Liam Davenport

Patients with severe alcohol-associated hepatitis (AH) need treatment for both their liver disease and their underlying alcohol use disorder (AUD), concludes a review discussing care for patients recently hospitalized.

“Probably the biggest thing I would want providers to take away from the review is to remember that these patients are likely to carry a dual diagnosis,” said lead author Akshay Shetty, MD, Pfleger Liver Institute, UCLA Medical Center.

“It is important to address the liver disease, because it probably carries the biggest mortality and morbidity risk in the short term, but we have to remember to treat their alcohol use disorder simultaneously,” Dr. Shetty said.

The guidance by Dr. Shetty and coauthors was published online in the Journal of Clinical Gastroenterology.
 

More alcohol misuse means more liver disease

AH is a “unique, severe form of alcohol-associated steatohepatitis that is seen in the background of recent heavy alcohol use,” the team writes. Patients with severe AH have faced mortality rates as high as 20%-50%. A recent study reported a drop in 30-day mortality rates to 17%, which the authors credit to improved supportive medical management.

Alcohol misuse has surged over the past two decades, which experts believe will lead to a rise in alcohol-related liver disease, including AH hospitalization, the authors note. Rates of high-risk drinking in the United States (four or more drinks daily for women, five or more for men) increased by almost 30% between 2002 and 2012, particularly among women and ethnic minorities.

At the same time, rates of AUD rose 25% among young adults. In 2019, a U.S. survey found 14.5 million people aged 12 years and older in the United States carried an AUD diagnosis.

Meanwhile, the U.S. National Inpatient Sample revealed a 28.3% rise in AH-related hospitalizations between 2007 and 2014.

“AH patients carry a high short-term mortality [and] require close outpatient monitoring and significant care coordination,” write the authors. Despite the rising rates of severe AH, there is a lack of standardized guidance on post-discharge management, which motivated their clinical care review.
 

Liver disease shapes short-term outcomes

The management of patients with a recent episode of severe AH requires a two-pronged approach and shared patient management between gastroenterologists/hepatologists and addiction specialists. The multidisciplinary management both improves outcomes and is linked to reduced health care costs, the authors write.

While abstinence from alcohol remains essential to recovery, the authors note, it is the “severity of hepatic decompensation that has been shown to dictate short-term mortality in the initial 6 months” following discharge.

The team created an outpatient algorithm that divides patient care into two main areas: hepatic decompensation and AUD.

For the risk of hepatic decompensation, patients should undergo close monitoring for infections and frequent laboratory tests in the months following discharge.

Moreover, the “majority of patients with severe AH usually have background cirrhosis and are at risk of portal hypertensive decompensations similar to cirrhosis,” the authors write, and so patients should be assessed for hepatic encephalopathy, as well as for ascites and variceal bleeding.

For HE, the authors recommend a low threshold for treatment initiation with lactulose (a colonic acidifier) and the antibiotic rifaximin, but they suggest that ascites management “should be conservative ... with strict adherence to a low-sodium diet as the first-line approach.”

A key problem among severe AH patients post-discharge is malnutrition, which reaches 100% prevalence and is associated with the severity of liver disease, including decompensation and mortality, they note.

Patients with malnutrition are at risk of entering a catabolic starvation state. The authors recommend avoiding long fasting periods with multiple small meals and late evening snacks.

Long-term, severe AH patients should be assessed for advanced fibrosis, although early diagnosis is often challenging, as the clinical and laboratory results typically mimic findings of liver cirrhosis, the authors write.

Crucially, patients should be considered for early referral for liver transplantation, because early liver transplantation is associated with “excellent transplant outcomes and is noninferior when compared with other etiologies of chronic liver disease,” they write.
 

Long-term risk rests on preventing alcohol relapse

Turning to AUD, the team notes that long-term outcomes among AH patients depend on the prevention of alcohol relapse, because alcohol use among these patients is directly linked to higher rates of mortality and decompensation.

The authors concede that the “definition of relapse remains a matter of contention, especially in the post-liver transplant population,” but they recommend complete abstinence for patients recovering from AH and define relapse as any use of alcohol.

Dr. Shetty explained that “often, the focus tends to be on the acute threats to a patient’s life, so their liver disease tends to be emphasized, and we often forget why patients present with the liver disease in the first place.”

He continued: “So we do our best to address the liver disease and not a lot gets done for the alcohol-use disorder that the patient may have in the background. The expectation is that, if the doctors help patients with their liver disease, the patients will learn that lesson on their own and stop drinking.”

Instead, Dr. Shetty and his colleagues advise, all patients should be screened for AUD and undergo surveillance with alcohol biomarkers monthly at first. Patients should also be referred to an addiction specialist, where some combination of psychotherapy, mutual support groups, and pharmacotherapy can be tailored to individual patient needs and access.

Multidisciplinary management, comprising hepatology, psychiatry, psychologist, nurse, and social worker consults, has shown “promising results in the management of AUD, improvement in liver disease, and decrease in health care burden,” the authors write, although “multidisciplinary clinics often carry financial and administrative barriers to broad application.”

Moreover, these interventions require a commitment from the patient, at least in the short term, to allow the establishment of a therapeutic relationship between the clinician and the patient and aid compliance over the longer term.

“Patients with AUD remain reluctant to pursue treatment,” the authors write, “and a large-scale effort to improve knowledge gaps in regard to AUD treatment and its success is needed, both from patients’ primary care providers and their consultants.”

Dr. Shetty explained that patient engagement is “probably the most challenging aspect of the disease, especially the alcohol use disorder part.”

This is partly because patients often lack insight, and alcohol addiction carries stigma and shame, as well as self-blame, he said, and so patients will “often delay pursuing any therapy ... even when they are sick.”

Dr. Shetty believes that reducing the stigma around alcohol addiction will require better education of patients and health care providers. To that end, he noted that the scientific literature now avoids the pejorative “alcoholic” and instead describes alcohol use as a disorder rather than having it define the patient.

“But this educational aspect is going to take a long time to really take effect, so from a provider perspective ... it is important to be open-minded when seeing these patients,” he said. This means not focusing on “the medical aspect alone but trying to really see the person who’s come to you for help and understand their motivations for pursing medical care.”

“Despite all these things, some patients may still find it very challenging and awkward. It takes several visits to really establish a rapport with them and get a sense of how to get them to share the challenging aspects of the disease,” Dr. Shetty added.
 

Multidisciplinary management for optimal outcomes

In a comment, Nancy S. Reau, MD, chair of hepatology, Rush Medical College, Chicago, agreed with the need to address both the risk for hepatic decompensation and AUD, the benefits of multidisciplinary management of patients, and the importance of patient engagement to successful outcomes.

“As hepatologists, we are often best at managing liver disease, but if you don’t also address the alcohol use disorder, the patient will not have the optimal outcome,” she said in an interview. “Most patients with severe AH have cirrhosis, [which] makes longitudinal follow-up imperative.”

“They are at risk for liver complications but also need aggressive nutritional support and management of their addiction,” she said. “As they improve, they can usually continue intensive treatment.”

Akhil Anand, MD, an addiction psychiatrist and co-director of the Multidisciplinary Alcohol Program at the Cleveland Clinic, also noted the increase in cases of alcohol-associated hepatitis from rising alcohol use.

The review “provides a timely, comprehensive, and impartial overview” of how to manage the condition, he said, as well as “how to treat co-occurring alcohol use disorder in this life-threatening situation.”

No funding was declared. The authors report no relevant financial relationships.

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

Patients with severe alcohol-associated hepatitis (AH) need treatment for both their liver disease and their underlying alcohol use disorder (AUD), concludes a review discussing care for patients recently hospitalized.

“Probably the biggest thing I would want providers to take away from the review is to remember that these patients are likely to carry a dual diagnosis,” said lead author Akshay Shetty, MD, Pfleger Liver Institute, UCLA Medical Center.

“It is important to address the liver disease, because it probably carries the biggest mortality and morbidity risk in the short term, but we have to remember to treat their alcohol use disorder simultaneously,” Dr. Shetty said.

The guidance by Dr. Shetty and coauthors was published online in the Journal of Clinical Gastroenterology.
 

More alcohol misuse means more liver disease

AH is a “unique, severe form of alcohol-associated steatohepatitis that is seen in the background of recent heavy alcohol use,” the team writes. Patients with severe AH have faced mortality rates as high as 20%-50%. A recent study reported a drop in 30-day mortality rates to 17%, which the authors credit to improved supportive medical management.

Alcohol misuse has surged over the past two decades, which experts believe will lead to a rise in alcohol-related liver disease, including AH hospitalization, the authors note. Rates of high-risk drinking in the United States (four or more drinks daily for women, five or more for men) increased by almost 30% between 2002 and 2012, particularly among women and ethnic minorities.

At the same time, rates of AUD rose 25% among young adults. In 2019, a U.S. survey found 14.5 million people aged 12 years and older in the United States carried an AUD diagnosis.

Meanwhile, the U.S. National Inpatient Sample revealed a 28.3% rise in AH-related hospitalizations between 2007 and 2014.

“AH patients carry a high short-term mortality [and] require close outpatient monitoring and significant care coordination,” write the authors. Despite the rising rates of severe AH, there is a lack of standardized guidance on post-discharge management, which motivated their clinical care review.
 

Liver disease shapes short-term outcomes

The management of patients with a recent episode of severe AH requires a two-pronged approach and shared patient management between gastroenterologists/hepatologists and addiction specialists. The multidisciplinary management both improves outcomes and is linked to reduced health care costs, the authors write.

While abstinence from alcohol remains essential to recovery, the authors note, it is the “severity of hepatic decompensation that has been shown to dictate short-term mortality in the initial 6 months” following discharge.

The team created an outpatient algorithm that divides patient care into two main areas: hepatic decompensation and AUD.

For the risk of hepatic decompensation, patients should undergo close monitoring for infections and frequent laboratory tests in the months following discharge.

Moreover, the “majority of patients with severe AH usually have background cirrhosis and are at risk of portal hypertensive decompensations similar to cirrhosis,” the authors write, and so patients should be assessed for hepatic encephalopathy, as well as for ascites and variceal bleeding.

For HE, the authors recommend a low threshold for treatment initiation with lactulose (a colonic acidifier) and the antibiotic rifaximin, but they suggest that ascites management “should be conservative ... with strict adherence to a low-sodium diet as the first-line approach.”

A key problem among severe AH patients post-discharge is malnutrition, which reaches 100% prevalence and is associated with the severity of liver disease, including decompensation and mortality, they note.

Patients with malnutrition are at risk of entering a catabolic starvation state. The authors recommend avoiding long fasting periods with multiple small meals and late evening snacks.

Long-term, severe AH patients should be assessed for advanced fibrosis, although early diagnosis is often challenging, as the clinical and laboratory results typically mimic findings of liver cirrhosis, the authors write.

Crucially, patients should be considered for early referral for liver transplantation, because early liver transplantation is associated with “excellent transplant outcomes and is noninferior when compared with other etiologies of chronic liver disease,” they write.
 

Long-term risk rests on preventing alcohol relapse

Turning to AUD, the team notes that long-term outcomes among AH patients depend on the prevention of alcohol relapse, because alcohol use among these patients is directly linked to higher rates of mortality and decompensation.

The authors concede that the “definition of relapse remains a matter of contention, especially in the post-liver transplant population,” but they recommend complete abstinence for patients recovering from AH and define relapse as any use of alcohol.

Dr. Shetty explained that “often, the focus tends to be on the acute threats to a patient’s life, so their liver disease tends to be emphasized, and we often forget why patients present with the liver disease in the first place.”

He continued: “So we do our best to address the liver disease and not a lot gets done for the alcohol-use disorder that the patient may have in the background. The expectation is that, if the doctors help patients with their liver disease, the patients will learn that lesson on their own and stop drinking.”

Instead, Dr. Shetty and his colleagues advise, all patients should be screened for AUD and undergo surveillance with alcohol biomarkers monthly at first. Patients should also be referred to an addiction specialist, where some combination of psychotherapy, mutual support groups, and pharmacotherapy can be tailored to individual patient needs and access.

Multidisciplinary management, comprising hepatology, psychiatry, psychologist, nurse, and social worker consults, has shown “promising results in the management of AUD, improvement in liver disease, and decrease in health care burden,” the authors write, although “multidisciplinary clinics often carry financial and administrative barriers to broad application.”

Moreover, these interventions require a commitment from the patient, at least in the short term, to allow the establishment of a therapeutic relationship between the clinician and the patient and aid compliance over the longer term.

“Patients with AUD remain reluctant to pursue treatment,” the authors write, “and a large-scale effort to improve knowledge gaps in regard to AUD treatment and its success is needed, both from patients’ primary care providers and their consultants.”

Dr. Shetty explained that patient engagement is “probably the most challenging aspect of the disease, especially the alcohol use disorder part.”

This is partly because patients often lack insight, and alcohol addiction carries stigma and shame, as well as self-blame, he said, and so patients will “often delay pursuing any therapy ... even when they are sick.”

Dr. Shetty believes that reducing the stigma around alcohol addiction will require better education of patients and health care providers. To that end, he noted that the scientific literature now avoids the pejorative “alcoholic” and instead describes alcohol use as a disorder rather than having it define the patient.

“But this educational aspect is going to take a long time to really take effect, so from a provider perspective ... it is important to be open-minded when seeing these patients,” he said. This means not focusing on “the medical aspect alone but trying to really see the person who’s come to you for help and understand their motivations for pursing medical care.”

“Despite all these things, some patients may still find it very challenging and awkward. It takes several visits to really establish a rapport with them and get a sense of how to get them to share the challenging aspects of the disease,” Dr. Shetty added.
 

Multidisciplinary management for optimal outcomes

In a comment, Nancy S. Reau, MD, chair of hepatology, Rush Medical College, Chicago, agreed with the need to address both the risk for hepatic decompensation and AUD, the benefits of multidisciplinary management of patients, and the importance of patient engagement to successful outcomes.

“As hepatologists, we are often best at managing liver disease, but if you don’t also address the alcohol use disorder, the patient will not have the optimal outcome,” she said in an interview. “Most patients with severe AH have cirrhosis, [which] makes longitudinal follow-up imperative.”

“They are at risk for liver complications but also need aggressive nutritional support and management of their addiction,” she said. “As they improve, they can usually continue intensive treatment.”

Akhil Anand, MD, an addiction psychiatrist and co-director of the Multidisciplinary Alcohol Program at the Cleveland Clinic, also noted the increase in cases of alcohol-associated hepatitis from rising alcohol use.

The review “provides a timely, comprehensive, and impartial overview” of how to manage the condition, he said, as well as “how to treat co-occurring alcohol use disorder in this life-threatening situation.”

No funding was declared. The authors report no relevant financial relationships.

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

Patients with severe alcohol-associated hepatitis (AH) need treatment for both their liver disease and their underlying alcohol use disorder (AUD), concludes a review discussing care for patients recently hospitalized.

“Probably the biggest thing I would want providers to take away from the review is to remember that these patients are likely to carry a dual diagnosis,” said lead author Akshay Shetty, MD, Pfleger Liver Institute, UCLA Medical Center.

“It is important to address the liver disease, because it probably carries the biggest mortality and morbidity risk in the short term, but we have to remember to treat their alcohol use disorder simultaneously,” Dr. Shetty said.

The guidance by Dr. Shetty and coauthors was published online in the Journal of Clinical Gastroenterology.
 

More alcohol misuse means more liver disease

AH is a “unique, severe form of alcohol-associated steatohepatitis that is seen in the background of recent heavy alcohol use,” the team writes. Patients with severe AH have faced mortality rates as high as 20%-50%. A recent study reported a drop in 30-day mortality rates to 17%, which the authors credit to improved supportive medical management.

Alcohol misuse has surged over the past two decades, which experts believe will lead to a rise in alcohol-related liver disease, including AH hospitalization, the authors note. Rates of high-risk drinking in the United States (four or more drinks daily for women, five or more for men) increased by almost 30% between 2002 and 2012, particularly among women and ethnic minorities.

At the same time, rates of AUD rose 25% among young adults. In 2019, a U.S. survey found 14.5 million people aged 12 years and older in the United States carried an AUD diagnosis.

Meanwhile, the U.S. National Inpatient Sample revealed a 28.3% rise in AH-related hospitalizations between 2007 and 2014.

“AH patients carry a high short-term mortality [and] require close outpatient monitoring and significant care coordination,” write the authors. Despite the rising rates of severe AH, there is a lack of standardized guidance on post-discharge management, which motivated their clinical care review.
 

Liver disease shapes short-term outcomes

The management of patients with a recent episode of severe AH requires a two-pronged approach and shared patient management between gastroenterologists/hepatologists and addiction specialists. The multidisciplinary management both improves outcomes and is linked to reduced health care costs, the authors write.

While abstinence from alcohol remains essential to recovery, the authors note, it is the “severity of hepatic decompensation that has been shown to dictate short-term mortality in the initial 6 months” following discharge.

The team created an outpatient algorithm that divides patient care into two main areas: hepatic decompensation and AUD.

For the risk of hepatic decompensation, patients should undergo close monitoring for infections and frequent laboratory tests in the months following discharge.

Moreover, the “majority of patients with severe AH usually have background cirrhosis and are at risk of portal hypertensive decompensations similar to cirrhosis,” the authors write, and so patients should be assessed for hepatic encephalopathy, as well as for ascites and variceal bleeding.

For HE, the authors recommend a low threshold for treatment initiation with lactulose (a colonic acidifier) and the antibiotic rifaximin, but they suggest that ascites management “should be conservative ... with strict adherence to a low-sodium diet as the first-line approach.”

A key problem among severe AH patients post-discharge is malnutrition, which reaches 100% prevalence and is associated with the severity of liver disease, including decompensation and mortality, they note.

Patients with malnutrition are at risk of entering a catabolic starvation state. The authors recommend avoiding long fasting periods with multiple small meals and late evening snacks.

Long-term, severe AH patients should be assessed for advanced fibrosis, although early diagnosis is often challenging, as the clinical and laboratory results typically mimic findings of liver cirrhosis, the authors write.

Crucially, patients should be considered for early referral for liver transplantation, because early liver transplantation is associated with “excellent transplant outcomes and is noninferior when compared with other etiologies of chronic liver disease,” they write.
 

Long-term risk rests on preventing alcohol relapse

Turning to AUD, the team notes that long-term outcomes among AH patients depend on the prevention of alcohol relapse, because alcohol use among these patients is directly linked to higher rates of mortality and decompensation.

The authors concede that the “definition of relapse remains a matter of contention, especially in the post-liver transplant population,” but they recommend complete abstinence for patients recovering from AH and define relapse as any use of alcohol.

Dr. Shetty explained that “often, the focus tends to be on the acute threats to a patient’s life, so their liver disease tends to be emphasized, and we often forget why patients present with the liver disease in the first place.”

He continued: “So we do our best to address the liver disease and not a lot gets done for the alcohol-use disorder that the patient may have in the background. The expectation is that, if the doctors help patients with their liver disease, the patients will learn that lesson on their own and stop drinking.”

Instead, Dr. Shetty and his colleagues advise, all patients should be screened for AUD and undergo surveillance with alcohol biomarkers monthly at first. Patients should also be referred to an addiction specialist, where some combination of psychotherapy, mutual support groups, and pharmacotherapy can be tailored to individual patient needs and access.

Multidisciplinary management, comprising hepatology, psychiatry, psychologist, nurse, and social worker consults, has shown “promising results in the management of AUD, improvement in liver disease, and decrease in health care burden,” the authors write, although “multidisciplinary clinics often carry financial and administrative barriers to broad application.”

Moreover, these interventions require a commitment from the patient, at least in the short term, to allow the establishment of a therapeutic relationship between the clinician and the patient and aid compliance over the longer term.

“Patients with AUD remain reluctant to pursue treatment,” the authors write, “and a large-scale effort to improve knowledge gaps in regard to AUD treatment and its success is needed, both from patients’ primary care providers and their consultants.”

Dr. Shetty explained that patient engagement is “probably the most challenging aspect of the disease, especially the alcohol use disorder part.”

This is partly because patients often lack insight, and alcohol addiction carries stigma and shame, as well as self-blame, he said, and so patients will “often delay pursuing any therapy ... even when they are sick.”

Dr. Shetty believes that reducing the stigma around alcohol addiction will require better education of patients and health care providers. To that end, he noted that the scientific literature now avoids the pejorative “alcoholic” and instead describes alcohol use as a disorder rather than having it define the patient.

“But this educational aspect is going to take a long time to really take effect, so from a provider perspective ... it is important to be open-minded when seeing these patients,” he said. This means not focusing on “the medical aspect alone but trying to really see the person who’s come to you for help and understand their motivations for pursing medical care.”

“Despite all these things, some patients may still find it very challenging and awkward. It takes several visits to really establish a rapport with them and get a sense of how to get them to share the challenging aspects of the disease,” Dr. Shetty added.
 

Multidisciplinary management for optimal outcomes

In a comment, Nancy S. Reau, MD, chair of hepatology, Rush Medical College, Chicago, agreed with the need to address both the risk for hepatic decompensation and AUD, the benefits of multidisciplinary management of patients, and the importance of patient engagement to successful outcomes.

“As hepatologists, we are often best at managing liver disease, but if you don’t also address the alcohol use disorder, the patient will not have the optimal outcome,” she said in an interview. “Most patients with severe AH have cirrhosis, [which] makes longitudinal follow-up imperative.”

“They are at risk for liver complications but also need aggressive nutritional support and management of their addiction,” she said. “As they improve, they can usually continue intensive treatment.”

Akhil Anand, MD, an addiction psychiatrist and co-director of the Multidisciplinary Alcohol Program at the Cleveland Clinic, also noted the increase in cases of alcohol-associated hepatitis from rising alcohol use.

The review “provides a timely, comprehensive, and impartial overview” of how to manage the condition, he said, as well as “how to treat co-occurring alcohol use disorder in this life-threatening situation.”

No funding was declared. The authors report no relevant financial relationships.

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

TOPLINE:

Direct oral anticoagulants (DOACs) are associated with a reduced risk of venous thromboembolism (VTE), major bleeding, and mortality for cancer patients with VTE in comparison with low-molecular-weight heparin (LMWH), according to a recent analysis of U.S. claims data.

METHODOLOGY:

• This retrospective cohort study of electronic records claims data from OptumLabs included adults with an active primary cancer and acute VTE.
• Patients had filled an anticoagulation prescription within 30 days of VTE onset and were categorized on the basis of the anticoagulant prescribed: DOAC, LMWH, or warfarin.
• Patients were followed until the end of treatment. VTE recurrence and all-cause mortality were the main efficacy endpoints, and major bleeding episodes and bleeding sites were the main safety endpoints.
• Overall, 5,100 patients were included (mean age, 66.3 years); a majority (69.8%) were White, 15.7% were Black, and 7.6% were Hispanic. The patients had a range of cancer types, including lung, colorectal, gynecologic, and urologic.
• Nearly half of patients (49.3%) filled prescriptions for DOACs, 29.2% for LMWH, and 28.6% for warfarin.

TAKEAWAY:

• Compared with DOACs, LMWH and warfarin were associated with an increased risk of VTE recurrence (hazard ratio, 1.47 and 1.46, respectively).
• LMWH use was associated with an increased risk of major bleeding (HR, 2.27) and all-cause mortality (HR, 1.61), compared with DOAC use; mortality rates did not differ significantly between warfarin and DOACs (HR, 1.19; 95% confidence interval, 0.85-1.68).
• Patients who received LMWH were at increased risk of hospitalization for major bleeding, GI bleeding, and intracranial bleeding, compared with those who received DOACs (HR, 2.27, 1.72, 2.72, respectively).
• The risks of hospitalization for major bleeding, GI bleeding, and intracranial bleeding among patients who received warfarin and DOACs were similar (HR, 1.12, 1.03, 1.04, respectively).

IN PRACTICE:

Consistent with recent trials, “these data reinforce the general efficacy and safety of DOACs in this patient population” and reveal an association between DOACs and reduced all-cause mortality, the study authors wrote. These data may “help facilitate shared decision-marking and inform clinical guidelines for the treatment of such patients.”

SOURCE:

The study, led by Irbaz Bin Riaz, MD, PhD, of Mayo Clinic, Phoenix, Ariz., was published online in JAMA Network Open on July 24.

LIMITATIONS:

The study is limited by the potential for information bias in the database, the use of ICD codes to identify VTE patients, and the lack of radiologic evidence for VTE, as well as the lack of assessment for clinically relevant nonmajor bleeding.

The use of U.S. claims data limits the applicability of the results to other populations, including the uninsured.
 

DISCLOSURES:

No funding was declared. The authors have disclosed no relevant financial relationships.

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

TOPLINE:

Direct oral anticoagulants (DOACs) are associated with a reduced risk of venous thromboembolism (VTE), major bleeding, and mortality for cancer patients with VTE in comparison with low-molecular-weight heparin (LMWH), according to a recent analysis of U.S. claims data.

METHODOLOGY:

• This retrospective cohort study of electronic records claims data from OptumLabs included adults with an active primary cancer and acute VTE.
• Patients had filled an anticoagulation prescription within 30 days of VTE onset and were categorized on the basis of the anticoagulant prescribed: DOAC, LMWH, or warfarin.
• Patients were followed until the end of treatment. VTE recurrence and all-cause mortality were the main efficacy endpoints, and major bleeding episodes and bleeding sites were the main safety endpoints.
• Overall, 5,100 patients were included (mean age, 66.3 years); a majority (69.8%) were White, 15.7% were Black, and 7.6% were Hispanic. The patients had a range of cancer types, including lung, colorectal, gynecologic, and urologic.
• Nearly half of patients (49.3%) filled prescriptions for DOACs, 29.2% for LMWH, and 28.6% for warfarin.

TAKEAWAY:

• Compared with DOACs, LMWH and warfarin were associated with an increased risk of VTE recurrence (hazard ratio, 1.47 and 1.46, respectively).
• LMWH use was associated with an increased risk of major bleeding (HR, 2.27) and all-cause mortality (HR, 1.61), compared with DOAC use; mortality rates did not differ significantly between warfarin and DOACs (HR, 1.19; 95% confidence interval, 0.85-1.68).
• Patients who received LMWH were at increased risk of hospitalization for major bleeding, GI bleeding, and intracranial bleeding, compared with those who received DOACs (HR, 2.27, 1.72, 2.72, respectively).
• The risks of hospitalization for major bleeding, GI bleeding, and intracranial bleeding among patients who received warfarin and DOACs were similar (HR, 1.12, 1.03, 1.04, respectively).

IN PRACTICE:

Consistent with recent trials, “these data reinforce the general efficacy and safety of DOACs in this patient population” and reveal an association between DOACs and reduced all-cause mortality, the study authors wrote. These data may “help facilitate shared decision-marking and inform clinical guidelines for the treatment of such patients.”

SOURCE:

The study, led by Irbaz Bin Riaz, MD, PhD, of Mayo Clinic, Phoenix, Ariz., was published online in JAMA Network Open on July 24.

LIMITATIONS:

The study is limited by the potential for information bias in the database, the use of ICD codes to identify VTE patients, and the lack of radiologic evidence for VTE, as well as the lack of assessment for clinically relevant nonmajor bleeding.

The use of U.S. claims data limits the applicability of the results to other populations, including the uninsured.
 

DISCLOSURES:

No funding was declared. The authors have disclosed no relevant financial relationships.

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

TOPLINE:

Direct oral anticoagulants (DOACs) are associated with a reduced risk of venous thromboembolism (VTE), major bleeding, and mortality for cancer patients with VTE in comparison with low-molecular-weight heparin (LMWH), according to a recent analysis of U.S. claims data.

METHODOLOGY:

• This retrospective cohort study of electronic records claims data from OptumLabs included adults with an active primary cancer and acute VTE.
• Patients had filled an anticoagulation prescription within 30 days of VTE onset and were categorized on the basis of the anticoagulant prescribed: DOAC, LMWH, or warfarin.
• Patients were followed until the end of treatment. VTE recurrence and all-cause mortality were the main efficacy endpoints, and major bleeding episodes and bleeding sites were the main safety endpoints.
• Overall, 5,100 patients were included (mean age, 66.3 years); a majority (69.8%) were White, 15.7% were Black, and 7.6% were Hispanic. The patients had a range of cancer types, including lung, colorectal, gynecologic, and urologic.
• Nearly half of patients (49.3%) filled prescriptions for DOACs, 29.2% for LMWH, and 28.6% for warfarin.

TAKEAWAY:

• Compared with DOACs, LMWH and warfarin were associated with an increased risk of VTE recurrence (hazard ratio, 1.47 and 1.46, respectively).
• LMWH use was associated with an increased risk of major bleeding (HR, 2.27) and all-cause mortality (HR, 1.61), compared with DOAC use; mortality rates did not differ significantly between warfarin and DOACs (HR, 1.19; 95% confidence interval, 0.85-1.68).
• Patients who received LMWH were at increased risk of hospitalization for major bleeding, GI bleeding, and intracranial bleeding, compared with those who received DOACs (HR, 2.27, 1.72, 2.72, respectively).
• The risks of hospitalization for major bleeding, GI bleeding, and intracranial bleeding among patients who received warfarin and DOACs were similar (HR, 1.12, 1.03, 1.04, respectively).

IN PRACTICE:

Consistent with recent trials, “these data reinforce the general efficacy and safety of DOACs in this patient population” and reveal an association between DOACs and reduced all-cause mortality, the study authors wrote. These data may “help facilitate shared decision-marking and inform clinical guidelines for the treatment of such patients.”

SOURCE:

The study, led by Irbaz Bin Riaz, MD, PhD, of Mayo Clinic, Phoenix, Ariz., was published online in JAMA Network Open on July 24.

LIMITATIONS:

The study is limited by the potential for information bias in the database, the use of ICD codes to identify VTE patients, and the lack of radiologic evidence for VTE, as well as the lack of assessment for clinically relevant nonmajor bleeding.

The use of U.S. claims data limits the applicability of the results to other populations, including the uninsured.
 

DISCLOSURES:

No funding was declared. The authors have disclosed no relevant financial relationships.

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

Retinal thickness may be a potential biomarker for predicting disability for patients newly diagnosed with relapsing multiple sclerosis (MS), new research suggests.

The researchers measured retinal thickness using optical coherence tomography (OCT) within 3 months of diagnosis for more than 230 patients with MS and found that thinning of the retina was associated with a more than fourfold increased risk of Expanded Disability Status Scale (EDSS) scores of at least 3.0.

The OCT “basically tells you how much nerve layer is left in the glass,” said study investigator Gabriel Bsteh, MD, PhD, department of neurology, Medical University of Vienna.

This “could potentially inform treatment strategies, but that is another direction which will be investigated hopefully in the near future,” he added. However, the imaging technique cannot be used for all patients and is currently not widely available.

Dr. Bsteh presented the results at the annual meeting of the European Academy of Neurology.


 

Retinal layers of interest

OCT produces images of the retina and measures its thickness, Dr. Bsteh explained. Of greatest interest and relevance to patients with MS are two layers – the peripapillary retinal nerve fiber layer (pRNFL) and the ganglion cell and inner plexiform layer (GCL), which are associated with “future physical and cognitive disability and brain atrophy, and are reliable biomarkers of axonal damage.”

However, he said, what is not yet known is whether the baseline thickness of these two layers independently predicts progression of disability in patients with newly diagnosed disease within the framework of all of the other known risk factors.

To investigate, the team used data from ViennOCTiMS, an ongoing prospective observational cohort study conducted in Vienna and Innsbruck. For the analysis, they included patients newly diagnosed with relapsing MS using the 2017 McDonald criteria.

Study participants were required to undergo a spectral-domain OCT scan within 90 days of diagnosis and within 270 days of symptom onset. They also had to undergo follow-up of at least 12 months.

Among 231 patients included in the study, 74 were female, and the mean age was 30.3 years.

Dr. Bsteh noted that disease duration was short. There was a median of 45 days between initial diagnosis and the OCT scan. The median number of T2 lesions on MRI was 11, with 59.3% of patients had at least 10 lesions.

At baseline, 13.0% of patients were not receiving drug therapy, although they were advised to do so, said Dr. Bsteh. A total of 59.7% of patients received “moderately effective” disease-modifying treatments, while 27.3% were treated with “highly effective” DMTs.
 

Independent predictors of disability

To determine the contribution of retinal thickness to the risk of developing EDSS of 3.0 or more, the researchers conducted a multivariate analysis that accounted for patient age and sex, the type of first relapse, the remission of first relapse symptoms, the presence of oligoclonal bands, the baseline number of T2 lesions, and the use and type of DMT.

After approximately 96 months of follow-up, a pRNFL thickness of 88 mcm or less at baseline was associated with a hazard ratio for EDSS of at least 3.0 versus a thickness of greater than 88 mcm of 4.0 (P < .001), Dr. Bsteh reported.

Similarly, a GCL thickness of less than 77 mcm at baseline was associated with a HR for EDSS of at least 3.0 of 5.1 (P < .001).

Subgroup analysis indicated that both measures of retinal thickness were indeed independent predictors of EDSS. Dr. Bsteh said: “It was encouraging to see that all the unknown prognostic factor factors performed within the expected framework.”

For example, there was a notable association between the risk of EDSS of at least 3.0 and patient age, as well as with incomplete remission and a greater number of lesions on MRI.

Dr. Bsteh said it was also “very encouraging” to find that high-efficacy DMT was associated with a reduced risk of EDSS of at least 3.0.
 

Strengths, limitations

Turning to the relatively recently described progression independent of relapse activity, Dr. Bsteh showed that both pRNFL of 88 mcm or less and GCL less than 77 mcm were significantly associated with the development of PIRA, compared with greater thickness, at HRs of 3.1 and 4.1, respectively (P < .001 for both).

Subgroup analysis again supported the independent contribution of retinal thickness to the risk of PIRA and revealed similar associations with known risk factors, although the contribution of highly effective DMT was of borderline significance for this outcome.

Interestingly, neither pRNFL of 88 mcm or less nor GCL less than 77 mcm was significantly associated with the time to second clinical attack, “which is basically the correlation of the inflammatory activity” in MS, said Dr. Bsteh.

This, he continued, “goes back to the basic theory that EDSS, PIRA, and neurodegenerative problems are associated with the OCT but not the degree of inflammatory activity.

“As good as all that sounds, there are of course, some limitations” to the study, Dr. Bsteh acknowledged.

The most important limitation is that the changes measured on OCT were “not specific to multiple sclerosis,” and the thickness of the layers “can be influenced by a lot of other factors,” in particular by eye conditions such as glaucoma and diabetes mellitus.

In addition, OCT is not reliable for patients with myopia of more than four to six diopters and for those with retinal comorbidities, such as optic drusen. Dr. Bsteh also pointed out that automatic segmentation in OCT requires stringent quality control.

However, the “biggest problem for the deployment of OCT in the clinical routine is its lack of availability. It’s not very easy for neurologists to procure an OCT,” said Dr. Bsteh.

“You can always create it with your ophthalmologist of trust, but you have to know what you’re looking for,” he added.
 

Important research

Commenting on the study, Giancarlo Comi, MD, honorary professor of neurology at the Università Vita Salute San Raffaele and founder and director of the Institute of Experimental Neurology at the Scientific Institute San Raffaele, both in Milan, characterized the research as “very, very important and interesting.”

However, he said that he was a “bit surprised” that it showed no association between OCT measures and the second clinical attack, noting that longitudinal research by his team found such an association.

Dr. Comi added that the “key point” from the current study is that there was no such association in the early phase of the disease, which suggests that the amount of inflammatory activity “is not so relevant” in determining the degree of damage seen on OCT at that point.

Dr. Bsteh said he partially agreed with Dr. Comi, adding that “it depends on what you adjust for.

“If we did the same analysis without adjusting for the number of MRI lesions, we would see an association with second clinical attack,” he said. However, the aim of the current study was to determine the independent contribution of retinal thickness, “and that’s why we tried to adjust to everything which was available to us.”

Dr. Bsteh also underlined that it was a cross-sectional analysis conducted “very, very early” in the MS disease course, and “so the inflammatory activity did not yet have a chance to influence the thickness on the OCT.”

Had OCT been performed later in the disease course, inflammatory activity might have influenced the findings, but the intention of the study was to use it “as an early marker to try to stratify patients who are at risk, and [those] who are maybe a little less at risk, and inform the treatment strategy.”

Maria Assunta Rocca, MD, associate professor of neurology at Università Vita Salute San Raffaele, and head of neuroimaging of the CNS white matter unit at IRCCS San Raffaele Scientific Institute, Milan, who cochaired the session in which the study was presented, asked whether the researchers analyzed patients with optic neuritis separately from those without and whether it affected the predictive factors.

Dr. Bsteh said that OCT cannot be used for patients with bilateral optic neuritis and so they were excluded from the study, but for patients who were affected unilaterally, the contralateral eye was assessed.

This underlines why OCT contributes the most when used early on the disease course. “The longer the disease has time, the higher the likelihood that optic neuritis has developed,” he said.

Funding for the study was provided by Mindset Technologies. All authors are, or were, employees and/or shareholders of Mindset Technologies. Dr. Bsteh has relationships with Biogen, Celgene/Bristol-Myers Squibb, Lilly, Merck, Novartis, Roche, Sanofi Genzyme, and Teva.

A version of this article appeared on Medscape.com.

Retinal thickness may be a potential biomarker for predicting disability for patients newly diagnosed with relapsing multiple sclerosis (MS), new research suggests.

The researchers measured retinal thickness using optical coherence tomography (OCT) within 3 months of diagnosis for more than 230 patients with MS and found that thinning of the retina was associated with a more than fourfold increased risk of Expanded Disability Status Scale (EDSS) scores of at least 3.0.

The OCT “basically tells you how much nerve layer is left in the glass,” said study investigator Gabriel Bsteh, MD, PhD, department of neurology, Medical University of Vienna.

This “could potentially inform treatment strategies, but that is another direction which will be investigated hopefully in the near future,” he added. However, the imaging technique cannot be used for all patients and is currently not widely available.

Dr. Bsteh presented the results at the annual meeting of the European Academy of Neurology.


 

Retinal layers of interest

OCT produces images of the retina and measures its thickness, Dr. Bsteh explained. Of greatest interest and relevance to patients with MS are two layers – the peripapillary retinal nerve fiber layer (pRNFL) and the ganglion cell and inner plexiform layer (GCL), which are associated with “future physical and cognitive disability and brain atrophy, and are reliable biomarkers of axonal damage.”

However, he said, what is not yet known is whether the baseline thickness of these two layers independently predicts progression of disability in patients with newly diagnosed disease within the framework of all of the other known risk factors.

To investigate, the team used data from ViennOCTiMS, an ongoing prospective observational cohort study conducted in Vienna and Innsbruck. For the analysis, they included patients newly diagnosed with relapsing MS using the 2017 McDonald criteria.

Study participants were required to undergo a spectral-domain OCT scan within 90 days of diagnosis and within 270 days of symptom onset. They also had to undergo follow-up of at least 12 months.

Among 231 patients included in the study, 74 were female, and the mean age was 30.3 years.

Dr. Bsteh noted that disease duration was short. There was a median of 45 days between initial diagnosis and the OCT scan. The median number of T2 lesions on MRI was 11, with 59.3% of patients had at least 10 lesions.

At baseline, 13.0% of patients were not receiving drug therapy, although they were advised to do so, said Dr. Bsteh. A total of 59.7% of patients received “moderately effective” disease-modifying treatments, while 27.3% were treated with “highly effective” DMTs.
 

Independent predictors of disability

To determine the contribution of retinal thickness to the risk of developing EDSS of 3.0 or more, the researchers conducted a multivariate analysis that accounted for patient age and sex, the type of first relapse, the remission of first relapse symptoms, the presence of oligoclonal bands, the baseline number of T2 lesions, and the use and type of DMT.

After approximately 96 months of follow-up, a pRNFL thickness of 88 mcm or less at baseline was associated with a hazard ratio for EDSS of at least 3.0 versus a thickness of greater than 88 mcm of 4.0 (P < .001), Dr. Bsteh reported.

Similarly, a GCL thickness of less than 77 mcm at baseline was associated with a HR for EDSS of at least 3.0 of 5.1 (P < .001).

Subgroup analysis indicated that both measures of retinal thickness were indeed independent predictors of EDSS. Dr. Bsteh said: “It was encouraging to see that all the unknown prognostic factor factors performed within the expected framework.”

For example, there was a notable association between the risk of EDSS of at least 3.0 and patient age, as well as with incomplete remission and a greater number of lesions on MRI.

Dr. Bsteh said it was also “very encouraging” to find that high-efficacy DMT was associated with a reduced risk of EDSS of at least 3.0.
 

Strengths, limitations

Turning to the relatively recently described progression independent of relapse activity, Dr. Bsteh showed that both pRNFL of 88 mcm or less and GCL less than 77 mcm were significantly associated with the development of PIRA, compared with greater thickness, at HRs of 3.1 and 4.1, respectively (P < .001 for both).

Subgroup analysis again supported the independent contribution of retinal thickness to the risk of PIRA and revealed similar associations with known risk factors, although the contribution of highly effective DMT was of borderline significance for this outcome.

Interestingly, neither pRNFL of 88 mcm or less nor GCL less than 77 mcm was significantly associated with the time to second clinical attack, “which is basically the correlation of the inflammatory activity” in MS, said Dr. Bsteh.

This, he continued, “goes back to the basic theory that EDSS, PIRA, and neurodegenerative problems are associated with the OCT but not the degree of inflammatory activity.

“As good as all that sounds, there are of course, some limitations” to the study, Dr. Bsteh acknowledged.

The most important limitation is that the changes measured on OCT were “not specific to multiple sclerosis,” and the thickness of the layers “can be influenced by a lot of other factors,” in particular by eye conditions such as glaucoma and diabetes mellitus.

In addition, OCT is not reliable for patients with myopia of more than four to six diopters and for those with retinal comorbidities, such as optic drusen. Dr. Bsteh also pointed out that automatic segmentation in OCT requires stringent quality control.

However, the “biggest problem for the deployment of OCT in the clinical routine is its lack of availability. It’s not very easy for neurologists to procure an OCT,” said Dr. Bsteh.

“You can always create it with your ophthalmologist of trust, but you have to know what you’re looking for,” he added.
 

Important research

Commenting on the study, Giancarlo Comi, MD, honorary professor of neurology at the Università Vita Salute San Raffaele and founder and director of the Institute of Experimental Neurology at the Scientific Institute San Raffaele, both in Milan, characterized the research as “very, very important and interesting.”

However, he said that he was a “bit surprised” that it showed no association between OCT measures and the second clinical attack, noting that longitudinal research by his team found such an association.

Dr. Comi added that the “key point” from the current study is that there was no such association in the early phase of the disease, which suggests that the amount of inflammatory activity “is not so relevant” in determining the degree of damage seen on OCT at that point.

Dr. Bsteh said he partially agreed with Dr. Comi, adding that “it depends on what you adjust for.

“If we did the same analysis without adjusting for the number of MRI lesions, we would see an association with second clinical attack,” he said. However, the aim of the current study was to determine the independent contribution of retinal thickness, “and that’s why we tried to adjust to everything which was available to us.”

Dr. Bsteh also underlined that it was a cross-sectional analysis conducted “very, very early” in the MS disease course, and “so the inflammatory activity did not yet have a chance to influence the thickness on the OCT.”

Had OCT been performed later in the disease course, inflammatory activity might have influenced the findings, but the intention of the study was to use it “as an early marker to try to stratify patients who are at risk, and [those] who are maybe a little less at risk, and inform the treatment strategy.”

Maria Assunta Rocca, MD, associate professor of neurology at Università Vita Salute San Raffaele, and head of neuroimaging of the CNS white matter unit at IRCCS San Raffaele Scientific Institute, Milan, who cochaired the session in which the study was presented, asked whether the researchers analyzed patients with optic neuritis separately from those without and whether it affected the predictive factors.

Dr. Bsteh said that OCT cannot be used for patients with bilateral optic neuritis and so they were excluded from the study, but for patients who were affected unilaterally, the contralateral eye was assessed.

This underlines why OCT contributes the most when used early on the disease course. “The longer the disease has time, the higher the likelihood that optic neuritis has developed,” he said.

Funding for the study was provided by Mindset Technologies. All authors are, or were, employees and/or shareholders of Mindset Technologies. Dr. Bsteh has relationships with Biogen, Celgene/Bristol-Myers Squibb, Lilly, Merck, Novartis, Roche, Sanofi Genzyme, and Teva.

A version of this article appeared on Medscape.com.

Retinal thickness may be a potential biomarker for predicting disability for patients newly diagnosed with relapsing multiple sclerosis (MS), new research suggests.

The researchers measured retinal thickness using optical coherence tomography (OCT) within 3 months of diagnosis for more than 230 patients with MS and found that thinning of the retina was associated with a more than fourfold increased risk of Expanded Disability Status Scale (EDSS) scores of at least 3.0.

The OCT “basically tells you how much nerve layer is left in the glass,” said study investigator Gabriel Bsteh, MD, PhD, department of neurology, Medical University of Vienna.

This “could potentially inform treatment strategies, but that is another direction which will be investigated hopefully in the near future,” he added. However, the imaging technique cannot be used for all patients and is currently not widely available.

Dr. Bsteh presented the results at the annual meeting of the European Academy of Neurology.


 

Retinal layers of interest

OCT produces images of the retina and measures its thickness, Dr. Bsteh explained. Of greatest interest and relevance to patients with MS are two layers – the peripapillary retinal nerve fiber layer (pRNFL) and the ganglion cell and inner plexiform layer (GCL), which are associated with “future physical and cognitive disability and brain atrophy, and are reliable biomarkers of axonal damage.”

However, he said, what is not yet known is whether the baseline thickness of these two layers independently predicts progression of disability in patients with newly diagnosed disease within the framework of all of the other known risk factors.

To investigate, the team used data from ViennOCTiMS, an ongoing prospective observational cohort study conducted in Vienna and Innsbruck. For the analysis, they included patients newly diagnosed with relapsing MS using the 2017 McDonald criteria.

Study participants were required to undergo a spectral-domain OCT scan within 90 days of diagnosis and within 270 days of symptom onset. They also had to undergo follow-up of at least 12 months.

Among 231 patients included in the study, 74 were female, and the mean age was 30.3 years.

Dr. Bsteh noted that disease duration was short. There was a median of 45 days between initial diagnosis and the OCT scan. The median number of T2 lesions on MRI was 11, with 59.3% of patients had at least 10 lesions.

At baseline, 13.0% of patients were not receiving drug therapy, although they were advised to do so, said Dr. Bsteh. A total of 59.7% of patients received “moderately effective” disease-modifying treatments, while 27.3% were treated with “highly effective” DMTs.
 

Independent predictors of disability

To determine the contribution of retinal thickness to the risk of developing EDSS of 3.0 or more, the researchers conducted a multivariate analysis that accounted for patient age and sex, the type of first relapse, the remission of first relapse symptoms, the presence of oligoclonal bands, the baseline number of T2 lesions, and the use and type of DMT.

After approximately 96 months of follow-up, a pRNFL thickness of 88 mcm or less at baseline was associated with a hazard ratio for EDSS of at least 3.0 versus a thickness of greater than 88 mcm of 4.0 (P < .001), Dr. Bsteh reported.

Similarly, a GCL thickness of less than 77 mcm at baseline was associated with a HR for EDSS of at least 3.0 of 5.1 (P < .001).

Subgroup analysis indicated that both measures of retinal thickness were indeed independent predictors of EDSS. Dr. Bsteh said: “It was encouraging to see that all the unknown prognostic factor factors performed within the expected framework.”

For example, there was a notable association between the risk of EDSS of at least 3.0 and patient age, as well as with incomplete remission and a greater number of lesions on MRI.

Dr. Bsteh said it was also “very encouraging” to find that high-efficacy DMT was associated with a reduced risk of EDSS of at least 3.0.
 

Strengths, limitations

Turning to the relatively recently described progression independent of relapse activity, Dr. Bsteh showed that both pRNFL of 88 mcm or less and GCL less than 77 mcm were significantly associated with the development of PIRA, compared with greater thickness, at HRs of 3.1 and 4.1, respectively (P < .001 for both).

Subgroup analysis again supported the independent contribution of retinal thickness to the risk of PIRA and revealed similar associations with known risk factors, although the contribution of highly effective DMT was of borderline significance for this outcome.

Interestingly, neither pRNFL of 88 mcm or less nor GCL less than 77 mcm was significantly associated with the time to second clinical attack, “which is basically the correlation of the inflammatory activity” in MS, said Dr. Bsteh.

This, he continued, “goes back to the basic theory that EDSS, PIRA, and neurodegenerative problems are associated with the OCT but not the degree of inflammatory activity.

“As good as all that sounds, there are of course, some limitations” to the study, Dr. Bsteh acknowledged.

The most important limitation is that the changes measured on OCT were “not specific to multiple sclerosis,” and the thickness of the layers “can be influenced by a lot of other factors,” in particular by eye conditions such as glaucoma and diabetes mellitus.

In addition, OCT is not reliable for patients with myopia of more than four to six diopters and for those with retinal comorbidities, such as optic drusen. Dr. Bsteh also pointed out that automatic segmentation in OCT requires stringent quality control.

However, the “biggest problem for the deployment of OCT in the clinical routine is its lack of availability. It’s not very easy for neurologists to procure an OCT,” said Dr. Bsteh.

“You can always create it with your ophthalmologist of trust, but you have to know what you’re looking for,” he added.
 

Important research

Commenting on the study, Giancarlo Comi, MD, honorary professor of neurology at the Università Vita Salute San Raffaele and founder and director of the Institute of Experimental Neurology at the Scientific Institute San Raffaele, both in Milan, characterized the research as “very, very important and interesting.”

However, he said that he was a “bit surprised” that it showed no association between OCT measures and the second clinical attack, noting that longitudinal research by his team found such an association.

Dr. Comi added that the “key point” from the current study is that there was no such association in the early phase of the disease, which suggests that the amount of inflammatory activity “is not so relevant” in determining the degree of damage seen on OCT at that point.

Dr. Bsteh said he partially agreed with Dr. Comi, adding that “it depends on what you adjust for.

“If we did the same analysis without adjusting for the number of MRI lesions, we would see an association with second clinical attack,” he said. However, the aim of the current study was to determine the independent contribution of retinal thickness, “and that’s why we tried to adjust to everything which was available to us.”

Dr. Bsteh also underlined that it was a cross-sectional analysis conducted “very, very early” in the MS disease course, and “so the inflammatory activity did not yet have a chance to influence the thickness on the OCT.”

Had OCT been performed later in the disease course, inflammatory activity might have influenced the findings, but the intention of the study was to use it “as an early marker to try to stratify patients who are at risk, and [those] who are maybe a little less at risk, and inform the treatment strategy.”

Maria Assunta Rocca, MD, associate professor of neurology at Università Vita Salute San Raffaele, and head of neuroimaging of the CNS white matter unit at IRCCS San Raffaele Scientific Institute, Milan, who cochaired the session in which the study was presented, asked whether the researchers analyzed patients with optic neuritis separately from those without and whether it affected the predictive factors.

Dr. Bsteh said that OCT cannot be used for patients with bilateral optic neuritis and so they were excluded from the study, but for patients who were affected unilaterally, the contralateral eye was assessed.

This underlines why OCT contributes the most when used early on the disease course. “The longer the disease has time, the higher the likelihood that optic neuritis has developed,” he said.

Funding for the study was provided by Mindset Technologies. All authors are, or were, employees and/or shareholders of Mindset Technologies. Dr. Bsteh has relationships with Biogen, Celgene/Bristol-Myers Squibb, Lilly, Merck, Novartis, Roche, Sanofi Genzyme, and Teva.

A version of this article appeared on Medscape.com.

An unapproved gene therapy for Leber hereditary optic neuropathy (LHON) led to a marked improvement in the eyesight of patients with a severe, progressive form of the disease who received the therapy as part of an early access program.

Results of a study of more than 60 patients who received lenadogene nolparvovec (Lumevoq, GenSight Biologics) as a unilateral or bilateral intravitreal injection showed that at 2-year follow-up, 60% had experienced a clinically relevant improvement in the number of letters they could read on a visual acuity chart.

The results, said study presenter Chiara La Morgia, MD, PhD, IRCCS Istituto delle Scienze Neurologiche di Bologna (Italy), confirm in a “real-life setting” the efficacy and safety of the treatment as previously shown in clinical trials.

The findings were presented at the Congress of the European Academy of Neurology (EAN) 2023.
 

Severe disease

LHON is a maternally inherited genetic condition that leads to rapid loss of vision. It is caused by alterations in mitochondrial DNA that increase oxidative stress in retinal ganglion cells, leading to cell damage and death. The m.11778G>A MT-ND4 mutation (MT-ND4-LHON) is the most common and is seen in approximately 75% of LHON patients in Europe and North America.

It also leads to the most severe form of the disease, in which patients experience rapid, progressive, and painless bilateral loss of vision, either simultaneously or sequentially in both eyes. Within 1 year of onset, 97% of patients have bilateral involvement.

Lenadogene nolparvovec uses an adeno-associated virus vector to deliver the wild-type ND4 gene directly to the mitochondrial membrane of the retinal ganglion cells. This compensates for the mutation and leads to protein synthesis and restoration of energy production.

Dr. La Morgia said that, so far, five clinical studies are or have been conducted with the gene therapy with patients in France, Italy, the United Kingdom, and the United States.

In the current analysis, patients who received the therapy as part of an early access program underwent unilateral or bilateral intravitreal injection at a dose of 9x10¹⁰ viral genomes per eye. Efficacy and safety data, as well as patient baseline characteristics, were collected.

Between August 2018 and March 2022, 63 patients with MT-ND4-LHON received lenadogene nolparvovec. Individual-level data were pooled and analyzed. The mean age at first injection was 33.7 years; 90.5% of participants were aged 60 years or younger. The majority (77.8%) were male; just over half (55.6%) were from France, while 28.6% were from the United States.

The average disease duration at first injection was 11.3 years. Sixty-seven percent of patients were injected in both eyes, and 81.0% had previously received idebenone, a short-chain benzoquinone, the only treatment for LHON that has marketing authorization.

At 2-year follow-up, there was a marked improvement in best-corrected visual acuity (BCVA) scores. Moreover, among all 90 treated eyes for which data were available, the mean change in BCVA from nadir at 1 year was –0.45 log of the minimum angle of resolution (LogMAR), or +22.5 Early Treatment Diabetic Retinopathy Study (ETDRS) letters on a chart.

Among 58 bilaterally treated eyes, the mean improvement was –0.49 LogMAR, or +24.5 ETDRS letters, over the same period. In 32 unilaterally treated eyes, mean improvement was –0.39 LogMAR, or +19.5 ETDRS letters.

Overall, 64.4% of treated eyes showed an improvement from nadir of ≥ 0.3 LogMAR. A clinically relevant response, defined as an improvement of ≥ 10 ETDRS letters, was achieved by 60.0% of patients.

Regarding safety, Dr. La Morgia showed that 42.9% of eyes had at least one episode of intraocular inflammation, a rate she described as “quite high.” The episodes lasted for an average of 155.8 days.

“But all of this inflammation was very easily treatable in a majority of cases without using oral steroids,” she added, “just topical steroids.”

She also noted that in most cases, the inflammation was not severe.
 

Approval status

Session cochair Gianfranco De Stefano, MD, department of human neuroscience, Sapienza University of Rome, asked Dr. La Morgia about the current approval status of lenadogene nolparvovec.

She said that it was presented to the European Medicines Agency for approval, but the application was withdrawn earlier this year. The “main criticism” was that bilateral improvement was seen even in patients who received only a unilateral injection.

This is “not easily explainable,” said Dr. La Morgia, although it was found that the viral vector was present in the uninjected eye.

There was also a question regarding the heterogeneity of the patient data, which it is hoped will be addressed in future clinical trials.

Commenting after the session, De Stefano said in an interview that the results are “very interesting” and “very promising.”

He pointed out that idebenone may be the only currently available therapy for LHON, but it is “not very effective, and it’s something you give the patient just for the sake of doing something” in light of the possibility that he or she might have “even a small improvement” in eyesight.

However, he believes that lenadogene nolparvovec is a long way from becoming available in the clinic, primarily because longer follow-up is required to determine whether just one injection is enough.

“It may be likely that this gene therapy does not have a long-lasting effect,” he explained.

Currently, the longest follow-up is just 2 years; “I don’t know if there will be a need for repeat injection,” De Stefano said.

No funding was declared. Dr. La Morgia has relationships with Chiesi Farmaceutici, GenSight Biologics, Regulatory Pharma Net, Thenewway, Santhera Pharmaceuticals, First Class srl, Biologix, Stoke Therapeutics, and Reneo.

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

An unapproved gene therapy for Leber hereditary optic neuropathy (LHON) led to a marked improvement in the eyesight of patients with a severe, progressive form of the disease who received the therapy as part of an early access program.

Results of a study of more than 60 patients who received lenadogene nolparvovec (Lumevoq, GenSight Biologics) as a unilateral or bilateral intravitreal injection showed that at 2-year follow-up, 60% had experienced a clinically relevant improvement in the number of letters they could read on a visual acuity chart.

The results, said study presenter Chiara La Morgia, MD, PhD, IRCCS Istituto delle Scienze Neurologiche di Bologna (Italy), confirm in a “real-life setting” the efficacy and safety of the treatment as previously shown in clinical trials.

The findings were presented at the Congress of the European Academy of Neurology (EAN) 2023.
 

Severe disease

LHON is a maternally inherited genetic condition that leads to rapid loss of vision. It is caused by alterations in mitochondrial DNA that increase oxidative stress in retinal ganglion cells, leading to cell damage and death. The m.11778G>A MT-ND4 mutation (MT-ND4-LHON) is the most common and is seen in approximately 75% of LHON patients in Europe and North America.

It also leads to the most severe form of the disease, in which patients experience rapid, progressive, and painless bilateral loss of vision, either simultaneously or sequentially in both eyes. Within 1 year of onset, 97% of patients have bilateral involvement.

Lenadogene nolparvovec uses an adeno-associated virus vector to deliver the wild-type ND4 gene directly to the mitochondrial membrane of the retinal ganglion cells. This compensates for the mutation and leads to protein synthesis and restoration of energy production.

Dr. La Morgia said that, so far, five clinical studies are or have been conducted with the gene therapy with patients in France, Italy, the United Kingdom, and the United States.

In the current analysis, patients who received the therapy as part of an early access program underwent unilateral or bilateral intravitreal injection at a dose of 9x10¹⁰ viral genomes per eye. Efficacy and safety data, as well as patient baseline characteristics, were collected.

Between August 2018 and March 2022, 63 patients with MT-ND4-LHON received lenadogene nolparvovec. Individual-level data were pooled and analyzed. The mean age at first injection was 33.7 years; 90.5% of participants were aged 60 years or younger. The majority (77.8%) were male; just over half (55.6%) were from France, while 28.6% were from the United States.

The average disease duration at first injection was 11.3 years. Sixty-seven percent of patients were injected in both eyes, and 81.0% had previously received idebenone, a short-chain benzoquinone, the only treatment for LHON that has marketing authorization.

At 2-year follow-up, there was a marked improvement in best-corrected visual acuity (BCVA) scores. Moreover, among all 90 treated eyes for which data were available, the mean change in BCVA from nadir at 1 year was –0.45 log of the minimum angle of resolution (LogMAR), or +22.5 Early Treatment Diabetic Retinopathy Study (ETDRS) letters on a chart.

Among 58 bilaterally treated eyes, the mean improvement was –0.49 LogMAR, or +24.5 ETDRS letters, over the same period. In 32 unilaterally treated eyes, mean improvement was –0.39 LogMAR, or +19.5 ETDRS letters.

Overall, 64.4% of treated eyes showed an improvement from nadir of ≥ 0.3 LogMAR. A clinically relevant response, defined as an improvement of ≥ 10 ETDRS letters, was achieved by 60.0% of patients.

Regarding safety, Dr. La Morgia showed that 42.9% of eyes had at least one episode of intraocular inflammation, a rate she described as “quite high.” The episodes lasted for an average of 155.8 days.

“But all of this inflammation was very easily treatable in a majority of cases without using oral steroids,” she added, “just topical steroids.”

She also noted that in most cases, the inflammation was not severe.
 

Approval status

Session cochair Gianfranco De Stefano, MD, department of human neuroscience, Sapienza University of Rome, asked Dr. La Morgia about the current approval status of lenadogene nolparvovec.

She said that it was presented to the European Medicines Agency for approval, but the application was withdrawn earlier this year. The “main criticism” was that bilateral improvement was seen even in patients who received only a unilateral injection.

This is “not easily explainable,” said Dr. La Morgia, although it was found that the viral vector was present in the uninjected eye.

There was also a question regarding the heterogeneity of the patient data, which it is hoped will be addressed in future clinical trials.

Commenting after the session, De Stefano said in an interview that the results are “very interesting” and “very promising.”

He pointed out that idebenone may be the only currently available therapy for LHON, but it is “not very effective, and it’s something you give the patient just for the sake of doing something” in light of the possibility that he or she might have “even a small improvement” in eyesight.

However, he believes that lenadogene nolparvovec is a long way from becoming available in the clinic, primarily because longer follow-up is required to determine whether just one injection is enough.

“It may be likely that this gene therapy does not have a long-lasting effect,” he explained.

Currently, the longest follow-up is just 2 years; “I don’t know if there will be a need for repeat injection,” De Stefano said.

No funding was declared. Dr. La Morgia has relationships with Chiesi Farmaceutici, GenSight Biologics, Regulatory Pharma Net, Thenewway, Santhera Pharmaceuticals, First Class srl, Biologix, Stoke Therapeutics, and Reneo.

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

An unapproved gene therapy for Leber hereditary optic neuropathy (LHON) led to a marked improvement in the eyesight of patients with a severe, progressive form of the disease who received the therapy as part of an early access program.

Results of a study of more than 60 patients who received lenadogene nolparvovec (Lumevoq, GenSight Biologics) as a unilateral or bilateral intravitreal injection showed that at 2-year follow-up, 60% had experienced a clinically relevant improvement in the number of letters they could read on a visual acuity chart.

The results, said study presenter Chiara La Morgia, MD, PhD, IRCCS Istituto delle Scienze Neurologiche di Bologna (Italy), confirm in a “real-life setting” the efficacy and safety of the treatment as previously shown in clinical trials.

The findings were presented at the Congress of the European Academy of Neurology (EAN) 2023.
 

Severe disease

LHON is a maternally inherited genetic condition that leads to rapid loss of vision. It is caused by alterations in mitochondrial DNA that increase oxidative stress in retinal ganglion cells, leading to cell damage and death. The m.11778G>A MT-ND4 mutation (MT-ND4-LHON) is the most common and is seen in approximately 75% of LHON patients in Europe and North America.

It also leads to the most severe form of the disease, in which patients experience rapid, progressive, and painless bilateral loss of vision, either simultaneously or sequentially in both eyes. Within 1 year of onset, 97% of patients have bilateral involvement.

Lenadogene nolparvovec uses an adeno-associated virus vector to deliver the wild-type ND4 gene directly to the mitochondrial membrane of the retinal ganglion cells. This compensates for the mutation and leads to protein synthesis and restoration of energy production.

Dr. La Morgia said that, so far, five clinical studies are or have been conducted with the gene therapy with patients in France, Italy, the United Kingdom, and the United States.

In the current analysis, patients who received the therapy as part of an early access program underwent unilateral or bilateral intravitreal injection at a dose of 9x10¹⁰ viral genomes per eye. Efficacy and safety data, as well as patient baseline characteristics, were collected.

Between August 2018 and March 2022, 63 patients with MT-ND4-LHON received lenadogene nolparvovec. Individual-level data were pooled and analyzed. The mean age at first injection was 33.7 years; 90.5% of participants were aged 60 years or younger. The majority (77.8%) were male; just over half (55.6%) were from France, while 28.6% were from the United States.

The average disease duration at first injection was 11.3 years. Sixty-seven percent of patients were injected in both eyes, and 81.0% had previously received idebenone, a short-chain benzoquinone, the only treatment for LHON that has marketing authorization.

At 2-year follow-up, there was a marked improvement in best-corrected visual acuity (BCVA) scores. Moreover, among all 90 treated eyes for which data were available, the mean change in BCVA from nadir at 1 year was –0.45 log of the minimum angle of resolution (LogMAR), or +22.5 Early Treatment Diabetic Retinopathy Study (ETDRS) letters on a chart.

Among 58 bilaterally treated eyes, the mean improvement was –0.49 LogMAR, or +24.5 ETDRS letters, over the same period. In 32 unilaterally treated eyes, mean improvement was –0.39 LogMAR, or +19.5 ETDRS letters.

Overall, 64.4% of treated eyes showed an improvement from nadir of ≥ 0.3 LogMAR. A clinically relevant response, defined as an improvement of ≥ 10 ETDRS letters, was achieved by 60.0% of patients.

Regarding safety, Dr. La Morgia showed that 42.9% of eyes had at least one episode of intraocular inflammation, a rate she described as “quite high.” The episodes lasted for an average of 155.8 days.

“But all of this inflammation was very easily treatable in a majority of cases without using oral steroids,” she added, “just topical steroids.”

She also noted that in most cases, the inflammation was not severe.
 

Approval status

Session cochair Gianfranco De Stefano, MD, department of human neuroscience, Sapienza University of Rome, asked Dr. La Morgia about the current approval status of lenadogene nolparvovec.

She said that it was presented to the European Medicines Agency for approval, but the application was withdrawn earlier this year. The “main criticism” was that bilateral improvement was seen even in patients who received only a unilateral injection.

This is “not easily explainable,” said Dr. La Morgia, although it was found that the viral vector was present in the uninjected eye.

There was also a question regarding the heterogeneity of the patient data, which it is hoped will be addressed in future clinical trials.

Commenting after the session, De Stefano said in an interview that the results are “very interesting” and “very promising.”

He pointed out that idebenone may be the only currently available therapy for LHON, but it is “not very effective, and it’s something you give the patient just for the sake of doing something” in light of the possibility that he or she might have “even a small improvement” in eyesight.

However, he believes that lenadogene nolparvovec is a long way from becoming available in the clinic, primarily because longer follow-up is required to determine whether just one injection is enough.

“It may be likely that this gene therapy does not have a long-lasting effect,” he explained.

Currently, the longest follow-up is just 2 years; “I don’t know if there will be a need for repeat injection,” De Stefano said.

No funding was declared. Dr. La Morgia has relationships with Chiesi Farmaceutici, GenSight Biologics, Regulatory Pharma Net, Thenewway, Santhera Pharmaceuticals, First Class srl, Biologix, Stoke Therapeutics, and Reneo.

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

TOPLINE:

Patients with early-stage breast cancer who do not adhere to adjuvant endocrine therapy as prescribed or stop early may face as much as a twofold higher risk of relapse or death, a new systematic review found.

METHODOLOGY:

• The investigators conducted a systematic literature search of five databases, looking for studies involving patients with nonmetastatic hormone receptor–positive breast cancer that were published between 2010 and 2020.
• Adequate adherence was defined as a medical possession ratio – the percentage of days the prescribed treatment dose of adjuvant endocrine therapy was available to the patient – of at least 80%.
• Medication nonpersistence was defined as a period in which no new adjuvant endocrine therapy prescriptions were filled before the scheduled end of treatment of 90-180 days, depending on the study.
• The impact of both parameters on event-free survival, which included breast cancer recurrence, disease-free survival, breast cancer–specific survival, and overall survival cancer was calculated.
• Of 2,026 articles retrieved, 14 studies, with sample sizes ranging from 857 to 30,573 patients, met the eligibility and quality criteria; 11 examined patient adherence, and 6 examined patient persistence.

TAKEAWAY:

• Of 10 studies that assessed event-free survival, 7 showed significantly worse survival for nonadherent or nonpersistent patients, at hazard ratios of 1.39-2.44.
• Of nine studies that examined overall survival, seven demonstrated a significantly higher risk for mortality in the groups with nonadherence and nonpersistence, at HRs of 1.26-2.18.
• The largest study, which included data on more than 30,000 patients in Taiwan, found that nonadherence and nonpersistence were associated with a significantly increased risk for mortality, at HRs of 1.98 and 2.18, respectively.

IN PRACTICE:

“The available data highlight the dangers of nonadherence and nonpersistence, showing an up to twofold higher risk of relapse or death for patients who do not use endocrine treatment as prescribed,” the researchers said. “Importantly, improving adherence and persistence represents a low-hanging fruit for increasing survival in luminal breast cancer.”

SOURCE:

The study, led by Finn Magnus Eliassen, MD, department of surgery, Stavanger (Norway) University Hospital, was published online on July 4 in BMC Cancer.

LIMITATIONS:

• The review is limited by the relatively small number of studies that met the eligibility criteria and by their heterogeneity, which ruled out a meta-analysis.
• There are no gold-standard definitions of adherence and persistence.

DISCLOSURES:

• No funding was declared. No relevant financial relationships were declared.
• A version of this article first appeared on Medscape.com.

TOPLINE:

Patients with early-stage breast cancer who do not adhere to adjuvant endocrine therapy as prescribed or stop early may face as much as a twofold higher risk of relapse or death, a new systematic review found.

METHODOLOGY:

• The investigators conducted a systematic literature search of five databases, looking for studies involving patients with nonmetastatic hormone receptor–positive breast cancer that were published between 2010 and 2020.
• Adequate adherence was defined as a medical possession ratio – the percentage of days the prescribed treatment dose of adjuvant endocrine therapy was available to the patient – of at least 80%.
• Medication nonpersistence was defined as a period in which no new adjuvant endocrine therapy prescriptions were filled before the scheduled end of treatment of 90-180 days, depending on the study.
• The impact of both parameters on event-free survival, which included breast cancer recurrence, disease-free survival, breast cancer–specific survival, and overall survival cancer was calculated.
• Of 2,026 articles retrieved, 14 studies, with sample sizes ranging from 857 to 30,573 patients, met the eligibility and quality criteria; 11 examined patient adherence, and 6 examined patient persistence.

TAKEAWAY:

• Of 10 studies that assessed event-free survival, 7 showed significantly worse survival for nonadherent or nonpersistent patients, at hazard ratios of 1.39-2.44.
• Of nine studies that examined overall survival, seven demonstrated a significantly higher risk for mortality in the groups with nonadherence and nonpersistence, at HRs of 1.26-2.18.
• The largest study, which included data on more than 30,000 patients in Taiwan, found that nonadherence and nonpersistence were associated with a significantly increased risk for mortality, at HRs of 1.98 and 2.18, respectively.

IN PRACTICE:

“The available data highlight the dangers of nonadherence and nonpersistence, showing an up to twofold higher risk of relapse or death for patients who do not use endocrine treatment as prescribed,” the researchers said. “Importantly, improving adherence and persistence represents a low-hanging fruit for increasing survival in luminal breast cancer.”

SOURCE:

The study, led by Finn Magnus Eliassen, MD, department of surgery, Stavanger (Norway) University Hospital, was published online on July 4 in BMC Cancer.

LIMITATIONS:

• The review is limited by the relatively small number of studies that met the eligibility criteria and by their heterogeneity, which ruled out a meta-analysis.
• There are no gold-standard definitions of adherence and persistence.

DISCLOSURES:

• No funding was declared. No relevant financial relationships were declared.
• A version of this article first appeared on Medscape.com.

TOPLINE:

Patients with early-stage breast cancer who do not adhere to adjuvant endocrine therapy as prescribed or stop early may face as much as a twofold higher risk of relapse or death, a new systematic review found.

METHODOLOGY:

• The investigators conducted a systematic literature search of five databases, looking for studies involving patients with nonmetastatic hormone receptor–positive breast cancer that were published between 2010 and 2020.
• Adequate adherence was defined as a medical possession ratio – the percentage of days the prescribed treatment dose of adjuvant endocrine therapy was available to the patient – of at least 80%.
• Medication nonpersistence was defined as a period in which no new adjuvant endocrine therapy prescriptions were filled before the scheduled end of treatment of 90-180 days, depending on the study.
• The impact of both parameters on event-free survival, which included breast cancer recurrence, disease-free survival, breast cancer–specific survival, and overall survival cancer was calculated.
• Of 2,026 articles retrieved, 14 studies, with sample sizes ranging from 857 to 30,573 patients, met the eligibility and quality criteria; 11 examined patient adherence, and 6 examined patient persistence.

TAKEAWAY:

• Of 10 studies that assessed event-free survival, 7 showed significantly worse survival for nonadherent or nonpersistent patients, at hazard ratios of 1.39-2.44.
• Of nine studies that examined overall survival, seven demonstrated a significantly higher risk for mortality in the groups with nonadherence and nonpersistence, at HRs of 1.26-2.18.
• The largest study, which included data on more than 30,000 patients in Taiwan, found that nonadherence and nonpersistence were associated with a significantly increased risk for mortality, at HRs of 1.98 and 2.18, respectively.

IN PRACTICE:

“The available data highlight the dangers of nonadherence and nonpersistence, showing an up to twofold higher risk of relapse or death for patients who do not use endocrine treatment as prescribed,” the researchers said. “Importantly, improving adherence and persistence represents a low-hanging fruit for increasing survival in luminal breast cancer.”

SOURCE:

The study, led by Finn Magnus Eliassen, MD, department of surgery, Stavanger (Norway) University Hospital, was published online on July 4 in BMC Cancer.

LIMITATIONS:

• The review is limited by the relatively small number of studies that met the eligibility criteria and by their heterogeneity, which ruled out a meta-analysis.
• There are no gold-standard definitions of adherence and persistence.

DISCLOSURES:

• No funding was declared. No relevant financial relationships were declared.
• A version of this article first appeared on Medscape.com.

Brain disorders, including mental illness, neurologic conditions, and stroke, account for more than 15% of all health loss worldwide – more than either cardiovascular disease or cancer – at huge cost to health care systems and society, an analysis of data from the most recent Global Burden of Disease (GBD) study shows.

“The burden of brain conditions will increase as populations continue to grow and age,” said study presenter Shayla Smith, MPH, an epidemiologist at the Institute for Health Metrics and Evaluation, the University of Washington, Seattle, in a press release.

“By 2050, more than 50 million people will be aged 65-79,” she explained, adding that the COVID-19 pandemic “has also influenced the prevalence of mental disorders globally, as people were forced to isolate and social networks broke down.”

Other factors related to brain disorders, she noted, include education level, obesity, and smoking.

“There’s still research to be done on what is the most effective way to maintain brain health, but some literature suggests a healthy brain can be achieved through a healthy lifestyle of managing conditions such as high blood pressure and diabetes, limiting alcohol consumption and smoking, prioritizing sleep, eating healthy, and staying physically and mentally active,” said Ms. Smith.

The findings were presented at the annual meeting of the Congress of the European Academy of Neurology.
 

An ‘ambitious exercise’

Coinvestigator Xaviera Steele, also from the IHME, told press conference attendees that the institute was established at the University of Washington in 2007 with the aim of “standardizing the measurement of health outcomes around the world and for all health conditions.”

A central part of that is the GBD study, “which is a very ambitious exercise in descriptive epidemiology in an effort to systematically quantify health loss” due to disease, injury, and risk factors over time, stratified by country, region, age, and sex. In addition, researchers are mapping and projecting trends over the next century and are estimating disease expenditure by country, by type of expense, and by condition “to derive a health care access and quality score for each health system in the world,” Ms. Steele said.

They are also estimating exposure to risk factors, how those risk factors contribute to health burden, and associated health outcomes by race and ethnicity to reflect the “disparities that we know are very prevalent in countries such as the United States.” From that work, Ms. Steele said that brain health and related conditions “do emerge as one of the more pressing challenges of the 21st century.”
 

Increase in dementia, mental health conditions

The data, which were gathered from 200,000 sources by the IHME, indicate that the number of individuals aged 65 years or older will increase by 350% by 2100. Ms. Steele underlined that “policy action will be needed to help families, who will struggle to provide high-quality care for their loved ones with dementia at a reasonable cost.”

The IHME calculates that in Europe health care spending on Alzheimer’s disease will increase by 226% between 2015 and 2040.

Turning to other conditions, Ms. Steele showed that since 1990, the number of individuals living with anxiety in the European region has increased by 14%, while the number living with depressive disorders has gone up by 13%.

Worldwide, the figures are even starker. Depression is estimated to affect 300 million people across the globe, which represents a 71% increase since 1990. The number of strokes increased by 95% over the same period.

Nevertheless, the “impact of brain conditions such as stroke has decreased since the 1990s due to improved treatments available,” Ms. Smith noted in the press release.

To estimate the toll caused by brain conditions, including neurologic disorders, mental disorders, cerebrovascular disease, brain cancer, brain injuries, and select infectious conditions, the researchers calculated disability-adjusted life years (DALYs).

This, Ms. Smith explained in her presentation, “captures the morbidity and mortality associated with brain conditions” and is adjusted for patient location, age, and sex.

The investigators found that, globally, brain conditions accounted for more than 15% of all health loss in 2021, at 406 DALYs – more than the 206 million DALYs that were associated with cancer, and the 402 million that were linked to cardiovascular disease.

This health loss is associated with a $1.22 trillion loss in income for people living with health disorders worldwide and accounts for $1.14 trillion in direct health care costs.

The burden of mental disorders, neurologic conditions, and stroke is expected to increase dramatically between now and 2050, said Ms. Smith, who noted that health loss linked to brain conditions is higher in younger patients. This will create “new challenges for health systems, employers, patients, and families,” she said in the press release.

“Our goal is to see an improved prevention and treatment landscape for other brain conditions and reverse the growing health loss that we are currently forecasting.”
 

Worrying increase in stroke

Jurgita Valaikiene, MD, PhD, center of neurology, clinic of neurology and neurosurgery, Vilnius (Lithuania) University Faculty of Medicine, who chaired the session, was taken aback by the findings, particularly by the worldwide increase in stroke cases.

“I work in stroke,” she said, and “we spend a lot of time on the diagnosis of stroke” and its prevention. “We try to be faster, to catch asymptomatic stenosis in the neck or head, and to apply the best medical treatment to avoid a stroke. But despite that, the numbers are increasing. I understand the population is getting older ... but still it’s a huge number.”

Dr. Valaikiene pointed out that stroke is not necessarily a condition of aging, insofar as increasing age “is not related directly to stenosis in the neck. “For example, we can have healthier vessels in older age and unhealthy vessels, with high-grade stenosis, in someone aged 30 or 40 years.”

“There are a lot of risk factors, such as smoking, physical activity, and so on. It depends on the individual,” she added.

The study was funded by the Institute for Health Metrics and Evaluation at the University of Washington. The authors have disclosed no relevant financial relationships.

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

Brain disorders, including mental illness, neurologic conditions, and stroke, account for more than 15% of all health loss worldwide – more than either cardiovascular disease or cancer – at huge cost to health care systems and society, an analysis of data from the most recent Global Burden of Disease (GBD) study shows.

“The burden of brain conditions will increase as populations continue to grow and age,” said study presenter Shayla Smith, MPH, an epidemiologist at the Institute for Health Metrics and Evaluation, the University of Washington, Seattle, in a press release.

“By 2050, more than 50 million people will be aged 65-79,” she explained, adding that the COVID-19 pandemic “has also influenced the prevalence of mental disorders globally, as people were forced to isolate and social networks broke down.”

Other factors related to brain disorders, she noted, include education level, obesity, and smoking.

“There’s still research to be done on what is the most effective way to maintain brain health, but some literature suggests a healthy brain can be achieved through a healthy lifestyle of managing conditions such as high blood pressure and diabetes, limiting alcohol consumption and smoking, prioritizing sleep, eating healthy, and staying physically and mentally active,” said Ms. Smith.

The findings were presented at the annual meeting of the Congress of the European Academy of Neurology.
 

An ‘ambitious exercise’

Coinvestigator Xaviera Steele, also from the IHME, told press conference attendees that the institute was established at the University of Washington in 2007 with the aim of “standardizing the measurement of health outcomes around the world and for all health conditions.”

A central part of that is the GBD study, “which is a very ambitious exercise in descriptive epidemiology in an effort to systematically quantify health loss” due to disease, injury, and risk factors over time, stratified by country, region, age, and sex. In addition, researchers are mapping and projecting trends over the next century and are estimating disease expenditure by country, by type of expense, and by condition “to derive a health care access and quality score for each health system in the world,” Ms. Steele said.

They are also estimating exposure to risk factors, how those risk factors contribute to health burden, and associated health outcomes by race and ethnicity to reflect the “disparities that we know are very prevalent in countries such as the United States.” From that work, Ms. Steele said that brain health and related conditions “do emerge as one of the more pressing challenges of the 21st century.”
 

Increase in dementia, mental health conditions

The data, which were gathered from 200,000 sources by the IHME, indicate that the number of individuals aged 65 years or older will increase by 350% by 2100. Ms. Steele underlined that “policy action will be needed to help families, who will struggle to provide high-quality care for their loved ones with dementia at a reasonable cost.”

The IHME calculates that in Europe health care spending on Alzheimer’s disease will increase by 226% between 2015 and 2040.

Turning to other conditions, Ms. Steele showed that since 1990, the number of individuals living with anxiety in the European region has increased by 14%, while the number living with depressive disorders has gone up by 13%.

Worldwide, the figures are even starker. Depression is estimated to affect 300 million people across the globe, which represents a 71% increase since 1990. The number of strokes increased by 95% over the same period.

Nevertheless, the “impact of brain conditions such as stroke has decreased since the 1990s due to improved treatments available,” Ms. Smith noted in the press release.

To estimate the toll caused by brain conditions, including neurologic disorders, mental disorders, cerebrovascular disease, brain cancer, brain injuries, and select infectious conditions, the researchers calculated disability-adjusted life years (DALYs).

This, Ms. Smith explained in her presentation, “captures the morbidity and mortality associated with brain conditions” and is adjusted for patient location, age, and sex.

The investigators found that, globally, brain conditions accounted for more than 15% of all health loss in 2021, at 406 DALYs – more than the 206 million DALYs that were associated with cancer, and the 402 million that were linked to cardiovascular disease.

This health loss is associated with a $1.22 trillion loss in income for people living with health disorders worldwide and accounts for $1.14 trillion in direct health care costs.

The burden of mental disorders, neurologic conditions, and stroke is expected to increase dramatically between now and 2050, said Ms. Smith, who noted that health loss linked to brain conditions is higher in younger patients. This will create “new challenges for health systems, employers, patients, and families,” she said in the press release.

“Our goal is to see an improved prevention and treatment landscape for other brain conditions and reverse the growing health loss that we are currently forecasting.”
 

Worrying increase in stroke

Jurgita Valaikiene, MD, PhD, center of neurology, clinic of neurology and neurosurgery, Vilnius (Lithuania) University Faculty of Medicine, who chaired the session, was taken aback by the findings, particularly by the worldwide increase in stroke cases.

“I work in stroke,” she said, and “we spend a lot of time on the diagnosis of stroke” and its prevention. “We try to be faster, to catch asymptomatic stenosis in the neck or head, and to apply the best medical treatment to avoid a stroke. But despite that, the numbers are increasing. I understand the population is getting older ... but still it’s a huge number.”

Dr. Valaikiene pointed out that stroke is not necessarily a condition of aging, insofar as increasing age “is not related directly to stenosis in the neck. “For example, we can have healthier vessels in older age and unhealthy vessels, with high-grade stenosis, in someone aged 30 or 40 years.”

“There are a lot of risk factors, such as smoking, physical activity, and so on. It depends on the individual,” she added.

The study was funded by the Institute for Health Metrics and Evaluation at the University of Washington. The authors have disclosed no relevant financial relationships.

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

Brain disorders, including mental illness, neurologic conditions, and stroke, account for more than 15% of all health loss worldwide – more than either cardiovascular disease or cancer – at huge cost to health care systems and society, an analysis of data from the most recent Global Burden of Disease (GBD) study shows.

“The burden of brain conditions will increase as populations continue to grow and age,” said study presenter Shayla Smith, MPH, an epidemiologist at the Institute for Health Metrics and Evaluation, the University of Washington, Seattle, in a press release.

“By 2050, more than 50 million people will be aged 65-79,” she explained, adding that the COVID-19 pandemic “has also influenced the prevalence of mental disorders globally, as people were forced to isolate and social networks broke down.”

Other factors related to brain disorders, she noted, include education level, obesity, and smoking.

“There’s still research to be done on what is the most effective way to maintain brain health, but some literature suggests a healthy brain can be achieved through a healthy lifestyle of managing conditions such as high blood pressure and diabetes, limiting alcohol consumption and smoking, prioritizing sleep, eating healthy, and staying physically and mentally active,” said Ms. Smith.

The findings were presented at the annual meeting of the Congress of the European Academy of Neurology.
 

An ‘ambitious exercise’

Coinvestigator Xaviera Steele, also from the IHME, told press conference attendees that the institute was established at the University of Washington in 2007 with the aim of “standardizing the measurement of health outcomes around the world and for all health conditions.”

A central part of that is the GBD study, “which is a very ambitious exercise in descriptive epidemiology in an effort to systematically quantify health loss” due to disease, injury, and risk factors over time, stratified by country, region, age, and sex. In addition, researchers are mapping and projecting trends over the next century and are estimating disease expenditure by country, by type of expense, and by condition “to derive a health care access and quality score for each health system in the world,” Ms. Steele said.

They are also estimating exposure to risk factors, how those risk factors contribute to health burden, and associated health outcomes by race and ethnicity to reflect the “disparities that we know are very prevalent in countries such as the United States.” From that work, Ms. Steele said that brain health and related conditions “do emerge as one of the more pressing challenges of the 21st century.”
 

Increase in dementia, mental health conditions

The data, which were gathered from 200,000 sources by the IHME, indicate that the number of individuals aged 65 years or older will increase by 350% by 2100. Ms. Steele underlined that “policy action will be needed to help families, who will struggle to provide high-quality care for their loved ones with dementia at a reasonable cost.”

The IHME calculates that in Europe health care spending on Alzheimer’s disease will increase by 226% between 2015 and 2040.

Turning to other conditions, Ms. Steele showed that since 1990, the number of individuals living with anxiety in the European region has increased by 14%, while the number living with depressive disorders has gone up by 13%.

Worldwide, the figures are even starker. Depression is estimated to affect 300 million people across the globe, which represents a 71% increase since 1990. The number of strokes increased by 95% over the same period.

Nevertheless, the “impact of brain conditions such as stroke has decreased since the 1990s due to improved treatments available,” Ms. Smith noted in the press release.

To estimate the toll caused by brain conditions, including neurologic disorders, mental disorders, cerebrovascular disease, brain cancer, brain injuries, and select infectious conditions, the researchers calculated disability-adjusted life years (DALYs).

This, Ms. Smith explained in her presentation, “captures the morbidity and mortality associated with brain conditions” and is adjusted for patient location, age, and sex.

The investigators found that, globally, brain conditions accounted for more than 15% of all health loss in 2021, at 406 DALYs – more than the 206 million DALYs that were associated with cancer, and the 402 million that were linked to cardiovascular disease.

This health loss is associated with a $1.22 trillion loss in income for people living with health disorders worldwide and accounts for $1.14 trillion in direct health care costs.

The burden of mental disorders, neurologic conditions, and stroke is expected to increase dramatically between now and 2050, said Ms. Smith, who noted that health loss linked to brain conditions is higher in younger patients. This will create “new challenges for health systems, employers, patients, and families,” she said in the press release.

“Our goal is to see an improved prevention and treatment landscape for other brain conditions and reverse the growing health loss that we are currently forecasting.”
 

Worrying increase in stroke

Jurgita Valaikiene, MD, PhD, center of neurology, clinic of neurology and neurosurgery, Vilnius (Lithuania) University Faculty of Medicine, who chaired the session, was taken aback by the findings, particularly by the worldwide increase in stroke cases.

“I work in stroke,” she said, and “we spend a lot of time on the diagnosis of stroke” and its prevention. “We try to be faster, to catch asymptomatic stenosis in the neck or head, and to apply the best medical treatment to avoid a stroke. But despite that, the numbers are increasing. I understand the population is getting older ... but still it’s a huge number.”

Dr. Valaikiene pointed out that stroke is not necessarily a condition of aging, insofar as increasing age “is not related directly to stenosis in the neck. “For example, we can have healthier vessels in older age and unhealthy vessels, with high-grade stenosis, in someone aged 30 or 40 years.”

“There are a lot of risk factors, such as smoking, physical activity, and so on. It depends on the individual,” she added.

The study was funded by the Institute for Health Metrics and Evaluation at the University of Washington. The authors have disclosed no relevant financial relationships.

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

A new European consensus statement offers expert guidance on which biomarkers to use for patients presenting with cognitive complaints.

Led by Giovanni B. Frisoni, MD, laboratory of neuroimaging of aging, University of Geneva, and director of the memory clinic at Geneva University Hospital, the multidisciplinary task force set out to define a patient-centered diagnostic workflow for the rational and cost-effective use of biomarkers in memory clinics.

The new algorithm is part of a consensus statement presented at the Congress of the European Academy of Neurology 2023. An interim update was published in June in Alzheimer’s and Dementia.
 

Which biomarker?

Many biomarkers can aid diagnosis, said Dr. Frisoni; the challenge is choosing which biomarker to use for an individual patient.

A literature-based search, he said, yields a number of recommendations, but the vast majority of these are either disease based or biomarker based. The task force notes that “in vivo biomarkers enable early etiological diagnosis of neurocognitive disorders. While they have good analytical validity, their clinical validity and utility are uncertain.”

“When you have a patient in front of you, you don’ t know whether they have Alzheimer’s disease,” Dr. Frisoni said.

“You have a differential diagnosis to make, and you have a number of biomarkers – a number of weapons in your armamentarium – you have to choose. You can’t use all of them – we would like to, but we cannot.”

He added that trying to determine from the literature which biomarker is most appropriate given individual clinical conditions and all of the potential combinations is impossible.

“You will not find evidence of the comparative diagnostic value and the added diagnostic value” of one test vs, another, he noted.

“Is CSF [cerebrospinal fluid] better than amyloid PET in a particular clinical situation? What do I gain in terms of positive and negative predictive value in all the possible clinical conditions that I encounter in my clinical practice?”

Dr. Frisoni said the reality is that clinicians in memory clinics end up using biomarkers that are “based on clinical opportunities.”

For instance, “if you have a proficient nuclear medic, you use PET a lot.” In contrast, “if you have a proficient laboratory medic,” CSF markers will be favored – a situation that he said is “not ideal” and has resulted in large discrepancies in diagnostic approaches across Europe.
 

Harmonizing clinical practice

In a bid to harmonize clinical practice, 22 European experts from 11 European scientific societies and the executive director of Alzheimer Europe set out to develop a multidisciplinary consensus algorithm for the biomarker-based diagnosis of neurocognitive disorders in general, rather than specific neurocognitive disorders.

They used the Delphi method, in which a systematic literature review of the literature was followed by the drafting of a series of clinical statements by an executive board. These were then presented to the expert panel. If a majority consensus was reached on a given statement, it was considered closed. Questions for which there was no consensus were revised and presented to the panel again. The process was repeated until a consensus was reached.

A total of 56 statements underwent six rounds of discussion. A final online meeting led to the development of a diagnostic algorithm for patients who attend memory clinics for cognitive complaints.

The algorithm features three potential assessment waves. Wave 1 defines 11 clinical profiles that are based on the results of clinical and neuropsychological assessments, blood exams, brain imaging, and, in specific cases, electroencephalography. Wave 2 defines first-line biomarkers based on Wave 1 clinical profiles, and Wave 3 defines the second-line biomarker based on Wave 2 biomarker results.

When a patient’s clinical profile suggests Alzheimer’s disease and, in undefined cases, cerebrospinal fluid biomarkers are used first line. When CSF is inconclusive, 18-fluorodeoxyglucose positron emission tomography (FDG-PET) is used second line.

When the clinical profile suggests frontotemporal lobar degeneration or motor tauopathies, FDG-PET is first line and CSF biomarkers second line in atypical metabolic patter cases. When the clinical profile suggests Lewy body disease, dopamine transporter SPECT is first line and cardia I23I-metaiodobenzylguanidine scintigraphy is second line.

Dr. Frisoni noted that the panel strongly recommends performing biomarker tests for patients younger than 70. For those aged 70-85 years, biomarker testing is only recommended for patients with specific clinical features. For patients older than 85, biomarker testing is recommended only in “exceptional circumstances.”

Dr. Frisoni noted that the consensus document has a number of limitations.

“First of all, we could not capture all the theoretical possible combinations” of potential diagnosis and relevant biomarker tests. “There are so many that it’s virtually impossible.”

He also noted that the agreement among the panel for the use of some markers was “relatively low” at “barely 50%,” while for others, the agreement was approximately 70%.

The consensus document also does not explicitly address patients with “mixed pathologies,” which are common. In addition, it does not include emerging biomarkers, such as neurofilament light polypeptide levels, an indicator of axonal compromise.

“Last, but not least,” Dr. Frisoni said, the consensus document requires validation.

“This is a paper and pencil exercise. We, as self-appointed experts, can recommend ... whatever we want, but we must check whether what we write is applicable, feasible.”

In other words, it must be determined whether the “real patient journey” fits with the “ideal patient journey” set out in the consensus document.

This kind of validation, Dr. Frisoni said, is “usually not done for this type of exercise,” but “we want to do it in this case.”
 

Pros and cons

Bogdan Draganski, MD, consultant in neurology at the department of clinical neurosciences and director of the neuroimaging research laboratory, University Hospital of Lausanne (Switzerland), who cochaired the session, told this news organization that he was “swaying between two extremes” when considering the usefulness of the consensus document.

On one hand, the “reductionist approach” of breaking down a “complex issue into an algorithm” via the Delphi method risks introducing subjective bias.

He said machine learning and artificial intelligence could answer some of the questions posed by clinicians and, by extension, the statements included in the Delphi process by assessing the available data in a more objective manner.

On the other hand, Dr. Draganski said that reducing the options available to clinicians when making a differential diagnosis into the current algorithm is, pragmatically speaking, a “good approach.”

From this standpoint, the danger of using machine learning to answer clinical questions is that it “doesn’t take the responsibility” for the final decision, which means “we’re closing the loop of subjective decision-making for an individual doctor.”

He also applauded the idea of trying to provide more uniform patient assessment across Europe, although he believes “we have a long way to go” before it can deliver on the promise of personalized medicine.

Like Dr. Frisoni, Dr. Draganski noted the fact that patients with potential neurocognitive disorders often have multiple pathologies, which can include cardiovascular problems, depression, and cancer and that that could affect the choice of diagnostic biomarkers.

The second issue, he said, concerns implementation of the consensus document, which is a political decision that centers around “how politicians will define ‘uniformity’ and equal access to technological or nontechnological platforms.”

Achieving uniformity will require a pan-regional collaboration, he noted.

The task force was supported by unrestricted grants from F. Hoffmann-La Roche, Biogen International GmbH, Eisai Europe Limited, Life Molecular Imaging GmbH, and OM Pharma Suisse SA. The authors have disclosed no relevant financial relationships.

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

A new European consensus statement offers expert guidance on which biomarkers to use for patients presenting with cognitive complaints.

Led by Giovanni B. Frisoni, MD, laboratory of neuroimaging of aging, University of Geneva, and director of the memory clinic at Geneva University Hospital, the multidisciplinary task force set out to define a patient-centered diagnostic workflow for the rational and cost-effective use of biomarkers in memory clinics.

The new algorithm is part of a consensus statement presented at the Congress of the European Academy of Neurology 2023. An interim update was published in June in Alzheimer’s and Dementia.
 

Which biomarker?

Many biomarkers can aid diagnosis, said Dr. Frisoni; the challenge is choosing which biomarker to use for an individual patient.

A literature-based search, he said, yields a number of recommendations, but the vast majority of these are either disease based or biomarker based. The task force notes that “in vivo biomarkers enable early etiological diagnosis of neurocognitive disorders. While they have good analytical validity, their clinical validity and utility are uncertain.”

“When you have a patient in front of you, you don’ t know whether they have Alzheimer’s disease,” Dr. Frisoni said.

“You have a differential diagnosis to make, and you have a number of biomarkers – a number of weapons in your armamentarium – you have to choose. You can’t use all of them – we would like to, but we cannot.”

He added that trying to determine from the literature which biomarker is most appropriate given individual clinical conditions and all of the potential combinations is impossible.

“You will not find evidence of the comparative diagnostic value and the added diagnostic value” of one test vs, another, he noted.

“Is CSF [cerebrospinal fluid] better than amyloid PET in a particular clinical situation? What do I gain in terms of positive and negative predictive value in all the possible clinical conditions that I encounter in my clinical practice?”

Dr. Frisoni said the reality is that clinicians in memory clinics end up using biomarkers that are “based on clinical opportunities.”

For instance, “if you have a proficient nuclear medic, you use PET a lot.” In contrast, “if you have a proficient laboratory medic,” CSF markers will be favored – a situation that he said is “not ideal” and has resulted in large discrepancies in diagnostic approaches across Europe.
 

Harmonizing clinical practice

In a bid to harmonize clinical practice, 22 European experts from 11 European scientific societies and the executive director of Alzheimer Europe set out to develop a multidisciplinary consensus algorithm for the biomarker-based diagnosis of neurocognitive disorders in general, rather than specific neurocognitive disorders.

They used the Delphi method, in which a systematic literature review of the literature was followed by the drafting of a series of clinical statements by an executive board. These were then presented to the expert panel. If a majority consensus was reached on a given statement, it was considered closed. Questions for which there was no consensus were revised and presented to the panel again. The process was repeated until a consensus was reached.

A total of 56 statements underwent six rounds of discussion. A final online meeting led to the development of a diagnostic algorithm for patients who attend memory clinics for cognitive complaints.

The algorithm features three potential assessment waves. Wave 1 defines 11 clinical profiles that are based on the results of clinical and neuropsychological assessments, blood exams, brain imaging, and, in specific cases, electroencephalography. Wave 2 defines first-line biomarkers based on Wave 1 clinical profiles, and Wave 3 defines the second-line biomarker based on Wave 2 biomarker results.

When a patient’s clinical profile suggests Alzheimer’s disease and, in undefined cases, cerebrospinal fluid biomarkers are used first line. When CSF is inconclusive, 18-fluorodeoxyglucose positron emission tomography (FDG-PET) is used second line.

When the clinical profile suggests frontotemporal lobar degeneration or motor tauopathies, FDG-PET is first line and CSF biomarkers second line in atypical metabolic patter cases. When the clinical profile suggests Lewy body disease, dopamine transporter SPECT is first line and cardia I23I-metaiodobenzylguanidine scintigraphy is second line.

Dr. Frisoni noted that the panel strongly recommends performing biomarker tests for patients younger than 70. For those aged 70-85 years, biomarker testing is only recommended for patients with specific clinical features. For patients older than 85, biomarker testing is recommended only in “exceptional circumstances.”

Dr. Frisoni noted that the consensus document has a number of limitations.

“First of all, we could not capture all the theoretical possible combinations” of potential diagnosis and relevant biomarker tests. “There are so many that it’s virtually impossible.”

He also noted that the agreement among the panel for the use of some markers was “relatively low” at “barely 50%,” while for others, the agreement was approximately 70%.

The consensus document also does not explicitly address patients with “mixed pathologies,” which are common. In addition, it does not include emerging biomarkers, such as neurofilament light polypeptide levels, an indicator of axonal compromise.

“Last, but not least,” Dr. Frisoni said, the consensus document requires validation.

“This is a paper and pencil exercise. We, as self-appointed experts, can recommend ... whatever we want, but we must check whether what we write is applicable, feasible.”

In other words, it must be determined whether the “real patient journey” fits with the “ideal patient journey” set out in the consensus document.

This kind of validation, Dr. Frisoni said, is “usually not done for this type of exercise,” but “we want to do it in this case.”
 

Pros and cons

Bogdan Draganski, MD, consultant in neurology at the department of clinical neurosciences and director of the neuroimaging research laboratory, University Hospital of Lausanne (Switzerland), who cochaired the session, told this news organization that he was “swaying between two extremes” when considering the usefulness of the consensus document.

On one hand, the “reductionist approach” of breaking down a “complex issue into an algorithm” via the Delphi method risks introducing subjective bias.

He said machine learning and artificial intelligence could answer some of the questions posed by clinicians and, by extension, the statements included in the Delphi process by assessing the available data in a more objective manner.

On the other hand, Dr. Draganski said that reducing the options available to clinicians when making a differential diagnosis into the current algorithm is, pragmatically speaking, a “good approach.”

From this standpoint, the danger of using machine learning to answer clinical questions is that it “doesn’t take the responsibility” for the final decision, which means “we’re closing the loop of subjective decision-making for an individual doctor.”

He also applauded the idea of trying to provide more uniform patient assessment across Europe, although he believes “we have a long way to go” before it can deliver on the promise of personalized medicine.

Like Dr. Frisoni, Dr. Draganski noted the fact that patients with potential neurocognitive disorders often have multiple pathologies, which can include cardiovascular problems, depression, and cancer and that that could affect the choice of diagnostic biomarkers.

The second issue, he said, concerns implementation of the consensus document, which is a political decision that centers around “how politicians will define ‘uniformity’ and equal access to technological or nontechnological platforms.”

Achieving uniformity will require a pan-regional collaboration, he noted.

The task force was supported by unrestricted grants from F. Hoffmann-La Roche, Biogen International GmbH, Eisai Europe Limited, Life Molecular Imaging GmbH, and OM Pharma Suisse SA. The authors have disclosed no relevant financial relationships.

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

A new European consensus statement offers expert guidance on which biomarkers to use for patients presenting with cognitive complaints.

Led by Giovanni B. Frisoni, MD, laboratory of neuroimaging of aging, University of Geneva, and director of the memory clinic at Geneva University Hospital, the multidisciplinary task force set out to define a patient-centered diagnostic workflow for the rational and cost-effective use of biomarkers in memory clinics.

The new algorithm is part of a consensus statement presented at the Congress of the European Academy of Neurology 2023. An interim update was published in June in Alzheimer’s and Dementia.
 

Which biomarker?

Many biomarkers can aid diagnosis, said Dr. Frisoni; the challenge is choosing which biomarker to use for an individual patient.

A literature-based search, he said, yields a number of recommendations, but the vast majority of these are either disease based or biomarker based. The task force notes that “in vivo biomarkers enable early etiological diagnosis of neurocognitive disorders. While they have good analytical validity, their clinical validity and utility are uncertain.”

“When you have a patient in front of you, you don’ t know whether they have Alzheimer’s disease,” Dr. Frisoni said.

“You have a differential diagnosis to make, and you have a number of biomarkers – a number of weapons in your armamentarium – you have to choose. You can’t use all of them – we would like to, but we cannot.”

He added that trying to determine from the literature which biomarker is most appropriate given individual clinical conditions and all of the potential combinations is impossible.

“You will not find evidence of the comparative diagnostic value and the added diagnostic value” of one test vs, another, he noted.

“Is CSF [cerebrospinal fluid] better than amyloid PET in a particular clinical situation? What do I gain in terms of positive and negative predictive value in all the possible clinical conditions that I encounter in my clinical practice?”

Dr. Frisoni said the reality is that clinicians in memory clinics end up using biomarkers that are “based on clinical opportunities.”

For instance, “if you have a proficient nuclear medic, you use PET a lot.” In contrast, “if you have a proficient laboratory medic,” CSF markers will be favored – a situation that he said is “not ideal” and has resulted in large discrepancies in diagnostic approaches across Europe.
 

Harmonizing clinical practice

In a bid to harmonize clinical practice, 22 European experts from 11 European scientific societies and the executive director of Alzheimer Europe set out to develop a multidisciplinary consensus algorithm for the biomarker-based diagnosis of neurocognitive disorders in general, rather than specific neurocognitive disorders.

They used the Delphi method, in which a systematic literature review of the literature was followed by the drafting of a series of clinical statements by an executive board. These were then presented to the expert panel. If a majority consensus was reached on a given statement, it was considered closed. Questions for which there was no consensus were revised and presented to the panel again. The process was repeated until a consensus was reached.

A total of 56 statements underwent six rounds of discussion. A final online meeting led to the development of a diagnostic algorithm for patients who attend memory clinics for cognitive complaints.

The algorithm features three potential assessment waves. Wave 1 defines 11 clinical profiles that are based on the results of clinical and neuropsychological assessments, blood exams, brain imaging, and, in specific cases, electroencephalography. Wave 2 defines first-line biomarkers based on Wave 1 clinical profiles, and Wave 3 defines the second-line biomarker based on Wave 2 biomarker results.

When a patient’s clinical profile suggests Alzheimer’s disease and, in undefined cases, cerebrospinal fluid biomarkers are used first line. When CSF is inconclusive, 18-fluorodeoxyglucose positron emission tomography (FDG-PET) is used second line.

When the clinical profile suggests frontotemporal lobar degeneration or motor tauopathies, FDG-PET is first line and CSF biomarkers second line in atypical metabolic patter cases. When the clinical profile suggests Lewy body disease, dopamine transporter SPECT is first line and cardia I23I-metaiodobenzylguanidine scintigraphy is second line.

Dr. Frisoni noted that the panel strongly recommends performing biomarker tests for patients younger than 70. For those aged 70-85 years, biomarker testing is only recommended for patients with specific clinical features. For patients older than 85, biomarker testing is recommended only in “exceptional circumstances.”

Dr. Frisoni noted that the consensus document has a number of limitations.

“First of all, we could not capture all the theoretical possible combinations” of potential diagnosis and relevant biomarker tests. “There are so many that it’s virtually impossible.”

He also noted that the agreement among the panel for the use of some markers was “relatively low” at “barely 50%,” while for others, the agreement was approximately 70%.

The consensus document also does not explicitly address patients with “mixed pathologies,” which are common. In addition, it does not include emerging biomarkers, such as neurofilament light polypeptide levels, an indicator of axonal compromise.

“Last, but not least,” Dr. Frisoni said, the consensus document requires validation.

“This is a paper and pencil exercise. We, as self-appointed experts, can recommend ... whatever we want, but we must check whether what we write is applicable, feasible.”

In other words, it must be determined whether the “real patient journey” fits with the “ideal patient journey” set out in the consensus document.

This kind of validation, Dr. Frisoni said, is “usually not done for this type of exercise,” but “we want to do it in this case.”
 

Pros and cons

Bogdan Draganski, MD, consultant in neurology at the department of clinical neurosciences and director of the neuroimaging research laboratory, University Hospital of Lausanne (Switzerland), who cochaired the session, told this news organization that he was “swaying between two extremes” when considering the usefulness of the consensus document.

On one hand, the “reductionist approach” of breaking down a “complex issue into an algorithm” via the Delphi method risks introducing subjective bias.

He said machine learning and artificial intelligence could answer some of the questions posed by clinicians and, by extension, the statements included in the Delphi process by assessing the available data in a more objective manner.

On the other hand, Dr. Draganski said that reducing the options available to clinicians when making a differential diagnosis into the current algorithm is, pragmatically speaking, a “good approach.”

From this standpoint, the danger of using machine learning to answer clinical questions is that it “doesn’t take the responsibility” for the final decision, which means “we’re closing the loop of subjective decision-making for an individual doctor.”

He also applauded the idea of trying to provide more uniform patient assessment across Europe, although he believes “we have a long way to go” before it can deliver on the promise of personalized medicine.

Like Dr. Frisoni, Dr. Draganski noted the fact that patients with potential neurocognitive disorders often have multiple pathologies, which can include cardiovascular problems, depression, and cancer and that that could affect the choice of diagnostic biomarkers.

The second issue, he said, concerns implementation of the consensus document, which is a political decision that centers around “how politicians will define ‘uniformity’ and equal access to technological or nontechnological platforms.”

Achieving uniformity will require a pan-regional collaboration, he noted.

The task force was supported by unrestricted grants from F. Hoffmann-La Roche, Biogen International GmbH, Eisai Europe Limited, Life Molecular Imaging GmbH, and OM Pharma Suisse SA. The authors have disclosed no relevant financial relationships.

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

CHICAGO – Fewer than 7% of patients newly diagnosed with cancer are tested for germline genetic mutations, and the percentage tested was even lower among racial and ethnic minorities, a huge study has found.

Information from germline genetic testing could affect a patient’s cancer care. For example, such testing could indicate that targeted therapies would be beneficial, and it would have implications for close relatives who may carry the same genes.

The finding that so few patients with newly diagnosed cancer were tested comes from an analysis of data on more than 1.3 million individuals across two U.S. states. The data were taken from the Surveillance, Epidemiology, and End Results (SEER) registry.

The rate is “well below guideline recommendations,” said study presenter Allison W. Kurian, MD, department of medicine, Stanford (Calif.) University.

“Innovative care delivery” is needed to tackle the problem, including the streamlining of pretest counseling, making posttest counseling more widely available, and employing long-term follow-up to track patient outcomes, she suggested.

“I do think this is a time for creative solutions of a number of different kinds,” she said. She suggested that lessons could be learned from the use of telemedicine during the COVID-19 pandemic. She also noted that “there have been some interesting studies on embedding genetic counselors in oncology clinics.”

Dr. Kurian presented the study at the annual meeting of the American Society of Clinical Oncology (ASCO). The study was simultaneously published in the Journal of the American Medical Association.

The current results represent a “missed opportunity for decrease the population-level burden of cancer,” experts noted in an accompanying editorial.

“Clinicians should recommend testing to their patients and provide them with the information necessary to make informed decisions about whether to undergo testing,” Zsofia K. Stadler, MD, and Deborah Schrag, MD, MPH, of Memorial Sloan Kettering Cancer Center, New York, wrote in their editorial.

They suggested novel approaches to widen access, such as use of point-of-care testing, telecounseling, and, in the future, chatbots to respond to patient questions.

“With greater emphasis on overcoming both health system and patient-level barriers to genetic cancer susceptibility testing for patients with cancer, treatment outcomes will improve and cancer diagnoses and related deaths in family members will be prevented,” they concluded.

At the meeting, invited discussant Erin Frances Cobain, MD, assistant professor of medical oncology, University of Michigan Health, Ann Arbor, referring to breast cancer as an example, said that progress has “stagnated” in recent years.

The study found a higher rate of gene testing among patients with newly diagnosed breast cancer, at just over 20%.

Dr. Cobain argued that this was still too low. She pointed out that “a recent study suggested that over 60% of individuals with an incident cancer diagnosis would meet criteria for genetic testing by National Comprehensive Cancer Network guidelines.

“This may be because testing is not offered, there may be poor access to genetic counseling resources, or patients may be offered testing but decline it,” she suggested.

One compelling reason to conduct genetic testing for patients newly diagnosed with breast cancer is that it may show that they are candidates for treatment with PARP (poly[ADP]-ribose polymerase) inhibitors, which “may have a direct impact on cancer-related mortality,” she pointed out.

“We need increased awareness and access to genetic testing resources for patients with breast cancer, particularly for racial and ethnic minorities,” she said.

Dr. Cobain also noted that finding variants of uncertain significance (VUS) was more likely among patients from racial and ethnic minorities than among White patients. She said such a finding “increases patient and physician anxiety,” and there may be “unclear optimal management recommendations for these patients.”
 

Details of the study

Germline genetic testing is “increasingly essential for cancer care,” Dr. Kurian said.

It is central to risk-adapted screening and secondary prevention, the use of targeted therapies, including PARP and checkpoint inhibitors, and cascade testing to identify at-risk relatives.

She pointed out that in clinical practice, testing has “evolved rapidly.” Panels include more and more genes. In addition, the cost of these tests is falling, and guidelines have become “more expansive.”

However, “little is known about genetic testing use and results,” Dr. Kurian noted.

The team therefore undertook the SEER-GeneLINK initiative, which involved patients aged ≥ 20 years who were diagnosed with cancer between Jan. 1, 2013, and March 31, 2019, and who were reported to statewide SEER registries in California and Georgia.

The team looked for patients for whom germline genetic test results had been reported by the four laboratories that performed the majority of patient testing in the two states. Results were categorized as pathogenic, benign, or VUS.

The results were classified on the basis of current guidelines for testing and/or management as related to breast/ovarian cancer, gastrointestinal cancer, other hereditary cancers, or those with no guidelines for testing or management.

Dr. Kurian reported that from an overall population of 1,412,388 patients diagnosed with cancer, 1,369,660 were eligible for inclusion. Of those, about half (51.9%) were women, and the majority (86.3%) were aged 50 years or older.

Many of these patients (61.4%) were non-Hispanic White persons, and slightly fewer than half (49.8%) were deemed to be in medium or high poverty, as determined using U.S. Census tract levels.

Overall, germline genetic testing was performed in 93,052 (6.8%) of patients over the study period.

Women were more likely to have undergone germline mutation testing than men, at 13.9% vs. 2.2%, as were patients aged 20-49 years, at 22.1% vs. 8.2% for those aged 50-69 years, and 3.3% for those aged 70 years and older.

The number of genes for which testing was conducted increased from a median of 2 in 2013 to 34 in 2019. Rates of VUS increased more than that for pathologic variants and substantially more so in non-White patients.

By 2019, the ratio of VUS to pathologic variants stood at 1.7 among White patients, vs. 3.9 among Asian patients, 3.6 among Black patients, and 2.2 among Hispanic patients.

The majority of identified pathologic variants that were related to the diagnosed cancer and genes with testing and/or management guidelines accounted for 67.5% to 94.9% of such variants.

Regarding specific cancer diagnoses, Dr. Kurian said that over the course of the study period, testing rates consistently exceeded 50% only among male breast cancer patients.

There were rapid increases in testing for ovarian cancer, from 28.0% of cases in 2013 to 54.0% in 2019. For pancreatic cancer, rates increased from 1.0% to 19.0% over the same period, and for prostate cancer, rates increased from 0.1% to 4.0%. She suggested that these increases in rates may be related to the approval of PARP inhibitors for use in these indications.

However, there was little change in the rates of germline mutation testing for lung cancer patients, from 01% in 2013 to 0.8% in 2019, and for other cancers, from 0.3% to 2.0%.

The results also revealed racial and ethnic differences in testing after controlling for age, cancer type, and year. Over the course of the study period, 8.0% of White patients underwent genetic testing, compared with 6.0% each for Asian, Black, and Hispanic patients and 5.0% for other patients (P < .001).

With regard specifically to male and female breast cancer and ovarian cancer, testing rates were 31% among White patients, 22% for Asian patients, 25% for Black patients, and 23% for Hispanic patients (P < .001).

Dr. Kurian acknowledged that the study is limited by a lack of testing from other laboratories and direct-to-consumer test data, although a recent survey suggested that this represents fewer than 5% of all germline genetic tests.

She also noted that the SEER registries do not collect data on family history or tumor sequencing.

The study was funded by the National Institutes of Health, and the Centers for Disease Control and Prevention. Dr. Kurian has relationships with Adela, Ambry Genetics, Color Genomics, GeneDx/BioReference, Genentech, InVitae, and Myriad Genetics. Other authors report numerous relationships with industry. Dr. Cobain has ties with AstraZeneca, Daiichi Sankyo, Athenex, Ayala Pharmaceuticals, bioTheranostics, and Immunomedics. Dr. Schrag has relationships with Merck, JAMA, AACR, and Grail. Dr. Stadler has ties with Adverum Biotechnologies, Genentech, Neurogene, Novartis, Optos Plc, Outlook Therapeutics, and Regeneron Pharmaceuticals.

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

CHICAGO – Fewer than 7% of patients newly diagnosed with cancer are tested for germline genetic mutations, and the percentage tested was even lower among racial and ethnic minorities, a huge study has found.

Information from germline genetic testing could affect a patient’s cancer care. For example, such testing could indicate that targeted therapies would be beneficial, and it would have implications for close relatives who may carry the same genes.

The finding that so few patients with newly diagnosed cancer were tested comes from an analysis of data on more than 1.3 million individuals across two U.S. states. The data were taken from the Surveillance, Epidemiology, and End Results (SEER) registry.

The rate is “well below guideline recommendations,” said study presenter Allison W. Kurian, MD, department of medicine, Stanford (Calif.) University.

“Innovative care delivery” is needed to tackle the problem, including the streamlining of pretest counseling, making posttest counseling more widely available, and employing long-term follow-up to track patient outcomes, she suggested.

“I do think this is a time for creative solutions of a number of different kinds,” she said. She suggested that lessons could be learned from the use of telemedicine during the COVID-19 pandemic. She also noted that “there have been some interesting studies on embedding genetic counselors in oncology clinics.”

Dr. Kurian presented the study at the annual meeting of the American Society of Clinical Oncology (ASCO). The study was simultaneously published in the Journal of the American Medical Association.

The current results represent a “missed opportunity for decrease the population-level burden of cancer,” experts noted in an accompanying editorial.

“Clinicians should recommend testing to their patients and provide them with the information necessary to make informed decisions about whether to undergo testing,” Zsofia K. Stadler, MD, and Deborah Schrag, MD, MPH, of Memorial Sloan Kettering Cancer Center, New York, wrote in their editorial.

They suggested novel approaches to widen access, such as use of point-of-care testing, telecounseling, and, in the future, chatbots to respond to patient questions.

“With greater emphasis on overcoming both health system and patient-level barriers to genetic cancer susceptibility testing for patients with cancer, treatment outcomes will improve and cancer diagnoses and related deaths in family members will be prevented,” they concluded.

At the meeting, invited discussant Erin Frances Cobain, MD, assistant professor of medical oncology, University of Michigan Health, Ann Arbor, referring to breast cancer as an example, said that progress has “stagnated” in recent years.

The study found a higher rate of gene testing among patients with newly diagnosed breast cancer, at just over 20%.

Dr. Cobain argued that this was still too low. She pointed out that “a recent study suggested that over 60% of individuals with an incident cancer diagnosis would meet criteria for genetic testing by National Comprehensive Cancer Network guidelines.

“This may be because testing is not offered, there may be poor access to genetic counseling resources, or patients may be offered testing but decline it,” she suggested.

One compelling reason to conduct genetic testing for patients newly diagnosed with breast cancer is that it may show that they are candidates for treatment with PARP (poly[ADP]-ribose polymerase) inhibitors, which “may have a direct impact on cancer-related mortality,” she pointed out.

“We need increased awareness and access to genetic testing resources for patients with breast cancer, particularly for racial and ethnic minorities,” she said.

Dr. Cobain also noted that finding variants of uncertain significance (VUS) was more likely among patients from racial and ethnic minorities than among White patients. She said such a finding “increases patient and physician anxiety,” and there may be “unclear optimal management recommendations for these patients.”
 

Details of the study

Germline genetic testing is “increasingly essential for cancer care,” Dr. Kurian said.

It is central to risk-adapted screening and secondary prevention, the use of targeted therapies, including PARP and checkpoint inhibitors, and cascade testing to identify at-risk relatives.

She pointed out that in clinical practice, testing has “evolved rapidly.” Panels include more and more genes. In addition, the cost of these tests is falling, and guidelines have become “more expansive.”

However, “little is known about genetic testing use and results,” Dr. Kurian noted.

The team therefore undertook the SEER-GeneLINK initiative, which involved patients aged ≥ 20 years who were diagnosed with cancer between Jan. 1, 2013, and March 31, 2019, and who were reported to statewide SEER registries in California and Georgia.

The team looked for patients for whom germline genetic test results had been reported by the four laboratories that performed the majority of patient testing in the two states. Results were categorized as pathogenic, benign, or VUS.

The results were classified on the basis of current guidelines for testing and/or management as related to breast/ovarian cancer, gastrointestinal cancer, other hereditary cancers, or those with no guidelines for testing or management.

Dr. Kurian reported that from an overall population of 1,412,388 patients diagnosed with cancer, 1,369,660 were eligible for inclusion. Of those, about half (51.9%) were women, and the majority (86.3%) were aged 50 years or older.

Many of these patients (61.4%) were non-Hispanic White persons, and slightly fewer than half (49.8%) were deemed to be in medium or high poverty, as determined using U.S. Census tract levels.

Overall, germline genetic testing was performed in 93,052 (6.8%) of patients over the study period.

Women were more likely to have undergone germline mutation testing than men, at 13.9% vs. 2.2%, as were patients aged 20-49 years, at 22.1% vs. 8.2% for those aged 50-69 years, and 3.3% for those aged 70 years and older.

The number of genes for which testing was conducted increased from a median of 2 in 2013 to 34 in 2019. Rates of VUS increased more than that for pathologic variants and substantially more so in non-White patients.

By 2019, the ratio of VUS to pathologic variants stood at 1.7 among White patients, vs. 3.9 among Asian patients, 3.6 among Black patients, and 2.2 among Hispanic patients.

The majority of identified pathologic variants that were related to the diagnosed cancer and genes with testing and/or management guidelines accounted for 67.5% to 94.9% of such variants.

Regarding specific cancer diagnoses, Dr. Kurian said that over the course of the study period, testing rates consistently exceeded 50% only among male breast cancer patients.

There were rapid increases in testing for ovarian cancer, from 28.0% of cases in 2013 to 54.0% in 2019. For pancreatic cancer, rates increased from 1.0% to 19.0% over the same period, and for prostate cancer, rates increased from 0.1% to 4.0%. She suggested that these increases in rates may be related to the approval of PARP inhibitors for use in these indications.

However, there was little change in the rates of germline mutation testing for lung cancer patients, from 01% in 2013 to 0.8% in 2019, and for other cancers, from 0.3% to 2.0%.

The results also revealed racial and ethnic differences in testing after controlling for age, cancer type, and year. Over the course of the study period, 8.0% of White patients underwent genetic testing, compared with 6.0% each for Asian, Black, and Hispanic patients and 5.0% for other patients (P < .001).

With regard specifically to male and female breast cancer and ovarian cancer, testing rates were 31% among White patients, 22% for Asian patients, 25% for Black patients, and 23% for Hispanic patients (P < .001).

Dr. Kurian acknowledged that the study is limited by a lack of testing from other laboratories and direct-to-consumer test data, although a recent survey suggested that this represents fewer than 5% of all germline genetic tests.

She also noted that the SEER registries do not collect data on family history or tumor sequencing.

The study was funded by the National Institutes of Health, and the Centers for Disease Control and Prevention. Dr. Kurian has relationships with Adela, Ambry Genetics, Color Genomics, GeneDx/BioReference, Genentech, InVitae, and Myriad Genetics. Other authors report numerous relationships with industry. Dr. Cobain has ties with AstraZeneca, Daiichi Sankyo, Athenex, Ayala Pharmaceuticals, bioTheranostics, and Immunomedics. Dr. Schrag has relationships with Merck, JAMA, AACR, and Grail. Dr. Stadler has ties with Adverum Biotechnologies, Genentech, Neurogene, Novartis, Optos Plc, Outlook Therapeutics, and Regeneron Pharmaceuticals.

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

CHICAGO – Fewer than 7% of patients newly diagnosed with cancer are tested for germline genetic mutations, and the percentage tested was even lower among racial and ethnic minorities, a huge study has found.

Information from germline genetic testing could affect a patient’s cancer care. For example, such testing could indicate that targeted therapies would be beneficial, and it would have implications for close relatives who may carry the same genes.

The finding that so few patients with newly diagnosed cancer were tested comes from an analysis of data on more than 1.3 million individuals across two U.S. states. The data were taken from the Surveillance, Epidemiology, and End Results (SEER) registry.

The rate is “well below guideline recommendations,” said study presenter Allison W. Kurian, MD, department of medicine, Stanford (Calif.) University.

“Innovative care delivery” is needed to tackle the problem, including the streamlining of pretest counseling, making posttest counseling more widely available, and employing long-term follow-up to track patient outcomes, she suggested.

“I do think this is a time for creative solutions of a number of different kinds,” she said. She suggested that lessons could be learned from the use of telemedicine during the COVID-19 pandemic. She also noted that “there have been some interesting studies on embedding genetic counselors in oncology clinics.”

Dr. Kurian presented the study at the annual meeting of the American Society of Clinical Oncology (ASCO). The study was simultaneously published in the Journal of the American Medical Association.

The current results represent a “missed opportunity for decrease the population-level burden of cancer,” experts noted in an accompanying editorial.

“Clinicians should recommend testing to their patients and provide them with the information necessary to make informed decisions about whether to undergo testing,” Zsofia K. Stadler, MD, and Deborah Schrag, MD, MPH, of Memorial Sloan Kettering Cancer Center, New York, wrote in their editorial.

They suggested novel approaches to widen access, such as use of point-of-care testing, telecounseling, and, in the future, chatbots to respond to patient questions.

“With greater emphasis on overcoming both health system and patient-level barriers to genetic cancer susceptibility testing for patients with cancer, treatment outcomes will improve and cancer diagnoses and related deaths in family members will be prevented,” they concluded.

At the meeting, invited discussant Erin Frances Cobain, MD, assistant professor of medical oncology, University of Michigan Health, Ann Arbor, referring to breast cancer as an example, said that progress has “stagnated” in recent years.

The study found a higher rate of gene testing among patients with newly diagnosed breast cancer, at just over 20%.

Dr. Cobain argued that this was still too low. She pointed out that “a recent study suggested that over 60% of individuals with an incident cancer diagnosis would meet criteria for genetic testing by National Comprehensive Cancer Network guidelines.

“This may be because testing is not offered, there may be poor access to genetic counseling resources, or patients may be offered testing but decline it,” she suggested.

One compelling reason to conduct genetic testing for patients newly diagnosed with breast cancer is that it may show that they are candidates for treatment with PARP (poly[ADP]-ribose polymerase) inhibitors, which “may have a direct impact on cancer-related mortality,” she pointed out.

“We need increased awareness and access to genetic testing resources for patients with breast cancer, particularly for racial and ethnic minorities,” she said.

Dr. Cobain also noted that finding variants of uncertain significance (VUS) was more likely among patients from racial and ethnic minorities than among White patients. She said such a finding “increases patient and physician anxiety,” and there may be “unclear optimal management recommendations for these patients.”
 

Details of the study

Germline genetic testing is “increasingly essential for cancer care,” Dr. Kurian said.

It is central to risk-adapted screening and secondary prevention, the use of targeted therapies, including PARP and checkpoint inhibitors, and cascade testing to identify at-risk relatives.

She pointed out that in clinical practice, testing has “evolved rapidly.” Panels include more and more genes. In addition, the cost of these tests is falling, and guidelines have become “more expansive.”

However, “little is known about genetic testing use and results,” Dr. Kurian noted.

The team therefore undertook the SEER-GeneLINK initiative, which involved patients aged ≥ 20 years who were diagnosed with cancer between Jan. 1, 2013, and March 31, 2019, and who were reported to statewide SEER registries in California and Georgia.

The team looked for patients for whom germline genetic test results had been reported by the four laboratories that performed the majority of patient testing in the two states. Results were categorized as pathogenic, benign, or VUS.

The results were classified on the basis of current guidelines for testing and/or management as related to breast/ovarian cancer, gastrointestinal cancer, other hereditary cancers, or those with no guidelines for testing or management.

Dr. Kurian reported that from an overall population of 1,412,388 patients diagnosed with cancer, 1,369,660 were eligible for inclusion. Of those, about half (51.9%) were women, and the majority (86.3%) were aged 50 years or older.

Many of these patients (61.4%) were non-Hispanic White persons, and slightly fewer than half (49.8%) were deemed to be in medium or high poverty, as determined using U.S. Census tract levels.

Overall, germline genetic testing was performed in 93,052 (6.8%) of patients over the study period.

Women were more likely to have undergone germline mutation testing than men, at 13.9% vs. 2.2%, as were patients aged 20-49 years, at 22.1% vs. 8.2% for those aged 50-69 years, and 3.3% for those aged 70 years and older.

The number of genes for which testing was conducted increased from a median of 2 in 2013 to 34 in 2019. Rates of VUS increased more than that for pathologic variants and substantially more so in non-White patients.

By 2019, the ratio of VUS to pathologic variants stood at 1.7 among White patients, vs. 3.9 among Asian patients, 3.6 among Black patients, and 2.2 among Hispanic patients.

The majority of identified pathologic variants that were related to the diagnosed cancer and genes with testing and/or management guidelines accounted for 67.5% to 94.9% of such variants.

Regarding specific cancer diagnoses, Dr. Kurian said that over the course of the study period, testing rates consistently exceeded 50% only among male breast cancer patients.

There were rapid increases in testing for ovarian cancer, from 28.0% of cases in 2013 to 54.0% in 2019. For pancreatic cancer, rates increased from 1.0% to 19.0% over the same period, and for prostate cancer, rates increased from 0.1% to 4.0%. She suggested that these increases in rates may be related to the approval of PARP inhibitors for use in these indications.

However, there was little change in the rates of germline mutation testing for lung cancer patients, from 01% in 2013 to 0.8% in 2019, and for other cancers, from 0.3% to 2.0%.

The results also revealed racial and ethnic differences in testing after controlling for age, cancer type, and year. Over the course of the study period, 8.0% of White patients underwent genetic testing, compared with 6.0% each for Asian, Black, and Hispanic patients and 5.0% for other patients (P < .001).

With regard specifically to male and female breast cancer and ovarian cancer, testing rates were 31% among White patients, 22% for Asian patients, 25% for Black patients, and 23% for Hispanic patients (P < .001).

Dr. Kurian acknowledged that the study is limited by a lack of testing from other laboratories and direct-to-consumer test data, although a recent survey suggested that this represents fewer than 5% of all germline genetic tests.

She also noted that the SEER registries do not collect data on family history or tumor sequencing.

The study was funded by the National Institutes of Health, and the Centers for Disease Control and Prevention. Dr. Kurian has relationships with Adela, Ambry Genetics, Color Genomics, GeneDx/BioReference, Genentech, InVitae, and Myriad Genetics. Other authors report numerous relationships with industry. Dr. Cobain has ties with AstraZeneca, Daiichi Sankyo, Athenex, Ayala Pharmaceuticals, bioTheranostics, and Immunomedics. Dr. Schrag has relationships with Merck, JAMA, AACR, and Grail. Dr. Stadler has ties with Adverum Biotechnologies, Genentech, Neurogene, Novartis, Optos Plc, Outlook Therapeutics, and Regeneron Pharmaceuticals.

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

Patients with acute myeloid leukemia (AML) who harbor a mutation strongly associated with a poor prognosis and who have minimal residual disease (MRD+) following hematopoietic cell transplantation (HCT) have a reduced risk of relapse with gilteritinib (Xospata) maintenance therapy, results of the MORPHO trial suggest.

The research was presented at the European Hematology Association Hybrid Congress 2023.

For the study, AML patients with the most common form of mutation in the proto-oncogene fms-like tyrosine kinase 3 (FLT3), known as the internal tandem duplication (ITD), were randomized to 24 months of maintenance therapy with either the FLT3 inhibitor gilteritinib or placebo.

The trial did not meet its primary endpoint, as there was no significant difference in relapse-free survival (RFS) between those assigned to the active drug and those given placebo, and there was no difference in overall survival rates.

However, subgroup analysis revealed that FLT3/ITD AML patients who were MRD+ after transplant, which represented approximately half of the participants, experienced a significant 48% improvement in RFS with gilteritinib versus placebo, while no benefit was seen in MRD– patients.

While acknowledging that the trial did not meet its primary endpoint, presenter Mark J. Levis, MD, PhD, program leader, hematologic malignancies and bone marrow transplant program, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, said it was nevertheless “a successful study.”

“We learned how to use these drugs and in whom,” he continued, adding: “No, not everybody needs and should get a FLT3 inhibitor post-transplant, but we can use this [MRD] assay to identify who.”

Consequently, Dr. Levis believes that gilteritinib “should be a standard of care for those who are MRD positive,” although the decision to use it “should be balanced against the potential for toxicity,” compared with not adding an additional treatment after HCT.

He told a press conference that “we’re going to certainly make sure that patients who are MRD positive get [gilteritinib],” although the MRD negative patients “are going to be more questionable,” especially because the assay that they used in the study is not “perfect.”

Dr. Levis also suggested that the trial did not meet its endpoint because of regional differences in the clinical practice, such as in the number of treatment cycles prior to HCT, the time to transplant, and the previous use of a FLT3 inhibitor, all of which may have skewed the findings.

“Everybody in the world is convinced that they’re the best transplanter,” he said, and yet “they all do it differently, and the heterogeneity is astounding.”

He added: “If we’d restricted everybody [to a] pretransplant regimen, I suspect we would have had a different result than what we’re getting here, but this is releasing the drug into the world and saying: ‘Here, transplant however you want, however it’s practiced in the real world. Tell us how this works.’ ”

Approached for comment, Claudio Brunstein, MD, PhD, vice-chair of the department of hematology and oncology in the Cleveland Clinic Taussig Cancer Institute, said that while there was “some disappointment” with the results, he was “not surprised” that the trial did not meet its primary endpoint.

He said in an interview that the patient population was not of “high enough risk” to demonstrate an overall difference between gilteritinib and placebo, although he conceded that it is “hard to get to high-risk patients in a timely way” and so conduct a trial with them.

As to the notion that variations in clinical practice could have been responsible, Dr. Brunstein pointed out that it was a randomized trial, so the issue would have applied equally to both sides.

He nevertheless believes that it is “a very important study,” and “just the fact that it was done in the context of a number of drugs coming and being approved by the [U.S. Food and Drug Administration] in AML is quite remarkable.”

This is especially the case given that “many centers are already using [gilteritinib] as off-label maintenance therapy.”

Dr. Brunstein added that it is “good news” that the drug was effective in MRD+ patients, as it shows “you can overcome that with maintenance therapy rather than keeping giving more and more chemotherapy, especially as there are patients you’re worried about giving more intensive chemotherapy to make them MRD negative.”

He pointed out, however, that the assay used in the trial was “research grade” and very sensitive to MRD and “is not available everywhere, so there is an adjustment that the community will have to do to in order to apply this data.”

“But for those who are more obviously MRD positive with less sensitive assays, gilteritinib is already something that can be used,” Dr. Brunstein said.

Presenting the findings, Dr. Levis stated: “We all know that patients with FLT3/ITD AML have a high risk of relapse and are routinely referred for transplant. And we know that the detection of measurable residual disease pretransplant is highly predictive of outcome post-transplant.”

He continued that FLT3 inhibitors are “routinely given as post-transplant maintenance ... based on some prior trials, mostly with sorafenib.”

“But uncertainty exists as to the broad applicability of these trials,” Dr. Levis said. Moreover, the use of sorafenib in this context is “off label and can be difficult to tolerate,” and “we know that most patients are cured with allogeneic transplant alone.”

Gilteritinib is already known to be well tolerated as a monotherapy, and was approved by the FDA for the treatment of adult patients with FLT3 mutation–positive relapsed or refractory AML in 2018.

The investigators therefore examined whether it would be beneficial as a post-HCT maintenance therapy in FLT3-ITD AML. Patients were required to be in morphologic remission after one or two courses of induction therapy, with Dr. Levis underlining: “We did not allow patients who had been salvaged onto the study.”

They subsequently had a marrow aspirate sample taken for MRD analysis before undergoing allogeneic transplant, with any conditioning regimen, donor, or graft-versus-host disease (GVHD) prophylaxis allowed.

Between 30 and 90 days later, patients with successful engraftment who were able to take oral medication were then randomized to 24 months of maintenance therapy with either gilteritinib or placebo.

Dr. Levis showed that, among 620 patients screened at 110 centers in 16 countries, 356 were randomized between Aug. 15, 2017, and July 8, 2020. The median age was 53 years, and 49% of gilteritinib patients and 48% of those given placebo were female.

He noted that there was a “fairly even global distribution” of patients from North America, Europe, and the Asia/Pacific region, and that 60% of patients underwent a myeloablative conditioning regimen. Approximately the same proportion had received an FLT3 inhibitor prior to HCT.

MRD positivity, assessed at a cell count of ≥ 10^-6, was observed pre-HCT in 47% of patients in both treatment groups, and in 50% of gilteritinib patients and 51% of placebo patients at both pre- and post-transplant assessments.

The treatment regimen was completed by 52.8% of patients assigned to gilteritinib and 53.9% in the placebo arm. Dr. Levis said that 18.5% and 20.3% of patients, respectively, experienced a grade 3/4 treatment emergent acute GVHD event, while 32.6% and 21.5%, respectively, had a grade ≥ 3 treatment emergent infection.

He noted that “adverse events were clearly more common in the gilteritinib arm and often led to either dose reduction or interruption, or withdrawal of treatment.”

The most common grade ≥ 3 treatment emergent adverse event was a decrease in neutrophil count, seen in 24.7% of gilteritinib patients and 7.9% of those given placebo, followed by reduced platelet count, in 15.2% and 5.6%, respectively, and anemia, in 6.2% and 1.7%, respectively.

Turning to the efficacy outcomes, Dr. Levis reported that the trial did not meet its primary endpoint, with no significant difference in RFS between the gilteritinib and placebo arms, at a hazard ratio of 0.679 (P = .0518). There was also no significant difference in the key secondary objective of overall survival, at a hazard ratio of 0.846 (P = .4394).

However, Dr. Levis noted that there was a “clear difference in the benefit of gilteritinib by region,” and, “at every level,” MRD predicted a benefit from gilteritinib, which he said was a “big surprise” and “really leapt out in the subgroup analysis.”

He explained that the researchers used a modified version of a two-step assay that has been used in previous studies, and was able to detect MRD at a sensitivity of approximately 1x10^-6. “In our study, 98% of participants had samples pre- and post-[transplant].”

Regardless of treatment arm, MRD positivity measured at that sensitivity was associated with a significant reduction in overall survival, at a hazard ratio versus MRD– status of 0.514 (P = .0025).

When stratifying the patients by MRD status, the researchers found that, among MRD+ participants, gilteritinib was associated with a significant improvement in RFS, at a hazard ratio versus placebo of 0.515 (P = .0065), while there was no significant difference in MRD– patients.

Stratifying the patients by their conditioning regimen prior to HCT also revealed differences, with those undergoing myeloablative conditioning having significantly greater overall survival than those who underwent reduced-intensity conditioning, at a hazard ratio for death of 0.529 (P = .0027).

Dr. Levis said there is “no surprise there,” and the result could reflect the selection of fitter, younger patients to undergo the more intensive regimen.

He then showed that MRD+ patients who had undergone myeloablative conditioning had better overall survival with gilteritinib than placebo, at a hazard ratio for death of 0.418 (P = .0087). Again, the difference disappeared when looking at MRD– patients.

“So conditioning doesn’t help you in the setting of MRD,” Dr. Levis said.

Finally, he took a deeper dive into the regional differences in outcomes, noting that patients in the Asia/Pacific region, where gilteritinib showed no benefit over placebo, “were 10 years younger” than those in other regions, “tended to get myeloablative conditioning, and hardly ever used FLT3 inhibitors.”

In contrast, North American patients, who experienced a significant gilteritinib benefit in terms of RFS, underwent HCT an average of 26 days earlier than those elsewhere, and received fewer courses of chemotherapy pre-HCT. Moreover, 93.5% received an FLT3 inhibitor pretransplant.

The study was funded by Astellas Pharma Global Development. Dr. Levis declares relationships with Abbvie, Amgen, Astellas, Bristol-Myers-Squibb, Daiichi-Sankyo, GlaxoSmithKline, Jazz, Menarini, Pfizer, Sumitomo-Dainippon, Syndax, Takeda. Dr. Brunstein declares no relevant relationships.
 

Patients with acute myeloid leukemia (AML) who harbor a mutation strongly associated with a poor prognosis and who have minimal residual disease (MRD+) following hematopoietic cell transplantation (HCT) have a reduced risk of relapse with gilteritinib (Xospata) maintenance therapy, results of the MORPHO trial suggest.

The research was presented at the European Hematology Association Hybrid Congress 2023.

For the study, AML patients with the most common form of mutation in the proto-oncogene fms-like tyrosine kinase 3 (FLT3), known as the internal tandem duplication (ITD), were randomized to 24 months of maintenance therapy with either the FLT3 inhibitor gilteritinib or placebo.

The trial did not meet its primary endpoint, as there was no significant difference in relapse-free survival (RFS) between those assigned to the active drug and those given placebo, and there was no difference in overall survival rates.

However, subgroup analysis revealed that FLT3/ITD AML patients who were MRD+ after transplant, which represented approximately half of the participants, experienced a significant 48% improvement in RFS with gilteritinib versus placebo, while no benefit was seen in MRD– patients.

While acknowledging that the trial did not meet its primary endpoint, presenter Mark J. Levis, MD, PhD, program leader, hematologic malignancies and bone marrow transplant program, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, said it was nevertheless “a successful study.”

“We learned how to use these drugs and in whom,” he continued, adding: “No, not everybody needs and should get a FLT3 inhibitor post-transplant, but we can use this [MRD] assay to identify who.”

Consequently, Dr. Levis believes that gilteritinib “should be a standard of care for those who are MRD positive,” although the decision to use it “should be balanced against the potential for toxicity,” compared with not adding an additional treatment after HCT.

He told a press conference that “we’re going to certainly make sure that patients who are MRD positive get [gilteritinib],” although the MRD negative patients “are going to be more questionable,” especially because the assay that they used in the study is not “perfect.”

Dr. Levis also suggested that the trial did not meet its endpoint because of regional differences in the clinical practice, such as in the number of treatment cycles prior to HCT, the time to transplant, and the previous use of a FLT3 inhibitor, all of which may have skewed the findings.

“Everybody in the world is convinced that they’re the best transplanter,” he said, and yet “they all do it differently, and the heterogeneity is astounding.”

He added: “If we’d restricted everybody [to a] pretransplant regimen, I suspect we would have had a different result than what we’re getting here, but this is releasing the drug into the world and saying: ‘Here, transplant however you want, however it’s practiced in the real world. Tell us how this works.’ ”

Approached for comment, Claudio Brunstein, MD, PhD, vice-chair of the department of hematology and oncology in the Cleveland Clinic Taussig Cancer Institute, said that while there was “some disappointment” with the results, he was “not surprised” that the trial did not meet its primary endpoint.

He said in an interview that the patient population was not of “high enough risk” to demonstrate an overall difference between gilteritinib and placebo, although he conceded that it is “hard to get to high-risk patients in a timely way” and so conduct a trial with them.

As to the notion that variations in clinical practice could have been responsible, Dr. Brunstein pointed out that it was a randomized trial, so the issue would have applied equally to both sides.

He nevertheless believes that it is “a very important study,” and “just the fact that it was done in the context of a number of drugs coming and being approved by the [U.S. Food and Drug Administration] in AML is quite remarkable.”

This is especially the case given that “many centers are already using [gilteritinib] as off-label maintenance therapy.”

Dr. Brunstein added that it is “good news” that the drug was effective in MRD+ patients, as it shows “you can overcome that with maintenance therapy rather than keeping giving more and more chemotherapy, especially as there are patients you’re worried about giving more intensive chemotherapy to make them MRD negative.”

He pointed out, however, that the assay used in the trial was “research grade” and very sensitive to MRD and “is not available everywhere, so there is an adjustment that the community will have to do to in order to apply this data.”

“But for those who are more obviously MRD positive with less sensitive assays, gilteritinib is already something that can be used,” Dr. Brunstein said.

Presenting the findings, Dr. Levis stated: “We all know that patients with FLT3/ITD AML have a high risk of relapse and are routinely referred for transplant. And we know that the detection of measurable residual disease pretransplant is highly predictive of outcome post-transplant.”

He continued that FLT3 inhibitors are “routinely given as post-transplant maintenance ... based on some prior trials, mostly with sorafenib.”

“But uncertainty exists as to the broad applicability of these trials,” Dr. Levis said. Moreover, the use of sorafenib in this context is “off label and can be difficult to tolerate,” and “we know that most patients are cured with allogeneic transplant alone.”

Gilteritinib is already known to be well tolerated as a monotherapy, and was approved by the FDA for the treatment of adult patients with FLT3 mutation–positive relapsed or refractory AML in 2018.

The investigators therefore examined whether it would be beneficial as a post-HCT maintenance therapy in FLT3-ITD AML. Patients were required to be in morphologic remission after one or two courses of induction therapy, with Dr. Levis underlining: “We did not allow patients who had been salvaged onto the study.”

They subsequently had a marrow aspirate sample taken for MRD analysis before undergoing allogeneic transplant, with any conditioning regimen, donor, or graft-versus-host disease (GVHD) prophylaxis allowed.

Between 30 and 90 days later, patients with successful engraftment who were able to take oral medication were then randomized to 24 months of maintenance therapy with either gilteritinib or placebo.

Dr. Levis showed that, among 620 patients screened at 110 centers in 16 countries, 356 were randomized between Aug. 15, 2017, and July 8, 2020. The median age was 53 years, and 49% of gilteritinib patients and 48% of those given placebo were female.

He noted that there was a “fairly even global distribution” of patients from North America, Europe, and the Asia/Pacific region, and that 60% of patients underwent a myeloablative conditioning regimen. Approximately the same proportion had received an FLT3 inhibitor prior to HCT.

MRD positivity, assessed at a cell count of ≥ 10^-6, was observed pre-HCT in 47% of patients in both treatment groups, and in 50% of gilteritinib patients and 51% of placebo patients at both pre- and post-transplant assessments.

The treatment regimen was completed by 52.8% of patients assigned to gilteritinib and 53.9% in the placebo arm. Dr. Levis said that 18.5% and 20.3% of patients, respectively, experienced a grade 3/4 treatment emergent acute GVHD event, while 32.6% and 21.5%, respectively, had a grade ≥ 3 treatment emergent infection.

He noted that “adverse events were clearly more common in the gilteritinib arm and often led to either dose reduction or interruption, or withdrawal of treatment.”

The most common grade ≥ 3 treatment emergent adverse event was a decrease in neutrophil count, seen in 24.7% of gilteritinib patients and 7.9% of those given placebo, followed by reduced platelet count, in 15.2% and 5.6%, respectively, and anemia, in 6.2% and 1.7%, respectively.

Turning to the efficacy outcomes, Dr. Levis reported that the trial did not meet its primary endpoint, with no significant difference in RFS between the gilteritinib and placebo arms, at a hazard ratio of 0.679 (P = .0518). There was also no significant difference in the key secondary objective of overall survival, at a hazard ratio of 0.846 (P = .4394).

However, Dr. Levis noted that there was a “clear difference in the benefit of gilteritinib by region,” and, “at every level,” MRD predicted a benefit from gilteritinib, which he said was a “big surprise” and “really leapt out in the subgroup analysis.”

He explained that the researchers used a modified version of a two-step assay that has been used in previous studies, and was able to detect MRD at a sensitivity of approximately 1x10^-6. “In our study, 98% of participants had samples pre- and post-[transplant].”

Regardless of treatment arm, MRD positivity measured at that sensitivity was associated with a significant reduction in overall survival, at a hazard ratio versus MRD– status of 0.514 (P = .0025).

When stratifying the patients by MRD status, the researchers found that, among MRD+ participants, gilteritinib was associated with a significant improvement in RFS, at a hazard ratio versus placebo of 0.515 (P = .0065), while there was no significant difference in MRD– patients.

Stratifying the patients by their conditioning regimen prior to HCT also revealed differences, with those undergoing myeloablative conditioning having significantly greater overall survival than those who underwent reduced-intensity conditioning, at a hazard ratio for death of 0.529 (P = .0027).

Dr. Levis said there is “no surprise there,” and the result could reflect the selection of fitter, younger patients to undergo the more intensive regimen.

He then showed that MRD+ patients who had undergone myeloablative conditioning had better overall survival with gilteritinib than placebo, at a hazard ratio for death of 0.418 (P = .0087). Again, the difference disappeared when looking at MRD– patients.

“So conditioning doesn’t help you in the setting of MRD,” Dr. Levis said.

Finally, he took a deeper dive into the regional differences in outcomes, noting that patients in the Asia/Pacific region, where gilteritinib showed no benefit over placebo, “were 10 years younger” than those in other regions, “tended to get myeloablative conditioning, and hardly ever used FLT3 inhibitors.”

In contrast, North American patients, who experienced a significant gilteritinib benefit in terms of RFS, underwent HCT an average of 26 days earlier than those elsewhere, and received fewer courses of chemotherapy pre-HCT. Moreover, 93.5% received an FLT3 inhibitor pretransplant.

The study was funded by Astellas Pharma Global Development. Dr. Levis declares relationships with Abbvie, Amgen, Astellas, Bristol-Myers-Squibb, Daiichi-Sankyo, GlaxoSmithKline, Jazz, Menarini, Pfizer, Sumitomo-Dainippon, Syndax, Takeda. Dr. Brunstein declares no relevant relationships.
 

Patients with acute myeloid leukemia (AML) who harbor a mutation strongly associated with a poor prognosis and who have minimal residual disease (MRD+) following hematopoietic cell transplantation (HCT) have a reduced risk of relapse with gilteritinib (Xospata) maintenance therapy, results of the MORPHO trial suggest.

The research was presented at the European Hematology Association Hybrid Congress 2023.

For the study, AML patients with the most common form of mutation in the proto-oncogene fms-like tyrosine kinase 3 (FLT3), known as the internal tandem duplication (ITD), were randomized to 24 months of maintenance therapy with either the FLT3 inhibitor gilteritinib or placebo.

The trial did not meet its primary endpoint, as there was no significant difference in relapse-free survival (RFS) between those assigned to the active drug and those given placebo, and there was no difference in overall survival rates.

However, subgroup analysis revealed that FLT3/ITD AML patients who were MRD+ after transplant, which represented approximately half of the participants, experienced a significant 48% improvement in RFS with gilteritinib versus placebo, while no benefit was seen in MRD– patients.

While acknowledging that the trial did not meet its primary endpoint, presenter Mark J. Levis, MD, PhD, program leader, hematologic malignancies and bone marrow transplant program, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, said it was nevertheless “a successful study.”

“We learned how to use these drugs and in whom,” he continued, adding: “No, not everybody needs and should get a FLT3 inhibitor post-transplant, but we can use this [MRD] assay to identify who.”

Consequently, Dr. Levis believes that gilteritinib “should be a standard of care for those who are MRD positive,” although the decision to use it “should be balanced against the potential for toxicity,” compared with not adding an additional treatment after HCT.

He told a press conference that “we’re going to certainly make sure that patients who are MRD positive get [gilteritinib],” although the MRD negative patients “are going to be more questionable,” especially because the assay that they used in the study is not “perfect.”

Dr. Levis also suggested that the trial did not meet its endpoint because of regional differences in the clinical practice, such as in the number of treatment cycles prior to HCT, the time to transplant, and the previous use of a FLT3 inhibitor, all of which may have skewed the findings.

“Everybody in the world is convinced that they’re the best transplanter,” he said, and yet “they all do it differently, and the heterogeneity is astounding.”

He added: “If we’d restricted everybody [to a] pretransplant regimen, I suspect we would have had a different result than what we’re getting here, but this is releasing the drug into the world and saying: ‘Here, transplant however you want, however it’s practiced in the real world. Tell us how this works.’ ”

Approached for comment, Claudio Brunstein, MD, PhD, vice-chair of the department of hematology and oncology in the Cleveland Clinic Taussig Cancer Institute, said that while there was “some disappointment” with the results, he was “not surprised” that the trial did not meet its primary endpoint.

He said in an interview that the patient population was not of “high enough risk” to demonstrate an overall difference between gilteritinib and placebo, although he conceded that it is “hard to get to high-risk patients in a timely way” and so conduct a trial with them.

As to the notion that variations in clinical practice could have been responsible, Dr. Brunstein pointed out that it was a randomized trial, so the issue would have applied equally to both sides.

He nevertheless believes that it is “a very important study,” and “just the fact that it was done in the context of a number of drugs coming and being approved by the [U.S. Food and Drug Administration] in AML is quite remarkable.”

This is especially the case given that “many centers are already using [gilteritinib] as off-label maintenance therapy.”

Dr. Brunstein added that it is “good news” that the drug was effective in MRD+ patients, as it shows “you can overcome that with maintenance therapy rather than keeping giving more and more chemotherapy, especially as there are patients you’re worried about giving more intensive chemotherapy to make them MRD negative.”

He pointed out, however, that the assay used in the trial was “research grade” and very sensitive to MRD and “is not available everywhere, so there is an adjustment that the community will have to do to in order to apply this data.”

“But for those who are more obviously MRD positive with less sensitive assays, gilteritinib is already something that can be used,” Dr. Brunstein said.

Presenting the findings, Dr. Levis stated: “We all know that patients with FLT3/ITD AML have a high risk of relapse and are routinely referred for transplant. And we know that the detection of measurable residual disease pretransplant is highly predictive of outcome post-transplant.”

He continued that FLT3 inhibitors are “routinely given as post-transplant maintenance ... based on some prior trials, mostly with sorafenib.”

“But uncertainty exists as to the broad applicability of these trials,” Dr. Levis said. Moreover, the use of sorafenib in this context is “off label and can be difficult to tolerate,” and “we know that most patients are cured with allogeneic transplant alone.”

Gilteritinib is already known to be well tolerated as a monotherapy, and was approved by the FDA for the treatment of adult patients with FLT3 mutation–positive relapsed or refractory AML in 2018.

The investigators therefore examined whether it would be beneficial as a post-HCT maintenance therapy in FLT3-ITD AML. Patients were required to be in morphologic remission after one or two courses of induction therapy, with Dr. Levis underlining: “We did not allow patients who had been salvaged onto the study.”

They subsequently had a marrow aspirate sample taken for MRD analysis before undergoing allogeneic transplant, with any conditioning regimen, donor, or graft-versus-host disease (GVHD) prophylaxis allowed.

Between 30 and 90 days later, patients with successful engraftment who were able to take oral medication were then randomized to 24 months of maintenance therapy with either gilteritinib or placebo.

Dr. Levis showed that, among 620 patients screened at 110 centers in 16 countries, 356 were randomized between Aug. 15, 2017, and July 8, 2020. The median age was 53 years, and 49% of gilteritinib patients and 48% of those given placebo were female.

He noted that there was a “fairly even global distribution” of patients from North America, Europe, and the Asia/Pacific region, and that 60% of patients underwent a myeloablative conditioning regimen. Approximately the same proportion had received an FLT3 inhibitor prior to HCT.

MRD positivity, assessed at a cell count of ≥ 10^-6, was observed pre-HCT in 47% of patients in both treatment groups, and in 50% of gilteritinib patients and 51% of placebo patients at both pre- and post-transplant assessments.

The treatment regimen was completed by 52.8% of patients assigned to gilteritinib and 53.9% in the placebo arm. Dr. Levis said that 18.5% and 20.3% of patients, respectively, experienced a grade 3/4 treatment emergent acute GVHD event, while 32.6% and 21.5%, respectively, had a grade ≥ 3 treatment emergent infection.

He noted that “adverse events were clearly more common in the gilteritinib arm and often led to either dose reduction or interruption, or withdrawal of treatment.”

The most common grade ≥ 3 treatment emergent adverse event was a decrease in neutrophil count, seen in 24.7% of gilteritinib patients and 7.9% of those given placebo, followed by reduced platelet count, in 15.2% and 5.6%, respectively, and anemia, in 6.2% and 1.7%, respectively.

Turning to the efficacy outcomes, Dr. Levis reported that the trial did not meet its primary endpoint, with no significant difference in RFS between the gilteritinib and placebo arms, at a hazard ratio of 0.679 (P = .0518). There was also no significant difference in the key secondary objective of overall survival, at a hazard ratio of 0.846 (P = .4394).

However, Dr. Levis noted that there was a “clear difference in the benefit of gilteritinib by region,” and, “at every level,” MRD predicted a benefit from gilteritinib, which he said was a “big surprise” and “really leapt out in the subgroup analysis.”

He explained that the researchers used a modified version of a two-step assay that has been used in previous studies, and was able to detect MRD at a sensitivity of approximately 1x10^-6. “In our study, 98% of participants had samples pre- and post-[transplant].”

Regardless of treatment arm, MRD positivity measured at that sensitivity was associated with a significant reduction in overall survival, at a hazard ratio versus MRD– status of 0.514 (P = .0025).

When stratifying the patients by MRD status, the researchers found that, among MRD+ participants, gilteritinib was associated with a significant improvement in RFS, at a hazard ratio versus placebo of 0.515 (P = .0065), while there was no significant difference in MRD– patients.

Stratifying the patients by their conditioning regimen prior to HCT also revealed differences, with those undergoing myeloablative conditioning having significantly greater overall survival than those who underwent reduced-intensity conditioning, at a hazard ratio for death of 0.529 (P = .0027).

Dr. Levis said there is “no surprise there,” and the result could reflect the selection of fitter, younger patients to undergo the more intensive regimen.

He then showed that MRD+ patients who had undergone myeloablative conditioning had better overall survival with gilteritinib than placebo, at a hazard ratio for death of 0.418 (P = .0087). Again, the difference disappeared when looking at MRD– patients.

“So conditioning doesn’t help you in the setting of MRD,” Dr. Levis said.

Finally, he took a deeper dive into the regional differences in outcomes, noting that patients in the Asia/Pacific region, where gilteritinib showed no benefit over placebo, “were 10 years younger” than those in other regions, “tended to get myeloablative conditioning, and hardly ever used FLT3 inhibitors.”

In contrast, North American patients, who experienced a significant gilteritinib benefit in terms of RFS, underwent HCT an average of 26 days earlier than those elsewhere, and received fewer courses of chemotherapy pre-HCT. Moreover, 93.5% received an FLT3 inhibitor pretransplant.

The study was funded by Astellas Pharma Global Development. Dr. Levis declares relationships with Abbvie, Amgen, Astellas, Bristol-Myers-Squibb, Daiichi-Sankyo, GlaxoSmithKline, Jazz, Menarini, Pfizer, Sumitomo-Dainippon, Syndax, Takeda. Dr. Brunstein declares no relevant relationships.
 

Patients with chronic lymphocytic leukemia (CLL) – even those who have multiple comorbidities – experience long-term progression-free survival (PFS) benefits with 1 year of venetoclax plus obinutuzumab versus a chemotherapy-based regimen, a 6-year follow-up analysis from CLL14 showed. The research was presented June 9 at the annual meeting of the European Hematology Association.

Initial results from the trial were shown at the EHA 2019 annual meeting and reported at the time by this news organization.

They revealed that, among more than 430 CLL patients with a median age of over 70 years and multiple comorbidities, the combination of venetoclax, a B-cell lymphoma 2 protein blocker, plus obinutuzumab, an anti-CD20 monoclonal antibody, was associated with a 65% improvement in PFS, compared with chlorambucil, a chemotherapy agent, plus obinutuzumab.

On the strength of these findings, the venetoclax-obinutuzumab combination received Food and Drug Administration approval for previously untreated CLL and small lymphocytic lymphoma in March 2019.

The latest analysis, presented by Othman Al-Sawaf, MD, University Hospital of Cologne (Germany), showed that despite having just 12 cycles of treatment, patients treated with venetoclax-obinutuzumab continued to experience a significant PFS benefit over those given the chemotherapy-based regimen, including in high-risk patients, after more than 6 years of follow-up.

Dr. Al-Sawaf noted that more than 50% of patients given the experimental combination remained without a PFS event at the latest follow-up, and that over 60% had not required a second treatment, equating to a 66% reduction in the likelihood of needing a second treatment versus chlorambucil-obinutuzumab.

Dr. Al-Sawaf said at a press conference that, “clinically, the standard of care for any CLL if it is asymptomatic” is watch and wait, which is “true in the frontline setting, but also in the relapse setting.”

Therefore, these patients “do not need to initiate the next line of treatment, and that’s why time to next treatment is so interesting.”

He added that there also were no new safety signals, with adverse event rates dropping markedly once treatment was over, although there was a suggestion of an increase in second malignancies with venetoclax-obinutuzumab.

“We’ve seen, in many studies now that use fixed-duration approaches, that there is virtually no posttreatment toxicity once patients are able to get off treatment,” Dr. Al-Sawaf said, adding: “This really highlights the benefit” of stopping treatment, “which is a clear advantage compared to having any kind of continuous treatment.”

Approached for comment, William G. Wierda, MD, PhD, professor, department of leukemia, division of cancer medicine, University of Texas MD Anderson Cancer Center, Houston, emphasized the value of the 6-year follow-up of the study, adding that these are “very impressive data.”

He told this news organization that, in terms of the ongoing PFS improvement, “we wouldn’t expect anything otherwise” with venetoclax-obinutuzumab when compared with the chemotherapy-based regimen, but that the trend for an improvement in overall survival is of particular interest.

This “is a notable feature of the update,” Dr. Wierda said, and “we will continue to watch the long-term overall survival curves with a longer follow-up,” especially as the separation of the curves between the two regimens is “more prominent” than in previous analyses of CLL14.

He also pointed to the low incidence of grade ≥ 3 adverse events in patients who are in remission, which “support the use of fixed-duration chemo-free” treatments, and the longer follow-up now allowing the contribution of high-risk features to outcomes to be teased out in multivariate analysis.

“The data that we’re looking for in the next update of this is some indication about improved outcomes between patients with a mutated and unmutated immunoglobulin heavy chain gene [IgHV], in regard to undetectable MRD [minimal residual disease] status,” Dr. Wierda said.

“We know that mutational status correlates with progression free survival,” he explained. “What we would like to see moving forward is how that is associated with undetectable MRD status at the end of treatment.”

Dr. Wierda said that the next hotly anticipated trial in the field is CLL17, which is comparing ibrutinib monotherapy to fixed-duration venetoclax-obinutuzumab to fixed-duration ibrutinib-venetoclax in patients with previously untreated CLL.

“That’s the next question: Is there any advantage of a BTK [Bruton’s tyrosine kinase] inhibitor with venetoclax over venetoclax plus the CD20 antibody?”

Dr. Al-Sawaf, in presenting the latest analysis, reminded the audience that CLL14 was a randomized phase 3 study focusing on patients with previously untreated CLL and coexisting conditions who were randomized to either venetoclax-obinutuzumab for six cycles, followed by six cycles of venetoclax, or chlorambucil-obinutuzumab for six cycles, followed by chlorambucil for six cycles.

The patients, who were enrolled between 2015 and 2016, were required to have a Cumulative Illness Rating Scale (CIRS) score > 6 and/or creatinine clearance < 70 mL/min, which Dr. Al-Sawaf explained serves as “indicator of the unfitness of the patients.”

A total of 432 patients took part in the study. The median age across the two treatment groups was 71-72 years, and the median total CIRS score was 8-9. The majority of patients (79%-80%) had Binet stage B or C CLL. An intermediate tumor lysis syndrome risk was identified in 64%-68%.

“We also had a fair share of patients with high-risk disease,” Dr. Al-Sawaf noted, with approximately 60% having an unmutated IGHV status, and 12% having a TP53 mutation, both of which are associated with a poorer prognosis.

He added that the “aim of these long-term observations that we try to do every year is not so much to do the comparisons to chlorambucil-obinutuzumab, which we appreciate is not necessarily a standard of care anymore,” but rather to understand the safety and effectiveness of venetoclax-obinutuzumab “in the long run, given that all patients are off treatment.”

Beginning with the safety data, Dr. Al-Sawaf showed that rates of grade ≥ 3 adverse events plummeted after the treatment period, with rates of neutropenia falling from 51.9% with venetoclax-obinutuzumab and 47.2% with chlorambucil-obinutuzumab during treatment to 3.8% and 1.9%, respectively, post treatment.

Similarly, rates of thrombocytopenia decreased from 14.2% on treatment to 0.5% off treatment in patients given venetoclax-obinutuzumab, and from 15.0% to 0.0% in the chlorambucil-obinutuzumab group.

One note of caution was sounded over the proportion of patients with at least one second primary malignancy following treatment, which was numerically higher with venetoclax-obinutuzumab, at 14.2% versus 8.4% with the chemotherapy-based regimen.

“But this is a rather a heterogeneous pattern of solid organ tumors and melanoma,” Dr. Al-Sawaf said, referring to the additional malignancies in the venetoclax-obinutuzumab arm. These included lung cancer, prostate cancer and breast cancer.

He said, however, there was no “specific pattern that we can really pinpoint ... and, importantly, the difference is not statistically significant.”

Turning to the efficacy outcomes, Dr. Al-Sawaf showed that, after median follow-up of 76.4 months, the separation in PFS between the two treatment arms continued, with the median PFS 76.2 months with venetoclax-obinutuzumab versus 36.4 months with chlorambucil-obinutuzumab, at a hazard ratio 0.40 (P < .0001).

The 6-year PFS rate in patients treated with venetoclax-obinutuzumab was 53.1% versus 21.7% with the chemotherapy-based regimen. Looking at the high-risk groups, Dr. Al-Sawaf reported that there was a similar pattern of benefit with venetoclax-obinutuzumab.

Among patients with a TP53 mutation, the median PFS was 51.9 months with the combination versus 20.8 months in those given chlorambucil-obinutuzumab, while the corresponding durations in patients with unmutated IGHV were 64.8 months and 26.9 months, respectively.

Multivariate analysis demonstrated that IGHV status was an independent predictor of PFS in patients treated with venetoclax-obinutuzumab, as was the presence of a TP53 mutation, and lymph node size ≥ 5 cm.

There was no significant difference in overall survival between the two treatment groups, although there was a numerical difference in 6-year overall survival rates, at 78.7% with the experimental combination versus 69.2% with chlorambucil-obinutuzumab.

Patients with a minimal residual disease (MRD) count ≥ 10-4 had a shorter overall survival than did those with MRD < 10-4.

“We are currently working up to understand which group of patients experiences these tremendous long term remissions,” Dr. Al-Sawaf said, “and we will keep you posted on this.”

He also showed that the time to next treatment (TTNT), defined as time to death or next anti-leukemic treatment, was significantly longer with venetoclax-obinutuzumab, with the median not reached before the current data lock versus 52.9 months with the chemotherapy-based regimen.

This equated to a hazard ratio in favor of the experimental combination of 0.44 (P < .0001), and a 6-year TTNT rate of 65.2% versus 37.1% for chlorambucil-obinutuzumab.

That second treatment was a Bruton’s tyrosine kinase inhibitor in 59.0% of cases in the venetoclax-obinutuzumab arm and 53.4% in the chlorambucil-obinutuzumab group.

Dr. Al-Sawaf noted, however, that 23.1% and 30.1%, respectively, of patients were given a chemotherapy or chemo-immunotherapy regimen, “which we nowadays would not necessarily consider a standard of care.”

“This ultimately reflects, as in many global clinical studies, the disparities that we still have across the world in terms of access to state-of-the-art therapies.”

The study was sponsored by Hoffmann–La Roche, and conducted in collaboration with AbbVie, and the German CLL Study Group. Dr. Al-Sawaf disclosed relationships with AbbVie, Adaptive, Ascentage, AstraZeneca, BeiGene, Gilead, Janssen, Lilly, and Roche.

Patients with chronic lymphocytic leukemia (CLL) – even those who have multiple comorbidities – experience long-term progression-free survival (PFS) benefits with 1 year of venetoclax plus obinutuzumab versus a chemotherapy-based regimen, a 6-year follow-up analysis from CLL14 showed. The research was presented June 9 at the annual meeting of the European Hematology Association.

Initial results from the trial were shown at the EHA 2019 annual meeting and reported at the time by this news organization.

They revealed that, among more than 430 CLL patients with a median age of over 70 years and multiple comorbidities, the combination of venetoclax, a B-cell lymphoma 2 protein blocker, plus obinutuzumab, an anti-CD20 monoclonal antibody, was associated with a 65% improvement in PFS, compared with chlorambucil, a chemotherapy agent, plus obinutuzumab.

On the strength of these findings, the venetoclax-obinutuzumab combination received Food and Drug Administration approval for previously untreated CLL and small lymphocytic lymphoma in March 2019.

The latest analysis, presented by Othman Al-Sawaf, MD, University Hospital of Cologne (Germany), showed that despite having just 12 cycles of treatment, patients treated with venetoclax-obinutuzumab continued to experience a significant PFS benefit over those given the chemotherapy-based regimen, including in high-risk patients, after more than 6 years of follow-up.

Dr. Al-Sawaf noted that more than 50% of patients given the experimental combination remained without a PFS event at the latest follow-up, and that over 60% had not required a second treatment, equating to a 66% reduction in the likelihood of needing a second treatment versus chlorambucil-obinutuzumab.

Dr. Al-Sawaf said at a press conference that, “clinically, the standard of care for any CLL if it is asymptomatic” is watch and wait, which is “true in the frontline setting, but also in the relapse setting.”

Therefore, these patients “do not need to initiate the next line of treatment, and that’s why time to next treatment is so interesting.”

He added that there also were no new safety signals, with adverse event rates dropping markedly once treatment was over, although there was a suggestion of an increase in second malignancies with venetoclax-obinutuzumab.

“We’ve seen, in many studies now that use fixed-duration approaches, that there is virtually no posttreatment toxicity once patients are able to get off treatment,” Dr. Al-Sawaf said, adding: “This really highlights the benefit” of stopping treatment, “which is a clear advantage compared to having any kind of continuous treatment.”

Approached for comment, William G. Wierda, MD, PhD, professor, department of leukemia, division of cancer medicine, University of Texas MD Anderson Cancer Center, Houston, emphasized the value of the 6-year follow-up of the study, adding that these are “very impressive data.”

He told this news organization that, in terms of the ongoing PFS improvement, “we wouldn’t expect anything otherwise” with venetoclax-obinutuzumab when compared with the chemotherapy-based regimen, but that the trend for an improvement in overall survival is of particular interest.

This “is a notable feature of the update,” Dr. Wierda said, and “we will continue to watch the long-term overall survival curves with a longer follow-up,” especially as the separation of the curves between the two regimens is “more prominent” than in previous analyses of CLL14.

He also pointed to the low incidence of grade ≥ 3 adverse events in patients who are in remission, which “support the use of fixed-duration chemo-free” treatments, and the longer follow-up now allowing the contribution of high-risk features to outcomes to be teased out in multivariate analysis.

“The data that we’re looking for in the next update of this is some indication about improved outcomes between patients with a mutated and unmutated immunoglobulin heavy chain gene [IgHV], in regard to undetectable MRD [minimal residual disease] status,” Dr. Wierda said.

“We know that mutational status correlates with progression free survival,” he explained. “What we would like to see moving forward is how that is associated with undetectable MRD status at the end of treatment.”

Dr. Wierda said that the next hotly anticipated trial in the field is CLL17, which is comparing ibrutinib monotherapy to fixed-duration venetoclax-obinutuzumab to fixed-duration ibrutinib-venetoclax in patients with previously untreated CLL.

“That’s the next question: Is there any advantage of a BTK [Bruton’s tyrosine kinase] inhibitor with venetoclax over venetoclax plus the CD20 antibody?”

Dr. Al-Sawaf, in presenting the latest analysis, reminded the audience that CLL14 was a randomized phase 3 study focusing on patients with previously untreated CLL and coexisting conditions who were randomized to either venetoclax-obinutuzumab for six cycles, followed by six cycles of venetoclax, or chlorambucil-obinutuzumab for six cycles, followed by chlorambucil for six cycles.

The patients, who were enrolled between 2015 and 2016, were required to have a Cumulative Illness Rating Scale (CIRS) score > 6 and/or creatinine clearance < 70 mL/min, which Dr. Al-Sawaf explained serves as “indicator of the unfitness of the patients.”

A total of 432 patients took part in the study. The median age across the two treatment groups was 71-72 years, and the median total CIRS score was 8-9. The majority of patients (79%-80%) had Binet stage B or C CLL. An intermediate tumor lysis syndrome risk was identified in 64%-68%.

“We also had a fair share of patients with high-risk disease,” Dr. Al-Sawaf noted, with approximately 60% having an unmutated IGHV status, and 12% having a TP53 mutation, both of which are associated with a poorer prognosis.

He added that the “aim of these long-term observations that we try to do every year is not so much to do the comparisons to chlorambucil-obinutuzumab, which we appreciate is not necessarily a standard of care anymore,” but rather to understand the safety and effectiveness of venetoclax-obinutuzumab “in the long run, given that all patients are off treatment.”

Beginning with the safety data, Dr. Al-Sawaf showed that rates of grade ≥ 3 adverse events plummeted after the treatment period, with rates of neutropenia falling from 51.9% with venetoclax-obinutuzumab and 47.2% with chlorambucil-obinutuzumab during treatment to 3.8% and 1.9%, respectively, post treatment.

Similarly, rates of thrombocytopenia decreased from 14.2% on treatment to 0.5% off treatment in patients given venetoclax-obinutuzumab, and from 15.0% to 0.0% in the chlorambucil-obinutuzumab group.

One note of caution was sounded over the proportion of patients with at least one second primary malignancy following treatment, which was numerically higher with venetoclax-obinutuzumab, at 14.2% versus 8.4% with the chemotherapy-based regimen.

“But this is a rather a heterogeneous pattern of solid organ tumors and melanoma,” Dr. Al-Sawaf said, referring to the additional malignancies in the venetoclax-obinutuzumab arm. These included lung cancer, prostate cancer and breast cancer.

He said, however, there was no “specific pattern that we can really pinpoint ... and, importantly, the difference is not statistically significant.”

Turning to the efficacy outcomes, Dr. Al-Sawaf showed that, after median follow-up of 76.4 months, the separation in PFS between the two treatment arms continued, with the median PFS 76.2 months with venetoclax-obinutuzumab versus 36.4 months with chlorambucil-obinutuzumab, at a hazard ratio 0.40 (P < .0001).

The 6-year PFS rate in patients treated with venetoclax-obinutuzumab was 53.1% versus 21.7% with the chemotherapy-based regimen. Looking at the high-risk groups, Dr. Al-Sawaf reported that there was a similar pattern of benefit with venetoclax-obinutuzumab.

Among patients with a TP53 mutation, the median PFS was 51.9 months with the combination versus 20.8 months in those given chlorambucil-obinutuzumab, while the corresponding durations in patients with unmutated IGHV were 64.8 months and 26.9 months, respectively.

Multivariate analysis demonstrated that IGHV status was an independent predictor of PFS in patients treated with venetoclax-obinutuzumab, as was the presence of a TP53 mutation, and lymph node size ≥ 5 cm.

There was no significant difference in overall survival between the two treatment groups, although there was a numerical difference in 6-year overall survival rates, at 78.7% with the experimental combination versus 69.2% with chlorambucil-obinutuzumab.

Patients with a minimal residual disease (MRD) count ≥ 10-4 had a shorter overall survival than did those with MRD < 10-4.

“We are currently working up to understand which group of patients experiences these tremendous long term remissions,” Dr. Al-Sawaf said, “and we will keep you posted on this.”

He also showed that the time to next treatment (TTNT), defined as time to death or next anti-leukemic treatment, was significantly longer with venetoclax-obinutuzumab, with the median not reached before the current data lock versus 52.9 months with the chemotherapy-based regimen.

This equated to a hazard ratio in favor of the experimental combination of 0.44 (P < .0001), and a 6-year TTNT rate of 65.2% versus 37.1% for chlorambucil-obinutuzumab.

That second treatment was a Bruton’s tyrosine kinase inhibitor in 59.0% of cases in the venetoclax-obinutuzumab arm and 53.4% in the chlorambucil-obinutuzumab group.

Dr. Al-Sawaf noted, however, that 23.1% and 30.1%, respectively, of patients were given a chemotherapy or chemo-immunotherapy regimen, “which we nowadays would not necessarily consider a standard of care.”

“This ultimately reflects, as in many global clinical studies, the disparities that we still have across the world in terms of access to state-of-the-art therapies.”

The study was sponsored by Hoffmann–La Roche, and conducted in collaboration with AbbVie, and the German CLL Study Group. Dr. Al-Sawaf disclosed relationships with AbbVie, Adaptive, Ascentage, AstraZeneca, BeiGene, Gilead, Janssen, Lilly, and Roche.

Patients with chronic lymphocytic leukemia (CLL) – even those who have multiple comorbidities – experience long-term progression-free survival (PFS) benefits with 1 year of venetoclax plus obinutuzumab versus a chemotherapy-based regimen, a 6-year follow-up analysis from CLL14 showed. The research was presented June 9 at the annual meeting of the European Hematology Association.

Initial results from the trial were shown at the EHA 2019 annual meeting and reported at the time by this news organization.

They revealed that, among more than 430 CLL patients with a median age of over 70 years and multiple comorbidities, the combination of venetoclax, a B-cell lymphoma 2 protein blocker, plus obinutuzumab, an anti-CD20 monoclonal antibody, was associated with a 65% improvement in PFS, compared with chlorambucil, a chemotherapy agent, plus obinutuzumab.

On the strength of these findings, the venetoclax-obinutuzumab combination received Food and Drug Administration approval for previously untreated CLL and small lymphocytic lymphoma in March 2019.

The latest analysis, presented by Othman Al-Sawaf, MD, University Hospital of Cologne (Germany), showed that despite having just 12 cycles of treatment, patients treated with venetoclax-obinutuzumab continued to experience a significant PFS benefit over those given the chemotherapy-based regimen, including in high-risk patients, after more than 6 years of follow-up.

Dr. Al-Sawaf noted that more than 50% of patients given the experimental combination remained without a PFS event at the latest follow-up, and that over 60% had not required a second treatment, equating to a 66% reduction in the likelihood of needing a second treatment versus chlorambucil-obinutuzumab.

Dr. Al-Sawaf said at a press conference that, “clinically, the standard of care for any CLL if it is asymptomatic” is watch and wait, which is “true in the frontline setting, but also in the relapse setting.”

Therefore, these patients “do not need to initiate the next line of treatment, and that’s why time to next treatment is so interesting.”

He added that there also were no new safety signals, with adverse event rates dropping markedly once treatment was over, although there was a suggestion of an increase in second malignancies with venetoclax-obinutuzumab.

“We’ve seen, in many studies now that use fixed-duration approaches, that there is virtually no posttreatment toxicity once patients are able to get off treatment,” Dr. Al-Sawaf said, adding: “This really highlights the benefit” of stopping treatment, “which is a clear advantage compared to having any kind of continuous treatment.”

Approached for comment, William G. Wierda, MD, PhD, professor, department of leukemia, division of cancer medicine, University of Texas MD Anderson Cancer Center, Houston, emphasized the value of the 6-year follow-up of the study, adding that these are “very impressive data.”

He told this news organization that, in terms of the ongoing PFS improvement, “we wouldn’t expect anything otherwise” with venetoclax-obinutuzumab when compared with the chemotherapy-based regimen, but that the trend for an improvement in overall survival is of particular interest.

This “is a notable feature of the update,” Dr. Wierda said, and “we will continue to watch the long-term overall survival curves with a longer follow-up,” especially as the separation of the curves between the two regimens is “more prominent” than in previous analyses of CLL14.

He also pointed to the low incidence of grade ≥ 3 adverse events in patients who are in remission, which “support the use of fixed-duration chemo-free” treatments, and the longer follow-up now allowing the contribution of high-risk features to outcomes to be teased out in multivariate analysis.

“The data that we’re looking for in the next update of this is some indication about improved outcomes between patients with a mutated and unmutated immunoglobulin heavy chain gene [IgHV], in regard to undetectable MRD [minimal residual disease] status,” Dr. Wierda said.

“We know that mutational status correlates with progression free survival,” he explained. “What we would like to see moving forward is how that is associated with undetectable MRD status at the end of treatment.”

Dr. Wierda said that the next hotly anticipated trial in the field is CLL17, which is comparing ibrutinib monotherapy to fixed-duration venetoclax-obinutuzumab to fixed-duration ibrutinib-venetoclax in patients with previously untreated CLL.

“That’s the next question: Is there any advantage of a BTK [Bruton’s tyrosine kinase] inhibitor with venetoclax over venetoclax plus the CD20 antibody?”

Dr. Al-Sawaf, in presenting the latest analysis, reminded the audience that CLL14 was a randomized phase 3 study focusing on patients with previously untreated CLL and coexisting conditions who were randomized to either venetoclax-obinutuzumab for six cycles, followed by six cycles of venetoclax, or chlorambucil-obinutuzumab for six cycles, followed by chlorambucil for six cycles.

The patients, who were enrolled between 2015 and 2016, were required to have a Cumulative Illness Rating Scale (CIRS) score > 6 and/or creatinine clearance < 70 mL/min, which Dr. Al-Sawaf explained serves as “indicator of the unfitness of the patients.”

A total of 432 patients took part in the study. The median age across the two treatment groups was 71-72 years, and the median total CIRS score was 8-9. The majority of patients (79%-80%) had Binet stage B or C CLL. An intermediate tumor lysis syndrome risk was identified in 64%-68%.

“We also had a fair share of patients with high-risk disease,” Dr. Al-Sawaf noted, with approximately 60% having an unmutated IGHV status, and 12% having a TP53 mutation, both of which are associated with a poorer prognosis.

He added that the “aim of these long-term observations that we try to do every year is not so much to do the comparisons to chlorambucil-obinutuzumab, which we appreciate is not necessarily a standard of care anymore,” but rather to understand the safety and effectiveness of venetoclax-obinutuzumab “in the long run, given that all patients are off treatment.”

Beginning with the safety data, Dr. Al-Sawaf showed that rates of grade ≥ 3 adverse events plummeted after the treatment period, with rates of neutropenia falling from 51.9% with venetoclax-obinutuzumab and 47.2% with chlorambucil-obinutuzumab during treatment to 3.8% and 1.9%, respectively, post treatment.

Similarly, rates of thrombocytopenia decreased from 14.2% on treatment to 0.5% off treatment in patients given venetoclax-obinutuzumab, and from 15.0% to 0.0% in the chlorambucil-obinutuzumab group.

One note of caution was sounded over the proportion of patients with at least one second primary malignancy following treatment, which was numerically higher with venetoclax-obinutuzumab, at 14.2% versus 8.4% with the chemotherapy-based regimen.

“But this is a rather a heterogeneous pattern of solid organ tumors and melanoma,” Dr. Al-Sawaf said, referring to the additional malignancies in the venetoclax-obinutuzumab arm. These included lung cancer, prostate cancer and breast cancer.

He said, however, there was no “specific pattern that we can really pinpoint ... and, importantly, the difference is not statistically significant.”

Turning to the efficacy outcomes, Dr. Al-Sawaf showed that, after median follow-up of 76.4 months, the separation in PFS between the two treatment arms continued, with the median PFS 76.2 months with venetoclax-obinutuzumab versus 36.4 months with chlorambucil-obinutuzumab, at a hazard ratio 0.40 (P < .0001).

The 6-year PFS rate in patients treated with venetoclax-obinutuzumab was 53.1% versus 21.7% with the chemotherapy-based regimen. Looking at the high-risk groups, Dr. Al-Sawaf reported that there was a similar pattern of benefit with venetoclax-obinutuzumab.

Among patients with a TP53 mutation, the median PFS was 51.9 months with the combination versus 20.8 months in those given chlorambucil-obinutuzumab, while the corresponding durations in patients with unmutated IGHV were 64.8 months and 26.9 months, respectively.

Multivariate analysis demonstrated that IGHV status was an independent predictor of PFS in patients treated with venetoclax-obinutuzumab, as was the presence of a TP53 mutation, and lymph node size ≥ 5 cm.

There was no significant difference in overall survival between the two treatment groups, although there was a numerical difference in 6-year overall survival rates, at 78.7% with the experimental combination versus 69.2% with chlorambucil-obinutuzumab.

Patients with a minimal residual disease (MRD) count ≥ 10-4 had a shorter overall survival than did those with MRD < 10-4.

“We are currently working up to understand which group of patients experiences these tremendous long term remissions,” Dr. Al-Sawaf said, “and we will keep you posted on this.”

He also showed that the time to next treatment (TTNT), defined as time to death or next anti-leukemic treatment, was significantly longer with venetoclax-obinutuzumab, with the median not reached before the current data lock versus 52.9 months with the chemotherapy-based regimen.

This equated to a hazard ratio in favor of the experimental combination of 0.44 (P < .0001), and a 6-year TTNT rate of 65.2% versus 37.1% for chlorambucil-obinutuzumab.

That second treatment was a Bruton’s tyrosine kinase inhibitor in 59.0% of cases in the venetoclax-obinutuzumab arm and 53.4% in the chlorambucil-obinutuzumab group.

Dr. Al-Sawaf noted, however, that 23.1% and 30.1%, respectively, of patients were given a chemotherapy or chemo-immunotherapy regimen, “which we nowadays would not necessarily consider a standard of care.”

“This ultimately reflects, as in many global clinical studies, the disparities that we still have across the world in terms of access to state-of-the-art therapies.”

The study was sponsored by Hoffmann–La Roche, and conducted in collaboration with AbbVie, and the German CLL Study Group. Dr. Al-Sawaf disclosed relationships with AbbVie, Adaptive, Ascentage, AstraZeneca, BeiGene, Gilead, Janssen, Lilly, and Roche.