Hematology

Ah, blood. That sweet nectar of life that quiets angina, abolishes dyspnea, prevents orthostatic syncope, and quells sinus tachycardia. As a cardiologist, I am an unabashed hemophile. 

But we liberal transfusionists are challenged on every request for consideration of transfusion. Whereas the polite may resort to whispered skepticism, vehement critics respond with scorn as if we’d asked them to burn aromatic herbs or fetch a bucket of leeches. And to what do we owe this pathological angst? The broad and persistent misinterpretation of the pesky TRICC trial (N Engl J Med. 1999;340:409-417). You know; the one that should have been published with a boxed warning stating: “Misinterpretation of this trial could result in significant harm.” 
 

Point 1: Our Actively Bleeding Patient is Not a TRICC Patient. 

Published in 1999, the TRICC trial enrolled critical anemic patients older than 16 years who were stable after fluid resuscitation and were not actively bleeding. They had a hemoglobin level < 9 g/dL and were expected to stay in the intensive care unit (ICU) for more than 24 hours. They were randomly assigned to either a conservative trigger for transfusion of < 7 g/dL or a liberal threshold of < 10 g/dL. Mortality at 30 days was lower with the conservative approach — 18.7% vs 23.3% — but the difference was not statistically significant (P = .11). The findings were similar for the secondary endpoints of inpatient mortality (22.2% vs 28.1%; P = .05) and ICU mortality (13.9% vs 16.2%; P = .29). 

One must admit that these P values are not impressive, and the authors’ conclusion should have warranted caution: “A restrictive strategy ... is at least as effective as and possibly superior to a liberal transfusion strategy in critically ill patients, with the possible exception of patients with acute myocardial infarction and unstable angina.” 
 

Point 2: Our Critically Ill Cardiac Patient is Unlikely to be a “TRICC” Patient.

Another criticism of TRICC is that only 13% of those assessed and 26% of those eligible were enrolled, mostly owing to physician refusal. Only 26% of enrolled patients had cardiac disease. This makes the TRICC population highly selected and not representative of typical ICU patients. 

To prove my point that the edict against higher transfusion thresholds can be dangerous, I’ll describe my most recent interface with TRICC trial misinterpretation 
 

A Case in Point

The patient, Mrs. Kemp,* is 79 years old and has been on aspirin for years following coronary stent placement. One evening, she began spurting bright red blood from her rectum, interrupted only briefly by large clots the consistency of jellied cranberries. When she arrived at the hospital, she was hemodynamically stable, with a hemoglobin level of 10 g/dL, down from her usual 12 g/dL. That level bolstered the confidence of her provider, who insisted that she be managed conservatively. 

Mrs. Kemp was transferred to the ward, where she continued to bleed briskly. Over the next 2 hours, her hemoglobin level dropped to 9 g/dL, then 8 g/dL. Her daughter, a healthcare worker, requested a transfusion. The answer was, wait for it — the well-scripted, somewhat patronizing oft-quoted line, “The medical literature states that we need to wait for a hemoglobin level of 7 g/dL before we transfuse.” 

Later that evening, Mrs. Kemp’s systolic blood pressure dropped to the upper 80s, despite her usual hypertension. The provider was again comforted by the fact that she was not tachycardic (she had a pacemaker and was on bisoprolol). The next morning, Mrs. Kemp felt the need to defecate and was placed on the bedside commode and left to her privacy. Predictably, she became dizzy and experienced frank syncope. Thankfully, she avoided a hip fracture or worse. A stat hemoglobin returned at 6 g/dL. 

Her daughter said she literally heard the hallelujah chorus because her mother’s hemoglobin was finally below that much revered and often misleading threshold of 7 g/dL. Finally, there was an order for platelets and packed red cells. Five units later, Mr. Kemp achieved a hemoglobin of 8 g/dL and survived. Two more units and she was soaring at 9 g/dL! 
 

Lessons for Transfusion Conservatives

There are many lessons here. 

The TRICC study found that hemodynamically stable, asymptomatic patients who are not actively bleeding may well tolerate a hemoglobin level of 7 g/dL. But a patient with bright red blood actively pouring from an orifice and a rapidly declining hemoglobin level isn’t one of those people. Additionally, a patient who faints from hypovolemia is not one of those people. 

Patients with a history of bleeding presenting with new resting sinus tachycardia (in those who have chronotropic competence) should be presumed to be actively bleeding, and the findings of TRICC do not apply to them. Patients who have bled buckets on anticoagulant or antiplatelet therapies and have dropped their hemoglobin will probably continue to ooze and should be subject to a low threshold for transfusion. 

Additionally, anemic people who are hemodynamically stable but can’t walk without new significant shortness of air or new rest angina need blood, and sometimes at hemoglobin levels higher than generally accepted by conservative strategists. Finally, failing to treat or at least monitor patients who are spontaneously bleeding as aggressively as some trauma patients is a failure to provide proper medical care. 

The vast majority of my healthcare clinician colleagues are competent, compassionate individuals who can reasonably discuss the nuances of any medical scenario. One important distinction of a good medical team is the willingness to change course based on a change in patient status or the presentation of what may be new information for the provider. 

But those proud transfusion conservatives who will not budge until their threshold is met need to make certain their patient is truly subject to their supposed edicts. Our blood banks should not be more difficult to access than Fort Knox, and transfusion should be used appropriately and liberally in the hemodynamically unstable, the symptomatic, and active brisk bleeders. 

I beg staunch transfusion conservatives to consider how they might feel if someone stuck a magic spigot in their brachial artery and acutely drained their hemoglobin to that magic threshold of 7 g/dL. When syncope, shortness of air, fatigue, and angina find them, they may generate empathy for those who need transfusion. Might that do the TRICC? 

*Some details have been changed to conceal the identity of the patient, but the essence of the case has been preserved.

Dr. Walton-Shirley, a native Kentuckian who retired from full-time invasive cardiology and now does locums work in Montana, is a champion of physician rights and patient safety. She has disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

Ah, blood. That sweet nectar of life that quiets angina, abolishes dyspnea, prevents orthostatic syncope, and quells sinus tachycardia. As a cardiologist, I am an unabashed hemophile. 

But we liberal transfusionists are challenged on every request for consideration of transfusion. Whereas the polite may resort to whispered skepticism, vehement critics respond with scorn as if we’d asked them to burn aromatic herbs or fetch a bucket of leeches. And to what do we owe this pathological angst? The broad and persistent misinterpretation of the pesky TRICC trial (N Engl J Med. 1999;340:409-417). You know; the one that should have been published with a boxed warning stating: “Misinterpretation of this trial could result in significant harm.” 
 

Point 1: Our Actively Bleeding Patient is Not a TRICC Patient. 

Published in 1999, the TRICC trial enrolled critical anemic patients older than 16 years who were stable after fluid resuscitation and were not actively bleeding. They had a hemoglobin level < 9 g/dL and were expected to stay in the intensive care unit (ICU) for more than 24 hours. They were randomly assigned to either a conservative trigger for transfusion of < 7 g/dL or a liberal threshold of < 10 g/dL. Mortality at 30 days was lower with the conservative approach — 18.7% vs 23.3% — but the difference was not statistically significant (P = .11). The findings were similar for the secondary endpoints of inpatient mortality (22.2% vs 28.1%; P = .05) and ICU mortality (13.9% vs 16.2%; P = .29). 

One must admit that these P values are not impressive, and the authors’ conclusion should have warranted caution: “A restrictive strategy ... is at least as effective as and possibly superior to a liberal transfusion strategy in critically ill patients, with the possible exception of patients with acute myocardial infarction and unstable angina.” 
 

Point 2: Our Critically Ill Cardiac Patient is Unlikely to be a “TRICC” Patient.

Another criticism of TRICC is that only 13% of those assessed and 26% of those eligible were enrolled, mostly owing to physician refusal. Only 26% of enrolled patients had cardiac disease. This makes the TRICC population highly selected and not representative of typical ICU patients. 

To prove my point that the edict against higher transfusion thresholds can be dangerous, I’ll describe my most recent interface with TRICC trial misinterpretation 
 

A Case in Point

The patient, Mrs. Kemp,* is 79 years old and has been on aspirin for years following coronary stent placement. One evening, she began spurting bright red blood from her rectum, interrupted only briefly by large clots the consistency of jellied cranberries. When she arrived at the hospital, she was hemodynamically stable, with a hemoglobin level of 10 g/dL, down from her usual 12 g/dL. That level bolstered the confidence of her provider, who insisted that she be managed conservatively. 

Mrs. Kemp was transferred to the ward, where she continued to bleed briskly. Over the next 2 hours, her hemoglobin level dropped to 9 g/dL, then 8 g/dL. Her daughter, a healthcare worker, requested a transfusion. The answer was, wait for it — the well-scripted, somewhat patronizing oft-quoted line, “The medical literature states that we need to wait for a hemoglobin level of 7 g/dL before we transfuse.” 

Later that evening, Mrs. Kemp’s systolic blood pressure dropped to the upper 80s, despite her usual hypertension. The provider was again comforted by the fact that she was not tachycardic (she had a pacemaker and was on bisoprolol). The next morning, Mrs. Kemp felt the need to defecate and was placed on the bedside commode and left to her privacy. Predictably, she became dizzy and experienced frank syncope. Thankfully, she avoided a hip fracture or worse. A stat hemoglobin returned at 6 g/dL. 

Her daughter said she literally heard the hallelujah chorus because her mother’s hemoglobin was finally below that much revered and often misleading threshold of 7 g/dL. Finally, there was an order for platelets and packed red cells. Five units later, Mr. Kemp achieved a hemoglobin of 8 g/dL and survived. Two more units and she was soaring at 9 g/dL! 
 

Lessons for Transfusion Conservatives

There are many lessons here. 

The TRICC study found that hemodynamically stable, asymptomatic patients who are not actively bleeding may well tolerate a hemoglobin level of 7 g/dL. But a patient with bright red blood actively pouring from an orifice and a rapidly declining hemoglobin level isn’t one of those people. Additionally, a patient who faints from hypovolemia is not one of those people. 

Patients with a history of bleeding presenting with new resting sinus tachycardia (in those who have chronotropic competence) should be presumed to be actively bleeding, and the findings of TRICC do not apply to them. Patients who have bled buckets on anticoagulant or antiplatelet therapies and have dropped their hemoglobin will probably continue to ooze and should be subject to a low threshold for transfusion. 

Additionally, anemic people who are hemodynamically stable but can’t walk without new significant shortness of air or new rest angina need blood, and sometimes at hemoglobin levels higher than generally accepted by conservative strategists. Finally, failing to treat or at least monitor patients who are spontaneously bleeding as aggressively as some trauma patients is a failure to provide proper medical care. 

The vast majority of my healthcare clinician colleagues are competent, compassionate individuals who can reasonably discuss the nuances of any medical scenario. One important distinction of a good medical team is the willingness to change course based on a change in patient status or the presentation of what may be new information for the provider. 

But those proud transfusion conservatives who will not budge until their threshold is met need to make certain their patient is truly subject to their supposed edicts. Our blood banks should not be more difficult to access than Fort Knox, and transfusion should be used appropriately and liberally in the hemodynamically unstable, the symptomatic, and active brisk bleeders. 

I beg staunch transfusion conservatives to consider how they might feel if someone stuck a magic spigot in their brachial artery and acutely drained their hemoglobin to that magic threshold of 7 g/dL. When syncope, shortness of air, fatigue, and angina find them, they may generate empathy for those who need transfusion. Might that do the TRICC? 

*Some details have been changed to conceal the identity of the patient, but the essence of the case has been preserved.

Dr. Walton-Shirley, a native Kentuckian who retired from full-time invasive cardiology and now does locums work in Montana, is a champion of physician rights and patient safety. She has disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

Ah, blood. That sweet nectar of life that quiets angina, abolishes dyspnea, prevents orthostatic syncope, and quells sinus tachycardia. As a cardiologist, I am an unabashed hemophile. 

But we liberal transfusionists are challenged on every request for consideration of transfusion. Whereas the polite may resort to whispered skepticism, vehement critics respond with scorn as if we’d asked them to burn aromatic herbs or fetch a bucket of leeches. And to what do we owe this pathological angst? The broad and persistent misinterpretation of the pesky TRICC trial (N Engl J Med. 1999;340:409-417). You know; the one that should have been published with a boxed warning stating: “Misinterpretation of this trial could result in significant harm.” 
 

Point 1: Our Actively Bleeding Patient is Not a TRICC Patient. 

Published in 1999, the TRICC trial enrolled critical anemic patients older than 16 years who were stable after fluid resuscitation and were not actively bleeding. They had a hemoglobin level < 9 g/dL and were expected to stay in the intensive care unit (ICU) for more than 24 hours. They were randomly assigned to either a conservative trigger for transfusion of < 7 g/dL or a liberal threshold of < 10 g/dL. Mortality at 30 days was lower with the conservative approach — 18.7% vs 23.3% — but the difference was not statistically significant (P = .11). The findings were similar for the secondary endpoints of inpatient mortality (22.2% vs 28.1%; P = .05) and ICU mortality (13.9% vs 16.2%; P = .29). 

One must admit that these P values are not impressive, and the authors’ conclusion should have warranted caution: “A restrictive strategy ... is at least as effective as and possibly superior to a liberal transfusion strategy in critically ill patients, with the possible exception of patients with acute myocardial infarction and unstable angina.” 
 

Point 2: Our Critically Ill Cardiac Patient is Unlikely to be a “TRICC” Patient.

Another criticism of TRICC is that only 13% of those assessed and 26% of those eligible were enrolled, mostly owing to physician refusal. Only 26% of enrolled patients had cardiac disease. This makes the TRICC population highly selected and not representative of typical ICU patients. 

To prove my point that the edict against higher transfusion thresholds can be dangerous, I’ll describe my most recent interface with TRICC trial misinterpretation 
 

A Case in Point

The patient, Mrs. Kemp,* is 79 years old and has been on aspirin for years following coronary stent placement. One evening, she began spurting bright red blood from her rectum, interrupted only briefly by large clots the consistency of jellied cranberries. When she arrived at the hospital, she was hemodynamically stable, with a hemoglobin level of 10 g/dL, down from her usual 12 g/dL. That level bolstered the confidence of her provider, who insisted that she be managed conservatively. 

Mrs. Kemp was transferred to the ward, where she continued to bleed briskly. Over the next 2 hours, her hemoglobin level dropped to 9 g/dL, then 8 g/dL. Her daughter, a healthcare worker, requested a transfusion. The answer was, wait for it — the well-scripted, somewhat patronizing oft-quoted line, “The medical literature states that we need to wait for a hemoglobin level of 7 g/dL before we transfuse.” 

Later that evening, Mrs. Kemp’s systolic blood pressure dropped to the upper 80s, despite her usual hypertension. The provider was again comforted by the fact that she was not tachycardic (she had a pacemaker and was on bisoprolol). The next morning, Mrs. Kemp felt the need to defecate and was placed on the bedside commode and left to her privacy. Predictably, she became dizzy and experienced frank syncope. Thankfully, she avoided a hip fracture or worse. A stat hemoglobin returned at 6 g/dL. 

Her daughter said she literally heard the hallelujah chorus because her mother’s hemoglobin was finally below that much revered and often misleading threshold of 7 g/dL. Finally, there was an order for platelets and packed red cells. Five units later, Mr. Kemp achieved a hemoglobin of 8 g/dL and survived. Two more units and she was soaring at 9 g/dL! 
 

Lessons for Transfusion Conservatives

There are many lessons here. 

The TRICC study found that hemodynamically stable, asymptomatic patients who are not actively bleeding may well tolerate a hemoglobin level of 7 g/dL. But a patient with bright red blood actively pouring from an orifice and a rapidly declining hemoglobin level isn’t one of those people. Additionally, a patient who faints from hypovolemia is not one of those people. 

Patients with a history of bleeding presenting with new resting sinus tachycardia (in those who have chronotropic competence) should be presumed to be actively bleeding, and the findings of TRICC do not apply to them. Patients who have bled buckets on anticoagulant or antiplatelet therapies and have dropped their hemoglobin will probably continue to ooze and should be subject to a low threshold for transfusion. 

Additionally, anemic people who are hemodynamically stable but can’t walk without new significant shortness of air or new rest angina need blood, and sometimes at hemoglobin levels higher than generally accepted by conservative strategists. Finally, failing to treat or at least monitor patients who are spontaneously bleeding as aggressively as some trauma patients is a failure to provide proper medical care. 

The vast majority of my healthcare clinician colleagues are competent, compassionate individuals who can reasonably discuss the nuances of any medical scenario. One important distinction of a good medical team is the willingness to change course based on a change in patient status or the presentation of what may be new information for the provider. 

But those proud transfusion conservatives who will not budge until their threshold is met need to make certain their patient is truly subject to their supposed edicts. Our blood banks should not be more difficult to access than Fort Knox, and transfusion should be used appropriately and liberally in the hemodynamically unstable, the symptomatic, and active brisk bleeders. 

I beg staunch transfusion conservatives to consider how they might feel if someone stuck a magic spigot in their brachial artery and acutely drained their hemoglobin to that magic threshold of 7 g/dL. When syncope, shortness of air, fatigue, and angina find them, they may generate empathy for those who need transfusion. Might that do the TRICC? 

*Some details have been changed to conceal the identity of the patient, but the essence of the case has been preserved.

Dr. Walton-Shirley, a native Kentuckian who retired from full-time invasive cardiology and now does locums work in Montana, is a champion of physician rights and patient safety. She has disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

Childhood cancers represent a diverse group of neoplasms, and thanks to advances in treatment, survival rates have improved significantly. Today, more than 80%-85% of children diagnosed with cancer in developed countries survive into adulthood.

This increase in survival has brought new challenges, however. Compared with the general population, childhood cancer survivors (CCS) are at a notably higher risk for early mortality, developing secondary cancers, and experiencing various long-term clinical and psychosocial issues stemming from their disease or its treatment.

Long-term follow-up care for CCS is a complex and evolving field. Despite ongoing efforts to establish global and national guidelines, current evidence indicates that the care and management of these patients remain suboptimal.

Sexual dysfunction is a common and significant late effect among CCS. The disruptions caused by cancer and its treatment can interfere with normal physiological and psychological development, leading to issues with sexual function. This aspect of health is critical as it influences not just physical well-being but also psychosocial, developmental, and emotional health.
 

Characteristics and Mechanisms

Sexual functioning encompasses the physiological and psychological aspects of sexual behavior, including desire, arousal, orgasm, sexual pleasure, and overall satisfaction.

As CCS reach adolescence or adulthood, they often face sexual and reproductive issues, particularly as they enter romantic relationships.

Sexual functioning is a complex process that relies on the interaction of various factors, including physiological health, psychosexual development, romantic relationships, body image, and desire.

Despite its importance, the impact of childhood cancer on sexual function is often overlooked, even though cancer and its treatments can have lifelong effects. 
 

Sexual Function in CCS

A recent review aimed to summarize the existing research on sexual function among CCS, highlighting assessment tools, key stages of psychosexual development, common sexual problems, and the prevalence of sexual dysfunction.

The review study included 22 studies published between 2000 and 2022, comprising two qualitative, six cohort, and 14 cross-sectional studies.

Most CCS reached all key stages of psychosexual development at an average age of 29.8 years. Although some milestones were achieved later than is typical, many survivors felt they reached these stages at the appropriate time. Sexual initiation was less common among those who had undergone intensive neurotoxic treatments, such as those diagnosed with brain tumors or leukemia in childhood.

In a cross-sectional study of CCS aged 17-39 years, about one third had never engaged in sexual intercourse, 41.4% reported never experiencing sexual attraction, 44.8% were dissatisfied with their sex lives, and many rarely felt sexually attractive to others. Another study found that common issues among CCS included a lack of interest in sex (30%), difficulty enjoying sex (24%), and difficulty becoming aroused (23%). However, comparing and analyzing these problems was challenging due to the lack of standardized assessment criteria.

The prevalence of sexual dysfunction among CCS ranged from 12.3% to 46.5%. For males, the prevalence ranged from 12.3% to 54.0%, while for females, it ranged from 19.9% to 57.0%.
 

Factors Influencing Sexual Function

The review identified the following four categories of factors influencing sexual function in CCS: Demographic, treatment-related, psychological, and physiological.

Demographic factors: Gender, age, education level, relationship status, income level, and race all play roles in sexual function.

Female survivors reported more severe sexual dysfunction and poorer sexual health than did male survivors. Age at cancer diagnosis, age at evaluation, and the time since diagnosis were closely linked to sexual experiences. Patients diagnosed with cancer during childhood tended to report better sexual function than those diagnosed during adolescence.

Treatment-related factors: The type of cancer and intensity of treatment, along with surgical history, were significant factors. Surgeries involving the spinal cord or sympathetic nerves, as well as a history of prostate or pelvic surgery, were strongly associated with erectile dysfunction in men. In women, pelvic surgeries and treatments to the pelvic area were commonly linked to sexual dysfunction.

The association between treatment intensity and sexual function was noted across several studies, although the results were not always consistent. For example, testicular radiation above 10 Gy was positively correlated with sexual dysfunction. Women who underwent more intensive treatments were more likely to report issues in multiple areas of sexual function, while men in this group were less likely to have children.

Among female CCS, certain types of cancer, such as germ cell tumors, renal tumors, and leukemia, present a higher risk for sexual dysfunction. Women who had CNS tumors in childhood frequently reported problems like difficulty in sexual arousal, low sexual satisfaction, infrequent sexual activity, and fewer sexual partners, compared with survivors of other cancers. Survivors of acute lymphoblastic leukemia and those who underwent hematopoietic stem cell transplantation (HSCT) also showed varying degrees of impaired sexual function, compared with the general population. The HSCT group showed significant testicular damage, including reduced testicular volumes, low testosterone levels, and low sperm counts.

Psychological factors: These factors, such as emotional distress, play a significant role in sexual dysfunction among CCS. Symptoms like anxiety, nervousness during sexual activity, and depression are commonly reported by those with sexual dysfunction. The connection between body image and sexual function is complex. Many CCS with sexual dysfunction express concern about how others, particularly their partners, perceived their altered body image due to cancer and its treatment.

Physiological factors: In male CCS, low serum testosterone levels and low lean muscle mass are linked to an increased risk for sexual dysfunction. Treatments involving alkylating agents or testicular radiation, and surgery or radiotherapy targeting the genitourinary organs or the hypothalamic-pituitary region, can lead to various physiological and endocrine disorders, contributing to sexual dysfunction. Despite these risks, there is a lack of research evaluating sexual function through the lens of the hypothalamic-pituitary-gonadal axis and neuroendocrine pathways.
 

This story was translated from Univadis Italy using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

Childhood cancers represent a diverse group of neoplasms, and thanks to advances in treatment, survival rates have improved significantly. Today, more than 80%-85% of children diagnosed with cancer in developed countries survive into adulthood.

This increase in survival has brought new challenges, however. Compared with the general population, childhood cancer survivors (CCS) are at a notably higher risk for early mortality, developing secondary cancers, and experiencing various long-term clinical and psychosocial issues stemming from their disease or its treatment.

Long-term follow-up care for CCS is a complex and evolving field. Despite ongoing efforts to establish global and national guidelines, current evidence indicates that the care and management of these patients remain suboptimal.

Sexual dysfunction is a common and significant late effect among CCS. The disruptions caused by cancer and its treatment can interfere with normal physiological and psychological development, leading to issues with sexual function. This aspect of health is critical as it influences not just physical well-being but also psychosocial, developmental, and emotional health.
 

Characteristics and Mechanisms

Sexual functioning encompasses the physiological and psychological aspects of sexual behavior, including desire, arousal, orgasm, sexual pleasure, and overall satisfaction.

As CCS reach adolescence or adulthood, they often face sexual and reproductive issues, particularly as they enter romantic relationships.

Sexual functioning is a complex process that relies on the interaction of various factors, including physiological health, psychosexual development, romantic relationships, body image, and desire.

Despite its importance, the impact of childhood cancer on sexual function is often overlooked, even though cancer and its treatments can have lifelong effects. 
 

Sexual Function in CCS

A recent review aimed to summarize the existing research on sexual function among CCS, highlighting assessment tools, key stages of psychosexual development, common sexual problems, and the prevalence of sexual dysfunction.

The review study included 22 studies published between 2000 and 2022, comprising two qualitative, six cohort, and 14 cross-sectional studies.

Most CCS reached all key stages of psychosexual development at an average age of 29.8 years. Although some milestones were achieved later than is typical, many survivors felt they reached these stages at the appropriate time. Sexual initiation was less common among those who had undergone intensive neurotoxic treatments, such as those diagnosed with brain tumors or leukemia in childhood.

In a cross-sectional study of CCS aged 17-39 years, about one third had never engaged in sexual intercourse, 41.4% reported never experiencing sexual attraction, 44.8% were dissatisfied with their sex lives, and many rarely felt sexually attractive to others. Another study found that common issues among CCS included a lack of interest in sex (30%), difficulty enjoying sex (24%), and difficulty becoming aroused (23%). However, comparing and analyzing these problems was challenging due to the lack of standardized assessment criteria.

The prevalence of sexual dysfunction among CCS ranged from 12.3% to 46.5%. For males, the prevalence ranged from 12.3% to 54.0%, while for females, it ranged from 19.9% to 57.0%.
 

Factors Influencing Sexual Function

The review identified the following four categories of factors influencing sexual function in CCS: Demographic, treatment-related, psychological, and physiological.

Demographic factors: Gender, age, education level, relationship status, income level, and race all play roles in sexual function.

Female survivors reported more severe sexual dysfunction and poorer sexual health than did male survivors. Age at cancer diagnosis, age at evaluation, and the time since diagnosis were closely linked to sexual experiences. Patients diagnosed with cancer during childhood tended to report better sexual function than those diagnosed during adolescence.

Treatment-related factors: The type of cancer and intensity of treatment, along with surgical history, were significant factors. Surgeries involving the spinal cord or sympathetic nerves, as well as a history of prostate or pelvic surgery, were strongly associated with erectile dysfunction in men. In women, pelvic surgeries and treatments to the pelvic area were commonly linked to sexual dysfunction.

The association between treatment intensity and sexual function was noted across several studies, although the results were not always consistent. For example, testicular radiation above 10 Gy was positively correlated with sexual dysfunction. Women who underwent more intensive treatments were more likely to report issues in multiple areas of sexual function, while men in this group were less likely to have children.

Among female CCS, certain types of cancer, such as germ cell tumors, renal tumors, and leukemia, present a higher risk for sexual dysfunction. Women who had CNS tumors in childhood frequently reported problems like difficulty in sexual arousal, low sexual satisfaction, infrequent sexual activity, and fewer sexual partners, compared with survivors of other cancers. Survivors of acute lymphoblastic leukemia and those who underwent hematopoietic stem cell transplantation (HSCT) also showed varying degrees of impaired sexual function, compared with the general population. The HSCT group showed significant testicular damage, including reduced testicular volumes, low testosterone levels, and low sperm counts.

Psychological factors: These factors, such as emotional distress, play a significant role in sexual dysfunction among CCS. Symptoms like anxiety, nervousness during sexual activity, and depression are commonly reported by those with sexual dysfunction. The connection between body image and sexual function is complex. Many CCS with sexual dysfunction express concern about how others, particularly their partners, perceived their altered body image due to cancer and its treatment.

Physiological factors: In male CCS, low serum testosterone levels and low lean muscle mass are linked to an increased risk for sexual dysfunction. Treatments involving alkylating agents or testicular radiation, and surgery or radiotherapy targeting the genitourinary organs or the hypothalamic-pituitary region, can lead to various physiological and endocrine disorders, contributing to sexual dysfunction. Despite these risks, there is a lack of research evaluating sexual function through the lens of the hypothalamic-pituitary-gonadal axis and neuroendocrine pathways.
 

This story was translated from Univadis Italy using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

Childhood cancers represent a diverse group of neoplasms, and thanks to advances in treatment, survival rates have improved significantly. Today, more than 80%-85% of children diagnosed with cancer in developed countries survive into adulthood.

This increase in survival has brought new challenges, however. Compared with the general population, childhood cancer survivors (CCS) are at a notably higher risk for early mortality, developing secondary cancers, and experiencing various long-term clinical and psychosocial issues stemming from their disease or its treatment.

Long-term follow-up care for CCS is a complex and evolving field. Despite ongoing efforts to establish global and national guidelines, current evidence indicates that the care and management of these patients remain suboptimal.

Sexual dysfunction is a common and significant late effect among CCS. The disruptions caused by cancer and its treatment can interfere with normal physiological and psychological development, leading to issues with sexual function. This aspect of health is critical as it influences not just physical well-being but also psychosocial, developmental, and emotional health.
 

Characteristics and Mechanisms

Sexual functioning encompasses the physiological and psychological aspects of sexual behavior, including desire, arousal, orgasm, sexual pleasure, and overall satisfaction.

As CCS reach adolescence or adulthood, they often face sexual and reproductive issues, particularly as they enter romantic relationships.

Sexual functioning is a complex process that relies on the interaction of various factors, including physiological health, psychosexual development, romantic relationships, body image, and desire.

Despite its importance, the impact of childhood cancer on sexual function is often overlooked, even though cancer and its treatments can have lifelong effects. 
 

Sexual Function in CCS

A recent review aimed to summarize the existing research on sexual function among CCS, highlighting assessment tools, key stages of psychosexual development, common sexual problems, and the prevalence of sexual dysfunction.

The review study included 22 studies published between 2000 and 2022, comprising two qualitative, six cohort, and 14 cross-sectional studies.

Most CCS reached all key stages of psychosexual development at an average age of 29.8 years. Although some milestones were achieved later than is typical, many survivors felt they reached these stages at the appropriate time. Sexual initiation was less common among those who had undergone intensive neurotoxic treatments, such as those diagnosed with brain tumors or leukemia in childhood.

In a cross-sectional study of CCS aged 17-39 years, about one third had never engaged in sexual intercourse, 41.4% reported never experiencing sexual attraction, 44.8% were dissatisfied with their sex lives, and many rarely felt sexually attractive to others. Another study found that common issues among CCS included a lack of interest in sex (30%), difficulty enjoying sex (24%), and difficulty becoming aroused (23%). However, comparing and analyzing these problems was challenging due to the lack of standardized assessment criteria.

The prevalence of sexual dysfunction among CCS ranged from 12.3% to 46.5%. For males, the prevalence ranged from 12.3% to 54.0%, while for females, it ranged from 19.9% to 57.0%.
 

Factors Influencing Sexual Function

The review identified the following four categories of factors influencing sexual function in CCS: Demographic, treatment-related, psychological, and physiological.

Demographic factors: Gender, age, education level, relationship status, income level, and race all play roles in sexual function.

Female survivors reported more severe sexual dysfunction and poorer sexual health than did male survivors. Age at cancer diagnosis, age at evaluation, and the time since diagnosis were closely linked to sexual experiences. Patients diagnosed with cancer during childhood tended to report better sexual function than those diagnosed during adolescence.

Treatment-related factors: The type of cancer and intensity of treatment, along with surgical history, were significant factors. Surgeries involving the spinal cord or sympathetic nerves, as well as a history of prostate or pelvic surgery, were strongly associated with erectile dysfunction in men. In women, pelvic surgeries and treatments to the pelvic area were commonly linked to sexual dysfunction.

The association between treatment intensity and sexual function was noted across several studies, although the results were not always consistent. For example, testicular radiation above 10 Gy was positively correlated with sexual dysfunction. Women who underwent more intensive treatments were more likely to report issues in multiple areas of sexual function, while men in this group were less likely to have children.

Among female CCS, certain types of cancer, such as germ cell tumors, renal tumors, and leukemia, present a higher risk for sexual dysfunction. Women who had CNS tumors in childhood frequently reported problems like difficulty in sexual arousal, low sexual satisfaction, infrequent sexual activity, and fewer sexual partners, compared with survivors of other cancers. Survivors of acute lymphoblastic leukemia and those who underwent hematopoietic stem cell transplantation (HSCT) also showed varying degrees of impaired sexual function, compared with the general population. The HSCT group showed significant testicular damage, including reduced testicular volumes, low testosterone levels, and low sperm counts.

Psychological factors: These factors, such as emotional distress, play a significant role in sexual dysfunction among CCS. Symptoms like anxiety, nervousness during sexual activity, and depression are commonly reported by those with sexual dysfunction. The connection between body image and sexual function is complex. Many CCS with sexual dysfunction express concern about how others, particularly their partners, perceived their altered body image due to cancer and its treatment.

Physiological factors: In male CCS, low serum testosterone levels and low lean muscle mass are linked to an increased risk for sexual dysfunction. Treatments involving alkylating agents or testicular radiation, and surgery or radiotherapy targeting the genitourinary organs or the hypothalamic-pituitary region, can lead to various physiological and endocrine disorders, contributing to sexual dysfunction. Despite these risks, there is a lack of research evaluating sexual function through the lens of the hypothalamic-pituitary-gonadal axis and neuroendocrine pathways.
 

This story was translated from Univadis Italy using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

The results of a large French study comparing the cancer risk in children conceived through assisted reproductive technology (ART) with that of naturally conceived children were published recently in JAMA Network Open. This study is one of the largest to date on this subject: It included 8,526,306 children born in France between 2010 and 2021, of whom 260,236 (3%) were conceived through ART, and followed them up to a median age of 6.7 years.

Motivations for the Study

ART (including artificial insemination, in vitro fertilization [IVF], or intracytoplasmic sperm injection [ICSI] with fresh or frozen embryo transfer) accounts for about 1 in 30 births in France. However, limited and heterogeneous data have suggested an increased risk for certain health disorders, including cancer, among children conceived through ART. Therefore, a large-scale evaluation of cancer risk in these children is important.

No Overall Increase

In all, 9256 children developed cancer, including 292 who were conceived through ART. Thus, this study did not show an increased risk for cancer (of all types combined) in children conceived through ART. Nevertheless, a slight increase in the risk for leukemia was observed in children conceived through IVF or ICSI. The investigators observed approximately one additional case for every 5000 newborns conceived through IVF or ICSI who reached age 10 years.

Epidemiological monitoring should be continued to better evaluate long-term risks and see whether the risk for leukemia is confirmed. If it is, then it will be useful to investigate the mechanisms related to ART techniques or the fertility disorders of parents that could lead to an increased risk for leukemia.

This story was translated from Univadis France, which is part of the Medscape Professional Network, using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

The results of a large French study comparing the cancer risk in children conceived through assisted reproductive technology (ART) with that of naturally conceived children were published recently in JAMA Network Open. This study is one of the largest to date on this subject: It included 8,526,306 children born in France between 2010 and 2021, of whom 260,236 (3%) were conceived through ART, and followed them up to a median age of 6.7 years.

Motivations for the Study

ART (including artificial insemination, in vitro fertilization [IVF], or intracytoplasmic sperm injection [ICSI] with fresh or frozen embryo transfer) accounts for about 1 in 30 births in France. However, limited and heterogeneous data have suggested an increased risk for certain health disorders, including cancer, among children conceived through ART. Therefore, a large-scale evaluation of cancer risk in these children is important.

No Overall Increase

In all, 9256 children developed cancer, including 292 who were conceived through ART. Thus, this study did not show an increased risk for cancer (of all types combined) in children conceived through ART. Nevertheless, a slight increase in the risk for leukemia was observed in children conceived through IVF or ICSI. The investigators observed approximately one additional case for every 5000 newborns conceived through IVF or ICSI who reached age 10 years.

Epidemiological monitoring should be continued to better evaluate long-term risks and see whether the risk for leukemia is confirmed. If it is, then it will be useful to investigate the mechanisms related to ART techniques or the fertility disorders of parents that could lead to an increased risk for leukemia.

This story was translated from Univadis France, which is part of the Medscape Professional Network, using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

The results of a large French study comparing the cancer risk in children conceived through assisted reproductive technology (ART) with that of naturally conceived children were published recently in JAMA Network Open. This study is one of the largest to date on this subject: It included 8,526,306 children born in France between 2010 and 2021, of whom 260,236 (3%) were conceived through ART, and followed them up to a median age of 6.7 years.

Motivations for the Study

ART (including artificial insemination, in vitro fertilization [IVF], or intracytoplasmic sperm injection [ICSI] with fresh or frozen embryo transfer) accounts for about 1 in 30 births in France. However, limited and heterogeneous data have suggested an increased risk for certain health disorders, including cancer, among children conceived through ART. Therefore, a large-scale evaluation of cancer risk in these children is important.

No Overall Increase

In all, 9256 children developed cancer, including 292 who were conceived through ART. Thus, this study did not show an increased risk for cancer (of all types combined) in children conceived through ART. Nevertheless, a slight increase in the risk for leukemia was observed in children conceived through IVF or ICSI. The investigators observed approximately one additional case for every 5000 newborns conceived through IVF or ICSI who reached age 10 years.

Epidemiological monitoring should be continued to better evaluate long-term risks and see whether the risk for leukemia is confirmed. If it is, then it will be useful to investigate the mechanisms related to ART techniques or the fertility disorders of parents that could lead to an increased risk for leukemia.

This story was translated from Univadis France, which is part of the Medscape Professional Network, using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

The US Food and Drug Administration (FDA) has approved imetelstat (Rytelo, Geron Corporation) for certain patients with relapsed or refractory low- to intermediate-risk myelodysplastic syndromes (MDS).

Specifically, the first-in-class oligonucleotide telomerase inhibitor, which received orphan drug designation, is indicated for adults with MDS who have transfusion-dependent anemia requiring four or more red blood cell units over 8 weeks and who have not responded to erythropoiesis-stimulating agents or who have lost response to or are not eligible for erythropoiesis-stimulating agents, according to an FDA press release.

“For patients with lower-risk MDS and anemia who are transfusion dependent, we have very few options today and often cycle through available therapies, making the approval of RYTELO potentially practice changing for us,” co-investigator Rami Komrokji, MD, of Moffitt Cancer Center, Tampa, Florida, said in the Geron Corporation’s announcement of the approval.

Approval was based on efficacy and safety findings from the randomized, placebo-controlled, phase 3 IMerge trial, which found significantly improved red blood cell transfusion independence with treatment vs with placebo.

Overall, 178 patients were randomly assigned to the imetelstat arm (n = 118) and the placebo arm (n = 60). The median follow-up was 19.5 months in the treatment arm and 17.5 months in the placebo arm.

Patients received infusions of either 7.1 mg/kg of imetelstat or placebo in 28-day cycles until disease progression or unacceptable toxicity. All patients received supportive care, including red blood cell transfusions.

The rate of 8-week-or-greater red blood cell transfusion independence was 39.8% in the imetelstat vs 15% placebo arm. The rate of 24-week-or-greater red blood cell transfusion independence was 28% in the treatment arm vs 3.3% in the placebo arm.

An exploratory analysis among patients who achieved at least 8 weeks of red blood cell transfusion independence revealed that median increases in hemoglobin were 3.6 g/dL in the treatment group vs 0.8 g/dL in the placebo group.

Adverse reactions, occurring in at least 10% of patients and in at least 5% more patients in the treatment arm than in the placebo arm, included decreased platelets, white blood cells, and neutrophils; increased aspartate aminotransferase, alkaline phosphatase, and alanine aminotransferase; and fatigue, prolonged partial thromboplastin time, arthralgia/myalgia, COVID-19, and headache.

The recommended imetelstat dose is 7.1 mg/kg administered as an intravenous infusion over 2 hours every 28 days, according to the full prescribing information. 

“What is exciting about RYTELO is the totality of the clinical benefit across [lower risk] MDS patients irrespective of ring sideroblast status or high transfusion burden, including sustained and durable transfusion independence and increases in hemoglobin levels, all within a well-characterized safety profile of generally manageable cytopenias,” Dr. Komrokji stated. The treatment goal for patients with this condition “is transfusion-independence and before today, this wasn’t possible for many patients.”
 

A version of this article appeared on Medscape.com.

The US Food and Drug Administration (FDA) has approved imetelstat (Rytelo, Geron Corporation) for certain patients with relapsed or refractory low- to intermediate-risk myelodysplastic syndromes (MDS).

Specifically, the first-in-class oligonucleotide telomerase inhibitor, which received orphan drug designation, is indicated for adults with MDS who have transfusion-dependent anemia requiring four or more red blood cell units over 8 weeks and who have not responded to erythropoiesis-stimulating agents or who have lost response to or are not eligible for erythropoiesis-stimulating agents, according to an FDA press release.

“For patients with lower-risk MDS and anemia who are transfusion dependent, we have very few options today and often cycle through available therapies, making the approval of RYTELO potentially practice changing for us,” co-investigator Rami Komrokji, MD, of Moffitt Cancer Center, Tampa, Florida, said in the Geron Corporation’s announcement of the approval.

Approval was based on efficacy and safety findings from the randomized, placebo-controlled, phase 3 IMerge trial, which found significantly improved red blood cell transfusion independence with treatment vs with placebo.

Overall, 178 patients were randomly assigned to the imetelstat arm (n = 118) and the placebo arm (n = 60). The median follow-up was 19.5 months in the treatment arm and 17.5 months in the placebo arm.

Patients received infusions of either 7.1 mg/kg of imetelstat or placebo in 28-day cycles until disease progression or unacceptable toxicity. All patients received supportive care, including red blood cell transfusions.

The rate of 8-week-or-greater red blood cell transfusion independence was 39.8% in the imetelstat vs 15% placebo arm. The rate of 24-week-or-greater red blood cell transfusion independence was 28% in the treatment arm vs 3.3% in the placebo arm.

An exploratory analysis among patients who achieved at least 8 weeks of red blood cell transfusion independence revealed that median increases in hemoglobin were 3.6 g/dL in the treatment group vs 0.8 g/dL in the placebo group.

Adverse reactions, occurring in at least 10% of patients and in at least 5% more patients in the treatment arm than in the placebo arm, included decreased platelets, white blood cells, and neutrophils; increased aspartate aminotransferase, alkaline phosphatase, and alanine aminotransferase; and fatigue, prolonged partial thromboplastin time, arthralgia/myalgia, COVID-19, and headache.

The recommended imetelstat dose is 7.1 mg/kg administered as an intravenous infusion over 2 hours every 28 days, according to the full prescribing information. 

“What is exciting about RYTELO is the totality of the clinical benefit across [lower risk] MDS patients irrespective of ring sideroblast status or high transfusion burden, including sustained and durable transfusion independence and increases in hemoglobin levels, all within a well-characterized safety profile of generally manageable cytopenias,” Dr. Komrokji stated. The treatment goal for patients with this condition “is transfusion-independence and before today, this wasn’t possible for many patients.”
 

A version of this article appeared on Medscape.com.

The US Food and Drug Administration (FDA) has approved imetelstat (Rytelo, Geron Corporation) for certain patients with relapsed or refractory low- to intermediate-risk myelodysplastic syndromes (MDS).

Specifically, the first-in-class oligonucleotide telomerase inhibitor, which received orphan drug designation, is indicated for adults with MDS who have transfusion-dependent anemia requiring four or more red blood cell units over 8 weeks and who have not responded to erythropoiesis-stimulating agents or who have lost response to or are not eligible for erythropoiesis-stimulating agents, according to an FDA press release.

“For patients with lower-risk MDS and anemia who are transfusion dependent, we have very few options today and often cycle through available therapies, making the approval of RYTELO potentially practice changing for us,” co-investigator Rami Komrokji, MD, of Moffitt Cancer Center, Tampa, Florida, said in the Geron Corporation’s announcement of the approval.

Approval was based on efficacy and safety findings from the randomized, placebo-controlled, phase 3 IMerge trial, which found significantly improved red blood cell transfusion independence with treatment vs with placebo.

Overall, 178 patients were randomly assigned to the imetelstat arm (n = 118) and the placebo arm (n = 60). The median follow-up was 19.5 months in the treatment arm and 17.5 months in the placebo arm.

Patients received infusions of either 7.1 mg/kg of imetelstat or placebo in 28-day cycles until disease progression or unacceptable toxicity. All patients received supportive care, including red blood cell transfusions.

The rate of 8-week-or-greater red blood cell transfusion independence was 39.8% in the imetelstat vs 15% placebo arm. The rate of 24-week-or-greater red blood cell transfusion independence was 28% in the treatment arm vs 3.3% in the placebo arm.

An exploratory analysis among patients who achieved at least 8 weeks of red blood cell transfusion independence revealed that median increases in hemoglobin were 3.6 g/dL in the treatment group vs 0.8 g/dL in the placebo group.

Adverse reactions, occurring in at least 10% of patients and in at least 5% more patients in the treatment arm than in the placebo arm, included decreased platelets, white blood cells, and neutrophils; increased aspartate aminotransferase, alkaline phosphatase, and alanine aminotransferase; and fatigue, prolonged partial thromboplastin time, arthralgia/myalgia, COVID-19, and headache.

The recommended imetelstat dose is 7.1 mg/kg administered as an intravenous infusion over 2 hours every 28 days, according to the full prescribing information. 

“What is exciting about RYTELO is the totality of the clinical benefit across [lower risk] MDS patients irrespective of ring sideroblast status or high transfusion burden, including sustained and durable transfusion independence and increases in hemoglobin levels, all within a well-characterized safety profile of generally manageable cytopenias,” Dr. Komrokji stated. The treatment goal for patients with this condition “is transfusion-independence and before today, this wasn’t possible for many patients.”
 

A version of this article appeared on Medscape.com.

Three different definitions of nonanemic iron deficiency (ID), a common disorder causing substantial morbidity in women, were significantly associated with different population prevalence estimates, a data analysis of the cross-sectional Hemochromatosis and Iron Overload Screening Study (HEIRS) study found.

These differences held, regardless of self-reported age, pregnancy, or race and ethnicity, according to HEIRS researchers led by James C. Barton, MD, professor of hematology at the University of Alabama at Birmingham.

“Using higher serum ferritin thresholds to define ID could lead to diagnosis and treatment of more women with ID and greater reduction of related morbidity,” the investigators wrote. The study was published in JAMA Network Open.

The authors noted that ID affects about 2 billion people worldwide, mainly women and children, increasing risks of fatigue, impaired muscular performance, cold intolerance, mucosal and epithelial abnormalities, pica, disturbances of menstruation, and adverse pregnancy outcomes.

Manifestations of ID, including anemia, are less prevalent or less severe in adults with higher serum ferritin (SF), and the three definitions correspond, in sequence, to ID of increasing prevalence and decreasing severity, they explained.
 

The Study

HEIRS conducted multiethnic, primary care–based screening for iron disorders during 2001-2003 at four field centers in the United States and one in Canada at primary care venues.

In data for the current study analyzed from June to December, 2023, the three ID definitions were: combined transferrin saturation less than 10% and SF less than 15 ng/mL (HEIRS); SF less than 15 ng/mL (World Health Organization [WHO]); and SF less than 25 ng/mL, the threshold for ID-deficient erythropoiesis [IDE).

Among the cohort’s 62,685 women (mean age, 49.58 years, 27,072 White, 17,272 Black), the estimated prevalence of ID emerged as follows across the different definitions:

• 1957 (3.12%) according to HEIRS
• 4659 (7.43%) according to WHO
• 9611 (15.33%) according to IDE

Those figures translated to an increased relative ID prevalence of 2.4-fold (95% CI, 2.3-2.5; P < .001) according to the WHO standard and 4.9-fold (95% CI, 4.7-5.2; P < .001) according IDEs.

In addition, prevalence was higher in younger women, and within each racial and ethnic subgroup of participants aged 25-54 years, prevalence rose significantly from the HEIRS definition to the WHO and IDE definitions.

Notably, ID was significantly higher among Black and Hispanic participants than Asian and White participants.

An accompanying editorial pointed to gender-based health equity issues raised by the HEIRS analysis and argued that a similar passive acceptance of laboratory definitions of a debilitating but correctable condition in White males would be “frankly unimaginable.”

“Iron deficiency is the leading cause of years lived with disability among women of reproductive age,” wrote hematologist Michelle Sholzberg, MDCM, MSc, and Grace H. Tang, MSc, of St. Michael’s Hospital in Toronto, Canada. “It is a factor clearly associated with maternal death and morbidity (including diminished IQ), and it is correctable, and, thus, unnecessary, in high-income, middle-income, and low-income geographic settings.”

The authors listed no specific funding for this analysis of HEIRS data. Dr. Barton reported contracts from the National Institutes of Health, National Human Genome Research Institute, outside of the submitted work. A coauthor reported grants from the National Heart, Lung, and Blood Institute and the National Human Genome Research Institute outside of the submitted work. Dr. Sholzberg reported unrestricted research funding to her institution from Octapharma and Pfizer and speakers’ honoraria from Takeda, Sobi, and Medison outside of the submitted work.

Three different definitions of nonanemic iron deficiency (ID), a common disorder causing substantial morbidity in women, were significantly associated with different population prevalence estimates, a data analysis of the cross-sectional Hemochromatosis and Iron Overload Screening Study (HEIRS) study found.

These differences held, regardless of self-reported age, pregnancy, or race and ethnicity, according to HEIRS researchers led by James C. Barton, MD, professor of hematology at the University of Alabama at Birmingham.

“Using higher serum ferritin thresholds to define ID could lead to diagnosis and treatment of more women with ID and greater reduction of related morbidity,” the investigators wrote. The study was published in JAMA Network Open.

The authors noted that ID affects about 2 billion people worldwide, mainly women and children, increasing risks of fatigue, impaired muscular performance, cold intolerance, mucosal and epithelial abnormalities, pica, disturbances of menstruation, and adverse pregnancy outcomes.

Manifestations of ID, including anemia, are less prevalent or less severe in adults with higher serum ferritin (SF), and the three definitions correspond, in sequence, to ID of increasing prevalence and decreasing severity, they explained.
 

The Study

HEIRS conducted multiethnic, primary care–based screening for iron disorders during 2001-2003 at four field centers in the United States and one in Canada at primary care venues.

In data for the current study analyzed from June to December, 2023, the three ID definitions were: combined transferrin saturation less than 10% and SF less than 15 ng/mL (HEIRS); SF less than 15 ng/mL (World Health Organization [WHO]); and SF less than 25 ng/mL, the threshold for ID-deficient erythropoiesis [IDE).

Among the cohort’s 62,685 women (mean age, 49.58 years, 27,072 White, 17,272 Black), the estimated prevalence of ID emerged as follows across the different definitions:

• 1957 (3.12%) according to HEIRS
• 4659 (7.43%) according to WHO
• 9611 (15.33%) according to IDE

Those figures translated to an increased relative ID prevalence of 2.4-fold (95% CI, 2.3-2.5; P < .001) according to the WHO standard and 4.9-fold (95% CI, 4.7-5.2; P < .001) according IDEs.

In addition, prevalence was higher in younger women, and within each racial and ethnic subgroup of participants aged 25-54 years, prevalence rose significantly from the HEIRS definition to the WHO and IDE definitions.

Notably, ID was significantly higher among Black and Hispanic participants than Asian and White participants.

An accompanying editorial pointed to gender-based health equity issues raised by the HEIRS analysis and argued that a similar passive acceptance of laboratory definitions of a debilitating but correctable condition in White males would be “frankly unimaginable.”

“Iron deficiency is the leading cause of years lived with disability among women of reproductive age,” wrote hematologist Michelle Sholzberg, MDCM, MSc, and Grace H. Tang, MSc, of St. Michael’s Hospital in Toronto, Canada. “It is a factor clearly associated with maternal death and morbidity (including diminished IQ), and it is correctable, and, thus, unnecessary, in high-income, middle-income, and low-income geographic settings.”

The authors listed no specific funding for this analysis of HEIRS data. Dr. Barton reported contracts from the National Institutes of Health, National Human Genome Research Institute, outside of the submitted work. A coauthor reported grants from the National Heart, Lung, and Blood Institute and the National Human Genome Research Institute outside of the submitted work. Dr. Sholzberg reported unrestricted research funding to her institution from Octapharma and Pfizer and speakers’ honoraria from Takeda, Sobi, and Medison outside of the submitted work.

Three different definitions of nonanemic iron deficiency (ID), a common disorder causing substantial morbidity in women, were significantly associated with different population prevalence estimates, a data analysis of the cross-sectional Hemochromatosis and Iron Overload Screening Study (HEIRS) study found.

These differences held, regardless of self-reported age, pregnancy, or race and ethnicity, according to HEIRS researchers led by James C. Barton, MD, professor of hematology at the University of Alabama at Birmingham.

“Using higher serum ferritin thresholds to define ID could lead to diagnosis and treatment of more women with ID and greater reduction of related morbidity,” the investigators wrote. The study was published in JAMA Network Open.

The authors noted that ID affects about 2 billion people worldwide, mainly women and children, increasing risks of fatigue, impaired muscular performance, cold intolerance, mucosal and epithelial abnormalities, pica, disturbances of menstruation, and adverse pregnancy outcomes.

Manifestations of ID, including anemia, are less prevalent or less severe in adults with higher serum ferritin (SF), and the three definitions correspond, in sequence, to ID of increasing prevalence and decreasing severity, they explained.
 

The Study

HEIRS conducted multiethnic, primary care–based screening for iron disorders during 2001-2003 at four field centers in the United States and one in Canada at primary care venues.

In data for the current study analyzed from June to December, 2023, the three ID definitions were: combined transferrin saturation less than 10% and SF less than 15 ng/mL (HEIRS); SF less than 15 ng/mL (World Health Organization [WHO]); and SF less than 25 ng/mL, the threshold for ID-deficient erythropoiesis [IDE).

Among the cohort’s 62,685 women (mean age, 49.58 years, 27,072 White, 17,272 Black), the estimated prevalence of ID emerged as follows across the different definitions:

• 1957 (3.12%) according to HEIRS
• 4659 (7.43%) according to WHO
• 9611 (15.33%) according to IDE

Those figures translated to an increased relative ID prevalence of 2.4-fold (95% CI, 2.3-2.5; P < .001) according to the WHO standard and 4.9-fold (95% CI, 4.7-5.2; P < .001) according IDEs.

In addition, prevalence was higher in younger women, and within each racial and ethnic subgroup of participants aged 25-54 years, prevalence rose significantly from the HEIRS definition to the WHO and IDE definitions.

Notably, ID was significantly higher among Black and Hispanic participants than Asian and White participants.

An accompanying editorial pointed to gender-based health equity issues raised by the HEIRS analysis and argued that a similar passive acceptance of laboratory definitions of a debilitating but correctable condition in White males would be “frankly unimaginable.”

“Iron deficiency is the leading cause of years lived with disability among women of reproductive age,” wrote hematologist Michelle Sholzberg, MDCM, MSc, and Grace H. Tang, MSc, of St. Michael’s Hospital in Toronto, Canada. “It is a factor clearly associated with maternal death and morbidity (including diminished IQ), and it is correctable, and, thus, unnecessary, in high-income, middle-income, and low-income geographic settings.”

The authors listed no specific funding for this analysis of HEIRS data. Dr. Barton reported contracts from the National Institutes of Health, National Human Genome Research Institute, outside of the submitted work. A coauthor reported grants from the National Heart, Lung, and Blood Institute and the National Human Genome Research Institute outside of the submitted work. Dr. Sholzberg reported unrestricted research funding to her institution from Octapharma and Pfizer and speakers’ honoraria from Takeda, Sobi, and Medison outside of the submitted work.

While it is increasingly apparent that clonal hematopoiesis of indeterminate potential (CHIP) is associated with conditions that can dramatically affect an individual’s risk for both malignant and cardiovascular diseases, and even death, it has not been clear what to do about it.

Now, researchers at the cutting edge of both oncologic and cardiovascular research are not only defining the prognosis of CHIP with greater granularity but are also finding clues to mitigate the risks.

“It’s a very, very rapidly moving area,” said Christie M. Ballantyne, MD, Director, Center for Cardiometabolic Disease Prevention, Baylor College of Medicine, Houston, adding that, in many respects, “it’s a totally new area.”
 

CHIP Defined

CHIP was first recognized in the 1990s, when Martin F. Fey, MD, and colleagues from University and Inselspital, Bern, Switzerland, found X-linked inactivation in older women and suggested it was the result of acquired clonality later referred to as being of “indeterminate potential,” although that added syntax is currently a matter of debate.

Further work showed that, while somatic gene mutations occur spontaneously and are an unavoidable consequence of aging, their impact can vary widely.

The majority are “functionally silent,” while others may affect genes crucial to tissue self-renewal and differentiation, Lukasz Gondek, MD, PhD, assistant professor, Johns Hopkins Cellular and Molecular Medicine Program, Baltimore, and colleagues, noted in a recent review.

This results in the outgrowth of affected cells, known as clonal expansion, further dubbed clonal hematopoiesis when it occurs in hematopoietic tissue.

“Even though there’s clonal expansion, there’s no one CHIP,” Dr. Gondek said. “There are different flavors, and it depends on the genes that are mutated in the hematopoietic cells.”

He continued: “The older we get, the more mutations we acquire, and the probability that this mutation will hit the gene that’s responsible for expansion of the clone is higher.”

“That’s why CHIP is very uncommon in people under the age of 40, but it becomes more common in the fifth, sixth, and seventh decade of life and beyond.”

Indeed, it occurs in 10% to 15% of people aged 65 years or older, and in at least 30% of individuals by 80 years of age. In contrast, just 1% of those aged less than 50 years have the condition.

The most commonly affected genes, in around 80% of patients with CHIP, are the epigenetic regulators DNMT3A, TET2, and ASXL1; the DNA damage repair genes PPM1D and TP53; the regulatory tyrosine kinase JAK2; and the messenger RNA spliceosome components SF3B1 and SRSF2.

These mutations can have “two potential consequences,” explained Lachelle D. Weeks, MD, PhD, a hematologist at the Dana-Farber Cancer Institute, Boston.

“One is that there’s a risk of blood cancer development,” as several of the mutations are known drivers of leukemia or myelodysplastic syndromes (MDS).

Although the majority of individuals who acquire clonal hematopoiesis with age will never develop MDS, it nevertheless confers an 11- to 13-fold increased risk or an absolute risk of approximately 0.5%-1.0% per year.

Dr. Weeks continued that “the other side of it, though, is that those cells that have these mutations can also accelerate the risk of developing nonmalignant diseases like cardiovascular disease.”

This, Dr. Gondek explained, is because the mutations will be retained when the stem cells become monocytes or macrophages and, by either silencing or activating individual genes, they can make the cells more pro-inflammatory.

The result is that CHIP is associated with a marked increased risk for arteriosclerotic events such as stroke, myocardial infarction, decompensated heart failure, and cardiogenic shock, and worse outcomes after these events.

Researchers have shown that CHIP-related somatic mutations are associated with a twofold increased risk for coronary heart disease, a more than 2.5-fold increased risk for ischemic stroke, and a fourfold greater risk for myocardial infarction. A study from earlier this year found that CHIP also increases the risk for heart failure with preserved ejection fraction more than twofold.

There is even evidence to suggest that CHIP is associated with more severe acute kidney injury (AKI) and greater post-AKI kidney fibrosis.

The consequence is that individuals with CHIP face a 40% increased risk for all-cause mortality over 8 years.
 

No CHIP Test Yet

All of which has led for some to call for CHIP testing.

However, there are currently no screening programs for CHIP and no plans to introduce any. “So most CHIP is actually being diagnosed incidentally, when patients get genetic testing for some other indication,” said Dr. Weeks.

“The patients that we see in our CHIP clinic at Dana-Farber have genetic testing because they have low blood counts,” she continued, “and somebody’s trying to figure out: Do you have MDS?”

Other patients have genetic testing due to a family history of other cancers, “and so they’re getting hereditary cancer panels to determine if they have Lynch syndrome, or other hereditary syndromes,” which are picking up gene mutations associated with CHIP.

In other cases, study protocols are identifying CHIP “in various research contexts, and then as a follow-up, some of those patients end up with our clinic,” added Dr. Weeks.

Due to the associated risks for CHIP, “obviously everyone wants to know whether they are at risk for hematologic malignancy, or not,” said Dr. Gondek. To those ends, Dr. Weeks and colleagues developed the clonal hematopoiesis risk score (CHRS).

Published by NEJM Evidence in 2023, the score takes a range of predictive variables, such as age, number of mutations and their degree of associated risk, the variant allele fraction, and a series of blood indices to define patients as low-, intermediate-, or high-risk.

“A little over half” of high-risk individuals “will develop a blood cancer” such as MDS or acute myeloid leukemia (AML)” over the next 10 years, Weeks explained, while “for your intermediate risk folks, in that same time period, 7%-8% of them will develop a blood cancer.”

In low-risk individuals, the 10-year risk for MDS or AML is just 1%.

Dr. Weeks noted the “caveat that there are environmental factors or patient-specific issues that might increase your risk that are not considered in the calculator,” such the presence of hereditary cancer syndromes, “or if you’re getting chemotherapy for other cancers.”

From a cardiology point of view, Dr. Ballantyne said that, above all, “cardiologists need to be aware that some of these people are at increased risk for cardiovascular events.” This prompted a team including Dr. Weeks and Dr. Ballantyne to study whether the CHRS can also predict cardiovascular risk.

They found that people designated low-risk on the score faced an 8% increased risk for all-cause mortality vs individuals without CHIP during a median follow-up of 7 years. This rose to a 12% increase in intermediate-risk individuals.

And those deemed high-risk had a 2.5-fold increased risk for early mortality and a threefold higher risk for cardiovascular death.

Dr. Weeks noted: “We have not done a dedicated study to define a cardiovascular disease-specific calculator for CHIP,” but in the meantime, the CHRS is a “very reasonable way to estimate what someone’s risk of progression or adverse events is for cardiovascular disease.”

For clinicians, however, the key question becomes: What can be done to mitigate the risks, particularly in high-risk individuals?

For malignant conditions, the approach is to monitor patients, although “we and other centers are in the process of developing various interventional clinical trials to test various agents on their ability to improve blood counts, as well as to mitigate the risk of progression to overt blood cancer,” said Dr. Weeks.
 

Treat CHIP Like Lipoprotein(a)?

As for cardiovascular risk, Dr. Ballantyne believes that, because CHIP is an unmodifiable risk factor, an example to follow could be lipoprotein(a) (LP[a]).

“We don’t have a therapy specifically to target LP(a) yet, but we do know that the things that benefit in general,” he said, such as “taking a statin, lowering blood pressure into the optimal zone, diet ,and exercise.”

“What we do in our clinic, and what others have been doing,” Dr. Weeks added, “is for every patient who comes in and is diagnosed with CHIP, we are referring them to preventative cardiology for very aggressive preventative management.”

Finally, both Dr. Ballantyne and Dr. Weeks agree that there are many potential innovations on the horizon.

“It’s pretty exciting in terms of beginning to understand some of the links between aging, cardiovascular disease, and cancer that we had not been thinking about,” Dr. Ballantyne said.

On the malignant side, Dr. Weeks is already working on a prospective study to determine how the risks associated with CHIP evolve when patients undergo chemotherapy and radiation for other cancers.

“That will be really exciting and will help us to develop a specific calculator in that context,” she said, adding that a cardiovascular-specific calculator “is also coming down the line.”

Dr. Weeks declared relationships with Abbvie, Vertex, and Sobi. Dr. Ballantyne declared a relationship with Ten Sixteen Bio, and funding from the National Heart, Lung, and Blood Institute. No other relevant financial relationships were declared.
 

A version of this article appeared on Medscape.com.

While it is increasingly apparent that clonal hematopoiesis of indeterminate potential (CHIP) is associated with conditions that can dramatically affect an individual’s risk for both malignant and cardiovascular diseases, and even death, it has not been clear what to do about it.

Now, researchers at the cutting edge of both oncologic and cardiovascular research are not only defining the prognosis of CHIP with greater granularity but are also finding clues to mitigate the risks.

“It’s a very, very rapidly moving area,” said Christie M. Ballantyne, MD, Director, Center for Cardiometabolic Disease Prevention, Baylor College of Medicine, Houston, adding that, in many respects, “it’s a totally new area.”
 

CHIP Defined

CHIP was first recognized in the 1990s, when Martin F. Fey, MD, and colleagues from University and Inselspital, Bern, Switzerland, found X-linked inactivation in older women and suggested it was the result of acquired clonality later referred to as being of “indeterminate potential,” although that added syntax is currently a matter of debate.

Further work showed that, while somatic gene mutations occur spontaneously and are an unavoidable consequence of aging, their impact can vary widely.

The majority are “functionally silent,” while others may affect genes crucial to tissue self-renewal and differentiation, Lukasz Gondek, MD, PhD, assistant professor, Johns Hopkins Cellular and Molecular Medicine Program, Baltimore, and colleagues, noted in a recent review.

This results in the outgrowth of affected cells, known as clonal expansion, further dubbed clonal hematopoiesis when it occurs in hematopoietic tissue.

“Even though there’s clonal expansion, there’s no one CHIP,” Dr. Gondek said. “There are different flavors, and it depends on the genes that are mutated in the hematopoietic cells.”

He continued: “The older we get, the more mutations we acquire, and the probability that this mutation will hit the gene that’s responsible for expansion of the clone is higher.”

“That’s why CHIP is very uncommon in people under the age of 40, but it becomes more common in the fifth, sixth, and seventh decade of life and beyond.”

Indeed, it occurs in 10% to 15% of people aged 65 years or older, and in at least 30% of individuals by 80 years of age. In contrast, just 1% of those aged less than 50 years have the condition.

The most commonly affected genes, in around 80% of patients with CHIP, are the epigenetic regulators DNMT3A, TET2, and ASXL1; the DNA damage repair genes PPM1D and TP53; the regulatory tyrosine kinase JAK2; and the messenger RNA spliceosome components SF3B1 and SRSF2.

These mutations can have “two potential consequences,” explained Lachelle D. Weeks, MD, PhD, a hematologist at the Dana-Farber Cancer Institute, Boston.

“One is that there’s a risk of blood cancer development,” as several of the mutations are known drivers of leukemia or myelodysplastic syndromes (MDS).

Although the majority of individuals who acquire clonal hematopoiesis with age will never develop MDS, it nevertheless confers an 11- to 13-fold increased risk or an absolute risk of approximately 0.5%-1.0% per year.

Dr. Weeks continued that “the other side of it, though, is that those cells that have these mutations can also accelerate the risk of developing nonmalignant diseases like cardiovascular disease.”

This, Dr. Gondek explained, is because the mutations will be retained when the stem cells become monocytes or macrophages and, by either silencing or activating individual genes, they can make the cells more pro-inflammatory.

The result is that CHIP is associated with a marked increased risk for arteriosclerotic events such as stroke, myocardial infarction, decompensated heart failure, and cardiogenic shock, and worse outcomes after these events.

Researchers have shown that CHIP-related somatic mutations are associated with a twofold increased risk for coronary heart disease, a more than 2.5-fold increased risk for ischemic stroke, and a fourfold greater risk for myocardial infarction. A study from earlier this year found that CHIP also increases the risk for heart failure with preserved ejection fraction more than twofold.

There is even evidence to suggest that CHIP is associated with more severe acute kidney injury (AKI) and greater post-AKI kidney fibrosis.

The consequence is that individuals with CHIP face a 40% increased risk for all-cause mortality over 8 years.
 

No CHIP Test Yet

All of which has led for some to call for CHIP testing.

However, there are currently no screening programs for CHIP and no plans to introduce any. “So most CHIP is actually being diagnosed incidentally, when patients get genetic testing for some other indication,” said Dr. Weeks.

“The patients that we see in our CHIP clinic at Dana-Farber have genetic testing because they have low blood counts,” she continued, “and somebody’s trying to figure out: Do you have MDS?”

Other patients have genetic testing due to a family history of other cancers, “and so they’re getting hereditary cancer panels to determine if they have Lynch syndrome, or other hereditary syndromes,” which are picking up gene mutations associated with CHIP.

In other cases, study protocols are identifying CHIP “in various research contexts, and then as a follow-up, some of those patients end up with our clinic,” added Dr. Weeks.

Due to the associated risks for CHIP, “obviously everyone wants to know whether they are at risk for hematologic malignancy, or not,” said Dr. Gondek. To those ends, Dr. Weeks and colleagues developed the clonal hematopoiesis risk score (CHRS).

Published by NEJM Evidence in 2023, the score takes a range of predictive variables, such as age, number of mutations and their degree of associated risk, the variant allele fraction, and a series of blood indices to define patients as low-, intermediate-, or high-risk.

“A little over half” of high-risk individuals “will develop a blood cancer” such as MDS or acute myeloid leukemia (AML)” over the next 10 years, Weeks explained, while “for your intermediate risk folks, in that same time period, 7%-8% of them will develop a blood cancer.”

In low-risk individuals, the 10-year risk for MDS or AML is just 1%.

Dr. Weeks noted the “caveat that there are environmental factors or patient-specific issues that might increase your risk that are not considered in the calculator,” such the presence of hereditary cancer syndromes, “or if you’re getting chemotherapy for other cancers.”

From a cardiology point of view, Dr. Ballantyne said that, above all, “cardiologists need to be aware that some of these people are at increased risk for cardiovascular events.” This prompted a team including Dr. Weeks and Dr. Ballantyne to study whether the CHRS can also predict cardiovascular risk.

They found that people designated low-risk on the score faced an 8% increased risk for all-cause mortality vs individuals without CHIP during a median follow-up of 7 years. This rose to a 12% increase in intermediate-risk individuals.

And those deemed high-risk had a 2.5-fold increased risk for early mortality and a threefold higher risk for cardiovascular death.

Dr. Weeks noted: “We have not done a dedicated study to define a cardiovascular disease-specific calculator for CHIP,” but in the meantime, the CHRS is a “very reasonable way to estimate what someone’s risk of progression or adverse events is for cardiovascular disease.”

For clinicians, however, the key question becomes: What can be done to mitigate the risks, particularly in high-risk individuals?

For malignant conditions, the approach is to monitor patients, although “we and other centers are in the process of developing various interventional clinical trials to test various agents on their ability to improve blood counts, as well as to mitigate the risk of progression to overt blood cancer,” said Dr. Weeks.
 

Treat CHIP Like Lipoprotein(a)?

As for cardiovascular risk, Dr. Ballantyne believes that, because CHIP is an unmodifiable risk factor, an example to follow could be lipoprotein(a) (LP[a]).

“We don’t have a therapy specifically to target LP(a) yet, but we do know that the things that benefit in general,” he said, such as “taking a statin, lowering blood pressure into the optimal zone, diet ,and exercise.”

“What we do in our clinic, and what others have been doing,” Dr. Weeks added, “is for every patient who comes in and is diagnosed with CHIP, we are referring them to preventative cardiology for very aggressive preventative management.”

Finally, both Dr. Ballantyne and Dr. Weeks agree that there are many potential innovations on the horizon.

“It’s pretty exciting in terms of beginning to understand some of the links between aging, cardiovascular disease, and cancer that we had not been thinking about,” Dr. Ballantyne said.

On the malignant side, Dr. Weeks is already working on a prospective study to determine how the risks associated with CHIP evolve when patients undergo chemotherapy and radiation for other cancers.

“That will be really exciting and will help us to develop a specific calculator in that context,” she said, adding that a cardiovascular-specific calculator “is also coming down the line.”

Dr. Weeks declared relationships with Abbvie, Vertex, and Sobi. Dr. Ballantyne declared a relationship with Ten Sixteen Bio, and funding from the National Heart, Lung, and Blood Institute. No other relevant financial relationships were declared.
 

A version of this article appeared on Medscape.com.

While it is increasingly apparent that clonal hematopoiesis of indeterminate potential (CHIP) is associated with conditions that can dramatically affect an individual’s risk for both malignant and cardiovascular diseases, and even death, it has not been clear what to do about it.

Now, researchers at the cutting edge of both oncologic and cardiovascular research are not only defining the prognosis of CHIP with greater granularity but are also finding clues to mitigate the risks.

“It’s a very, very rapidly moving area,” said Christie M. Ballantyne, MD, Director, Center for Cardiometabolic Disease Prevention, Baylor College of Medicine, Houston, adding that, in many respects, “it’s a totally new area.”
 

CHIP Defined

CHIP was first recognized in the 1990s, when Martin F. Fey, MD, and colleagues from University and Inselspital, Bern, Switzerland, found X-linked inactivation in older women and suggested it was the result of acquired clonality later referred to as being of “indeterminate potential,” although that added syntax is currently a matter of debate.

Further work showed that, while somatic gene mutations occur spontaneously and are an unavoidable consequence of aging, their impact can vary widely.

The majority are “functionally silent,” while others may affect genes crucial to tissue self-renewal and differentiation, Lukasz Gondek, MD, PhD, assistant professor, Johns Hopkins Cellular and Molecular Medicine Program, Baltimore, and colleagues, noted in a recent review.

This results in the outgrowth of affected cells, known as clonal expansion, further dubbed clonal hematopoiesis when it occurs in hematopoietic tissue.

“Even though there’s clonal expansion, there’s no one CHIP,” Dr. Gondek said. “There are different flavors, and it depends on the genes that are mutated in the hematopoietic cells.”

He continued: “The older we get, the more mutations we acquire, and the probability that this mutation will hit the gene that’s responsible for expansion of the clone is higher.”

“That’s why CHIP is very uncommon in people under the age of 40, but it becomes more common in the fifth, sixth, and seventh decade of life and beyond.”

Indeed, it occurs in 10% to 15% of people aged 65 years or older, and in at least 30% of individuals by 80 years of age. In contrast, just 1% of those aged less than 50 years have the condition.

The most commonly affected genes, in around 80% of patients with CHIP, are the epigenetic regulators DNMT3A, TET2, and ASXL1; the DNA damage repair genes PPM1D and TP53; the regulatory tyrosine kinase JAK2; and the messenger RNA spliceosome components SF3B1 and SRSF2.

These mutations can have “two potential consequences,” explained Lachelle D. Weeks, MD, PhD, a hematologist at the Dana-Farber Cancer Institute, Boston.

“One is that there’s a risk of blood cancer development,” as several of the mutations are known drivers of leukemia or myelodysplastic syndromes (MDS).

Although the majority of individuals who acquire clonal hematopoiesis with age will never develop MDS, it nevertheless confers an 11- to 13-fold increased risk or an absolute risk of approximately 0.5%-1.0% per year.

Dr. Weeks continued that “the other side of it, though, is that those cells that have these mutations can also accelerate the risk of developing nonmalignant diseases like cardiovascular disease.”

This, Dr. Gondek explained, is because the mutations will be retained when the stem cells become monocytes or macrophages and, by either silencing or activating individual genes, they can make the cells more pro-inflammatory.

The result is that CHIP is associated with a marked increased risk for arteriosclerotic events such as stroke, myocardial infarction, decompensated heart failure, and cardiogenic shock, and worse outcomes after these events.

Researchers have shown that CHIP-related somatic mutations are associated with a twofold increased risk for coronary heart disease, a more than 2.5-fold increased risk for ischemic stroke, and a fourfold greater risk for myocardial infarction. A study from earlier this year found that CHIP also increases the risk for heart failure with preserved ejection fraction more than twofold.

There is even evidence to suggest that CHIP is associated with more severe acute kidney injury (AKI) and greater post-AKI kidney fibrosis.

The consequence is that individuals with CHIP face a 40% increased risk for all-cause mortality over 8 years.
 

No CHIP Test Yet

All of which has led for some to call for CHIP testing.

However, there are currently no screening programs for CHIP and no plans to introduce any. “So most CHIP is actually being diagnosed incidentally, when patients get genetic testing for some other indication,” said Dr. Weeks.

“The patients that we see in our CHIP clinic at Dana-Farber have genetic testing because they have low blood counts,” she continued, “and somebody’s trying to figure out: Do you have MDS?”

Other patients have genetic testing due to a family history of other cancers, “and so they’re getting hereditary cancer panels to determine if they have Lynch syndrome, or other hereditary syndromes,” which are picking up gene mutations associated with CHIP.

In other cases, study protocols are identifying CHIP “in various research contexts, and then as a follow-up, some of those patients end up with our clinic,” added Dr. Weeks.

Due to the associated risks for CHIP, “obviously everyone wants to know whether they are at risk for hematologic malignancy, or not,” said Dr. Gondek. To those ends, Dr. Weeks and colleagues developed the clonal hematopoiesis risk score (CHRS).

Published by NEJM Evidence in 2023, the score takes a range of predictive variables, such as age, number of mutations and their degree of associated risk, the variant allele fraction, and a series of blood indices to define patients as low-, intermediate-, or high-risk.

“A little over half” of high-risk individuals “will develop a blood cancer” such as MDS or acute myeloid leukemia (AML)” over the next 10 years, Weeks explained, while “for your intermediate risk folks, in that same time period, 7%-8% of them will develop a blood cancer.”

In low-risk individuals, the 10-year risk for MDS or AML is just 1%.

Dr. Weeks noted the “caveat that there are environmental factors or patient-specific issues that might increase your risk that are not considered in the calculator,” such the presence of hereditary cancer syndromes, “or if you’re getting chemotherapy for other cancers.”

From a cardiology point of view, Dr. Ballantyne said that, above all, “cardiologists need to be aware that some of these people are at increased risk for cardiovascular events.” This prompted a team including Dr. Weeks and Dr. Ballantyne to study whether the CHRS can also predict cardiovascular risk.

They found that people designated low-risk on the score faced an 8% increased risk for all-cause mortality vs individuals without CHIP during a median follow-up of 7 years. This rose to a 12% increase in intermediate-risk individuals.

And those deemed high-risk had a 2.5-fold increased risk for early mortality and a threefold higher risk for cardiovascular death.

Dr. Weeks noted: “We have not done a dedicated study to define a cardiovascular disease-specific calculator for CHIP,” but in the meantime, the CHRS is a “very reasonable way to estimate what someone’s risk of progression or adverse events is for cardiovascular disease.”

For clinicians, however, the key question becomes: What can be done to mitigate the risks, particularly in high-risk individuals?

For malignant conditions, the approach is to monitor patients, although “we and other centers are in the process of developing various interventional clinical trials to test various agents on their ability to improve blood counts, as well as to mitigate the risk of progression to overt blood cancer,” said Dr. Weeks.
 

Treat CHIP Like Lipoprotein(a)?

As for cardiovascular risk, Dr. Ballantyne believes that, because CHIP is an unmodifiable risk factor, an example to follow could be lipoprotein(a) (LP[a]).

“We don’t have a therapy specifically to target LP(a) yet, but we do know that the things that benefit in general,” he said, such as “taking a statin, lowering blood pressure into the optimal zone, diet ,and exercise.”

“What we do in our clinic, and what others have been doing,” Dr. Weeks added, “is for every patient who comes in and is diagnosed with CHIP, we are referring them to preventative cardiology for very aggressive preventative management.”

Finally, both Dr. Ballantyne and Dr. Weeks agree that there are many potential innovations on the horizon.

“It’s pretty exciting in terms of beginning to understand some of the links between aging, cardiovascular disease, and cancer that we had not been thinking about,” Dr. Ballantyne said.

On the malignant side, Dr. Weeks is already working on a prospective study to determine how the risks associated with CHIP evolve when patients undergo chemotherapy and radiation for other cancers.

“That will be really exciting and will help us to develop a specific calculator in that context,” she said, adding that a cardiovascular-specific calculator “is also coming down the line.”

Dr. Weeks declared relationships with Abbvie, Vertex, and Sobi. Dr. Ballantyne declared a relationship with Ten Sixteen Bio, and funding from the National Heart, Lung, and Blood Institute. No other relevant financial relationships were declared.
 

A version of this article appeared on Medscape.com.

A longitudinal study incorporating two validated patient-reported outcome (PRO) tools showed that compared with patients with epidermal chronic cutaneous graft-versus-host disease (GVHD), those with sclerotic and combination disease experienced worse symptoms and quality-of-life (QOL) impairment. Independent of potential confounders, these PROs moreover predicted non-relapse mortality for all three disease subtypes, making PROs potentially useful adjuncts for risk stratification and treatment decisions, the study authors said.

“These two findings highlight the importance of patient-reported outcomes in measuring this disease,” lead author Emily Baumrin, MD, MSCE, assistant professor of dermatology and medicine at the University of Pennsylvania, Philadelphia, told this news organization. The study was published online February 28 in JAMA Dermatology.

Dr. Baumrin

Symptoms and QOL

The investigators monitored 436 patients from the Chronic GVHD Consortium until December 2020. The Lee Symptom Scale (LSS) skin subscale was used to evaluate symptom burden and the Functional Assessment of Cancer Therapy–Bone Marrow Transplantation (FACT-BMT) was used to measure quality of life.

Patients with sclerotic GVHD and combination disease at diagnosis had significantly worse median LSS scores than did those with epidermal disease (25, 35, and 20 points, respectively; P = .01). Patients with sclerotic disease had worse median FACT-BMT scores versus those with epidermal involvement (104 versus 109 points, respectively; P = .08).

Although these scores improved with all skin subtypes, LSS skin subscale and FACT-BMT scores remained significantly worse (by 9.0 points and 6.1 points, respectively) for patients with combination and sclerotic disease versus those with epidermal disease after adjusting for potential confounders.

Regarding mortality, every 7-point worsening (clinically meaningful difference) in FACT-BMT score at diagnosis of skin chronic GVHD conferred 9.1% increases in odds of both all-cause mortality and non-relapse mortality, after adjustment for factors such as age and sex. Likewise, for every 11 points worsening (clinically meaningful difference) in LSS skin subscale scores at diagnosis, researchers observed odds increases of 10% in all-cause mortality and 16.4% in non-relapse mortality.

Because patients with combination disease had only slightly more epidermal body surface area (BSA) involvement but significantly higher symptom burden than the other subtypes, the authors added, combination disease may represent a distinct phenotype. “Since we’ve also shown that the severity of patient-reported outcomes is associated with mortality,” Dr. Baumrin said in the interview, “perhaps these patients are at the highest risk of mortality as well.”

A growing population

Although many might think of chronic GVHD as rare, she noted, the number of allogeneic hematopoietic cell transplant (HCT) survivors living in the United States is growing. In a modeling study published in October of 2013 in Biology of Blood and Marrow Transplantation, authors predicted that by 2030, this figure will reach 502,000 — about half of whom will develop chronic GVHD, she said.

With more HCTs being performed each year and ongoing improvements in supportive care, patients are living longer post transplant. “Therefore, many transplant survivors are being taken care of in the community outside of transplant centers.”

Accordingly, Dr. Baumrin said, study findings are relevant to dermatologists in academic and transplant centers and the community who provide skin cancer screenings or other dermatologic care for transplant recipients. “Upon diagnosis of chronic GVHD, the evaluation of disease burden by patient-reported outcome measures may assist in assessing disease severity and response to treatments over time — and to stratify patients at higher risk for mortality and communicate that back to transplant physicians.”

Incorporating PROs into clinical practice might prove especially helpful for patients with sclerotic chronic cutaneous GVHD. Currently, clinicians assess cutaneous GVHD clinically, using parameters including skin thickness. The National Institutes of Health (NIH) Skin Score, used in clinical trials, also measures BSA.

“The issue with sclerosis is, it’s hard to determine clinical severity based on physical examination alone,” Dr. Baumrin said. It can be difficult to quantify skin thickness and changes over time. “So it’s hard to detect improvements, which are often slow. Patient-reported outcome measures may be a more sensitive way to detect response to treatment than our clinical assessments, which are often crude for sclerotic disease.”

In a secondary analysis of the phase 2 clinical trial of belumosudil, a treatment for chronic GVHD, published in October 2022 in Transplantation and Cellular Therapy, response rate was around 30% measured by NIH Skin Score and 77% by PROs. “Our clinical examination in sclerotic type disease falls short in terms of determining therapeutic benefit. PROs might complement those clinical measures,” she said.

Future research will involve determining and validating which PROs matter most clinically and to patients, added Dr. Baumrin. Although widely used in evaluating transplant patients, LSS skin subscale and FACT-BMT scores may not represent patients’ experience of living with cutaneous chronic GVHD as effectively as might other tools such as the Dermatology Life Quality Index (DLQI) or Patient-Reported Outcomes Measurement Information System (PROMIS) measures, she explained.

Study strengths included authors’ use of well-validated PROs rather than novel unvalidated measures, Sandra A. Mitchell, PhD, CRNP, of the National Cancer Institute, Rockville, Maryland, and Edward W. Cowen, MD, MHSc, of the Dermatology Branch at the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), Bethesda, Maryland, wrote in an accompanying editorial in JAMA Dermatology. However, they added, incorporating causes of death might have revealed that the excess mortality associated with sclerotic disease stemmed at least partly from adverse effects of prolonged immunosuppression, particularly infection.

If future studies establish this to be the case, said Dr. Baumrin, reducing immunosuppression might be warranted for these patients. “And if death is primarily due to chronic GVHD itself, maybe we should treat more aggressively. PROs can help guide this decision.”

The study was supported by the NIH/NIAMS and the University of Pennsylvania. Dr. Baumrin and three coauthors report no relevant financial relationships; other authors had disclosures related to several pharmaceutical companies. Dr. Mitchell and Dr. Cowen had no disclosures.

A longitudinal study incorporating two validated patient-reported outcome (PRO) tools showed that compared with patients with epidermal chronic cutaneous graft-versus-host disease (GVHD), those with sclerotic and combination disease experienced worse symptoms and quality-of-life (QOL) impairment. Independent of potential confounders, these PROs moreover predicted non-relapse mortality for all three disease subtypes, making PROs potentially useful adjuncts for risk stratification and treatment decisions, the study authors said.

“These two findings highlight the importance of patient-reported outcomes in measuring this disease,” lead author Emily Baumrin, MD, MSCE, assistant professor of dermatology and medicine at the University of Pennsylvania, Philadelphia, told this news organization. The study was published online February 28 in JAMA Dermatology.

Dr. Baumrin

Symptoms and QOL

The investigators monitored 436 patients from the Chronic GVHD Consortium until December 2020. The Lee Symptom Scale (LSS) skin subscale was used to evaluate symptom burden and the Functional Assessment of Cancer Therapy–Bone Marrow Transplantation (FACT-BMT) was used to measure quality of life.

Patients with sclerotic GVHD and combination disease at diagnosis had significantly worse median LSS scores than did those with epidermal disease (25, 35, and 20 points, respectively; P = .01). Patients with sclerotic disease had worse median FACT-BMT scores versus those with epidermal involvement (104 versus 109 points, respectively; P = .08).

Although these scores improved with all skin subtypes, LSS skin subscale and FACT-BMT scores remained significantly worse (by 9.0 points and 6.1 points, respectively) for patients with combination and sclerotic disease versus those with epidermal disease after adjusting for potential confounders.

Regarding mortality, every 7-point worsening (clinically meaningful difference) in FACT-BMT score at diagnosis of skin chronic GVHD conferred 9.1% increases in odds of both all-cause mortality and non-relapse mortality, after adjustment for factors such as age and sex. Likewise, for every 11 points worsening (clinically meaningful difference) in LSS skin subscale scores at diagnosis, researchers observed odds increases of 10% in all-cause mortality and 16.4% in non-relapse mortality.

Because patients with combination disease had only slightly more epidermal body surface area (BSA) involvement but significantly higher symptom burden than the other subtypes, the authors added, combination disease may represent a distinct phenotype. “Since we’ve also shown that the severity of patient-reported outcomes is associated with mortality,” Dr. Baumrin said in the interview, “perhaps these patients are at the highest risk of mortality as well.”

A growing population

Although many might think of chronic GVHD as rare, she noted, the number of allogeneic hematopoietic cell transplant (HCT) survivors living in the United States is growing. In a modeling study published in October of 2013 in Biology of Blood and Marrow Transplantation, authors predicted that by 2030, this figure will reach 502,000 — about half of whom will develop chronic GVHD, she said.

With more HCTs being performed each year and ongoing improvements in supportive care, patients are living longer post transplant. “Therefore, many transplant survivors are being taken care of in the community outside of transplant centers.”

Accordingly, Dr. Baumrin said, study findings are relevant to dermatologists in academic and transplant centers and the community who provide skin cancer screenings or other dermatologic care for transplant recipients. “Upon diagnosis of chronic GVHD, the evaluation of disease burden by patient-reported outcome measures may assist in assessing disease severity and response to treatments over time — and to stratify patients at higher risk for mortality and communicate that back to transplant physicians.”

Incorporating PROs into clinical practice might prove especially helpful for patients with sclerotic chronic cutaneous GVHD. Currently, clinicians assess cutaneous GVHD clinically, using parameters including skin thickness. The National Institutes of Health (NIH) Skin Score, used in clinical trials, also measures BSA.

“The issue with sclerosis is, it’s hard to determine clinical severity based on physical examination alone,” Dr. Baumrin said. It can be difficult to quantify skin thickness and changes over time. “So it’s hard to detect improvements, which are often slow. Patient-reported outcome measures may be a more sensitive way to detect response to treatment than our clinical assessments, which are often crude for sclerotic disease.”

In a secondary analysis of the phase 2 clinical trial of belumosudil, a treatment for chronic GVHD, published in October 2022 in Transplantation and Cellular Therapy, response rate was around 30% measured by NIH Skin Score and 77% by PROs. “Our clinical examination in sclerotic type disease falls short in terms of determining therapeutic benefit. PROs might complement those clinical measures,” she said.

Future research will involve determining and validating which PROs matter most clinically and to patients, added Dr. Baumrin. Although widely used in evaluating transplant patients, LSS skin subscale and FACT-BMT scores may not represent patients’ experience of living with cutaneous chronic GVHD as effectively as might other tools such as the Dermatology Life Quality Index (DLQI) or Patient-Reported Outcomes Measurement Information System (PROMIS) measures, she explained.

Study strengths included authors’ use of well-validated PROs rather than novel unvalidated measures, Sandra A. Mitchell, PhD, CRNP, of the National Cancer Institute, Rockville, Maryland, and Edward W. Cowen, MD, MHSc, of the Dermatology Branch at the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), Bethesda, Maryland, wrote in an accompanying editorial in JAMA Dermatology. However, they added, incorporating causes of death might have revealed that the excess mortality associated with sclerotic disease stemmed at least partly from adverse effects of prolonged immunosuppression, particularly infection.

If future studies establish this to be the case, said Dr. Baumrin, reducing immunosuppression might be warranted for these patients. “And if death is primarily due to chronic GVHD itself, maybe we should treat more aggressively. PROs can help guide this decision.”

The study was supported by the NIH/NIAMS and the University of Pennsylvania. Dr. Baumrin and three coauthors report no relevant financial relationships; other authors had disclosures related to several pharmaceutical companies. Dr. Mitchell and Dr. Cowen had no disclosures.

A longitudinal study incorporating two validated patient-reported outcome (PRO) tools showed that compared with patients with epidermal chronic cutaneous graft-versus-host disease (GVHD), those with sclerotic and combination disease experienced worse symptoms and quality-of-life (QOL) impairment. Independent of potential confounders, these PROs moreover predicted non-relapse mortality for all three disease subtypes, making PROs potentially useful adjuncts for risk stratification and treatment decisions, the study authors said.

“These two findings highlight the importance of patient-reported outcomes in measuring this disease,” lead author Emily Baumrin, MD, MSCE, assistant professor of dermatology and medicine at the University of Pennsylvania, Philadelphia, told this news organization. The study was published online February 28 in JAMA Dermatology.

Dr. Baumrin

Symptoms and QOL

The investigators monitored 436 patients from the Chronic GVHD Consortium until December 2020. The Lee Symptom Scale (LSS) skin subscale was used to evaluate symptom burden and the Functional Assessment of Cancer Therapy–Bone Marrow Transplantation (FACT-BMT) was used to measure quality of life.

Patients with sclerotic GVHD and combination disease at diagnosis had significantly worse median LSS scores than did those with epidermal disease (25, 35, and 20 points, respectively; P = .01). Patients with sclerotic disease had worse median FACT-BMT scores versus those with epidermal involvement (104 versus 109 points, respectively; P = .08).

Although these scores improved with all skin subtypes, LSS skin subscale and FACT-BMT scores remained significantly worse (by 9.0 points and 6.1 points, respectively) for patients with combination and sclerotic disease versus those with epidermal disease after adjusting for potential confounders.

Regarding mortality, every 7-point worsening (clinically meaningful difference) in FACT-BMT score at diagnosis of skin chronic GVHD conferred 9.1% increases in odds of both all-cause mortality and non-relapse mortality, after adjustment for factors such as age and sex. Likewise, for every 11 points worsening (clinically meaningful difference) in LSS skin subscale scores at diagnosis, researchers observed odds increases of 10% in all-cause mortality and 16.4% in non-relapse mortality.

Because patients with combination disease had only slightly more epidermal body surface area (BSA) involvement but significantly higher symptom burden than the other subtypes, the authors added, combination disease may represent a distinct phenotype. “Since we’ve also shown that the severity of patient-reported outcomes is associated with mortality,” Dr. Baumrin said in the interview, “perhaps these patients are at the highest risk of mortality as well.”

A growing population

Although many might think of chronic GVHD as rare, she noted, the number of allogeneic hematopoietic cell transplant (HCT) survivors living in the United States is growing. In a modeling study published in October of 2013 in Biology of Blood and Marrow Transplantation, authors predicted that by 2030, this figure will reach 502,000 — about half of whom will develop chronic GVHD, she said.

With more HCTs being performed each year and ongoing improvements in supportive care, patients are living longer post transplant. “Therefore, many transplant survivors are being taken care of in the community outside of transplant centers.”

Accordingly, Dr. Baumrin said, study findings are relevant to dermatologists in academic and transplant centers and the community who provide skin cancer screenings or other dermatologic care for transplant recipients. “Upon diagnosis of chronic GVHD, the evaluation of disease burden by patient-reported outcome measures may assist in assessing disease severity and response to treatments over time — and to stratify patients at higher risk for mortality and communicate that back to transplant physicians.”

Incorporating PROs into clinical practice might prove especially helpful for patients with sclerotic chronic cutaneous GVHD. Currently, clinicians assess cutaneous GVHD clinically, using parameters including skin thickness. The National Institutes of Health (NIH) Skin Score, used in clinical trials, also measures BSA.

“The issue with sclerosis is, it’s hard to determine clinical severity based on physical examination alone,” Dr. Baumrin said. It can be difficult to quantify skin thickness and changes over time. “So it’s hard to detect improvements, which are often slow. Patient-reported outcome measures may be a more sensitive way to detect response to treatment than our clinical assessments, which are often crude for sclerotic disease.”

In a secondary analysis of the phase 2 clinical trial of belumosudil, a treatment for chronic GVHD, published in October 2022 in Transplantation and Cellular Therapy, response rate was around 30% measured by NIH Skin Score and 77% by PROs. “Our clinical examination in sclerotic type disease falls short in terms of determining therapeutic benefit. PROs might complement those clinical measures,” she said.

Future research will involve determining and validating which PROs matter most clinically and to patients, added Dr. Baumrin. Although widely used in evaluating transplant patients, LSS skin subscale and FACT-BMT scores may not represent patients’ experience of living with cutaneous chronic GVHD as effectively as might other tools such as the Dermatology Life Quality Index (DLQI) or Patient-Reported Outcomes Measurement Information System (PROMIS) measures, she explained.

Study strengths included authors’ use of well-validated PROs rather than novel unvalidated measures, Sandra A. Mitchell, PhD, CRNP, of the National Cancer Institute, Rockville, Maryland, and Edward W. Cowen, MD, MHSc, of the Dermatology Branch at the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), Bethesda, Maryland, wrote in an accompanying editorial in JAMA Dermatology. However, they added, incorporating causes of death might have revealed that the excess mortality associated with sclerotic disease stemmed at least partly from adverse effects of prolonged immunosuppression, particularly infection.

If future studies establish this to be the case, said Dr. Baumrin, reducing immunosuppression might be warranted for these patients. “And if death is primarily due to chronic GVHD itself, maybe we should treat more aggressively. PROs can help guide this decision.”

The study was supported by the NIH/NIAMS and the University of Pennsylvania. Dr. Baumrin and three coauthors report no relevant financial relationships; other authors had disclosures related to several pharmaceutical companies. Dr. Mitchell and Dr. Cowen had no disclosures.

TOPLINE:

Doxorubicin increases the risk for breast cancer in women with Hodgkin lymphoma, suggesting the need for increased surveillance.

METHODOLOGY:

• Doxorubicin is a mainstay of Hodgkin lymphoma treatment.
• Studies suggest that girls with Hodgkin lymphoma who receive doxorubicin have a higher risk for breast cancer later in life, but it is unclear if women treated as adults face that same risk.
• To find out, investigators reviewed breast cancer incidence in 1964 Dutch women, ages 15-50, who were treated for Hodgkin lymphoma from 1975 to 2008.
• Patients had survived for at least 5 years, and 57% received doxorubicin.

TAKEAWAY:

• Women treated with doxorubicin had a 40% higher risk for breast cancer, and that risk was independent of age of treatment, receipt of chest radiation, and the use of gonadotoxic agents.
• The risk for breast cancer with doxorubicin was dose-dependent, with each 100 mg/m2 dose increment increasing the risk by 18%.
• The findings held whether women were treated years ago or more recently, despite the evolution of treatment strategies for Hodgkin lymphoma.
• After 30 years of follow-up, nearly one in five survivors (20.8%) developed breast cancer. It took 20 years for the elevated risk for breast cancer following treatment with doxorubicin to emerge.

IN PRACTICE:

The study suggests that adolescent and adult women survivors of Hodgkin lymphoma who received doxorubicin have an increased risk for breast cancer, and this risk is independent of age at first Hodgkin lymphoma treatment, receipt of chest radiotherapy, and gonadotoxic treatment, the authors concluded. “Our results have implications for [breast cancer] surveillance guidelines for [Hodgkin lymphoma] survivors and treatment strategies for patients with newly diagnosed” Hodgkin lymphoma.

SOURCE:

The study, led by Suzanne Neppelenbroek of the Netherlands Cancer Institute, Amsterdam, was published February 15 in the Journal of Clinical Oncology. 

LIMITATIONS:

Recruitment ended in 2008 before the advent of newer treatments such as antibody-drug conjugates and immune checkpoint inhibitors.

DISCLOSURES:

The work was funded by the Dutch Cancer Society. Several authors reported ties to Lilly, AbbVie, Amgen, and other companies.
 

A version of this article appeared on Medscape.com.

TOPLINE:

Doxorubicin increases the risk for breast cancer in women with Hodgkin lymphoma, suggesting the need for increased surveillance.

METHODOLOGY:

• Doxorubicin is a mainstay of Hodgkin lymphoma treatment.
• Studies suggest that girls with Hodgkin lymphoma who receive doxorubicin have a higher risk for breast cancer later in life, but it is unclear if women treated as adults face that same risk.
• To find out, investigators reviewed breast cancer incidence in 1964 Dutch women, ages 15-50, who were treated for Hodgkin lymphoma from 1975 to 2008.
• Patients had survived for at least 5 years, and 57% received doxorubicin.

TAKEAWAY:

• Women treated with doxorubicin had a 40% higher risk for breast cancer, and that risk was independent of age of treatment, receipt of chest radiation, and the use of gonadotoxic agents.
• The risk for breast cancer with doxorubicin was dose-dependent, with each 100 mg/m2 dose increment increasing the risk by 18%.
• The findings held whether women were treated years ago or more recently, despite the evolution of treatment strategies for Hodgkin lymphoma.
• After 30 years of follow-up, nearly one in five survivors (20.8%) developed breast cancer. It took 20 years for the elevated risk for breast cancer following treatment with doxorubicin to emerge.

IN PRACTICE:

The study suggests that adolescent and adult women survivors of Hodgkin lymphoma who received doxorubicin have an increased risk for breast cancer, and this risk is independent of age at first Hodgkin lymphoma treatment, receipt of chest radiotherapy, and gonadotoxic treatment, the authors concluded. “Our results have implications for [breast cancer] surveillance guidelines for [Hodgkin lymphoma] survivors and treatment strategies for patients with newly diagnosed” Hodgkin lymphoma.

SOURCE:

The study, led by Suzanne Neppelenbroek of the Netherlands Cancer Institute, Amsterdam, was published February 15 in the Journal of Clinical Oncology. 

LIMITATIONS:

Recruitment ended in 2008 before the advent of newer treatments such as antibody-drug conjugates and immune checkpoint inhibitors.

DISCLOSURES:

The work was funded by the Dutch Cancer Society. Several authors reported ties to Lilly, AbbVie, Amgen, and other companies.
 

A version of this article appeared on Medscape.com.

TOPLINE:

Doxorubicin increases the risk for breast cancer in women with Hodgkin lymphoma, suggesting the need for increased surveillance.

METHODOLOGY:

• Doxorubicin is a mainstay of Hodgkin lymphoma treatment.
• Studies suggest that girls with Hodgkin lymphoma who receive doxorubicin have a higher risk for breast cancer later in life, but it is unclear if women treated as adults face that same risk.
• To find out, investigators reviewed breast cancer incidence in 1964 Dutch women, ages 15-50, who were treated for Hodgkin lymphoma from 1975 to 2008.
• Patients had survived for at least 5 years, and 57% received doxorubicin.

TAKEAWAY:

• Women treated with doxorubicin had a 40% higher risk for breast cancer, and that risk was independent of age of treatment, receipt of chest radiation, and the use of gonadotoxic agents.
• The risk for breast cancer with doxorubicin was dose-dependent, with each 100 mg/m2 dose increment increasing the risk by 18%.
• The findings held whether women were treated years ago or more recently, despite the evolution of treatment strategies for Hodgkin lymphoma.
• After 30 years of follow-up, nearly one in five survivors (20.8%) developed breast cancer. It took 20 years for the elevated risk for breast cancer following treatment with doxorubicin to emerge.

IN PRACTICE:

The study suggests that adolescent and adult women survivors of Hodgkin lymphoma who received doxorubicin have an increased risk for breast cancer, and this risk is independent of age at first Hodgkin lymphoma treatment, receipt of chest radiotherapy, and gonadotoxic treatment, the authors concluded. “Our results have implications for [breast cancer] surveillance guidelines for [Hodgkin lymphoma] survivors and treatment strategies for patients with newly diagnosed” Hodgkin lymphoma.

SOURCE:

The study, led by Suzanne Neppelenbroek of the Netherlands Cancer Institute, Amsterdam, was published February 15 in the Journal of Clinical Oncology. 

LIMITATIONS:

Recruitment ended in 2008 before the advent of newer treatments such as antibody-drug conjugates and immune checkpoint inhibitors.

DISCLOSURES:

The work was funded by the Dutch Cancer Society. Several authors reported ties to Lilly, AbbVie, Amgen, and other companies.
 

A version of this article appeared on Medscape.com.

The chemotherapy drug asparaginase revolutionized childhood cancer care in the 1970s, and it’s still a mainstay of treatment for acute lymphoblastic leukemia (ALL) today. But asparaginase remains difficult for some to tolerate, and clinicians keep needing to adjust therapy to address toxicity.

The good news, hematologists note, is that new strategies have been developed to address side effects. “We’ve gotten better at managing them,” pediatric oncologist Birte Wistinghausen, MD, of Children’s National Hospital in Washington, DC, said in an interview.

According to her, key approaches include sensitivity testing and “pre-medication” to prevent adverse effects from appearing in the first place.

The American Cancer Society estimates that 6,550 new cases of ALL appear in the United States each year, and 1,330 people die from the disease.

“Most cases of ALL occur in children, but most deaths from ALL (about 4 out of 5) occur in adults,” the organization reports. Indeed, the 5-year survival rate in children is now at about 90%, a number that hematologists partially attribute to the power of asparaginase.

Researchers believe that asparaginase, an enzyme, works by breaking down a substance called asparagine, which ALL cells use to reproduce. The drug is “universally used throughout the treatment of ALL in children and adolescents,” Luke Maese, DO, associate professor of pediatrics at the University of Utah–Huntsman Cancer Institute, Salt Lake City, and director of Leukemia/Lymphoma at Primary Children’s Hospital, said in an interview. “It has become more and more adopted in the treatment of young adults as well.”

The formulations of available asparaginase have evolved over the years, Dr. Maese said. “Currently, the first-line asparaginase products delivered in the majority of patients throughout the world are pegylated, meaning they have an extended duration of action. There are non-pegylated asparaginase products that are used as well.”

The pegylated drugs are much easier on patients since they don’t require frequent injections, according to experts.

Treatment protocols vary, Dr. Maese said. “Some use the drug intermittently intermixed throughout therapy, and others have periods of continuous asparaginase use — i.e. 10-20 weeks of repeated doses of the drug.”

All patients are likely to experience side effects, he said, and about 5%-10% of standard-risk and 20%-25% of high-risk patients will experience clinically significant problems.

When asparaginase is given by IV, its rapid onset can lead to a condition called acute hyperammonemia, in which ammonia levels rise and patients develop flushing, anxiety, and low blood pressure, said Dr. Wistinghausen of Children’s National Hospital. “But that is not a reason to abandon asparaginase.”

It can be difficult to differentiate this effect from hypersensitivity — allergic reactions — which can range from hives to full anaphylactic shock that requires treatment with epinephrine, she said.

According to Dr. Maese, other major side effects other than hypersensitivity include pancreatitis, hepatotoxicity, and thrombosis. The most dangerous of these side effects are hypersensitivity and pancreatitis, which can lead to discontinuation of treatment, he said. Indeed, a 2017 study found that 2% of 465 patients with ALL who developed asparaginase-associated pancreatitis died, and 8% needed mechanical ventilation.

There’s no way to predict which patients may be susceptible to pancreatitis, Michael J. Burke, MD, professor of pediatrics and director of leukemia/lymphoma director at Children’s Wisconsin and Medical College of Wisconsin, said in an interview.

As for therapy options if pancreatitis develops, a 2022 review cowritten by Dr. Maese reported that clinicians have been leaning toward re-treating patients with asparaginase since it’s so crucial to treatment. This has worked about 50% of the time, the review reported, and “many groups consider it in the setting of all grade 2 pancreatitis and grade 3 pancreatitis without prolonged illness or severe complications.”

As for hypersensitivity, the most prevalent adverse effect, clinicians frequently administer anti-allergy medications prior to infusion. This approach, known as “pre-medication,” is controversial. Research has produced conflicting results, with a 2022 study in the journal Blood finding that pre-medication had no effect on hypersensitivity in children with ALL.

“Although there is mixed data, most institutions utilize this,” Dr. Maese said. “At our institution, we continue to use pre-medication prior to pegylated asparaginase but do not use it with non-pegylated asparaginase.”

Specifically, most institutions administer H2 and H1 blockers, Dr. Wistinghausen said. “Some institutions also use hydrocortisone” — a steroid — “but our institution only uses it if patients have a reaction.”

Other potential adverse effects to treatment include infusion reactions, which can mimic allergic reactions such as nausea, vomiting, abdominal pain, and flushing, Dr. Maese said.

Asked how to treat patients who cannot tolerate first-line treatment with asparaginase, Dr. Burke responded, “There are second-generation asparaginase formulations for once a patient develops an allergy.”

Dr. Maese said his institution switches patients when necessary to asparaginase Erwinia chrysanthemi (recombinant)-rywn, also known as Rylaze.

Another recent development in ALL treatment is the widespread use of drug monitoring to make sure asparaginase is reaching therapeutic levels. “Asparagine itself is difficult to measure so we use a surrogate of asparaginase levels to demonstrate efficacy of the drug,” he said. “There is conflicting literature as to what constitutes a therapeutic level, but the internationally accepted standard is a level of ≥ 0.1 IU/mL. We monitor asparaginase levels routinely with pegylated asparaginase but not with non-pegylated asparaginase.”

Tests can turn up “silent inactivation,” a term that refers to when the drug is “inactivated” and is not effective, Dr. Maese said. “There are several guidelines that have defined inactivation.” According to the 2022 report cowritten by Dr. Maese, Rylaze can be an alternative option if initial asparaginase treatment isn’t working.

With regard to cost, treatment with asparaginase can cost tens of thousands of dollars. However, insurers routinely pay for treatment plus pre-medication and testing, Dr. Burke said. “There’s no pushback. It seems to be accepted.”

What’s next on the horizon? “We need to understand better those patients who are at risk for toxicity,” Dr. Maese noted. “We understand obesity causes risk for certain toxicities, but have little else to go on. There has been some work with genomics and its relationship to risk of toxicity. However, it has been difficult to translate what has been found to patients.”

There’s work in progress that is exploring other preventive approaches to decrease toxicity, he said. Also, “optimizing the dosing of asparaginase has been explored more in Europe and within a smaller consortium in North America.”

In addition, he said, “as we begin to increase use of immunotherapy within our chemotherapy backbones, we need to understand the relationship these drugs have with asparaginase treatment.”

Dr. Burke and Dr. Wistinghausen have no disclosures. Dr. Maese discloses relationships with Jazz (advisory board, consultant, speakers bureau) and Servier (advisory board).

The chemotherapy drug asparaginase revolutionized childhood cancer care in the 1970s, and it’s still a mainstay of treatment for acute lymphoblastic leukemia (ALL) today. But asparaginase remains difficult for some to tolerate, and clinicians keep needing to adjust therapy to address toxicity.

The good news, hematologists note, is that new strategies have been developed to address side effects. “We’ve gotten better at managing them,” pediatric oncologist Birte Wistinghausen, MD, of Children’s National Hospital in Washington, DC, said in an interview.

According to her, key approaches include sensitivity testing and “pre-medication” to prevent adverse effects from appearing in the first place.

The American Cancer Society estimates that 6,550 new cases of ALL appear in the United States each year, and 1,330 people die from the disease.

“Most cases of ALL occur in children, but most deaths from ALL (about 4 out of 5) occur in adults,” the organization reports. Indeed, the 5-year survival rate in children is now at about 90%, a number that hematologists partially attribute to the power of asparaginase.

Researchers believe that asparaginase, an enzyme, works by breaking down a substance called asparagine, which ALL cells use to reproduce. The drug is “universally used throughout the treatment of ALL in children and adolescents,” Luke Maese, DO, associate professor of pediatrics at the University of Utah–Huntsman Cancer Institute, Salt Lake City, and director of Leukemia/Lymphoma at Primary Children’s Hospital, said in an interview. “It has become more and more adopted in the treatment of young adults as well.”

The formulations of available asparaginase have evolved over the years, Dr. Maese said. “Currently, the first-line asparaginase products delivered in the majority of patients throughout the world are pegylated, meaning they have an extended duration of action. There are non-pegylated asparaginase products that are used as well.”

The pegylated drugs are much easier on patients since they don’t require frequent injections, according to experts.

Treatment protocols vary, Dr. Maese said. “Some use the drug intermittently intermixed throughout therapy, and others have periods of continuous asparaginase use — i.e. 10-20 weeks of repeated doses of the drug.”

All patients are likely to experience side effects, he said, and about 5%-10% of standard-risk and 20%-25% of high-risk patients will experience clinically significant problems.

When asparaginase is given by IV, its rapid onset can lead to a condition called acute hyperammonemia, in which ammonia levels rise and patients develop flushing, anxiety, and low blood pressure, said Dr. Wistinghausen of Children’s National Hospital. “But that is not a reason to abandon asparaginase.”

It can be difficult to differentiate this effect from hypersensitivity — allergic reactions — which can range from hives to full anaphylactic shock that requires treatment with epinephrine, she said.

According to Dr. Maese, other major side effects other than hypersensitivity include pancreatitis, hepatotoxicity, and thrombosis. The most dangerous of these side effects are hypersensitivity and pancreatitis, which can lead to discontinuation of treatment, he said. Indeed, a 2017 study found that 2% of 465 patients with ALL who developed asparaginase-associated pancreatitis died, and 8% needed mechanical ventilation.

There’s no way to predict which patients may be susceptible to pancreatitis, Michael J. Burke, MD, professor of pediatrics and director of leukemia/lymphoma director at Children’s Wisconsin and Medical College of Wisconsin, said in an interview.

As for therapy options if pancreatitis develops, a 2022 review cowritten by Dr. Maese reported that clinicians have been leaning toward re-treating patients with asparaginase since it’s so crucial to treatment. This has worked about 50% of the time, the review reported, and “many groups consider it in the setting of all grade 2 pancreatitis and grade 3 pancreatitis without prolonged illness or severe complications.”

As for hypersensitivity, the most prevalent adverse effect, clinicians frequently administer anti-allergy medications prior to infusion. This approach, known as “pre-medication,” is controversial. Research has produced conflicting results, with a 2022 study in the journal Blood finding that pre-medication had no effect on hypersensitivity in children with ALL.

“Although there is mixed data, most institutions utilize this,” Dr. Maese said. “At our institution, we continue to use pre-medication prior to pegylated asparaginase but do not use it with non-pegylated asparaginase.”

Specifically, most institutions administer H2 and H1 blockers, Dr. Wistinghausen said. “Some institutions also use hydrocortisone” — a steroid — “but our institution only uses it if patients have a reaction.”

Other potential adverse effects to treatment include infusion reactions, which can mimic allergic reactions such as nausea, vomiting, abdominal pain, and flushing, Dr. Maese said.

Asked how to treat patients who cannot tolerate first-line treatment with asparaginase, Dr. Burke responded, “There are second-generation asparaginase formulations for once a patient develops an allergy.”

Dr. Maese said his institution switches patients when necessary to asparaginase Erwinia chrysanthemi (recombinant)-rywn, also known as Rylaze.

Another recent development in ALL treatment is the widespread use of drug monitoring to make sure asparaginase is reaching therapeutic levels. “Asparagine itself is difficult to measure so we use a surrogate of asparaginase levels to demonstrate efficacy of the drug,” he said. “There is conflicting literature as to what constitutes a therapeutic level, but the internationally accepted standard is a level of ≥ 0.1 IU/mL. We monitor asparaginase levels routinely with pegylated asparaginase but not with non-pegylated asparaginase.”

Tests can turn up “silent inactivation,” a term that refers to when the drug is “inactivated” and is not effective, Dr. Maese said. “There are several guidelines that have defined inactivation.” According to the 2022 report cowritten by Dr. Maese, Rylaze can be an alternative option if initial asparaginase treatment isn’t working.

With regard to cost, treatment with asparaginase can cost tens of thousands of dollars. However, insurers routinely pay for treatment plus pre-medication and testing, Dr. Burke said. “There’s no pushback. It seems to be accepted.”

What’s next on the horizon? “We need to understand better those patients who are at risk for toxicity,” Dr. Maese noted. “We understand obesity causes risk for certain toxicities, but have little else to go on. There has been some work with genomics and its relationship to risk of toxicity. However, it has been difficult to translate what has been found to patients.”

There’s work in progress that is exploring other preventive approaches to decrease toxicity, he said. Also, “optimizing the dosing of asparaginase has been explored more in Europe and within a smaller consortium in North America.”

In addition, he said, “as we begin to increase use of immunotherapy within our chemotherapy backbones, we need to understand the relationship these drugs have with asparaginase treatment.”

Dr. Burke and Dr. Wistinghausen have no disclosures. Dr. Maese discloses relationships with Jazz (advisory board, consultant, speakers bureau) and Servier (advisory board).

The chemotherapy drug asparaginase revolutionized childhood cancer care in the 1970s, and it’s still a mainstay of treatment for acute lymphoblastic leukemia (ALL) today. But asparaginase remains difficult for some to tolerate, and clinicians keep needing to adjust therapy to address toxicity.

The good news, hematologists note, is that new strategies have been developed to address side effects. “We’ve gotten better at managing them,” pediatric oncologist Birte Wistinghausen, MD, of Children’s National Hospital in Washington, DC, said in an interview.

According to her, key approaches include sensitivity testing and “pre-medication” to prevent adverse effects from appearing in the first place.

The American Cancer Society estimates that 6,550 new cases of ALL appear in the United States each year, and 1,330 people die from the disease.

“Most cases of ALL occur in children, but most deaths from ALL (about 4 out of 5) occur in adults,” the organization reports. Indeed, the 5-year survival rate in children is now at about 90%, a number that hematologists partially attribute to the power of asparaginase.

Researchers believe that asparaginase, an enzyme, works by breaking down a substance called asparagine, which ALL cells use to reproduce. The drug is “universally used throughout the treatment of ALL in children and adolescents,” Luke Maese, DO, associate professor of pediatrics at the University of Utah–Huntsman Cancer Institute, Salt Lake City, and director of Leukemia/Lymphoma at Primary Children’s Hospital, said in an interview. “It has become more and more adopted in the treatment of young adults as well.”

The formulations of available asparaginase have evolved over the years, Dr. Maese said. “Currently, the first-line asparaginase products delivered in the majority of patients throughout the world are pegylated, meaning they have an extended duration of action. There are non-pegylated asparaginase products that are used as well.”

The pegylated drugs are much easier on patients since they don’t require frequent injections, according to experts.

Treatment protocols vary, Dr. Maese said. “Some use the drug intermittently intermixed throughout therapy, and others have periods of continuous asparaginase use — i.e. 10-20 weeks of repeated doses of the drug.”

All patients are likely to experience side effects, he said, and about 5%-10% of standard-risk and 20%-25% of high-risk patients will experience clinically significant problems.

When asparaginase is given by IV, its rapid onset can lead to a condition called acute hyperammonemia, in which ammonia levels rise and patients develop flushing, anxiety, and low blood pressure, said Dr. Wistinghausen of Children’s National Hospital. “But that is not a reason to abandon asparaginase.”

It can be difficult to differentiate this effect from hypersensitivity — allergic reactions — which can range from hives to full anaphylactic shock that requires treatment with epinephrine, she said.

According to Dr. Maese, other major side effects other than hypersensitivity include pancreatitis, hepatotoxicity, and thrombosis. The most dangerous of these side effects are hypersensitivity and pancreatitis, which can lead to discontinuation of treatment, he said. Indeed, a 2017 study found that 2% of 465 patients with ALL who developed asparaginase-associated pancreatitis died, and 8% needed mechanical ventilation.

There’s no way to predict which patients may be susceptible to pancreatitis, Michael J. Burke, MD, professor of pediatrics and director of leukemia/lymphoma director at Children’s Wisconsin and Medical College of Wisconsin, said in an interview.

As for therapy options if pancreatitis develops, a 2022 review cowritten by Dr. Maese reported that clinicians have been leaning toward re-treating patients with asparaginase since it’s so crucial to treatment. This has worked about 50% of the time, the review reported, and “many groups consider it in the setting of all grade 2 pancreatitis and grade 3 pancreatitis without prolonged illness or severe complications.”

As for hypersensitivity, the most prevalent adverse effect, clinicians frequently administer anti-allergy medications prior to infusion. This approach, known as “pre-medication,” is controversial. Research has produced conflicting results, with a 2022 study in the journal Blood finding that pre-medication had no effect on hypersensitivity in children with ALL.

“Although there is mixed data, most institutions utilize this,” Dr. Maese said. “At our institution, we continue to use pre-medication prior to pegylated asparaginase but do not use it with non-pegylated asparaginase.”

Specifically, most institutions administer H2 and H1 blockers, Dr. Wistinghausen said. “Some institutions also use hydrocortisone” — a steroid — “but our institution only uses it if patients have a reaction.”

Other potential adverse effects to treatment include infusion reactions, which can mimic allergic reactions such as nausea, vomiting, abdominal pain, and flushing, Dr. Maese said.

Asked how to treat patients who cannot tolerate first-line treatment with asparaginase, Dr. Burke responded, “There are second-generation asparaginase formulations for once a patient develops an allergy.”

Dr. Maese said his institution switches patients when necessary to asparaginase Erwinia chrysanthemi (recombinant)-rywn, also known as Rylaze.

Another recent development in ALL treatment is the widespread use of drug monitoring to make sure asparaginase is reaching therapeutic levels. “Asparagine itself is difficult to measure so we use a surrogate of asparaginase levels to demonstrate efficacy of the drug,” he said. “There is conflicting literature as to what constitutes a therapeutic level, but the internationally accepted standard is a level of ≥ 0.1 IU/mL. We monitor asparaginase levels routinely with pegylated asparaginase but not with non-pegylated asparaginase.”

Tests can turn up “silent inactivation,” a term that refers to when the drug is “inactivated” and is not effective, Dr. Maese said. “There are several guidelines that have defined inactivation.” According to the 2022 report cowritten by Dr. Maese, Rylaze can be an alternative option if initial asparaginase treatment isn’t working.

With regard to cost, treatment with asparaginase can cost tens of thousands of dollars. However, insurers routinely pay for treatment plus pre-medication and testing, Dr. Burke said. “There’s no pushback. It seems to be accepted.”

What’s next on the horizon? “We need to understand better those patients who are at risk for toxicity,” Dr. Maese noted. “We understand obesity causes risk for certain toxicities, but have little else to go on. There has been some work with genomics and its relationship to risk of toxicity. However, it has been difficult to translate what has been found to patients.”

There’s work in progress that is exploring other preventive approaches to decrease toxicity, he said. Also, “optimizing the dosing of asparaginase has been explored more in Europe and within a smaller consortium in North America.”

In addition, he said, “as we begin to increase use of immunotherapy within our chemotherapy backbones, we need to understand the relationship these drugs have with asparaginase treatment.”

Dr. Burke and Dr. Wistinghausen have no disclosures. Dr. Maese discloses relationships with Jazz (advisory board, consultant, speakers bureau) and Servier (advisory board).

TOPLINE:

Cancer surgery poses an elevated risk for venous thromboembolism, which can vary depending on the type of cancer and the timing of surgery, a study suggested.

METHODOLOGY:

• Both major surgery and cancer increase the risk for venous thromboembolism, which can lead to severe illness and death. Research showed that approximately 2% of patients who have cancer surgery experience clinically significant venous thromboembolism, which accounts for about half of the deaths that occur immediately after surgery.
• The American Society of Clinical Oncology and European Association of Urology guidelines recommend an extended 28-day prophylaxis for patients undergoing cancer surgery. These guidelines also provide specific estimates of the excess risk for thromboembolic events for each disease.
• This retrospective study included data on 432,218 patients (median age, 67 years) from Swedish nationwide registers who underwent major surgery for eight types of cancer (bladder, breast, colorectal, gynecologic, lung, prostate, gastroesophageal, and kidney or upper tract urothelial cancer) from 1998 to 2016.
• The researchers matched the patients with 4,009,343 cancer-free individuals from the general population in a 1:10 ratio.
• The primary outcome was the incidence of venous thromboembolic events, including subsegmental pulmonary embolism and deep venous thromboembolism in the calf, within 1 year after the surgery.

TAKEAWAY:

• The researchers found an increased absolute risk for pulmonary embolism at 1 year following cancer surgery, with the highest increase in patients with bladder cancer (a 2.69 percentage point difference), followed by lung (a 2.61 percentage point difference), gastroesophageal (2.13), colorectal (1.57), kidney or upper urinary tract (1.38), gynecologic (1.32), breast (0.59), and prostate cancer (0.57).
• The increased 1-year absolute risk for deep vein thrombosis (in percentage points) was highest for the bladder (a 4.67 percentage point difference), followed by gastroesophageal (2.19), colorectal (2.15), upper urinary tract (2.14), gynecologic (2.02), lung (1.40), breast (1.36), and prostate cancer (0.75).
• The temporal trends showed that the risk for pulmonary embolism and deep vein thrombosis peaked immediately after surgery and plateaued within 120 days for most cancers. At 30 days after surgery, the risk for pulmonary embolism following cancer surgery was 10- to 30-fold times higher than with no surgery for all cancers aside from breast cancer (hazard ratio, 5.18). The researchers observed a similar elevated risk for deep vein thrombosis 30 days following surgery.
• The risk for pulmonary embolism and deep vein thrombosis remained significant at 1 year for all cancer types, except prostate.

IN PRACTICE:

“The marked variation in the occurrence patterns of postoperative venous thromboembolic events indicates a need for a more tailored approach to prophylaxis,” the authors noted, advocating for individualized venous thromboembolism risk evaluation and prophylaxis regimens.

SOURCE:

This study, led by Johan Björklund, MD, PhD, from Karolinska Institute, Stockholm, Sweden, was published online in JAMA Network Open.

LIMITATIONS:

The information regarding treatments other than surgery that might be linked to an elevated risk for venous thromboembolism was not available. Additionally, changes in clinical practices and diagnostics over time could affect both the occurrence and detection of outcomes. Adoption of minimally invasive surgical techniques, increased use of thromboprophylaxis over time, improved diagnostic capabilities, and a trend toward operating on older patients with more comorbidities over time may have influenced outcomes.

DISCLOSURES: 

The work was funded by the Karolinska Institute and the Swedish Cancer Society. Two study authors reported receiving personal or consulting fees. Other authors reported no conflicts of interest.

A version of this article appeared on Medscape.com.

TOPLINE:

Cancer surgery poses an elevated risk for venous thromboembolism, which can vary depending on the type of cancer and the timing of surgery, a study suggested.

METHODOLOGY:

• Both major surgery and cancer increase the risk for venous thromboembolism, which can lead to severe illness and death. Research showed that approximately 2% of patients who have cancer surgery experience clinically significant venous thromboembolism, which accounts for about half of the deaths that occur immediately after surgery.
• The American Society of Clinical Oncology and European Association of Urology guidelines recommend an extended 28-day prophylaxis for patients undergoing cancer surgery. These guidelines also provide specific estimates of the excess risk for thromboembolic events for each disease.
• This retrospective study included data on 432,218 patients (median age, 67 years) from Swedish nationwide registers who underwent major surgery for eight types of cancer (bladder, breast, colorectal, gynecologic, lung, prostate, gastroesophageal, and kidney or upper tract urothelial cancer) from 1998 to 2016.
• The researchers matched the patients with 4,009,343 cancer-free individuals from the general population in a 1:10 ratio.
• The primary outcome was the incidence of venous thromboembolic events, including subsegmental pulmonary embolism and deep venous thromboembolism in the calf, within 1 year after the surgery.

TAKEAWAY:

• The researchers found an increased absolute risk for pulmonary embolism at 1 year following cancer surgery, with the highest increase in patients with bladder cancer (a 2.69 percentage point difference), followed by lung (a 2.61 percentage point difference), gastroesophageal (2.13), colorectal (1.57), kidney or upper urinary tract (1.38), gynecologic (1.32), breast (0.59), and prostate cancer (0.57).
• The increased 1-year absolute risk for deep vein thrombosis (in percentage points) was highest for the bladder (a 4.67 percentage point difference), followed by gastroesophageal (2.19), colorectal (2.15), upper urinary tract (2.14), gynecologic (2.02), lung (1.40), breast (1.36), and prostate cancer (0.75).
• The temporal trends showed that the risk for pulmonary embolism and deep vein thrombosis peaked immediately after surgery and plateaued within 120 days for most cancers. At 30 days after surgery, the risk for pulmonary embolism following cancer surgery was 10- to 30-fold times higher than with no surgery for all cancers aside from breast cancer (hazard ratio, 5.18). The researchers observed a similar elevated risk for deep vein thrombosis 30 days following surgery.
• The risk for pulmonary embolism and deep vein thrombosis remained significant at 1 year for all cancer types, except prostate.

IN PRACTICE:

“The marked variation in the occurrence patterns of postoperative venous thromboembolic events indicates a need for a more tailored approach to prophylaxis,” the authors noted, advocating for individualized venous thromboembolism risk evaluation and prophylaxis regimens.

SOURCE:

This study, led by Johan Björklund, MD, PhD, from Karolinska Institute, Stockholm, Sweden, was published online in JAMA Network Open.

LIMITATIONS:

The information regarding treatments other than surgery that might be linked to an elevated risk for venous thromboembolism was not available. Additionally, changes in clinical practices and diagnostics over time could affect both the occurrence and detection of outcomes. Adoption of minimally invasive surgical techniques, increased use of thromboprophylaxis over time, improved diagnostic capabilities, and a trend toward operating on older patients with more comorbidities over time may have influenced outcomes.

DISCLOSURES: 

The work was funded by the Karolinska Institute and the Swedish Cancer Society. Two study authors reported receiving personal or consulting fees. Other authors reported no conflicts of interest.

A version of this article appeared on Medscape.com.

TOPLINE:

Cancer surgery poses an elevated risk for venous thromboembolism, which can vary depending on the type of cancer and the timing of surgery, a study suggested.

METHODOLOGY:

• Both major surgery and cancer increase the risk for venous thromboembolism, which can lead to severe illness and death. Research showed that approximately 2% of patients who have cancer surgery experience clinically significant venous thromboembolism, which accounts for about half of the deaths that occur immediately after surgery.
• The American Society of Clinical Oncology and European Association of Urology guidelines recommend an extended 28-day prophylaxis for patients undergoing cancer surgery. These guidelines also provide specific estimates of the excess risk for thromboembolic events for each disease.
• This retrospective study included data on 432,218 patients (median age, 67 years) from Swedish nationwide registers who underwent major surgery for eight types of cancer (bladder, breast, colorectal, gynecologic, lung, prostate, gastroesophageal, and kidney or upper tract urothelial cancer) from 1998 to 2016.
• The researchers matched the patients with 4,009,343 cancer-free individuals from the general population in a 1:10 ratio.
• The primary outcome was the incidence of venous thromboembolic events, including subsegmental pulmonary embolism and deep venous thromboembolism in the calf, within 1 year after the surgery.

TAKEAWAY:

• The researchers found an increased absolute risk for pulmonary embolism at 1 year following cancer surgery, with the highest increase in patients with bladder cancer (a 2.69 percentage point difference), followed by lung (a 2.61 percentage point difference), gastroesophageal (2.13), colorectal (1.57), kidney or upper urinary tract (1.38), gynecologic (1.32), breast (0.59), and prostate cancer (0.57).
• The increased 1-year absolute risk for deep vein thrombosis (in percentage points) was highest for the bladder (a 4.67 percentage point difference), followed by gastroesophageal (2.19), colorectal (2.15), upper urinary tract (2.14), gynecologic (2.02), lung (1.40), breast (1.36), and prostate cancer (0.75).
• The temporal trends showed that the risk for pulmonary embolism and deep vein thrombosis peaked immediately after surgery and plateaued within 120 days for most cancers. At 30 days after surgery, the risk for pulmonary embolism following cancer surgery was 10- to 30-fold times higher than with no surgery for all cancers aside from breast cancer (hazard ratio, 5.18). The researchers observed a similar elevated risk for deep vein thrombosis 30 days following surgery.
• The risk for pulmonary embolism and deep vein thrombosis remained significant at 1 year for all cancer types, except prostate.

IN PRACTICE:

“The marked variation in the occurrence patterns of postoperative venous thromboembolic events indicates a need for a more tailored approach to prophylaxis,” the authors noted, advocating for individualized venous thromboembolism risk evaluation and prophylaxis regimens.

SOURCE:

This study, led by Johan Björklund, MD, PhD, from Karolinska Institute, Stockholm, Sweden, was published online in JAMA Network Open.

LIMITATIONS:

The information regarding treatments other than surgery that might be linked to an elevated risk for venous thromboembolism was not available. Additionally, changes in clinical practices and diagnostics over time could affect both the occurrence and detection of outcomes. Adoption of minimally invasive surgical techniques, increased use of thromboprophylaxis over time, improved diagnostic capabilities, and a trend toward operating on older patients with more comorbidities over time may have influenced outcomes.

DISCLOSURES: 

The work was funded by the Karolinska Institute and the Swedish Cancer Society. Two study authors reported receiving personal or consulting fees. Other authors reported no conflicts of interest.

A version of this article appeared on Medscape.com.