Study Overview

Objective. To evaluate whether higher BMI alone contributes to risk of cardiovascular disease (CVD) and death.

Study design. Cohort study of weight-discordant monozygotic twin pairs

Setting and participants. This study took place in Sweden, using a subset of data from the Swedish Twin Registry and the Screening Across Lifespan Twin (SALT) study, which aimed to screen Swedish twins born prior to 1958 for the development of “common complex diseases.” From a total of 44,820 individuals, the current study limited to a subset of 4046 monozygotic twin pairs where both twins had self-reported height and weight data, and where calculated body mass index (BMI) was discordant between the twins, defined as a difference > 0.01 kg/m². No other inclusion or exclusion criteria are mentioned. Data for the study were collected from several different sources, including telephone interviews (eg, height and weight, behaviors such as physical activity and smoking), national registries on health conditions (eg, myocardial infarction [MI], stroke, diabetes) or prescriptions (eg, diabetes medications), the national causes of death register, and a nationwide database containing socioeconomic variables (eg, income and education). The primary exposure of interest for this study was weight status, categorized as “leaner” or “heavier,” depending on the relative BMI of each twin in a given pair. “Leaner” twins were assumed to have lower adiposity than their “heavier” counterparts, and yet to have identical genetic makeup, thereby allowing the authors to eliminate the contribution of genetic confounding in evaluating the relationship between weight status and CVD risk. The classification system could mean that one person with a BMI of 26 kg/m² would be placed in the “leaner” category if their twin had a BMI of 28, while someone else in another twin pair but also with a BMI of 26 kg/m² might be classified in the “heavier” category if their twin had a BMI of 22. Twin pairs were followed for up to 15 years to assess for incident outcomes of interest, with baseline data collected between 1998 and 2002, and follow-up through 2013.

Main outcome measures. The primary outcome of interest was the occurrence of incident MI or death from any cause. As above, these outcomes were assessed using national disease and death registries spanning 1987-2013, and ICD-9 or -10 codes of interest. A secondary outcome of incident diabetes was also specified, presumably limited to development of type 2 diabetes mellitus, and identified using the same datasets, as well as the national prescription registry. Kaplan-Meier curves for incident MI and death were constructed comparing all “leaner” twins against all “heavier” twins, and Cox proportional hazards modeling was used to compare the hazard of the primary composite outcome between groups. Logistic regression was used to evaluate the odds of each outcome including diabetes incidence, and several models were built, ranging from an unadjusted model to one adjusting for a number of lifestyle factors (eg, smoking status, physical activity), baseline health conditions, and sociodemographic factors.

The authors separately examined risk of MI/death in the subgroup of twins where the “heavier” twin had a BMI ≤ 24.9 kg/m² at baseline (ie, despite being labeled “heavier” they still had a technically normal BMI), and examined the impact of weight trajectory prior to the defined baseline (eg, they were able to incorporate into models whether someone had been actively gaining or losing weight over time prior to the baseline exposure categorization). The authors also conducted several sensitivity analyses, including running models excluding twins with < 1 year of follow-up in an effort to insure that results of the main analysis were not biased due to differential loss to follow-up between exposure categories.

Results. Of the 4046 twin pairs in this study, 56% (2283 pairs) were female, and mean (SD) age at baseline was 57.6 (9.5) years. Race/ethnicity was not reported but presumably the vast majority, if not all, are non-Hispanic white, based on the country of origin. In comparing the group of “heavier” twins to “leaner” twins, several important baseline differences were found. By design, the “heavier” twins had significantly higher mean (SD) BMI at study baseline (25.9 [3.6] kg/m² vs. 23.9 [3.1] kg/m²) and reported greater increases in BMI over the 15–20 years preceding baseline (change since 1973 was +4.3 [2.9] BMI units for “heavier” twins, vs. +2.6 [2.6] for “leaner” twins). Smoking status differed significantly between groups, with 15% of “heavier” twins reporting they were current smokers versus ~21% of “leaner” twins. “Leaner” twins were also slightly more active than their “heavier” counterparts (50.4% reported getting “rather much or very much” exercise versus 46.5%). The groups were otherwise very similar with respect to marital status, educational level, income, and baseline diagnoses of MI, stroke, diabetes, cancer or alcohol abuse.

In fully adjusted models over a mean (SD) 12.4 (2.5)-year follow-up, “heavier” twins had a significantly lower odds of MI or death (combined) than “leaner” twins (odds ratio [OR] 0.75, 95% CI 0.63–0.91). Because the “heavier” vs. “leaner” dichotomy did not map to clinical definitions of overweight or obesity, the investigators also examined this primary outcome among subgroups with more clinical relevance. Being “heavier” actually had the greatest protective effect against MI/death (OR 0.61, 95% CI 0.46–0.80) among pairs where the so-called “heavier” twin had a normal BMI (< 25.0 kg/m²), and this subgroup appeared to be driving the overall finding of lower odds of MI/death in the “heavier” group as a whole. This pattern was underscored when examining the subgroup of twin pairs where the “heavier” twin had a BMI ≥ 30 kg/m² at baseline – in this group the protective effect of being “heavier” disappeared (OR 0.92, 95% CI 0.60 to 1.42). Besides not always reflecting clinically relevant weight categories, the “heavier” vs. “leaner” twin dichotomy could, in some cases, amount to a very small difference in BMI between twins (anything > 0.01 unit counted as discordant). As such, the investigators sought to examine whether their results held up when looking at pairs with a higher threshold for BMI discordance (1.0 to 7.0 units or more difference between twins), finding that risk of MI or death did not increase among the “heavier” group in these more widely split twin pairs, even when adjusting for smoking status and physical activity.

In contrast to the MI/mortality analyses, “heavier” twins did have significantly greater odds of developing diabetes during follow-up compared to their “leaner” counterparts (OR 1.94, 95% CI 1.51 to 2.48, adjusted for smoking and physical activity). Also unlike the MI/death analyses, this relationship of increased diabetes risk among “heavier” twins was enhanced by increasing BMI dissimilarity between twins, and among twins who had been gaining weight prior to baseline BMI measurement.

Sensitivity analyses excluding twins with less than 1 year of follow-up did not result in changes to the main findings—“heavier” twins still had similar odds of MI/death as “leaner” twins.

Conclusion. The authors conclude that among monozygotic twin pairs, where the possibility for genetic confounding has been eliminated, obesity is not causally associated with increased risk of MI or death, although the results do support an increased risk of developing incident diabetes among individuals with higher BMI.

Commentary

Obesity is a known risk factor for many chronic conditions, including diabetes, osteoarthritis, sleep apnea, and hypertension [1]. However, the relationship between obesity and cardiovascular outcomes, particularly coronary artery disease and death from heart disease, has been more controversial. Some epidemiologic studies have demonstrated reduced mortality risk among patients with obesity and heart failure, and even among those with established coronary artery disease—the so-called “obesity paradox” [2]. Others have observed that overweight older adults may have lower overall mortality compared to their normal weight counterparts [3]. On the other hand, it is known that obesity increases risk for diabetes, which is itself a clear and proven risk factor for CVD and death.

As the authors of the current study point out, genetic confounding may be a potential reason for the conflicting results produced in studies of the obesity–CVD risk relationship. In other words, patients who have genes that promote weight gain may also have genes that promote CVD, through pathways independent of excess adipose tissue, with these hidden pathways acting as confounders of the obesity–CVD relationship. By studying monozygotic twin pairs, who have identical genetic makeup but have developed differential weight status due to different environmental exposures, the investigators designed a study that would eliminate any genetic confounding and allow them to better isolate the relationship between higher BMI and CVD. This is an important topic area because, at a population level, we are faced with an immense number of adults who have obesity. Treatment of this condition is resource intense and it is critical that patients and health care systems understand the potential risk reduction that will be achieved with sustained weight loss.

The strengths of this study include the use of a very unique dataset with longitudinal measures on a large number of monozygotic twin pairs, and the authors’ ability to link this dataset with nationwide comprehensive datasets on health conditions, health care use (pharmacy), sociodemographics, and death. Sweden’s national registries are quite impressive and permit these types of studies in a way that would be very difficult to achieve in the United States, with its innumerable separate health care systems and few data sources that contain information on all citizens. Because of these multiple data sources, the authors were able to adjust for some important lifestyle factors that could easily confound the weight status-MI/death relationship, such as smoking and physical activity. Additionally, their models were able to factor in trajectory of weight on some individuals prior to baseline, rather than viewing baseline weight only as a “snapshot” which could risk missing an important trend of weight gain or loss over time, with important health implications.

There are several limitations of the study that are worth reviewing. First, and most importantly, as pointed out in a commentary associated with the article, the categorization of “leaner” and “heavier” can be somewhat misleading if the true question is whether or not excess adiposity is an independent driver of cardiovascular risk [4]. BMI, at the individual level, is not an ideal measure of adiposity and it does not speak to distribution of fat tissue, which is critically important in evaluating CVD risk [5]. For example, 2 siblings could have identical BMIs, but one might have significantly more lean mass in their legs and buttocks, and the other could have more central adipose tissue, translating to a much higher cardiovascular risk. Measures such as waist circumference are critical factors in addition to BMI to better understand an individual’s adipose tissue volume and distribution.

Although the authors did adjust for some self-reported behaviors that are important predictors of CVD (smoking, exercise), there is still potential for confounding due to unscreened or unreported exposures that differ systematically between “leaner” and “heavier” twins. Of note, smoking status—probably the single most important risk factor for CVD—was missing in 13% of the cohort, and no imputation techniques were used for missing data. Another limitation of this study is that its generalizability to more racial/ethnically diverse populations may be limited. Presumably, the patients in this study were non-Hispanic white Swedes, and whether or not these findings would be replicated in other groups, such as those of African or Asian ancestry, is not known.

Finally, the finding that “heavier” twins had greater odds of developing diabetes during follow-up is certainly consistent with existing literature. However, it is also known that diabetes is a strong risk factor for the development of CVD, including MI, and for death [6]. This raises the question of why the authors observed an increased diabetes risk yet no change in MI/death rates among heavier twins. Most likely the discrepancy is due to inadequate follow-up time of incident diabetes cases. Complications of diabetes can take a number of years to materialize, and, with an average of 12 years’ total follow-up in this study, there simply may not have been time to observe an increased risk of MI/death in heavier twins.

Applications for Clinical Practice

For patients interested in weight loss as a way of reducing CVD risk, this paper does not support the notion that lower body weight alone exerts direct influence on this endpoint. However, it reinforces the link between higher body weight and diabetes, which is a clear risk factor for CVD. Therefore, it still seems reasonable to advise patients who are at risk of diabetes that improving dietary quality, increasing cardiorespiratory fitness, and losing weight can reduce their long-term risk of CVD, even if indirectly so.

—Kristina Lewis, MD, MPH

Study Overview

Objective. To evaluate whether higher BMI alone contributes to risk of cardiovascular disease (CVD) and death.

Study design. Cohort study of weight-discordant monozygotic twin pairs

Setting and participants. This study took place in Sweden, using a subset of data from the Swedish Twin Registry and the Screening Across Lifespan Twin (SALT) study, which aimed to screen Swedish twins born prior to 1958 for the development of “common complex diseases.” From a total of 44,820 individuals, the current study limited to a subset of 4046 monozygotic twin pairs where both twins had self-reported height and weight data, and where calculated body mass index (BMI) was discordant between the twins, defined as a difference > 0.01 kg/m². No other inclusion or exclusion criteria are mentioned. Data for the study were collected from several different sources, including telephone interviews (eg, height and weight, behaviors such as physical activity and smoking), national registries on health conditions (eg, myocardial infarction [MI], stroke, diabetes) or prescriptions (eg, diabetes medications), the national causes of death register, and a nationwide database containing socioeconomic variables (eg, income and education). The primary exposure of interest for this study was weight status, categorized as “leaner” or “heavier,” depending on the relative BMI of each twin in a given pair. “Leaner” twins were assumed to have lower adiposity than their “heavier” counterparts, and yet to have identical genetic makeup, thereby allowing the authors to eliminate the contribution of genetic confounding in evaluating the relationship between weight status and CVD risk. The classification system could mean that one person with a BMI of 26 kg/m² would be placed in the “leaner” category if their twin had a BMI of 28, while someone else in another twin pair but also with a BMI of 26 kg/m² might be classified in the “heavier” category if their twin had a BMI of 22. Twin pairs were followed for up to 15 years to assess for incident outcomes of interest, with baseline data collected between 1998 and 2002, and follow-up through 2013.

Main outcome measures. The primary outcome of interest was the occurrence of incident MI or death from any cause. As above, these outcomes were assessed using national disease and death registries spanning 1987-2013, and ICD-9 or -10 codes of interest. A secondary outcome of incident diabetes was also specified, presumably limited to development of type 2 diabetes mellitus, and identified using the same datasets, as well as the national prescription registry. Kaplan-Meier curves for incident MI and death were constructed comparing all “leaner” twins against all “heavier” twins, and Cox proportional hazards modeling was used to compare the hazard of the primary composite outcome between groups. Logistic regression was used to evaluate the odds of each outcome including diabetes incidence, and several models were built, ranging from an unadjusted model to one adjusting for a number of lifestyle factors (eg, smoking status, physical activity), baseline health conditions, and sociodemographic factors.

The authors separately examined risk of MI/death in the subgroup of twins where the “heavier” twin had a BMI ≤ 24.9 kg/m² at baseline (ie, despite being labeled “heavier” they still had a technically normal BMI), and examined the impact of weight trajectory prior to the defined baseline (eg, they were able to incorporate into models whether someone had been actively gaining or losing weight over time prior to the baseline exposure categorization). The authors also conducted several sensitivity analyses, including running models excluding twins with < 1 year of follow-up in an effort to insure that results of the main analysis were not biased due to differential loss to follow-up between exposure categories.

Results. Of the 4046 twin pairs in this study, 56% (2283 pairs) were female, and mean (SD) age at baseline was 57.6 (9.5) years. Race/ethnicity was not reported but presumably the vast majority, if not all, are non-Hispanic white, based on the country of origin. In comparing the group of “heavier” twins to “leaner” twins, several important baseline differences were found. By design, the “heavier” twins had significantly higher mean (SD) BMI at study baseline (25.9 [3.6] kg/m² vs. 23.9 [3.1] kg/m²) and reported greater increases in BMI over the 15–20 years preceding baseline (change since 1973 was +4.3 [2.9] BMI units for “heavier” twins, vs. +2.6 [2.6] for “leaner” twins). Smoking status differed significantly between groups, with 15% of “heavier” twins reporting they were current smokers versus ~21% of “leaner” twins. “Leaner” twins were also slightly more active than their “heavier” counterparts (50.4% reported getting “rather much or very much” exercise versus 46.5%). The groups were otherwise very similar with respect to marital status, educational level, income, and baseline diagnoses of MI, stroke, diabetes, cancer or alcohol abuse.

In fully adjusted models over a mean (SD) 12.4 (2.5)-year follow-up, “heavier” twins had a significantly lower odds of MI or death (combined) than “leaner” twins (odds ratio [OR] 0.75, 95% CI 0.63–0.91). Because the “heavier” vs. “leaner” dichotomy did not map to clinical definitions of overweight or obesity, the investigators also examined this primary outcome among subgroups with more clinical relevance. Being “heavier” actually had the greatest protective effect against MI/death (OR 0.61, 95% CI 0.46–0.80) among pairs where the so-called “heavier” twin had a normal BMI (< 25.0 kg/m²), and this subgroup appeared to be driving the overall finding of lower odds of MI/death in the “heavier” group as a whole. This pattern was underscored when examining the subgroup of twin pairs where the “heavier” twin had a BMI ≥ 30 kg/m² at baseline – in this group the protective effect of being “heavier” disappeared (OR 0.92, 95% CI 0.60 to 1.42). Besides not always reflecting clinically relevant weight categories, the “heavier” vs. “leaner” twin dichotomy could, in some cases, amount to a very small difference in BMI between twins (anything > 0.01 unit counted as discordant). As such, the investigators sought to examine whether their results held up when looking at pairs with a higher threshold for BMI discordance (1.0 to 7.0 units or more difference between twins), finding that risk of MI or death did not increase among the “heavier” group in these more widely split twin pairs, even when adjusting for smoking status and physical activity.

In contrast to the MI/mortality analyses, “heavier” twins did have significantly greater odds of developing diabetes during follow-up compared to their “leaner” counterparts (OR 1.94, 95% CI 1.51 to 2.48, adjusted for smoking and physical activity). Also unlike the MI/death analyses, this relationship of increased diabetes risk among “heavier” twins was enhanced by increasing BMI dissimilarity between twins, and among twins who had been gaining weight prior to baseline BMI measurement.

Sensitivity analyses excluding twins with less than 1 year of follow-up did not result in changes to the main findings—“heavier” twins still had similar odds of MI/death as “leaner” twins.

Conclusion. The authors conclude that among monozygotic twin pairs, where the possibility for genetic confounding has been eliminated, obesity is not causally associated with increased risk of MI or death, although the results do support an increased risk of developing incident diabetes among individuals with higher BMI.

Commentary

Obesity is a known risk factor for many chronic conditions, including diabetes, osteoarthritis, sleep apnea, and hypertension [1]. However, the relationship between obesity and cardiovascular outcomes, particularly coronary artery disease and death from heart disease, has been more controversial. Some epidemiologic studies have demonstrated reduced mortality risk among patients with obesity and heart failure, and even among those with established coronary artery disease—the so-called “obesity paradox” [2]. Others have observed that overweight older adults may have lower overall mortality compared to their normal weight counterparts [3]. On the other hand, it is known that obesity increases risk for diabetes, which is itself a clear and proven risk factor for CVD and death.

As the authors of the current study point out, genetic confounding may be a potential reason for the conflicting results produced in studies of the obesity–CVD risk relationship. In other words, patients who have genes that promote weight gain may also have genes that promote CVD, through pathways independent of excess adipose tissue, with these hidden pathways acting as confounders of the obesity–CVD relationship. By studying monozygotic twin pairs, who have identical genetic makeup but have developed differential weight status due to different environmental exposures, the investigators designed a study that would eliminate any genetic confounding and allow them to better isolate the relationship between higher BMI and CVD. This is an important topic area because, at a population level, we are faced with an immense number of adults who have obesity. Treatment of this condition is resource intense and it is critical that patients and health care systems understand the potential risk reduction that will be achieved with sustained weight loss.

The strengths of this study include the use of a very unique dataset with longitudinal measures on a large number of monozygotic twin pairs, and the authors’ ability to link this dataset with nationwide comprehensive datasets on health conditions, health care use (pharmacy), sociodemographics, and death. Sweden’s national registries are quite impressive and permit these types of studies in a way that would be very difficult to achieve in the United States, with its innumerable separate health care systems and few data sources that contain information on all citizens. Because of these multiple data sources, the authors were able to adjust for some important lifestyle factors that could easily confound the weight status-MI/death relationship, such as smoking and physical activity. Additionally, their models were able to factor in trajectory of weight on some individuals prior to baseline, rather than viewing baseline weight only as a “snapshot” which could risk missing an important trend of weight gain or loss over time, with important health implications.

There are several limitations of the study that are worth reviewing. First, and most importantly, as pointed out in a commentary associated with the article, the categorization of “leaner” and “heavier” can be somewhat misleading if the true question is whether or not excess adiposity is an independent driver of cardiovascular risk [4]. BMI, at the individual level, is not an ideal measure of adiposity and it does not speak to distribution of fat tissue, which is critically important in evaluating CVD risk [5]. For example, 2 siblings could have identical BMIs, but one might have significantly more lean mass in their legs and buttocks, and the other could have more central adipose tissue, translating to a much higher cardiovascular risk. Measures such as waist circumference are critical factors in addition to BMI to better understand an individual’s adipose tissue volume and distribution.

Although the authors did adjust for some self-reported behaviors that are important predictors of CVD (smoking, exercise), there is still potential for confounding due to unscreened or unreported exposures that differ systematically between “leaner” and “heavier” twins. Of note, smoking status—probably the single most important risk factor for CVD—was missing in 13% of the cohort, and no imputation techniques were used for missing data. Another limitation of this study is that its generalizability to more racial/ethnically diverse populations may be limited. Presumably, the patients in this study were non-Hispanic white Swedes, and whether or not these findings would be replicated in other groups, such as those of African or Asian ancestry, is not known.

Finally, the finding that “heavier” twins had greater odds of developing diabetes during follow-up is certainly consistent with existing literature. However, it is also known that diabetes is a strong risk factor for the development of CVD, including MI, and for death [6]. This raises the question of why the authors observed an increased diabetes risk yet no change in MI/death rates among heavier twins. Most likely the discrepancy is due to inadequate follow-up time of incident diabetes cases. Complications of diabetes can take a number of years to materialize, and, with an average of 12 years’ total follow-up in this study, there simply may not have been time to observe an increased risk of MI/death in heavier twins.

Applications for Clinical Practice

For patients interested in weight loss as a way of reducing CVD risk, this paper does not support the notion that lower body weight alone exerts direct influence on this endpoint. However, it reinforces the link between higher body weight and diabetes, which is a clear risk factor for CVD. Therefore, it still seems reasonable to advise patients who are at risk of diabetes that improving dietary quality, increasing cardiorespiratory fitness, and losing weight can reduce their long-term risk of CVD, even if indirectly so.

—Kristina Lewis, MD, MPH

Study Overview

Objective. To evaluate whether higher BMI alone contributes to risk of cardiovascular disease (CVD) and death.

Study design. Cohort study of weight-discordant monozygotic twin pairs

Setting and participants. This study took place in Sweden, using a subset of data from the Swedish Twin Registry and the Screening Across Lifespan Twin (SALT) study, which aimed to screen Swedish twins born prior to 1958 for the development of “common complex diseases.” From a total of 44,820 individuals, the current study limited to a subset of 4046 monozygotic twin pairs where both twins had self-reported height and weight data, and where calculated body mass index (BMI) was discordant between the twins, defined as a difference > 0.01 kg/m². No other inclusion or exclusion criteria are mentioned. Data for the study were collected from several different sources, including telephone interviews (eg, height and weight, behaviors such as physical activity and smoking), national registries on health conditions (eg, myocardial infarction [MI], stroke, diabetes) or prescriptions (eg, diabetes medications), the national causes of death register, and a nationwide database containing socioeconomic variables (eg, income and education). The primary exposure of interest for this study was weight status, categorized as “leaner” or “heavier,” depending on the relative BMI of each twin in a given pair. “Leaner” twins were assumed to have lower adiposity than their “heavier” counterparts, and yet to have identical genetic makeup, thereby allowing the authors to eliminate the contribution of genetic confounding in evaluating the relationship between weight status and CVD risk. The classification system could mean that one person with a BMI of 26 kg/m² would be placed in the “leaner” category if their twin had a BMI of 28, while someone else in another twin pair but also with a BMI of 26 kg/m² might be classified in the “heavier” category if their twin had a BMI of 22. Twin pairs were followed for up to 15 years to assess for incident outcomes of interest, with baseline data collected between 1998 and 2002, and follow-up through 2013.

Main outcome measures. The primary outcome of interest was the occurrence of incident MI or death from any cause. As above, these outcomes were assessed using national disease and death registries spanning 1987-2013, and ICD-9 or -10 codes of interest. A secondary outcome of incident diabetes was also specified, presumably limited to development of type 2 diabetes mellitus, and identified using the same datasets, as well as the national prescription registry. Kaplan-Meier curves for incident MI and death were constructed comparing all “leaner” twins against all “heavier” twins, and Cox proportional hazards modeling was used to compare the hazard of the primary composite outcome between groups. Logistic regression was used to evaluate the odds of each outcome including diabetes incidence, and several models were built, ranging from an unadjusted model to one adjusting for a number of lifestyle factors (eg, smoking status, physical activity), baseline health conditions, and sociodemographic factors.

The authors separately examined risk of MI/death in the subgroup of twins where the “heavier” twin had a BMI ≤ 24.9 kg/m² at baseline (ie, despite being labeled “heavier” they still had a technically normal BMI), and examined the impact of weight trajectory prior to the defined baseline (eg, they were able to incorporate into models whether someone had been actively gaining or losing weight over time prior to the baseline exposure categorization). The authors also conducted several sensitivity analyses, including running models excluding twins with < 1 year of follow-up in an effort to insure that results of the main analysis were not biased due to differential loss to follow-up between exposure categories.

Results. Of the 4046 twin pairs in this study, 56% (2283 pairs) were female, and mean (SD) age at baseline was 57.6 (9.5) years. Race/ethnicity was not reported but presumably the vast majority, if not all, are non-Hispanic white, based on the country of origin. In comparing the group of “heavier” twins to “leaner” twins, several important baseline differences were found. By design, the “heavier” twins had significantly higher mean (SD) BMI at study baseline (25.9 [3.6] kg/m² vs. 23.9 [3.1] kg/m²) and reported greater increases in BMI over the 15–20 years preceding baseline (change since 1973 was +4.3 [2.9] BMI units for “heavier” twins, vs. +2.6 [2.6] for “leaner” twins). Smoking status differed significantly between groups, with 15% of “heavier” twins reporting they were current smokers versus ~21% of “leaner” twins. “Leaner” twins were also slightly more active than their “heavier” counterparts (50.4% reported getting “rather much or very much” exercise versus 46.5%). The groups were otherwise very similar with respect to marital status, educational level, income, and baseline diagnoses of MI, stroke, diabetes, cancer or alcohol abuse.

In fully adjusted models over a mean (SD) 12.4 (2.5)-year follow-up, “heavier” twins had a significantly lower odds of MI or death (combined) than “leaner” twins (odds ratio [OR] 0.75, 95% CI 0.63–0.91). Because the “heavier” vs. “leaner” dichotomy did not map to clinical definitions of overweight or obesity, the investigators also examined this primary outcome among subgroups with more clinical relevance. Being “heavier” actually had the greatest protective effect against MI/death (OR 0.61, 95% CI 0.46–0.80) among pairs where the so-called “heavier” twin had a normal BMI (< 25.0 kg/m²), and this subgroup appeared to be driving the overall finding of lower odds of MI/death in the “heavier” group as a whole. This pattern was underscored when examining the subgroup of twin pairs where the “heavier” twin had a BMI ≥ 30 kg/m² at baseline – in this group the protective effect of being “heavier” disappeared (OR 0.92, 95% CI 0.60 to 1.42). Besides not always reflecting clinically relevant weight categories, the “heavier” vs. “leaner” twin dichotomy could, in some cases, amount to a very small difference in BMI between twins (anything > 0.01 unit counted as discordant). As such, the investigators sought to examine whether their results held up when looking at pairs with a higher threshold for BMI discordance (1.0 to 7.0 units or more difference between twins), finding that risk of MI or death did not increase among the “heavier” group in these more widely split twin pairs, even when adjusting for smoking status and physical activity.

In contrast to the MI/mortality analyses, “heavier” twins did have significantly greater odds of developing diabetes during follow-up compared to their “leaner” counterparts (OR 1.94, 95% CI 1.51 to 2.48, adjusted for smoking and physical activity). Also unlike the MI/death analyses, this relationship of increased diabetes risk among “heavier” twins was enhanced by increasing BMI dissimilarity between twins, and among twins who had been gaining weight prior to baseline BMI measurement.

Sensitivity analyses excluding twins with less than 1 year of follow-up did not result in changes to the main findings—“heavier” twins still had similar odds of MI/death as “leaner” twins.

Conclusion. The authors conclude that among monozygotic twin pairs, where the possibility for genetic confounding has been eliminated, obesity is not causally associated with increased risk of MI or death, although the results do support an increased risk of developing incident diabetes among individuals with higher BMI.

Commentary

Obesity is a known risk factor for many chronic conditions, including diabetes, osteoarthritis, sleep apnea, and hypertension [1]. However, the relationship between obesity and cardiovascular outcomes, particularly coronary artery disease and death from heart disease, has been more controversial. Some epidemiologic studies have demonstrated reduced mortality risk among patients with obesity and heart failure, and even among those with established coronary artery disease—the so-called “obesity paradox” [2]. Others have observed that overweight older adults may have lower overall mortality compared to their normal weight counterparts [3]. On the other hand, it is known that obesity increases risk for diabetes, which is itself a clear and proven risk factor for CVD and death.

As the authors of the current study point out, genetic confounding may be a potential reason for the conflicting results produced in studies of the obesity–CVD risk relationship. In other words, patients who have genes that promote weight gain may also have genes that promote CVD, through pathways independent of excess adipose tissue, with these hidden pathways acting as confounders of the obesity–CVD relationship. By studying monozygotic twin pairs, who have identical genetic makeup but have developed differential weight status due to different environmental exposures, the investigators designed a study that would eliminate any genetic confounding and allow them to better isolate the relationship between higher BMI and CVD. This is an important topic area because, at a population level, we are faced with an immense number of adults who have obesity. Treatment of this condition is resource intense and it is critical that patients and health care systems understand the potential risk reduction that will be achieved with sustained weight loss.

The strengths of this study include the use of a very unique dataset with longitudinal measures on a large number of monozygotic twin pairs, and the authors’ ability to link this dataset with nationwide comprehensive datasets on health conditions, health care use (pharmacy), sociodemographics, and death. Sweden’s national registries are quite impressive and permit these types of studies in a way that would be very difficult to achieve in the United States, with its innumerable separate health care systems and few data sources that contain information on all citizens. Because of these multiple data sources, the authors were able to adjust for some important lifestyle factors that could easily confound the weight status-MI/death relationship, such as smoking and physical activity. Additionally, their models were able to factor in trajectory of weight on some individuals prior to baseline, rather than viewing baseline weight only as a “snapshot” which could risk missing an important trend of weight gain or loss over time, with important health implications.

There are several limitations of the study that are worth reviewing. First, and most importantly, as pointed out in a commentary associated with the article, the categorization of “leaner” and “heavier” can be somewhat misleading if the true question is whether or not excess adiposity is an independent driver of cardiovascular risk [4]. BMI, at the individual level, is not an ideal measure of adiposity and it does not speak to distribution of fat tissue, which is critically important in evaluating CVD risk [5]. For example, 2 siblings could have identical BMIs, but one might have significantly more lean mass in their legs and buttocks, and the other could have more central adipose tissue, translating to a much higher cardiovascular risk. Measures such as waist circumference are critical factors in addition to BMI to better understand an individual’s adipose tissue volume and distribution.

Although the authors did adjust for some self-reported behaviors that are important predictors of CVD (smoking, exercise), there is still potential for confounding due to unscreened or unreported exposures that differ systematically between “leaner” and “heavier” twins. Of note, smoking status—probably the single most important risk factor for CVD—was missing in 13% of the cohort, and no imputation techniques were used for missing data. Another limitation of this study is that its generalizability to more racial/ethnically diverse populations may be limited. Presumably, the patients in this study were non-Hispanic white Swedes, and whether or not these findings would be replicated in other groups, such as those of African or Asian ancestry, is not known.

Finally, the finding that “heavier” twins had greater odds of developing diabetes during follow-up is certainly consistent with existing literature. However, it is also known that diabetes is a strong risk factor for the development of CVD, including MI, and for death [6]. This raises the question of why the authors observed an increased diabetes risk yet no change in MI/death rates among heavier twins. Most likely the discrepancy is due to inadequate follow-up time of incident diabetes cases. Complications of diabetes can take a number of years to materialize, and, with an average of 12 years’ total follow-up in this study, there simply may not have been time to observe an increased risk of MI/death in heavier twins.

Applications for Clinical Practice

For patients interested in weight loss as a way of reducing CVD risk, this paper does not support the notion that lower body weight alone exerts direct influence on this endpoint. However, it reinforces the link between higher body weight and diabetes, which is a clear risk factor for CVD. Therefore, it still seems reasonable to advise patients who are at risk of diabetes that improving dietary quality, increasing cardiorespiratory fitness, and losing weight can reduce their long-term risk of CVD, even if indirectly so.

—Kristina Lewis, MD, MPH

VIENNA – A grassroots, patient-centric program aimed at encouraging U.S. community hospitals in underserved areas to adopt a comprehensive centers-of-excellence model for treatment of lung cancer has demonstrated that community cancer centers can achieve quality of care comparable to that found in academic medical centers, Raymond Osarogiagbon, MD, declared at the World Congress on Lung Cancer.

One major reason why aggregate lung cancer survival in the United States has barely inched upward during the past 3 decades is there is often a huge gap between the quality of care patients get at academic research centers – including access to clinical trials – and what they can get in community hospitals. Eighty percent of lung cancer patients receive their care in these community cancer centers, where not all physicians and surgeons may be up to speed with guideline-recommended best practices, observed Dr. Osarogiagbon, a medical oncologist and director of the multidisciplinary thoracic oncology program at Baptist Cancer Center in Memphis.

Bruce Jancin/Frontline Medical News

The centers of excellence program, supported by the Bonnie J. Addario Lung Cancer Foundation, is an attempt to address this disparity. In 3 years, 13 hospitals in areas with large underserved patient populations in nine states have qualified. Dr. Osarogiagbon anticipates that the competitive advantage this designation provides will spur more and more community hospitals with cancer centers to get on board.

To qualify, community cancer centers have to commit to following specific best practices as standards of care in accord with guidelines issued by groups including the National Comprehensive Cancer Network and the American Society of Clinical Oncology. Requirements include the use of multidisciplinary teams for treatment decisions, routine use of molecular diagnostics and targeted therapies, patient access to clinical trials, longitudinal institutional data tracking, patient and caregiver education programs, and minimally invasive surgical and staging techniques. A lung cancer screening program is required. So is a systematic program for management of all incidentally detected lung nodules, many of which today fall between the cracks.

In an interview, Dr. Osarogiagbon shared several examples of how achieving the foundation’s center of excellence designation enables community cancer centers to achieve top-quality care on a par with academic medical centers. At Memorial Cancer Institute in Hollywood, Fla., which serves large Hispanic and black populations, implementation of a lung cancer screening program and other measures has resulted in 40% of patients with lung cancer being diagnosed with stage 1 or 2 disease amenable to curative surgery. The overall U.S. rate is significantly lower at 29%.

And in an area composed of western Tennessee, northern Mississippi, and eastern Arkansas, Dr. Osarogiagbon and coinvestigators at the Baptist Cancer Center conducted a study demonstrating that the use of two complementary surgical staging interventions resulted in improved rates of guideline-recommended surgical staging quality.

The observational study, presented elsewhere at the world congress by Nicholas Faris, MD, of the Thoracic Oncology Research Group, Baptist Cancer Center, Memphis, entailed analysis of curative-intent resections in 2,094 patients with non–small-cell lung cancer during 2004-2016. A novel anatomically sound gross dissection protocol was provided to assist pathologists in retrieving the intrapulmonary lymph nodes required for staging in 161 patients undergoing curative resection. A special lymph node specimen collection kit was utilized in 152. Another 289 resections utilized both interventions. And 1,492 patients received neither intervention.

Use of the interventions was associated with higher rates of adherence to various professional organizations’ guidelines for high-quality surgical staging. For example, the American College of Surgeons Commission on Cancer recommends that at least 10 lymph nodes be examined in patients with stage 1a-2b NSCLC. This was achieved in 71% of patients who had both interventions, 56% of those where the lymph node specimen collection kit was utilized but not the pathology intervention, 48% of patients where the pathology intervention but not the kit was employed, and in only 25% of patients where neither was used.

Similarly, more than three mediastinal lymph node stations were sampled in accord with National Comprehensive Cancer Network guidelines in 96% of patients with both interventions, 90% with the lymph node collection kit, 54% with the pathology intervention, and only 44% with neither, Dr. Osarogiagbon said in the interview.

Dr. Osarogiagbon reported serving as a consultant to Eli Lilly, Genentech, and the Association of Community Cancer Centers.

bjancin@frontlinemedcom.com

VIENNA – A grassroots, patient-centric program aimed at encouraging U.S. community hospitals in underserved areas to adopt a comprehensive centers-of-excellence model for treatment of lung cancer has demonstrated that community cancer centers can achieve quality of care comparable to that found in academic medical centers, Raymond Osarogiagbon, MD, declared at the World Congress on Lung Cancer.

One major reason why aggregate lung cancer survival in the United States has barely inched upward during the past 3 decades is there is often a huge gap between the quality of care patients get at academic research centers – including access to clinical trials – and what they can get in community hospitals. Eighty percent of lung cancer patients receive their care in these community cancer centers, where not all physicians and surgeons may be up to speed with guideline-recommended best practices, observed Dr. Osarogiagbon, a medical oncologist and director of the multidisciplinary thoracic oncology program at Baptist Cancer Center in Memphis.

Bruce Jancin/Frontline Medical News

The centers of excellence program, supported by the Bonnie J. Addario Lung Cancer Foundation, is an attempt to address this disparity. In 3 years, 13 hospitals in areas with large underserved patient populations in nine states have qualified. Dr. Osarogiagbon anticipates that the competitive advantage this designation provides will spur more and more community hospitals with cancer centers to get on board.

To qualify, community cancer centers have to commit to following specific best practices as standards of care in accord with guidelines issued by groups including the National Comprehensive Cancer Network and the American Society of Clinical Oncology. Requirements include the use of multidisciplinary teams for treatment decisions, routine use of molecular diagnostics and targeted therapies, patient access to clinical trials, longitudinal institutional data tracking, patient and caregiver education programs, and minimally invasive surgical and staging techniques. A lung cancer screening program is required. So is a systematic program for management of all incidentally detected lung nodules, many of which today fall between the cracks.

In an interview, Dr. Osarogiagbon shared several examples of how achieving the foundation’s center of excellence designation enables community cancer centers to achieve top-quality care on a par with academic medical centers. At Memorial Cancer Institute in Hollywood, Fla., which serves large Hispanic and black populations, implementation of a lung cancer screening program and other measures has resulted in 40% of patients with lung cancer being diagnosed with stage 1 or 2 disease amenable to curative surgery. The overall U.S. rate is significantly lower at 29%.

And in an area composed of western Tennessee, northern Mississippi, and eastern Arkansas, Dr. Osarogiagbon and coinvestigators at the Baptist Cancer Center conducted a study demonstrating that the use of two complementary surgical staging interventions resulted in improved rates of guideline-recommended surgical staging quality.

The observational study, presented elsewhere at the world congress by Nicholas Faris, MD, of the Thoracic Oncology Research Group, Baptist Cancer Center, Memphis, entailed analysis of curative-intent resections in 2,094 patients with non–small-cell lung cancer during 2004-2016. A novel anatomically sound gross dissection protocol was provided to assist pathologists in retrieving the intrapulmonary lymph nodes required for staging in 161 patients undergoing curative resection. A special lymph node specimen collection kit was utilized in 152. Another 289 resections utilized both interventions. And 1,492 patients received neither intervention.

Use of the interventions was associated with higher rates of adherence to various professional organizations’ guidelines for high-quality surgical staging. For example, the American College of Surgeons Commission on Cancer recommends that at least 10 lymph nodes be examined in patients with stage 1a-2b NSCLC. This was achieved in 71% of patients who had both interventions, 56% of those where the lymph node specimen collection kit was utilized but not the pathology intervention, 48% of patients where the pathology intervention but not the kit was employed, and in only 25% of patients where neither was used.

Similarly, more than three mediastinal lymph node stations were sampled in accord with National Comprehensive Cancer Network guidelines in 96% of patients with both interventions, 90% with the lymph node collection kit, 54% with the pathology intervention, and only 44% with neither, Dr. Osarogiagbon said in the interview.

Dr. Osarogiagbon reported serving as a consultant to Eli Lilly, Genentech, and the Association of Community Cancer Centers.

bjancin@frontlinemedcom.com

VIENNA – A grassroots, patient-centric program aimed at encouraging U.S. community hospitals in underserved areas to adopt a comprehensive centers-of-excellence model for treatment of lung cancer has demonstrated that community cancer centers can achieve quality of care comparable to that found in academic medical centers, Raymond Osarogiagbon, MD, declared at the World Congress on Lung Cancer.

One major reason why aggregate lung cancer survival in the United States has barely inched upward during the past 3 decades is there is often a huge gap between the quality of care patients get at academic research centers – including access to clinical trials – and what they can get in community hospitals. Eighty percent of lung cancer patients receive their care in these community cancer centers, where not all physicians and surgeons may be up to speed with guideline-recommended best practices, observed Dr. Osarogiagbon, a medical oncologist and director of the multidisciplinary thoracic oncology program at Baptist Cancer Center in Memphis.

Bruce Jancin/Frontline Medical News

The centers of excellence program, supported by the Bonnie J. Addario Lung Cancer Foundation, is an attempt to address this disparity. In 3 years, 13 hospitals in areas with large underserved patient populations in nine states have qualified. Dr. Osarogiagbon anticipates that the competitive advantage this designation provides will spur more and more community hospitals with cancer centers to get on board.

To qualify, community cancer centers have to commit to following specific best practices as standards of care in accord with guidelines issued by groups including the National Comprehensive Cancer Network and the American Society of Clinical Oncology. Requirements include the use of multidisciplinary teams for treatment decisions, routine use of molecular diagnostics and targeted therapies, patient access to clinical trials, longitudinal institutional data tracking, patient and caregiver education programs, and minimally invasive surgical and staging techniques. A lung cancer screening program is required. So is a systematic program for management of all incidentally detected lung nodules, many of which today fall between the cracks.

In an interview, Dr. Osarogiagbon shared several examples of how achieving the foundation’s center of excellence designation enables community cancer centers to achieve top-quality care on a par with academic medical centers. At Memorial Cancer Institute in Hollywood, Fla., which serves large Hispanic and black populations, implementation of a lung cancer screening program and other measures has resulted in 40% of patients with lung cancer being diagnosed with stage 1 or 2 disease amenable to curative surgery. The overall U.S. rate is significantly lower at 29%.

And in an area composed of western Tennessee, northern Mississippi, and eastern Arkansas, Dr. Osarogiagbon and coinvestigators at the Baptist Cancer Center conducted a study demonstrating that the use of two complementary surgical staging interventions resulted in improved rates of guideline-recommended surgical staging quality.

The observational study, presented elsewhere at the world congress by Nicholas Faris, MD, of the Thoracic Oncology Research Group, Baptist Cancer Center, Memphis, entailed analysis of curative-intent resections in 2,094 patients with non–small-cell lung cancer during 2004-2016. A novel anatomically sound gross dissection protocol was provided to assist pathologists in retrieving the intrapulmonary lymph nodes required for staging in 161 patients undergoing curative resection. A special lymph node specimen collection kit was utilized in 152. Another 289 resections utilized both interventions. And 1,492 patients received neither intervention.

Use of the interventions was associated with higher rates of adherence to various professional organizations’ guidelines for high-quality surgical staging. For example, the American College of Surgeons Commission on Cancer recommends that at least 10 lymph nodes be examined in patients with stage 1a-2b NSCLC. This was achieved in 71% of patients who had both interventions, 56% of those where the lymph node specimen collection kit was utilized but not the pathology intervention, 48% of patients where the pathology intervention but not the kit was employed, and in only 25% of patients where neither was used.

Similarly, more than three mediastinal lymph node stations were sampled in accord with National Comprehensive Cancer Network guidelines in 96% of patients with both interventions, 90% with the lymph node collection kit, 54% with the pathology intervention, and only 44% with neither, Dr. Osarogiagbon said in the interview.

Dr. Osarogiagbon reported serving as a consultant to Eli Lilly, Genentech, and the Association of Community Cancer Centers.

bjancin@frontlinemedcom.com

HOUSTON – Fellowship training in clinical neurophysiology delivered high rates of satisfaction, but recommended areas for improvements include more focus on training in sleep, brain mapping, and evoked potentials, results from a survey of current trainees found.

“There has been no systematic evaluation of neurophysiology fellowships,” Zulfi Haneef, MD, said in an interview in advance of the annual meeting of the American Epilepsy Society. “In fact, there are some studies on neurology residency, but not on any of the neurology fellowships. This study opens a window into what the situation is after residency: what makes the residents decide on a fellowship, and how they feel they have done with the choice of fellowship.”

dbrunk@frontlinemedcom.com

HOUSTON – Fellowship training in clinical neurophysiology delivered high rates of satisfaction, but recommended areas for improvements include more focus on training in sleep, brain mapping, and evoked potentials, results from a survey of current trainees found.

“There has been no systematic evaluation of neurophysiology fellowships,” Zulfi Haneef, MD, said in an interview in advance of the annual meeting of the American Epilepsy Society. “In fact, there are some studies on neurology residency, but not on any of the neurology fellowships. This study opens a window into what the situation is after residency: what makes the residents decide on a fellowship, and how they feel they have done with the choice of fellowship.”

dbrunk@frontlinemedcom.com

HOUSTON – Fellowship training in clinical neurophysiology delivered high rates of satisfaction, but recommended areas for improvements include more focus on training in sleep, brain mapping, and evoked potentials, results from a survey of current trainees found.

“There has been no systematic evaluation of neurophysiology fellowships,” Zulfi Haneef, MD, said in an interview in advance of the annual meeting of the American Epilepsy Society. “In fact, there are some studies on neurology residency, but not on any of the neurology fellowships. This study opens a window into what the situation is after residency: what makes the residents decide on a fellowship, and how they feel they have done with the choice of fellowship.”

dbrunk@frontlinemedcom.com

SAN DIEGO – An artificial red blood cell has come close to emulating the key functions of natural cells and does not appear to be associated with the side effects such as vasospasm and poor response to changes in blood pH that hampered the development of previous artificial blood products, Allan Doctor, MD, reported at the annual meeting of the American Society of Hematology.

The bio-synthetic cells, called ErythroMer, are about 1/50th the size of natural red blood cells. They can be stored at room temperature and reconstituted with water when needed for use.

In a mouse model, the ErythroMer cells were shown to capture oxygen in the lungs and release it to tissue in a pattern that was nearly identical to blood transfusion. In a rat model of shock, ErythroMer was effective for resuscitation.

In a video interview, Dr. Doctor of Washington University in St. Louis discussed the pharmacokinetics of ErythroMer, the need for a readily available blood substitute for treating trauma patients, other potential uses for artificial blood cells, and next steps for testing the product.

Dr. Doctor has equity ownership in KaloCyte, the company developing ErythroMer. He receives research funding from Children’s Discovery Institute and the National Institutes of Health.

mdales@frontlinemedcom.com

SAN DIEGO – An artificial red blood cell has come close to emulating the key functions of natural cells and does not appear to be associated with the side effects such as vasospasm and poor response to changes in blood pH that hampered the development of previous artificial blood products, Allan Doctor, MD, reported at the annual meeting of the American Society of Hematology.

The bio-synthetic cells, called ErythroMer, are about 1/50th the size of natural red blood cells. They can be stored at room temperature and reconstituted with water when needed for use.

In a mouse model, the ErythroMer cells were shown to capture oxygen in the lungs and release it to tissue in a pattern that was nearly identical to blood transfusion. In a rat model of shock, ErythroMer was effective for resuscitation.

In a video interview, Dr. Doctor of Washington University in St. Louis discussed the pharmacokinetics of ErythroMer, the need for a readily available blood substitute for treating trauma patients, other potential uses for artificial blood cells, and next steps for testing the product.

Dr. Doctor has equity ownership in KaloCyte, the company developing ErythroMer. He receives research funding from Children’s Discovery Institute and the National Institutes of Health.

mdales@frontlinemedcom.com

SAN DIEGO – An artificial red blood cell has come close to emulating the key functions of natural cells and does not appear to be associated with the side effects such as vasospasm and poor response to changes in blood pH that hampered the development of previous artificial blood products, Allan Doctor, MD, reported at the annual meeting of the American Society of Hematology.

The bio-synthetic cells, called ErythroMer, are about 1/50th the size of natural red blood cells. They can be stored at room temperature and reconstituted with water when needed for use.

In a mouse model, the ErythroMer cells were shown to capture oxygen in the lungs and release it to tissue in a pattern that was nearly identical to blood transfusion. In a rat model of shock, ErythroMer was effective for resuscitation.

In a video interview, Dr. Doctor of Washington University in St. Louis discussed the pharmacokinetics of ErythroMer, the need for a readily available blood substitute for treating trauma patients, other potential uses for artificial blood cells, and next steps for testing the product.

Dr. Doctor has equity ownership in KaloCyte, the company developing ErythroMer. He receives research funding from Children’s Discovery Institute and the National Institutes of Health.

mdales@frontlinemedcom.com

SAN DIEGO – For some chronic myeloid leukemia patients with solid, stable remissions, halving their dose of a tyrosine kinase inhibitor – or even stopping therapy altogether, at least temporarily – appears to be safe and to offer both health and financial benefits, European investigators said at the annual meeting of the American Society of Hematology.

In the British De-escalation and Stopping Treatment of Imatinib, Nilotinib, or Sprycel [dasatinib], or Destiny Study, a total of 12 molecular relapses occurred between the second and twelfth month of dose reduction among 174 patients with either an MR3 or MR4 molecular response, and all 12 patients had restoration of molecular remissions after resumption of full dose TKIs, reported co-investigator Mhairi Copland, MD, PhD, from the University of Glasgow, Scotland.

All 12 patients who experienced molecular recurrence regained MR3 within 4 months of resuming TKI therapy at the full dose.

As noted before, patient-reported side effects such as lethargy, diarrhea, rash, nausea, periorbital edema, and hair thinning decreased during the first 3 months of de-escalation, but not thereafter. Dr. Copland said that patients had generally good quality-of-life scores at study entry, suggesting that they were likely not especially bothered by TKI side effects in the first place.

The investigators calculated that for the 174 patients, halving treatment would save an estimated £1,943,364 ($2,474,679) from an expected TKI budget of £4,156,969 ($5,293,484), a savings of 46.7%. Estimated savings were similar for patients with MR4 or better alone (47.7%) and for those with a major molecular response (44.2%).

EURO-SKI Update

Also at ASH 2016, Francois-Xavier Mahon, MD, PhD, from the University of Bordeaux, France, reported additional follow-up data from the EURO-SKI trial, results of which were first reported at the 2016 annual meeting of the European Hematology Association in Copenhagen.

The investigators found that 50% of 755 assessable patients with CML were free of molecular recurrence at 24 months, as were 47% at 36 months.

As reported previously, patients who had been on a TKI for more than 5.8 years before attempting to stop had a lower rate of relapse (34.5%) than patients who had been on therapy for less than 5.8 years (57.4%). Each additional year of TKI therapy was associated with an approximately 16% better chance of successful TKI cessation.

“With inclusion and relapse criteria less strict than in many previous trials, and with decentralized but standardized PCR monitoring, stopping of TKI therapy in a large cohort of CML patients appears feasible and safe,” Dr. Mahon said at the briefing.

The British Destiny Study was supported by Newcastle University. Dr. Copland reported honoraria, advisory board memberships, and/or research funding from Amgen, Pfizer, Shire, BMS, and Ariad.

EURO-SKI was sponsored by the European LeukemiaNet. Dr. Mahon has previously disclosed being on the scientific advisory board and receiving honoraria from Novartis Oncology and BMS, and serving as consultant to those companies and to Pfizer.

SAN DIEGO – For some chronic myeloid leukemia patients with solid, stable remissions, halving their dose of a tyrosine kinase inhibitor – or even stopping therapy altogether, at least temporarily – appears to be safe and to offer both health and financial benefits, European investigators said at the annual meeting of the American Society of Hematology.

In the British De-escalation and Stopping Treatment of Imatinib, Nilotinib, or Sprycel [dasatinib], or Destiny Study, a total of 12 molecular relapses occurred between the second and twelfth month of dose reduction among 174 patients with either an MR3 or MR4 molecular response, and all 12 patients had restoration of molecular remissions after resumption of full dose TKIs, reported co-investigator Mhairi Copland, MD, PhD, from the University of Glasgow, Scotland.

All 12 patients who experienced molecular recurrence regained MR3 within 4 months of resuming TKI therapy at the full dose.

As noted before, patient-reported side effects such as lethargy, diarrhea, rash, nausea, periorbital edema, and hair thinning decreased during the first 3 months of de-escalation, but not thereafter. Dr. Copland said that patients had generally good quality-of-life scores at study entry, suggesting that they were likely not especially bothered by TKI side effects in the first place.

The investigators calculated that for the 174 patients, halving treatment would save an estimated £1,943,364 ($2,474,679) from an expected TKI budget of £4,156,969 ($5,293,484), a savings of 46.7%. Estimated savings were similar for patients with MR4 or better alone (47.7%) and for those with a major molecular response (44.2%).

EURO-SKI Update

Also at ASH 2016, Francois-Xavier Mahon, MD, PhD, from the University of Bordeaux, France, reported additional follow-up data from the EURO-SKI trial, results of which were first reported at the 2016 annual meeting of the European Hematology Association in Copenhagen.

The investigators found that 50% of 755 assessable patients with CML were free of molecular recurrence at 24 months, as were 47% at 36 months.

As reported previously, patients who had been on a TKI for more than 5.8 years before attempting to stop had a lower rate of relapse (34.5%) than patients who had been on therapy for less than 5.8 years (57.4%). Each additional year of TKI therapy was associated with an approximately 16% better chance of successful TKI cessation.

“With inclusion and relapse criteria less strict than in many previous trials, and with decentralized but standardized PCR monitoring, stopping of TKI therapy in a large cohort of CML patients appears feasible and safe,” Dr. Mahon said at the briefing.

The British Destiny Study was supported by Newcastle University. Dr. Copland reported honoraria, advisory board memberships, and/or research funding from Amgen, Pfizer, Shire, BMS, and Ariad.

EURO-SKI was sponsored by the European LeukemiaNet. Dr. Mahon has previously disclosed being on the scientific advisory board and receiving honoraria from Novartis Oncology and BMS, and serving as consultant to those companies and to Pfizer.

SAN DIEGO – For some chronic myeloid leukemia patients with solid, stable remissions, halving their dose of a tyrosine kinase inhibitor – or even stopping therapy altogether, at least temporarily – appears to be safe and to offer both health and financial benefits, European investigators said at the annual meeting of the American Society of Hematology.

In the British De-escalation and Stopping Treatment of Imatinib, Nilotinib, or Sprycel [dasatinib], or Destiny Study, a total of 12 molecular relapses occurred between the second and twelfth month of dose reduction among 174 patients with either an MR3 or MR4 molecular response, and all 12 patients had restoration of molecular remissions after resumption of full dose TKIs, reported co-investigator Mhairi Copland, MD, PhD, from the University of Glasgow, Scotland.

All 12 patients who experienced molecular recurrence regained MR3 within 4 months of resuming TKI therapy at the full dose.

As noted before, patient-reported side effects such as lethargy, diarrhea, rash, nausea, periorbital edema, and hair thinning decreased during the first 3 months of de-escalation, but not thereafter. Dr. Copland said that patients had generally good quality-of-life scores at study entry, suggesting that they were likely not especially bothered by TKI side effects in the first place.

The investigators calculated that for the 174 patients, halving treatment would save an estimated £1,943,364 ($2,474,679) from an expected TKI budget of £4,156,969 ($5,293,484), a savings of 46.7%. Estimated savings were similar for patients with MR4 or better alone (47.7%) and for those with a major molecular response (44.2%).

EURO-SKI Update

Also at ASH 2016, Francois-Xavier Mahon, MD, PhD, from the University of Bordeaux, France, reported additional follow-up data from the EURO-SKI trial, results of which were first reported at the 2016 annual meeting of the European Hematology Association in Copenhagen.

The investigators found that 50% of 755 assessable patients with CML were free of molecular recurrence at 24 months, as were 47% at 36 months.

As reported previously, patients who had been on a TKI for more than 5.8 years before attempting to stop had a lower rate of relapse (34.5%) than patients who had been on therapy for less than 5.8 years (57.4%). Each additional year of TKI therapy was associated with an approximately 16% better chance of successful TKI cessation.

“With inclusion and relapse criteria less strict than in many previous trials, and with decentralized but standardized PCR monitoring, stopping of TKI therapy in a large cohort of CML patients appears feasible and safe,” Dr. Mahon said at the briefing.

The British Destiny Study was supported by Newcastle University. Dr. Copland reported honoraria, advisory board memberships, and/or research funding from Amgen, Pfizer, Shire, BMS, and Ariad.

EURO-SKI was sponsored by the European LeukemiaNet. Dr. Mahon has previously disclosed being on the scientific advisory board and receiving honoraria from Novartis Oncology and BMS, and serving as consultant to those companies and to Pfizer.

SAN DIEGO – When one CAR stops one working, try another: chimeric antigen receptor (CAR) T-cell therapy for children and young adults with acute lymphoblastic leukemia is driving forward with a novel anti-CD22 target that in an early dose-finding trial has induced complete remissions in some patients with relapsed or refractory disease, including patients previously treated with anti-CD19 CAR-T therapy.

In the first-in-humans trial, CAR T-cell therapy directed against CD22 was shown to be safe and was associated with minimal residual disease (MRD)-negative complete remissions in eight of 10 children and young adults with relapsed/refractory B-precursor acute lymphoblastic leukemia treated at the highest dose level.

“This is the first successful salvage CAR therapy for CD19-negative B-[lineage] ALL,” said co-principal investigator Terry J. Fry, MD, from the Center for Cancer Research at the National Cancer Institute in Bethesda, Md.

Preliminary experience with anti-CD22 immunotherapy suggests that it is comparable in potency to anti-CD19 CAR, and investigators are exploring the possibility that the two chimeric antigen targets could be combined for greater efficacy, he said during a briefing at the annual meeting of the American Society of Hematology.

Tough target

As reported previously from the 2013 ASH annual meeting, anti-CD19 CAR T cells induced complete responses in 10 of 16 children and young adults with relapsed/refractory ALL, and in a second study, CD19-targeted T cells induced complete molecular responses in 12 of 16 adults with B-lineage ALL refractory to chemotherapy.

In current phase 2 trials, anti-CD19 CAR-T therapy is associated with complete remission rates of 80% to 90% of those treated.

However, “we’re learning now that one of the limitations of this approach is the loss of CD19 expression occurring in a substantial number of patients, although it has not been systematically analyzed,” Dr. Fry said.

CD22, an antigen restricted to B-lineage cells, is a promising alternative to CD19 as a target, but finding just the right anti-CD22 CAR was tricky, Dr. Fry said in an interview. The investigators found that many candidate antigens bound well to T cells but had no efficacy, and it took several years of trying before they identified the current version of the antigen

In the phase I trial, the investigators enrolled 16 children and young adults (ages 7 to 22 years) with relapsed/refractory CD22-positive hematologic malignancies. All patients had previously undergone at least one allogeneic stem cell transplant, 11 had previously received anti-CD19 CAR-T cell therapy, and 9 were CD19-negative or had reduced CD19 expression on ALL cells.

The patients underwent peripheral blood mononuclear cells (PBMCs) collected through autologous leukapheresis. The cells were then enriched and expanded, and transduced with a lentiviral vector containing an anti-CD22 CAR for 7 to 10 days, allowing the cells to identify and bind to CD22 expressed on ALL blasts.

The patients then underwent lymphodepletion with fludarabine, and cyclophosphamide, and received infusions of the transduced T-cells at one of three dose levels, starting at 3 x 10⁵ transduced T-cells per recipient weight in kilograms (DL-1), 1 x 10⁶/kg (DL-2), and 3 x 10⁶/kg (DL-3).

The complete remission rate at DL-2 and -3 combined was 80%, with the cytokine-release syndrome (CRS) at a maximum of grade 2.

As noted before, three of the remissions were comparatively durable, with one lasting more than a year.

There were no dose-limiting toxicities at DL-2, and grade 4 hypoxia at DL-3 was seen in one patient.There was one death from sepsis and multi-organ failure in one patient in an expansion cohort. There have been no cases of severe neurotoxicity thus far.

In five patients who experienced relapse, one treated at DL-1 had a loss of CAR cells, and four had changes in CD22 expression, primarily a decrease in site density that may cause the CD22 expression to fall below the threshold for CAR activity, Dr. Fry said.

“At least in our eyes, this may not be best used as a salvage therapy, but we’re beginning to think about how this should be included with CD19 in the upfront CAR treatment,” he said.

The study was funded by the National Institutes of Health with support from Lentigen and Juno Therapeutics. Dr. Fry reported no relevant disclosures.

SAN DIEGO – When one CAR stops one working, try another: chimeric antigen receptor (CAR) T-cell therapy for children and young adults with acute lymphoblastic leukemia is driving forward with a novel anti-CD22 target that in an early dose-finding trial has induced complete remissions in some patients with relapsed or refractory disease, including patients previously treated with anti-CD19 CAR-T therapy.

In the first-in-humans trial, CAR T-cell therapy directed against CD22 was shown to be safe and was associated with minimal residual disease (MRD)-negative complete remissions in eight of 10 children and young adults with relapsed/refractory B-precursor acute lymphoblastic leukemia treated at the highest dose level.

“This is the first successful salvage CAR therapy for CD19-negative B-[lineage] ALL,” said co-principal investigator Terry J. Fry, MD, from the Center for Cancer Research at the National Cancer Institute in Bethesda, Md.

Preliminary experience with anti-CD22 immunotherapy suggests that it is comparable in potency to anti-CD19 CAR, and investigators are exploring the possibility that the two chimeric antigen targets could be combined for greater efficacy, he said during a briefing at the annual meeting of the American Society of Hematology.

Tough target

As reported previously from the 2013 ASH annual meeting, anti-CD19 CAR T cells induced complete responses in 10 of 16 children and young adults with relapsed/refractory ALL, and in a second study, CD19-targeted T cells induced complete molecular responses in 12 of 16 adults with B-lineage ALL refractory to chemotherapy.

In current phase 2 trials, anti-CD19 CAR-T therapy is associated with complete remission rates of 80% to 90% of those treated.

However, “we’re learning now that one of the limitations of this approach is the loss of CD19 expression occurring in a substantial number of patients, although it has not been systematically analyzed,” Dr. Fry said.

CD22, an antigen restricted to B-lineage cells, is a promising alternative to CD19 as a target, but finding just the right anti-CD22 CAR was tricky, Dr. Fry said in an interview. The investigators found that many candidate antigens bound well to T cells but had no efficacy, and it took several years of trying before they identified the current version of the antigen

In the phase I trial, the investigators enrolled 16 children and young adults (ages 7 to 22 years) with relapsed/refractory CD22-positive hematologic malignancies. All patients had previously undergone at least one allogeneic stem cell transplant, 11 had previously received anti-CD19 CAR-T cell therapy, and 9 were CD19-negative or had reduced CD19 expression on ALL cells.

The patients underwent peripheral blood mononuclear cells (PBMCs) collected through autologous leukapheresis. The cells were then enriched and expanded, and transduced with a lentiviral vector containing an anti-CD22 CAR for 7 to 10 days, allowing the cells to identify and bind to CD22 expressed on ALL blasts.

The patients then underwent lymphodepletion with fludarabine, and cyclophosphamide, and received infusions of the transduced T-cells at one of three dose levels, starting at 3 x 10⁵ transduced T-cells per recipient weight in kilograms (DL-1), 1 x 10⁶/kg (DL-2), and 3 x 10⁶/kg (DL-3).

The complete remission rate at DL-2 and -3 combined was 80%, with the cytokine-release syndrome (CRS) at a maximum of grade 2.

As noted before, three of the remissions were comparatively durable, with one lasting more than a year.

There were no dose-limiting toxicities at DL-2, and grade 4 hypoxia at DL-3 was seen in one patient.There was one death from sepsis and multi-organ failure in one patient in an expansion cohort. There have been no cases of severe neurotoxicity thus far.

In five patients who experienced relapse, one treated at DL-1 had a loss of CAR cells, and four had changes in CD22 expression, primarily a decrease in site density that may cause the CD22 expression to fall below the threshold for CAR activity, Dr. Fry said.

“At least in our eyes, this may not be best used as a salvage therapy, but we’re beginning to think about how this should be included with CD19 in the upfront CAR treatment,” he said.

The study was funded by the National Institutes of Health with support from Lentigen and Juno Therapeutics. Dr. Fry reported no relevant disclosures.

SAN DIEGO – When one CAR stops one working, try another: chimeric antigen receptor (CAR) T-cell therapy for children and young adults with acute lymphoblastic leukemia is driving forward with a novel anti-CD22 target that in an early dose-finding trial has induced complete remissions in some patients with relapsed or refractory disease, including patients previously treated with anti-CD19 CAR-T therapy.

In the first-in-humans trial, CAR T-cell therapy directed against CD22 was shown to be safe and was associated with minimal residual disease (MRD)-negative complete remissions in eight of 10 children and young adults with relapsed/refractory B-precursor acute lymphoblastic leukemia treated at the highest dose level.

“This is the first successful salvage CAR therapy for CD19-negative B-[lineage] ALL,” said co-principal investigator Terry J. Fry, MD, from the Center for Cancer Research at the National Cancer Institute in Bethesda, Md.

Preliminary experience with anti-CD22 immunotherapy suggests that it is comparable in potency to anti-CD19 CAR, and investigators are exploring the possibility that the two chimeric antigen targets could be combined for greater efficacy, he said during a briefing at the annual meeting of the American Society of Hematology.

Tough target

As reported previously from the 2013 ASH annual meeting, anti-CD19 CAR T cells induced complete responses in 10 of 16 children and young adults with relapsed/refractory ALL, and in a second study, CD19-targeted T cells induced complete molecular responses in 12 of 16 adults with B-lineage ALL refractory to chemotherapy.

In current phase 2 trials, anti-CD19 CAR-T therapy is associated with complete remission rates of 80% to 90% of those treated.

However, “we’re learning now that one of the limitations of this approach is the loss of CD19 expression occurring in a substantial number of patients, although it has not been systematically analyzed,” Dr. Fry said.

CD22, an antigen restricted to B-lineage cells, is a promising alternative to CD19 as a target, but finding just the right anti-CD22 CAR was tricky, Dr. Fry said in an interview. The investigators found that many candidate antigens bound well to T cells but had no efficacy, and it took several years of trying before they identified the current version of the antigen

In the phase I trial, the investigators enrolled 16 children and young adults (ages 7 to 22 years) with relapsed/refractory CD22-positive hematologic malignancies. All patients had previously undergone at least one allogeneic stem cell transplant, 11 had previously received anti-CD19 CAR-T cell therapy, and 9 were CD19-negative or had reduced CD19 expression on ALL cells.

The patients underwent peripheral blood mononuclear cells (PBMCs) collected through autologous leukapheresis. The cells were then enriched and expanded, and transduced with a lentiviral vector containing an anti-CD22 CAR for 7 to 10 days, allowing the cells to identify and bind to CD22 expressed on ALL blasts.

The patients then underwent lymphodepletion with fludarabine, and cyclophosphamide, and received infusions of the transduced T-cells at one of three dose levels, starting at 3 x 10⁵ transduced T-cells per recipient weight in kilograms (DL-1), 1 x 10⁶/kg (DL-2), and 3 x 10⁶/kg (DL-3).

The complete remission rate at DL-2 and -3 combined was 80%, with the cytokine-release syndrome (CRS) at a maximum of grade 2.

As noted before, three of the remissions were comparatively durable, with one lasting more than a year.

There were no dose-limiting toxicities at DL-2, and grade 4 hypoxia at DL-3 was seen in one patient.There was one death from sepsis and multi-organ failure in one patient in an expansion cohort. There have been no cases of severe neurotoxicity thus far.

In five patients who experienced relapse, one treated at DL-1 had a loss of CAR cells, and four had changes in CD22 expression, primarily a decrease in site density that may cause the CD22 expression to fall below the threshold for CAR activity, Dr. Fry said.

“At least in our eyes, this may not be best used as a salvage therapy, but we’re beginning to think about how this should be included with CD19 in the upfront CAR treatment,” he said.

The study was funded by the National Institutes of Health with support from Lentigen and Juno Therapeutics. Dr. Fry reported no relevant disclosures.

A small community in the Lake

Kariba area of southern Zambia

where malaria elimination

programs are underway.

Photo from Milen Nikolov

Malaria elimination in historically high transmission areas like southern Africa is possible with tools that are already available, according to new research.

The study suggests that high levels of vector control are key, and mass drug campaigns cannot make much of an impact without proper vector control.

Milen Nikolov, of the Institute for Disease Modeling in Bellevue, Washington, and colleagues reported these findings in PLOS Computational Biology.

The researchers said the Lake Kariba region of Southern Province, Zambia, is part of a multi-country malaria elimination effort. However, elimination in this area is challenging because villages with high and low malaria burden are interconnected through human travel.

With this in mind, the researchers combined a mathematical model of malaria transmission with field data from Zambia to test a variety of strategies for eliminating malaria in the Lake Kariba region.

The team used detailed spatial surveillance data from field studies—including household locations, climate, clinical malaria incidence, prevalence of malaria infections, and bednet usage rates—to construct a model of interconnected villages, then tested a variety of intervention scenarios to see which ones could lead to elimination.

The results indicate that elimination requires high, yet realistic, levels of vector control. And mass drug campaigns deployed to kill parasites in the human population can boost the chances of achieving elimination as long as vector control is well-implemented.

The researchers said this work suggests that elimination programs in sub-Saharan Africa should focus on how to achieve and maintain excellent coverage of vector control measures rather than spending resources on mass drug campaigns that are predicted to have little effect without well-implemented vector control already in place.

Human movement within the region should be targeted to achieve elimination, as should the importation of infections from outside the region. This is because both impact the likelihood of achieving elimination and understanding regional movement patterns can help guide strategies on targeting specific groups of at-risk people.

While no sub-Saharan African country has yet eliminated malaria, the researchers predict that regional malaria elimination is within reach with current tools, provided the efficacy and operational efficiency attained in southern Zambia can be extended and targeted to other key areas.

A small community in the Lake

Kariba area of southern Zambia

where malaria elimination

programs are underway.

Photo from Milen Nikolov

Malaria elimination in historically high transmission areas like southern Africa is possible with tools that are already available, according to new research.

The study suggests that high levels of vector control are key, and mass drug campaigns cannot make much of an impact without proper vector control.

Milen Nikolov, of the Institute for Disease Modeling in Bellevue, Washington, and colleagues reported these findings in PLOS Computational Biology.

The researchers said the Lake Kariba region of Southern Province, Zambia, is part of a multi-country malaria elimination effort. However, elimination in this area is challenging because villages with high and low malaria burden are interconnected through human travel.

With this in mind, the researchers combined a mathematical model of malaria transmission with field data from Zambia to test a variety of strategies for eliminating malaria in the Lake Kariba region.

The team used detailed spatial surveillance data from field studies—including household locations, climate, clinical malaria incidence, prevalence of malaria infections, and bednet usage rates—to construct a model of interconnected villages, then tested a variety of intervention scenarios to see which ones could lead to elimination.

The results indicate that elimination requires high, yet realistic, levels of vector control. And mass drug campaigns deployed to kill parasites in the human population can boost the chances of achieving elimination as long as vector control is well-implemented.

The researchers said this work suggests that elimination programs in sub-Saharan Africa should focus on how to achieve and maintain excellent coverage of vector control measures rather than spending resources on mass drug campaigns that are predicted to have little effect without well-implemented vector control already in place.

Human movement within the region should be targeted to achieve elimination, as should the importation of infections from outside the region. This is because both impact the likelihood of achieving elimination and understanding regional movement patterns can help guide strategies on targeting specific groups of at-risk people.

While no sub-Saharan African country has yet eliminated malaria, the researchers predict that regional malaria elimination is within reach with current tools, provided the efficacy and operational efficiency attained in southern Zambia can be extended and targeted to other key areas.

A small community in the Lake

Kariba area of southern Zambia

where malaria elimination

programs are underway.

Photo from Milen Nikolov

Malaria elimination in historically high transmission areas like southern Africa is possible with tools that are already available, according to new research.

The study suggests that high levels of vector control are key, and mass drug campaigns cannot make much of an impact without proper vector control.

Milen Nikolov, of the Institute for Disease Modeling in Bellevue, Washington, and colleagues reported these findings in PLOS Computational Biology.

The researchers said the Lake Kariba region of Southern Province, Zambia, is part of a multi-country malaria elimination effort. However, elimination in this area is challenging because villages with high and low malaria burden are interconnected through human travel.

With this in mind, the researchers combined a mathematical model of malaria transmission with field data from Zambia to test a variety of strategies for eliminating malaria in the Lake Kariba region.

The team used detailed spatial surveillance data from field studies—including household locations, climate, clinical malaria incidence, prevalence of malaria infections, and bednet usage rates—to construct a model of interconnected villages, then tested a variety of intervention scenarios to see which ones could lead to elimination.

The results indicate that elimination requires high, yet realistic, levels of vector control. And mass drug campaigns deployed to kill parasites in the human population can boost the chances of achieving elimination as long as vector control is well-implemented.

The researchers said this work suggests that elimination programs in sub-Saharan Africa should focus on how to achieve and maintain excellent coverage of vector control measures rather than spending resources on mass drug campaigns that are predicted to have little effect without well-implemented vector control already in place.

Human movement within the region should be targeted to achieve elimination, as should the importation of infections from outside the region. This is because both impact the likelihood of achieving elimination and understanding regional movement patterns can help guide strategies on targeting specific groups of at-risk people.

While no sub-Saharan African country has yet eliminated malaria, the researchers predict that regional malaria elimination is within reach with current tools, provided the efficacy and operational efficiency attained in southern Zambia can be extended and targeted to other key areas.

SAN DIEGO – In a first-in-humans trial, chimeric antigen receptor (CAR) T-cell therapy directed against CD22 was shown to be safe and was associated with minimal residual disease (MRD)–negative complete remissions in 8 of 10 children and young adults with relapsed/refractory B-precursor acute lymphoblastic leukemia treated at the highest dose levels. One patient remains in remission more than 1 year of treatment, one had a 6-month remission, and one had a remission lasting 3 months.

In a video interview, co-principal investigator Terry J. Fry, MD, of the Center for Cancer Research at the National Cancer Institute in Bethesda, Md., discusses the rationale behind using an alternative antigen target in salvage therapy for ALL, and the potential for combining antigen targets to treat patients with relapsed/refractory ALL.

SAN DIEGO – In a first-in-humans trial, chimeric antigen receptor (CAR) T-cell therapy directed against CD22 was shown to be safe and was associated with minimal residual disease (MRD)–negative complete remissions in 8 of 10 children and young adults with relapsed/refractory B-precursor acute lymphoblastic leukemia treated at the highest dose levels. One patient remains in remission more than 1 year of treatment, one had a 6-month remission, and one had a remission lasting 3 months.

In a video interview, co-principal investigator Terry J. Fry, MD, of the Center for Cancer Research at the National Cancer Institute in Bethesda, Md., discusses the rationale behind using an alternative antigen target in salvage therapy for ALL, and the potential for combining antigen targets to treat patients with relapsed/refractory ALL.

SAN DIEGO – In a first-in-humans trial, chimeric antigen receptor (CAR) T-cell therapy directed against CD22 was shown to be safe and was associated with minimal residual disease (MRD)–negative complete remissions in 8 of 10 children and young adults with relapsed/refractory B-precursor acute lymphoblastic leukemia treated at the highest dose levels. One patient remains in remission more than 1 year of treatment, one had a 6-month remission, and one had a remission lasting 3 months.

In a video interview, co-principal investigator Terry J. Fry, MD, of the Center for Cancer Research at the National Cancer Institute in Bethesda, Md., discusses the rationale behind using an alternative antigen target in salvage therapy for ALL, and the potential for combining antigen targets to treat patients with relapsed/refractory ALL.

SAN DIEGO – Patients with hemophilia B who received a single 1-hour infusion of the gene transfer therapy SPK-9001 achieved steady-state factor IX activity levels averaging 28% and persisting over 1,650 cumulative days of observation, according to updated results from a phase I/II trial.

All nine patients treated to date have exceeded the 12% steady-state factor IX activity level typically needed to prevent breakthrough bleeds, Katherine A. High, MD, said during a press briefing at the annual meeting of the American Society of Hematology. One patient infused himself once with factor IX after developing a suspected ankle bleed 2 days after treatment, Dr. High and her associates reported in the accompanying abstract.

Neil Osterweil/Frontline Medical News

SAN DIEGO – Patients with hemophilia B who received a single 1-hour infusion of the gene transfer therapy SPK-9001 achieved steady-state factor IX activity levels averaging 28% and persisting over 1,650 cumulative days of observation, according to updated results from a phase I/II trial.

All nine patients treated to date have exceeded the 12% steady-state factor IX activity level typically needed to prevent breakthrough bleeds, Katherine A. High, MD, said during a press briefing at the annual meeting of the American Society of Hematology. One patient infused himself once with factor IX after developing a suspected ankle bleed 2 days after treatment, Dr. High and her associates reported in the accompanying abstract.

Neil Osterweil/Frontline Medical News

SAN DIEGO – Patients with hemophilia B who received a single 1-hour infusion of the gene transfer therapy SPK-9001 achieved steady-state factor IX activity levels averaging 28% and persisting over 1,650 cumulative days of observation, according to updated results from a phase I/II trial.

All nine patients treated to date have exceeded the 12% steady-state factor IX activity level typically needed to prevent breakthrough bleeds, Katherine A. High, MD, said during a press briefing at the annual meeting of the American Society of Hematology. One patient infused himself once with factor IX after developing a suspected ankle bleed 2 days after treatment, Dr. High and her associates reported in the accompanying abstract.

Neil Osterweil/Frontline Medical News

SAN DIEGO – Patients with hemophilia B who received a single infusion of the gene transfer therapy SPK-9001 achieved steady-state factor IX activity levels averaging 28% and persisting over 1,650 cumulative days of observation, according to updated results from a phase I/II trial.

All nine patients treated to date have exceeded the steady-state factor IX activity level typically needed to prevent breakthrough bleeds, Katherine A. High, MD, reported at the American Society of Hematology. There have been no confirmed bleeds, all patients remain off prophylactic factor IX, none have developed factor IX inhibitory antibodies, and Enzyme-Linked ImmunoSpot testing has uncovered no evidence of emergent reactivity to the gene product. Two patients developed an immune response to the viral capsid in the product, with a corresponding drop in factor IX activity levels. Tapering doses of corticosteroids halted the immune response and patients maintained sufficient levels of factor IX activity to prevent breakthrough bleeds or the need for replacement factor.

Spark Therapeutics Inc. and Pfizer sponsored the work. Dr. High is president and chief scientific officer of Spark. She discussed the trial in a video interview.

SAN DIEGO – Patients with hemophilia B who received a single infusion of the gene transfer therapy SPK-9001 achieved steady-state factor IX activity levels averaging 28% and persisting over 1,650 cumulative days of observation, according to updated results from a phase I/II trial.

All nine patients treated to date have exceeded the steady-state factor IX activity level typically needed to prevent breakthrough bleeds, Katherine A. High, MD, reported at the American Society of Hematology. There have been no confirmed bleeds, all patients remain off prophylactic factor IX, none have developed factor IX inhibitory antibodies, and Enzyme-Linked ImmunoSpot testing has uncovered no evidence of emergent reactivity to the gene product. Two patients developed an immune response to the viral capsid in the product, with a corresponding drop in factor IX activity levels. Tapering doses of corticosteroids halted the immune response and patients maintained sufficient levels of factor IX activity to prevent breakthrough bleeds or the need for replacement factor.

Spark Therapeutics Inc. and Pfizer sponsored the work. Dr. High is president and chief scientific officer of Spark. She discussed the trial in a video interview.

SAN DIEGO – Patients with hemophilia B who received a single infusion of the gene transfer therapy SPK-9001 achieved steady-state factor IX activity levels averaging 28% and persisting over 1,650 cumulative days of observation, according to updated results from a phase I/II trial.

All nine patients treated to date have exceeded the steady-state factor IX activity level typically needed to prevent breakthrough bleeds, Katherine A. High, MD, reported at the American Society of Hematology. There have been no confirmed bleeds, all patients remain off prophylactic factor IX, none have developed factor IX inhibitory antibodies, and Enzyme-Linked ImmunoSpot testing has uncovered no evidence of emergent reactivity to the gene product. Two patients developed an immune response to the viral capsid in the product, with a corresponding drop in factor IX activity levels. Tapering doses of corticosteroids halted the immune response and patients maintained sufficient levels of factor IX activity to prevent breakthrough bleeds or the need for replacement factor.

Spark Therapeutics Inc. and Pfizer sponsored the work. Dr. High is president and chief scientific officer of Spark. She discussed the trial in a video interview.