AVAHO

Black race is the most important risk factor for patients with acute myeloid leukemia (AML) and is associated with poor survival, according to new findings.

Among patients with AML younger than 60 years, the rate of overall 3-year survival was significantly less among Black patients than White patients (34% vs. 43%). The risk for death was 27% higher for Black patients compared with White patients.

“Our study demonstrates the delicate interplay between a variety of factors that influence survival disparities, particularly for younger Black AML patients,” said first author Bhavana Bhatnagar, DO, of the Ohio State University’s Comprehensive Cancer Center, Columbus. “We were able to confirm the impact of socioeconomic factors while also demonstrating that being Black is, in and of itself, an independent poor prognostic variable for survival.”

She noted that the persistently poor outcomes of young Black patients that were seen despite similar treatments in clinical trials strongly suggest that additional factors have a bearing on their survival.

The findings of the study were presented during the plenary session of the annual meeting of the American Society of Hematology, which was held online this year. The study was simultaneously published in Cancer Discovery.

Racial disparities in cancer outcomes remain a challenge. The term “health disparities” describes the differences of health outcomes among different groups, said Chancellor Donald, MD, of Tulane University, New Orleans, who introduced the article at the meeting. “Racial health disparities usually result from an unequal distribution of power and resources, not genetics.

“The examination of health disparities is certainly a worthwhile endeavor,” he continued. “For generations, differences in key health outcomes have negatively impacted the quality of life and shortened the life span of countless individuals. As scientists, clinicians, and invested members of our shared society, we are obligated to obtain a profound understanding of the mechanisms and impact of this morbid reality.”
 

Black race a risk factor

For their study, Dr. Bhatnagar and colleagues conducted a nationwide population analysis using data from the Surveillance Epidemiology End Results (SEER) Program of the National Cancer Institute to identify 11,190 adults aged 18-60 years who were diagnosed with AML between 1986 and 2015.

To characterize molecular features, they conducted targeted sequencing of 81 genes in 1,339 patients with AML who were treated on frontline Cancer and Leukemia Group B/Alliance for Clinical Trials in Oncology (Alliance) protocols based on standard-intensity cytarabine/anthracycline induction followed by consolidation between 1986 and 2016. None of these patients received an allogeneic stem cell transplant when they achieved complete remission.

Although overall survival has improved during the past 3 decades, survival disparities between Black and White patients has widened over time (P < .001). The authors found a nonstatistically significant difference in survival between 1986 and 1995 (White patients, n = 1,365; Black patients, n = 160; P = .19). However, the difference was significant between 1996 and 2005 (White patients, n = 2,994; Black patients, n = 480; P = .004). “And it became even more noticeable in the most recent decade,” said Dr. Bhatnagar. “Furthermore, younger Black AML patients were found to have worse survival compared with younger White AML patients.”

Results from the second analysis of patients treated on Alliance protocols did not show any significant differences in early death rates (10% vs. 46%; P = .02) and complete remission rates (71% vs. 71%; P = 1.00). “While relapse rates were slightly higher in Black compared to White patients, this difference did not reach statistical significance,” said Dr. Bhatnagar. “There was also no significant difference in the number of cycles of consolidation chemotherapy administered to these patients.”

However, both disease-free and overall survival were significantly worse for Black patients, suggesting that factors other than treatment selection were likely at play in influencing the survival disparity. The median disease-free survival for Black patients was 0.8 years, vs. 1.4 years for White patients (P = .02). Overall survival was 1.2 years vs. 1.8 years (P = .02).

Relapse rates were slightly higher in Black patients than in White patients, at 71% vs. 59%, but this difference did not reach statistical significance (P = .14).
 

Differences in biomarkers

With regard to underlying molecular differences between Black and White patients, the investigators found that the most common mutations were in NPM1, FLT3-ITD, and DNM3TA. Mutations were detected in more than 20% of Black patients. Other commonly mutated genes were IDH2, NRAS, TET2, IDH1, and TP53, which were mutated in more than 10% of patients. “All of these genes are established commonly mutated genes in AML,” said Bhatnagar.

On univariable and multivariable outcome analyses, which were used to identify clinical or molecular features that had a bearing on outcome, FLT3-ITD and IDH2 mutations were the only mutations associated with a higher risk for death among Black patients.

“This is actually a very important finding, as both FLT3 and IDH2 are now targetable with small-molecule inhibitors,” said Dr. Bhatnagar. “In addition, it is also worth noting that other gene mutations that have known prognostic significance in AML, such as NPM1, as well as RUNX1 and TP53, did not remain in the final statistical model.

“Importantly, our study provides powerful evidence that suggests differences in underlying disease biology between young Black and White AML patients, as evidenced by differences in the frequencies of recurrent gene mutations, “ she said.
 

Understudied disparities

Although the study showed that Black patients had worse outcomes, “surprisingly, the authors found these outcomes hold even when the patients are participating in clinical trials,” noted Elisa Weiss, PhD, senior vice president of education, services, and health research for the Leukemia and Lymphoma Society.

“The study makes clear that the medical and science community need to do more to better understand the social, economic, environmental, and biological causes of these disparities,” she said in an interview. “In fact, the findings suggest that there are myriad complex and understudied causes of the identified disparities, and they are likely to lie at the intersection of all levels of the social ecology that impact an individual’s ability to access timely and unbiased care, maintain their mental and physical health, and receive needed social support and resources.”

She noted that the Leukemia and Lymphoma Society has an Equity in Access research program that aims to “advance study of underlying causes of inequitable access to care and identify policies, strategies, and interventions that have the potential to reduce inequities and increase access to health care, services, and programs for blood cancer patients and survivors.”

The research was supported in part by the National Cancer Institute of the National Institutes of Health, other institutions, and through several scholar awards. Dr. Bhatnagar has received advisory board honoraria from Novartis, Kite Pharma, Celgene, Astellas, and Cell Therapeutics. Dr. Weiss has disclosed no relevant financial relationships.

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

Black race is the most important risk factor for patients with acute myeloid leukemia (AML) and is associated with poor survival, according to new findings.

Among patients with AML younger than 60 years, the rate of overall 3-year survival was significantly less among Black patients than White patients (34% vs. 43%). The risk for death was 27% higher for Black patients compared with White patients.

“Our study demonstrates the delicate interplay between a variety of factors that influence survival disparities, particularly for younger Black AML patients,” said first author Bhavana Bhatnagar, DO, of the Ohio State University’s Comprehensive Cancer Center, Columbus. “We were able to confirm the impact of socioeconomic factors while also demonstrating that being Black is, in and of itself, an independent poor prognostic variable for survival.”

She noted that the persistently poor outcomes of young Black patients that were seen despite similar treatments in clinical trials strongly suggest that additional factors have a bearing on their survival.

The findings of the study were presented during the plenary session of the annual meeting of the American Society of Hematology, which was held online this year. The study was simultaneously published in Cancer Discovery.

Racial disparities in cancer outcomes remain a challenge. The term “health disparities” describes the differences of health outcomes among different groups, said Chancellor Donald, MD, of Tulane University, New Orleans, who introduced the article at the meeting. “Racial health disparities usually result from an unequal distribution of power and resources, not genetics.

“The examination of health disparities is certainly a worthwhile endeavor,” he continued. “For generations, differences in key health outcomes have negatively impacted the quality of life and shortened the life span of countless individuals. As scientists, clinicians, and invested members of our shared society, we are obligated to obtain a profound understanding of the mechanisms and impact of this morbid reality.”
 

Black race a risk factor

For their study, Dr. Bhatnagar and colleagues conducted a nationwide population analysis using data from the Surveillance Epidemiology End Results (SEER) Program of the National Cancer Institute to identify 11,190 adults aged 18-60 years who were diagnosed with AML between 1986 and 2015.

To characterize molecular features, they conducted targeted sequencing of 81 genes in 1,339 patients with AML who were treated on frontline Cancer and Leukemia Group B/Alliance for Clinical Trials in Oncology (Alliance) protocols based on standard-intensity cytarabine/anthracycline induction followed by consolidation between 1986 and 2016. None of these patients received an allogeneic stem cell transplant when they achieved complete remission.

Although overall survival has improved during the past 3 decades, survival disparities between Black and White patients has widened over time (P < .001). The authors found a nonstatistically significant difference in survival between 1986 and 1995 (White patients, n = 1,365; Black patients, n = 160; P = .19). However, the difference was significant between 1996 and 2005 (White patients, n = 2,994; Black patients, n = 480; P = .004). “And it became even more noticeable in the most recent decade,” said Dr. Bhatnagar. “Furthermore, younger Black AML patients were found to have worse survival compared with younger White AML patients.”

Results from the second analysis of patients treated on Alliance protocols did not show any significant differences in early death rates (10% vs. 46%; P = .02) and complete remission rates (71% vs. 71%; P = 1.00). “While relapse rates were slightly higher in Black compared to White patients, this difference did not reach statistical significance,” said Dr. Bhatnagar. “There was also no significant difference in the number of cycles of consolidation chemotherapy administered to these patients.”

However, both disease-free and overall survival were significantly worse for Black patients, suggesting that factors other than treatment selection were likely at play in influencing the survival disparity. The median disease-free survival for Black patients was 0.8 years, vs. 1.4 years for White patients (P = .02). Overall survival was 1.2 years vs. 1.8 years (P = .02).

Relapse rates were slightly higher in Black patients than in White patients, at 71% vs. 59%, but this difference did not reach statistical significance (P = .14).
 

Differences in biomarkers

With regard to underlying molecular differences between Black and White patients, the investigators found that the most common mutations were in NPM1, FLT3-ITD, and DNM3TA. Mutations were detected in more than 20% of Black patients. Other commonly mutated genes were IDH2, NRAS, TET2, IDH1, and TP53, which were mutated in more than 10% of patients. “All of these genes are established commonly mutated genes in AML,” said Bhatnagar.

On univariable and multivariable outcome analyses, which were used to identify clinical or molecular features that had a bearing on outcome, FLT3-ITD and IDH2 mutations were the only mutations associated with a higher risk for death among Black patients.

“This is actually a very important finding, as both FLT3 and IDH2 are now targetable with small-molecule inhibitors,” said Dr. Bhatnagar. “In addition, it is also worth noting that other gene mutations that have known prognostic significance in AML, such as NPM1, as well as RUNX1 and TP53, did not remain in the final statistical model.

“Importantly, our study provides powerful evidence that suggests differences in underlying disease biology between young Black and White AML patients, as evidenced by differences in the frequencies of recurrent gene mutations, “ she said.
 

Understudied disparities

Although the study showed that Black patients had worse outcomes, “surprisingly, the authors found these outcomes hold even when the patients are participating in clinical trials,” noted Elisa Weiss, PhD, senior vice president of education, services, and health research for the Leukemia and Lymphoma Society.

“The study makes clear that the medical and science community need to do more to better understand the social, economic, environmental, and biological causes of these disparities,” she said in an interview. “In fact, the findings suggest that there are myriad complex and understudied causes of the identified disparities, and they are likely to lie at the intersection of all levels of the social ecology that impact an individual’s ability to access timely and unbiased care, maintain their mental and physical health, and receive needed social support and resources.”

She noted that the Leukemia and Lymphoma Society has an Equity in Access research program that aims to “advance study of underlying causes of inequitable access to care and identify policies, strategies, and interventions that have the potential to reduce inequities and increase access to health care, services, and programs for blood cancer patients and survivors.”

The research was supported in part by the National Cancer Institute of the National Institutes of Health, other institutions, and through several scholar awards. Dr. Bhatnagar has received advisory board honoraria from Novartis, Kite Pharma, Celgene, Astellas, and Cell Therapeutics. Dr. Weiss has disclosed no relevant financial relationships.

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

Black race is the most important risk factor for patients with acute myeloid leukemia (AML) and is associated with poor survival, according to new findings.

Among patients with AML younger than 60 years, the rate of overall 3-year survival was significantly less among Black patients than White patients (34% vs. 43%). The risk for death was 27% higher for Black patients compared with White patients.

“Our study demonstrates the delicate interplay between a variety of factors that influence survival disparities, particularly for younger Black AML patients,” said first author Bhavana Bhatnagar, DO, of the Ohio State University’s Comprehensive Cancer Center, Columbus. “We were able to confirm the impact of socioeconomic factors while also demonstrating that being Black is, in and of itself, an independent poor prognostic variable for survival.”

She noted that the persistently poor outcomes of young Black patients that were seen despite similar treatments in clinical trials strongly suggest that additional factors have a bearing on their survival.

The findings of the study were presented during the plenary session of the annual meeting of the American Society of Hematology, which was held online this year. The study was simultaneously published in Cancer Discovery.

Racial disparities in cancer outcomes remain a challenge. The term “health disparities” describes the differences of health outcomes among different groups, said Chancellor Donald, MD, of Tulane University, New Orleans, who introduced the article at the meeting. “Racial health disparities usually result from an unequal distribution of power and resources, not genetics.

“The examination of health disparities is certainly a worthwhile endeavor,” he continued. “For generations, differences in key health outcomes have negatively impacted the quality of life and shortened the life span of countless individuals. As scientists, clinicians, and invested members of our shared society, we are obligated to obtain a profound understanding of the mechanisms and impact of this morbid reality.”
 

Black race a risk factor

For their study, Dr. Bhatnagar and colleagues conducted a nationwide population analysis using data from the Surveillance Epidemiology End Results (SEER) Program of the National Cancer Institute to identify 11,190 adults aged 18-60 years who were diagnosed with AML between 1986 and 2015.

To characterize molecular features, they conducted targeted sequencing of 81 genes in 1,339 patients with AML who were treated on frontline Cancer and Leukemia Group B/Alliance for Clinical Trials in Oncology (Alliance) protocols based on standard-intensity cytarabine/anthracycline induction followed by consolidation between 1986 and 2016. None of these patients received an allogeneic stem cell transplant when they achieved complete remission.

Although overall survival has improved during the past 3 decades, survival disparities between Black and White patients has widened over time (P < .001). The authors found a nonstatistically significant difference in survival between 1986 and 1995 (White patients, n = 1,365; Black patients, n = 160; P = .19). However, the difference was significant between 1996 and 2005 (White patients, n = 2,994; Black patients, n = 480; P = .004). “And it became even more noticeable in the most recent decade,” said Dr. Bhatnagar. “Furthermore, younger Black AML patients were found to have worse survival compared with younger White AML patients.”

Results from the second analysis of patients treated on Alliance protocols did not show any significant differences in early death rates (10% vs. 46%; P = .02) and complete remission rates (71% vs. 71%; P = 1.00). “While relapse rates were slightly higher in Black compared to White patients, this difference did not reach statistical significance,” said Dr. Bhatnagar. “There was also no significant difference in the number of cycles of consolidation chemotherapy administered to these patients.”

However, both disease-free and overall survival were significantly worse for Black patients, suggesting that factors other than treatment selection were likely at play in influencing the survival disparity. The median disease-free survival for Black patients was 0.8 years, vs. 1.4 years for White patients (P = .02). Overall survival was 1.2 years vs. 1.8 years (P = .02).

Relapse rates were slightly higher in Black patients than in White patients, at 71% vs. 59%, but this difference did not reach statistical significance (P = .14).
 

Differences in biomarkers

With regard to underlying molecular differences between Black and White patients, the investigators found that the most common mutations were in NPM1, FLT3-ITD, and DNM3TA. Mutations were detected in more than 20% of Black patients. Other commonly mutated genes were IDH2, NRAS, TET2, IDH1, and TP53, which were mutated in more than 10% of patients. “All of these genes are established commonly mutated genes in AML,” said Bhatnagar.

On univariable and multivariable outcome analyses, which were used to identify clinical or molecular features that had a bearing on outcome, FLT3-ITD and IDH2 mutations were the only mutations associated with a higher risk for death among Black patients.

“This is actually a very important finding, as both FLT3 and IDH2 are now targetable with small-molecule inhibitors,” said Dr. Bhatnagar. “In addition, it is also worth noting that other gene mutations that have known prognostic significance in AML, such as NPM1, as well as RUNX1 and TP53, did not remain in the final statistical model.

“Importantly, our study provides powerful evidence that suggests differences in underlying disease biology between young Black and White AML patients, as evidenced by differences in the frequencies of recurrent gene mutations, “ she said.
 

Understudied disparities

Although the study showed that Black patients had worse outcomes, “surprisingly, the authors found these outcomes hold even when the patients are participating in clinical trials,” noted Elisa Weiss, PhD, senior vice president of education, services, and health research for the Leukemia and Lymphoma Society.

“The study makes clear that the medical and science community need to do more to better understand the social, economic, environmental, and biological causes of these disparities,” she said in an interview. “In fact, the findings suggest that there are myriad complex and understudied causes of the identified disparities, and they are likely to lie at the intersection of all levels of the social ecology that impact an individual’s ability to access timely and unbiased care, maintain their mental and physical health, and receive needed social support and resources.”

She noted that the Leukemia and Lymphoma Society has an Equity in Access research program that aims to “advance study of underlying causes of inequitable access to care and identify policies, strategies, and interventions that have the potential to reduce inequities and increase access to health care, services, and programs for blood cancer patients and survivors.”

The research was supported in part by the National Cancer Institute of the National Institutes of Health, other institutions, and through several scholar awards. Dr. Bhatnagar has received advisory board honoraria from Novartis, Kite Pharma, Celgene, Astellas, and Cell Therapeutics. Dr. Weiss has disclosed no relevant financial relationships.

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

An analysis of nearly 29,000 U.S. women with early-onset colorectal cancer (CRC) showed that physical inactivity and fertility correlated modestly with living in “hot spots,” or counties with high early-onset CRC mortality rates among women.

Approximately one-third of the variation in early-onset CRC survival among women was accounted for by differences in individual- or community-level features.

Andreana N. Holowatyj, PhD, of Vanderbilt University Medical Center in Nashville, Tenn., and colleagues reported these findings in Clinical and Translational Gastroenterology.

Dr. Holowatyj and colleagues noted that prior studies have linked health behaviors with an increased risk of early-onset CRC among women. However, the impact of health behaviors on outcomes of early-onset CRC is unknown.

The researchers hypothesized that biological-, individual-, and community-level factors may be contributing to known sex-specific differences in CRC outcomes and geographic variations in survival by sex.
 

Hot spot counties with high mortality

The researchers identified geographic hot spots using three geospatial autocorrelation approaches with Centers for Disease Control and Prevention national

mortality data. The team also analyzed data from the Surveillance, Epidemiology, and End Results program on 28,790 women (aged 15-49 years) diagnosed with CRC during 1999-2016.

Of the 3,108 counties in the contiguous United States, 191 were identified as hot spots. Among these, 101 (52.9%) were located in the South.

Earlier research had shown a predominance of hot spots for early-onset CRC mortality among both men and women in the South.

However, the current study of women showed that almost half of these counties were located in the Midwest and the Northeast as well as the South.

Also in the current analysis, about one in every seven women (13.7%) with early-onset CRC resided in hot spot counties.

Race/ethnicity, stage at diagnosis, histopathology, and receipt of first-course therapies also differed significantly (P ≤ .0001) between women residing in hot spot versus non–hot spot counties.

Non-Hispanic Black patients, for example, accounted for 23.7% of early-onset CRC cases in hot spot counties, as compared with 14.3% in non–hot spot counties (P < .0001). The county-level proportion of non-Hispanic Black patients also modestly correlated with hot spot residence (r_s = .26; P < .0001).

Race and ethnicity accounted for less than 0.5% of the variation in early-onset CRC survival among women in non–hot spot counties. In hot spot counties, however, this factor explained 1.4% of the variation in early-onset CRC-specific survival among women.
 

Inactivity correlates with hot spot residence

Dr. Holowatyj and colleagues also identified physical inactivity and lower fertility as county-level factors modestly correlated with hot spot residence (r_s = .21, r_s = –.23: P < .01).

Nearly a quarter of adults living in hot spot counties reported no physical activity during their leisure time (24.1% vs. 21.7% in non–hot spot counties; P < .01).

The rate of live births in the last year among women aged 15-50 years was lower in hot spot counties than in non–hot spot counties (4.9% vs. 5.4%; P < .01).

Individual- and community-level features overall accounted for different proportions of variance in early-onset CRC survival among women residing in hot spot counties (33.8%) versus non–hot spot counties (34.1%).

In addition to race and ethnicity, age at diagnosis, tumor histology, county-level proportions of the non-Hispanic Black population, women with a live birth in the last year, and annual household income of less than $20,000 all explained greater variance in CRC survival in young women in hot spot counties versus non–hot spot counties.
 

Keep CRC in differential diagnosis

“These individual- and community-level feature differences between hot spot and non–hot spot counties illustrate the importance of understanding how these factors may be contributing to early-onset CRC mortality among women – particularly in hot spot counties,” Dr. Holowatyj said in an interview. “They may provide us with key clues for developing effective strategies to reduce the burden of CRC in young women across the United States.

“Every primary care physician and gastroenterologist, particularly in hot spot counties, should keep CRC in their differential diagnosis, particularly if a patient is presenting with typical signs and symptoms, even if they are not yet of screening age. Early-stage diagnosis increases survival odds because the cancer may be easier to treat.”

Health professionals can also encourage physical activity and a healthy lifestyle, she added.

The authors declared no competing interests. Their research was funded by grants from the federal government and foundations.

SOURCE: Holowatyj AN et al. Clin and Transl Gastroenterol. 2020;11:e00266.

An analysis of nearly 29,000 U.S. women with early-onset colorectal cancer (CRC) showed that physical inactivity and fertility correlated modestly with living in “hot spots,” or counties with high early-onset CRC mortality rates among women.

Approximately one-third of the variation in early-onset CRC survival among women was accounted for by differences in individual- or community-level features.

Andreana N. Holowatyj, PhD, of Vanderbilt University Medical Center in Nashville, Tenn., and colleagues reported these findings in Clinical and Translational Gastroenterology.

Dr. Holowatyj and colleagues noted that prior studies have linked health behaviors with an increased risk of early-onset CRC among women. However, the impact of health behaviors on outcomes of early-onset CRC is unknown.

The researchers hypothesized that biological-, individual-, and community-level factors may be contributing to known sex-specific differences in CRC outcomes and geographic variations in survival by sex.
 

Hot spot counties with high mortality

The researchers identified geographic hot spots using three geospatial autocorrelation approaches with Centers for Disease Control and Prevention national

mortality data. The team also analyzed data from the Surveillance, Epidemiology, and End Results program on 28,790 women (aged 15-49 years) diagnosed with CRC during 1999-2016.

Of the 3,108 counties in the contiguous United States, 191 were identified as hot spots. Among these, 101 (52.9%) were located in the South.

Earlier research had shown a predominance of hot spots for early-onset CRC mortality among both men and women in the South.

However, the current study of women showed that almost half of these counties were located in the Midwest and the Northeast as well as the South.

Also in the current analysis, about one in every seven women (13.7%) with early-onset CRC resided in hot spot counties.

Race/ethnicity, stage at diagnosis, histopathology, and receipt of first-course therapies also differed significantly (P ≤ .0001) between women residing in hot spot versus non–hot spot counties.

Non-Hispanic Black patients, for example, accounted for 23.7% of early-onset CRC cases in hot spot counties, as compared with 14.3% in non–hot spot counties (P < .0001). The county-level proportion of non-Hispanic Black patients also modestly correlated with hot spot residence (r_s = .26; P < .0001).

Race and ethnicity accounted for less than 0.5% of the variation in early-onset CRC survival among women in non–hot spot counties. In hot spot counties, however, this factor explained 1.4% of the variation in early-onset CRC-specific survival among women.
 

Inactivity correlates with hot spot residence

Dr. Holowatyj and colleagues also identified physical inactivity and lower fertility as county-level factors modestly correlated with hot spot residence (r_s = .21, r_s = –.23: P < .01).

Nearly a quarter of adults living in hot spot counties reported no physical activity during their leisure time (24.1% vs. 21.7% in non–hot spot counties; P < .01).

The rate of live births in the last year among women aged 15-50 years was lower in hot spot counties than in non–hot spot counties (4.9% vs. 5.4%; P < .01).

Individual- and community-level features overall accounted for different proportions of variance in early-onset CRC survival among women residing in hot spot counties (33.8%) versus non–hot spot counties (34.1%).

In addition to race and ethnicity, age at diagnosis, tumor histology, county-level proportions of the non-Hispanic Black population, women with a live birth in the last year, and annual household income of less than $20,000 all explained greater variance in CRC survival in young women in hot spot counties versus non–hot spot counties.
 

Keep CRC in differential diagnosis

“These individual- and community-level feature differences between hot spot and non–hot spot counties illustrate the importance of understanding how these factors may be contributing to early-onset CRC mortality among women – particularly in hot spot counties,” Dr. Holowatyj said in an interview. “They may provide us with key clues for developing effective strategies to reduce the burden of CRC in young women across the United States.

“Every primary care physician and gastroenterologist, particularly in hot spot counties, should keep CRC in their differential diagnosis, particularly if a patient is presenting with typical signs and symptoms, even if they are not yet of screening age. Early-stage diagnosis increases survival odds because the cancer may be easier to treat.”

Health professionals can also encourage physical activity and a healthy lifestyle, she added.

The authors declared no competing interests. Their research was funded by grants from the federal government and foundations.

SOURCE: Holowatyj AN et al. Clin and Transl Gastroenterol. 2020;11:e00266.

An analysis of nearly 29,000 U.S. women with early-onset colorectal cancer (CRC) showed that physical inactivity and fertility correlated modestly with living in “hot spots,” or counties with high early-onset CRC mortality rates among women.

Approximately one-third of the variation in early-onset CRC survival among women was accounted for by differences in individual- or community-level features.

Andreana N. Holowatyj, PhD, of Vanderbilt University Medical Center in Nashville, Tenn., and colleagues reported these findings in Clinical and Translational Gastroenterology.

Dr. Holowatyj and colleagues noted that prior studies have linked health behaviors with an increased risk of early-onset CRC among women. However, the impact of health behaviors on outcomes of early-onset CRC is unknown.

The researchers hypothesized that biological-, individual-, and community-level factors may be contributing to known sex-specific differences in CRC outcomes and geographic variations in survival by sex.
 

Hot spot counties with high mortality

The researchers identified geographic hot spots using three geospatial autocorrelation approaches with Centers for Disease Control and Prevention national

mortality data. The team also analyzed data from the Surveillance, Epidemiology, and End Results program on 28,790 women (aged 15-49 years) diagnosed with CRC during 1999-2016.

Of the 3,108 counties in the contiguous United States, 191 were identified as hot spots. Among these, 101 (52.9%) were located in the South.

Earlier research had shown a predominance of hot spots for early-onset CRC mortality among both men and women in the South.

However, the current study of women showed that almost half of these counties were located in the Midwest and the Northeast as well as the South.

Also in the current analysis, about one in every seven women (13.7%) with early-onset CRC resided in hot spot counties.

Race/ethnicity, stage at diagnosis, histopathology, and receipt of first-course therapies also differed significantly (P ≤ .0001) between women residing in hot spot versus non–hot spot counties.

Non-Hispanic Black patients, for example, accounted for 23.7% of early-onset CRC cases in hot spot counties, as compared with 14.3% in non–hot spot counties (P < .0001). The county-level proportion of non-Hispanic Black patients also modestly correlated with hot spot residence (r_s = .26; P < .0001).

Race and ethnicity accounted for less than 0.5% of the variation in early-onset CRC survival among women in non–hot spot counties. In hot spot counties, however, this factor explained 1.4% of the variation in early-onset CRC-specific survival among women.
 

Inactivity correlates with hot spot residence

Dr. Holowatyj and colleagues also identified physical inactivity and lower fertility as county-level factors modestly correlated with hot spot residence (r_s = .21, r_s = –.23: P < .01).

Nearly a quarter of adults living in hot spot counties reported no physical activity during their leisure time (24.1% vs. 21.7% in non–hot spot counties; P < .01).

The rate of live births in the last year among women aged 15-50 years was lower in hot spot counties than in non–hot spot counties (4.9% vs. 5.4%; P < .01).

Individual- and community-level features overall accounted for different proportions of variance in early-onset CRC survival among women residing in hot spot counties (33.8%) versus non–hot spot counties (34.1%).

In addition to race and ethnicity, age at diagnosis, tumor histology, county-level proportions of the non-Hispanic Black population, women with a live birth in the last year, and annual household income of less than $20,000 all explained greater variance in CRC survival in young women in hot spot counties versus non–hot spot counties.
 

Keep CRC in differential diagnosis

“These individual- and community-level feature differences between hot spot and non–hot spot counties illustrate the importance of understanding how these factors may be contributing to early-onset CRC mortality among women – particularly in hot spot counties,” Dr. Holowatyj said in an interview. “They may provide us with key clues for developing effective strategies to reduce the burden of CRC in young women across the United States.

“Every primary care physician and gastroenterologist, particularly in hot spot counties, should keep CRC in their differential diagnosis, particularly if a patient is presenting with typical signs and symptoms, even if they are not yet of screening age. Early-stage diagnosis increases survival odds because the cancer may be easier to treat.”

Health professionals can also encourage physical activity and a healthy lifestyle, she added.

The authors declared no competing interests. Their research was funded by grants from the federal government and foundations.

SOURCE: Holowatyj AN et al. Clin and Transl Gastroenterol. 2020;11:e00266.

More than one in eight women who undergo mastectomy with reconstruction for breast cancer treatment or prophylaxis become persistent users of controlled substances thereafter, according to a retrospective cohort study reported at the 2020 San Antonio Breast Cancer Symposium.

After their surgery, 13.1% of opioid-naive patients become new persistent opioid users, and 6.6% of sedative-hypnotic–naive patients become new persistent users of sedative-hypnotics. Risk factors for persistent substance use included younger age, a breast cancer diagnosis, and chemotherapy.

“As the opioid epidemic in the United States continues, the rate of opioid dependence in the cancer population continues to increase as well,” study investigator Jacob Cogan, MD, of NewYork-Presbyterian/Columbia University Irving Medical Center in New York, said during a press conference.

“The perioperative period is one of high risk for cancer patients, with up to 10% becoming new persistent opioid users after cancer-related surgery. The rates surrounding mastectomy and reconstruction, however, are unknown. Another class of controlled substances worth our attention are the sedative-hypnotics. Despite the high rates of psychiatric disorders in the cancer population, there is little research into the rates of persistent sedative-hypnotic use in these patients.”

With this in mind, Dr. Cogan and colleagues analyzed MarketScan health care claims data for patients who underwent mastectomy and reconstruction (whether therapeutic or prophylactic) between 2008 and 2017.

The researchers then identified prescription claims for opioids and sedative-hypnotics during three periods:

• Preoperative period – 365 days to 31 days before surgery.
• Perioperative period – 31 days before to 90 days after surgery.
• Postoperative period – 90 days to 365 days after surgery.

‘Striking’ results

Analyses were based on 25,270 women who were not prior users of opioids and 27,651 women who were not prior users of sedative-hypnotics.

Women were considered new persistent substance users if they had no use in the preoperative period but filled at least one prescription in the perioperative period and at least two in the postoperative period.

Overall, 13.1% of opioid-naive patients became persistent opioid users, and 6.6% of sedative-hypnotic-naive patients became persistent sedative-hypnotic users after their mastectomy and reconstruction.

Proportions of substance use were even higher, 17.5% for opioids and 17.0% for sedative-hypnotics, after excluding women who did not receive or fill a perioperative prescription.

In multivariate analysis, patients were significantly more likely to become new persistent opioid users if they had Medicaid insurance (odds ratio, 2.31), had a breast cancer diagnosis vs a prophylactic indication (OR, 1.44), received chemotherapy (OR, 1.33), and were 50-64 years of age (OR, 1.29) or 49 years or younger (OR, 1.27), compared with 65 years or older.

Similarly, patients were significantly more likely to become new persistent sedative-hypnotic users if they received chemotherapy (OR, 2.24), had Medicaid insurance (OR, 1.85), had a breast cancer diagnosis (OR, 1.79), and were 50 to 64 years (OR, 1.65) or 49 years or younger (OR, 1.79).

Finally, patients’ likelihood of new persistent use increased with their number of risk factors. For persistent opioid use, the odds ratio rose from 2.27 in patients with two risk factors to 6.34 in those with five risk factors. For persistent sedative-hypnotic use, the odds ratio rose from 2.55 to 7.71, respectively.

The observed incidences of new persistent substance use in this patient population are “striking,” according to Dr. Cogan. Although the identified risk factors can help providers spot patients who should be monitored more closely, a proactive, systematic approach to postoperative follow-up for all patients is likely needed.

“When you are seeing patients in follow-up, this is something that you might want to explicitly ask about, for example, and not just assume that the postoperative opioids were taken and then disposed of,” Dr. Cogan recommended. “Ask them, ‘Are you still taking opioids, are you still taking your Ambien or whatever medication you were prescribed?’ That’s something to diligently follow up on and make sure the drug is disposed of, or if it somebody is still taking it, refer them for the appropriate services.”

In addition, patients should be encouraged to use over-the-counter medications as much as possible, he advised.
 

Prescribing: It’s complicated

“I wonder if perhaps we should not be giving opioids at all to certain patients. For example, a mastectomy and implant reconstruction, oftentimes, surprisingly, that’s not a terribly painful procedure. But a TRAM [transverse rectus abdominis] flap or abdominal flap, that really is,” commented press conference comoderator C. Kent Osborne, MD, of Baylor College of Medicine in Houston.

“I’ve been surprised that a lot of my patients get the prescription, but they don’t even use the pills, and I wonder if the prescription is given just so that we’re not bothered at nighttime by somebody calling with pain,” Dr. Osbourne added.

Prescribing opioids for postoperative pain is complicated, Dr. Cogan said, noting that the study did not assess the specific type of reconstruction patients had.

“You don’t want people in pain. Even if they need just one or two pills, it’s still reasonable for them to have it, and we certainly don’t want to imply from our study that people shouldn’t be getting these prescriptions if they need them,” Dr. Cogan elaborated. “But once patients have them, don’t just leave them there in their home because other studies have shown that that’s when people really get addicted to these medications, when they use them later on for other reasons, or they keep using them just because they have them around.”

The risk for persistent use of controlled substances “is something that all physicians need to be aware of for their patients. This is something that we are missing,” maintained press conference comoderator Virginia Kaklamani, MD, DSc, of UT Health San Antonio.

“It’s easy to just give a prescription instead of arguing with a patient about why you are not going to give them a prescription,” Dr. Kaklamani said. “And ultimately ... pain is subjective. If a patient tells you they are in pain, you are, quote-endquote, a bad physician if you tell them they should not be in pain.”

Courtesy The University of Texas Health Science Center at San Antonio

“We need to focus on other ways to deal with the pain, like physical therapy, sending patients to physical medicine and rehab physicians who are trained to help with symptoms from the surgery, with range of motion and all that; that can help with pain,” she recommended. “It’s much harder to do that, right, than to send a prescription in for a narcotic? But that easy answer is always the worst answer.”

This study was funded by the Breast Cancer Research Foundation and the National Institutes of Health. Dr. Cogan declared no conflicts of interest. Dr. Osborne disclosed relationships with Wolters Kluwer, Lilly, Tolmar, and GeneTex. Dr. Kaklamani disclosed relationships with Amgen, AstraZeneca, Athenex, Celgene, Celldex, Daiichi, Eisai, Genentech, Genomic Health, Immunomedics, Novartis, Pfizer, Puma, and Seattle Genetics.

SOURCE: Cogan JC et al. SABCS 2020, Abstract GS3-08.

More than one in eight women who undergo mastectomy with reconstruction for breast cancer treatment or prophylaxis become persistent users of controlled substances thereafter, according to a retrospective cohort study reported at the 2020 San Antonio Breast Cancer Symposium.

After their surgery, 13.1% of opioid-naive patients become new persistent opioid users, and 6.6% of sedative-hypnotic–naive patients become new persistent users of sedative-hypnotics. Risk factors for persistent substance use included younger age, a breast cancer diagnosis, and chemotherapy.

“As the opioid epidemic in the United States continues, the rate of opioid dependence in the cancer population continues to increase as well,” study investigator Jacob Cogan, MD, of NewYork-Presbyterian/Columbia University Irving Medical Center in New York, said during a press conference.

“The perioperative period is one of high risk for cancer patients, with up to 10% becoming new persistent opioid users after cancer-related surgery. The rates surrounding mastectomy and reconstruction, however, are unknown. Another class of controlled substances worth our attention are the sedative-hypnotics. Despite the high rates of psychiatric disorders in the cancer population, there is little research into the rates of persistent sedative-hypnotic use in these patients.”

With this in mind, Dr. Cogan and colleagues analyzed MarketScan health care claims data for patients who underwent mastectomy and reconstruction (whether therapeutic or prophylactic) between 2008 and 2017.

The researchers then identified prescription claims for opioids and sedative-hypnotics during three periods:

• Preoperative period – 365 days to 31 days before surgery.
• Perioperative period – 31 days before to 90 days after surgery.
• Postoperative period – 90 days to 365 days after surgery.

‘Striking’ results

Analyses were based on 25,270 women who were not prior users of opioids and 27,651 women who were not prior users of sedative-hypnotics.

Women were considered new persistent substance users if they had no use in the preoperative period but filled at least one prescription in the perioperative period and at least two in the postoperative period.

Overall, 13.1% of opioid-naive patients became persistent opioid users, and 6.6% of sedative-hypnotic-naive patients became persistent sedative-hypnotic users after their mastectomy and reconstruction.

Proportions of substance use were even higher, 17.5% for opioids and 17.0% for sedative-hypnotics, after excluding women who did not receive or fill a perioperative prescription.

In multivariate analysis, patients were significantly more likely to become new persistent opioid users if they had Medicaid insurance (odds ratio, 2.31), had a breast cancer diagnosis vs a prophylactic indication (OR, 1.44), received chemotherapy (OR, 1.33), and were 50-64 years of age (OR, 1.29) or 49 years or younger (OR, 1.27), compared with 65 years or older.

Similarly, patients were significantly more likely to become new persistent sedative-hypnotic users if they received chemotherapy (OR, 2.24), had Medicaid insurance (OR, 1.85), had a breast cancer diagnosis (OR, 1.79), and were 50 to 64 years (OR, 1.65) or 49 years or younger (OR, 1.79).

Finally, patients’ likelihood of new persistent use increased with their number of risk factors. For persistent opioid use, the odds ratio rose from 2.27 in patients with two risk factors to 6.34 in those with five risk factors. For persistent sedative-hypnotic use, the odds ratio rose from 2.55 to 7.71, respectively.

The observed incidences of new persistent substance use in this patient population are “striking,” according to Dr. Cogan. Although the identified risk factors can help providers spot patients who should be monitored more closely, a proactive, systematic approach to postoperative follow-up for all patients is likely needed.

“When you are seeing patients in follow-up, this is something that you might want to explicitly ask about, for example, and not just assume that the postoperative opioids were taken and then disposed of,” Dr. Cogan recommended. “Ask them, ‘Are you still taking opioids, are you still taking your Ambien or whatever medication you were prescribed?’ That’s something to diligently follow up on and make sure the drug is disposed of, or if it somebody is still taking it, refer them for the appropriate services.”

In addition, patients should be encouraged to use over-the-counter medications as much as possible, he advised.
 

Prescribing: It’s complicated

“I wonder if perhaps we should not be giving opioids at all to certain patients. For example, a mastectomy and implant reconstruction, oftentimes, surprisingly, that’s not a terribly painful procedure. But a TRAM [transverse rectus abdominis] flap or abdominal flap, that really is,” commented press conference comoderator C. Kent Osborne, MD, of Baylor College of Medicine in Houston.

“I’ve been surprised that a lot of my patients get the prescription, but they don’t even use the pills, and I wonder if the prescription is given just so that we’re not bothered at nighttime by somebody calling with pain,” Dr. Osbourne added.

Prescribing opioids for postoperative pain is complicated, Dr. Cogan said, noting that the study did not assess the specific type of reconstruction patients had.

“You don’t want people in pain. Even if they need just one or two pills, it’s still reasonable for them to have it, and we certainly don’t want to imply from our study that people shouldn’t be getting these prescriptions if they need them,” Dr. Cogan elaborated. “But once patients have them, don’t just leave them there in their home because other studies have shown that that’s when people really get addicted to these medications, when they use them later on for other reasons, or they keep using them just because they have them around.”

The risk for persistent use of controlled substances “is something that all physicians need to be aware of for their patients. This is something that we are missing,” maintained press conference comoderator Virginia Kaklamani, MD, DSc, of UT Health San Antonio.

“It’s easy to just give a prescription instead of arguing with a patient about why you are not going to give them a prescription,” Dr. Kaklamani said. “And ultimately ... pain is subjective. If a patient tells you they are in pain, you are, quote-endquote, a bad physician if you tell them they should not be in pain.”

Courtesy The University of Texas Health Science Center at San Antonio

“We need to focus on other ways to deal with the pain, like physical therapy, sending patients to physical medicine and rehab physicians who are trained to help with symptoms from the surgery, with range of motion and all that; that can help with pain,” she recommended. “It’s much harder to do that, right, than to send a prescription in for a narcotic? But that easy answer is always the worst answer.”

This study was funded by the Breast Cancer Research Foundation and the National Institutes of Health. Dr. Cogan declared no conflicts of interest. Dr. Osborne disclosed relationships with Wolters Kluwer, Lilly, Tolmar, and GeneTex. Dr. Kaklamani disclosed relationships with Amgen, AstraZeneca, Athenex, Celgene, Celldex, Daiichi, Eisai, Genentech, Genomic Health, Immunomedics, Novartis, Pfizer, Puma, and Seattle Genetics.

SOURCE: Cogan JC et al. SABCS 2020, Abstract GS3-08.

More than one in eight women who undergo mastectomy with reconstruction for breast cancer treatment or prophylaxis become persistent users of controlled substances thereafter, according to a retrospective cohort study reported at the 2020 San Antonio Breast Cancer Symposium.

After their surgery, 13.1% of opioid-naive patients become new persistent opioid users, and 6.6% of sedative-hypnotic–naive patients become new persistent users of sedative-hypnotics. Risk factors for persistent substance use included younger age, a breast cancer diagnosis, and chemotherapy.

“As the opioid epidemic in the United States continues, the rate of opioid dependence in the cancer population continues to increase as well,” study investigator Jacob Cogan, MD, of NewYork-Presbyterian/Columbia University Irving Medical Center in New York, said during a press conference.

“The perioperative period is one of high risk for cancer patients, with up to 10% becoming new persistent opioid users after cancer-related surgery. The rates surrounding mastectomy and reconstruction, however, are unknown. Another class of controlled substances worth our attention are the sedative-hypnotics. Despite the high rates of psychiatric disorders in the cancer population, there is little research into the rates of persistent sedative-hypnotic use in these patients.”

With this in mind, Dr. Cogan and colleagues analyzed MarketScan health care claims data for patients who underwent mastectomy and reconstruction (whether therapeutic or prophylactic) between 2008 and 2017.

The researchers then identified prescription claims for opioids and sedative-hypnotics during three periods:

• Preoperative period – 365 days to 31 days before surgery.
• Perioperative period – 31 days before to 90 days after surgery.
• Postoperative period – 90 days to 365 days after surgery.

‘Striking’ results

Analyses were based on 25,270 women who were not prior users of opioids and 27,651 women who were not prior users of sedative-hypnotics.

Women were considered new persistent substance users if they had no use in the preoperative period but filled at least one prescription in the perioperative period and at least two in the postoperative period.

Overall, 13.1% of opioid-naive patients became persistent opioid users, and 6.6% of sedative-hypnotic-naive patients became persistent sedative-hypnotic users after their mastectomy and reconstruction.

Proportions of substance use were even higher, 17.5% for opioids and 17.0% for sedative-hypnotics, after excluding women who did not receive or fill a perioperative prescription.

In multivariate analysis, patients were significantly more likely to become new persistent opioid users if they had Medicaid insurance (odds ratio, 2.31), had a breast cancer diagnosis vs a prophylactic indication (OR, 1.44), received chemotherapy (OR, 1.33), and were 50-64 years of age (OR, 1.29) or 49 years or younger (OR, 1.27), compared with 65 years or older.

Similarly, patients were significantly more likely to become new persistent sedative-hypnotic users if they received chemotherapy (OR, 2.24), had Medicaid insurance (OR, 1.85), had a breast cancer diagnosis (OR, 1.79), and were 50 to 64 years (OR, 1.65) or 49 years or younger (OR, 1.79).

Finally, patients’ likelihood of new persistent use increased with their number of risk factors. For persistent opioid use, the odds ratio rose from 2.27 in patients with two risk factors to 6.34 in those with five risk factors. For persistent sedative-hypnotic use, the odds ratio rose from 2.55 to 7.71, respectively.

The observed incidences of new persistent substance use in this patient population are “striking,” according to Dr. Cogan. Although the identified risk factors can help providers spot patients who should be monitored more closely, a proactive, systematic approach to postoperative follow-up for all patients is likely needed.

“When you are seeing patients in follow-up, this is something that you might want to explicitly ask about, for example, and not just assume that the postoperative opioids were taken and then disposed of,” Dr. Cogan recommended. “Ask them, ‘Are you still taking opioids, are you still taking your Ambien or whatever medication you were prescribed?’ That’s something to diligently follow up on and make sure the drug is disposed of, or if it somebody is still taking it, refer them for the appropriate services.”

In addition, patients should be encouraged to use over-the-counter medications as much as possible, he advised.
 

Prescribing: It’s complicated

“I wonder if perhaps we should not be giving opioids at all to certain patients. For example, a mastectomy and implant reconstruction, oftentimes, surprisingly, that’s not a terribly painful procedure. But a TRAM [transverse rectus abdominis] flap or abdominal flap, that really is,” commented press conference comoderator C. Kent Osborne, MD, of Baylor College of Medicine in Houston.

“I’ve been surprised that a lot of my patients get the prescription, but they don’t even use the pills, and I wonder if the prescription is given just so that we’re not bothered at nighttime by somebody calling with pain,” Dr. Osbourne added.

Prescribing opioids for postoperative pain is complicated, Dr. Cogan said, noting that the study did not assess the specific type of reconstruction patients had.

“You don’t want people in pain. Even if they need just one or two pills, it’s still reasonable for them to have it, and we certainly don’t want to imply from our study that people shouldn’t be getting these prescriptions if they need them,” Dr. Cogan elaborated. “But once patients have them, don’t just leave them there in their home because other studies have shown that that’s when people really get addicted to these medications, when they use them later on for other reasons, or they keep using them just because they have them around.”

The risk for persistent use of controlled substances “is something that all physicians need to be aware of for their patients. This is something that we are missing,” maintained press conference comoderator Virginia Kaklamani, MD, DSc, of UT Health San Antonio.

“It’s easy to just give a prescription instead of arguing with a patient about why you are not going to give them a prescription,” Dr. Kaklamani said. “And ultimately ... pain is subjective. If a patient tells you they are in pain, you are, quote-endquote, a bad physician if you tell them they should not be in pain.”

Courtesy The University of Texas Health Science Center at San Antonio

“We need to focus on other ways to deal with the pain, like physical therapy, sending patients to physical medicine and rehab physicians who are trained to help with symptoms from the surgery, with range of motion and all that; that can help with pain,” she recommended. “It’s much harder to do that, right, than to send a prescription in for a narcotic? But that easy answer is always the worst answer.”

This study was funded by the Breast Cancer Research Foundation and the National Institutes of Health. Dr. Cogan declared no conflicts of interest. Dr. Osborne disclosed relationships with Wolters Kluwer, Lilly, Tolmar, and GeneTex. Dr. Kaklamani disclosed relationships with Amgen, AstraZeneca, Athenex, Celgene, Celldex, Daiichi, Eisai, Genentech, Genomic Health, Immunomedics, Novartis, Pfizer, Puma, and Seattle Genetics.

SOURCE: Cogan JC et al. SABCS 2020, Abstract GS3-08.

The cognitive and emotional status of children with sickle cell disease (SCD) appears to have a significant effect on how they cope with pain and use health care resources, investigators have found.

Results of a retrospective study of 112 children and adolescents with SCD, the majority of whom had sickle cell anemia, showed that ED visits and hospitalizations were significantly lower among children with SCD who performed better on an attention task, as well as those who were better able to cope emotionally with having SCD and pain, reported Zaria Williams, a second-year medical student at Howard University, Washington, and colleagues.

“Since I started learning more about sickle cell disease, I’ve been very concerned about the great disease burden that this condition can place on pediatric patients, particularly those who suffer from pain,” Ms. Williams said in an oral abstract presented at the annual meeting of the American Society of Hematology.

Although many children and adolescents with SCD can have their pain effectively managed at home with opioids and other medications, some require ED visits and potentially hospitalizations for pain management.

“There is great variability in health care utilization among patients with sickle cell disease, with some having to come to the ED and be admit to the hospital more than others. In searching for reasons why this might be the case, we thought about cognitive function and emotional differences between children with sickle cell disease as potentially affecting disease management,” she said.
 

Anxiety and catastrophizing

Children with SCD are known to be susceptible to affective comorbidities such as anxiety and catastrophizing, and to conditions that have the potential for deleterious effects on executive function, attention, and working memory. To determine whether cognitive and emotional factors affect the disease self-management in children and adolescents with SCD, Ms. Williams and coinvestigators looked at a cohort of 112 SCD patients aged 7-16 years treated at Children’s National Hospital in Washington, D.C.

The patients had participated in a previous pilot study of computerized working memory training. The authors reviewed charts for data on health care utilization, focusing on ED visits and hospitalization for pain 1 and 3 years after enrollment in the study.

They collected data on SCD genotype, disease-related variables, psychosocial information, and measures of cognition and emotion from the dataset. The information included socioeconomic status, parent education level, household income, and number of adults in the household.

Cognitive measures included the Weschler Intelligence Scale for Children full scale IQ, and the Cogstate computerized cognitive assessment system, which measures attention, executive function, and working memory.

Emotional measures were captured from the Pediatric Quality of Life Inventory Sickle Cell Disease module, including questions about worrying and emotions such as anger regarding SCD and pain.

The mean age of participants was 10.61 years. Of the 112 children/adolescents in the study, 65 (58%) were female, and 83 (74%) had sickle cell anemia (either HbSS or HbSβ0 thalassemia).

The participants had a median number of ED visits for pain of one within a year of enrollment, and a median of three within 3 years of enrollment,

The median number of hospital admissions for pain was zero and one, respectively.
 

Attention, emotions linked to higher use

Factors significantly associated with ED visits for pain within the first year were higher (worse) scores for attention (P = .001) and self-reported emotion (P = .049). ED visits within 3 years of enrollment were associated with attention (P = .003) and working memory (P = .039).

Similarly, hospitalizations for pain within the first year were significantly associated with worse attention scores (P = .009) and child-reported emotion (P = .013). Hospitalizations for pain within 3 years of enrollment were also significantly associated with attention deficits (P = .006) and with worse emotional function as reported by a parent (P = .020).

There was no significant effect of SCD genotype or socioeconomic status on either pain-related ED visits or hospitalizations, however.

The investigators theorized that poor attention may make it difficult to distract children from focusing on their pain, and could also hamper disease self-management strategies such as medication adherence and avoiding pain triggers.
 

Age-related differences?

In the question-and-answer session following her presentation, comoderator Susanna A Curtis, MD, from Yale New Haven (Conn.) Hospital, commented that “some previous work has shown that adolescents and young adults with sickle cell disease have higher utilization as compared to their younger counterparts,” and asked whether the investigators found differences between cognition and utilization among different age groups within the cohort.

“We didn’t find a significant association with age, but I’m also very interested in that as well, especially considering that maybe there is more or less parent involvement, considering how old the child is,” Ms. Williams said.

Dr. Curtis noted that many of the comorbidities of sickle cell disease such as stroke or degree of anemia can affect cognitive function, but can also have an effect on health care utilization as well, asked whether the investigators were able to look at the potential confounding effects of comorbidities.

Ms. Williams said that, although they have not looked at potential confounders as yet, they hope to do so in future research.

Asked by another audience member whether the authors had considered using the Pain Catastrophizing Scale for children and/or their parents, in addition to other markers, Ms. Williams replied that “I definitely have considered it. Under recommendations from my mentors, we just focused on the quality-of-life scale first, but catastrophizing is something I’m very interested in. Especially, I would love to have the parent factors as well, so along the journey I hope to include that.”

The study was sponsored in part by a grant from the Doris Duke Charitable Foundation. Ms Williams is the recipient of an ASH Minority Medical Student Award. Dr. Curtis and Ms. Williams both reported no relevant conflicts of interest to disclose.

SOURCE: Williams Z et al. ASH 2020, Abstract 366

The cognitive and emotional status of children with sickle cell disease (SCD) appears to have a significant effect on how they cope with pain and use health care resources, investigators have found.

Results of a retrospective study of 112 children and adolescents with SCD, the majority of whom had sickle cell anemia, showed that ED visits and hospitalizations were significantly lower among children with SCD who performed better on an attention task, as well as those who were better able to cope emotionally with having SCD and pain, reported Zaria Williams, a second-year medical student at Howard University, Washington, and colleagues.

“Since I started learning more about sickle cell disease, I’ve been very concerned about the great disease burden that this condition can place on pediatric patients, particularly those who suffer from pain,” Ms. Williams said in an oral abstract presented at the annual meeting of the American Society of Hematology.

Although many children and adolescents with SCD can have their pain effectively managed at home with opioids and other medications, some require ED visits and potentially hospitalizations for pain management.

“There is great variability in health care utilization among patients with sickle cell disease, with some having to come to the ED and be admit to the hospital more than others. In searching for reasons why this might be the case, we thought about cognitive function and emotional differences between children with sickle cell disease as potentially affecting disease management,” she said.
 

Anxiety and catastrophizing

Children with SCD are known to be susceptible to affective comorbidities such as anxiety and catastrophizing, and to conditions that have the potential for deleterious effects on executive function, attention, and working memory. To determine whether cognitive and emotional factors affect the disease self-management in children and adolescents with SCD, Ms. Williams and coinvestigators looked at a cohort of 112 SCD patients aged 7-16 years treated at Children’s National Hospital in Washington, D.C.

The patients had participated in a previous pilot study of computerized working memory training. The authors reviewed charts for data on health care utilization, focusing on ED visits and hospitalization for pain 1 and 3 years after enrollment in the study.

They collected data on SCD genotype, disease-related variables, psychosocial information, and measures of cognition and emotion from the dataset. The information included socioeconomic status, parent education level, household income, and number of adults in the household.

Cognitive measures included the Weschler Intelligence Scale for Children full scale IQ, and the Cogstate computerized cognitive assessment system, which measures attention, executive function, and working memory.

Emotional measures were captured from the Pediatric Quality of Life Inventory Sickle Cell Disease module, including questions about worrying and emotions such as anger regarding SCD and pain.

The mean age of participants was 10.61 years. Of the 112 children/adolescents in the study, 65 (58%) were female, and 83 (74%) had sickle cell anemia (either HbSS or HbSβ0 thalassemia).

The participants had a median number of ED visits for pain of one within a year of enrollment, and a median of three within 3 years of enrollment,

The median number of hospital admissions for pain was zero and one, respectively.
 

Attention, emotions linked to higher use

Factors significantly associated with ED visits for pain within the first year were higher (worse) scores for attention (P = .001) and self-reported emotion (P = .049). ED visits within 3 years of enrollment were associated with attention (P = .003) and working memory (P = .039).

Similarly, hospitalizations for pain within the first year were significantly associated with worse attention scores (P = .009) and child-reported emotion (P = .013). Hospitalizations for pain within 3 years of enrollment were also significantly associated with attention deficits (P = .006) and with worse emotional function as reported by a parent (P = .020).

There was no significant effect of SCD genotype or socioeconomic status on either pain-related ED visits or hospitalizations, however.

The investigators theorized that poor attention may make it difficult to distract children from focusing on their pain, and could also hamper disease self-management strategies such as medication adherence and avoiding pain triggers.
 

Age-related differences?

In the question-and-answer session following her presentation, comoderator Susanna A Curtis, MD, from Yale New Haven (Conn.) Hospital, commented that “some previous work has shown that adolescents and young adults with sickle cell disease have higher utilization as compared to their younger counterparts,” and asked whether the investigators found differences between cognition and utilization among different age groups within the cohort.

“We didn’t find a significant association with age, but I’m also very interested in that as well, especially considering that maybe there is more or less parent involvement, considering how old the child is,” Ms. Williams said.

Dr. Curtis noted that many of the comorbidities of sickle cell disease such as stroke or degree of anemia can affect cognitive function, but can also have an effect on health care utilization as well, asked whether the investigators were able to look at the potential confounding effects of comorbidities.

Ms. Williams said that, although they have not looked at potential confounders as yet, they hope to do so in future research.

Asked by another audience member whether the authors had considered using the Pain Catastrophizing Scale for children and/or their parents, in addition to other markers, Ms. Williams replied that “I definitely have considered it. Under recommendations from my mentors, we just focused on the quality-of-life scale first, but catastrophizing is something I’m very interested in. Especially, I would love to have the parent factors as well, so along the journey I hope to include that.”

The study was sponsored in part by a grant from the Doris Duke Charitable Foundation. Ms Williams is the recipient of an ASH Minority Medical Student Award. Dr. Curtis and Ms. Williams both reported no relevant conflicts of interest to disclose.

SOURCE: Williams Z et al. ASH 2020, Abstract 366

The cognitive and emotional status of children with sickle cell disease (SCD) appears to have a significant effect on how they cope with pain and use health care resources, investigators have found.

Results of a retrospective study of 112 children and adolescents with SCD, the majority of whom had sickle cell anemia, showed that ED visits and hospitalizations were significantly lower among children with SCD who performed better on an attention task, as well as those who were better able to cope emotionally with having SCD and pain, reported Zaria Williams, a second-year medical student at Howard University, Washington, and colleagues.

“Since I started learning more about sickle cell disease, I’ve been very concerned about the great disease burden that this condition can place on pediatric patients, particularly those who suffer from pain,” Ms. Williams said in an oral abstract presented at the annual meeting of the American Society of Hematology.

Although many children and adolescents with SCD can have their pain effectively managed at home with opioids and other medications, some require ED visits and potentially hospitalizations for pain management.

“There is great variability in health care utilization among patients with sickle cell disease, with some having to come to the ED and be admit to the hospital more than others. In searching for reasons why this might be the case, we thought about cognitive function and emotional differences between children with sickle cell disease as potentially affecting disease management,” she said.
 

Anxiety and catastrophizing

Children with SCD are known to be susceptible to affective comorbidities such as anxiety and catastrophizing, and to conditions that have the potential for deleterious effects on executive function, attention, and working memory. To determine whether cognitive and emotional factors affect the disease self-management in children and adolescents with SCD, Ms. Williams and coinvestigators looked at a cohort of 112 SCD patients aged 7-16 years treated at Children’s National Hospital in Washington, D.C.

The patients had participated in a previous pilot study of computerized working memory training. The authors reviewed charts for data on health care utilization, focusing on ED visits and hospitalization for pain 1 and 3 years after enrollment in the study.

They collected data on SCD genotype, disease-related variables, psychosocial information, and measures of cognition and emotion from the dataset. The information included socioeconomic status, parent education level, household income, and number of adults in the household.

Cognitive measures included the Weschler Intelligence Scale for Children full scale IQ, and the Cogstate computerized cognitive assessment system, which measures attention, executive function, and working memory.

Emotional measures were captured from the Pediatric Quality of Life Inventory Sickle Cell Disease module, including questions about worrying and emotions such as anger regarding SCD and pain.

The mean age of participants was 10.61 years. Of the 112 children/adolescents in the study, 65 (58%) were female, and 83 (74%) had sickle cell anemia (either HbSS or HbSβ0 thalassemia).

The participants had a median number of ED visits for pain of one within a year of enrollment, and a median of three within 3 years of enrollment,

The median number of hospital admissions for pain was zero and one, respectively.
 

Attention, emotions linked to higher use

Factors significantly associated with ED visits for pain within the first year were higher (worse) scores for attention (P = .001) and self-reported emotion (P = .049). ED visits within 3 years of enrollment were associated with attention (P = .003) and working memory (P = .039).

Similarly, hospitalizations for pain within the first year were significantly associated with worse attention scores (P = .009) and child-reported emotion (P = .013). Hospitalizations for pain within 3 years of enrollment were also significantly associated with attention deficits (P = .006) and with worse emotional function as reported by a parent (P = .020).

There was no significant effect of SCD genotype or socioeconomic status on either pain-related ED visits or hospitalizations, however.

The investigators theorized that poor attention may make it difficult to distract children from focusing on their pain, and could also hamper disease self-management strategies such as medication adherence and avoiding pain triggers.
 

Age-related differences?

In the question-and-answer session following her presentation, comoderator Susanna A Curtis, MD, from Yale New Haven (Conn.) Hospital, commented that “some previous work has shown that adolescents and young adults with sickle cell disease have higher utilization as compared to their younger counterparts,” and asked whether the investigators found differences between cognition and utilization among different age groups within the cohort.

“We didn’t find a significant association with age, but I’m also very interested in that as well, especially considering that maybe there is more or less parent involvement, considering how old the child is,” Ms. Williams said.

Dr. Curtis noted that many of the comorbidities of sickle cell disease such as stroke or degree of anemia can affect cognitive function, but can also have an effect on health care utilization as well, asked whether the investigators were able to look at the potential confounding effects of comorbidities.

Ms. Williams said that, although they have not looked at potential confounders as yet, they hope to do so in future research.

Asked by another audience member whether the authors had considered using the Pain Catastrophizing Scale for children and/or their parents, in addition to other markers, Ms. Williams replied that “I definitely have considered it. Under recommendations from my mentors, we just focused on the quality-of-life scale first, but catastrophizing is something I’m very interested in. Especially, I would love to have the parent factors as well, so along the journey I hope to include that.”

The study was sponsored in part by a grant from the Doris Duke Charitable Foundation. Ms Williams is the recipient of an ASH Minority Medical Student Award. Dr. Curtis and Ms. Williams both reported no relevant conflicts of interest to disclose.

SOURCE: Williams Z et al. ASH 2020, Abstract 366

When chronic graft-versus-host disease (cGVHD) develops as a complication of allogeneic hematopoietic stem cell transplant (alloHSCT), treatment options are limited. New findings show that ruxolitinib (Jakafi) was superior to standard therapy in reducing symptoms of cGVHD in the second-line setting, and the results are potentially practice changing.  

The new data, from the REACH3 trial, were presented at the annual meeting of the American Society of Hematology, held virtually this year.

This trial is “almost certainly a practice changer,” Robert Brodsky, MD, ASH secretary, said during a press preview webinar.  

Chronic GVHD occurs in approximately 30%-70% of patients who undergo alloSCT, and “has been really hard to treat,” said Dr. Brodsky, of Johns Hopkins University, Baltimore. “Steroids are the first-line treatment, but after that, nothing else has shown any improvement and even steroids don’t work that well.”

Of the patients assessed, 50% of those who received ruxolitinib responded to therapy compared with only 25% who received standard therapies.

“This is the first multicenter randomized controlled trial for chronic GVHD that is positive,” said senior study author Robert Zeiser, PhD, of University Medical Center, Freiburg, Germany. “It shows a significant advantage for ruxolitinib. It is likely that this trial will lead to approval for this indication and change the guidelines for the treatment of this disease.”

Ruxolitinib, a JAK inhibitor first marketed for use in myelofibrosis, is already  approved for acute GVHD. The Food and Drug Administration approved that indication last year on the basis of data from two previous trials, REACH 1 and REACH 2. The trials found that ruxolitinib was superior to best available therapy for treating patients with acute GVHD.
 

Superior to best available therapy

In the current REACH 3 study, Dr. Zeiser and colleagues compared ruxolitinib with best available therapy in 329 patients with moderate-to-severe cGVHD (both steroid dependent and steroid resistant).

All patients had undergone alloSCT and were randomly assigned to ruxolitinib (10 mg twice daily) for six 28-day cycles or investigator-selected best available therapy (BAT), of which there were 10 options. Patients continued receiving their regimen of corticosteroids, and viral prophylaxis and antibiotics were allowed as needed for infection prevention and treatment.

The study permitted crossover: Patients on BAT were allowed to start on ruxolitinib on or after cycle 7 day 1 for those who did not achieve or maintain a response, developed toxicity to BAT, or had a cGVHD flare.

The study met its primary endpoint of overall response rate (ORR), with a clear and substantial improvement among patients taking ruxolitinib (50% vs 26%; odds ratio, 2.99; P < .0001a), Dr. Zeiser noted. The complete response rate was also higher (7% vs. 3%).

Both key secondary endpoints also showed that ruxolitinib was superior to BAT. Failure-free survival was significantly longer in the ruxolitinib group (median not reached vs 5.7 months; hazard ratio, 0.370; P < .0001). There was also an improvement in symptoms based on changes in the modified Lee symptom score (mLSS; 0 [no symptoms] to 100 [worst symptoms]) at cycle 7 day 1; the results show that the mLSS responder rate was higher in patients on ruxolitinib (24% vs. 11%; odds ratio, 2.62; P = .0011).

A total of 31 patients in the ruxolitinib group died (19%) along with 27 in the BAT group (16%), with the cGVHD as the main cause of death.

Adverse events were comparable in both groups (ruxolitinib 98% [grade ≥ 3, 57%]; BAT, 92% [grade ≥ 3, 58%], with the most common being anemia (29% vs. 13%), hypertension (16% vs. 13%), pyrexia (16% vs. 9%), and ALT increase (15% vs 4%).
 

More options for patients

“The addition of ruxolitinib is definitely practice changing for this very difficult to treat population,” said James Essell, MD,  medical director of the Blood Cancer Center at Mercy Health, Cincinnati, who was not involved in the study.

However, he added, “more options are still required, as evidenced by the continued deaths of patients despite this new option.”

Dr. Essell pointed out that ibrutinib (Imbruvica) is already approved for the treatment of cGVHD. “Ruxolitinib offers another option for treating this group of patients,” he said, and predicted that “it will be used frequently and has a different toxicity profile, ultimately improving the care for patients with cGVHD.”

It is likely that ruxolitinib will be considered earlier in the treatment of cGVHD to avoid the toxicity of chronic steroid use, he added, but price is a consideration. “The cost of ruxolitinib is over 200 times more than prednisone, limiting the adoption front line without a clinical trial.”

Another expert approached for comment was enthusiastic. “The abstract gave good evidence and efficacy with chronic GVHD,” said Ryotaro Nakamura, MD, associate professor of hematology & hematopoietic cell transplantation at City of Hope, Duarte, Calif. He noted that there have been two previous REACH trials which showed a benefit for ruxolitinib in acute GVHD.

What this means is that there is now global evidence that ruxolitinib is better than anything else so far, he said, and this latest trial is just part of the “practice-changing data,” from the three studies. “It is practice changing in that it is providing options now for these patients,” he said.

Dr. Zeiser has disclosed relationships with Incyte, Novartis and Mallinckrodt; other authors disclosed relationships with industry as noted in the abstract. Dr. Essell and Dr. Nakamura have disclosed no relevant financial relationships.

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

When chronic graft-versus-host disease (cGVHD) develops as a complication of allogeneic hematopoietic stem cell transplant (alloHSCT), treatment options are limited. New findings show that ruxolitinib (Jakafi) was superior to standard therapy in reducing symptoms of cGVHD in the second-line setting, and the results are potentially practice changing.  

The new data, from the REACH3 trial, were presented at the annual meeting of the American Society of Hematology, held virtually this year.

This trial is “almost certainly a practice changer,” Robert Brodsky, MD, ASH secretary, said during a press preview webinar.  

Chronic GVHD occurs in approximately 30%-70% of patients who undergo alloSCT, and “has been really hard to treat,” said Dr. Brodsky, of Johns Hopkins University, Baltimore. “Steroids are the first-line treatment, but after that, nothing else has shown any improvement and even steroids don’t work that well.”

Of the patients assessed, 50% of those who received ruxolitinib responded to therapy compared with only 25% who received standard therapies.

“This is the first multicenter randomized controlled trial for chronic GVHD that is positive,” said senior study author Robert Zeiser, PhD, of University Medical Center, Freiburg, Germany. “It shows a significant advantage for ruxolitinib. It is likely that this trial will lead to approval for this indication and change the guidelines for the treatment of this disease.”

Ruxolitinib, a JAK inhibitor first marketed for use in myelofibrosis, is already  approved for acute GVHD. The Food and Drug Administration approved that indication last year on the basis of data from two previous trials, REACH 1 and REACH 2. The trials found that ruxolitinib was superior to best available therapy for treating patients with acute GVHD.
 

Superior to best available therapy

In the current REACH 3 study, Dr. Zeiser and colleagues compared ruxolitinib with best available therapy in 329 patients with moderate-to-severe cGVHD (both steroid dependent and steroid resistant).

All patients had undergone alloSCT and were randomly assigned to ruxolitinib (10 mg twice daily) for six 28-day cycles or investigator-selected best available therapy (BAT), of which there were 10 options. Patients continued receiving their regimen of corticosteroids, and viral prophylaxis and antibiotics were allowed as needed for infection prevention and treatment.

The study permitted crossover: Patients on BAT were allowed to start on ruxolitinib on or after cycle 7 day 1 for those who did not achieve or maintain a response, developed toxicity to BAT, or had a cGVHD flare.

The study met its primary endpoint of overall response rate (ORR), with a clear and substantial improvement among patients taking ruxolitinib (50% vs 26%; odds ratio, 2.99; P < .0001a), Dr. Zeiser noted. The complete response rate was also higher (7% vs. 3%).

Both key secondary endpoints also showed that ruxolitinib was superior to BAT. Failure-free survival was significantly longer in the ruxolitinib group (median not reached vs 5.7 months; hazard ratio, 0.370; P < .0001). There was also an improvement in symptoms based on changes in the modified Lee symptom score (mLSS; 0 [no symptoms] to 100 [worst symptoms]) at cycle 7 day 1; the results show that the mLSS responder rate was higher in patients on ruxolitinib (24% vs. 11%; odds ratio, 2.62; P = .0011).

A total of 31 patients in the ruxolitinib group died (19%) along with 27 in the BAT group (16%), with the cGVHD as the main cause of death.

Adverse events were comparable in both groups (ruxolitinib 98% [grade ≥ 3, 57%]; BAT, 92% [grade ≥ 3, 58%], with the most common being anemia (29% vs. 13%), hypertension (16% vs. 13%), pyrexia (16% vs. 9%), and ALT increase (15% vs 4%).
 

More options for patients

“The addition of ruxolitinib is definitely practice changing for this very difficult to treat population,” said James Essell, MD,  medical director of the Blood Cancer Center at Mercy Health, Cincinnati, who was not involved in the study.

However, he added, “more options are still required, as evidenced by the continued deaths of patients despite this new option.”

Dr. Essell pointed out that ibrutinib (Imbruvica) is already approved for the treatment of cGVHD. “Ruxolitinib offers another option for treating this group of patients,” he said, and predicted that “it will be used frequently and has a different toxicity profile, ultimately improving the care for patients with cGVHD.”

It is likely that ruxolitinib will be considered earlier in the treatment of cGVHD to avoid the toxicity of chronic steroid use, he added, but price is a consideration. “The cost of ruxolitinib is over 200 times more than prednisone, limiting the adoption front line without a clinical trial.”

Another expert approached for comment was enthusiastic. “The abstract gave good evidence and efficacy with chronic GVHD,” said Ryotaro Nakamura, MD, associate professor of hematology & hematopoietic cell transplantation at City of Hope, Duarte, Calif. He noted that there have been two previous REACH trials which showed a benefit for ruxolitinib in acute GVHD.

What this means is that there is now global evidence that ruxolitinib is better than anything else so far, he said, and this latest trial is just part of the “practice-changing data,” from the three studies. “It is practice changing in that it is providing options now for these patients,” he said.

Dr. Zeiser has disclosed relationships with Incyte, Novartis and Mallinckrodt; other authors disclosed relationships with industry as noted in the abstract. Dr. Essell and Dr. Nakamura have disclosed no relevant financial relationships.

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

When chronic graft-versus-host disease (cGVHD) develops as a complication of allogeneic hematopoietic stem cell transplant (alloHSCT), treatment options are limited. New findings show that ruxolitinib (Jakafi) was superior to standard therapy in reducing symptoms of cGVHD in the second-line setting, and the results are potentially practice changing.  

The new data, from the REACH3 trial, were presented at the annual meeting of the American Society of Hematology, held virtually this year.

This trial is “almost certainly a practice changer,” Robert Brodsky, MD, ASH secretary, said during a press preview webinar.  

Chronic GVHD occurs in approximately 30%-70% of patients who undergo alloSCT, and “has been really hard to treat,” said Dr. Brodsky, of Johns Hopkins University, Baltimore. “Steroids are the first-line treatment, but after that, nothing else has shown any improvement and even steroids don’t work that well.”

Of the patients assessed, 50% of those who received ruxolitinib responded to therapy compared with only 25% who received standard therapies.

“This is the first multicenter randomized controlled trial for chronic GVHD that is positive,” said senior study author Robert Zeiser, PhD, of University Medical Center, Freiburg, Germany. “It shows a significant advantage for ruxolitinib. It is likely that this trial will lead to approval for this indication and change the guidelines for the treatment of this disease.”

Ruxolitinib, a JAK inhibitor first marketed for use in myelofibrosis, is already  approved for acute GVHD. The Food and Drug Administration approved that indication last year on the basis of data from two previous trials, REACH 1 and REACH 2. The trials found that ruxolitinib was superior to best available therapy for treating patients with acute GVHD.
 

Superior to best available therapy

In the current REACH 3 study, Dr. Zeiser and colleagues compared ruxolitinib with best available therapy in 329 patients with moderate-to-severe cGVHD (both steroid dependent and steroid resistant).

All patients had undergone alloSCT and were randomly assigned to ruxolitinib (10 mg twice daily) for six 28-day cycles or investigator-selected best available therapy (BAT), of which there were 10 options. Patients continued receiving their regimen of corticosteroids, and viral prophylaxis and antibiotics were allowed as needed for infection prevention and treatment.

The study permitted crossover: Patients on BAT were allowed to start on ruxolitinib on or after cycle 7 day 1 for those who did not achieve or maintain a response, developed toxicity to BAT, or had a cGVHD flare.

The study met its primary endpoint of overall response rate (ORR), with a clear and substantial improvement among patients taking ruxolitinib (50% vs 26%; odds ratio, 2.99; P < .0001a), Dr. Zeiser noted. The complete response rate was also higher (7% vs. 3%).

Both key secondary endpoints also showed that ruxolitinib was superior to BAT. Failure-free survival was significantly longer in the ruxolitinib group (median not reached vs 5.7 months; hazard ratio, 0.370; P < .0001). There was also an improvement in symptoms based on changes in the modified Lee symptom score (mLSS; 0 [no symptoms] to 100 [worst symptoms]) at cycle 7 day 1; the results show that the mLSS responder rate was higher in patients on ruxolitinib (24% vs. 11%; odds ratio, 2.62; P = .0011).

A total of 31 patients in the ruxolitinib group died (19%) along with 27 in the BAT group (16%), with the cGVHD as the main cause of death.

Adverse events were comparable in both groups (ruxolitinib 98% [grade ≥ 3, 57%]; BAT, 92% [grade ≥ 3, 58%], with the most common being anemia (29% vs. 13%), hypertension (16% vs. 13%), pyrexia (16% vs. 9%), and ALT increase (15% vs 4%).
 

More options for patients

“The addition of ruxolitinib is definitely practice changing for this very difficult to treat population,” said James Essell, MD,  medical director of the Blood Cancer Center at Mercy Health, Cincinnati, who was not involved in the study.

However, he added, “more options are still required, as evidenced by the continued deaths of patients despite this new option.”

Dr. Essell pointed out that ibrutinib (Imbruvica) is already approved for the treatment of cGVHD. “Ruxolitinib offers another option for treating this group of patients,” he said, and predicted that “it will be used frequently and has a different toxicity profile, ultimately improving the care for patients with cGVHD.”

It is likely that ruxolitinib will be considered earlier in the treatment of cGVHD to avoid the toxicity of chronic steroid use, he added, but price is a consideration. “The cost of ruxolitinib is over 200 times more than prednisone, limiting the adoption front line without a clinical trial.”

Another expert approached for comment was enthusiastic. “The abstract gave good evidence and efficacy with chronic GVHD,” said Ryotaro Nakamura, MD, associate professor of hematology & hematopoietic cell transplantation at City of Hope, Duarte, Calif. He noted that there have been two previous REACH trials which showed a benefit for ruxolitinib in acute GVHD.

What this means is that there is now global evidence that ruxolitinib is better than anything else so far, he said, and this latest trial is just part of the “practice-changing data,” from the three studies. “It is practice changing in that it is providing options now for these patients,” he said.

Dr. Zeiser has disclosed relationships with Incyte, Novartis and Mallinckrodt; other authors disclosed relationships with industry as noted in the abstract. Dr. Essell and Dr. Nakamura have disclosed no relevant financial relationships.

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

Despite being routinely used in clinical settings, prophylactic use of tranexamic acid, an antifibrinolytic agent administered with platelet transfusions, did not reduce bleeding among patients with blood cancers and severe thrombocytopenia, according to a new study.

The study compared tranexamic acid to placebo and found no significant differences in terms of the number of bleeding events, the number of red blood cell transfusions, or the number of platelet transfusions that were required.

However, the rate of occlusions in the central venous line was significantly higher for patients in the tranexamic acid group, although there was no difference between groups for other types of thrombotic events.

The findings were presented at the annual meeting of the American Society of Hematology, which was held online.

The study was highlighted as potentially practice changing at a press preview webinar by ASH Secretary Robert Brodsky, MD.

“They found absolutely no difference in bleeding or need for transfusion,” said Brodsky. “What they did find was more catheter-associated blood clots in the tranexamic acid group. This is a practice changer in that it probably should not be given prophylactically to patients with thrombocytopenia.”

Senior author Terry B. Gernsheimer, MD, of the University of Washington, Seattle, noted that tranexamic acid has been found to be effective in the treatment of bleeding related to childbirth, surgery, and inherited blood disorders.

It is also used for patients with blood cancers and severe thrombocytopenia. There is little evidence to support this use, which is why the researchers decided to investigate.

“Clearly patients with low platelet counts and blood cancers have a different kind of bleeding than the bleeding experienced by patients who have suffered some kind of trauma or surgery,” Dr. Gernsheimer said in a statement.

“Their bleeding likely is due to endothelial damage – damage to the lining of blood vessels – that tranexamic acid would not treat,” she added.

“To prevent bleeding in these patients, we may need to look at ways to speed the healing of the endothelium that occurs with chemotherapy, radiation, and graft-vs-host disease in patients receiving a transplant,” Dr. Gernsheimer commented.
 

Temper enthusiasm

“Overall, I think these results will temper enthusiasm for using tranexamic acid in this setting,” said Mitul Gandhi, MD, a medical oncologist with Virginia Cancer Specialists, who was approached for comment.

These data do not support the routine use of prophylactic tranexamic acid in chemotherapy-induced thrombocytopenia for patients with platelet counts lower than 30,000/μL, he added.

“The primary objective was not met, and there was an observed increased rate of catheter-associated thrombosis,” he said. “Continued use of judicious transfusion support and correction of a concomitant coagulopathy remains the main clinical approach to these patients.”

Dr. Gandhi commented that tranexamic acid “remains a potentially useful adjunct agent in certain cases of recalcitrant bleeding related to thrombocytopenia or coagulopathy.

“While there is no uniform scenario, it is typically reserved on a case-by-case basis after addressing vascular defects, utilization of platelet, fresh frozen plasma, cryoprecipitate transfusions, vitamin K repletion, and of course excluding any antiplatelet or anticoagulant therapy,» he told this news organization. “For persistent bleeding in spite of all corrective measures or hemorrhage into noncompressible vascular beds, such as with intracranial bleeds, antifibrinolytic therapy may assist in mitigating further blood loss.”

However, this has to be balanced with the potential increased risk for thrombosis after correction of the hemostatic insult.

At present, tranexamic acid “only has an FDA indication for uterine bleeding, but it is frequently used in trauma settings and obstetrical emergencies,” said Douglas Tremblay, MD, an internist at the Icahn School of Medicine at Mount Sinai, New York, who was also approached for comment.

“There is evidence from prior studies that were done 20 or 30 years ago that it may help in this setting, so it is used in some institutions, although we don’t give it prophylactically for patients with a hematologic malignancy.”

Although this was a negative study, Dr. Tremblay pointed out that one thing that may come out of it is that there may be subgroups who can benefit from the prophylactic use of tranexamic acid. “There is very wide inclusion criteria for the study – any type of hematologic malignancy in patients undergoing chemotherapy or stem cell transplant,” he said in an interview. “Even among chemotherapy and transplant patients, there are different risks for bleeding.”

For example, patients undergoing induction chemotherapy for acute myeloid leukemia are at an increased risk of bleeding in comparison with patients with other hematologic malignancies, and those undergoing allogeneic transplant are at an increased risk of bleeding in comparison with patients undergoing autologous transplant. “So while its unclear if a subgroup may benefit from this strategy, lumped together, it doesn’t appear it is of any benefit and potentially harmful, in terms of line occlusions,” he said. “While that may seem to be a nuisance, it can delay chemotherapy or supportive infusions, and that can be a big deal.”
 

No evidence of benefit

Dr. Gernsheimer and colleagues conducted the American Trial Using Tranexamic Acid in Thrombocytopenia (A-TREAT), which evaluated the effects of prophylactic tranexamic acid as an adjunct to routine transfusion therapy on bleeding and transfusion requirements.

A total of 330 patients were randomly assigned to receive either tranexamic acid 1,000 mg IV or 1,300 mg or placebo. Randomization was stratified by site and therapy: chemotherapy, allogeneic transplant, or autologous transplant. It was anticipated that all patients had hypoproliferative thrombocytopenia (expected platelet count, 10,000/µL for at least 5 days).

Treatment continued for 30 days or platelet count recovery (>30,000/µL), diagnosis of thrombosis or veno-occlusive disease, recurrent line occlusion, visible hematuria, or physician or patient request.

The primary endpoint of the study was the proportion of patients with bleeding of World Health Organization grade 2 or above over 30 days after beginning therapy. Secondary endpoints included the number of transfusions and the number of days alive without WHO grade 2+ bleeding during the first 30 days post activation of study drug.

The time to first WHO 2+ bleeding was “remarkably similar” between the tranexamic acid groups and the placebo group, said Dr. Gernsheimer.

In the cohort as a whole, 48.8% in the placebo group experienced a grade 2+ bleed vs. 45.4% in the tranexamic group (odds ratio, 0.86).

Similar results were observed across subgroups: allogeneic transplant, 57.3% vs. 58.8% (OR, 0.94); autologous transplant, 19.9% vs. 24.7% ( OR, 0.71); or chemotherapy, 48% vs. 52.1% (OR, 0.84).

There were no significant differences in mean number of transfusions (difference, 0.1; 95% confidence interval, –1.9 to 2) or days alive without grade 2 or higher bleeding (difference, 0.1; 95% CI, –1.4 to 1.5).

“A post hoc analysis of WHO 3+ bleeding showed these events to be rare and without any improvement with tranexamic acid,” she said.

A higher percentage of patients in the tranexamic acid group experienced thrombotic events (19.5% vs. 11%). “But importantly, in both groups, it was primarily due to central line occlusions without an associated thrombus,” said Dr. Gernsheimer. “This was statistically significant.”

Fewer non–catheter related thrombotic events occurred in the tranexamic acid group (3.7% vs. 5.5%), but the difference was not statistically significant.

There was also no significant difference between groups in veno-occlusive disease after 30 days (1.8% vs. 1.2%) or all-cause mortality at 30 days (2.4% vs. 3%) or 100 days (11.5% vs. 11.5%). No deaths associated with thrombosis had occurred in either group at 120 days.

The study was supported by the University of Washington and the National Heart, Lung, and Blood Institute. Dr. Gernsheimer has relationships with Amgen, Cellphire, Dova Pharmaceuticals, Novartis, Principia, Rigel, Sanofi, and Vertex. Dr. Tremblay and Dr. Gandhi have disclosed no relevant financial relationships.

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

Despite being routinely used in clinical settings, prophylactic use of tranexamic acid, an antifibrinolytic agent administered with platelet transfusions, did not reduce bleeding among patients with blood cancers and severe thrombocytopenia, according to a new study.

The study compared tranexamic acid to placebo and found no significant differences in terms of the number of bleeding events, the number of red blood cell transfusions, or the number of platelet transfusions that were required.

However, the rate of occlusions in the central venous line was significantly higher for patients in the tranexamic acid group, although there was no difference between groups for other types of thrombotic events.

The findings were presented at the annual meeting of the American Society of Hematology, which was held online.

The study was highlighted as potentially practice changing at a press preview webinar by ASH Secretary Robert Brodsky, MD.

“They found absolutely no difference in bleeding or need for transfusion,” said Brodsky. “What they did find was more catheter-associated blood clots in the tranexamic acid group. This is a practice changer in that it probably should not be given prophylactically to patients with thrombocytopenia.”

Senior author Terry B. Gernsheimer, MD, of the University of Washington, Seattle, noted that tranexamic acid has been found to be effective in the treatment of bleeding related to childbirth, surgery, and inherited blood disorders.

It is also used for patients with blood cancers and severe thrombocytopenia. There is little evidence to support this use, which is why the researchers decided to investigate.

“Clearly patients with low platelet counts and blood cancers have a different kind of bleeding than the bleeding experienced by patients who have suffered some kind of trauma or surgery,” Dr. Gernsheimer said in a statement.

“Their bleeding likely is due to endothelial damage – damage to the lining of blood vessels – that tranexamic acid would not treat,” she added.

“To prevent bleeding in these patients, we may need to look at ways to speed the healing of the endothelium that occurs with chemotherapy, radiation, and graft-vs-host disease in patients receiving a transplant,” Dr. Gernsheimer commented.
 

Temper enthusiasm

“Overall, I think these results will temper enthusiasm for using tranexamic acid in this setting,” said Mitul Gandhi, MD, a medical oncologist with Virginia Cancer Specialists, who was approached for comment.

These data do not support the routine use of prophylactic tranexamic acid in chemotherapy-induced thrombocytopenia for patients with platelet counts lower than 30,000/μL, he added.

“The primary objective was not met, and there was an observed increased rate of catheter-associated thrombosis,” he said. “Continued use of judicious transfusion support and correction of a concomitant coagulopathy remains the main clinical approach to these patients.”

Dr. Gandhi commented that tranexamic acid “remains a potentially useful adjunct agent in certain cases of recalcitrant bleeding related to thrombocytopenia or coagulopathy.

“While there is no uniform scenario, it is typically reserved on a case-by-case basis after addressing vascular defects, utilization of platelet, fresh frozen plasma, cryoprecipitate transfusions, vitamin K repletion, and of course excluding any antiplatelet or anticoagulant therapy,» he told this news organization. “For persistent bleeding in spite of all corrective measures or hemorrhage into noncompressible vascular beds, such as with intracranial bleeds, antifibrinolytic therapy may assist in mitigating further blood loss.”

However, this has to be balanced with the potential increased risk for thrombosis after correction of the hemostatic insult.

At present, tranexamic acid “only has an FDA indication for uterine bleeding, but it is frequently used in trauma settings and obstetrical emergencies,” said Douglas Tremblay, MD, an internist at the Icahn School of Medicine at Mount Sinai, New York, who was also approached for comment.

“There is evidence from prior studies that were done 20 or 30 years ago that it may help in this setting, so it is used in some institutions, although we don’t give it prophylactically for patients with a hematologic malignancy.”

Although this was a negative study, Dr. Tremblay pointed out that one thing that may come out of it is that there may be subgroups who can benefit from the prophylactic use of tranexamic acid. “There is very wide inclusion criteria for the study – any type of hematologic malignancy in patients undergoing chemotherapy or stem cell transplant,” he said in an interview. “Even among chemotherapy and transplant patients, there are different risks for bleeding.”

For example, patients undergoing induction chemotherapy for acute myeloid leukemia are at an increased risk of bleeding in comparison with patients with other hematologic malignancies, and those undergoing allogeneic transplant are at an increased risk of bleeding in comparison with patients undergoing autologous transplant. “So while its unclear if a subgroup may benefit from this strategy, lumped together, it doesn’t appear it is of any benefit and potentially harmful, in terms of line occlusions,” he said. “While that may seem to be a nuisance, it can delay chemotherapy or supportive infusions, and that can be a big deal.”
 

No evidence of benefit

Dr. Gernsheimer and colleagues conducted the American Trial Using Tranexamic Acid in Thrombocytopenia (A-TREAT), which evaluated the effects of prophylactic tranexamic acid as an adjunct to routine transfusion therapy on bleeding and transfusion requirements.

A total of 330 patients were randomly assigned to receive either tranexamic acid 1,000 mg IV or 1,300 mg or placebo. Randomization was stratified by site and therapy: chemotherapy, allogeneic transplant, or autologous transplant. It was anticipated that all patients had hypoproliferative thrombocytopenia (expected platelet count, 10,000/µL for at least 5 days).

Treatment continued for 30 days or platelet count recovery (>30,000/µL), diagnosis of thrombosis or veno-occlusive disease, recurrent line occlusion, visible hematuria, or physician or patient request.

The primary endpoint of the study was the proportion of patients with bleeding of World Health Organization grade 2 or above over 30 days after beginning therapy. Secondary endpoints included the number of transfusions and the number of days alive without WHO grade 2+ bleeding during the first 30 days post activation of study drug.

The time to first WHO 2+ bleeding was “remarkably similar” between the tranexamic acid groups and the placebo group, said Dr. Gernsheimer.

In the cohort as a whole, 48.8% in the placebo group experienced a grade 2+ bleed vs. 45.4% in the tranexamic group (odds ratio, 0.86).

Similar results were observed across subgroups: allogeneic transplant, 57.3% vs. 58.8% (OR, 0.94); autologous transplant, 19.9% vs. 24.7% ( OR, 0.71); or chemotherapy, 48% vs. 52.1% (OR, 0.84).

There were no significant differences in mean number of transfusions (difference, 0.1; 95% confidence interval, –1.9 to 2) or days alive without grade 2 or higher bleeding (difference, 0.1; 95% CI, –1.4 to 1.5).

“A post hoc analysis of WHO 3+ bleeding showed these events to be rare and without any improvement with tranexamic acid,” she said.

A higher percentage of patients in the tranexamic acid group experienced thrombotic events (19.5% vs. 11%). “But importantly, in both groups, it was primarily due to central line occlusions without an associated thrombus,” said Dr. Gernsheimer. “This was statistically significant.”

Fewer non–catheter related thrombotic events occurred in the tranexamic acid group (3.7% vs. 5.5%), but the difference was not statistically significant.

There was also no significant difference between groups in veno-occlusive disease after 30 days (1.8% vs. 1.2%) or all-cause mortality at 30 days (2.4% vs. 3%) or 100 days (11.5% vs. 11.5%). No deaths associated with thrombosis had occurred in either group at 120 days.

The study was supported by the University of Washington and the National Heart, Lung, and Blood Institute. Dr. Gernsheimer has relationships with Amgen, Cellphire, Dova Pharmaceuticals, Novartis, Principia, Rigel, Sanofi, and Vertex. Dr. Tremblay and Dr. Gandhi have disclosed no relevant financial relationships.

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

Despite being routinely used in clinical settings, prophylactic use of tranexamic acid, an antifibrinolytic agent administered with platelet transfusions, did not reduce bleeding among patients with blood cancers and severe thrombocytopenia, according to a new study.

The study compared tranexamic acid to placebo and found no significant differences in terms of the number of bleeding events, the number of red blood cell transfusions, or the number of platelet transfusions that were required.

However, the rate of occlusions in the central venous line was significantly higher for patients in the tranexamic acid group, although there was no difference between groups for other types of thrombotic events.

The findings were presented at the annual meeting of the American Society of Hematology, which was held online.

The study was highlighted as potentially practice changing at a press preview webinar by ASH Secretary Robert Brodsky, MD.

“They found absolutely no difference in bleeding or need for transfusion,” said Brodsky. “What they did find was more catheter-associated blood clots in the tranexamic acid group. This is a practice changer in that it probably should not be given prophylactically to patients with thrombocytopenia.”

Senior author Terry B. Gernsheimer, MD, of the University of Washington, Seattle, noted that tranexamic acid has been found to be effective in the treatment of bleeding related to childbirth, surgery, and inherited blood disorders.

It is also used for patients with blood cancers and severe thrombocytopenia. There is little evidence to support this use, which is why the researchers decided to investigate.

“Clearly patients with low platelet counts and blood cancers have a different kind of bleeding than the bleeding experienced by patients who have suffered some kind of trauma or surgery,” Dr. Gernsheimer said in a statement.

“Their bleeding likely is due to endothelial damage – damage to the lining of blood vessels – that tranexamic acid would not treat,” she added.

“To prevent bleeding in these patients, we may need to look at ways to speed the healing of the endothelium that occurs with chemotherapy, radiation, and graft-vs-host disease in patients receiving a transplant,” Dr. Gernsheimer commented.
 

Temper enthusiasm

“Overall, I think these results will temper enthusiasm for using tranexamic acid in this setting,” said Mitul Gandhi, MD, a medical oncologist with Virginia Cancer Specialists, who was approached for comment.

These data do not support the routine use of prophylactic tranexamic acid in chemotherapy-induced thrombocytopenia for patients with platelet counts lower than 30,000/μL, he added.

“The primary objective was not met, and there was an observed increased rate of catheter-associated thrombosis,” he said. “Continued use of judicious transfusion support and correction of a concomitant coagulopathy remains the main clinical approach to these patients.”

Dr. Gandhi commented that tranexamic acid “remains a potentially useful adjunct agent in certain cases of recalcitrant bleeding related to thrombocytopenia or coagulopathy.

“While there is no uniform scenario, it is typically reserved on a case-by-case basis after addressing vascular defects, utilization of platelet, fresh frozen plasma, cryoprecipitate transfusions, vitamin K repletion, and of course excluding any antiplatelet or anticoagulant therapy,» he told this news organization. “For persistent bleeding in spite of all corrective measures or hemorrhage into noncompressible vascular beds, such as with intracranial bleeds, antifibrinolytic therapy may assist in mitigating further blood loss.”

However, this has to be balanced with the potential increased risk for thrombosis after correction of the hemostatic insult.

At present, tranexamic acid “only has an FDA indication for uterine bleeding, but it is frequently used in trauma settings and obstetrical emergencies,” said Douglas Tremblay, MD, an internist at the Icahn School of Medicine at Mount Sinai, New York, who was also approached for comment.

“There is evidence from prior studies that were done 20 or 30 years ago that it may help in this setting, so it is used in some institutions, although we don’t give it prophylactically for patients with a hematologic malignancy.”

Although this was a negative study, Dr. Tremblay pointed out that one thing that may come out of it is that there may be subgroups who can benefit from the prophylactic use of tranexamic acid. “There is very wide inclusion criteria for the study – any type of hematologic malignancy in patients undergoing chemotherapy or stem cell transplant,” he said in an interview. “Even among chemotherapy and transplant patients, there are different risks for bleeding.”

For example, patients undergoing induction chemotherapy for acute myeloid leukemia are at an increased risk of bleeding in comparison with patients with other hematologic malignancies, and those undergoing allogeneic transplant are at an increased risk of bleeding in comparison with patients undergoing autologous transplant. “So while its unclear if a subgroup may benefit from this strategy, lumped together, it doesn’t appear it is of any benefit and potentially harmful, in terms of line occlusions,” he said. “While that may seem to be a nuisance, it can delay chemotherapy or supportive infusions, and that can be a big deal.”
 

No evidence of benefit

Dr. Gernsheimer and colleagues conducted the American Trial Using Tranexamic Acid in Thrombocytopenia (A-TREAT), which evaluated the effects of prophylactic tranexamic acid as an adjunct to routine transfusion therapy on bleeding and transfusion requirements.

A total of 330 patients were randomly assigned to receive either tranexamic acid 1,000 mg IV or 1,300 mg or placebo. Randomization was stratified by site and therapy: chemotherapy, allogeneic transplant, or autologous transplant. It was anticipated that all patients had hypoproliferative thrombocytopenia (expected platelet count, 10,000/µL for at least 5 days).

Treatment continued for 30 days or platelet count recovery (>30,000/µL), diagnosis of thrombosis or veno-occlusive disease, recurrent line occlusion, visible hematuria, or physician or patient request.

The primary endpoint of the study was the proportion of patients with bleeding of World Health Organization grade 2 or above over 30 days after beginning therapy. Secondary endpoints included the number of transfusions and the number of days alive without WHO grade 2+ bleeding during the first 30 days post activation of study drug.

The time to first WHO 2+ bleeding was “remarkably similar” between the tranexamic acid groups and the placebo group, said Dr. Gernsheimer.

In the cohort as a whole, 48.8% in the placebo group experienced a grade 2+ bleed vs. 45.4% in the tranexamic group (odds ratio, 0.86).

Similar results were observed across subgroups: allogeneic transplant, 57.3% vs. 58.8% (OR, 0.94); autologous transplant, 19.9% vs. 24.7% ( OR, 0.71); or chemotherapy, 48% vs. 52.1% (OR, 0.84).

There were no significant differences in mean number of transfusions (difference, 0.1; 95% confidence interval, –1.9 to 2) or days alive without grade 2 or higher bleeding (difference, 0.1; 95% CI, –1.4 to 1.5).

“A post hoc analysis of WHO 3+ bleeding showed these events to be rare and without any improvement with tranexamic acid,” she said.

A higher percentage of patients in the tranexamic acid group experienced thrombotic events (19.5% vs. 11%). “But importantly, in both groups, it was primarily due to central line occlusions without an associated thrombus,” said Dr. Gernsheimer. “This was statistically significant.”

Fewer non–catheter related thrombotic events occurred in the tranexamic acid group (3.7% vs. 5.5%), but the difference was not statistically significant.

There was also no significant difference between groups in veno-occlusive disease after 30 days (1.8% vs. 1.2%) or all-cause mortality at 30 days (2.4% vs. 3%) or 100 days (11.5% vs. 11.5%). No deaths associated with thrombosis had occurred in either group at 120 days.

The study was supported by the University of Washington and the National Heart, Lung, and Blood Institute. Dr. Gernsheimer has relationships with Amgen, Cellphire, Dova Pharmaceuticals, Novartis, Principia, Rigel, Sanofi, and Vertex. Dr. Tremblay and Dr. Gandhi have disclosed no relevant financial relationships.

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

Among chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) patients in the minimal residual disease (MRD) cohort of the phase 2 CAPTIVATE trial, a 1-year disease-free survival (DFS) rate of 95% in those randomized to placebo after 12 cycles of combined ibrutinib plus venetoclax supports a fixed-duration treatment approach, according to William G. Wierda, MD, PhD, University of Texas, MD Anderson Cancer Center, Houston.

Ibrutinib, a once-daily Bruton kinase inhibitor, is the only targeted therapy for first-line treatment of CLL that has demonstrated significant overall survival benefit in randomized phase 3 studies, Dr. Wierda said at the American Society of Hematology annual meeting, held virtually.

Ibrutinib and venetoclax have synergistic and complementary antitumor activity, he noted, through mobilizing and clearing CLL cells from protective niches and disease compartments beyond blood and bone marrow.

Fixed-duration study

CAPTIVATE (PCYC-1142), an international phase 2 study, evaluated first-line treatment with 12 cycles of the ibrutinib/venetoclax combination in MRD and fixed-duration cohorts. The current primary analysis of 1-year DFS from the MRD cohort tested whether the regimen allows for treatment-free remission in the setting of confirmed undetectable MRD (uMRD).

Patients (n = 164, median age 58 years) in the CAPTIVATE study MRD cohort had previously untreated active CLL/SLL requiring treatment per International Workshop on Chronic Lymphocytic Leukemia criteria.

They received 3 cycles of lead-in ibrutinib (420 mg once daily) followed by 12 cycles of ibrutinib (420 mg once daily plus venetoclax ramp-up to 400 mg once daily). Thereafter, in an MRD-guided 1:1 randomization stratified by immunoglobulin heavy chain (IGHV) mutational status, those with confirmed uMRD received either placebo or ibrutinib, and those with uMRD not confirmed received either ibrutinib or ibrutinib plus venetoclax (both open-label).

Among high-risk features in CAPTIVATE subjects, 60% of patients had unmutated IGHV, with del(17p)/TP53 mutation in 20%, del(11Q) in 17%, complex karyotype in 19%, cytopenias in 36%, bulky lymph nodes in 32%, and absolute neutrophil count ≥25x109/L in 76%.
 

Response findings

The ibrutinib lead-in, Dr. Wierda said, reduced tumor lysis syndrome (TLS) risk, shifting 90% of patients with high baseline TLS risk to medium or low-risk categories (from 77 to 51 patients), precluding need for hospitalization with venetoclax initiation.

The rate for best response of uMRD (defined as uMRD over at least 3 cycles in both peripheral blood and bone marrow) in evaluable patients was 75% in peripheral blood (n = 163) and 72% in bone marrow (n = 155).

Confirmed uMRD was achieved in 86/149 (58%), with uMRD not confirmed in 63/149 (uMRD 32% in bone marrow and 48% in peripheral blood). One-year DFS after the further randomization to placebo or ibrutinib in the confirmed uMRD group was 95.3% in the placebo group and 100% in the ibrutinib group (P = .1475). In the uMRD not confirmed group, 30-month progression-free survival (PFS) was 95.2% and 96.7% in the ibrutinib and ibrutinib plus venetoclax groups, respectively. Thirty-month PFS rates in the confirmed uMRD placebo and ibrutinib arms were 95.3% and 100%. “Thirty-month PFS rates were greater than 95% across all randomized arms,” Dr. Wierda stated.

In patients without confirmed uMRD after 12 cycles of combined ibrutinib plus venetoclax, additional randomized treatment led to greater increases in uMRD in the ibrutinib plus venetoclax group than in the ibrutinib alone group (bone marrow additional 10% ibrutinib alone, 34% ibrutinib plus venetoclax; peripheral blood 0% ibrutinib, 19% ibrutinib plus venetoclax).

Adverse events generally decreased after the first 6 months of ibrutinib plus venetoclax treatment, with no new safety signals emerging over time. “There were no safety concerns with this highly active combination of first-line ibrutinib plus venetoclax. It’s an oral, once-daily fixed duration regimen that achieves undetectable MRD in blood or bone marrow in three-fourths of patients after 12 cycles of combined treatment.”

When asked, in a question-and-answer session after his presentation, if the findings were “practice changing,” Dr. Wierda responded: “We need additional data from ongoing studies looking at various combinations of targeted therapy. But this study does clearly show efficacy in terms of depth of remission, and it supports the concept of fixed duration treatment, particularly for those patients who achieved undetectable MRD status.”
 

SOURCE: William G. Wierda, MD, PhD. ASH 2020, Abstract 123.

Among chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) patients in the minimal residual disease (MRD) cohort of the phase 2 CAPTIVATE trial, a 1-year disease-free survival (DFS) rate of 95% in those randomized to placebo after 12 cycles of combined ibrutinib plus venetoclax supports a fixed-duration treatment approach, according to William G. Wierda, MD, PhD, University of Texas, MD Anderson Cancer Center, Houston.

Ibrutinib, a once-daily Bruton kinase inhibitor, is the only targeted therapy for first-line treatment of CLL that has demonstrated significant overall survival benefit in randomized phase 3 studies, Dr. Wierda said at the American Society of Hematology annual meeting, held virtually.

Ibrutinib and venetoclax have synergistic and complementary antitumor activity, he noted, through mobilizing and clearing CLL cells from protective niches and disease compartments beyond blood and bone marrow.

Fixed-duration study

CAPTIVATE (PCYC-1142), an international phase 2 study, evaluated first-line treatment with 12 cycles of the ibrutinib/venetoclax combination in MRD and fixed-duration cohorts. The current primary analysis of 1-year DFS from the MRD cohort tested whether the regimen allows for treatment-free remission in the setting of confirmed undetectable MRD (uMRD).

Patients (n = 164, median age 58 years) in the CAPTIVATE study MRD cohort had previously untreated active CLL/SLL requiring treatment per International Workshop on Chronic Lymphocytic Leukemia criteria.

They received 3 cycles of lead-in ibrutinib (420 mg once daily) followed by 12 cycles of ibrutinib (420 mg once daily plus venetoclax ramp-up to 400 mg once daily). Thereafter, in an MRD-guided 1:1 randomization stratified by immunoglobulin heavy chain (IGHV) mutational status, those with confirmed uMRD received either placebo or ibrutinib, and those with uMRD not confirmed received either ibrutinib or ibrutinib plus venetoclax (both open-label).

Among high-risk features in CAPTIVATE subjects, 60% of patients had unmutated IGHV, with del(17p)/TP53 mutation in 20%, del(11Q) in 17%, complex karyotype in 19%, cytopenias in 36%, bulky lymph nodes in 32%, and absolute neutrophil count ≥25x109/L in 76%.
 

Response findings

The ibrutinib lead-in, Dr. Wierda said, reduced tumor lysis syndrome (TLS) risk, shifting 90% of patients with high baseline TLS risk to medium or low-risk categories (from 77 to 51 patients), precluding need for hospitalization with venetoclax initiation.

The rate for best response of uMRD (defined as uMRD over at least 3 cycles in both peripheral blood and bone marrow) in evaluable patients was 75% in peripheral blood (n = 163) and 72% in bone marrow (n = 155).

Confirmed uMRD was achieved in 86/149 (58%), with uMRD not confirmed in 63/149 (uMRD 32% in bone marrow and 48% in peripheral blood). One-year DFS after the further randomization to placebo or ibrutinib in the confirmed uMRD group was 95.3% in the placebo group and 100% in the ibrutinib group (P = .1475). In the uMRD not confirmed group, 30-month progression-free survival (PFS) was 95.2% and 96.7% in the ibrutinib and ibrutinib plus venetoclax groups, respectively. Thirty-month PFS rates in the confirmed uMRD placebo and ibrutinib arms were 95.3% and 100%. “Thirty-month PFS rates were greater than 95% across all randomized arms,” Dr. Wierda stated.

In patients without confirmed uMRD after 12 cycles of combined ibrutinib plus venetoclax, additional randomized treatment led to greater increases in uMRD in the ibrutinib plus venetoclax group than in the ibrutinib alone group (bone marrow additional 10% ibrutinib alone, 34% ibrutinib plus venetoclax; peripheral blood 0% ibrutinib, 19% ibrutinib plus venetoclax).

Adverse events generally decreased after the first 6 months of ibrutinib plus venetoclax treatment, with no new safety signals emerging over time. “There were no safety concerns with this highly active combination of first-line ibrutinib plus venetoclax. It’s an oral, once-daily fixed duration regimen that achieves undetectable MRD in blood or bone marrow in three-fourths of patients after 12 cycles of combined treatment.”

When asked, in a question-and-answer session after his presentation, if the findings were “practice changing,” Dr. Wierda responded: “We need additional data from ongoing studies looking at various combinations of targeted therapy. But this study does clearly show efficacy in terms of depth of remission, and it supports the concept of fixed duration treatment, particularly for those patients who achieved undetectable MRD status.”
 

SOURCE: William G. Wierda, MD, PhD. ASH 2020, Abstract 123.

Among chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) patients in the minimal residual disease (MRD) cohort of the phase 2 CAPTIVATE trial, a 1-year disease-free survival (DFS) rate of 95% in those randomized to placebo after 12 cycles of combined ibrutinib plus venetoclax supports a fixed-duration treatment approach, according to William G. Wierda, MD, PhD, University of Texas, MD Anderson Cancer Center, Houston.

Ibrutinib, a once-daily Bruton kinase inhibitor, is the only targeted therapy for first-line treatment of CLL that has demonstrated significant overall survival benefit in randomized phase 3 studies, Dr. Wierda said at the American Society of Hematology annual meeting, held virtually.

Ibrutinib and venetoclax have synergistic and complementary antitumor activity, he noted, through mobilizing and clearing CLL cells from protective niches and disease compartments beyond blood and bone marrow.

Fixed-duration study

CAPTIVATE (PCYC-1142), an international phase 2 study, evaluated first-line treatment with 12 cycles of the ibrutinib/venetoclax combination in MRD and fixed-duration cohorts. The current primary analysis of 1-year DFS from the MRD cohort tested whether the regimen allows for treatment-free remission in the setting of confirmed undetectable MRD (uMRD).

Patients (n = 164, median age 58 years) in the CAPTIVATE study MRD cohort had previously untreated active CLL/SLL requiring treatment per International Workshop on Chronic Lymphocytic Leukemia criteria.

They received 3 cycles of lead-in ibrutinib (420 mg once daily) followed by 12 cycles of ibrutinib (420 mg once daily plus venetoclax ramp-up to 400 mg once daily). Thereafter, in an MRD-guided 1:1 randomization stratified by immunoglobulin heavy chain (IGHV) mutational status, those with confirmed uMRD received either placebo or ibrutinib, and those with uMRD not confirmed received either ibrutinib or ibrutinib plus venetoclax (both open-label).

Among high-risk features in CAPTIVATE subjects, 60% of patients had unmutated IGHV, with del(17p)/TP53 mutation in 20%, del(11Q) in 17%, complex karyotype in 19%, cytopenias in 36%, bulky lymph nodes in 32%, and absolute neutrophil count ≥25x109/L in 76%.
 

Response findings

The ibrutinib lead-in, Dr. Wierda said, reduced tumor lysis syndrome (TLS) risk, shifting 90% of patients with high baseline TLS risk to medium or low-risk categories (from 77 to 51 patients), precluding need for hospitalization with venetoclax initiation.

The rate for best response of uMRD (defined as uMRD over at least 3 cycles in both peripheral blood and bone marrow) in evaluable patients was 75% in peripheral blood (n = 163) and 72% in bone marrow (n = 155).

Confirmed uMRD was achieved in 86/149 (58%), with uMRD not confirmed in 63/149 (uMRD 32% in bone marrow and 48% in peripheral blood). One-year DFS after the further randomization to placebo or ibrutinib in the confirmed uMRD group was 95.3% in the placebo group and 100% in the ibrutinib group (P = .1475). In the uMRD not confirmed group, 30-month progression-free survival (PFS) was 95.2% and 96.7% in the ibrutinib and ibrutinib plus venetoclax groups, respectively. Thirty-month PFS rates in the confirmed uMRD placebo and ibrutinib arms were 95.3% and 100%. “Thirty-month PFS rates were greater than 95% across all randomized arms,” Dr. Wierda stated.

In patients without confirmed uMRD after 12 cycles of combined ibrutinib plus venetoclax, additional randomized treatment led to greater increases in uMRD in the ibrutinib plus venetoclax group than in the ibrutinib alone group (bone marrow additional 10% ibrutinib alone, 34% ibrutinib plus venetoclax; peripheral blood 0% ibrutinib, 19% ibrutinib plus venetoclax).

Adverse events generally decreased after the first 6 months of ibrutinib plus venetoclax treatment, with no new safety signals emerging over time. “There were no safety concerns with this highly active combination of first-line ibrutinib plus venetoclax. It’s an oral, once-daily fixed duration regimen that achieves undetectable MRD in blood or bone marrow in three-fourths of patients after 12 cycles of combined treatment.”

When asked, in a question-and-answer session after his presentation, if the findings were “practice changing,” Dr. Wierda responded: “We need additional data from ongoing studies looking at various combinations of targeted therapy. But this study does clearly show efficacy in terms of depth of remission, and it supports the concept of fixed duration treatment, particularly for those patients who achieved undetectable MRD status.”
 

SOURCE: William G. Wierda, MD, PhD. ASH 2020, Abstract 123.

For patients with heavily-pretreated multiple myeloma, the early and deep responses seen with the novel chimeric antigen receptor T-cell (CAR T-cell) construct ciltacabtagene autoleucel (cilta-cel) have also been durable, according to investigators in the CARTITUDE-1 trial.

Among 97 patients with multiple myeloma that had progressed on three or more prior lines of therapy or following treatment with at least two lines of therapy with a proteasome inhibitor and immunomodulating agent, the overall response rate (ORR) was 96.9%, with a median duration of response not reached after a median of 12.4 months of follow-up, reported Deepu Madduri, MD of Mount Sinai Medical Center in New York, and colleagues.

“We saw how heavily pretreated these patients were, and to see a one-time treatment get these kind of response rates is quite exceptional. What’s even more impressive is that 72% of these patients were still maintaining their response at the time of data cutoff,“ she said in an oral abstract presented during the virtual American Society of Hematology annual meeting.

Cilta-cel is a second-generation CAR T containing two single-domain antibodies targeted against B-cell maturation protein (BCMA). BCMA was first described in myeloma in 2004 as a mechanism for the growth and survival of malignant plasma cells.

As previously reported, the same CAR T-cell construct showed a high overall response with manageable toxicities in 74 patients with relapsed/refractory multiple myeloma.

Ciltacabtagene autoleucel was granted a breakthrough therapy designation for relapsed/refractory multiple myeloma by the Food and Drug Administration in December 2019, a priority medicines (PRIME) designation by the European Medicines Agency in April 2019, and breakthrough designation in China in September 2020.

At the 2019 ASH annual meeting, Dr. Madduri reported phase 1b results from the trial, which showed that for 29 patients with heavily pretreated, relapsed/refractory multiple myeloma, the ORR at 6 months median follow-up was 100%, including 69% complete responses, with 27 patients remaining free of disease progression.
 

Combined data

For the 2020 ASH annual meeting, Dr. Madduri reported combined results from phases 1b and 2 of the CARTITUDE-1 study.

The investigators enrolled patients with multiple myeloma with measurable diseases as assessed by M-protein or serum free light chain levels who had experienced disease progression on at least three prior lines of therapy, or whose disease was refractory to at least two lines of therapy with a proteasome inhibitor, immunomodulatory drug, and an anti-CD38 antibody.

Patients underwent apheresis for T-cell collection, with bridging therapy allowed until the expanded T cells could be delivered.

Following T-cell depletion with cyclophosphamide 300 mg/m² and fludarabine 30 mg/m² over 3 days, patients received a single weight-based infusion (compared with fixed-dose infusions used with other CAR T-cell constructs).

The dose was targeted at 0.75x106 CAR-positive cells/kg, with a target range of 0.5–1.0x106, administered 5-7 days after the start of the conditioning regimen.

Of the 101 patients who underwent lymphodepletion, 97 (29 in phase 1b and 68 in phase 2) were treated with cilta-cel. Five of the patients in phase 1b and nine in phase 2 died on study, five of whom succumbed to progressive disease, and three due to adverse events unrelated to treatment. The remaining six patients died from treatment-related causes, including two patients from sepsis or septic shock, and one each from the cytokine release syndrome (CRS)/hemophagocytic lymphohistiocytosis (HLH), lung abscess, respiratory failure, and neurotoxicity.

At the time of data cutoff, 83 patients remained on study.
 

High ORR

The ORR was 96.9% (94 of 97 patients), comprising 67% stringent complete responses (sCR), 25.8% very good partial responses (VGPR), and 4.1% partial responses (PR).

Among 57 patients evaluable for minimal residual disease (MRD), 53 (93%) were MRD negative. Of this group, 49 had a VGPR or better.

The median time to first response was 1 month (range 0.9 to 8.5 months). At the time of data cutoff 70 patients had an ongoing response.

Among patients followed for a minimum of 6 months, most had cilta-cel CAR T-cells below the level of quantification (2 cells per microliter) in peripheral blood.

At a median follow-up of 12.4 months, 12-month overall progression-free survival rate was 76%, with the median PFS not reached. The 12-month overall survival rate was 88.5%, with the median OS not reached.
 

Safety data

All patients had at least one hematologic adverse event, 96 of which were grade 3 or 4 in severity. The events include neutropenia, anemia, thrombocytopenia, leukopenia, and lymphopenia. The median time to recovery was 2 weeks for grade 3 or 4 neutropenia and 4 weeks for thrombocytopenia.

Infections of any grade occurred in 57.7% of patients, including grade 3/4 pneumonia in 8.2% and grade 3/4 sepsis in 4.1%.

Grade 3 or 4 nonhematologic toxicities were uncommon, Dr. Madduri noted.

CRS of any grade occurred in 92 patients, but only 4 had grade 3 or 4 CRS.

Neurotoxicities occurred in 20 patients, of whom 10 had grade 3 or 4 neurotoxicity.

Immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 16 patients, with 2 having grade 3 or greater ICANS. Other neurotoxicities of any grade, many which overlapped with ICANS, occurred in 12 patients, with 9 having grade 3 or 4 neurotoxicity.

The median time to ICANS onset was 8 days, with a median time to recovery of 4 days. Other neurotoxicities took longer to manifest and disappear, however, with a median time to onset of 27 days, and median time to recovery of 75 days.
 

Neurotoxicity mechanism questioned

In the question-and-answer session following her presentation, an audience member asked whether the investigators had any insights into the mechanism underlying the non-ICANS neurotoxicities they saw.

“We saw no clear etiology in the other neurotoxicities, but we saw that maybe there could be some mild associations with high tumor burden, prior CRS, ICANS, or even the higher expansion and persistence of these cells,” Dr. Madduri replied.

She noted that subsequent to these findings, the investigators have implemented mitigation strategies including allowing patients to have more bridging chemotherapy, more aggressive steroid use for early ICANS, and extensive monitoring.

Eric Smith, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York, said that the non-ICANS neurotoxicity profile of cilta-cel was different from that seen in other CAR T-cell trials, and asked how it compared to that of bi-specific BCMA/CD3 CAR T constructs.

“We did see some nerve palsies and peripheral motor neuropathy, but it wasn’t that many patients, and it’s really hard to compare what happened here with the bi-specifics, as every product is very different,” she said.

The study was sponsored by Janssen Research & Development and Legend Biotech. Dr. Madduri disclosed honoraria, consultancy, and speakers bureau activities for those companies and others.
 

SOURCE: Madduri D et al. ASH 2020. Abstract 177.

For patients with heavily-pretreated multiple myeloma, the early and deep responses seen with the novel chimeric antigen receptor T-cell (CAR T-cell) construct ciltacabtagene autoleucel (cilta-cel) have also been durable, according to investigators in the CARTITUDE-1 trial.

Among 97 patients with multiple myeloma that had progressed on three or more prior lines of therapy or following treatment with at least two lines of therapy with a proteasome inhibitor and immunomodulating agent, the overall response rate (ORR) was 96.9%, with a median duration of response not reached after a median of 12.4 months of follow-up, reported Deepu Madduri, MD of Mount Sinai Medical Center in New York, and colleagues.

“We saw how heavily pretreated these patients were, and to see a one-time treatment get these kind of response rates is quite exceptional. What’s even more impressive is that 72% of these patients were still maintaining their response at the time of data cutoff,“ she said in an oral abstract presented during the virtual American Society of Hematology annual meeting.

Cilta-cel is a second-generation CAR T containing two single-domain antibodies targeted against B-cell maturation protein (BCMA). BCMA was first described in myeloma in 2004 as a mechanism for the growth and survival of malignant plasma cells.

As previously reported, the same CAR T-cell construct showed a high overall response with manageable toxicities in 74 patients with relapsed/refractory multiple myeloma.

Ciltacabtagene autoleucel was granted a breakthrough therapy designation for relapsed/refractory multiple myeloma by the Food and Drug Administration in December 2019, a priority medicines (PRIME) designation by the European Medicines Agency in April 2019, and breakthrough designation in China in September 2020.

At the 2019 ASH annual meeting, Dr. Madduri reported phase 1b results from the trial, which showed that for 29 patients with heavily pretreated, relapsed/refractory multiple myeloma, the ORR at 6 months median follow-up was 100%, including 69% complete responses, with 27 patients remaining free of disease progression.
 

Combined data

For the 2020 ASH annual meeting, Dr. Madduri reported combined results from phases 1b and 2 of the CARTITUDE-1 study.

The investigators enrolled patients with multiple myeloma with measurable diseases as assessed by M-protein or serum free light chain levels who had experienced disease progression on at least three prior lines of therapy, or whose disease was refractory to at least two lines of therapy with a proteasome inhibitor, immunomodulatory drug, and an anti-CD38 antibody.

Patients underwent apheresis for T-cell collection, with bridging therapy allowed until the expanded T cells could be delivered.

Following T-cell depletion with cyclophosphamide 300 mg/m² and fludarabine 30 mg/m² over 3 days, patients received a single weight-based infusion (compared with fixed-dose infusions used with other CAR T-cell constructs).

The dose was targeted at 0.75x106 CAR-positive cells/kg, with a target range of 0.5–1.0x106, administered 5-7 days after the start of the conditioning regimen.

Of the 101 patients who underwent lymphodepletion, 97 (29 in phase 1b and 68 in phase 2) were treated with cilta-cel. Five of the patients in phase 1b and nine in phase 2 died on study, five of whom succumbed to progressive disease, and three due to adverse events unrelated to treatment. The remaining six patients died from treatment-related causes, including two patients from sepsis or septic shock, and one each from the cytokine release syndrome (CRS)/hemophagocytic lymphohistiocytosis (HLH), lung abscess, respiratory failure, and neurotoxicity.

At the time of data cutoff, 83 patients remained on study.
 

High ORR

The ORR was 96.9% (94 of 97 patients), comprising 67% stringent complete responses (sCR), 25.8% very good partial responses (VGPR), and 4.1% partial responses (PR).

Among 57 patients evaluable for minimal residual disease (MRD), 53 (93%) were MRD negative. Of this group, 49 had a VGPR or better.

The median time to first response was 1 month (range 0.9 to 8.5 months). At the time of data cutoff 70 patients had an ongoing response.

Among patients followed for a minimum of 6 months, most had cilta-cel CAR T-cells below the level of quantification (2 cells per microliter) in peripheral blood.

At a median follow-up of 12.4 months, 12-month overall progression-free survival rate was 76%, with the median PFS not reached. The 12-month overall survival rate was 88.5%, with the median OS not reached.
 

Safety data

All patients had at least one hematologic adverse event, 96 of which were grade 3 or 4 in severity. The events include neutropenia, anemia, thrombocytopenia, leukopenia, and lymphopenia. The median time to recovery was 2 weeks for grade 3 or 4 neutropenia and 4 weeks for thrombocytopenia.

Infections of any grade occurred in 57.7% of patients, including grade 3/4 pneumonia in 8.2% and grade 3/4 sepsis in 4.1%.

Grade 3 or 4 nonhematologic toxicities were uncommon, Dr. Madduri noted.

CRS of any grade occurred in 92 patients, but only 4 had grade 3 or 4 CRS.

Neurotoxicities occurred in 20 patients, of whom 10 had grade 3 or 4 neurotoxicity.

Immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 16 patients, with 2 having grade 3 or greater ICANS. Other neurotoxicities of any grade, many which overlapped with ICANS, occurred in 12 patients, with 9 having grade 3 or 4 neurotoxicity.

The median time to ICANS onset was 8 days, with a median time to recovery of 4 days. Other neurotoxicities took longer to manifest and disappear, however, with a median time to onset of 27 days, and median time to recovery of 75 days.
 

Neurotoxicity mechanism questioned

In the question-and-answer session following her presentation, an audience member asked whether the investigators had any insights into the mechanism underlying the non-ICANS neurotoxicities they saw.

“We saw no clear etiology in the other neurotoxicities, but we saw that maybe there could be some mild associations with high tumor burden, prior CRS, ICANS, or even the higher expansion and persistence of these cells,” Dr. Madduri replied.

She noted that subsequent to these findings, the investigators have implemented mitigation strategies including allowing patients to have more bridging chemotherapy, more aggressive steroid use for early ICANS, and extensive monitoring.

Eric Smith, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York, said that the non-ICANS neurotoxicity profile of cilta-cel was different from that seen in other CAR T-cell trials, and asked how it compared to that of bi-specific BCMA/CD3 CAR T constructs.

“We did see some nerve palsies and peripheral motor neuropathy, but it wasn’t that many patients, and it’s really hard to compare what happened here with the bi-specifics, as every product is very different,” she said.

The study was sponsored by Janssen Research & Development and Legend Biotech. Dr. Madduri disclosed honoraria, consultancy, and speakers bureau activities for those companies and others.
 

SOURCE: Madduri D et al. ASH 2020. Abstract 177.

For patients with heavily-pretreated multiple myeloma, the early and deep responses seen with the novel chimeric antigen receptor T-cell (CAR T-cell) construct ciltacabtagene autoleucel (cilta-cel) have also been durable, according to investigators in the CARTITUDE-1 trial.

Among 97 patients with multiple myeloma that had progressed on three or more prior lines of therapy or following treatment with at least two lines of therapy with a proteasome inhibitor and immunomodulating agent, the overall response rate (ORR) was 96.9%, with a median duration of response not reached after a median of 12.4 months of follow-up, reported Deepu Madduri, MD of Mount Sinai Medical Center in New York, and colleagues.

“We saw how heavily pretreated these patients were, and to see a one-time treatment get these kind of response rates is quite exceptional. What’s even more impressive is that 72% of these patients were still maintaining their response at the time of data cutoff,“ she said in an oral abstract presented during the virtual American Society of Hematology annual meeting.

Cilta-cel is a second-generation CAR T containing two single-domain antibodies targeted against B-cell maturation protein (BCMA). BCMA was first described in myeloma in 2004 as a mechanism for the growth and survival of malignant plasma cells.

As previously reported, the same CAR T-cell construct showed a high overall response with manageable toxicities in 74 patients with relapsed/refractory multiple myeloma.

Ciltacabtagene autoleucel was granted a breakthrough therapy designation for relapsed/refractory multiple myeloma by the Food and Drug Administration in December 2019, a priority medicines (PRIME) designation by the European Medicines Agency in April 2019, and breakthrough designation in China in September 2020.

At the 2019 ASH annual meeting, Dr. Madduri reported phase 1b results from the trial, which showed that for 29 patients with heavily pretreated, relapsed/refractory multiple myeloma, the ORR at 6 months median follow-up was 100%, including 69% complete responses, with 27 patients remaining free of disease progression.
 

Combined data

For the 2020 ASH annual meeting, Dr. Madduri reported combined results from phases 1b and 2 of the CARTITUDE-1 study.

The investigators enrolled patients with multiple myeloma with measurable diseases as assessed by M-protein or serum free light chain levels who had experienced disease progression on at least three prior lines of therapy, or whose disease was refractory to at least two lines of therapy with a proteasome inhibitor, immunomodulatory drug, and an anti-CD38 antibody.

Patients underwent apheresis for T-cell collection, with bridging therapy allowed until the expanded T cells could be delivered.

Following T-cell depletion with cyclophosphamide 300 mg/m² and fludarabine 30 mg/m² over 3 days, patients received a single weight-based infusion (compared with fixed-dose infusions used with other CAR T-cell constructs).

The dose was targeted at 0.75x106 CAR-positive cells/kg, with a target range of 0.5–1.0x106, administered 5-7 days after the start of the conditioning regimen.

Of the 101 patients who underwent lymphodepletion, 97 (29 in phase 1b and 68 in phase 2) were treated with cilta-cel. Five of the patients in phase 1b and nine in phase 2 died on study, five of whom succumbed to progressive disease, and three due to adverse events unrelated to treatment. The remaining six patients died from treatment-related causes, including two patients from sepsis or septic shock, and one each from the cytokine release syndrome (CRS)/hemophagocytic lymphohistiocytosis (HLH), lung abscess, respiratory failure, and neurotoxicity.

At the time of data cutoff, 83 patients remained on study.
 

High ORR

The ORR was 96.9% (94 of 97 patients), comprising 67% stringent complete responses (sCR), 25.8% very good partial responses (VGPR), and 4.1% partial responses (PR).

Among 57 patients evaluable for minimal residual disease (MRD), 53 (93%) were MRD negative. Of this group, 49 had a VGPR or better.

The median time to first response was 1 month (range 0.9 to 8.5 months). At the time of data cutoff 70 patients had an ongoing response.

Among patients followed for a minimum of 6 months, most had cilta-cel CAR T-cells below the level of quantification (2 cells per microliter) in peripheral blood.

At a median follow-up of 12.4 months, 12-month overall progression-free survival rate was 76%, with the median PFS not reached. The 12-month overall survival rate was 88.5%, with the median OS not reached.
 

Safety data

All patients had at least one hematologic adverse event, 96 of which were grade 3 or 4 in severity. The events include neutropenia, anemia, thrombocytopenia, leukopenia, and lymphopenia. The median time to recovery was 2 weeks for grade 3 or 4 neutropenia and 4 weeks for thrombocytopenia.

Infections of any grade occurred in 57.7% of patients, including grade 3/4 pneumonia in 8.2% and grade 3/4 sepsis in 4.1%.

Grade 3 or 4 nonhematologic toxicities were uncommon, Dr. Madduri noted.

CRS of any grade occurred in 92 patients, but only 4 had grade 3 or 4 CRS.

Neurotoxicities occurred in 20 patients, of whom 10 had grade 3 or 4 neurotoxicity.

Immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 16 patients, with 2 having grade 3 or greater ICANS. Other neurotoxicities of any grade, many which overlapped with ICANS, occurred in 12 patients, with 9 having grade 3 or 4 neurotoxicity.

The median time to ICANS onset was 8 days, with a median time to recovery of 4 days. Other neurotoxicities took longer to manifest and disappear, however, with a median time to onset of 27 days, and median time to recovery of 75 days.
 

Neurotoxicity mechanism questioned

In the question-and-answer session following her presentation, an audience member asked whether the investigators had any insights into the mechanism underlying the non-ICANS neurotoxicities they saw.

“We saw no clear etiology in the other neurotoxicities, but we saw that maybe there could be some mild associations with high tumor burden, prior CRS, ICANS, or even the higher expansion and persistence of these cells,” Dr. Madduri replied.

She noted that subsequent to these findings, the investigators have implemented mitigation strategies including allowing patients to have more bridging chemotherapy, more aggressive steroid use for early ICANS, and extensive monitoring.

Eric Smith, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York, said that the non-ICANS neurotoxicity profile of cilta-cel was different from that seen in other CAR T-cell trials, and asked how it compared to that of bi-specific BCMA/CD3 CAR T constructs.

“We did see some nerve palsies and peripheral motor neuropathy, but it wasn’t that many patients, and it’s really hard to compare what happened here with the bi-specifics, as every product is very different,” she said.

The study was sponsored by Janssen Research & Development and Legend Biotech. Dr. Madduri disclosed honoraria, consultancy, and speakers bureau activities for those companies and others.
 

SOURCE: Madduri D et al. ASH 2020. Abstract 177.

In patients with T-cell lymphoma, allogeneic transplant can lead to durable remissions among patients who might otherwise have poor outcomes, results of a large retrospective observational study suggest.

Five-year progression-free survival (PFS) approached 40% and 5-year overall survival (OS) was over 50% in the study, which according to an investigator is the largest-ever reported patient series of allogeneic stem cell transplantation in T-cell lymphomas.

“We believe that eligible patients with relapsed/refractory T-cell lymphomas should be considered for consultation for allogeneic transplant by an expert clinician,” said investigator Neha Mehta-Shah, MD, of Washington University in St. Louis.

“These decisions should occur on a patient by patient level – but it’s important to consider this,” Dr. Mehta-Shah said at the annual meeting of the American Society of Hematology, held virtually this year.

Notably, patients with cutaneous T-cell lymphoma (CTCL) had a higher rate of relapse yet similar overall survival (OS) compared to patients with common peripheral T-cell lymphoma (PTCL) subtypes, according to Dr. Mehta-Shah.

Among PTCL subtypes, there was a trend toward improved PFS and OS for angioimmunoblastic T-cell lymphoma (AITL), compared with PTCL not otherwise specified (PTCL-NOS) and anaplastic large-cell lymphoma (ALCL), she added.

Catherine M. Diefenbach, MD, director of the clinical lymphoma program at NYU Langone’s Perlmutter Cancer Center, said the results of this retrospective study need to considered in light of the treatment-related risks associated with allogeneic transplantation.

Treatment-related mortality in the study ranged from about 8% to 24%, depending on the donor type, while acute and chronic graft-versus-host-disease (GvHD) was seen in more than 40% of patients, the reported data show.

“If I have a relapsed patient with AITL, I would look to this data and say that patients with AITL appear in a retrospective study to have a strong benefit,” Dr. Diefenbach said in an interview.

“For the other patients, you would describe both potential benefits and also discuss the treatment-associated risks – both the chronic GvHD and transplant-related mortality – and you’d have to balance the risk with the benefits for each individual case,” Dr. Diefenbach added.

The retrospective analysis by Dr. Mehta-Shah and colleagues included 508 consecutive T-cell lymphoma patients receiving allogeneic transplants at 12 academic centers between 2000 and 2019. The most common subtypes were PTCL-NOS in 26%, AITL in 16%, CTCL in 13%, and hepatosplenic T-cell lymphoma (HSTCL) in 7%. About 40% had a matched related donor (MRD) and 39% had a matched unrelated donor (MUD). The conditioning regimen was myeloablative in about a third of patients and nonmyeloablative in two-thirds.

At 5 years, PFS was 39.4% and OS was 50.8% for the overall study cohort, Dr. Mehta-Shah reported, noting that the median time from relapse to death post allogeneic transplant was 10.2 months.

Patients in complete remission at the time of transplant fared better than others, with a median PFS of 44.6 months vs. 8.5 months for those in partial remission, 21.0 months in those with stable disease, and 3.5 months for those with progressive disease at time of transplant, data show.

Patients with common PTCL subtypes had better PFS compared to patients with CTCL, yet OS was similar, according to the investigator. At 5 years, PFS was 43.7% and 18.6%, respectively, for PTCL and CTCL, while OS was 53.1% and 44.0%, respectively.

There was a trend toward improved outcomes for AITL relative to PTCL-NOS and ALCL, with a median PFS of 51.4 months for AITL versus 18.3 months those other subtypes. Similarly, median OS was not reached for AITL versus 73.1 months in the other subtypes.

Treatment-related mortality was lowest for patients with MRDs, or 8.2% at 12 months, Dr. Mehta-Shah reported, while patients with MUDs, mismatched donors, or haploidentical donors had treatment-related mortality of 13% to 16% at 12 months, and those with cord blood donors had treatment-related mortality of nearly 24% at 12 months.

Acute GvHD was observed in 46% of patients and chronic GvHD was seen in nearly 41%, the investigator added.

While these findings are important to consider in individual patient consultations, the study is nevertheless subject to limitations including patient selection and referral bias, according to Dr. Mehta-Shah.

“This was a retrospective analysis of patients who underwent transplant,” she said in a question-and-answer period. “Of course, that is heavily biased by who got to a transplant center, who was well enough to achieve transplant, and who had a donor or donor options, as well as their overall health and depth of remission,” the researcher said.

“I think this just represents what we could tell patients about what may happen to them once they embark on a transplant,” she added, “but really, there would be more prospective work needed to be done for what happens to patients overarching, and how many of them even get to a transplant consultation.”

Further studies should be done to develop predictive tools or biomarkers to determine who benefits from an allogeneic transplant, if there are predictors of relapse following allogeneic transplant, and what are the mechanisms of relapse following allogeneic transplant, according to Dr. Mehta-Shah.

Dr. Mehta-Shah reported research funding from Bristol Myers-Squibb, Celgene, Verastem, Corvus, Innate Pharmaceuticals, and Genentech/Roche. She reported consultancy with Kyowa Hakko Kirin, C4 Therapeutics, and Karyopharm Therapeutics.
 

SOURCE: Mehta-Shah N et al. ASH 2020, Abstract 41.

In patients with T-cell lymphoma, allogeneic transplant can lead to durable remissions among patients who might otherwise have poor outcomes, results of a large retrospective observational study suggest.

Five-year progression-free survival (PFS) approached 40% and 5-year overall survival (OS) was over 50% in the study, which according to an investigator is the largest-ever reported patient series of allogeneic stem cell transplantation in T-cell lymphomas.

“We believe that eligible patients with relapsed/refractory T-cell lymphomas should be considered for consultation for allogeneic transplant by an expert clinician,” said investigator Neha Mehta-Shah, MD, of Washington University in St. Louis.

“These decisions should occur on a patient by patient level – but it’s important to consider this,” Dr. Mehta-Shah said at the annual meeting of the American Society of Hematology, held virtually this year.

Notably, patients with cutaneous T-cell lymphoma (CTCL) had a higher rate of relapse yet similar overall survival (OS) compared to patients with common peripheral T-cell lymphoma (PTCL) subtypes, according to Dr. Mehta-Shah.

Among PTCL subtypes, there was a trend toward improved PFS and OS for angioimmunoblastic T-cell lymphoma (AITL), compared with PTCL not otherwise specified (PTCL-NOS) and anaplastic large-cell lymphoma (ALCL), she added.

Catherine M. Diefenbach, MD, director of the clinical lymphoma program at NYU Langone’s Perlmutter Cancer Center, said the results of this retrospective study need to considered in light of the treatment-related risks associated with allogeneic transplantation.

Treatment-related mortality in the study ranged from about 8% to 24%, depending on the donor type, while acute and chronic graft-versus-host-disease (GvHD) was seen in more than 40% of patients, the reported data show.

“If I have a relapsed patient with AITL, I would look to this data and say that patients with AITL appear in a retrospective study to have a strong benefit,” Dr. Diefenbach said in an interview.

“For the other patients, you would describe both potential benefits and also discuss the treatment-associated risks – both the chronic GvHD and transplant-related mortality – and you’d have to balance the risk with the benefits for each individual case,” Dr. Diefenbach added.

The retrospective analysis by Dr. Mehta-Shah and colleagues included 508 consecutive T-cell lymphoma patients receiving allogeneic transplants at 12 academic centers between 2000 and 2019. The most common subtypes were PTCL-NOS in 26%, AITL in 16%, CTCL in 13%, and hepatosplenic T-cell lymphoma (HSTCL) in 7%. About 40% had a matched related donor (MRD) and 39% had a matched unrelated donor (MUD). The conditioning regimen was myeloablative in about a third of patients and nonmyeloablative in two-thirds.

At 5 years, PFS was 39.4% and OS was 50.8% for the overall study cohort, Dr. Mehta-Shah reported, noting that the median time from relapse to death post allogeneic transplant was 10.2 months.

Patients in complete remission at the time of transplant fared better than others, with a median PFS of 44.6 months vs. 8.5 months for those in partial remission, 21.0 months in those with stable disease, and 3.5 months for those with progressive disease at time of transplant, data show.

Patients with common PTCL subtypes had better PFS compared to patients with CTCL, yet OS was similar, according to the investigator. At 5 years, PFS was 43.7% and 18.6%, respectively, for PTCL and CTCL, while OS was 53.1% and 44.0%, respectively.

There was a trend toward improved outcomes for AITL relative to PTCL-NOS and ALCL, with a median PFS of 51.4 months for AITL versus 18.3 months those other subtypes. Similarly, median OS was not reached for AITL versus 73.1 months in the other subtypes.

Treatment-related mortality was lowest for patients with MRDs, or 8.2% at 12 months, Dr. Mehta-Shah reported, while patients with MUDs, mismatched donors, or haploidentical donors had treatment-related mortality of 13% to 16% at 12 months, and those with cord blood donors had treatment-related mortality of nearly 24% at 12 months.

Acute GvHD was observed in 46% of patients and chronic GvHD was seen in nearly 41%, the investigator added.

While these findings are important to consider in individual patient consultations, the study is nevertheless subject to limitations including patient selection and referral bias, according to Dr. Mehta-Shah.

“This was a retrospective analysis of patients who underwent transplant,” she said in a question-and-answer period. “Of course, that is heavily biased by who got to a transplant center, who was well enough to achieve transplant, and who had a donor or donor options, as well as their overall health and depth of remission,” the researcher said.

“I think this just represents what we could tell patients about what may happen to them once they embark on a transplant,” she added, “but really, there would be more prospective work needed to be done for what happens to patients overarching, and how many of them even get to a transplant consultation.”

Further studies should be done to develop predictive tools or biomarkers to determine who benefits from an allogeneic transplant, if there are predictors of relapse following allogeneic transplant, and what are the mechanisms of relapse following allogeneic transplant, according to Dr. Mehta-Shah.

Dr. Mehta-Shah reported research funding from Bristol Myers-Squibb, Celgene, Verastem, Corvus, Innate Pharmaceuticals, and Genentech/Roche. She reported consultancy with Kyowa Hakko Kirin, C4 Therapeutics, and Karyopharm Therapeutics.
 

SOURCE: Mehta-Shah N et al. ASH 2020, Abstract 41.

In patients with T-cell lymphoma, allogeneic transplant can lead to durable remissions among patients who might otherwise have poor outcomes, results of a large retrospective observational study suggest.

Five-year progression-free survival (PFS) approached 40% and 5-year overall survival (OS) was over 50% in the study, which according to an investigator is the largest-ever reported patient series of allogeneic stem cell transplantation in T-cell lymphomas.

“We believe that eligible patients with relapsed/refractory T-cell lymphomas should be considered for consultation for allogeneic transplant by an expert clinician,” said investigator Neha Mehta-Shah, MD, of Washington University in St. Louis.

“These decisions should occur on a patient by patient level – but it’s important to consider this,” Dr. Mehta-Shah said at the annual meeting of the American Society of Hematology, held virtually this year.

Notably, patients with cutaneous T-cell lymphoma (CTCL) had a higher rate of relapse yet similar overall survival (OS) compared to patients with common peripheral T-cell lymphoma (PTCL) subtypes, according to Dr. Mehta-Shah.

Among PTCL subtypes, there was a trend toward improved PFS and OS for angioimmunoblastic T-cell lymphoma (AITL), compared with PTCL not otherwise specified (PTCL-NOS) and anaplastic large-cell lymphoma (ALCL), she added.

Catherine M. Diefenbach, MD, director of the clinical lymphoma program at NYU Langone’s Perlmutter Cancer Center, said the results of this retrospective study need to considered in light of the treatment-related risks associated with allogeneic transplantation.

Treatment-related mortality in the study ranged from about 8% to 24%, depending on the donor type, while acute and chronic graft-versus-host-disease (GvHD) was seen in more than 40% of patients, the reported data show.

“If I have a relapsed patient with AITL, I would look to this data and say that patients with AITL appear in a retrospective study to have a strong benefit,” Dr. Diefenbach said in an interview.

“For the other patients, you would describe both potential benefits and also discuss the treatment-associated risks – both the chronic GvHD and transplant-related mortality – and you’d have to balance the risk with the benefits for each individual case,” Dr. Diefenbach added.

The retrospective analysis by Dr. Mehta-Shah and colleagues included 508 consecutive T-cell lymphoma patients receiving allogeneic transplants at 12 academic centers between 2000 and 2019. The most common subtypes were PTCL-NOS in 26%, AITL in 16%, CTCL in 13%, and hepatosplenic T-cell lymphoma (HSTCL) in 7%. About 40% had a matched related donor (MRD) and 39% had a matched unrelated donor (MUD). The conditioning regimen was myeloablative in about a third of patients and nonmyeloablative in two-thirds.

At 5 years, PFS was 39.4% and OS was 50.8% for the overall study cohort, Dr. Mehta-Shah reported, noting that the median time from relapse to death post allogeneic transplant was 10.2 months.

Patients in complete remission at the time of transplant fared better than others, with a median PFS of 44.6 months vs. 8.5 months for those in partial remission, 21.0 months in those with stable disease, and 3.5 months for those with progressive disease at time of transplant, data show.

Patients with common PTCL subtypes had better PFS compared to patients with CTCL, yet OS was similar, according to the investigator. At 5 years, PFS was 43.7% and 18.6%, respectively, for PTCL and CTCL, while OS was 53.1% and 44.0%, respectively.

There was a trend toward improved outcomes for AITL relative to PTCL-NOS and ALCL, with a median PFS of 51.4 months for AITL versus 18.3 months those other subtypes. Similarly, median OS was not reached for AITL versus 73.1 months in the other subtypes.

Treatment-related mortality was lowest for patients with MRDs, or 8.2% at 12 months, Dr. Mehta-Shah reported, while patients with MUDs, mismatched donors, or haploidentical donors had treatment-related mortality of 13% to 16% at 12 months, and those with cord blood donors had treatment-related mortality of nearly 24% at 12 months.

Acute GvHD was observed in 46% of patients and chronic GvHD was seen in nearly 41%, the investigator added.

While these findings are important to consider in individual patient consultations, the study is nevertheless subject to limitations including patient selection and referral bias, according to Dr. Mehta-Shah.

“This was a retrospective analysis of patients who underwent transplant,” she said in a question-and-answer period. “Of course, that is heavily biased by who got to a transplant center, who was well enough to achieve transplant, and who had a donor or donor options, as well as their overall health and depth of remission,” the researcher said.

“I think this just represents what we could tell patients about what may happen to them once they embark on a transplant,” she added, “but really, there would be more prospective work needed to be done for what happens to patients overarching, and how many of them even get to a transplant consultation.”

Further studies should be done to develop predictive tools or biomarkers to determine who benefits from an allogeneic transplant, if there are predictors of relapse following allogeneic transplant, and what are the mechanisms of relapse following allogeneic transplant, according to Dr. Mehta-Shah.

Dr. Mehta-Shah reported research funding from Bristol Myers-Squibb, Celgene, Verastem, Corvus, Innate Pharmaceuticals, and Genentech/Roche. She reported consultancy with Kyowa Hakko Kirin, C4 Therapeutics, and Karyopharm Therapeutics.
 

SOURCE: Mehta-Shah N et al. ASH 2020, Abstract 41.