Article

Stage III non–small cell lung cancer, depending on tumor stage and histology, may be managed in multiple ways. Because of the range of treatments available and the numerous factors that inform the optimal approach, management by a multidisciplinary team is considered advantageous.  

Weekly meetings of the multidisciplinary team facilitate the efficient review of tumor histology and molecular status, surgical and radiation options, and pre- and post-surgery care for individual patients.  

Pulmonologist Dr Anne Gonzalez, from McGill University Health Centre; thoracic oncologist Dr Jyoti D. Patel, of Northwestern University; and thoracic surgeon Dr John Howington, from Virginia Mason Franciscan Health, discuss the vital roles that specialists play in the coordinated treatment of a patient. The panelists also consider factors in treatment selection and how multidisciplinary care is managed at each of their institutions. 

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Anne V. Gonzalez, MD, MSc, FCCP, Associate Professor of Medicine, McGill University Health Centre, Montreal, Quebec, Canada 

Anne V. Gonzalez, MD, MSc, FCCP, has disclosed the following relevant financial relationships: 

Received research grant from: Lung Cancer Canada 

DSMB for: Laurent Pharmaceuticals; GSK; Idorsia; Janssen; Pfizer 

Jyoti D. Patel, MD, Professor of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 

Jyoti Patel, MD, has disclosed the following relevant financial relationships: 

Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: Astra Zeneca; AnHeart; Takeda; Lilly 

John Howington, MD, MBA, FCCP, Thoracic Surgeon, Virginia Mason Franciscan Health, Franciscan Cardiothoracic Surgery Associates at Saint Michael, Silverdale, Washington 

John Howington, MD, MBA, FCCP, has disclosed the following relevant financial relationships: 

Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: President Designate of American College of Chest Physicians 

Stage III non–small cell lung cancer, depending on tumor stage and histology, may be managed in multiple ways. Because of the range of treatments available and the numerous factors that inform the optimal approach, management by a multidisciplinary team is considered advantageous.  

Weekly meetings of the multidisciplinary team facilitate the efficient review of tumor histology and molecular status, surgical and radiation options, and pre- and post-surgery care for individual patients.  

Pulmonologist Dr Anne Gonzalez, from McGill University Health Centre; thoracic oncologist Dr Jyoti D. Patel, of Northwestern University; and thoracic surgeon Dr John Howington, from Virginia Mason Franciscan Health, discuss the vital roles that specialists play in the coordinated treatment of a patient. The panelists also consider factors in treatment selection and how multidisciplinary care is managed at each of their institutions. 

--

Anne V. Gonzalez, MD, MSc, FCCP, Associate Professor of Medicine, McGill University Health Centre, Montreal, Quebec, Canada 

Anne V. Gonzalez, MD, MSc, FCCP, has disclosed the following relevant financial relationships: 

Received research grant from: Lung Cancer Canada 

DSMB for: Laurent Pharmaceuticals; GSK; Idorsia; Janssen; Pfizer 

Jyoti D. Patel, MD, Professor of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 

Jyoti Patel, MD, has disclosed the following relevant financial relationships: 

Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: Astra Zeneca; AnHeart; Takeda; Lilly 

John Howington, MD, MBA, FCCP, Thoracic Surgeon, Virginia Mason Franciscan Health, Franciscan Cardiothoracic Surgery Associates at Saint Michael, Silverdale, Washington 

John Howington, MD, MBA, FCCP, has disclosed the following relevant financial relationships: 

Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: President Designate of American College of Chest Physicians 

Stage III non–small cell lung cancer, depending on tumor stage and histology, may be managed in multiple ways. Because of the range of treatments available and the numerous factors that inform the optimal approach, management by a multidisciplinary team is considered advantageous.  

Weekly meetings of the multidisciplinary team facilitate the efficient review of tumor histology and molecular status, surgical and radiation options, and pre- and post-surgery care for individual patients.  

Pulmonologist Dr Anne Gonzalez, from McGill University Health Centre; thoracic oncologist Dr Jyoti D. Patel, of Northwestern University; and thoracic surgeon Dr John Howington, from Virginia Mason Franciscan Health, discuss the vital roles that specialists play in the coordinated treatment of a patient. The panelists also consider factors in treatment selection and how multidisciplinary care is managed at each of their institutions. 

--

Anne V. Gonzalez, MD, MSc, FCCP, Associate Professor of Medicine, McGill University Health Centre, Montreal, Quebec, Canada 

Anne V. Gonzalez, MD, MSc, FCCP, has disclosed the following relevant financial relationships: 

Received research grant from: Lung Cancer Canada 

DSMB for: Laurent Pharmaceuticals; GSK; Idorsia; Janssen; Pfizer 

Jyoti D. Patel, MD, Professor of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 

Jyoti Patel, MD, has disclosed the following relevant financial relationships: 

Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: Astra Zeneca; AnHeart; Takeda; Lilly 

John Howington, MD, MBA, FCCP, Thoracic Surgeon, Virginia Mason Franciscan Health, Franciscan Cardiothoracic Surgery Associates at Saint Michael, Silverdale, Washington 

John Howington, MD, MBA, FCCP, has disclosed the following relevant financial relationships: 

Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: President Designate of American College of Chest Physicians 

As the pandemic wanes, the public is clamoring for a return to normal. But individuals with long COVID face a challenging journey to get back to their baseline. Here’s what clinicians need to know to help patients with long COVID. 

The COVID-19 pandemic is waning. The official federal public health emergency ended on May 11, 2023. Moreover, the public is ready to move on 3 years after the beginning of a pandemic that resulted in over a million deaths in the United States.  

But not everyone can go back to normal. The Centers for Disease Control and Prevention (CDC) estimates that 1 in 13 US adults (7.5%) have long COVID symptoms. Many of these people feel as if they are the forgotten patients. While everyone else is moving on, a significant number of people have not returned to their baseline. 

A group from Yale School of Medicine, myself included, reviewed a number of studies to gain a better understanding of 1) how long COVID manifests and 2) potential treatment options. Highlights of our evaluation are presented here.

Long COVID: The Basics
What exactly is long COVID-19, and how is it thought to develop? 

The World Health Organization (WHO) defines long COVID as symptoms that persist 3 months postinfection, last for ≥ 2 months, and are not attributable to another cause. 

Hypotheses about the mechanisms of long COVID include the presence of a persistent viral reservoir, an imbalance in the viral and microbial ecosystems, reactivation of latent DNA viruses, and endothelial dysfunction. 

Who is most at risk?

• Females

• Older individuals

• Individuals with preexisting conditions, including hypertension, diabetes, obesity, and lung disease 

• Individuals who experienced > 5 symptoms within the first week of COVID-19 illness 

• Individuals with breakthrough infections after vaccination against COVID-19 appear to be at increased risk of at least 1 postacute condition

Additionally, as the risk of contracting COVID-19 is demonstrably higher in certain racial and ethnic populations, it stands to reason that more of these individuals will experience long COVID. 

Long COVID symptoms: how long is long?

Long COVID symptoms may persist for 2 years after initial infection. One analysis from China showed that nearly 7 in 10 patients experienced at least 1 ongoing symptom 6 months following infection, with more than half reporting symptoms at 24 months. Dyspnea, anxiety, and depression are especially persistent. 

In another analysis, 90% of individuals reported symptoms 35 weeks postinfection. Symptoms did not only occur in people who were hospitalized; they also occurred in people who had a “mild case.”

Clinical Manifestations of Long COVID

More than 50 symptoms have been identified as potentially associated with long COVID. The most common manifestations involve pulmonary, cardiac, and neuropsychiatric sequelae. There is no single test to determine if symptoms are due to long COVID.

Pulmonary

How it manifests

• Chronic cough 

• Shortness of breath 

• Interstitial lung disease

Treatment options

Treatment options are variable and depend on predominant symptoms. Chronic cough should be managed based on primary etiology. Treatment for interstitial lung disease depends on whether the process continues to evolve or stabilizes. The role of antifibrotics in these patients is being investigated. Lung transplantation has largely been reserved for unresolved acute injury. 

Cardiac

How it manifests

• Postacute sequelae cardiovascular disease, where cardiovascular disorders are uncovered during diagnostic testing

• Postacute sequelae cardiovascular syndrome, such as exercise intolerance, tachycardia and chest pain, and dyspnea

Other important considerations:

• Cardiac symptoms can occur independent of preexisting conditions, severity, course of acute illness, and time from original diagnosis

• Cardiac involvement can occur in any age group

• One analysis revealed increased risk of stroke, arrythmias, pericarditis, myocarditis, and ischemic heart disease 1 year after COVID-19 infection

• Postural orthostatic tachycardia syndrome (POTS) and neurogenic orthostatic hypotension have also been observed

Treatment options

Treatment options are dictated by clinical manifestations and course. Patients who have autonomic dysfunction can be advised to increase salt and water intake since hypovolemia can worsen symptoms. Consider fludrocortisone and midodrine along with recumbent and semirecumbent exercises as tolerated, as exercise can sometimes worsen symptoms.

Neuropsychiatric

How it manifests

Patients can present with fatigue, memory disorders, headache, vertigo, myalgia, neuropathy, and smell and taste disorders, and there have been reports of cognitive decline postinfection. 

Other important considerations:

• A retrospective cohort study revealed that 34% of individuals had a new neurological or psychiatric diagnosis in the first 6 months after infection, including intracranial hemorrhage, ischemic stroke, parkinsonism, and dementia. Many COVID survivors experienced critical illness requiring mechanical ventilation, sedation, and paralytics, increasing the odds of developing postintensive care syndrome

Treatment options

Use of standard of care treatments, as well as neurocognitive rehabilitation and psychosocial support, is recommended for specific neuropsychiatric conditions. Patients with headache may benefit from treatment with amitriptyline or similar medications. Olfactory training and intranasal treatments can benefit those with loss of smell. 

Future Directions

Two medications that may hold promise for treating individuals long COVID symptoms are currently undergoing early investigation.

Pyridostigmine may help improve peak exercise capacity

Pyridostigmine improved peak exercise oxygen uptake in patients with chronic fatigue syndrome in a randomized, double-blind, placebo-controlled trial involving 45 individuals. Participants were assigned to receive either pyridostigmine 60 mg orally or placebo, and the pyridostigmine group showed an improved peak exercise uptake via increased cardiac output and right ventricular filling pressures. 

An investigational compound may improve fatigue-based symptoms

A 4-week protocol using the compound AXA1125 improved fatigue-based symptoms in patients with long COVID in a double-blind, randomized, controlled phase 2a pilot study involving 41 individuals. Investigators looked at average change in postexertional skeletal muscle phosphocreatine (PCr) recovery rate from baseline to day 28 after moderate exercise as well as fatigue levels. Although PCr recovery rate did not differ significantly between groups, use of the compound was linked with significant reduction in fatigue-based symptoms.

Summary

It is important to exercise caution when interpreting data involving individuals with long COVID. Most studies to date are retrospective and observational, definitions and assessments are not yet standardized, and long-term follow-up is lacking, among other factors. 

Clinicians should remain vigilant, keeping the following in mind as they see patients who may be experiencing long COVID: 

• Those most at risk include females, older individuals, those with obesity, people with preexisting conditions, individuals who experienced multiple symptoms early in their COVID-19 illness, and those who had breakthrough infections after COVID-19 vaccination 

• Symptoms may persist up to 2 years after acute infection

• The most common manifestations of long COVID involve pulmonary, cardiac, and neuropsychiatric complications

• Two medications, pyridostigmine and the compound AXA1125, are under investigation and may hold promise in treating some symptoms

As the pandemic wanes, the public is clamoring for a return to normal. But individuals with long COVID face a challenging journey to get back to their baseline. Here’s what clinicians need to know to help patients with long COVID. 

The COVID-19 pandemic is waning. The official federal public health emergency ended on May 11, 2023. Moreover, the public is ready to move on 3 years after the beginning of a pandemic that resulted in over a million deaths in the United States.  

But not everyone can go back to normal. The Centers for Disease Control and Prevention (CDC) estimates that 1 in 13 US adults (7.5%) have long COVID symptoms. Many of these people feel as if they are the forgotten patients. While everyone else is moving on, a significant number of people have not returned to their baseline. 

A group from Yale School of Medicine, myself included, reviewed a number of studies to gain a better understanding of 1) how long COVID manifests and 2) potential treatment options. Highlights of our evaluation are presented here.

Long COVID: The Basics
What exactly is long COVID-19, and how is it thought to develop? 

The World Health Organization (WHO) defines long COVID as symptoms that persist 3 months postinfection, last for ≥ 2 months, and are not attributable to another cause. 

Hypotheses about the mechanisms of long COVID include the presence of a persistent viral reservoir, an imbalance in the viral and microbial ecosystems, reactivation of latent DNA viruses, and endothelial dysfunction. 

Who is most at risk?

• Females

• Older individuals

• Individuals with preexisting conditions, including hypertension, diabetes, obesity, and lung disease 

• Individuals who experienced > 5 symptoms within the first week of COVID-19 illness 

• Individuals with breakthrough infections after vaccination against COVID-19 appear to be at increased risk of at least 1 postacute condition

Additionally, as the risk of contracting COVID-19 is demonstrably higher in certain racial and ethnic populations, it stands to reason that more of these individuals will experience long COVID. 

Long COVID symptoms: how long is long?

Long COVID symptoms may persist for 2 years after initial infection. One analysis from China showed that nearly 7 in 10 patients experienced at least 1 ongoing symptom 6 months following infection, with more than half reporting symptoms at 24 months. Dyspnea, anxiety, and depression are especially persistent. 

In another analysis, 90% of individuals reported symptoms 35 weeks postinfection. Symptoms did not only occur in people who were hospitalized; they also occurred in people who had a “mild case.”

Clinical Manifestations of Long COVID

More than 50 symptoms have been identified as potentially associated with long COVID. The most common manifestations involve pulmonary, cardiac, and neuropsychiatric sequelae. There is no single test to determine if symptoms are due to long COVID.

Pulmonary

How it manifests

• Chronic cough 

• Shortness of breath 

• Interstitial lung disease

Treatment options

Treatment options are variable and depend on predominant symptoms. Chronic cough should be managed based on primary etiology. Treatment for interstitial lung disease depends on whether the process continues to evolve or stabilizes. The role of antifibrotics in these patients is being investigated. Lung transplantation has largely been reserved for unresolved acute injury. 

Cardiac

How it manifests

• Postacute sequelae cardiovascular disease, where cardiovascular disorders are uncovered during diagnostic testing

• Postacute sequelae cardiovascular syndrome, such as exercise intolerance, tachycardia and chest pain, and dyspnea

Other important considerations:

• Cardiac symptoms can occur independent of preexisting conditions, severity, course of acute illness, and time from original diagnosis

• Cardiac involvement can occur in any age group

• One analysis revealed increased risk of stroke, arrythmias, pericarditis, myocarditis, and ischemic heart disease 1 year after COVID-19 infection

• Postural orthostatic tachycardia syndrome (POTS) and neurogenic orthostatic hypotension have also been observed

Treatment options

Treatment options are dictated by clinical manifestations and course. Patients who have autonomic dysfunction can be advised to increase salt and water intake since hypovolemia can worsen symptoms. Consider fludrocortisone and midodrine along with recumbent and semirecumbent exercises as tolerated, as exercise can sometimes worsen symptoms.

Neuropsychiatric

How it manifests

Patients can present with fatigue, memory disorders, headache, vertigo, myalgia, neuropathy, and smell and taste disorders, and there have been reports of cognitive decline postinfection. 

Other important considerations:

• A retrospective cohort study revealed that 34% of individuals had a new neurological or psychiatric diagnosis in the first 6 months after infection, including intracranial hemorrhage, ischemic stroke, parkinsonism, and dementia. Many COVID survivors experienced critical illness requiring mechanical ventilation, sedation, and paralytics, increasing the odds of developing postintensive care syndrome

Treatment options

Use of standard of care treatments, as well as neurocognitive rehabilitation and psychosocial support, is recommended for specific neuropsychiatric conditions. Patients with headache may benefit from treatment with amitriptyline or similar medications. Olfactory training and intranasal treatments can benefit those with loss of smell. 

Future Directions

Two medications that may hold promise for treating individuals long COVID symptoms are currently undergoing early investigation.

Pyridostigmine may help improve peak exercise capacity

Pyridostigmine improved peak exercise oxygen uptake in patients with chronic fatigue syndrome in a randomized, double-blind, placebo-controlled trial involving 45 individuals. Participants were assigned to receive either pyridostigmine 60 mg orally or placebo, and the pyridostigmine group showed an improved peak exercise uptake via increased cardiac output and right ventricular filling pressures. 

An investigational compound may improve fatigue-based symptoms

A 4-week protocol using the compound AXA1125 improved fatigue-based symptoms in patients with long COVID in a double-blind, randomized, controlled phase 2a pilot study involving 41 individuals. Investigators looked at average change in postexertional skeletal muscle phosphocreatine (PCr) recovery rate from baseline to day 28 after moderate exercise as well as fatigue levels. Although PCr recovery rate did not differ significantly between groups, use of the compound was linked with significant reduction in fatigue-based symptoms.

Summary

It is important to exercise caution when interpreting data involving individuals with long COVID. Most studies to date are retrospective and observational, definitions and assessments are not yet standardized, and long-term follow-up is lacking, among other factors. 

Clinicians should remain vigilant, keeping the following in mind as they see patients who may be experiencing long COVID: 

• Those most at risk include females, older individuals, those with obesity, people with preexisting conditions, individuals who experienced multiple symptoms early in their COVID-19 illness, and those who had breakthrough infections after COVID-19 vaccination 

• Symptoms may persist up to 2 years after acute infection

• The most common manifestations of long COVID involve pulmonary, cardiac, and neuropsychiatric complications

• Two medications, pyridostigmine and the compound AXA1125, are under investigation and may hold promise in treating some symptoms

As the pandemic wanes, the public is clamoring for a return to normal. But individuals with long COVID face a challenging journey to get back to their baseline. Here’s what clinicians need to know to help patients with long COVID. 

The COVID-19 pandemic is waning. The official federal public health emergency ended on May 11, 2023. Moreover, the public is ready to move on 3 years after the beginning of a pandemic that resulted in over a million deaths in the United States.  

But not everyone can go back to normal. The Centers for Disease Control and Prevention (CDC) estimates that 1 in 13 US adults (7.5%) have long COVID symptoms. Many of these people feel as if they are the forgotten patients. While everyone else is moving on, a significant number of people have not returned to their baseline. 

A group from Yale School of Medicine, myself included, reviewed a number of studies to gain a better understanding of 1) how long COVID manifests and 2) potential treatment options. Highlights of our evaluation are presented here.

Long COVID: The Basics
What exactly is long COVID-19, and how is it thought to develop? 

The World Health Organization (WHO) defines long COVID as symptoms that persist 3 months postinfection, last for ≥ 2 months, and are not attributable to another cause. 

Hypotheses about the mechanisms of long COVID include the presence of a persistent viral reservoir, an imbalance in the viral and microbial ecosystems, reactivation of latent DNA viruses, and endothelial dysfunction. 

Who is most at risk?

• Females

• Older individuals

• Individuals with preexisting conditions, including hypertension, diabetes, obesity, and lung disease 

• Individuals who experienced > 5 symptoms within the first week of COVID-19 illness 

• Individuals with breakthrough infections after vaccination against COVID-19 appear to be at increased risk of at least 1 postacute condition

Additionally, as the risk of contracting COVID-19 is demonstrably higher in certain racial and ethnic populations, it stands to reason that more of these individuals will experience long COVID. 

Long COVID symptoms: how long is long?

Long COVID symptoms may persist for 2 years after initial infection. One analysis from China showed that nearly 7 in 10 patients experienced at least 1 ongoing symptom 6 months following infection, with more than half reporting symptoms at 24 months. Dyspnea, anxiety, and depression are especially persistent. 

In another analysis, 90% of individuals reported symptoms 35 weeks postinfection. Symptoms did not only occur in people who were hospitalized; they also occurred in people who had a “mild case.”

Clinical Manifestations of Long COVID

More than 50 symptoms have been identified as potentially associated with long COVID. The most common manifestations involve pulmonary, cardiac, and neuropsychiatric sequelae. There is no single test to determine if symptoms are due to long COVID.

Pulmonary

How it manifests

• Chronic cough 

• Shortness of breath 

• Interstitial lung disease

Treatment options

Treatment options are variable and depend on predominant symptoms. Chronic cough should be managed based on primary etiology. Treatment for interstitial lung disease depends on whether the process continues to evolve or stabilizes. The role of antifibrotics in these patients is being investigated. Lung transplantation has largely been reserved for unresolved acute injury. 

Cardiac

How it manifests

• Postacute sequelae cardiovascular disease, where cardiovascular disorders are uncovered during diagnostic testing

• Postacute sequelae cardiovascular syndrome, such as exercise intolerance, tachycardia and chest pain, and dyspnea

Other important considerations:

• Cardiac symptoms can occur independent of preexisting conditions, severity, course of acute illness, and time from original diagnosis

• Cardiac involvement can occur in any age group

• One analysis revealed increased risk of stroke, arrythmias, pericarditis, myocarditis, and ischemic heart disease 1 year after COVID-19 infection

• Postural orthostatic tachycardia syndrome (POTS) and neurogenic orthostatic hypotension have also been observed

Treatment options

Treatment options are dictated by clinical manifestations and course. Patients who have autonomic dysfunction can be advised to increase salt and water intake since hypovolemia can worsen symptoms. Consider fludrocortisone and midodrine along with recumbent and semirecumbent exercises as tolerated, as exercise can sometimes worsen symptoms.

Neuropsychiatric

How it manifests

Patients can present with fatigue, memory disorders, headache, vertigo, myalgia, neuropathy, and smell and taste disorders, and there have been reports of cognitive decline postinfection. 

Other important considerations:

• A retrospective cohort study revealed that 34% of individuals had a new neurological or psychiatric diagnosis in the first 6 months after infection, including intracranial hemorrhage, ischemic stroke, parkinsonism, and dementia. Many COVID survivors experienced critical illness requiring mechanical ventilation, sedation, and paralytics, increasing the odds of developing postintensive care syndrome

Treatment options

Use of standard of care treatments, as well as neurocognitive rehabilitation and psychosocial support, is recommended for specific neuropsychiatric conditions. Patients with headache may benefit from treatment with amitriptyline or similar medications. Olfactory training and intranasal treatments can benefit those with loss of smell. 

Future Directions

Two medications that may hold promise for treating individuals long COVID symptoms are currently undergoing early investigation.

Pyridostigmine may help improve peak exercise capacity

Pyridostigmine improved peak exercise oxygen uptake in patients with chronic fatigue syndrome in a randomized, double-blind, placebo-controlled trial involving 45 individuals. Participants were assigned to receive either pyridostigmine 60 mg orally or placebo, and the pyridostigmine group showed an improved peak exercise uptake via increased cardiac output and right ventricular filling pressures. 

An investigational compound may improve fatigue-based symptoms

A 4-week protocol using the compound AXA1125 improved fatigue-based symptoms in patients with long COVID in a double-blind, randomized, controlled phase 2a pilot study involving 41 individuals. Investigators looked at average change in postexertional skeletal muscle phosphocreatine (PCr) recovery rate from baseline to day 28 after moderate exercise as well as fatigue levels. Although PCr recovery rate did not differ significantly between groups, use of the compound was linked with significant reduction in fatigue-based symptoms.

Summary

It is important to exercise caution when interpreting data involving individuals with long COVID. Most studies to date are retrospective and observational, definitions and assessments are not yet standardized, and long-term follow-up is lacking, among other factors. 

Clinicians should remain vigilant, keeping the following in mind as they see patients who may be experiencing long COVID: 

• Those most at risk include females, older individuals, those with obesity, people with preexisting conditions, individuals who experienced multiple symptoms early in their COVID-19 illness, and those who had breakthrough infections after COVID-19 vaccination 

• Symptoms may persist up to 2 years after acute infection

• The most common manifestations of long COVID involve pulmonary, cardiac, and neuropsychiatric complications

• Two medications, pyridostigmine and the compound AXA1125, are under investigation and may hold promise in treating some symptoms

The areas of hair loss and different length hairs in a patient with otherwise normal-density hair was consistent with a diagnosis of trichotillomania. The physician initially thought the patient had a “fade” hairstyle, but then observed him twirling his hair. Further queries confirmed a history of hair pulling (trichotillomania) and ingesting the hair (trichophagia).

In adulthood, trichotillomania affects females about 4 times more than males, although in childhood, the sex distribution appears about equal.¹ The typical age of onset is between 10 to 13 years. Several mental health conditions are associated with trichotillomania, such as major depressive disorder, anxiety disorders, and substance use disorder, with trichotillomania generally preceding these comorbid disorders. It is important to rule out obsessive compulsive disorder and consider body dysmorphic disorder when making a diagnosis of trichotillomania.¹

It is common to see androgenetic alopecia precipitated by hormone therapy in FTM individuals. This would usually cause thinning of the hair rather than the irregular hair lengths and pattern seen in this patient. Tinea capitis is also part of the differential diagnosis in a case such as this. It can be diagnosed by potassium hydroxide (KOH) preparations in the setting of friable and broken hair shafts (and sometimes erythema and inflammation).

Patients with trichotillomania may have hair with blunt or tapered ends; hair may also look like uneven stubble.² The scalp is the most commonly involved site (72.8%), followed by eyebrows (50.7%), and the pubic region (50.7%).¹ Useful diagnostic clues include an unusual shape of the affected area, accessible location, and a changing pattern from visit to visit.² If trichotillomania is suspected, it might be useful to ask about hair-playing activities, such as twirling or twisting, or playing with the ends of eyelashes or eyebrows.²

Unwanted medical consequences of trichotillomania include skin damage (if sharp instruments are used for hair pulling), and the formation of gastrointestinal trichobezoars (hairballs) if trichophagia is present. Trichobezoars that cause bowel obstructions may need surgical intervention.¹

Behavioral therapy is the first-line treatment for trichotillomania in all age groups.^1,3 Treating any coexisting mental health disorders is also essential. There are currently no FDA-approved medications for treatment; however, there is evidence that N-acetylcysteine may be useful in treating adults with trichotillomania and other repetitive skin disorders.³ Antipsychotics and cannabinoid agonists also may be beneficial.¹

This patient was continued on his current lithium, naltrexone, and bupropion regimen (rather than adding additional psychiatric medicines) as he was doing better than his previous baseline. He was advised to continue with his cognitive behavioral therapy. His hormone replacement therapy also was continued because it was not thought to be contributory. He was provided with education about symptoms of trichobezoar and red flag symptoms (eg, worsening nausea, vomiting, abdominal pain) that would necessitate emergency follow-up. His GERD symptoms were thought not to be related to his trichophagia. He was scheduled to follow up for routine primary care in 6 months.

‌

Photo courtesy of Daniel Stulberg, MD. Text courtesy of Sarasawati Keeni, MD, and Daniel Stulberg, MD, FAAFP, Department of Family and Community Medicine, Western Michigan University Homer Stryker, MD School of Medicine, Kalamazoo.

The areas of hair loss and different length hairs in a patient with otherwise normal-density hair was consistent with a diagnosis of trichotillomania. The physician initially thought the patient had a “fade” hairstyle, but then observed him twirling his hair. Further queries confirmed a history of hair pulling (trichotillomania) and ingesting the hair (trichophagia).

In adulthood, trichotillomania affects females about 4 times more than males, although in childhood, the sex distribution appears about equal.¹ The typical age of onset is between 10 to 13 years. Several mental health conditions are associated with trichotillomania, such as major depressive disorder, anxiety disorders, and substance use disorder, with trichotillomania generally preceding these comorbid disorders. It is important to rule out obsessive compulsive disorder and consider body dysmorphic disorder when making a diagnosis of trichotillomania.¹

It is common to see androgenetic alopecia precipitated by hormone therapy in FTM individuals. This would usually cause thinning of the hair rather than the irregular hair lengths and pattern seen in this patient. Tinea capitis is also part of the differential diagnosis in a case such as this. It can be diagnosed by potassium hydroxide (KOH) preparations in the setting of friable and broken hair shafts (and sometimes erythema and inflammation).

Patients with trichotillomania may have hair with blunt or tapered ends; hair may also look like uneven stubble.² The scalp is the most commonly involved site (72.8%), followed by eyebrows (50.7%), and the pubic region (50.7%).¹ Useful diagnostic clues include an unusual shape of the affected area, accessible location, and a changing pattern from visit to visit.² If trichotillomania is suspected, it might be useful to ask about hair-playing activities, such as twirling or twisting, or playing with the ends of eyelashes or eyebrows.²

Unwanted medical consequences of trichotillomania include skin damage (if sharp instruments are used for hair pulling), and the formation of gastrointestinal trichobezoars (hairballs) if trichophagia is present. Trichobezoars that cause bowel obstructions may need surgical intervention.¹

Behavioral therapy is the first-line treatment for trichotillomania in all age groups.^1,3 Treating any coexisting mental health disorders is also essential. There are currently no FDA-approved medications for treatment; however, there is evidence that N-acetylcysteine may be useful in treating adults with trichotillomania and other repetitive skin disorders.³ Antipsychotics and cannabinoid agonists also may be beneficial.¹

This patient was continued on his current lithium, naltrexone, and bupropion regimen (rather than adding additional psychiatric medicines) as he was doing better than his previous baseline. He was advised to continue with his cognitive behavioral therapy. His hormone replacement therapy also was continued because it was not thought to be contributory. He was provided with education about symptoms of trichobezoar and red flag symptoms (eg, worsening nausea, vomiting, abdominal pain) that would necessitate emergency follow-up. His GERD symptoms were thought not to be related to his trichophagia. He was scheduled to follow up for routine primary care in 6 months.

‌

Photo courtesy of Daniel Stulberg, MD. Text courtesy of Sarasawati Keeni, MD, and Daniel Stulberg, MD, FAAFP, Department of Family and Community Medicine, Western Michigan University Homer Stryker, MD School of Medicine, Kalamazoo.

The areas of hair loss and different length hairs in a patient with otherwise normal-density hair was consistent with a diagnosis of trichotillomania. The physician initially thought the patient had a “fade” hairstyle, but then observed him twirling his hair. Further queries confirmed a history of hair pulling (trichotillomania) and ingesting the hair (trichophagia).

In adulthood, trichotillomania affects females about 4 times more than males, although in childhood, the sex distribution appears about equal.¹ The typical age of onset is between 10 to 13 years. Several mental health conditions are associated with trichotillomania, such as major depressive disorder, anxiety disorders, and substance use disorder, with trichotillomania generally preceding these comorbid disorders. It is important to rule out obsessive compulsive disorder and consider body dysmorphic disorder when making a diagnosis of trichotillomania.¹

It is common to see androgenetic alopecia precipitated by hormone therapy in FTM individuals. This would usually cause thinning of the hair rather than the irregular hair lengths and pattern seen in this patient. Tinea capitis is also part of the differential diagnosis in a case such as this. It can be diagnosed by potassium hydroxide (KOH) preparations in the setting of friable and broken hair shafts (and sometimes erythema and inflammation).

Patients with trichotillomania may have hair with blunt or tapered ends; hair may also look like uneven stubble.² The scalp is the most commonly involved site (72.8%), followed by eyebrows (50.7%), and the pubic region (50.7%).¹ Useful diagnostic clues include an unusual shape of the affected area, accessible location, and a changing pattern from visit to visit.² If trichotillomania is suspected, it might be useful to ask about hair-playing activities, such as twirling or twisting, or playing with the ends of eyelashes or eyebrows.²

Unwanted medical consequences of trichotillomania include skin damage (if sharp instruments are used for hair pulling), and the formation of gastrointestinal trichobezoars (hairballs) if trichophagia is present. Trichobezoars that cause bowel obstructions may need surgical intervention.¹

Behavioral therapy is the first-line treatment for trichotillomania in all age groups.^1,3 Treating any coexisting mental health disorders is also essential. There are currently no FDA-approved medications for treatment; however, there is evidence that N-acetylcysteine may be useful in treating adults with trichotillomania and other repetitive skin disorders.³ Antipsychotics and cannabinoid agonists also may be beneficial.¹

This patient was continued on his current lithium, naltrexone, and bupropion regimen (rather than adding additional psychiatric medicines) as he was doing better than his previous baseline. He was advised to continue with his cognitive behavioral therapy. His hormone replacement therapy also was continued because it was not thought to be contributory. He was provided with education about symptoms of trichobezoar and red flag symptoms (eg, worsening nausea, vomiting, abdominal pain) that would necessitate emergency follow-up. His GERD symptoms were thought not to be related to his trichophagia. He was scheduled to follow up for routine primary care in 6 months.

‌

Photo courtesy of Daniel Stulberg, MD. Text courtesy of Sarasawati Keeni, MD, and Daniel Stulberg, MD, FAAFP, Department of Family and Community Medicine, Western Michigan University Homer Stryker, MD School of Medicine, Kalamazoo.

The Diagnosis: Hypopigmented Mycosis Fungoides

Histopathology showed an atypical lymphoid infiltrate with expanded cytoplasm and hyperchromatic nuclei of irregular contours in the dermoepidermal junction (Figure 1). Immunohistochemical stains of atypical lymphocytes demonstrated the presence of CD3, CD8, and CD5, as well as the absence of CD7 and CD4 lymphocytes (Figure 2). The T-cell γ rearrangement showed polyclonal lymphocytes with 5% tumor cells. The histologic and clinical findings along with our patient’s medical history led to a diagnosis of stage IA (<10% body surface area involvement) hypopigmented mycosis fungoides (hMF).¹ Our patient was treated with triamcinolone cream 0.1%; she noted an improvement in her symptoms at 2-month follow-up.

Hypopigmented MF is an uncommon manifestation of MF with unknown prevalence and incidence rates. Mycosis fungoides is considered the most common subtype of cutaneous T-cell lymphoma that classically presents as a chronic, indolent, hypopigmented or depigmented macule or patch, commonly with scaling, in sunprotected areas such as the trunk and proximal arms and legs. It predominantly affects younger adults with darker skin tones and may be present in the pediatric population within the first decade of life.¹ Classically, MF affects White patients aged 55 to 60 years. Disease progression is slow, with an incidence rate of 10% of tumor or extracutaneous involvement in the early stages of disease. A lack of specificity on the clinical and histopathologic findings in the initial stage often contributes to the diagnostic delay of hMF. As seen in our patient, this disease can be misdiagnosed as tinea versicolor, postinflammatory hypopigmentation, vitiligo, pityriasis alba, subcutaneous lupus erythematosus, or Hansen disease due to prolonged hypopigmented lesions.² The clinical findings and histopathologic results including immunohistochemistry confirmed the diagnosis of hMF and ruled out pityriasis alba, postinflammatory hypopigmentation, subcutaneous lupus erythematosus, and vitiligo.

The etiology and pathophysiology of hMF are not fully understood; however, it is hypothesized that melanocyte degeneration, abnormal melanogenesis, and disturbance of melanosome transfer result from the clonal expansion of T helper memory cells. T-cell dyscrasia has been reported to evolve into hMF during etanercept therapy.³ Clinically, hMF presents as hypopigmented papulosquamous, eczematous, or erythrodermic patches, plaques, and tumors with poorly defined atrophied borders. Multiple biopsies of steroid-naive lesions are needed for the diagnosis, as the initial hMF histologic finding cannot be specific for diagnostic confirmation. Common histopathologic findings include a bandlike lymphocytic infiltrate with epidermotropism, intraepidermal nests of atypical cells, or cerebriform nuclei lymphocytes on hematoxylin and eosin staining. In comparison to classical MF epidermotropism, CD4− and CD8+ atypical cells aid in the diagnosis of hMF. Although hMF carries a good prognosis and a benign clinical course,⁴ full-body computed tomography or positron emission tomography/computed tomography as well as laboratory analysis for lactate dehydrogenase should be pursued if lymphadenopathy, systemic symptoms, or advancedstage hMF are present.

Treatment of hMF depends on the disease stage. Psoralen plus UVA and narrowband UVB can be utilized for the initial stages with a relatively fast response and remission of lesions as early as the first 2 months of treatment. In addition to phototherapy, stage IA to IIA mycosis fungoides with localized skin lesions can benefit from topical steroids, topical retinoids, imiquimod, nitrogen mustard, and carmustine. For advanced stages of mycosis fungoides, combination therapy consisting of psoralen plus UVA with an oral retinoid, interferon alfa, and systemic chemotherapy commonly are prescribed. Maintenance therapy is used for prolonging remission; however, long-term phototherapy is not recommended due to the risk for skin cancer. Unfortunately, hMF requires long-term treatment due to its waxing and waning course, and recurrence may occur after complete resolution.⁵

The Diagnosis: Hypopigmented Mycosis Fungoides

Histopathology showed an atypical lymphoid infiltrate with expanded cytoplasm and hyperchromatic nuclei of irregular contours in the dermoepidermal junction (Figure 1). Immunohistochemical stains of atypical lymphocytes demonstrated the presence of CD3, CD8, and CD5, as well as the absence of CD7 and CD4 lymphocytes (Figure 2). The T-cell γ rearrangement showed polyclonal lymphocytes with 5% tumor cells. The histologic and clinical findings along with our patient’s medical history led to a diagnosis of stage IA (<10% body surface area involvement) hypopigmented mycosis fungoides (hMF).¹ Our patient was treated with triamcinolone cream 0.1%; she noted an improvement in her symptoms at 2-month follow-up.

Hypopigmented MF is an uncommon manifestation of MF with unknown prevalence and incidence rates. Mycosis fungoides is considered the most common subtype of cutaneous T-cell lymphoma that classically presents as a chronic, indolent, hypopigmented or depigmented macule or patch, commonly with scaling, in sunprotected areas such as the trunk and proximal arms and legs. It predominantly affects younger adults with darker skin tones and may be present in the pediatric population within the first decade of life.¹ Classically, MF affects White patients aged 55 to 60 years. Disease progression is slow, with an incidence rate of 10% of tumor or extracutaneous involvement in the early stages of disease. A lack of specificity on the clinical and histopathologic findings in the initial stage often contributes to the diagnostic delay of hMF. As seen in our patient, this disease can be misdiagnosed as tinea versicolor, postinflammatory hypopigmentation, vitiligo, pityriasis alba, subcutaneous lupus erythematosus, or Hansen disease due to prolonged hypopigmented lesions.² The clinical findings and histopathologic results including immunohistochemistry confirmed the diagnosis of hMF and ruled out pityriasis alba, postinflammatory hypopigmentation, subcutaneous lupus erythematosus, and vitiligo.

The etiology and pathophysiology of hMF are not fully understood; however, it is hypothesized that melanocyte degeneration, abnormal melanogenesis, and disturbance of melanosome transfer result from the clonal expansion of T helper memory cells. T-cell dyscrasia has been reported to evolve into hMF during etanercept therapy.³ Clinically, hMF presents as hypopigmented papulosquamous, eczematous, or erythrodermic patches, plaques, and tumors with poorly defined atrophied borders. Multiple biopsies of steroid-naive lesions are needed for the diagnosis, as the initial hMF histologic finding cannot be specific for diagnostic confirmation. Common histopathologic findings include a bandlike lymphocytic infiltrate with epidermotropism, intraepidermal nests of atypical cells, or cerebriform nuclei lymphocytes on hematoxylin and eosin staining. In comparison to classical MF epidermotropism, CD4− and CD8+ atypical cells aid in the diagnosis of hMF. Although hMF carries a good prognosis and a benign clinical course,⁴ full-body computed tomography or positron emission tomography/computed tomography as well as laboratory analysis for lactate dehydrogenase should be pursued if lymphadenopathy, systemic symptoms, or advancedstage hMF are present.

Treatment of hMF depends on the disease stage. Psoralen plus UVA and narrowband UVB can be utilized for the initial stages with a relatively fast response and remission of lesions as early as the first 2 months of treatment. In addition to phototherapy, stage IA to IIA mycosis fungoides with localized skin lesions can benefit from topical steroids, topical retinoids, imiquimod, nitrogen mustard, and carmustine. For advanced stages of mycosis fungoides, combination therapy consisting of psoralen plus UVA with an oral retinoid, interferon alfa, and systemic chemotherapy commonly are prescribed. Maintenance therapy is used for prolonging remission; however, long-term phototherapy is not recommended due to the risk for skin cancer. Unfortunately, hMF requires long-term treatment due to its waxing and waning course, and recurrence may occur after complete resolution.⁵

The Diagnosis: Hypopigmented Mycosis Fungoides

Histopathology showed an atypical lymphoid infiltrate with expanded cytoplasm and hyperchromatic nuclei of irregular contours in the dermoepidermal junction (Figure 1). Immunohistochemical stains of atypical lymphocytes demonstrated the presence of CD3, CD8, and CD5, as well as the absence of CD7 and CD4 lymphocytes (Figure 2). The T-cell γ rearrangement showed polyclonal lymphocytes with 5% tumor cells. The histologic and clinical findings along with our patient’s medical history led to a diagnosis of stage IA (<10% body surface area involvement) hypopigmented mycosis fungoides (hMF).¹ Our patient was treated with triamcinolone cream 0.1%; she noted an improvement in her symptoms at 2-month follow-up.

Hypopigmented MF is an uncommon manifestation of MF with unknown prevalence and incidence rates. Mycosis fungoides is considered the most common subtype of cutaneous T-cell lymphoma that classically presents as a chronic, indolent, hypopigmented or depigmented macule or patch, commonly with scaling, in sunprotected areas such as the trunk and proximal arms and legs. It predominantly affects younger adults with darker skin tones and may be present in the pediatric population within the first decade of life.¹ Classically, MF affects White patients aged 55 to 60 years. Disease progression is slow, with an incidence rate of 10% of tumor or extracutaneous involvement in the early stages of disease. A lack of specificity on the clinical and histopathologic findings in the initial stage often contributes to the diagnostic delay of hMF. As seen in our patient, this disease can be misdiagnosed as tinea versicolor, postinflammatory hypopigmentation, vitiligo, pityriasis alba, subcutaneous lupus erythematosus, or Hansen disease due to prolonged hypopigmented lesions.² The clinical findings and histopathologic results including immunohistochemistry confirmed the diagnosis of hMF and ruled out pityriasis alba, postinflammatory hypopigmentation, subcutaneous lupus erythematosus, and vitiligo.

The etiology and pathophysiology of hMF are not fully understood; however, it is hypothesized that melanocyte degeneration, abnormal melanogenesis, and disturbance of melanosome transfer result from the clonal expansion of T helper memory cells. T-cell dyscrasia has been reported to evolve into hMF during etanercept therapy.³ Clinically, hMF presents as hypopigmented papulosquamous, eczematous, or erythrodermic patches, plaques, and tumors with poorly defined atrophied borders. Multiple biopsies of steroid-naive lesions are needed for the diagnosis, as the initial hMF histologic finding cannot be specific for diagnostic confirmation. Common histopathologic findings include a bandlike lymphocytic infiltrate with epidermotropism, intraepidermal nests of atypical cells, or cerebriform nuclei lymphocytes on hematoxylin and eosin staining. In comparison to classical MF epidermotropism, CD4− and CD8+ atypical cells aid in the diagnosis of hMF. Although hMF carries a good prognosis and a benign clinical course,⁴ full-body computed tomography or positron emission tomography/computed tomography as well as laboratory analysis for lactate dehydrogenase should be pursued if lymphadenopathy, systemic symptoms, or advancedstage hMF are present.

Treatment of hMF depends on the disease stage. Psoralen plus UVA and narrowband UVB can be utilized for the initial stages with a relatively fast response and remission of lesions as early as the first 2 months of treatment. In addition to phototherapy, stage IA to IIA mycosis fungoides with localized skin lesions can benefit from topical steroids, topical retinoids, imiquimod, nitrogen mustard, and carmustine. For advanced stages of mycosis fungoides, combination therapy consisting of psoralen plus UVA with an oral retinoid, interferon alfa, and systemic chemotherapy commonly are prescribed. Maintenance therapy is used for prolonging remission; however, long-term phototherapy is not recommended due to the risk for skin cancer. Unfortunately, hMF requires long-term treatment due to its waxing and waning course, and recurrence may occur after complete resolution.⁵

The neoadjuvant setting provides a favorable environment to study de-escalation approaches as treatment response (via pathologic complete response [pCR] assessment) can be used as a surrogate marker for outcome. Studies have shown the effect of HER2-enriched subtype and high ERBB2 expression on pCR rates after receipt of a chemotherapy-free, dual HER2-targeted regimen.² The prospective, multicenter, neoadjuvant phase 2 WSG-TP-II trial randomly assigned 207 patients with HR+/HER2+ early breast cancer to 12 weeks of endocrine therapy (ET)–trastuzumab-pertuzumab vs paclitaxel-trastuzumab-pertuzumab. The pCR rate was inferior in the ET arm compared with the paclitaxel arm (23.7% vs 56.4%; odds ratio 0.24; 95% CI 0.12-0.46; P < .001). In addition, an immunohistochemistry ERBB2 score of 3 or higher and ERBB2-enriched subtype were predictors of higher pCR rates in both arms (Gluz et al). This study not only supports a deescalated chemotherapy neoadjuvant strategy of paclitaxel + dual HER2 blockade but also suggests that a portion of patients may potentially be spared chemotherapy with very good results. The role of biomarkers is integral to patient selection for these approaches, and the evaluation of response in real-time will allow for the tailoring of therapy to achieve the best outcome.

Systemic staging for locally advanced breast cancer (LABC) is important for informing prognosis as well as aiding in development of an appropriate treatment plan for patients. The PETABC study included 369 patients with LABC (TNM stage III or IIB [T3N0]) with random assignment to ¹⁸F-labeled fluorodeoxyglucose PET-CT or conventional staging (bone scan, CT of chest/abdomen/pelvis), and was designed to assess the rate of upstaging with each imaging modality and effect on treatment (Dayes et al). In the PET-CT group, 23% (N = 43) of patients were upstaged to stage IV compared with 11% (N = 21) in the conventional-staging group (absolute difference 12.3%; 95% CI 3.9-19.9; P = .002). Fewer patients in the PET-CT group received combined modality treatment vs those patients in the conventional staging group (81% vs 89.2%; P = .03). These results support the consideration of PET-CT as a staging tool for LABC, and this is reflected in various clinical guidelines. Furthermore, the evolving role of other imaging techniques such as ¹⁸F-fluoroestradiol (18F-FES) PET-CT in detection of metastatic lesions related to estrogen receptor–positive breast cancer³ will continue to advance the field of imaging.

Additional References

1. Rugo HS, Lerebours F, Ciruelos E, et al. Alpelisib plus fulvestrant in PIK3CA-mutated, hormone receptor-positive advanced breast cancer after a CDK4/6 inhibitor (BYLieve): One cohort of a phase 2, multicentre, open-label, non-comparative study. Lancet Oncol. 2021;22:489-498. doi: 10.1016/S1470-2045(21)00034-6. Erratum in: Lancet Oncol. 2021;22(5):e184. doi: 10.1016/S1470-2045(21)00194-7
2. Prat A, Pascual T, De Angelis C, et al. HER2-enriched subtype and ERBB2 expression in HER2-positive breast cancer treated with dual HER2 blockade. J Natl Cancer Inst. 2020;112:46-54. doi: 10.1093/jnci/djz042
3. Ulaner GA, Jhaveri K, Chandarlapaty S, et al. Head-to-head evaluation of ¹⁸F-FES and ¹⁸F-FDG PET/CT in metastatic invasive lobular breast cancer. J Nucl Med. 2021;62:326-331. doi: 10.2967/jnumed.120.247882

The neoadjuvant setting provides a favorable environment to study de-escalation approaches as treatment response (via pathologic complete response [pCR] assessment) can be used as a surrogate marker for outcome. Studies have shown the effect of HER2-enriched subtype and high ERBB2 expression on pCR rates after receipt of a chemotherapy-free, dual HER2-targeted regimen.² The prospective, multicenter, neoadjuvant phase 2 WSG-TP-II trial randomly assigned 207 patients with HR+/HER2+ early breast cancer to 12 weeks of endocrine therapy (ET)–trastuzumab-pertuzumab vs paclitaxel-trastuzumab-pertuzumab. The pCR rate was inferior in the ET arm compared with the paclitaxel arm (23.7% vs 56.4%; odds ratio 0.24; 95% CI 0.12-0.46; P < .001). In addition, an immunohistochemistry ERBB2 score of 3 or higher and ERBB2-enriched subtype were predictors of higher pCR rates in both arms (Gluz et al). This study not only supports a deescalated chemotherapy neoadjuvant strategy of paclitaxel + dual HER2 blockade but also suggests that a portion of patients may potentially be spared chemotherapy with very good results. The role of biomarkers is integral to patient selection for these approaches, and the evaluation of response in real-time will allow for the tailoring of therapy to achieve the best outcome.

Systemic staging for locally advanced breast cancer (LABC) is important for informing prognosis as well as aiding in development of an appropriate treatment plan for patients. The PETABC study included 369 patients with LABC (TNM stage III or IIB [T3N0]) with random assignment to ¹⁸F-labeled fluorodeoxyglucose PET-CT or conventional staging (bone scan, CT of chest/abdomen/pelvis), and was designed to assess the rate of upstaging with each imaging modality and effect on treatment (Dayes et al). In the PET-CT group, 23% (N = 43) of patients were upstaged to stage IV compared with 11% (N = 21) in the conventional-staging group (absolute difference 12.3%; 95% CI 3.9-19.9; P = .002). Fewer patients in the PET-CT group received combined modality treatment vs those patients in the conventional staging group (81% vs 89.2%; P = .03). These results support the consideration of PET-CT as a staging tool for LABC, and this is reflected in various clinical guidelines. Furthermore, the evolving role of other imaging techniques such as ¹⁸F-fluoroestradiol (18F-FES) PET-CT in detection of metastatic lesions related to estrogen receptor–positive breast cancer³ will continue to advance the field of imaging.

Additional References

1. Rugo HS, Lerebours F, Ciruelos E, et al. Alpelisib plus fulvestrant in PIK3CA-mutated, hormone receptor-positive advanced breast cancer after a CDK4/6 inhibitor (BYLieve): One cohort of a phase 2, multicentre, open-label, non-comparative study. Lancet Oncol. 2021;22:489-498. doi: 10.1016/S1470-2045(21)00034-6. Erratum in: Lancet Oncol. 2021;22(5):e184. doi: 10.1016/S1470-2045(21)00194-7
2. Prat A, Pascual T, De Angelis C, et al. HER2-enriched subtype and ERBB2 expression in HER2-positive breast cancer treated with dual HER2 blockade. J Natl Cancer Inst. 2020;112:46-54. doi: 10.1093/jnci/djz042
3. Ulaner GA, Jhaveri K, Chandarlapaty S, et al. Head-to-head evaluation of ¹⁸F-FES and ¹⁸F-FDG PET/CT in metastatic invasive lobular breast cancer. J Nucl Med. 2021;62:326-331. doi: 10.2967/jnumed.120.247882

The neoadjuvant setting provides a favorable environment to study de-escalation approaches as treatment response (via pathologic complete response [pCR] assessment) can be used as a surrogate marker for outcome. Studies have shown the effect of HER2-enriched subtype and high ERBB2 expression on pCR rates after receipt of a chemotherapy-free, dual HER2-targeted regimen.² The prospective, multicenter, neoadjuvant phase 2 WSG-TP-II trial randomly assigned 207 patients with HR+/HER2+ early breast cancer to 12 weeks of endocrine therapy (ET)–trastuzumab-pertuzumab vs paclitaxel-trastuzumab-pertuzumab. The pCR rate was inferior in the ET arm compared with the paclitaxel arm (23.7% vs 56.4%; odds ratio 0.24; 95% CI 0.12-0.46; P < .001). In addition, an immunohistochemistry ERBB2 score of 3 or higher and ERBB2-enriched subtype were predictors of higher pCR rates in both arms (Gluz et al). This study not only supports a deescalated chemotherapy neoadjuvant strategy of paclitaxel + dual HER2 blockade but also suggests that a portion of patients may potentially be spared chemotherapy with very good results. The role of biomarkers is integral to patient selection for these approaches, and the evaluation of response in real-time will allow for the tailoring of therapy to achieve the best outcome.

Systemic staging for locally advanced breast cancer (LABC) is important for informing prognosis as well as aiding in development of an appropriate treatment plan for patients. The PETABC study included 369 patients with LABC (TNM stage III or IIB [T3N0]) with random assignment to ¹⁸F-labeled fluorodeoxyglucose PET-CT or conventional staging (bone scan, CT of chest/abdomen/pelvis), and was designed to assess the rate of upstaging with each imaging modality and effect on treatment (Dayes et al). In the PET-CT group, 23% (N = 43) of patients were upstaged to stage IV compared with 11% (N = 21) in the conventional-staging group (absolute difference 12.3%; 95% CI 3.9-19.9; P = .002). Fewer patients in the PET-CT group received combined modality treatment vs those patients in the conventional staging group (81% vs 89.2%; P = .03). These results support the consideration of PET-CT as a staging tool for LABC, and this is reflected in various clinical guidelines. Furthermore, the evolving role of other imaging techniques such as ¹⁸F-fluoroestradiol (18F-FES) PET-CT in detection of metastatic lesions related to estrogen receptor–positive breast cancer³ will continue to advance the field of imaging.

Additional References

1. Rugo HS, Lerebours F, Ciruelos E, et al. Alpelisib plus fulvestrant in PIK3CA-mutated, hormone receptor-positive advanced breast cancer after a CDK4/6 inhibitor (BYLieve): One cohort of a phase 2, multicentre, open-label, non-comparative study. Lancet Oncol. 2021;22:489-498. doi: 10.1016/S1470-2045(21)00034-6. Erratum in: Lancet Oncol. 2021;22(5):e184. doi: 10.1016/S1470-2045(21)00194-7
2. Prat A, Pascual T, De Angelis C, et al. HER2-enriched subtype and ERBB2 expression in HER2-positive breast cancer treated with dual HER2 blockade. J Natl Cancer Inst. 2020;112:46-54. doi: 10.1093/jnci/djz042
3. Ulaner GA, Jhaveri K, Chandarlapaty S, et al. Head-to-head evaluation of ¹⁸F-FES and ¹⁸F-FDG PET/CT in metastatic invasive lobular breast cancer. J Nucl Med. 2021;62:326-331. doi: 10.2967/jnumed.120.247882

Small-cell lung cancer (SCLC) occurs almost exclusively in cigarette smokers. Veterans are particularly vulnerable to SCLC because of their prevalent smoking history and exposures to carcinogens, including Agent Orange. 

SCLC is characterized by the early development of widespread metastases, including liver, bone, and brain. 

Unlike, non–-small cell lung cancer, which has seen great improvement in survival from the introduction of immunotherapy and targeted agents, there has been relatively little improvement in SCLC. 

Patients generally are classified into limited- and extensive-stage disease, but platinum-based chemotherapy is almost always the standard first-line treatment. Unfortunately, most patients relapse within a year. 

In this ReCAP, Dr Shadia Jalal, of Indiana University Melvin and Bren Simon Comprehensive Cancer Center, discusses second-line treatment options for SCLC patients who relapse after chemotherapy. She also discusses four subtypes of SCLC categorized on the basis of specific transcription regulators, which may offer the potential of targeted therapies for this patient population.  

--

Shadia Jalal, MD, Associate Professor of Medicine, Physician, Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, Indiana 

Shadia Jalal, MD, has disclosed no relevant financial relationships. 

Small-cell lung cancer (SCLC) occurs almost exclusively in cigarette smokers. Veterans are particularly vulnerable to SCLC because of their prevalent smoking history and exposures to carcinogens, including Agent Orange. 

SCLC is characterized by the early development of widespread metastases, including liver, bone, and brain. 

Unlike, non–-small cell lung cancer, which has seen great improvement in survival from the introduction of immunotherapy and targeted agents, there has been relatively little improvement in SCLC. 

Patients generally are classified into limited- and extensive-stage disease, but platinum-based chemotherapy is almost always the standard first-line treatment. Unfortunately, most patients relapse within a year. 

In this ReCAP, Dr Shadia Jalal, of Indiana University Melvin and Bren Simon Comprehensive Cancer Center, discusses second-line treatment options for SCLC patients who relapse after chemotherapy. She also discusses four subtypes of SCLC categorized on the basis of specific transcription regulators, which may offer the potential of targeted therapies for this patient population.  

--

Shadia Jalal, MD, Associate Professor of Medicine, Physician, Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, Indiana 

Shadia Jalal, MD, has disclosed no relevant financial relationships. 

Small-cell lung cancer (SCLC) occurs almost exclusively in cigarette smokers. Veterans are particularly vulnerable to SCLC because of their prevalent smoking history and exposures to carcinogens, including Agent Orange. 

SCLC is characterized by the early development of widespread metastases, including liver, bone, and brain. 

Unlike, non–-small cell lung cancer, which has seen great improvement in survival from the introduction of immunotherapy and targeted agents, there has been relatively little improvement in SCLC. 

Patients generally are classified into limited- and extensive-stage disease, but platinum-based chemotherapy is almost always the standard first-line treatment. Unfortunately, most patients relapse within a year. 

In this ReCAP, Dr Shadia Jalal, of Indiana University Melvin and Bren Simon Comprehensive Cancer Center, discusses second-line treatment options for SCLC patients who relapse after chemotherapy. She also discusses four subtypes of SCLC categorized on the basis of specific transcription regulators, which may offer the potential of targeted therapies for this patient population.  

--

Shadia Jalal, MD, Associate Professor of Medicine, Physician, Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, Indiana 

Shadia Jalal, MD, has disclosed no relevant financial relationships. 

Incidence peaks in children aged 1-4 years, decreasing thereafter. Cases are highest among Native American/Alaskan Native and Hispanic children, and higher in White than Black children.⁴ ALL is seen more in patients with certain inherited conditions, including Down syndrome, ataxia telangiectasia, neurofibromatosis type 1, and Bloom syndrome.¹

Treatment advances have improved remission rates and outcomes for patients. However, relapse is still a leading cause of death for patients of all ages.⁶ Prompt diagnosis and care are important to optimize outcomes, as treatment delay is associated with poorer survival.⁷

Pathophysiology

In ALL, abnormal, immature lymphocytes and progenitor B cells/T cells proliferate uncontrollably and eventually replace healthy cells in bone marrow and the lymphatic system. The loss of healthy cells leads to classic symptoms of cytopenia, splenomegaly, and hepatomegaly.¹ B cells and T cells are descended from lymphoid stem cells (and are transformed by germline or somatic mutation into pathogenic cells, leading to symptom development and bone marrow dysfunction. Most pediatric patients have extensive bone marrow involvement at diagnosis, with > 25% blast cells in marrow (defined as M3 disease).⁴

Presentation

Patients usually present with signs and symptoms that are related to disease-associated anemia, thrombocytopenia, or neutropenia; these signs and symptoms may include fatigue or weakness, pale skin, bleeding or bruising easily, fever or infection, joint or extremity pain, B-cell symptoms such as night sweats or unintentional weight loss, and splenomegaly or hepatomegaly. Central nervous system (CNS) symptoms can include stroke-like symptoms due to leukemic cell invasion of CNS vasculature or neuropathies related to increased intracranial pressure. Sometimes, children may present with no symptoms other than joint or extremity pain.^1,3,8

Classification

ALL is classified by whether it derives from B-cell or T-cell progenitor cells and, within these, by typical genetic alterations (Table 1).^3,9-15 Some cytogenetics are associated with risk assessment as well. Well-identified B-ALL subtypes include Philadelphia (Ph) chromosome-positive, hyper- and hypodiploidy, and KMT2A rearranged, while newer classifications include Ph-like ALL and B-lymphoblastic leukemia with iAMP21. Provisional T-ALL subtypes include early T-cell precursor lymphoblastic leukemia and natural killer cell lymphoblastic leukemia.³

B-cell lineage is present in 88% of pediatric and 75%-80% of adult disease. T-ALL is found in about 12% of pediatric patients and 25% of adults.^3,8 Familial syndromes associated with ALL are present in about 4% of pediatric patients, including autosomal dominant germline mutations in RUNX1 (T-cell ALL), ETV6 (B-ALL), PAX5 (B-ALL), IKZF1 (B-ALL and T-ALL), and TP53 (low-hypodiploid ALL).³ If a known-familial genotype is identified, families should be referred for genetic counseling and further testing if needed. If germline mutation is suspected, early identification is important; hereditary ALL can influence treatment choice and use of allogeneic transplantation or radiation.³

A third classification crucial to guiding treatment is Ph-positive vs Ph-negative or Ph-like, the latter strongly associated with abnormal B-cell development due to deletions in related genes.^3,16 About 3% to 5% of pediatric patients and 25% of adults have Ph-positive ALL.¹⁷ The remission failure rate among pediatric patients treated with chemotherapy was 11% in one study, vs 2%-3% among patients with Ph-negative ALL.¹⁰

Diagnosis and Risk Stratification

Diagnosis is based on presentation and molecular features, requiring demonstration of ≥ 20% lymphoblasts in bone marrow biopsy or aspirate or ≥ 1,000 circulating lymphoblasts/mL in peripheral blood. Testing can include immunophenotyping using flow cytometry, molecular characterization of baseline leukemic clone, morphology using hematoxylin and eosin staining and Wright/Giemsa staining, and karyotyping.^1,3 CNS involvement is assessed using a lumbar spinal tap.¹

Risk stratification is based on molecular features (eg, high- and low-risk mutations, Table 1),^3,9-15 which are assessed using fluorescence in-situ hybridization, broad-panel next-generation sequencing, and reverse-transcriptase polymerase chain reaction of bone marrow or peripheral blood.³ Other risk factors include age, CNS involvement, white blood cell (WBC) count, and response to initial induction or consolidation therapy.³

Pediatric patients are assigned standard or high risk based on factors identified by the Children’s Oncology Group and National Comprehensive Cancer Network (NCCN). Patients
aged 1 to < 10 years with WBC < 50 × 109/L are considered standard risk, and all others are considered high risk. Patients with ALL before age 1 have very high risk. All pediatric patients with T-ALL are considered high risk.³ Ph-positive, Ph-like, hypoploidy, failure to achieve remission with induction, and extramedullary disease are high-risk factors as well, whereas hyperploidy and certain mutations convey low risk.³

Newer treatment strategies for initial ALL diagnosis include targeted therapies. One goal of targeted therapy is avoidance of long-term toxicity, leading to improved survival outcomes. Well-studied targeted therapies include the tyrosine kinase inhibitors used in first-line and subsequent treatment of Ph-positive ALL.³

Treatment Options in Relapsed/Refractory ALL

The initial treatment goal is complete remission (CR) defined as minimal residual disease (MRD) < 0.01% on flow cytometry (Table 2).³ Prognosis is dependent on time and location of relapse. Early relapse (< 18 months from diagnosis) predicts poor survival. Relapse in bone marrow is associated with poorer prognosis than relapse in CNS.^11-18 Where possible, consolidation with allogeneic hematopoietic cell transplantation improves survival for patients with early relapse.⁶ Three approaches have advanced treatment options for relapsed/refractory (R/R) B-ALL, all based around common cell markers seen in B-ALL.

The CD22-directed antibody-drug conjugate inotuzumab ozogamicin is approved for adults with R/R B-ALL. In clinical trials, a higher percentage of patients had results below the MRD threshold, and longer progression-free survival and OS compared with standard care.^19,20

Blinatumomab is a bispecific T-cell engager that binds to CD19 on the surface of B-ALL cells and to CD3 on T cells to trigger apoptosis.²¹ It was first approved for R/R ALL in adults or children, and is also now approved for treatment in remission with MRD ≥ 0.1%. Patients must demonstrate CD19-positive disease to qualify.^15-22 For R/R ALL, blinatumomab improves OS and CR rates compared with standard chemotherapy.²³

The use of CAR T-cell therapies has expanded greatly with increasing knowledge about their efficacy and safety. In R/R ALL, tisagenlecleucel (tisa-gen) is approved for treatment of patients aged ≤ 25 years, and brexucabtagene autoleucel (brexucel) is approved for treatment of adults.^3,24,25 Patients undergoing the CAR T-cell process have apheresis to collect T cells, which are then manufactured before being reinfused into the patient. Depending on local capabilities, the time between T-cell harvest and reinfusion can extend to weeks.^3,26,27 Cytoreduction with CAR T-cell therapy can allow previously ineligible patients (due to bulky disease) to undergo transplant. Patients treated in key clinical trials with tisa-gen or brexu-cel achieved high overall remission rates and improved event-free survival and OS rates compared with historical experience.^25,28,29 Important toxicities with CAR T-cell therapy are cytokine release syndrome (CRS) and neurotoxicity, which can develop rapidly. NCCN recommends hospitalizing patients at the first sign of either adverse event. Patients can be managed with tocilizumab or steroids for low-grade CRS or steroids for neurotoxicity. The Society for Immunotherapy of Cancer, American Society of Clinical Oncology, and NCCN have guidelines on management of toxicities related to CAR T-cell therapy as well as management of symptoms and other adverse effects of CRS.^5,23,24

Programs also incorporate telemedicine for symptom monitoring and follow-up.^32-34 Centers providing CAR T-cell therapy must have a certified Risk Evaluation and Mitigation Strategy (REMS), which ensures adherence to specific guidelines for administration, adverse event management, and patient education.^35,36 Overcoming technical, social, and financial barriers to CAR T-cell therapy is an ongoing challenge of great interest.³⁷

R/R T-Cell Precursor ALL

Patients with R/R T-ALL have poor prognosis, partly due to limited treatment options. Nelarabine, a nucleoside analog, is the only approved treatment for R/R T-ALL, but has increasingly been used in first-line therapy added to multiagent chemotherapy as a consolidation and maintenance approach to pediatric disease.^3,38,39 Four-year DSF in pediatric patients with newly diagnosed T-ALL undergoing treatment incorporating nelarabine was 88.9%.³⁹ Treatment is associated with grade ≥ 3 neurotoxicity in > 10% of patients, and can include CNS toxicity as well as neuropathy.³

In a recently completed phase 2 trial (NCT03384654), daratumumab was added to standard chemotherapy (vincristine, prednisone, PEG-asparaginase, doxorubicin) for R/R T-ALL in pediatric (ages 1-17 years) and young adult patients (age ≥ 18 years).⁴⁰ Among 24 pediatric patients, CR was 41.7% and overall response rate (ORR; ORR = CR + CRi) was 83% after 1 cycle of treatment. Ten (41.7%) pediatric patients achieved MRD-negative status as well. ORR was 60% in the 5 older patients. All pediatric patients had at least 1 grade ≥ 3 toxicity, but none of the adverse events led to discontinuation.⁴⁰

Success in achieving MRD-negative responses in patients treated for R/R ALL has increased interest in using targeted therapies for newly diagnosed patients. Recommended treatment approaches are summarized in Table 3.³

Long-Term Follow-Up and Survivorship

A study of > 500 pediatric patients followed for an average 23 years reassuringly found low prevalence of adverse outcomes related to disease or treatment. Major adverse outcomes such as death due to late relapse; secondary malignancy; or development of osteoporosis, cataracts, and diminished functional status were infrequent.⁴¹ Most prevalent were growth effects (short stature or growth hormone insufficiency), likely related to certain treatment approaches.⁴¹ Guidelines for long-term follow-up of pediatric patients are available from the Children’s Oncology Group.⁴²

A 2017 systematic review concluded that the quality of life for survivors is diminished upon treatment, and persistently over time for some patients.⁴³ In contrast, a 2022 comparison of long-term survivors (median 20.5 years since diagnosis) of pediatric ALL with healthy controls found that survivors had better quality of life in some domains, including general health, vitality, and mental health.⁴⁴ Smaller percentages of survivors rated themselves happiest about sleep quality, absence of pain, and physical abilities.⁴⁴

As therapy patterns and options evolve, continued follow-up is important to ensure patients derive optimal benefit from treatment and post-treatment life.

Click to read more from 2023 Rare Diseases Report: Cancers

Incidence peaks in children aged 1-4 years, decreasing thereafter. Cases are highest among Native American/Alaskan Native and Hispanic children, and higher in White than Black children.⁴ ALL is seen more in patients with certain inherited conditions, including Down syndrome, ataxia telangiectasia, neurofibromatosis type 1, and Bloom syndrome.¹

Treatment advances have improved remission rates and outcomes for patients. However, relapse is still a leading cause of death for patients of all ages.⁶ Prompt diagnosis and care are important to optimize outcomes, as treatment delay is associated with poorer survival.⁷

Pathophysiology

In ALL, abnormal, immature lymphocytes and progenitor B cells/T cells proliferate uncontrollably and eventually replace healthy cells in bone marrow and the lymphatic system. The loss of healthy cells leads to classic symptoms of cytopenia, splenomegaly, and hepatomegaly.¹ B cells and T cells are descended from lymphoid stem cells (and are transformed by germline or somatic mutation into pathogenic cells, leading to symptom development and bone marrow dysfunction. Most pediatric patients have extensive bone marrow involvement at diagnosis, with > 25% blast cells in marrow (defined as M3 disease).⁴

Presentation

Patients usually present with signs and symptoms that are related to disease-associated anemia, thrombocytopenia, or neutropenia; these signs and symptoms may include fatigue or weakness, pale skin, bleeding or bruising easily, fever or infection, joint or extremity pain, B-cell symptoms such as night sweats or unintentional weight loss, and splenomegaly or hepatomegaly. Central nervous system (CNS) symptoms can include stroke-like symptoms due to leukemic cell invasion of CNS vasculature or neuropathies related to increased intracranial pressure. Sometimes, children may present with no symptoms other than joint or extremity pain.^1,3,8

Classification

ALL is classified by whether it derives from B-cell or T-cell progenitor cells and, within these, by typical genetic alterations (Table 1).^3,9-15 Some cytogenetics are associated with risk assessment as well. Well-identified B-ALL subtypes include Philadelphia (Ph) chromosome-positive, hyper- and hypodiploidy, and KMT2A rearranged, while newer classifications include Ph-like ALL and B-lymphoblastic leukemia with iAMP21. Provisional T-ALL subtypes include early T-cell precursor lymphoblastic leukemia and natural killer cell lymphoblastic leukemia.³

B-cell lineage is present in 88% of pediatric and 75%-80% of adult disease. T-ALL is found in about 12% of pediatric patients and 25% of adults.^3,8 Familial syndromes associated with ALL are present in about 4% of pediatric patients, including autosomal dominant germline mutations in RUNX1 (T-cell ALL), ETV6 (B-ALL), PAX5 (B-ALL), IKZF1 (B-ALL and T-ALL), and TP53 (low-hypodiploid ALL).³ If a known-familial genotype is identified, families should be referred for genetic counseling and further testing if needed. If germline mutation is suspected, early identification is important; hereditary ALL can influence treatment choice and use of allogeneic transplantation or radiation.³

A third classification crucial to guiding treatment is Ph-positive vs Ph-negative or Ph-like, the latter strongly associated with abnormal B-cell development due to deletions in related genes.^3,16 About 3% to 5% of pediatric patients and 25% of adults have Ph-positive ALL.¹⁷ The remission failure rate among pediatric patients treated with chemotherapy was 11% in one study, vs 2%-3% among patients with Ph-negative ALL.¹⁰

Diagnosis and Risk Stratification

Diagnosis is based on presentation and molecular features, requiring demonstration of ≥ 20% lymphoblasts in bone marrow biopsy or aspirate or ≥ 1,000 circulating lymphoblasts/mL in peripheral blood. Testing can include immunophenotyping using flow cytometry, molecular characterization of baseline leukemic clone, morphology using hematoxylin and eosin staining and Wright/Giemsa staining, and karyotyping.^1,3 CNS involvement is assessed using a lumbar spinal tap.¹

Risk stratification is based on molecular features (eg, high- and low-risk mutations, Table 1),^3,9-15 which are assessed using fluorescence in-situ hybridization, broad-panel next-generation sequencing, and reverse-transcriptase polymerase chain reaction of bone marrow or peripheral blood.³ Other risk factors include age, CNS involvement, white blood cell (WBC) count, and response to initial induction or consolidation therapy.³

Pediatric patients are assigned standard or high risk based on factors identified by the Children’s Oncology Group and National Comprehensive Cancer Network (NCCN). Patients
aged 1 to < 10 years with WBC < 50 × 109/L are considered standard risk, and all others are considered high risk. Patients with ALL before age 1 have very high risk. All pediatric patients with T-ALL are considered high risk.³ Ph-positive, Ph-like, hypoploidy, failure to achieve remission with induction, and extramedullary disease are high-risk factors as well, whereas hyperploidy and certain mutations convey low risk.³

Newer treatment strategies for initial ALL diagnosis include targeted therapies. One goal of targeted therapy is avoidance of long-term toxicity, leading to improved survival outcomes. Well-studied targeted therapies include the tyrosine kinase inhibitors used in first-line and subsequent treatment of Ph-positive ALL.³

Treatment Options in Relapsed/Refractory ALL

The initial treatment goal is complete remission (CR) defined as minimal residual disease (MRD) < 0.01% on flow cytometry (Table 2).³ Prognosis is dependent on time and location of relapse. Early relapse (< 18 months from diagnosis) predicts poor survival. Relapse in bone marrow is associated with poorer prognosis than relapse in CNS.^11-18 Where possible, consolidation with allogeneic hematopoietic cell transplantation improves survival for patients with early relapse.⁶ Three approaches have advanced treatment options for relapsed/refractory (R/R) B-ALL, all based around common cell markers seen in B-ALL.

The CD22-directed antibody-drug conjugate inotuzumab ozogamicin is approved for adults with R/R B-ALL. In clinical trials, a higher percentage of patients had results below the MRD threshold, and longer progression-free survival and OS compared with standard care.^19,20

Blinatumomab is a bispecific T-cell engager that binds to CD19 on the surface of B-ALL cells and to CD3 on T cells to trigger apoptosis.²¹ It was first approved for R/R ALL in adults or children, and is also now approved for treatment in remission with MRD ≥ 0.1%. Patients must demonstrate CD19-positive disease to qualify.^15-22 For R/R ALL, blinatumomab improves OS and CR rates compared with standard chemotherapy.²³

The use of CAR T-cell therapies has expanded greatly with increasing knowledge about their efficacy and safety. In R/R ALL, tisagenlecleucel (tisa-gen) is approved for treatment of patients aged ≤ 25 years, and brexucabtagene autoleucel (brexucel) is approved for treatment of adults.^3,24,25 Patients undergoing the CAR T-cell process have apheresis to collect T cells, which are then manufactured before being reinfused into the patient. Depending on local capabilities, the time between T-cell harvest and reinfusion can extend to weeks.^3,26,27 Cytoreduction with CAR T-cell therapy can allow previously ineligible patients (due to bulky disease) to undergo transplant. Patients treated in key clinical trials with tisa-gen or brexu-cel achieved high overall remission rates and improved event-free survival and OS rates compared with historical experience.^25,28,29 Important toxicities with CAR T-cell therapy are cytokine release syndrome (CRS) and neurotoxicity, which can develop rapidly. NCCN recommends hospitalizing patients at the first sign of either adverse event. Patients can be managed with tocilizumab or steroids for low-grade CRS or steroids for neurotoxicity. The Society for Immunotherapy of Cancer, American Society of Clinical Oncology, and NCCN have guidelines on management of toxicities related to CAR T-cell therapy as well as management of symptoms and other adverse effects of CRS.^5,23,24

Programs also incorporate telemedicine for symptom monitoring and follow-up.^32-34 Centers providing CAR T-cell therapy must have a certified Risk Evaluation and Mitigation Strategy (REMS), which ensures adherence to specific guidelines for administration, adverse event management, and patient education.^35,36 Overcoming technical, social, and financial barriers to CAR T-cell therapy is an ongoing challenge of great interest.³⁷

R/R T-Cell Precursor ALL

Patients with R/R T-ALL have poor prognosis, partly due to limited treatment options. Nelarabine, a nucleoside analog, is the only approved treatment for R/R T-ALL, but has increasingly been used in first-line therapy added to multiagent chemotherapy as a consolidation and maintenance approach to pediatric disease.^3,38,39 Four-year DSF in pediatric patients with newly diagnosed T-ALL undergoing treatment incorporating nelarabine was 88.9%.³⁹ Treatment is associated with grade ≥ 3 neurotoxicity in > 10% of patients, and can include CNS toxicity as well as neuropathy.³

In a recently completed phase 2 trial (NCT03384654), daratumumab was added to standard chemotherapy (vincristine, prednisone, PEG-asparaginase, doxorubicin) for R/R T-ALL in pediatric (ages 1-17 years) and young adult patients (age ≥ 18 years).⁴⁰ Among 24 pediatric patients, CR was 41.7% and overall response rate (ORR; ORR = CR + CRi) was 83% after 1 cycle of treatment. Ten (41.7%) pediatric patients achieved MRD-negative status as well. ORR was 60% in the 5 older patients. All pediatric patients had at least 1 grade ≥ 3 toxicity, but none of the adverse events led to discontinuation.⁴⁰

Success in achieving MRD-negative responses in patients treated for R/R ALL has increased interest in using targeted therapies for newly diagnosed patients. Recommended treatment approaches are summarized in Table 3.³

Long-Term Follow-Up and Survivorship

A study of > 500 pediatric patients followed for an average 23 years reassuringly found low prevalence of adverse outcomes related to disease or treatment. Major adverse outcomes such as death due to late relapse; secondary malignancy; or development of osteoporosis, cataracts, and diminished functional status were infrequent.⁴¹ Most prevalent were growth effects (short stature or growth hormone insufficiency), likely related to certain treatment approaches.⁴¹ Guidelines for long-term follow-up of pediatric patients are available from the Children’s Oncology Group.⁴²

A 2017 systematic review concluded that the quality of life for survivors is diminished upon treatment, and persistently over time for some patients.⁴³ In contrast, a 2022 comparison of long-term survivors (median 20.5 years since diagnosis) of pediatric ALL with healthy controls found that survivors had better quality of life in some domains, including general health, vitality, and mental health.⁴⁴ Smaller percentages of survivors rated themselves happiest about sleep quality, absence of pain, and physical abilities.⁴⁴

As therapy patterns and options evolve, continued follow-up is important to ensure patients derive optimal benefit from treatment and post-treatment life.

Click to read more from 2023 Rare Diseases Report: Cancers

Incidence peaks in children aged 1-4 years, decreasing thereafter. Cases are highest among Native American/Alaskan Native and Hispanic children, and higher in White than Black children.⁴ ALL is seen more in patients with certain inherited conditions, including Down syndrome, ataxia telangiectasia, neurofibromatosis type 1, and Bloom syndrome.¹

Treatment advances have improved remission rates and outcomes for patients. However, relapse is still a leading cause of death for patients of all ages.⁶ Prompt diagnosis and care are important to optimize outcomes, as treatment delay is associated with poorer survival.⁷

Pathophysiology

In ALL, abnormal, immature lymphocytes and progenitor B cells/T cells proliferate uncontrollably and eventually replace healthy cells in bone marrow and the lymphatic system. The loss of healthy cells leads to classic symptoms of cytopenia, splenomegaly, and hepatomegaly.¹ B cells and T cells are descended from lymphoid stem cells (and are transformed by germline or somatic mutation into pathogenic cells, leading to symptom development and bone marrow dysfunction. Most pediatric patients have extensive bone marrow involvement at diagnosis, with > 25% blast cells in marrow (defined as M3 disease).⁴

Presentation

Patients usually present with signs and symptoms that are related to disease-associated anemia, thrombocytopenia, or neutropenia; these signs and symptoms may include fatigue or weakness, pale skin, bleeding or bruising easily, fever or infection, joint or extremity pain, B-cell symptoms such as night sweats or unintentional weight loss, and splenomegaly or hepatomegaly. Central nervous system (CNS) symptoms can include stroke-like symptoms due to leukemic cell invasion of CNS vasculature or neuropathies related to increased intracranial pressure. Sometimes, children may present with no symptoms other than joint or extremity pain.^1,3,8

Classification

ALL is classified by whether it derives from B-cell or T-cell progenitor cells and, within these, by typical genetic alterations (Table 1).^3,9-15 Some cytogenetics are associated with risk assessment as well. Well-identified B-ALL subtypes include Philadelphia (Ph) chromosome-positive, hyper- and hypodiploidy, and KMT2A rearranged, while newer classifications include Ph-like ALL and B-lymphoblastic leukemia with iAMP21. Provisional T-ALL subtypes include early T-cell precursor lymphoblastic leukemia and natural killer cell lymphoblastic leukemia.³

B-cell lineage is present in 88% of pediatric and 75%-80% of adult disease. T-ALL is found in about 12% of pediatric patients and 25% of adults.^3,8 Familial syndromes associated with ALL are present in about 4% of pediatric patients, including autosomal dominant germline mutations in RUNX1 (T-cell ALL), ETV6 (B-ALL), PAX5 (B-ALL), IKZF1 (B-ALL and T-ALL), and TP53 (low-hypodiploid ALL).³ If a known-familial genotype is identified, families should be referred for genetic counseling and further testing if needed. If germline mutation is suspected, early identification is important; hereditary ALL can influence treatment choice and use of allogeneic transplantation or radiation.³

A third classification crucial to guiding treatment is Ph-positive vs Ph-negative or Ph-like, the latter strongly associated with abnormal B-cell development due to deletions in related genes.^3,16 About 3% to 5% of pediatric patients and 25% of adults have Ph-positive ALL.¹⁷ The remission failure rate among pediatric patients treated with chemotherapy was 11% in one study, vs 2%-3% among patients with Ph-negative ALL.¹⁰

Diagnosis and Risk Stratification

Diagnosis is based on presentation and molecular features, requiring demonstration of ≥ 20% lymphoblasts in bone marrow biopsy or aspirate or ≥ 1,000 circulating lymphoblasts/mL in peripheral blood. Testing can include immunophenotyping using flow cytometry, molecular characterization of baseline leukemic clone, morphology using hematoxylin and eosin staining and Wright/Giemsa staining, and karyotyping.^1,3 CNS involvement is assessed using a lumbar spinal tap.¹

Risk stratification is based on molecular features (eg, high- and low-risk mutations, Table 1),^3,9-15 which are assessed using fluorescence in-situ hybridization, broad-panel next-generation sequencing, and reverse-transcriptase polymerase chain reaction of bone marrow or peripheral blood.³ Other risk factors include age, CNS involvement, white blood cell (WBC) count, and response to initial induction or consolidation therapy.³

Pediatric patients are assigned standard or high risk based on factors identified by the Children’s Oncology Group and National Comprehensive Cancer Network (NCCN). Patients
aged 1 to < 10 years with WBC < 50 × 109/L are considered standard risk, and all others are considered high risk. Patients with ALL before age 1 have very high risk. All pediatric patients with T-ALL are considered high risk.³ Ph-positive, Ph-like, hypoploidy, failure to achieve remission with induction, and extramedullary disease are high-risk factors as well, whereas hyperploidy and certain mutations convey low risk.³

Newer treatment strategies for initial ALL diagnosis include targeted therapies. One goal of targeted therapy is avoidance of long-term toxicity, leading to improved survival outcomes. Well-studied targeted therapies include the tyrosine kinase inhibitors used in first-line and subsequent treatment of Ph-positive ALL.³

Treatment Options in Relapsed/Refractory ALL

The initial treatment goal is complete remission (CR) defined as minimal residual disease (MRD) < 0.01% on flow cytometry (Table 2).³ Prognosis is dependent on time and location of relapse. Early relapse (< 18 months from diagnosis) predicts poor survival. Relapse in bone marrow is associated with poorer prognosis than relapse in CNS.^11-18 Where possible, consolidation with allogeneic hematopoietic cell transplantation improves survival for patients with early relapse.⁶ Three approaches have advanced treatment options for relapsed/refractory (R/R) B-ALL, all based around common cell markers seen in B-ALL.

The CD22-directed antibody-drug conjugate inotuzumab ozogamicin is approved for adults with R/R B-ALL. In clinical trials, a higher percentage of patients had results below the MRD threshold, and longer progression-free survival and OS compared with standard care.^19,20

Blinatumomab is a bispecific T-cell engager that binds to CD19 on the surface of B-ALL cells and to CD3 on T cells to trigger apoptosis.²¹ It was first approved for R/R ALL in adults or children, and is also now approved for treatment in remission with MRD ≥ 0.1%. Patients must demonstrate CD19-positive disease to qualify.^15-22 For R/R ALL, blinatumomab improves OS and CR rates compared with standard chemotherapy.²³

The use of CAR T-cell therapies has expanded greatly with increasing knowledge about their efficacy and safety. In R/R ALL, tisagenlecleucel (tisa-gen) is approved for treatment of patients aged ≤ 25 years, and brexucabtagene autoleucel (brexucel) is approved for treatment of adults.^3,24,25 Patients undergoing the CAR T-cell process have apheresis to collect T cells, which are then manufactured before being reinfused into the patient. Depending on local capabilities, the time between T-cell harvest and reinfusion can extend to weeks.^3,26,27 Cytoreduction with CAR T-cell therapy can allow previously ineligible patients (due to bulky disease) to undergo transplant. Patients treated in key clinical trials with tisa-gen or brexu-cel achieved high overall remission rates and improved event-free survival and OS rates compared with historical experience.^25,28,29 Important toxicities with CAR T-cell therapy are cytokine release syndrome (CRS) and neurotoxicity, which can develop rapidly. NCCN recommends hospitalizing patients at the first sign of either adverse event. Patients can be managed with tocilizumab or steroids for low-grade CRS or steroids for neurotoxicity. The Society for Immunotherapy of Cancer, American Society of Clinical Oncology, and NCCN have guidelines on management of toxicities related to CAR T-cell therapy as well as management of symptoms and other adverse effects of CRS.^5,23,24

Programs also incorporate telemedicine for symptom monitoring and follow-up.^32-34 Centers providing CAR T-cell therapy must have a certified Risk Evaluation and Mitigation Strategy (REMS), which ensures adherence to specific guidelines for administration, adverse event management, and patient education.^35,36 Overcoming technical, social, and financial barriers to CAR T-cell therapy is an ongoing challenge of great interest.³⁷

R/R T-Cell Precursor ALL

Patients with R/R T-ALL have poor prognosis, partly due to limited treatment options. Nelarabine, a nucleoside analog, is the only approved treatment for R/R T-ALL, but has increasingly been used in first-line therapy added to multiagent chemotherapy as a consolidation and maintenance approach to pediatric disease.^3,38,39 Four-year DSF in pediatric patients with newly diagnosed T-ALL undergoing treatment incorporating nelarabine was 88.9%.³⁹ Treatment is associated with grade ≥ 3 neurotoxicity in > 10% of patients, and can include CNS toxicity as well as neuropathy.³

In a recently completed phase 2 trial (NCT03384654), daratumumab was added to standard chemotherapy (vincristine, prednisone, PEG-asparaginase, doxorubicin) for R/R T-ALL in pediatric (ages 1-17 years) and young adult patients (age ≥ 18 years).⁴⁰ Among 24 pediatric patients, CR was 41.7% and overall response rate (ORR; ORR = CR + CRi) was 83% after 1 cycle of treatment. Ten (41.7%) pediatric patients achieved MRD-negative status as well. ORR was 60% in the 5 older patients. All pediatric patients had at least 1 grade ≥ 3 toxicity, but none of the adverse events led to discontinuation.⁴⁰

Success in achieving MRD-negative responses in patients treated for R/R ALL has increased interest in using targeted therapies for newly diagnosed patients. Recommended treatment approaches are summarized in Table 3.³

Long-Term Follow-Up and Survivorship

A study of > 500 pediatric patients followed for an average 23 years reassuringly found low prevalence of adverse outcomes related to disease or treatment. Major adverse outcomes such as death due to late relapse; secondary malignancy; or development of osteoporosis, cataracts, and diminished functional status were infrequent.⁴¹ Most prevalent were growth effects (short stature or growth hormone insufficiency), likely related to certain treatment approaches.⁴¹ Guidelines for long-term follow-up of pediatric patients are available from the Children’s Oncology Group.⁴²

A 2017 systematic review concluded that the quality of life for survivors is diminished upon treatment, and persistently over time for some patients.⁴³ In contrast, a 2022 comparison of long-term survivors (median 20.5 years since diagnosis) of pediatric ALL with healthy controls found that survivors had better quality of life in some domains, including general health, vitality, and mental health.⁴⁴ Smaller percentages of survivors rated themselves happiest about sleep quality, absence of pain, and physical abilities.⁴⁴

As therapy patterns and options evolve, continued follow-up is important to ensure patients derive optimal benefit from treatment and post-treatment life.

Click to read more from 2023 Rare Diseases Report: Cancers

Within the last 40 years, younger fit patients have benefited from intensive chemotherapy regimens for acute myeloid leukemia (AML) with improved survival, and the possibility of long-term disease-free survival (DFS) (“cure”).¹ Older patients are often considered too unfit for standard curative treatment with intensive induction chemotherapy followed by consolidation chemotherapy, allogeneic hematopoietic cell transplantation (allo-HCT), or both.^2-4 Higher induction mortality and poor overall survival (OS) are associated with worse performance status, organ impairment, significant comorbidities, and declining cognitive function, all of which are more common with advancing age. Although the suggested criteria for determining unfitness have not been validated (Table 1), they can provide guidance in clinical practice.^2-5

The National Comprehensive Cancer Network (NCCN) panel recommends the consideration of a patient’s performance status and comorbid conditions in addition to their age to determine a patient’s fitness for intensive induction therapy.⁶ Adverse disease features should also be considered, because disease biology may make intensive chemotherapy futile or inappropriate. For example, the mutational driver tumor protein p53 (TP53) appears at a higher frequency in older adults than younger adults and is associated with dismal outcomes even with intensive chemotherapy. Likewise, the spliceosome and chromatin modifier gene mutations are more common in older patients with AML and confer a worse OS with intensive therapy.^6,7 Older unfit patients faced a difficult decision: proceed with intensive therapy with some possibility of long-term survival but risk of early mortality and significant toxicity, or opt for supportive care and palliative chemotherapy, such as the hypomethylating agents (HMAs) or low-dose cytarabine, with much shorter survival.

Guidelines for Treating Older Unfit Patients

Evidence-based guidelines for managing older adults with newly diagnosed AML were developed by the American Society of Hematology in 2020; however, these guidelines were released prior to the results of several clinical trials involving older patients with AML (Table 2).⁸ In 2022, the European LeukemiaNet (ELN) recommendations were updated to include new therapeutic agents that target specific mutations in genes such as tyrosine kinase 3 (FLT3), isocitrate dehydrogenase 1 (IDH1), isocitrate dehydrogenase 2 (IDH2), and B-cell lymphoma 2 (BCL2). Given the important effects of genetic aberrations on disease phenotype, treatment options, and outcomes, screening for genetic aberrations at diagnosis is now essential.⁹

The potential for clonal evolution leading to new actionable targets that were not present at diagnosis highlights the importance of reevaluation of genetic aberrations throughout clinical progression. Actionable targets can include mutations in IDH1/IDH2, FLT3-internal tandem duplication or FLT3 tyrosine kinase domain.⁹

Treatment Landscape

Since 2018, several therapeutic agents have been added to the treatment armamentarium that can induce longer-term complete remission (CR) for older unfit patients with newly diagnosed AML (Table 2).⁴ 

Management of Primary AML With Less Intensive Induction Therapy

VIALE-A established a new standard of care for older unfit patients by demonstrating the benefit of adding the BCL2 inhibitor venetoclax (VEN) to azacitidine (AZA).2 VIALE-A demonstrated that the rate of CR plus CR with partial hematologic recovery (CRi) was 65% for VEN plus AZA and 18% for AZA. Most remissions in the AZA/VEN arm occurred rapidly in the first 2 cycles. The median survival improved from 9.6 months with AZA to 14.7 months with AZA/VEN. An improvement in survival with VEN and low-dose cytarabine also emerged in a 6-month post hoc analysis of the VIALE-C trial.¹⁰ Various other trials examining targeted therapies on specific mutations have provided mixed results in the front-line setting.^13,14,18 It is important to note that a recent systematic review found that 12% to 25% of patients who were unfit for intensive therapy were successfully bridged to HCT.¹⁹

Management of Postremission Response

Patients with a longer duration of first remission have demonstrated better survival outcomes.¹⁵ Two trials have examined postremission therapy in the setting of prior intensive therapy. HOVON97 enrolled older patients who achieved CR/CRi after 2 cycles of intensive therapy to receive either AZA postremission or no further treatment. The proportion of patients with DFS at 12 months was greater in the AZA maintenance group than in the observation group (64% vs 42%), but significant DFS improvement did not translate into improved OS.²⁰ QUAZAR AML-001 demonstrated that OS was longer for older patients receiving maintenance therapy with CC-486 (a non-bioequivalent oral formulation of AZA) vs placebo (24.7 vs 14.8 months).¹⁵ CC-486 was FDA-approved for maintenance therapy after intensive induction with or without consolidation in patients who are not candidates for allo-HCT. However, limited evidence exists specifically for postremission therapy in unfit patients who have received less intensive therapy. Continuation of the lower intensive therapy is recommended until disease progression.⁶ No data are available to support the use of oral AZA therapy alone for maintenance of remission following HMA/VEN-induced remissions.

Management of Relapsed and Refractory AML

Nearly 50% of patients with AML experience relapse and up to 40% may be refractory.¹⁹ Importantly, patients who were considered fit for intensive therapy may not remain so with relapsed or refractory AML (r/rAML), so patients should be evaluated for fitness for an intensive salvage regimen. Similar to assessing fitness for induction therapy, no standard definition of fitness exists for r/rAML.¹⁹

Disease control is the goal for patients with r/rAML who are unfit for intensive salvage therapy; however, treatment options remain limited and prognosis is poor.¹⁹ Depending on the patient’s cytogenetic profile, management can include HMA with or without VEN, glasdegib with LDAC, gilteritinib, ivosidenib or enasidenib, or gemtuzumab ozogamicin.⁹ Only a few studies have been published involving the r/rAML population not eligible for intensive salvage regimen, and guidelines are needed for this population.¹⁹ Thus, the ELN recommends that clinical trial enrollment be considered for patients with r/rAML.⁹

Management of Secondary AML or High-risk AML

Compared with de novo AML, both secondary AML (sAML) and therapy-related AML (tAML) have been associated with inferior outcomes. Factors that influence poor outcomes can include older age, comorbidities, persistent malignant disease or relapse of primary malignancy, treatment-induced depletion of hematopoietic reserves and/or prolonged myelosuppression, and genetic abnormalities, such as TP53 mutations.²¹

CPX-351 is a dual drug that contains cytarabine and daunorubicin.^9,22 An open-label study (NCT01696084) compared CPX-351 with conventional cytarabine and daunorubicin (induction and consolidation therapy) in older patients (aged 60-75 years) with newly diagnosed high-risk/sAML who were considered fit for intensive therapy. The OS for CPX-351 was longer (9.56 vs 5.95 months) and the safety profiles were similar between the treatment groups.²³ Patients achieving CR/CRi received up to 2 cycles of consolidation with CPX-351. An exploratory analysis of this subgroup revealed median OS was longer with CPX-351 consolidation (25.43 vs 8.53 months).²² Patients with TP53 mutations had poor treatment outcomes regardless of treatment arm, whereas patients with sAML-type mutations including spliceosome and chromatin modifier genes had longer OS with CPX-351 therapy.²⁴ The 5-year results of this trial indicate that the survival benefit of CPX-351 was maintained.²⁵ However, data from a retrospective review involving 136 patients with either sAML or AML with myelodysplasia-related changes revealed no difference in survival outcomes between patients treated with either HMA/VEN or CPX-351.²⁶

Case Study: Elderly Woman With Newly Diagnosed AML

In 2018, Ms. W, age 69 years, was diagnosed with seropositive, non-erosive rheumatoid arthritis; she began methotrexate 17.5 mg per week split dosing in conjunction with oral folic acid 2 mg/d with varying doses based on symptoms. Her comorbidities included recurrent episodes of diverticulitis, hypertension, hypothyroidism, obstructive sleep apnea, and gastrointestinal reflux disease. On February 4, 2021, her methotrexate was increased to 20 mg and required intermittent prednisone tapers for flares. In November 2021, a blood test revealed she had a decreased white blood cell (WBC) count at 1.8 K/μL, and her methotrexate dose was decreased to 15 mg weekly. Despite the dose reduction, she had grade 3 neutropenia and anemia (WBC: 0.7 K/μL; HGB:10.5 g/dL) with a normal platelet count (PLT: 165,000/μL). Methotrexate was discontinued and leucovorin was initiated. She then had only modest improvement in her lab values and peripheral blood blasts. 

On March 17, 2022, she underwent a bone marrow biopsy and aspirate, which resulted in a diagnosis of AML. She had 55% blasts in a 90% cellular bone marrow with mild reticulin fibrosis and numerous circulating blasts. She was classified as having AML without maturation (FAB AML-M1). Flow cytometry detected a phenotypically abnormal population with CD45 expression and side scatter/forward scatter features of small-to-medium sized blasts, accounting for 23% of total cells. The chromosome analysis demonstrated a normal female karyotype in all 19 available metaphases. Polymerase chain reaction analysis was negative for FLT3-ITD, FLT3-TKD, and NPM1 mutations and positive for an IDH1 R132C missense mutation. The myeloid gene panel identified only a single pathogenic variant, IDH1 R132C (variant allele frequency [VAF] 21.2%), and a variant of unknown significance DNMT3A A575P (VAF 25.7%).

Noting that she does not have favorable risk features, we discussed treatment options. Although she is a candidate for curative therapy, the patient was not interested in pursuing allo-HCT. Her history of diverticulitis is concerning for tolerating intensive chemotherapy. In addition, her immunosuppressive therapy increases her risk for opportunistic infections. Based on the available data from the AGILE and VIALE studies and associated potential adverse reactions, she opted for starting treatment with AZA and IVO.

On March 31, 2022, she began receiving AZA 75 mg/m² intravenous (IV) once daily days 1-7 and oral IVO 500 mg once daily continuously. She has received 12 cycles and has not needed transfusion. She has not had febrile neutropenia or symptoms of differentiation syndrome. On March 24, 2023, she underwent laparoscopic cholecystectomy, because an ultrasound revealed cholelithiasis, abnormal gallbladder wall thickening, and pericholecystic fluid. She was discharged home the following day and is continuing with AZA/ivosidenib.

Click to read more from 2023 Rare Diseases Report: Cancers

Within the last 40 years, younger fit patients have benefited from intensive chemotherapy regimens for acute myeloid leukemia (AML) with improved survival, and the possibility of long-term disease-free survival (DFS) (“cure”).¹ Older patients are often considered too unfit for standard curative treatment with intensive induction chemotherapy followed by consolidation chemotherapy, allogeneic hematopoietic cell transplantation (allo-HCT), or both.^2-4 Higher induction mortality and poor overall survival (OS) are associated with worse performance status, organ impairment, significant comorbidities, and declining cognitive function, all of which are more common with advancing age. Although the suggested criteria for determining unfitness have not been validated (Table 1), they can provide guidance in clinical practice.^2-5

The National Comprehensive Cancer Network (NCCN) panel recommends the consideration of a patient’s performance status and comorbid conditions in addition to their age to determine a patient’s fitness for intensive induction therapy.⁶ Adverse disease features should also be considered, because disease biology may make intensive chemotherapy futile or inappropriate. For example, the mutational driver tumor protein p53 (TP53) appears at a higher frequency in older adults than younger adults and is associated with dismal outcomes even with intensive chemotherapy. Likewise, the spliceosome and chromatin modifier gene mutations are more common in older patients with AML and confer a worse OS with intensive therapy.^6,7 Older unfit patients faced a difficult decision: proceed with intensive therapy with some possibility of long-term survival but risk of early mortality and significant toxicity, or opt for supportive care and palliative chemotherapy, such as the hypomethylating agents (HMAs) or low-dose cytarabine, with much shorter survival.

Guidelines for Treating Older Unfit Patients

Evidence-based guidelines for managing older adults with newly diagnosed AML were developed by the American Society of Hematology in 2020; however, these guidelines were released prior to the results of several clinical trials involving older patients with AML (Table 2).⁸ In 2022, the European LeukemiaNet (ELN) recommendations were updated to include new therapeutic agents that target specific mutations in genes such as tyrosine kinase 3 (FLT3), isocitrate dehydrogenase 1 (IDH1), isocitrate dehydrogenase 2 (IDH2), and B-cell lymphoma 2 (BCL2). Given the important effects of genetic aberrations on disease phenotype, treatment options, and outcomes, screening for genetic aberrations at diagnosis is now essential.⁹

The potential for clonal evolution leading to new actionable targets that were not present at diagnosis highlights the importance of reevaluation of genetic aberrations throughout clinical progression. Actionable targets can include mutations in IDH1/IDH2, FLT3-internal tandem duplication or FLT3 tyrosine kinase domain.⁹

Treatment Landscape

Since 2018, several therapeutic agents have been added to the treatment armamentarium that can induce longer-term complete remission (CR) for older unfit patients with newly diagnosed AML (Table 2).⁴ 

Management of Primary AML With Less Intensive Induction Therapy

VIALE-A established a new standard of care for older unfit patients by demonstrating the benefit of adding the BCL2 inhibitor venetoclax (VEN) to azacitidine (AZA).2 VIALE-A demonstrated that the rate of CR plus CR with partial hematologic recovery (CRi) was 65% for VEN plus AZA and 18% for AZA. Most remissions in the AZA/VEN arm occurred rapidly in the first 2 cycles. The median survival improved from 9.6 months with AZA to 14.7 months with AZA/VEN. An improvement in survival with VEN and low-dose cytarabine also emerged in a 6-month post hoc analysis of the VIALE-C trial.¹⁰ Various other trials examining targeted therapies on specific mutations have provided mixed results in the front-line setting.^13,14,18 It is important to note that a recent systematic review found that 12% to 25% of patients who were unfit for intensive therapy were successfully bridged to HCT.¹⁹

Management of Postremission Response

Patients with a longer duration of first remission have demonstrated better survival outcomes.¹⁵ Two trials have examined postremission therapy in the setting of prior intensive therapy. HOVON97 enrolled older patients who achieved CR/CRi after 2 cycles of intensive therapy to receive either AZA postremission or no further treatment. The proportion of patients with DFS at 12 months was greater in the AZA maintenance group than in the observation group (64% vs 42%), but significant DFS improvement did not translate into improved OS.²⁰ QUAZAR AML-001 demonstrated that OS was longer for older patients receiving maintenance therapy with CC-486 (a non-bioequivalent oral formulation of AZA) vs placebo (24.7 vs 14.8 months).¹⁵ CC-486 was FDA-approved for maintenance therapy after intensive induction with or without consolidation in patients who are not candidates for allo-HCT. However, limited evidence exists specifically for postremission therapy in unfit patients who have received less intensive therapy. Continuation of the lower intensive therapy is recommended until disease progression.⁶ No data are available to support the use of oral AZA therapy alone for maintenance of remission following HMA/VEN-induced remissions.

Management of Relapsed and Refractory AML

Nearly 50% of patients with AML experience relapse and up to 40% may be refractory.¹⁹ Importantly, patients who were considered fit for intensive therapy may not remain so with relapsed or refractory AML (r/rAML), so patients should be evaluated for fitness for an intensive salvage regimen. Similar to assessing fitness for induction therapy, no standard definition of fitness exists for r/rAML.¹⁹

Disease control is the goal for patients with r/rAML who are unfit for intensive salvage therapy; however, treatment options remain limited and prognosis is poor.¹⁹ Depending on the patient’s cytogenetic profile, management can include HMA with or without VEN, glasdegib with LDAC, gilteritinib, ivosidenib or enasidenib, or gemtuzumab ozogamicin.⁹ Only a few studies have been published involving the r/rAML population not eligible for intensive salvage regimen, and guidelines are needed for this population.¹⁹ Thus, the ELN recommends that clinical trial enrollment be considered for patients with r/rAML.⁹

Management of Secondary AML or High-risk AML

Compared with de novo AML, both secondary AML (sAML) and therapy-related AML (tAML) have been associated with inferior outcomes. Factors that influence poor outcomes can include older age, comorbidities, persistent malignant disease or relapse of primary malignancy, treatment-induced depletion of hematopoietic reserves and/or prolonged myelosuppression, and genetic abnormalities, such as TP53 mutations.²¹

CPX-351 is a dual drug that contains cytarabine and daunorubicin.^9,22 An open-label study (NCT01696084) compared CPX-351 with conventional cytarabine and daunorubicin (induction and consolidation therapy) in older patients (aged 60-75 years) with newly diagnosed high-risk/sAML who were considered fit for intensive therapy. The OS for CPX-351 was longer (9.56 vs 5.95 months) and the safety profiles were similar between the treatment groups.²³ Patients achieving CR/CRi received up to 2 cycles of consolidation with CPX-351. An exploratory analysis of this subgroup revealed median OS was longer with CPX-351 consolidation (25.43 vs 8.53 months).²² Patients with TP53 mutations had poor treatment outcomes regardless of treatment arm, whereas patients with sAML-type mutations including spliceosome and chromatin modifier genes had longer OS with CPX-351 therapy.²⁴ The 5-year results of this trial indicate that the survival benefit of CPX-351 was maintained.²⁵ However, data from a retrospective review involving 136 patients with either sAML or AML with myelodysplasia-related changes revealed no difference in survival outcomes between patients treated with either HMA/VEN or CPX-351.²⁶

Case Study: Elderly Woman With Newly Diagnosed AML

In 2018, Ms. W, age 69 years, was diagnosed with seropositive, non-erosive rheumatoid arthritis; she began methotrexate 17.5 mg per week split dosing in conjunction with oral folic acid 2 mg/d with varying doses based on symptoms. Her comorbidities included recurrent episodes of diverticulitis, hypertension, hypothyroidism, obstructive sleep apnea, and gastrointestinal reflux disease. On February 4, 2021, her methotrexate was increased to 20 mg and required intermittent prednisone tapers for flares. In November 2021, a blood test revealed she had a decreased white blood cell (WBC) count at 1.8 K/μL, and her methotrexate dose was decreased to 15 mg weekly. Despite the dose reduction, she had grade 3 neutropenia and anemia (WBC: 0.7 K/μL; HGB:10.5 g/dL) with a normal platelet count (PLT: 165,000/μL). Methotrexate was discontinued and leucovorin was initiated. She then had only modest improvement in her lab values and peripheral blood blasts. 

On March 17, 2022, she underwent a bone marrow biopsy and aspirate, which resulted in a diagnosis of AML. She had 55% blasts in a 90% cellular bone marrow with mild reticulin fibrosis and numerous circulating blasts. She was classified as having AML without maturation (FAB AML-M1). Flow cytometry detected a phenotypically abnormal population with CD45 expression and side scatter/forward scatter features of small-to-medium sized blasts, accounting for 23% of total cells. The chromosome analysis demonstrated a normal female karyotype in all 19 available metaphases. Polymerase chain reaction analysis was negative for FLT3-ITD, FLT3-TKD, and NPM1 mutations and positive for an IDH1 R132C missense mutation. The myeloid gene panel identified only a single pathogenic variant, IDH1 R132C (variant allele frequency [VAF] 21.2%), and a variant of unknown significance DNMT3A A575P (VAF 25.7%).

Noting that she does not have favorable risk features, we discussed treatment options. Although she is a candidate for curative therapy, the patient was not interested in pursuing allo-HCT. Her history of diverticulitis is concerning for tolerating intensive chemotherapy. In addition, her immunosuppressive therapy increases her risk for opportunistic infections. Based on the available data from the AGILE and VIALE studies and associated potential adverse reactions, she opted for starting treatment with AZA and IVO.

On March 31, 2022, she began receiving AZA 75 mg/m² intravenous (IV) once daily days 1-7 and oral IVO 500 mg once daily continuously. She has received 12 cycles and has not needed transfusion. She has not had febrile neutropenia or symptoms of differentiation syndrome. On March 24, 2023, she underwent laparoscopic cholecystectomy, because an ultrasound revealed cholelithiasis, abnormal gallbladder wall thickening, and pericholecystic fluid. She was discharged home the following day and is continuing with AZA/ivosidenib.

Click to read more from 2023 Rare Diseases Report: Cancers

Within the last 40 years, younger fit patients have benefited from intensive chemotherapy regimens for acute myeloid leukemia (AML) with improved survival, and the possibility of long-term disease-free survival (DFS) (“cure”).¹ Older patients are often considered too unfit for standard curative treatment with intensive induction chemotherapy followed by consolidation chemotherapy, allogeneic hematopoietic cell transplantation (allo-HCT), or both.^2-4 Higher induction mortality and poor overall survival (OS) are associated with worse performance status, organ impairment, significant comorbidities, and declining cognitive function, all of which are more common with advancing age. Although the suggested criteria for determining unfitness have not been validated (Table 1), they can provide guidance in clinical practice.^2-5

The National Comprehensive Cancer Network (NCCN) panel recommends the consideration of a patient’s performance status and comorbid conditions in addition to their age to determine a patient’s fitness for intensive induction therapy.⁶ Adverse disease features should also be considered, because disease biology may make intensive chemotherapy futile or inappropriate. For example, the mutational driver tumor protein p53 (TP53) appears at a higher frequency in older adults than younger adults and is associated with dismal outcomes even with intensive chemotherapy. Likewise, the spliceosome and chromatin modifier gene mutations are more common in older patients with AML and confer a worse OS with intensive therapy.^6,7 Older unfit patients faced a difficult decision: proceed with intensive therapy with some possibility of long-term survival but risk of early mortality and significant toxicity, or opt for supportive care and palliative chemotherapy, such as the hypomethylating agents (HMAs) or low-dose cytarabine, with much shorter survival.

Guidelines for Treating Older Unfit Patients

Evidence-based guidelines for managing older adults with newly diagnosed AML were developed by the American Society of Hematology in 2020; however, these guidelines were released prior to the results of several clinical trials involving older patients with AML (Table 2).⁸ In 2022, the European LeukemiaNet (ELN) recommendations were updated to include new therapeutic agents that target specific mutations in genes such as tyrosine kinase 3 (FLT3), isocitrate dehydrogenase 1 (IDH1), isocitrate dehydrogenase 2 (IDH2), and B-cell lymphoma 2 (BCL2). Given the important effects of genetic aberrations on disease phenotype, treatment options, and outcomes, screening for genetic aberrations at diagnosis is now essential.⁹

The potential for clonal evolution leading to new actionable targets that were not present at diagnosis highlights the importance of reevaluation of genetic aberrations throughout clinical progression. Actionable targets can include mutations in IDH1/IDH2, FLT3-internal tandem duplication or FLT3 tyrosine kinase domain.⁹

Treatment Landscape

Since 2018, several therapeutic agents have been added to the treatment armamentarium that can induce longer-term complete remission (CR) for older unfit patients with newly diagnosed AML (Table 2).⁴ 

Management of Primary AML With Less Intensive Induction Therapy

VIALE-A established a new standard of care for older unfit patients by demonstrating the benefit of adding the BCL2 inhibitor venetoclax (VEN) to azacitidine (AZA).2 VIALE-A demonstrated that the rate of CR plus CR with partial hematologic recovery (CRi) was 65% for VEN plus AZA and 18% for AZA. Most remissions in the AZA/VEN arm occurred rapidly in the first 2 cycles. The median survival improved from 9.6 months with AZA to 14.7 months with AZA/VEN. An improvement in survival with VEN and low-dose cytarabine also emerged in a 6-month post hoc analysis of the VIALE-C trial.¹⁰ Various other trials examining targeted therapies on specific mutations have provided mixed results in the front-line setting.^13,14,18 It is important to note that a recent systematic review found that 12% to 25% of patients who were unfit for intensive therapy were successfully bridged to HCT.¹⁹

Management of Postremission Response

Patients with a longer duration of first remission have demonstrated better survival outcomes.¹⁵ Two trials have examined postremission therapy in the setting of prior intensive therapy. HOVON97 enrolled older patients who achieved CR/CRi after 2 cycles of intensive therapy to receive either AZA postremission or no further treatment. The proportion of patients with DFS at 12 months was greater in the AZA maintenance group than in the observation group (64% vs 42%), but significant DFS improvement did not translate into improved OS.²⁰ QUAZAR AML-001 demonstrated that OS was longer for older patients receiving maintenance therapy with CC-486 (a non-bioequivalent oral formulation of AZA) vs placebo (24.7 vs 14.8 months).¹⁵ CC-486 was FDA-approved for maintenance therapy after intensive induction with or without consolidation in patients who are not candidates for allo-HCT. However, limited evidence exists specifically for postremission therapy in unfit patients who have received less intensive therapy. Continuation of the lower intensive therapy is recommended until disease progression.⁶ No data are available to support the use of oral AZA therapy alone for maintenance of remission following HMA/VEN-induced remissions.

Management of Relapsed and Refractory AML

Nearly 50% of patients with AML experience relapse and up to 40% may be refractory.¹⁹ Importantly, patients who were considered fit for intensive therapy may not remain so with relapsed or refractory AML (r/rAML), so patients should be evaluated for fitness for an intensive salvage regimen. Similar to assessing fitness for induction therapy, no standard definition of fitness exists for r/rAML.¹⁹

Disease control is the goal for patients with r/rAML who are unfit for intensive salvage therapy; however, treatment options remain limited and prognosis is poor.¹⁹ Depending on the patient’s cytogenetic profile, management can include HMA with or without VEN, glasdegib with LDAC, gilteritinib, ivosidenib or enasidenib, or gemtuzumab ozogamicin.⁹ Only a few studies have been published involving the r/rAML population not eligible for intensive salvage regimen, and guidelines are needed for this population.¹⁹ Thus, the ELN recommends that clinical trial enrollment be considered for patients with r/rAML.⁹

Management of Secondary AML or High-risk AML

Compared with de novo AML, both secondary AML (sAML) and therapy-related AML (tAML) have been associated with inferior outcomes. Factors that influence poor outcomes can include older age, comorbidities, persistent malignant disease or relapse of primary malignancy, treatment-induced depletion of hematopoietic reserves and/or prolonged myelosuppression, and genetic abnormalities, such as TP53 mutations.²¹

CPX-351 is a dual drug that contains cytarabine and daunorubicin.^9,22 An open-label study (NCT01696084) compared CPX-351 with conventional cytarabine and daunorubicin (induction and consolidation therapy) in older patients (aged 60-75 years) with newly diagnosed high-risk/sAML who were considered fit for intensive therapy. The OS for CPX-351 was longer (9.56 vs 5.95 months) and the safety profiles were similar between the treatment groups.²³ Patients achieving CR/CRi received up to 2 cycles of consolidation with CPX-351. An exploratory analysis of this subgroup revealed median OS was longer with CPX-351 consolidation (25.43 vs 8.53 months).²² Patients with TP53 mutations had poor treatment outcomes regardless of treatment arm, whereas patients with sAML-type mutations including spliceosome and chromatin modifier genes had longer OS with CPX-351 therapy.²⁴ The 5-year results of this trial indicate that the survival benefit of CPX-351 was maintained.²⁵ However, data from a retrospective review involving 136 patients with either sAML or AML with myelodysplasia-related changes revealed no difference in survival outcomes between patients treated with either HMA/VEN or CPX-351.²⁶

Case Study: Elderly Woman With Newly Diagnosed AML

In 2018, Ms. W, age 69 years, was diagnosed with seropositive, non-erosive rheumatoid arthritis; she began methotrexate 17.5 mg per week split dosing in conjunction with oral folic acid 2 mg/d with varying doses based on symptoms. Her comorbidities included recurrent episodes of diverticulitis, hypertension, hypothyroidism, obstructive sleep apnea, and gastrointestinal reflux disease. On February 4, 2021, her methotrexate was increased to 20 mg and required intermittent prednisone tapers for flares. In November 2021, a blood test revealed she had a decreased white blood cell (WBC) count at 1.8 K/μL, and her methotrexate dose was decreased to 15 mg weekly. Despite the dose reduction, she had grade 3 neutropenia and anemia (WBC: 0.7 K/μL; HGB:10.5 g/dL) with a normal platelet count (PLT: 165,000/μL). Methotrexate was discontinued and leucovorin was initiated. She then had only modest improvement in her lab values and peripheral blood blasts. 

On March 17, 2022, she underwent a bone marrow biopsy and aspirate, which resulted in a diagnosis of AML. She had 55% blasts in a 90% cellular bone marrow with mild reticulin fibrosis and numerous circulating blasts. She was classified as having AML without maturation (FAB AML-M1). Flow cytometry detected a phenotypically abnormal population with CD45 expression and side scatter/forward scatter features of small-to-medium sized blasts, accounting for 23% of total cells. The chromosome analysis demonstrated a normal female karyotype in all 19 available metaphases. Polymerase chain reaction analysis was negative for FLT3-ITD, FLT3-TKD, and NPM1 mutations and positive for an IDH1 R132C missense mutation. The myeloid gene panel identified only a single pathogenic variant, IDH1 R132C (variant allele frequency [VAF] 21.2%), and a variant of unknown significance DNMT3A A575P (VAF 25.7%).

Noting that she does not have favorable risk features, we discussed treatment options. Although she is a candidate for curative therapy, the patient was not interested in pursuing allo-HCT. Her history of diverticulitis is concerning for tolerating intensive chemotherapy. In addition, her immunosuppressive therapy increases her risk for opportunistic infections. Based on the available data from the AGILE and VIALE studies and associated potential adverse reactions, she opted for starting treatment with AZA and IVO.

On March 31, 2022, she began receiving AZA 75 mg/m² intravenous (IV) once daily days 1-7 and oral IVO 500 mg once daily continuously. She has received 12 cycles and has not needed transfusion. She has not had febrile neutropenia or symptoms of differentiation syndrome. On March 24, 2023, she underwent laparoscopic cholecystectomy, because an ultrasound revealed cholelithiasis, abnormal gallbladder wall thickening, and pericholecystic fluid. She was discharged home the following day and is continuing with AZA/ivosidenib.

Click to read more from 2023 Rare Diseases Report: Cancers