did not provide any efficacy data in its announcement of results. However, the company said ALXN1210 proved non-inferior to eculizumab based on the primary endpoint of change in LDH levels.

Alexion also said ALXN1210 demonstrated non-inferiority on all 4 key secondary endpoints:

• The proportion of patients with breakthrough hemolysis
• The change from baseline in quality of life as assessed via the FACIT-Fatigue Scale
• The proportion of patients avoiding transfusion
• The proportion of patients with stabilized hemoglobin levels.

ALXN1210 had a safety profile that is consistent with that seen for eculizumab, according to Alexion. The most frequently observed AEs were headache and upper respiratory infection. The most frequently observed serious AEs were pyrexia and hemolysis.

There were no treatment-emergent ADAs in the ALXN1210 arm, but one patient in the eculizumab arm did have ADAs. There were no neutralizing antibodies and no cases of meningococcal infection in either arm.