Photo from Business Wire

The US Food and Drug Administration (FDA) has placed a partial clinical hold on 3 trials of the PD-1 immune checkpoint inhibitor nivolumab (Opdivo).

The trials were designed to investigate nivolumab-based combination regimens in patients with relapsed or refractory multiple myeloma (MM).

The partial clinical hold means patients currently enrolled in these 3 trials can continue treatment if they are experiencing clinical benefit. However, no new patients can be enrolled at this time.

The partial clinical hold is related to risks identified in trials studying another anti-PD-1 agent, pembrolizumab, in MM patients.

Data from the pembrolizumab trials indicate the risks outweigh the benefits when PD-1/PD-L1 treatment is given to MM patients in combination with dexamethasone and pomalidomide or lenalidomide.

In addition, there may be an unfavorable risk-benefit ratio for MM patients receiving PD-1/PD-L1 treatments alone or in other combinations.

With this in mind, the FDA placed the partial hold on the following nivolumab trials:

• CheckMate-602: A randomized, phase 3 trial of combinations of nivolumab, elotuzumab, pomalidomide, and dexamethasone in relapsed and refractory MM
• CheckMate-039: A phase 1 study intended to establish the tolerability of nivolumab and the combination of nivolumab and daratumumab, with or without pomalidomide and dexamethasone, in patients with relapsed or refractory MM
• CA204142: A phase 2 study of elotuzumab in combination with pomalidomide and low-dose dexamethasone, and in combination with nivolumab, in patients with MM who relapsed after or were refractory to prior treatment with lenalidomide.

Other studies of nivolumab will continue as planned.

Bristol-Myers Squibb, the company developing and marketing nivolumab, said it remains steadfast in its commitment to improve outcomes for MM patients and will work closely with the FDA to address concerns.

Nivolumab is currently FDA-approved to treat:

• Adults with classical Hodgkin lymphoma that has relapsed or progressed after autologous hematopoietic stem cell transplant and brentuximab vedotin or after 3 or more lines of therapy, including autologous transplant
• Patients with previously treated metastatic non-small cell lung cancer
• Metastatic melanoma patients
• Advanced renal cell carcinoma patients who received prior anti-angiogenic therapy
• Patients with recurrent or metastatic squamous cell carcinoma of the head and neck on or after platinum-based therapy
• Patients with previously treated locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-based chemotherapy
• Patients (≥12 years) with microsatellite instability high or mismatch repair-deficient metastatic colorectal cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.
  

Photo from Business Wire

The US Food and Drug Administration (FDA) has placed a partial clinical hold on 3 trials of the PD-1 immune checkpoint inhibitor nivolumab (Opdivo).

The trials were designed to investigate nivolumab-based combination regimens in patients with relapsed or refractory multiple myeloma (MM).

The partial clinical hold means patients currently enrolled in these 3 trials can continue treatment if they are experiencing clinical benefit. However, no new patients can be enrolled at this time.

The partial clinical hold is related to risks identified in trials studying another anti-PD-1 agent, pembrolizumab, in MM patients.

Data from the pembrolizumab trials indicate the risks outweigh the benefits when PD-1/PD-L1 treatment is given to MM patients in combination with dexamethasone and pomalidomide or lenalidomide.

In addition, there may be an unfavorable risk-benefit ratio for MM patients receiving PD-1/PD-L1 treatments alone or in other combinations.

With this in mind, the FDA placed the partial hold on the following nivolumab trials:

• CheckMate-602: A randomized, phase 3 trial of combinations of nivolumab, elotuzumab, pomalidomide, and dexamethasone in relapsed and refractory MM
• CheckMate-039: A phase 1 study intended to establish the tolerability of nivolumab and the combination of nivolumab and daratumumab, with or without pomalidomide and dexamethasone, in patients with relapsed or refractory MM
• CA204142: A phase 2 study of elotuzumab in combination with pomalidomide and low-dose dexamethasone, and in combination with nivolumab, in patients with MM who relapsed after or were refractory to prior treatment with lenalidomide.

Other studies of nivolumab will continue as planned.

Bristol-Myers Squibb, the company developing and marketing nivolumab, said it remains steadfast in its commitment to improve outcomes for MM patients and will work closely with the FDA to address concerns.

Nivolumab is currently FDA-approved to treat:

• Adults with classical Hodgkin lymphoma that has relapsed or progressed after autologous hematopoietic stem cell transplant and brentuximab vedotin or after 3 or more lines of therapy, including autologous transplant
• Patients with previously treated metastatic non-small cell lung cancer
• Metastatic melanoma patients
• Advanced renal cell carcinoma patients who received prior anti-angiogenic therapy
• Patients with recurrent or metastatic squamous cell carcinoma of the head and neck on or after platinum-based therapy
• Patients with previously treated locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-based chemotherapy
• Patients (≥12 years) with microsatellite instability high or mismatch repair-deficient metastatic colorectal cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.
  

Photo from Business Wire

The US Food and Drug Administration (FDA) has placed a partial clinical hold on 3 trials of the PD-1 immune checkpoint inhibitor nivolumab (Opdivo).

The trials were designed to investigate nivolumab-based combination regimens in patients with relapsed or refractory multiple myeloma (MM).

The partial clinical hold means patients currently enrolled in these 3 trials can continue treatment if they are experiencing clinical benefit. However, no new patients can be enrolled at this time.

The partial clinical hold is related to risks identified in trials studying another anti-PD-1 agent, pembrolizumab, in MM patients.

Data from the pembrolizumab trials indicate the risks outweigh the benefits when PD-1/PD-L1 treatment is given to MM patients in combination with dexamethasone and pomalidomide or lenalidomide.

In addition, there may be an unfavorable risk-benefit ratio for MM patients receiving PD-1/PD-L1 treatments alone or in other combinations.

With this in mind, the FDA placed the partial hold on the following nivolumab trials:

• CheckMate-602: A randomized, phase 3 trial of combinations of nivolumab, elotuzumab, pomalidomide, and dexamethasone in relapsed and refractory MM
• CheckMate-039: A phase 1 study intended to establish the tolerability of nivolumab and the combination of nivolumab and daratumumab, with or without pomalidomide and dexamethasone, in patients with relapsed or refractory MM
• CA204142: A phase 2 study of elotuzumab in combination with pomalidomide and low-dose dexamethasone, and in combination with nivolumab, in patients with MM who relapsed after or were refractory to prior treatment with lenalidomide.

Other studies of nivolumab will continue as planned.

Bristol-Myers Squibb, the company developing and marketing nivolumab, said it remains steadfast in its commitment to improve outcomes for MM patients and will work closely with the FDA to address concerns.

Nivolumab is currently FDA-approved to treat:

• Adults with classical Hodgkin lymphoma that has relapsed or progressed after autologous hematopoietic stem cell transplant and brentuximab vedotin or after 3 or more lines of therapy, including autologous transplant
• Patients with previously treated metastatic non-small cell lung cancer
• Metastatic melanoma patients
• Advanced renal cell carcinoma patients who received prior anti-angiogenic therapy
• Patients with recurrent or metastatic squamous cell carcinoma of the head and neck on or after platinum-based therapy
• Patients with previously treated locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-based chemotherapy
• Patients (≥12 years) with microsatellite instability high or mismatch repair-deficient metastatic colorectal cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.
  

Q) What is known about the impact of diet on multiple sclerosis? How can I advise my patients with MS?

Multiple sclerosis (MS) is a chronic inflammatory and degenerative central nervous system disease affecting more than 2.5 million people worldwide. Today, if a Google search is performed for “diet and MS,” more than 67 million results are obtained. Many tout specific protocols as beneficial for MS but have no substantial data to support these claims. This can be confusing for patients as well as providers. How should you advise those who ask for advice on dietary modifications to help control symptoms or disease course?

First, it’s important to remember that individuals with MS have a reduced median lifespan (by about seven years), compared to healthy controls. Furthermore, patients with MS commonly have comorbid conditions—such as diabetes, obesity, and ische­mic heart disease—that increase mortality risk.^1,2 Diet and nutrition are significant factors that impact the course of these diseases.

We must also bear in mind that patients with MS experience symptoms that may impede their efforts to prepare meals. In a 2008 study of 123 MS patients (more than 50% of whom were overweight or obese), fatigue was cited as a significant factor that limited cooking and food preparation. Cognitive impairment and depression also may affect dietary intake. Interestingly, the average recorded intake for all food groups was less than that recommended in the Dietary Guidelines for Americans.³

A web-based survey conducted by the German MS Society in 2011 revealed that 42% of the 337 respondents had modified their diet due to MS. These modifications included change in intake of fatty acids; decrease or elimination of meat, sugar, and additives; and introduction of a low-carb or Paleo diet.⁴

Among an international sample of 2,087 MS patients, a significant association was found between a healthy diet and improved quality of life (both physical and mental) and reduced disability. This “healthy consumption” of fruits, vegetables, and dietary fat was also associated with a marginally decreased risk for relapse. Patients who demonstrated increased disease activity were more likely to have poor consumption of fruits, vegetables, and fats and to consume more meat and dairy products.⁵

There has also been research on specific components of dietary intake. Antioxidant-containing foods, for example, may have an anti-inflammatory effect.⁶ Vitamin B₁₂ deficiency plays a role in immunomodulatory effect, as well as formation of the myelin sheath, although its role (and the effect of biotin supplementation) in MS disease progression requires further study.⁷ Also ongoing is research into various calorie-restriction protocols, altering both timing and amount of caloric intake, since some data suggest this strategy reduces leptin, a satiety hormone that increases inflammation and has been shown to promote more aggressive MS in a mouse model.⁸

In the meantime, what can we conclude about diet and MS? A recent review determined that, although there is insufficient data to support one specific diet, there is sufficient evidence to recommend consumption of fish, foods lower in fat, whole grains, vitamin D, and supplemental omega fatty acids.⁵

It is important to discuss diet with our MS patients. In the German survey, 82% of patients felt that diet was important, yet only 10% had asked a provider for nutritional advice.⁴ In another study, patients indicated that food labels were their top source for nutrition information; only 20% sought advice from a nutritionist.³ We need to ask our MS patients if they are following a particular diet and be prepared to discuss potentially beneficial dietary choices with them—and offer referral to a nutritionist to those who require additional direction and support.—SP

Stacey Panasci, MSPAS, PA-C
Springfield Neurology Associates, LLC
Massachusetts

Q) What is known about the impact of diet on multiple sclerosis? How can I advise my patients with MS?

Multiple sclerosis (MS) is a chronic inflammatory and degenerative central nervous system disease affecting more than 2.5 million people worldwide. Today, if a Google search is performed for “diet and MS,” more than 67 million results are obtained. Many tout specific protocols as beneficial for MS but have no substantial data to support these claims. This can be confusing for patients as well as providers. How should you advise those who ask for advice on dietary modifications to help control symptoms or disease course?

First, it’s important to remember that individuals with MS have a reduced median lifespan (by about seven years), compared to healthy controls. Furthermore, patients with MS commonly have comorbid conditions—such as diabetes, obesity, and ische­mic heart disease—that increase mortality risk.^1,2 Diet and nutrition are significant factors that impact the course of these diseases.

We must also bear in mind that patients with MS experience symptoms that may impede their efforts to prepare meals. In a 2008 study of 123 MS patients (more than 50% of whom were overweight or obese), fatigue was cited as a significant factor that limited cooking and food preparation. Cognitive impairment and depression also may affect dietary intake. Interestingly, the average recorded intake for all food groups was less than that recommended in the Dietary Guidelines for Americans.³

A web-based survey conducted by the German MS Society in 2011 revealed that 42% of the 337 respondents had modified their diet due to MS. These modifications included change in intake of fatty acids; decrease or elimination of meat, sugar, and additives; and introduction of a low-carb or Paleo diet.⁴

Among an international sample of 2,087 MS patients, a significant association was found between a healthy diet and improved quality of life (both physical and mental) and reduced disability. This “healthy consumption” of fruits, vegetables, and dietary fat was also associated with a marginally decreased risk for relapse. Patients who demonstrated increased disease activity were more likely to have poor consumption of fruits, vegetables, and fats and to consume more meat and dairy products.⁵

There has also been research on specific components of dietary intake. Antioxidant-containing foods, for example, may have an anti-inflammatory effect.⁶ Vitamin B₁₂ deficiency plays a role in immunomodulatory effect, as well as formation of the myelin sheath, although its role (and the effect of biotin supplementation) in MS disease progression requires further study.⁷ Also ongoing is research into various calorie-restriction protocols, altering both timing and amount of caloric intake, since some data suggest this strategy reduces leptin, a satiety hormone that increases inflammation and has been shown to promote more aggressive MS in a mouse model.⁸

In the meantime, what can we conclude about diet and MS? A recent review determined that, although there is insufficient data to support one specific diet, there is sufficient evidence to recommend consumption of fish, foods lower in fat, whole grains, vitamin D, and supplemental omega fatty acids.⁵

It is important to discuss diet with our MS patients. In the German survey, 82% of patients felt that diet was important, yet only 10% had asked a provider for nutritional advice.⁴ In another study, patients indicated that food labels were their top source for nutrition information; only 20% sought advice from a nutritionist.³ We need to ask our MS patients if they are following a particular diet and be prepared to discuss potentially beneficial dietary choices with them—and offer referral to a nutritionist to those who require additional direction and support.—SP

Stacey Panasci, MSPAS, PA-C
Springfield Neurology Associates, LLC
Massachusetts

Q) What is known about the impact of diet on multiple sclerosis? How can I advise my patients with MS?

Multiple sclerosis (MS) is a chronic inflammatory and degenerative central nervous system disease affecting more than 2.5 million people worldwide. Today, if a Google search is performed for “diet and MS,” more than 67 million results are obtained. Many tout specific protocols as beneficial for MS but have no substantial data to support these claims. This can be confusing for patients as well as providers. How should you advise those who ask for advice on dietary modifications to help control symptoms or disease course?

First, it’s important to remember that individuals with MS have a reduced median lifespan (by about seven years), compared to healthy controls. Furthermore, patients with MS commonly have comorbid conditions—such as diabetes, obesity, and ische­mic heart disease—that increase mortality risk.^1,2 Diet and nutrition are significant factors that impact the course of these diseases.

We must also bear in mind that patients with MS experience symptoms that may impede their efforts to prepare meals. In a 2008 study of 123 MS patients (more than 50% of whom were overweight or obese), fatigue was cited as a significant factor that limited cooking and food preparation. Cognitive impairment and depression also may affect dietary intake. Interestingly, the average recorded intake for all food groups was less than that recommended in the Dietary Guidelines for Americans.³

A web-based survey conducted by the German MS Society in 2011 revealed that 42% of the 337 respondents had modified their diet due to MS. These modifications included change in intake of fatty acids; decrease or elimination of meat, sugar, and additives; and introduction of a low-carb or Paleo diet.⁴

Among an international sample of 2,087 MS patients, a significant association was found between a healthy diet and improved quality of life (both physical and mental) and reduced disability. This “healthy consumption” of fruits, vegetables, and dietary fat was also associated with a marginally decreased risk for relapse. Patients who demonstrated increased disease activity were more likely to have poor consumption of fruits, vegetables, and fats and to consume more meat and dairy products.⁵

There has also been research on specific components of dietary intake. Antioxidant-containing foods, for example, may have an anti-inflammatory effect.⁶ Vitamin B₁₂ deficiency plays a role in immunomodulatory effect, as well as formation of the myelin sheath, although its role (and the effect of biotin supplementation) in MS disease progression requires further study.⁷ Also ongoing is research into various calorie-restriction protocols, altering both timing and amount of caloric intake, since some data suggest this strategy reduces leptin, a satiety hormone that increases inflammation and has been shown to promote more aggressive MS in a mouse model.⁸

In the meantime, what can we conclude about diet and MS? A recent review determined that, although there is insufficient data to support one specific diet, there is sufficient evidence to recommend consumption of fish, foods lower in fat, whole grains, vitamin D, and supplemental omega fatty acids.⁵

It is important to discuss diet with our MS patients. In the German survey, 82% of patients felt that diet was important, yet only 10% had asked a provider for nutritional advice.⁴ In another study, patients indicated that food labels were their top source for nutrition information; only 20% sought advice from a nutritionist.³ We need to ask our MS patients if they are following a particular diet and be prepared to discuss potentially beneficial dietary choices with them—and offer referral to a nutritionist to those who require additional direction and support.—SP

Stacey Panasci, MSPAS, PA-C
Springfield Neurology Associates, LLC
Massachusetts

SAN DIEGO – The way Mathew M. Avram, MD, JD, sees it, the best way to avoid complications from using lasers for aesthetic procedures is to trust your own eyes, not the laser device itself.

“Lasers are never perfect,” he said at the annual Masters of Aesthetics Symposium. “The same device made by the same manufacturer may produce highly different outputs at the same setting. Moreover, lasers produce much different energies after they’ve been serviced. So, if you have two devices sitting right next to each other, don’t assume that the energy output on one device is exactly the same as the other device.”

dbrunk@frontlinemedcom.com

SAN DIEGO – The way Mathew M. Avram, MD, JD, sees it, the best way to avoid complications from using lasers for aesthetic procedures is to trust your own eyes, not the laser device itself.

“Lasers are never perfect,” he said at the annual Masters of Aesthetics Symposium. “The same device made by the same manufacturer may produce highly different outputs at the same setting. Moreover, lasers produce much different energies after they’ve been serviced. So, if you have two devices sitting right next to each other, don’t assume that the energy output on one device is exactly the same as the other device.”

dbrunk@frontlinemedcom.com

SAN DIEGO – The way Mathew M. Avram, MD, JD, sees it, the best way to avoid complications from using lasers for aesthetic procedures is to trust your own eyes, not the laser device itself.

“Lasers are never perfect,” he said at the annual Masters of Aesthetics Symposium. “The same device made by the same manufacturer may produce highly different outputs at the same setting. Moreover, lasers produce much different energies after they’ve been serviced. So, if you have two devices sitting right next to each other, don’t assume that the energy output on one device is exactly the same as the other device.”

dbrunk@frontlinemedcom.com

The available evidence is sufficient to support switching appropriate patients with rheumatologic diseases from a bio-originator agent to an approved biosimilar agent, according to new consensus-based recommendations from an international multidisciplinary task force.

“Treatment with biological agents has dramatically improved the outcome for patients with inflammatory diseases. However, the high cost of these medications has limited access for many patients,” Jonathan Kay, MD, of UMass Memorial Medical Center and the University of Massachusetts, Worcester, and his colleagues wrote on behalf of the Task Force on the Use of Biosimilars to Treat Rheumatological Diseases. Biosimilars of agents no longer protected by patent allow for increased availability at lower costs, they noted. In the European Union, the United States, Japan, and other countries, biosimilars of adalimumab, etanercept, infliximab, and rituximab have been approved, and those for which the bio-originator is no longer protected by patent have been marketed.

Sara Freeman/Frontline Medical News

• Treatment of rheumatic diseases is based on a shared decision-making process between patients and their rheumatologists.
• The contextual aspects of the health care system should be taken into consideration when treatment decisions are made.
• A biosimilar, as approved by authorities in a highly regulated area, is neither better nor worse in efficacy and is not inferior in safety to its bio-originator.
• Patients and health care providers should be informed about the nature of biosimilars, their approval process, and their safety and efficacy.
• Harmonized methods should be established to obtain reliable pharmacovigilance data, including traceability, about both biosimilars and bio-originators.

These principles represent the key issues regarding biosimilars as identified by the task force. As for the specific recommendations, the task force agreed that:

1. The availability of biosimilars must significantly lower the cost of treating an individual patient and increase access to optimal therapy for all patients with rheumatic diseases (level 5, grade D evidence).

2. Approved biosimilars can be used to treat appropriate patients in the same way as their bio-originators (level 1b, grade A evidence, indicating that the recommendation is based on an individual randomized, controlled trial and that the level 1 evidence is consistent).

3. Antidrug antibodies to biosimilars need not be measured in clinical practice as no significant differences have been detected between biosimilars and their bio-originators (level 2b, grade B evidence, indicating that the recommendation is based on an individual cohort study/low-quality randomized, controlled trial and consistent level 2 or 3 evidence).

4. Relevant preclinical and phase 1 data on a biosimilar should be available when phase 3 data are published (level 5, grade D evidence).

5. Confirmation of efficacy and safety in a single indication is sufficient for extrapolation to other diseases for which the bio-originator has been approved because biosimilars are equivalent in physiochemical, functional, and pharmacokinetic properties to the bio-originator (level 5, grade D evidence).

6. Available evidence suggests that a single switch from a bio-originator to one of its biosimilars is safe and effective; there is no reason to expect a different clinical outcome. However, patient perspectives must be considered (level 1b, grade A evidence).

7. Multiple switching between biosimilars and their bio-originators or other biosimilars should be assessed in registries (level 5, grade D evidence).

8. No switch to or among biosimilars should be initiated without the prior awareness of the patient and the treating health care provider (level 5, grade D evidence).

Differing opinions about the use of biosimilars as published by various subspecialty organizations highlight a lack of confidence among many clinicians with respect to appropriate use of the products, but that is changing amid a rapidly growing body of evidence, the task force said. The group achieved a high level of agreement about both the evaluation of biosimilars and their use to treat rheumatologic diseases, reaching 100% consensus for six of the recommendations and 91% and 96% for the other two.

“Data available as of December 2016 support the use of biosimilars by rheumatologists to encourage a fair and competitive market for biologics. Biosimilars now provide an opportunity to expand access to effective but expensive medications, increasing the number of available treatment choices and helping to control rapidly increasing drug expenditures,” they concluded.

The task force’s work was funded by an unrestricted educational grant from Amgen. Dr. Kay and his coauthors reported financial relationships with multiple pharmaceutical companies, many of which are developing biosimilars.

sworcester@frontlinemedcom.com

The available evidence is sufficient to support switching appropriate patients with rheumatologic diseases from a bio-originator agent to an approved biosimilar agent, according to new consensus-based recommendations from an international multidisciplinary task force.

“Treatment with biological agents has dramatically improved the outcome for patients with inflammatory diseases. However, the high cost of these medications has limited access for many patients,” Jonathan Kay, MD, of UMass Memorial Medical Center and the University of Massachusetts, Worcester, and his colleagues wrote on behalf of the Task Force on the Use of Biosimilars to Treat Rheumatological Diseases. Biosimilars of agents no longer protected by patent allow for increased availability at lower costs, they noted. In the European Union, the United States, Japan, and other countries, biosimilars of adalimumab, etanercept, infliximab, and rituximab have been approved, and those for which the bio-originator is no longer protected by patent have been marketed.

Sara Freeman/Frontline Medical News

• Treatment of rheumatic diseases is based on a shared decision-making process between patients and their rheumatologists.
• The contextual aspects of the health care system should be taken into consideration when treatment decisions are made.
• A biosimilar, as approved by authorities in a highly regulated area, is neither better nor worse in efficacy and is not inferior in safety to its bio-originator.
• Patients and health care providers should be informed about the nature of biosimilars, their approval process, and their safety and efficacy.
• Harmonized methods should be established to obtain reliable pharmacovigilance data, including traceability, about both biosimilars and bio-originators.

These principles represent the key issues regarding biosimilars as identified by the task force. As for the specific recommendations, the task force agreed that:

1. The availability of biosimilars must significantly lower the cost of treating an individual patient and increase access to optimal therapy for all patients with rheumatic diseases (level 5, grade D evidence).

2. Approved biosimilars can be used to treat appropriate patients in the same way as their bio-originators (level 1b, grade A evidence, indicating that the recommendation is based on an individual randomized, controlled trial and that the level 1 evidence is consistent).

3. Antidrug antibodies to biosimilars need not be measured in clinical practice as no significant differences have been detected between biosimilars and their bio-originators (level 2b, grade B evidence, indicating that the recommendation is based on an individual cohort study/low-quality randomized, controlled trial and consistent level 2 or 3 evidence).

4. Relevant preclinical and phase 1 data on a biosimilar should be available when phase 3 data are published (level 5, grade D evidence).

5. Confirmation of efficacy and safety in a single indication is sufficient for extrapolation to other diseases for which the bio-originator has been approved because biosimilars are equivalent in physiochemical, functional, and pharmacokinetic properties to the bio-originator (level 5, grade D evidence).

6. Available evidence suggests that a single switch from a bio-originator to one of its biosimilars is safe and effective; there is no reason to expect a different clinical outcome. However, patient perspectives must be considered (level 1b, grade A evidence).

7. Multiple switching between biosimilars and their bio-originators or other biosimilars should be assessed in registries (level 5, grade D evidence).

8. No switch to or among biosimilars should be initiated without the prior awareness of the patient and the treating health care provider (level 5, grade D evidence).

Differing opinions about the use of biosimilars as published by various subspecialty organizations highlight a lack of confidence among many clinicians with respect to appropriate use of the products, but that is changing amid a rapidly growing body of evidence, the task force said. The group achieved a high level of agreement about both the evaluation of biosimilars and their use to treat rheumatologic diseases, reaching 100% consensus for six of the recommendations and 91% and 96% for the other two.

“Data available as of December 2016 support the use of biosimilars by rheumatologists to encourage a fair and competitive market for biologics. Biosimilars now provide an opportunity to expand access to effective but expensive medications, increasing the number of available treatment choices and helping to control rapidly increasing drug expenditures,” they concluded.

The task force’s work was funded by an unrestricted educational grant from Amgen. Dr. Kay and his coauthors reported financial relationships with multiple pharmaceutical companies, many of which are developing biosimilars.

sworcester@frontlinemedcom.com

The available evidence is sufficient to support switching appropriate patients with rheumatologic diseases from a bio-originator agent to an approved biosimilar agent, according to new consensus-based recommendations from an international multidisciplinary task force.

“Treatment with biological agents has dramatically improved the outcome for patients with inflammatory diseases. However, the high cost of these medications has limited access for many patients,” Jonathan Kay, MD, of UMass Memorial Medical Center and the University of Massachusetts, Worcester, and his colleagues wrote on behalf of the Task Force on the Use of Biosimilars to Treat Rheumatological Diseases. Biosimilars of agents no longer protected by patent allow for increased availability at lower costs, they noted. In the European Union, the United States, Japan, and other countries, biosimilars of adalimumab, etanercept, infliximab, and rituximab have been approved, and those for which the bio-originator is no longer protected by patent have been marketed.

Sara Freeman/Frontline Medical News

• Treatment of rheumatic diseases is based on a shared decision-making process between patients and their rheumatologists.
• The contextual aspects of the health care system should be taken into consideration when treatment decisions are made.
• A biosimilar, as approved by authorities in a highly regulated area, is neither better nor worse in efficacy and is not inferior in safety to its bio-originator.
• Patients and health care providers should be informed about the nature of biosimilars, their approval process, and their safety and efficacy.
• Harmonized methods should be established to obtain reliable pharmacovigilance data, including traceability, about both biosimilars and bio-originators.

These principles represent the key issues regarding biosimilars as identified by the task force. As for the specific recommendations, the task force agreed that:

1. The availability of biosimilars must significantly lower the cost of treating an individual patient and increase access to optimal therapy for all patients with rheumatic diseases (level 5, grade D evidence).

2. Approved biosimilars can be used to treat appropriate patients in the same way as their bio-originators (level 1b, grade A evidence, indicating that the recommendation is based on an individual randomized, controlled trial and that the level 1 evidence is consistent).

3. Antidrug antibodies to biosimilars need not be measured in clinical practice as no significant differences have been detected between biosimilars and their bio-originators (level 2b, grade B evidence, indicating that the recommendation is based on an individual cohort study/low-quality randomized, controlled trial and consistent level 2 or 3 evidence).

4. Relevant preclinical and phase 1 data on a biosimilar should be available when phase 3 data are published (level 5, grade D evidence).

5. Confirmation of efficacy and safety in a single indication is sufficient for extrapolation to other diseases for which the bio-originator has been approved because biosimilars are equivalent in physiochemical, functional, and pharmacokinetic properties to the bio-originator (level 5, grade D evidence).

6. Available evidence suggests that a single switch from a bio-originator to one of its biosimilars is safe and effective; there is no reason to expect a different clinical outcome. However, patient perspectives must be considered (level 1b, grade A evidence).

7. Multiple switching between biosimilars and their bio-originators or other biosimilars should be assessed in registries (level 5, grade D evidence).

8. No switch to or among biosimilars should be initiated without the prior awareness of the patient and the treating health care provider (level 5, grade D evidence).

Differing opinions about the use of biosimilars as published by various subspecialty organizations highlight a lack of confidence among many clinicians with respect to appropriate use of the products, but that is changing amid a rapidly growing body of evidence, the task force said. The group achieved a high level of agreement about both the evaluation of biosimilars and their use to treat rheumatologic diseases, reaching 100% consensus for six of the recommendations and 91% and 96% for the other two.

“Data available as of December 2016 support the use of biosimilars by rheumatologists to encourage a fair and competitive market for biologics. Biosimilars now provide an opportunity to expand access to effective but expensive medications, increasing the number of available treatment choices and helping to control rapidly increasing drug expenditures,” they concluded.

The task force’s work was funded by an unrestricted educational grant from Amgen. Dr. Kay and his coauthors reported financial relationships with multiple pharmaceutical companies, many of which are developing biosimilars.

sworcester@frontlinemedcom.com

The Diagnosis: Rosai-Dorfman Disease

Rosai-Dorfman disease is a rare histiocytic proliferative disorder of unknown etiology. It has 2 forms: limited cutaneous and systemic. The systemic form, also known as sinus histiocytosis with massive lym­phadenopathy, affects the lymph nodes and other organs at times. The disease is characterized by a proliferation of histiocytes in the lymph nodes, most commonly in the cervical basin¹; however, the inguinal, axillary, mediastinal, or para-aortic nodes also may be affected.^1,2 The skin is the most common site of extranodal disease, seen in approximately 10% of cases.¹ Cutaneous involvement often is in the facial area but also can be found on the trunk, ears, neck, arms, legs, and genitals. Clinically, skin lesions appear as papules, plaques, and/or nodules.²

Histopathologic examination of Rosai-Dorfman disease generally shows a dense sheetlike dermal infiltrate of large polygonal histiocytes (Figure 1). Histiocytes may display pale pink or clear cytoplasm. The pathognomonic finding is emperipolesis, which consists of histiocytes with engulfed lymphocytes, erythrocytes, plasma cells, and/or granulocytes surrounded by a clear halo. Immunohistochemical staining also is characteristic, with lesional histiocytes showing expression of S-100 protein (Figure 1, inset) and CD68. The associated inflammatory infiltrate is mixed, containing primarily plasma cells but also lymphocytes, neutrophils, and eosinophils.

Blastomycosis (Figure 2) is a systemic infection due to inhalation of Blastomyces dermatitidis conidia. Primary infection occurs in the lungs, and with dissemination the skin is the most common subsequently involved organ.³ Cutaneous blastomycosis shows pseudoepitheliomatous hyperplasia with neutrophilic microabscesses and a dense dermal infiltrate containing suppurative granulomatous inflammation. The nonpigmented yeast phase typically is 8 to 15 µm in length with a refractile cell wall and characteristic single, broad-based budding.³

Granuloma faciale (Figure 3) is a rare disease with unknown etiology characterized by reddish brown plaques or nodules most commonly occurring on the face.^4,5 Histology shows a dense nodular dermal infiltrate with a grenz zone. The infiltrate is mixed, containing mostly neutrophils with leukocytoclasis and eosinophils. Leukocytoclastic vasculitis is present with associated extravasated erythrocytes. In chronic fibrosing granuloma faciale, lesions can demonstrate fibrosis and hemosiderin deposition, similar to erythema elevatum diutinum.

Juvenile xanthogranuloma (Figure 4) is a common histiocytic disease of early childhood, though adult cases have been reported.⁶ Tumors are found on the head and trunk and are typically firm, reddish yellow papules or nodules.^6,7 Histologic examination shows a nodular infiltrate of foamy histiocytes in the superficial dermis. Touton-type multinucleated giant cells with a peripheral rim of xanthomatized foamy cytoplasm and a wreathlike arrangement of nuclei are characteristic. Associated eosinophils are seen. No emperipolesis is present.

Reticulohistiocytoma (Figure 5) is a benign dermal lesion that presents as solitary or less commonly multiple red-brown papules or nodules.⁸ Lesions consist of well-delineated nodular aggregates of histiocytes containing a finely granular eosinophilic ground glass cytoplasm. Few, if any, eosinophils are found. The lack of Touton multinucleated giant cells or emperipolesis and lack of expression of S-100 protein helps to distinguish reticulohistiocytoma from other entities in the differential diagnosis.

The Diagnosis: Rosai-Dorfman Disease

Rosai-Dorfman disease is a rare histiocytic proliferative disorder of unknown etiology. It has 2 forms: limited cutaneous and systemic. The systemic form, also known as sinus histiocytosis with massive lym­phadenopathy, affects the lymph nodes and other organs at times. The disease is characterized by a proliferation of histiocytes in the lymph nodes, most commonly in the cervical basin¹; however, the inguinal, axillary, mediastinal, or para-aortic nodes also may be affected.^1,2 The skin is the most common site of extranodal disease, seen in approximately 10% of cases.¹ Cutaneous involvement often is in the facial area but also can be found on the trunk, ears, neck, arms, legs, and genitals. Clinically, skin lesions appear as papules, plaques, and/or nodules.²

Histopathologic examination of Rosai-Dorfman disease generally shows a dense sheetlike dermal infiltrate of large polygonal histiocytes (Figure 1). Histiocytes may display pale pink or clear cytoplasm. The pathognomonic finding is emperipolesis, which consists of histiocytes with engulfed lymphocytes, erythrocytes, plasma cells, and/or granulocytes surrounded by a clear halo. Immunohistochemical staining also is characteristic, with lesional histiocytes showing expression of S-100 protein (Figure 1, inset) and CD68. The associated inflammatory infiltrate is mixed, containing primarily plasma cells but also lymphocytes, neutrophils, and eosinophils.

Blastomycosis (Figure 2) is a systemic infection due to inhalation of Blastomyces dermatitidis conidia. Primary infection occurs in the lungs, and with dissemination the skin is the most common subsequently involved organ.³ Cutaneous blastomycosis shows pseudoepitheliomatous hyperplasia with neutrophilic microabscesses and a dense dermal infiltrate containing suppurative granulomatous inflammation. The nonpigmented yeast phase typically is 8 to 15 µm in length with a refractile cell wall and characteristic single, broad-based budding.³

Granuloma faciale (Figure 3) is a rare disease with unknown etiology characterized by reddish brown plaques or nodules most commonly occurring on the face.^4,5 Histology shows a dense nodular dermal infiltrate with a grenz zone. The infiltrate is mixed, containing mostly neutrophils with leukocytoclasis and eosinophils. Leukocytoclastic vasculitis is present with associated extravasated erythrocytes. In chronic fibrosing granuloma faciale, lesions can demonstrate fibrosis and hemosiderin deposition, similar to erythema elevatum diutinum.

Juvenile xanthogranuloma (Figure 4) is a common histiocytic disease of early childhood, though adult cases have been reported.⁶ Tumors are found on the head and trunk and are typically firm, reddish yellow papules or nodules.^6,7 Histologic examination shows a nodular infiltrate of foamy histiocytes in the superficial dermis. Touton-type multinucleated giant cells with a peripheral rim of xanthomatized foamy cytoplasm and a wreathlike arrangement of nuclei are characteristic. Associated eosinophils are seen. No emperipolesis is present.

Reticulohistiocytoma (Figure 5) is a benign dermal lesion that presents as solitary or less commonly multiple red-brown papules or nodules.⁸ Lesions consist of well-delineated nodular aggregates of histiocytes containing a finely granular eosinophilic ground glass cytoplasm. Few, if any, eosinophils are found. The lack of Touton multinucleated giant cells or emperipolesis and lack of expression of S-100 protein helps to distinguish reticulohistiocytoma from other entities in the differential diagnosis.

The Diagnosis: Rosai-Dorfman Disease

Rosai-Dorfman disease is a rare histiocytic proliferative disorder of unknown etiology. It has 2 forms: limited cutaneous and systemic. The systemic form, also known as sinus histiocytosis with massive lym­phadenopathy, affects the lymph nodes and other organs at times. The disease is characterized by a proliferation of histiocytes in the lymph nodes, most commonly in the cervical basin¹; however, the inguinal, axillary, mediastinal, or para-aortic nodes also may be affected.^1,2 The skin is the most common site of extranodal disease, seen in approximately 10% of cases.¹ Cutaneous involvement often is in the facial area but also can be found on the trunk, ears, neck, arms, legs, and genitals. Clinically, skin lesions appear as papules, plaques, and/or nodules.²

Histopathologic examination of Rosai-Dorfman disease generally shows a dense sheetlike dermal infiltrate of large polygonal histiocytes (Figure 1). Histiocytes may display pale pink or clear cytoplasm. The pathognomonic finding is emperipolesis, which consists of histiocytes with engulfed lymphocytes, erythrocytes, plasma cells, and/or granulocytes surrounded by a clear halo. Immunohistochemical staining also is characteristic, with lesional histiocytes showing expression of S-100 protein (Figure 1, inset) and CD68. The associated inflammatory infiltrate is mixed, containing primarily plasma cells but also lymphocytes, neutrophils, and eosinophils.

Blastomycosis (Figure 2) is a systemic infection due to inhalation of Blastomyces dermatitidis conidia. Primary infection occurs in the lungs, and with dissemination the skin is the most common subsequently involved organ.³ Cutaneous blastomycosis shows pseudoepitheliomatous hyperplasia with neutrophilic microabscesses and a dense dermal infiltrate containing suppurative granulomatous inflammation. The nonpigmented yeast phase typically is 8 to 15 µm in length with a refractile cell wall and characteristic single, broad-based budding.³

Granuloma faciale (Figure 3) is a rare disease with unknown etiology characterized by reddish brown plaques or nodules most commonly occurring on the face.^4,5 Histology shows a dense nodular dermal infiltrate with a grenz zone. The infiltrate is mixed, containing mostly neutrophils with leukocytoclasis and eosinophils. Leukocytoclastic vasculitis is present with associated extravasated erythrocytes. In chronic fibrosing granuloma faciale, lesions can demonstrate fibrosis and hemosiderin deposition, similar to erythema elevatum diutinum.

Juvenile xanthogranuloma (Figure 4) is a common histiocytic disease of early childhood, though adult cases have been reported.⁶ Tumors are found on the head and trunk and are typically firm, reddish yellow papules or nodules.^6,7 Histologic examination shows a nodular infiltrate of foamy histiocytes in the superficial dermis. Touton-type multinucleated giant cells with a peripheral rim of xanthomatized foamy cytoplasm and a wreathlike arrangement of nuclei are characteristic. Associated eosinophils are seen. No emperipolesis is present.

Reticulohistiocytoma (Figure 5) is a benign dermal lesion that presents as solitary or less commonly multiple red-brown papules or nodules.⁸ Lesions consist of well-delineated nodular aggregates of histiocytes containing a finely granular eosinophilic ground glass cytoplasm. Few, if any, eosinophils are found. The lack of Touton multinucleated giant cells or emperipolesis and lack of expression of S-100 protein helps to distinguish reticulohistiocytoma from other entities in the differential diagnosis.

Atopic dermatitis (AD) is a vexing multisystem disorder characterized by frequently recurrent, intrusive, and sometimes disabling itch and dermatitis. The itch may be present throughout the day but crescendos at bedtime or 1 to 2 hours after sleep initiation, resulting in disrupted sleep cycles, lack of rest, more hours scratching, daytime somnolence, poor work attendance and performance, and poor school attendance and performance.¹

Atopic dermatitis is a lifelong disease that only remits in approximately half of patients.² There is a need for a disease-specific systemic drug in AD. Phototherapy, cyclosporine, methotrexate, and azathioprine are nonspecific immunosuppressive agents that can be used off label for AD but may or may not be effective.³ Oral or intramuscular corticosteroids are associated with problematic side effects such as weight gain, osteoporosis, fractures, psychological problems, striae, buffalo hump, and steroid withdrawal symptoms and disease aggravation upon withdrawal (ie, flaring to a state worse than prior to steroid initiation).^3,4

A biologic medication for AD has been long overdue. Psoriatic biologic medications have been tried in AD with occasional benefit in case reports but no major response in larger trials. Belloni et al⁵ reviewed early data on off-label usage of biologics approved by the US Food and Drug Administration for psoriasis or other indications applied to AD patients. In their review of cases, they make the point that results are variable and anti-B-cell activity may hold the greatest promise.⁵ On the other hand, a recent series of 3 patients showed limited response to rituximab in chronic AD,⁶ while a combination of omalizumab, an anti-IgE medication, and rituximab was helpful in some patients.⁷ Ultimately, the issue is that nonspecific biologics may or may not address the underlying disease factors in AD. Therefore, there has been a true need for biologic intervention targeted directly at the pathogenic mechanism of AD. Furthermore, the desire for a biologic targeted at AD is paired with the true need to have a medication so targeted that the drug would have little effect on the rest of the immune system, resulting in targeted immunomodulation without secondary risk of infections.

Wait no longer, that era arrived a few months ago with the rapid US Food and Drug Administration approval of dupilumab, an injectable medication used every 2 weeks for the therapy of moderate to severe AD. This fully human monoclonal antibody against the IL-4Rα subunit blocks IL-4 and IL-13, key inflammatory agents in the triggering of production of IgE and eosinophil activation. Even better than the fact that it is targeted are the excellent outcomes in the therapy of moderate to severe AD in adults and the minimal side-effect profile resulting in no requirements for laboratory screening or ongoing monitoring.⁸

Dupilumab seems to perform well, both clinically and in improving the lives of AD patients. Meta-analysis of trials involving dupilumab has shown improved health-related quality of life outcomes.^9,10 Usage of dupilumab alone in clinical trials for 16 weeks (SOLO 1 and SOLO 2) has resulted in stunning reduction in disease severity with a limited side-effect profile, with patients most commonly reporting conjunctivitis.¹¹ In real-world models where dupilumab is added into a regimen of topical corticosteroid usage (LIBERTY AD CHRONOS trial), patients fared even better with the combination, highlighting that this medication may best be used adjunctively to our skin care guidance as dermatologists.¹²

A new era for AD patients has arrived and we as practitioners are now fortunate to be able to therapeutically reach the worst cases of AD. The new era has only begun with dozens of new agents addressing a variety of interleukin pathways including IL-17 and IL-22 still under development. Ultimately, we hope that ongoing pediatric trials will allow us to glean the role of early disease intervention at the root cause of AD and address our abilities to prevent comorbidities and disease persistence. Will we be able to avert years of disabling disease? The future holds immense hope.

Atopic dermatitis (AD) is a vexing multisystem disorder characterized by frequently recurrent, intrusive, and sometimes disabling itch and dermatitis. The itch may be present throughout the day but crescendos at bedtime or 1 to 2 hours after sleep initiation, resulting in disrupted sleep cycles, lack of rest, more hours scratching, daytime somnolence, poor work attendance and performance, and poor school attendance and performance.¹

Atopic dermatitis is a lifelong disease that only remits in approximately half of patients.² There is a need for a disease-specific systemic drug in AD. Phototherapy, cyclosporine, methotrexate, and azathioprine are nonspecific immunosuppressive agents that can be used off label for AD but may or may not be effective.³ Oral or intramuscular corticosteroids are associated with problematic side effects such as weight gain, osteoporosis, fractures, psychological problems, striae, buffalo hump, and steroid withdrawal symptoms and disease aggravation upon withdrawal (ie, flaring to a state worse than prior to steroid initiation).^3,4

A biologic medication for AD has been long overdue. Psoriatic biologic medications have been tried in AD with occasional benefit in case reports but no major response in larger trials. Belloni et al⁵ reviewed early data on off-label usage of biologics approved by the US Food and Drug Administration for psoriasis or other indications applied to AD patients. In their review of cases, they make the point that results are variable and anti-B-cell activity may hold the greatest promise.⁵ On the other hand, a recent series of 3 patients showed limited response to rituximab in chronic AD,⁶ while a combination of omalizumab, an anti-IgE medication, and rituximab was helpful in some patients.⁷ Ultimately, the issue is that nonspecific biologics may or may not address the underlying disease factors in AD. Therefore, there has been a true need for biologic intervention targeted directly at the pathogenic mechanism of AD. Furthermore, the desire for a biologic targeted at AD is paired with the true need to have a medication so targeted that the drug would have little effect on the rest of the immune system, resulting in targeted immunomodulation without secondary risk of infections.

Wait no longer, that era arrived a few months ago with the rapid US Food and Drug Administration approval of dupilumab, an injectable medication used every 2 weeks for the therapy of moderate to severe AD. This fully human monoclonal antibody against the IL-4Rα subunit blocks IL-4 and IL-13, key inflammatory agents in the triggering of production of IgE and eosinophil activation. Even better than the fact that it is targeted are the excellent outcomes in the therapy of moderate to severe AD in adults and the minimal side-effect profile resulting in no requirements for laboratory screening or ongoing monitoring.⁸

Dupilumab seems to perform well, both clinically and in improving the lives of AD patients. Meta-analysis of trials involving dupilumab has shown improved health-related quality of life outcomes.^9,10 Usage of dupilumab alone in clinical trials for 16 weeks (SOLO 1 and SOLO 2) has resulted in stunning reduction in disease severity with a limited side-effect profile, with patients most commonly reporting conjunctivitis.¹¹ In real-world models where dupilumab is added into a regimen of topical corticosteroid usage (LIBERTY AD CHRONOS trial), patients fared even better with the combination, highlighting that this medication may best be used adjunctively to our skin care guidance as dermatologists.¹²

A new era for AD patients has arrived and we as practitioners are now fortunate to be able to therapeutically reach the worst cases of AD. The new era has only begun with dozens of new agents addressing a variety of interleukin pathways including IL-17 and IL-22 still under development. Ultimately, we hope that ongoing pediatric trials will allow us to glean the role of early disease intervention at the root cause of AD and address our abilities to prevent comorbidities and disease persistence. Will we be able to avert years of disabling disease? The future holds immense hope.

Atopic dermatitis (AD) is a vexing multisystem disorder characterized by frequently recurrent, intrusive, and sometimes disabling itch and dermatitis. The itch may be present throughout the day but crescendos at bedtime or 1 to 2 hours after sleep initiation, resulting in disrupted sleep cycles, lack of rest, more hours scratching, daytime somnolence, poor work attendance and performance, and poor school attendance and performance.¹

Atopic dermatitis is a lifelong disease that only remits in approximately half of patients.² There is a need for a disease-specific systemic drug in AD. Phototherapy, cyclosporine, methotrexate, and azathioprine are nonspecific immunosuppressive agents that can be used off label for AD but may or may not be effective.³ Oral or intramuscular corticosteroids are associated with problematic side effects such as weight gain, osteoporosis, fractures, psychological problems, striae, buffalo hump, and steroid withdrawal symptoms and disease aggravation upon withdrawal (ie, flaring to a state worse than prior to steroid initiation).^3,4

A biologic medication for AD has been long overdue. Psoriatic biologic medications have been tried in AD with occasional benefit in case reports but no major response in larger trials. Belloni et al⁵ reviewed early data on off-label usage of biologics approved by the US Food and Drug Administration for psoriasis or other indications applied to AD patients. In their review of cases, they make the point that results are variable and anti-B-cell activity may hold the greatest promise.⁵ On the other hand, a recent series of 3 patients showed limited response to rituximab in chronic AD,⁶ while a combination of omalizumab, an anti-IgE medication, and rituximab was helpful in some patients.⁷ Ultimately, the issue is that nonspecific biologics may or may not address the underlying disease factors in AD. Therefore, there has been a true need for biologic intervention targeted directly at the pathogenic mechanism of AD. Furthermore, the desire for a biologic targeted at AD is paired with the true need to have a medication so targeted that the drug would have little effect on the rest of the immune system, resulting in targeted immunomodulation without secondary risk of infections.

Wait no longer, that era arrived a few months ago with the rapid US Food and Drug Administration approval of dupilumab, an injectable medication used every 2 weeks for the therapy of moderate to severe AD. This fully human monoclonal antibody against the IL-4Rα subunit blocks IL-4 and IL-13, key inflammatory agents in the triggering of production of IgE and eosinophil activation. Even better than the fact that it is targeted are the excellent outcomes in the therapy of moderate to severe AD in adults and the minimal side-effect profile resulting in no requirements for laboratory screening or ongoing monitoring.⁸

Dupilumab seems to perform well, both clinically and in improving the lives of AD patients. Meta-analysis of trials involving dupilumab has shown improved health-related quality of life outcomes.^9,10 Usage of dupilumab alone in clinical trials for 16 weeks (SOLO 1 and SOLO 2) has resulted in stunning reduction in disease severity with a limited side-effect profile, with patients most commonly reporting conjunctivitis.¹¹ In real-world models where dupilumab is added into a regimen of topical corticosteroid usage (LIBERTY AD CHRONOS trial), patients fared even better with the combination, highlighting that this medication may best be used adjunctively to our skin care guidance as dermatologists.¹²

A new era for AD patients has arrived and we as practitioners are now fortunate to be able to therapeutically reach the worst cases of AD. The new era has only begun with dozens of new agents addressing a variety of interleukin pathways including IL-17 and IL-22 still under development. Ultimately, we hope that ongoing pediatric trials will allow us to glean the role of early disease intervention at the root cause of AD and address our abilities to prevent comorbidities and disease persistence. Will we be able to avert years of disabling disease? The future holds immense hope.

Survival improves when patients with cancer self-report symptoms

Key clinical point Patients with metastatic cancer who self-reported symptoms experienced significant improvement in overall survival. Major finding Median overall survival with self-reporting of symptoms compared with usual care was 31.2 and 26 months, respectively. Data source A randomized controlled clinical trial of 766 patients. Funding and disclosures This study was supported by the National Institutes of Health and the Conquer Cancer Foundation of the American Society of Clinical Oncology. Dr Basch and Dr Burstein each reported having no disclosures.

Patients with metastatic cancer who self-reported symptoms during routine cancer treatment experienced a number of benefits, including a statistically significant improvement in overall survival, according to findings from a randomized, controlled clinical trial (see p. e184). The median overall survival in 441 patients receiving treatment for metastatic breast, lung, genitourinary, or gynecologic cancer who were randomized to the self-reporting intervention arm was more than 5 months longer (a nearly 20% increase) than in 325 patients receiving standard care (31.2 vs. 26 months), Ethan Basch, MD, of the Lineberger Comprehensive Cancer Center at the University of North Carolina, Chapel Hill, said at the meeting. “Another way to think of this is [in terms of] 5-year survival. At 5 years, 8% more patients were alive in the self-reporting group,” he said.

— Sharon Worcester

TRK inhibitor shows ‘striking’ activity and durability across diverse cancers

Key clinical point Larotrectinib has good, durable efficacy when used to treat advanced cancers harboring TRK fusions. Major finding The overall response rate was 76%, and 79% of responses were still ongoing at 12 months. Data source An integrated analysis of phase 1 and 2 trials among 55 children and adults having 17 discrete types of advanced cancer with TRK fusions. Funding and disclosures Loxo Oncology funded the study. Dr Hyman disclosed that he has a consulting or advisory role with Atara Biotherapeutics, Chugai Pharma, and CytomX Therapeutics, and that he receives research funding from AstraZeneca and Puma Biotechnology.
 

Larotrectinib, an oral inhibitor of tropomyosin receptor kinase (TRK), has durable efficacy across diverse adult and pediatric cancers that harbor a genetic aberration known as TRK fusion, according to findings from an analysis of 3 trials reported at the meeting (see p. e184). Fusion of a TRK gene with an unrelated gene leads to uncontrolled signaling in the TRK pathway, potentially causing tumor growth and addiction to this input, David Hyman, MD, chief of early drug development at Memorial Sloan Kettering Cancer Center in New York, explained in a press briefing.

“One of the defining features of TRK fusions is that they are not just found in one cancer type, but in dozens of different cancer types, and not just in adults, but children as well, spanning the entire lifetime of the person,” he noted. They are rare in common cancers and nearly universal in certain uncommon cancers; collectively, they are present in possibly 5,000 cancers diagnosed each year in the United States.

Study details

The investigators analyzed data from 3 trials in which patients with advanced TRK fusion-positive solid cancers received larotrectinib (LOXO-101): a phase 1 trial among 8 adult patients, a phase 1/2 trial among 12 pediatric patients (SCOUT), and a phase 2 “basket” trial among 35 adult and adolescent patients (NAVIGATE).

“These patients were identified by local testing,” Dr Hyman noted. “We did not perform central screening to find the TRK fusions, and in fact, 50 different laboratories identified the 55 patients. So in a sense, this really represents the real-world identification of these patients.”

In an integrated analysis, the overall rate of confirmed response as assessed by investigators was 76%, with complete response in 12% of patients and partial response in 64%. Two patients had such deep tumor regression that they experienced downstaging enabling them to undergo potentially curative surgery. Efficacy was consistent regardless of tumor type, which TRK gene was affected, and the fusion partner gene.

Median time to response was 1.8 months. “This is just a reflection of when the first scan was obtained. But in the clinic, patients reported dramatic improvement of their symptoms within days of starting therapy,” Dr Hyman said.

With a median follow-up of 5.8 months, the median duration of response was not yet reached. In all, 79% of responses were still ongoing at 12 months. Median progression-free survival (PFS) was likewise not reached; the 12-month rate was 63%.

The leading treatment-emergent adverse events were fatigue (38%), dizziness (27%), nausea (26%), and anemia (26%). “This is an extremely well tolerated therapy with only 13% of patients requiring any form of dose modification and not a single patient discontinuing due to adverse events,” he said.

It is not clear why some patients had apparent primary resistance to larotrectinib, but their TRK fusion test results may have been incorrect, Dr Hyman speculated. In all, 6 patients developed acquired resistance to larotrectinib; 5 of them were found to have an identical resistance mutation, and 2 went on to receive and have a response to LOXO-195, a next-generation TRK inhibitor that seems to retain activity in the presence of this mutation (Cancer Discov. 2017 June 3. doi: 10.1158/2159-8290.CD-17-0507).

TRK testing

Several next-generation sequencing-based tests already available clinically can pick up TRK fusions, Dr Hyman pointed out. “But it is important for the ordering physician to understand whether the tests they are ordering include fusion detection and, if it’s an option, to select it. Otherwise, they will not find TRK fusions. “The list price for these tests is in the low thousands of dollars,” he noted. In cancers in which sequential single-gene testing is already being done as standard of care, there is “minimal” incremental cost of instead using comprehensive testing that would detect TRK fusions.

Oncologists should be aware that obtaining test results can take weeks, Dr Hyman stressed. “This [testing] should be more broadly adopted and should be adopted at a point in the patient’s treatment [so that they] don’t become too sick, then don’t have an opportunity to be treated even when the test results come back positive.”

— Susan London

QoL preserved with ribociclib-letrozole for advanced breast cancer

Key clinical point Patients who took ribociclib plus letrozole had less pain and no drop in QoL compared with letrozole alone. Major finding QoL was sustained and pain scores decreased when ribociclib was added to letrozole for patients with advanced breast cancer. Data source Double-blind, placebo-controlled phase 3 trial of letrozole plus ribociclib compared with letrozole plus placebo in 668 patients with advanced hormone receptor–positive, HER2-negative breast cancer. Disclosures Dr Verma reported financial relationships with Novartis, which markets ribociclib, and other firms.

Patients with advanced breast cancer whose aromatase inhibitor therapy was supplemented with a cycline-dependent kinase inhibitor had better PFS with no drop in quality of life (QoL). Health-related QoL for patients on the combination therapy was equivalent to that of patients on monotherapy in most aspects, but patients receiving both therapies had a sustained and clinically meaningful decrease in pain.

In addition, the time to definitive deterioration by 10% or more of the global health status/QoL scale score was similar between treatment arms (hazard ratio [HR], 0.944; 95% confidence interval, 0.720-1.237).

The MONALEESA-2 trial had previously shown that the CDK4/6 inhibitor ribociclib, when added to the aromatase inhibitor letrozole, significantly improved PFS for postmenopausal patients with hormone receptor–positive, HER2-negative advanced breast cancer, when compared with letrozole in combination with placebo.

Sunil Verma, MD, reported on health-related QoL and symptoms in the 2 arms of MONALEESA-2, showing change from baseline, time to a definitive 10% deterioration, and the mean scores for on-treatment time compared with end of treatment on the global health-status QoL subscale of the European Organization for Research and Treatment of Cancer's (EORTC's) 30-item core QoL questionnaire.

“During treatment, overall health-related quality of life was maintained from baseline and was similar in both arms,” said Dr Verma, the study’s first author. Changes during treatment were not statistically significant, and did not reach the predetermined threshold for a clinically meaningful difference. The effect of key symptoms such as fatigue, nausea, and vomiting on QoL was similar for patients receiving ribociclib or placebo, he said. Although symptom scores were slightly higher for patients in the active arm of the study, the results were not clinically significant.

Reporting validated, cancer-specific patient-reported outcomes from the trial, Dr Verma, professor and head of the department of oncology at the University of Calgary in Alberta, Canada, sought to “highlight the patient experience with a focus on health-related quality of life and symptoms,” he said during his presentation at the meeting. “A clinically meaningful – more than 5 points – improvement from baseline in pain score was maintained up to and including cycle 15 in the ribociclib plus letrozole arm.” The placebo arm had a mild, clinically insignificant improvement at most assessment points. For both treatment arms, pain scores increased a bit above baseline levels at the time of disease progression or end of therapy, he said.

Patients completed the EORTC 30-item core QoL questionnaire at their screening visit, and then every 8 weeks for the first 18 months. Then, they completed the questionnaires every 12 weeks until they experienced disease progression, died, were lost to follow-up or withdrew from the study, or stopped treatment.

Statistical analysis of the questionnaire results took into account the patients’ baseline scores, treatments received, and how they were stratified. Investigators assessed both statistical significance and the clinical meaningfulness of changes, defined as a change of 5-10 points.

In MONALEESA-2, 334 patients each were allocated to the ribociclib-letrozole arm and the placebo-letrozole arm. Patients in both arms, said Dr Verma, were very compliant with questionnaire completion. More than 90% of patients who were eligible completed questionnaire through cycle 19 of ribociclib or placebo. He explained that the overall numbers completing the questionnaire declined with time, as more patients had disease progression. Dr Verma said it is important to include those measures, because patients and their families care about “the quality of the time gained,” so patient-reported outcomes should be a part of risk-benefit assessments for new cancer therapies. “While delaying disease progression may help maintain patient quality of life, the addition of novel treatments to existing therapies can add toxicities, which may diminish quality of life,” he said.

— Kari Oakes

Ibrutinib and beyond: optimizing therapy in relapsed CLL

Key clinical point Ibrutinib had durable efficacy in relapsed CLL, and combinations with other targeted agents or with CAR-T cells are promising. Major finding Long-term PFS was better with ibrutinib than with ofatumumab (HR, 0.133). The overall response rate with the triplet of ibrutinib, ublituximab, and umbralisib was 100%. In all, 89% of patients achieved no evidence of disease in marrow when anti-CD19 CAR-T cells were added to ibrutinib. Data source An update of a phase 3 randomized trial among 391 patients with previously treated CLL or SLL (RESONATE). A phase 1/1b trial including 19 patients with mainly relapsed or refractory CLL or SLL. A pilot trial among 10 patients with previously treated, mainly higher-risk, CLL or SLL. Disclosures See article text.

Ibrutinib monotherapy

In the phase 3 randomized RESONATE trial, investigators compared ibrutinib with ofatumumab, an anti-CD20 antibody, among 391 patients with CLL or small lymphocytic lymphoma (SLL), with crossover allowed. Initial results favored ibrutinib.

Investigators led by John C Byrd, MD, director of the division of hematology at the Ohio State University Comprehensive Cancer Center in Columbus, reported updated data in a poster session at the meeting, now with a median 44 months of follow-up in the ibrutinib arm.

Median PFS was not reached with ibrutinib, compared with 8.1 months with ofatumumab (HR, 0.133). The 3-year rate of PFS for ibrutinib and ofatumumab was 59% and 3%, respectively.

The pattern was generally similar across patients stratified by cytogenetics (deletion of 17p, deletion of 11q, or neither), IGHV and TP53 mutation status, and previous lines of therapy, reported Dr Byrd. The 3-year overall survival rate for ibrutinib was 74%. In analyses adjusted for crossover, patients given the inhibitor had a markedly lower risk of death than did peers given the antibody (HR, 0.37). The overall response rate with ibrutinib was 91%. Although the rate of complete response increased with follow-up, it was still just 9%.

The most common grade 3 or worse adverse events were neutropenia (23%), pneumonia (17%), and anemia, thrombocytopenia, and hypertension (8% each). Major hemorrhage was reported in 2 patients (1%) in the ibrutinib group, and 3 (2%) in the ofatumumab group.

The investigators emphasized that these long-term results “show that extended treatment with ibrutinib is tolerable and continues to show sustained PFS in previously treated patients with CLL regardless of high-risk cytogenetics, adding that traditional poor prognostic factors for survival with chemoimmunotherapy, including del(17p) and del(11q), were not significant factors predictive of PFS outcomes with ibrutinib.

Funding and disclosures: Pharmacyclics funded the trial. Dr Byrd disclosed that he receives research funding from Pharmacyclics and other companies.

Ibrutinib plus ublituximab and umbralisib

Investigators led by Loretta J Nastoupil, MD, tested a triplet consisting of ibrutinib with ublituximab (another anti-CD20 antibody) and umbralisib (TGR-1202), an oral PI3 kinase-delta inhibitor, in a phase 1/1b trial of 38 patients with generally heavily pretreated leukemias and lymphomas, including 20 with CLL or SLL. Notably, 8 patients with CLL (50%) had a 17p or 11q deletion.

The median time on study was 11.1 months, reported Dr Nastoupil, of the department of lymphoma/myeloma at the University of Texas MD Anderson Cancer Center, Houston. The overall response rate for the 19 evaluable patients with CLL or SLL was 100% (complete response in 32%, partial response in 68%). The main grade 3 or 4 adverse events in the entire trial population were neutropenia (18%) and pyrexia (8%). Only two patients discontinued treatment because of adverse events.

“An expansion cohort is ongoing at the highest dose, and we will clearly need more patients treated and longer follow-up to really know the efficacy,” commented invited discussant Jennifer R Brown, MD, PhD, director of the Chronic Lymphocytic Leukemia Center at the Dana-Farber Cancer Institute in Boston.

Funding and disclosures: TG Therapeutics funded the trial. Dr Nastoupil has received honoraria and research funding from TG Therapeutics, and honoraria from Pharmacyclics.

Ibrutinib plus CAR-T cells

Investigators in a pilot trial led by Saar Gill, MD, PhD, of the hospital of the University of Pennsylvania in Philadelphia, tested the combination of ibrutinib with chimeric antigen receptor-T cells (CAR-T cells) against CD19, on the basis of preclinical evidence of synergy. The trial participants were 10 patients with CLL or SLL who had not achieved complete response with ibrutinib. All had a 17p deletion or a p53 mutation, or a complex karyotype, and some had a known ibrutinib resistance mutation.

At 3 months, 8 of 9 evaluable patients (89%) had no evidence of disease in bone marrow, reported Dr Gill. Seven patients (78%) achieved a complete or partial radiographic response in the spleen and lymph nodes. Overall, the treatment was well tolerated. One patient developed grade 4 tumor lysis syndrome, and two developed grade 3 cytokine release syndrome. But, none required anticytokine therapy.

Most patients remain on ibrutinib and are being monitored. In addition, the researchers plan to treat 25 more patients with the same combination.

Funding and disclosures: Novartis funded the trial. Dr Gill disclosed that he receives research funding from Novartis (institutional) and has patents for CAR-T cells for AML.

— Susan London

Pazopanib falls short as adjuvant therapy for high-risk RCC

Key clinical point Pazopanib is not efficacious for treating resected high-risk locally advanced RCC. Major finding Compared with placebo, pazopanib started at 600 mg daily did not significantly reduce the risk of DFS events (HR, 0.86; P = .16). Data source A phase 3 randomized controlled trial among 1,538 patients who had undergone nephrectomy for high-risk locally advanced RCC (PROTECT trial). Disclosures Novartis Oncology funded the trial. Dr Motzer disclosed that he is a consultant to Novartis and receives research funding from Novartis (institutional).

The antiangiogenic agent pazopanib is not efficacious when used as adjuvant therapy for resected renal cell carcinoma (RCC) with features that confer a high risk of recurrence, investigators in the PROTECT investigators reported at the meeting. “The trial did not meet its primary endpoint,” concluded lead investigator Robert J Motzer, MD, of Memorial Sloan-Kettering Cancer Center in New York. “Pazopanib is not recommended for adjuvant therapy following resection of locally advanced RCC.”

— Susan London

Survival improves when patients with cancer self-report symptoms

Key clinical point Patients with metastatic cancer who self-reported symptoms experienced significant improvement in overall survival. Major finding Median overall survival with self-reporting of symptoms compared with usual care was 31.2 and 26 months, respectively. Data source A randomized controlled clinical trial of 766 patients. Funding and disclosures This study was supported by the National Institutes of Health and the Conquer Cancer Foundation of the American Society of Clinical Oncology. Dr Basch and Dr Burstein each reported having no disclosures.

Patients with metastatic cancer who self-reported symptoms during routine cancer treatment experienced a number of benefits, including a statistically significant improvement in overall survival, according to findings from a randomized, controlled clinical trial (see p. e184). The median overall survival in 441 patients receiving treatment for metastatic breast, lung, genitourinary, or gynecologic cancer who were randomized to the self-reporting intervention arm was more than 5 months longer (a nearly 20% increase) than in 325 patients receiving standard care (31.2 vs. 26 months), Ethan Basch, MD, of the Lineberger Comprehensive Cancer Center at the University of North Carolina, Chapel Hill, said at the meeting. “Another way to think of this is [in terms of] 5-year survival. At 5 years, 8% more patients were alive in the self-reporting group,” he said.

— Sharon Worcester

TRK inhibitor shows ‘striking’ activity and durability across diverse cancers

Key clinical point Larotrectinib has good, durable efficacy when used to treat advanced cancers harboring TRK fusions. Major finding The overall response rate was 76%, and 79% of responses were still ongoing at 12 months. Data source An integrated analysis of phase 1 and 2 trials among 55 children and adults having 17 discrete types of advanced cancer with TRK fusions. Funding and disclosures Loxo Oncology funded the study. Dr Hyman disclosed that he has a consulting or advisory role with Atara Biotherapeutics, Chugai Pharma, and CytomX Therapeutics, and that he receives research funding from AstraZeneca and Puma Biotechnology.
 

Larotrectinib, an oral inhibitor of tropomyosin receptor kinase (TRK), has durable efficacy across diverse adult and pediatric cancers that harbor a genetic aberration known as TRK fusion, according to findings from an analysis of 3 trials reported at the meeting (see p. e184). Fusion of a TRK gene with an unrelated gene leads to uncontrolled signaling in the TRK pathway, potentially causing tumor growth and addiction to this input, David Hyman, MD, chief of early drug development at Memorial Sloan Kettering Cancer Center in New York, explained in a press briefing.

“One of the defining features of TRK fusions is that they are not just found in one cancer type, but in dozens of different cancer types, and not just in adults, but children as well, spanning the entire lifetime of the person,” he noted. They are rare in common cancers and nearly universal in certain uncommon cancers; collectively, they are present in possibly 5,000 cancers diagnosed each year in the United States.

Study details

The investigators analyzed data from 3 trials in which patients with advanced TRK fusion-positive solid cancers received larotrectinib (LOXO-101): a phase 1 trial among 8 adult patients, a phase 1/2 trial among 12 pediatric patients (SCOUT), and a phase 2 “basket” trial among 35 adult and adolescent patients (NAVIGATE).

“These patients were identified by local testing,” Dr Hyman noted. “We did not perform central screening to find the TRK fusions, and in fact, 50 different laboratories identified the 55 patients. So in a sense, this really represents the real-world identification of these patients.”

In an integrated analysis, the overall rate of confirmed response as assessed by investigators was 76%, with complete response in 12% of patients and partial response in 64%. Two patients had such deep tumor regression that they experienced downstaging enabling them to undergo potentially curative surgery. Efficacy was consistent regardless of tumor type, which TRK gene was affected, and the fusion partner gene.

Median time to response was 1.8 months. “This is just a reflection of when the first scan was obtained. But in the clinic, patients reported dramatic improvement of their symptoms within days of starting therapy,” Dr Hyman said.

With a median follow-up of 5.8 months, the median duration of response was not yet reached. In all, 79% of responses were still ongoing at 12 months. Median progression-free survival (PFS) was likewise not reached; the 12-month rate was 63%.

The leading treatment-emergent adverse events were fatigue (38%), dizziness (27%), nausea (26%), and anemia (26%). “This is an extremely well tolerated therapy with only 13% of patients requiring any form of dose modification and not a single patient discontinuing due to adverse events,” he said.

It is not clear why some patients had apparent primary resistance to larotrectinib, but their TRK fusion test results may have been incorrect, Dr Hyman speculated. In all, 6 patients developed acquired resistance to larotrectinib; 5 of them were found to have an identical resistance mutation, and 2 went on to receive and have a response to LOXO-195, a next-generation TRK inhibitor that seems to retain activity in the presence of this mutation (Cancer Discov. 2017 June 3. doi: 10.1158/2159-8290.CD-17-0507).

TRK testing

Several next-generation sequencing-based tests already available clinically can pick up TRK fusions, Dr Hyman pointed out. “But it is important for the ordering physician to understand whether the tests they are ordering include fusion detection and, if it’s an option, to select it. Otherwise, they will not find TRK fusions. “The list price for these tests is in the low thousands of dollars,” he noted. In cancers in which sequential single-gene testing is already being done as standard of care, there is “minimal” incremental cost of instead using comprehensive testing that would detect TRK fusions.

Oncologists should be aware that obtaining test results can take weeks, Dr Hyman stressed. “This [testing] should be more broadly adopted and should be adopted at a point in the patient’s treatment [so that they] don’t become too sick, then don’t have an opportunity to be treated even when the test results come back positive.”

— Susan London

QoL preserved with ribociclib-letrozole for advanced breast cancer

Key clinical point Patients who took ribociclib plus letrozole had less pain and no drop in QoL compared with letrozole alone. Major finding QoL was sustained and pain scores decreased when ribociclib was added to letrozole for patients with advanced breast cancer. Data source Double-blind, placebo-controlled phase 3 trial of letrozole plus ribociclib compared with letrozole plus placebo in 668 patients with advanced hormone receptor–positive, HER2-negative breast cancer. Disclosures Dr Verma reported financial relationships with Novartis, which markets ribociclib, and other firms.

Patients with advanced breast cancer whose aromatase inhibitor therapy was supplemented with a cycline-dependent kinase inhibitor had better PFS with no drop in quality of life (QoL). Health-related QoL for patients on the combination therapy was equivalent to that of patients on monotherapy in most aspects, but patients receiving both therapies had a sustained and clinically meaningful decrease in pain.

In addition, the time to definitive deterioration by 10% or more of the global health status/QoL scale score was similar between treatment arms (hazard ratio [HR], 0.944; 95% confidence interval, 0.720-1.237).

The MONALEESA-2 trial had previously shown that the CDK4/6 inhibitor ribociclib, when added to the aromatase inhibitor letrozole, significantly improved PFS for postmenopausal patients with hormone receptor–positive, HER2-negative advanced breast cancer, when compared with letrozole in combination with placebo.

Sunil Verma, MD, reported on health-related QoL and symptoms in the 2 arms of MONALEESA-2, showing change from baseline, time to a definitive 10% deterioration, and the mean scores for on-treatment time compared with end of treatment on the global health-status QoL subscale of the European Organization for Research and Treatment of Cancer's (EORTC's) 30-item core QoL questionnaire.

“During treatment, overall health-related quality of life was maintained from baseline and was similar in both arms,” said Dr Verma, the study’s first author. Changes during treatment were not statistically significant, and did not reach the predetermined threshold for a clinically meaningful difference. The effect of key symptoms such as fatigue, nausea, and vomiting on QoL was similar for patients receiving ribociclib or placebo, he said. Although symptom scores were slightly higher for patients in the active arm of the study, the results were not clinically significant.

Reporting validated, cancer-specific patient-reported outcomes from the trial, Dr Verma, professor and head of the department of oncology at the University of Calgary in Alberta, Canada, sought to “highlight the patient experience with a focus on health-related quality of life and symptoms,” he said during his presentation at the meeting. “A clinically meaningful – more than 5 points – improvement from baseline in pain score was maintained up to and including cycle 15 in the ribociclib plus letrozole arm.” The placebo arm had a mild, clinically insignificant improvement at most assessment points. For both treatment arms, pain scores increased a bit above baseline levels at the time of disease progression or end of therapy, he said.

Patients completed the EORTC 30-item core QoL questionnaire at their screening visit, and then every 8 weeks for the first 18 months. Then, they completed the questionnaires every 12 weeks until they experienced disease progression, died, were lost to follow-up or withdrew from the study, or stopped treatment.

Statistical analysis of the questionnaire results took into account the patients’ baseline scores, treatments received, and how they were stratified. Investigators assessed both statistical significance and the clinical meaningfulness of changes, defined as a change of 5-10 points.

In MONALEESA-2, 334 patients each were allocated to the ribociclib-letrozole arm and the placebo-letrozole arm. Patients in both arms, said Dr Verma, were very compliant with questionnaire completion. More than 90% of patients who were eligible completed questionnaire through cycle 19 of ribociclib or placebo. He explained that the overall numbers completing the questionnaire declined with time, as more patients had disease progression. Dr Verma said it is important to include those measures, because patients and their families care about “the quality of the time gained,” so patient-reported outcomes should be a part of risk-benefit assessments for new cancer therapies. “While delaying disease progression may help maintain patient quality of life, the addition of novel treatments to existing therapies can add toxicities, which may diminish quality of life,” he said.

— Kari Oakes

Ibrutinib and beyond: optimizing therapy in relapsed CLL

Key clinical point Ibrutinib had durable efficacy in relapsed CLL, and combinations with other targeted agents or with CAR-T cells are promising. Major finding Long-term PFS was better with ibrutinib than with ofatumumab (HR, 0.133). The overall response rate with the triplet of ibrutinib, ublituximab, and umbralisib was 100%. In all, 89% of patients achieved no evidence of disease in marrow when anti-CD19 CAR-T cells were added to ibrutinib. Data source An update of a phase 3 randomized trial among 391 patients with previously treated CLL or SLL (RESONATE). A phase 1/1b trial including 19 patients with mainly relapsed or refractory CLL or SLL. A pilot trial among 10 patients with previously treated, mainly higher-risk, CLL or SLL. Disclosures See article text.

Ibrutinib monotherapy

In the phase 3 randomized RESONATE trial, investigators compared ibrutinib with ofatumumab, an anti-CD20 antibody, among 391 patients with CLL or small lymphocytic lymphoma (SLL), with crossover allowed. Initial results favored ibrutinib.

Investigators led by John C Byrd, MD, director of the division of hematology at the Ohio State University Comprehensive Cancer Center in Columbus, reported updated data in a poster session at the meeting, now with a median 44 months of follow-up in the ibrutinib arm.

Median PFS was not reached with ibrutinib, compared with 8.1 months with ofatumumab (HR, 0.133). The 3-year rate of PFS for ibrutinib and ofatumumab was 59% and 3%, respectively.

The pattern was generally similar across patients stratified by cytogenetics (deletion of 17p, deletion of 11q, or neither), IGHV and TP53 mutation status, and previous lines of therapy, reported Dr Byrd. The 3-year overall survival rate for ibrutinib was 74%. In analyses adjusted for crossover, patients given the inhibitor had a markedly lower risk of death than did peers given the antibody (HR, 0.37). The overall response rate with ibrutinib was 91%. Although the rate of complete response increased with follow-up, it was still just 9%.

The most common grade 3 or worse adverse events were neutropenia (23%), pneumonia (17%), and anemia, thrombocytopenia, and hypertension (8% each). Major hemorrhage was reported in 2 patients (1%) in the ibrutinib group, and 3 (2%) in the ofatumumab group.

The investigators emphasized that these long-term results “show that extended treatment with ibrutinib is tolerable and continues to show sustained PFS in previously treated patients with CLL regardless of high-risk cytogenetics, adding that traditional poor prognostic factors for survival with chemoimmunotherapy, including del(17p) and del(11q), were not significant factors predictive of PFS outcomes with ibrutinib.

Funding and disclosures: Pharmacyclics funded the trial. Dr Byrd disclosed that he receives research funding from Pharmacyclics and other companies.

Ibrutinib plus ublituximab and umbralisib

Investigators led by Loretta J Nastoupil, MD, tested a triplet consisting of ibrutinib with ublituximab (another anti-CD20 antibody) and umbralisib (TGR-1202), an oral PI3 kinase-delta inhibitor, in a phase 1/1b trial of 38 patients with generally heavily pretreated leukemias and lymphomas, including 20 with CLL or SLL. Notably, 8 patients with CLL (50%) had a 17p or 11q deletion.

The median time on study was 11.1 months, reported Dr Nastoupil, of the department of lymphoma/myeloma at the University of Texas MD Anderson Cancer Center, Houston. The overall response rate for the 19 evaluable patients with CLL or SLL was 100% (complete response in 32%, partial response in 68%). The main grade 3 or 4 adverse events in the entire trial population were neutropenia (18%) and pyrexia (8%). Only two patients discontinued treatment because of adverse events.

“An expansion cohort is ongoing at the highest dose, and we will clearly need more patients treated and longer follow-up to really know the efficacy,” commented invited discussant Jennifer R Brown, MD, PhD, director of the Chronic Lymphocytic Leukemia Center at the Dana-Farber Cancer Institute in Boston.

Funding and disclosures: TG Therapeutics funded the trial. Dr Nastoupil has received honoraria and research funding from TG Therapeutics, and honoraria from Pharmacyclics.

Ibrutinib plus CAR-T cells

Investigators in a pilot trial led by Saar Gill, MD, PhD, of the hospital of the University of Pennsylvania in Philadelphia, tested the combination of ibrutinib with chimeric antigen receptor-T cells (CAR-T cells) against CD19, on the basis of preclinical evidence of synergy. The trial participants were 10 patients with CLL or SLL who had not achieved complete response with ibrutinib. All had a 17p deletion or a p53 mutation, or a complex karyotype, and some had a known ibrutinib resistance mutation.

At 3 months, 8 of 9 evaluable patients (89%) had no evidence of disease in bone marrow, reported Dr Gill. Seven patients (78%) achieved a complete or partial radiographic response in the spleen and lymph nodes. Overall, the treatment was well tolerated. One patient developed grade 4 tumor lysis syndrome, and two developed grade 3 cytokine release syndrome. But, none required anticytokine therapy.

Most patients remain on ibrutinib and are being monitored. In addition, the researchers plan to treat 25 more patients with the same combination.

Funding and disclosures: Novartis funded the trial. Dr Gill disclosed that he receives research funding from Novartis (institutional) and has patents for CAR-T cells for AML.

— Susan London

Pazopanib falls short as adjuvant therapy for high-risk RCC

Key clinical point Pazopanib is not efficacious for treating resected high-risk locally advanced RCC. Major finding Compared with placebo, pazopanib started at 600 mg daily did not significantly reduce the risk of DFS events (HR, 0.86; P = .16). Data source A phase 3 randomized controlled trial among 1,538 patients who had undergone nephrectomy for high-risk locally advanced RCC (PROTECT trial). Disclosures Novartis Oncology funded the trial. Dr Motzer disclosed that he is a consultant to Novartis and receives research funding from Novartis (institutional).

The antiangiogenic agent pazopanib is not efficacious when used as adjuvant therapy for resected renal cell carcinoma (RCC) with features that confer a high risk of recurrence, investigators in the PROTECT investigators reported at the meeting. “The trial did not meet its primary endpoint,” concluded lead investigator Robert J Motzer, MD, of Memorial Sloan-Kettering Cancer Center in New York. “Pazopanib is not recommended for adjuvant therapy following resection of locally advanced RCC.”

— Susan London

Survival improves when patients with cancer self-report symptoms

Key clinical point Patients with metastatic cancer who self-reported symptoms experienced significant improvement in overall survival. Major finding Median overall survival with self-reporting of symptoms compared with usual care was 31.2 and 26 months, respectively. Data source A randomized controlled clinical trial of 766 patients. Funding and disclosures This study was supported by the National Institutes of Health and the Conquer Cancer Foundation of the American Society of Clinical Oncology. Dr Basch and Dr Burstein each reported having no disclosures.

Patients with metastatic cancer who self-reported symptoms during routine cancer treatment experienced a number of benefits, including a statistically significant improvement in overall survival, according to findings from a randomized, controlled clinical trial (see p. e184). The median overall survival in 441 patients receiving treatment for metastatic breast, lung, genitourinary, or gynecologic cancer who were randomized to the self-reporting intervention arm was more than 5 months longer (a nearly 20% increase) than in 325 patients receiving standard care (31.2 vs. 26 months), Ethan Basch, MD, of the Lineberger Comprehensive Cancer Center at the University of North Carolina, Chapel Hill, said at the meeting. “Another way to think of this is [in terms of] 5-year survival. At 5 years, 8% more patients were alive in the self-reporting group,” he said.

— Sharon Worcester

TRK inhibitor shows ‘striking’ activity and durability across diverse cancers

Key clinical point Larotrectinib has good, durable efficacy when used to treat advanced cancers harboring TRK fusions. Major finding The overall response rate was 76%, and 79% of responses were still ongoing at 12 months. Data source An integrated analysis of phase 1 and 2 trials among 55 children and adults having 17 discrete types of advanced cancer with TRK fusions. Funding and disclosures Loxo Oncology funded the study. Dr Hyman disclosed that he has a consulting or advisory role with Atara Biotherapeutics, Chugai Pharma, and CytomX Therapeutics, and that he receives research funding from AstraZeneca and Puma Biotechnology.
 

Larotrectinib, an oral inhibitor of tropomyosin receptor kinase (TRK), has durable efficacy across diverse adult and pediatric cancers that harbor a genetic aberration known as TRK fusion, according to findings from an analysis of 3 trials reported at the meeting (see p. e184). Fusion of a TRK gene with an unrelated gene leads to uncontrolled signaling in the TRK pathway, potentially causing tumor growth and addiction to this input, David Hyman, MD, chief of early drug development at Memorial Sloan Kettering Cancer Center in New York, explained in a press briefing.

“One of the defining features of TRK fusions is that they are not just found in one cancer type, but in dozens of different cancer types, and not just in adults, but children as well, spanning the entire lifetime of the person,” he noted. They are rare in common cancers and nearly universal in certain uncommon cancers; collectively, they are present in possibly 5,000 cancers diagnosed each year in the United States.

Study details

The investigators analyzed data from 3 trials in which patients with advanced TRK fusion-positive solid cancers received larotrectinib (LOXO-101): a phase 1 trial among 8 adult patients, a phase 1/2 trial among 12 pediatric patients (SCOUT), and a phase 2 “basket” trial among 35 adult and adolescent patients (NAVIGATE).

“These patients were identified by local testing,” Dr Hyman noted. “We did not perform central screening to find the TRK fusions, and in fact, 50 different laboratories identified the 55 patients. So in a sense, this really represents the real-world identification of these patients.”

In an integrated analysis, the overall rate of confirmed response as assessed by investigators was 76%, with complete response in 12% of patients and partial response in 64%. Two patients had such deep tumor regression that they experienced downstaging enabling them to undergo potentially curative surgery. Efficacy was consistent regardless of tumor type, which TRK gene was affected, and the fusion partner gene.

Median time to response was 1.8 months. “This is just a reflection of when the first scan was obtained. But in the clinic, patients reported dramatic improvement of their symptoms within days of starting therapy,” Dr Hyman said.

With a median follow-up of 5.8 months, the median duration of response was not yet reached. In all, 79% of responses were still ongoing at 12 months. Median progression-free survival (PFS) was likewise not reached; the 12-month rate was 63%.

The leading treatment-emergent adverse events were fatigue (38%), dizziness (27%), nausea (26%), and anemia (26%). “This is an extremely well tolerated therapy with only 13% of patients requiring any form of dose modification and not a single patient discontinuing due to adverse events,” he said.

It is not clear why some patients had apparent primary resistance to larotrectinib, but their TRK fusion test results may have been incorrect, Dr Hyman speculated. In all, 6 patients developed acquired resistance to larotrectinib; 5 of them were found to have an identical resistance mutation, and 2 went on to receive and have a response to LOXO-195, a next-generation TRK inhibitor that seems to retain activity in the presence of this mutation (Cancer Discov. 2017 June 3. doi: 10.1158/2159-8290.CD-17-0507).

TRK testing

Several next-generation sequencing-based tests already available clinically can pick up TRK fusions, Dr Hyman pointed out. “But it is important for the ordering physician to understand whether the tests they are ordering include fusion detection and, if it’s an option, to select it. Otherwise, they will not find TRK fusions. “The list price for these tests is in the low thousands of dollars,” he noted. In cancers in which sequential single-gene testing is already being done as standard of care, there is “minimal” incremental cost of instead using comprehensive testing that would detect TRK fusions.

Oncologists should be aware that obtaining test results can take weeks, Dr Hyman stressed. “This [testing] should be more broadly adopted and should be adopted at a point in the patient’s treatment [so that they] don’t become too sick, then don’t have an opportunity to be treated even when the test results come back positive.”

— Susan London

QoL preserved with ribociclib-letrozole for advanced breast cancer

Key clinical point Patients who took ribociclib plus letrozole had less pain and no drop in QoL compared with letrozole alone. Major finding QoL was sustained and pain scores decreased when ribociclib was added to letrozole for patients with advanced breast cancer. Data source Double-blind, placebo-controlled phase 3 trial of letrozole plus ribociclib compared with letrozole plus placebo in 668 patients with advanced hormone receptor–positive, HER2-negative breast cancer. Disclosures Dr Verma reported financial relationships with Novartis, which markets ribociclib, and other firms.

Patients with advanced breast cancer whose aromatase inhibitor therapy was supplemented with a cycline-dependent kinase inhibitor had better PFS with no drop in quality of life (QoL). Health-related QoL for patients on the combination therapy was equivalent to that of patients on monotherapy in most aspects, but patients receiving both therapies had a sustained and clinically meaningful decrease in pain.

In addition, the time to definitive deterioration by 10% or more of the global health status/QoL scale score was similar between treatment arms (hazard ratio [HR], 0.944; 95% confidence interval, 0.720-1.237).

The MONALEESA-2 trial had previously shown that the CDK4/6 inhibitor ribociclib, when added to the aromatase inhibitor letrozole, significantly improved PFS for postmenopausal patients with hormone receptor–positive, HER2-negative advanced breast cancer, when compared with letrozole in combination with placebo.

Sunil Verma, MD, reported on health-related QoL and symptoms in the 2 arms of MONALEESA-2, showing change from baseline, time to a definitive 10% deterioration, and the mean scores for on-treatment time compared with end of treatment on the global health-status QoL subscale of the European Organization for Research and Treatment of Cancer's (EORTC's) 30-item core QoL questionnaire.

“During treatment, overall health-related quality of life was maintained from baseline and was similar in both arms,” said Dr Verma, the study’s first author. Changes during treatment were not statistically significant, and did not reach the predetermined threshold for a clinically meaningful difference. The effect of key symptoms such as fatigue, nausea, and vomiting on QoL was similar for patients receiving ribociclib or placebo, he said. Although symptom scores were slightly higher for patients in the active arm of the study, the results were not clinically significant.

Reporting validated, cancer-specific patient-reported outcomes from the trial, Dr Verma, professor and head of the department of oncology at the University of Calgary in Alberta, Canada, sought to “highlight the patient experience with a focus on health-related quality of life and symptoms,” he said during his presentation at the meeting. “A clinically meaningful – more than 5 points – improvement from baseline in pain score was maintained up to and including cycle 15 in the ribociclib plus letrozole arm.” The placebo arm had a mild, clinically insignificant improvement at most assessment points. For both treatment arms, pain scores increased a bit above baseline levels at the time of disease progression or end of therapy, he said.

Patients completed the EORTC 30-item core QoL questionnaire at their screening visit, and then every 8 weeks for the first 18 months. Then, they completed the questionnaires every 12 weeks until they experienced disease progression, died, were lost to follow-up or withdrew from the study, or stopped treatment.

Statistical analysis of the questionnaire results took into account the patients’ baseline scores, treatments received, and how they were stratified. Investigators assessed both statistical significance and the clinical meaningfulness of changes, defined as a change of 5-10 points.

In MONALEESA-2, 334 patients each were allocated to the ribociclib-letrozole arm and the placebo-letrozole arm. Patients in both arms, said Dr Verma, were very compliant with questionnaire completion. More than 90% of patients who were eligible completed questionnaire through cycle 19 of ribociclib or placebo. He explained that the overall numbers completing the questionnaire declined with time, as more patients had disease progression. Dr Verma said it is important to include those measures, because patients and their families care about “the quality of the time gained,” so patient-reported outcomes should be a part of risk-benefit assessments for new cancer therapies. “While delaying disease progression may help maintain patient quality of life, the addition of novel treatments to existing therapies can add toxicities, which may diminish quality of life,” he said.

— Kari Oakes

Ibrutinib and beyond: optimizing therapy in relapsed CLL

Key clinical point Ibrutinib had durable efficacy in relapsed CLL, and combinations with other targeted agents or with CAR-T cells are promising. Major finding Long-term PFS was better with ibrutinib than with ofatumumab (HR, 0.133). The overall response rate with the triplet of ibrutinib, ublituximab, and umbralisib was 100%. In all, 89% of patients achieved no evidence of disease in marrow when anti-CD19 CAR-T cells were added to ibrutinib. Data source An update of a phase 3 randomized trial among 391 patients with previously treated CLL or SLL (RESONATE). A phase 1/1b trial including 19 patients with mainly relapsed or refractory CLL or SLL. A pilot trial among 10 patients with previously treated, mainly higher-risk, CLL or SLL. Disclosures See article text.

Ibrutinib monotherapy

In the phase 3 randomized RESONATE trial, investigators compared ibrutinib with ofatumumab, an anti-CD20 antibody, among 391 patients with CLL or small lymphocytic lymphoma (SLL), with crossover allowed. Initial results favored ibrutinib.

Investigators led by John C Byrd, MD, director of the division of hematology at the Ohio State University Comprehensive Cancer Center in Columbus, reported updated data in a poster session at the meeting, now with a median 44 months of follow-up in the ibrutinib arm.

Median PFS was not reached with ibrutinib, compared with 8.1 months with ofatumumab (HR, 0.133). The 3-year rate of PFS for ibrutinib and ofatumumab was 59% and 3%, respectively.

The pattern was generally similar across patients stratified by cytogenetics (deletion of 17p, deletion of 11q, or neither), IGHV and TP53 mutation status, and previous lines of therapy, reported Dr Byrd. The 3-year overall survival rate for ibrutinib was 74%. In analyses adjusted for crossover, patients given the inhibitor had a markedly lower risk of death than did peers given the antibody (HR, 0.37). The overall response rate with ibrutinib was 91%. Although the rate of complete response increased with follow-up, it was still just 9%.

The most common grade 3 or worse adverse events were neutropenia (23%), pneumonia (17%), and anemia, thrombocytopenia, and hypertension (8% each). Major hemorrhage was reported in 2 patients (1%) in the ibrutinib group, and 3 (2%) in the ofatumumab group.

The investigators emphasized that these long-term results “show that extended treatment with ibrutinib is tolerable and continues to show sustained PFS in previously treated patients with CLL regardless of high-risk cytogenetics, adding that traditional poor prognostic factors for survival with chemoimmunotherapy, including del(17p) and del(11q), were not significant factors predictive of PFS outcomes with ibrutinib.

Funding and disclosures: Pharmacyclics funded the trial. Dr Byrd disclosed that he receives research funding from Pharmacyclics and other companies.

Ibrutinib plus ublituximab and umbralisib

Investigators led by Loretta J Nastoupil, MD, tested a triplet consisting of ibrutinib with ublituximab (another anti-CD20 antibody) and umbralisib (TGR-1202), an oral PI3 kinase-delta inhibitor, in a phase 1/1b trial of 38 patients with generally heavily pretreated leukemias and lymphomas, including 20 with CLL or SLL. Notably, 8 patients with CLL (50%) had a 17p or 11q deletion.

The median time on study was 11.1 months, reported Dr Nastoupil, of the department of lymphoma/myeloma at the University of Texas MD Anderson Cancer Center, Houston. The overall response rate for the 19 evaluable patients with CLL or SLL was 100% (complete response in 32%, partial response in 68%). The main grade 3 or 4 adverse events in the entire trial population were neutropenia (18%) and pyrexia (8%). Only two patients discontinued treatment because of adverse events.

“An expansion cohort is ongoing at the highest dose, and we will clearly need more patients treated and longer follow-up to really know the efficacy,” commented invited discussant Jennifer R Brown, MD, PhD, director of the Chronic Lymphocytic Leukemia Center at the Dana-Farber Cancer Institute in Boston.

Funding and disclosures: TG Therapeutics funded the trial. Dr Nastoupil has received honoraria and research funding from TG Therapeutics, and honoraria from Pharmacyclics.

Ibrutinib plus CAR-T cells

Investigators in a pilot trial led by Saar Gill, MD, PhD, of the hospital of the University of Pennsylvania in Philadelphia, tested the combination of ibrutinib with chimeric antigen receptor-T cells (CAR-T cells) against CD19, on the basis of preclinical evidence of synergy. The trial participants were 10 patients with CLL or SLL who had not achieved complete response with ibrutinib. All had a 17p deletion or a p53 mutation, or a complex karyotype, and some had a known ibrutinib resistance mutation.

At 3 months, 8 of 9 evaluable patients (89%) had no evidence of disease in bone marrow, reported Dr Gill. Seven patients (78%) achieved a complete or partial radiographic response in the spleen and lymph nodes. Overall, the treatment was well tolerated. One patient developed grade 4 tumor lysis syndrome, and two developed grade 3 cytokine release syndrome. But, none required anticytokine therapy.

Most patients remain on ibrutinib and are being monitored. In addition, the researchers plan to treat 25 more patients with the same combination.

Funding and disclosures: Novartis funded the trial. Dr Gill disclosed that he receives research funding from Novartis (institutional) and has patents for CAR-T cells for AML.

— Susan London

Pazopanib falls short as adjuvant therapy for high-risk RCC

Key clinical point Pazopanib is not efficacious for treating resected high-risk locally advanced RCC. Major finding Compared with placebo, pazopanib started at 600 mg daily did not significantly reduce the risk of DFS events (HR, 0.86; P = .16). Data source A phase 3 randomized controlled trial among 1,538 patients who had undergone nephrectomy for high-risk locally advanced RCC (PROTECT trial). Disclosures Novartis Oncology funded the trial. Dr Motzer disclosed that he is a consultant to Novartis and receives research funding from Novartis (institutional).

The antiangiogenic agent pazopanib is not efficacious when used as adjuvant therapy for resected renal cell carcinoma (RCC) with features that confer a high risk of recurrence, investigators in the PROTECT investigators reported at the meeting. “The trial did not meet its primary endpoint,” concluded lead investigator Robert J Motzer, MD, of Memorial Sloan-Kettering Cancer Center in New York. “Pazopanib is not recommended for adjuvant therapy following resection of locally advanced RCC.”

— Susan London

Soft tissue sarcomas (STS) are a heterogeneous group of tumors of mesenchymal origin that represent a rare form of adult malignancy. According to the World Health Organization classification system, there are more than 100 histologic subtypes of sarcoma based on tissue of origin. Staging criteria most commonly use the American Joint Committee on Cancer’s TNM Classification of Malignant Tumours. About 50% of soft tissue sarcomas originate in the lower extremity.¹ Advancements in the use of multimodal therapy have reduced the need for amputation and allowed for equally effective treatment strategies that use limb-sparing surgical resections.

Although most sarcoma metastases spread in a hematogenous fashion, nodal spread is underestimated. Certain histologic subtypes carry a higher predilection for nodal involvement: these include rhabdomyosarcoma, synovial sarcoma, epithelioid sarcoma, vascular sarcoma, and clear-cell sarcoma.^2-4 Fong and colleagues have reported that 2.6% of sarcomas have lymphatic spread.³ In the current report, we describe a rare observation of locoregional pelvic nodal metastases from a large undifferentiated pleomorphic sarcoma of the right thigh.

Case presentation and summary

A 63-year-old white woman had a 1-year history of a right thigh mass and an unintentional weight loss of 40 lb. After a year of chiropractic care, she was referred to a physician because of palpable inguinal adenopathy and a 20-cm mass in the medial compartment of the right thigh, with heterogeneous appearance on a magnetic-resonance imaging scan (Figure 1). The patient was referred to the sarcoma transdisciplinary team for evaluation. She was diagnosed by core needle biopsy with a high-grade malignant epithelioid and spindle-cell neoplasm, favoring pleomorphic sarcoma. The metastatic work-up confirmed locoregional right inguinal and retroperitoneal lymph node disease, with 2 lung nodules that were too small to characterize. She also had a paraneoplastic leukocytosis with a white blood cell count of 45,500 cells/ml (normal 10,500 cells/ml).

Discussion

Surgery remains the primary treatment modality for localized soft tissue sarcoma. Obtaining a margin-free resection, while maintaining optimal function, is the objective with extremity sarcoma. In addition to surgical resection, doxorubicin-based adjuvant chemotherapy remains the standard of care with modest improvement in overall survival and disease-free survival, especially in sarcomas of the extremities.^5,6 Gemcitabine also has activity in soft tissue sarcomas⁷ and might synergize with docetaxel. High response rates of 53% with fixed dose infusion rates of these agents in uterine leiomyosarcoma led the Sarcoma Alliance for Research through Collaboration investigators to consider this regimen for other STS.⁸ An overall response rate of 16% was noted across all sarcoma subtypes, and undifferentiated pleomorphic sarcoma had a response rate of 32%.

In our experience, a modified schedule of gemcitabine and docetaxel is better tolerated than the standard every 3 weeks regimen or doxorubicin-based chemotherapies. As previously described, gemcitabine and docetaxel were administered to this patient every 2 weeks.⁹ This regimen, in our experience, is less toxic and preserves the dose intensity of the regimen. A complete pathologic necrosis of the primary tumor and regional nodal basin was observed, as well as pulmonary nodule regression, enabling an R0-wide excision and regional lymphadenectomy. The colonic recurrence was surprising, but easily managed with surgical resection.

Pathologic complete response after neoadjuvant chemotherapy is a rare event, observed in about 10% of patients. However, when observed, complete pathologic necrosis (>95%) provided a distant recurrence-free survival of 100% at 3 years.^10-12

Our patient, despite achieving a complete pathologic response and excellent initial local control, ultimately experienced an isolated metastatic recurrence in the colon within 1 year of therapy. Data supports performing metastatectomy for stage IV extremity sarcoma for isolated pulmonary or hepatic burden in selected patients with improved survival rates.^13,14 As far as we know, there is no published literature describing isolated colon metastases in the absence of liver burden from lower extremity soft tissue sarcomas, or the outcome of surgical resection and adjuvant therapy in these cases.

In conclusion, high-grade pleomorphic sarcoma often follows an aggressive clinical course with ultimately local and distant recurrence. Use of multimodal therapy may have a role in improving local control. Complete pathologic necrosis is a rare event that is predictive of improved outcome. Our case represents an unusual pattern of recurrence among patients with a complete pathologic response to neoadjuvant therapy with isolated colon metastases. Timely, comprehensive management together with vigilant surveillance remain key priorities in the long-term management of high-risk sarcoma.

Soft tissue sarcomas (STS) are a heterogeneous group of tumors of mesenchymal origin that represent a rare form of adult malignancy. According to the World Health Organization classification system, there are more than 100 histologic subtypes of sarcoma based on tissue of origin. Staging criteria most commonly use the American Joint Committee on Cancer’s TNM Classification of Malignant Tumours. About 50% of soft tissue sarcomas originate in the lower extremity.¹ Advancements in the use of multimodal therapy have reduced the need for amputation and allowed for equally effective treatment strategies that use limb-sparing surgical resections.

Although most sarcoma metastases spread in a hematogenous fashion, nodal spread is underestimated. Certain histologic subtypes carry a higher predilection for nodal involvement: these include rhabdomyosarcoma, synovial sarcoma, epithelioid sarcoma, vascular sarcoma, and clear-cell sarcoma.^2-4 Fong and colleagues have reported that 2.6% of sarcomas have lymphatic spread.³ In the current report, we describe a rare observation of locoregional pelvic nodal metastases from a large undifferentiated pleomorphic sarcoma of the right thigh.

Case presentation and summary

A 63-year-old white woman had a 1-year history of a right thigh mass and an unintentional weight loss of 40 lb. After a year of chiropractic care, she was referred to a physician because of palpable inguinal adenopathy and a 20-cm mass in the medial compartment of the right thigh, with heterogeneous appearance on a magnetic-resonance imaging scan (Figure 1). The patient was referred to the sarcoma transdisciplinary team for evaluation. She was diagnosed by core needle biopsy with a high-grade malignant epithelioid and spindle-cell neoplasm, favoring pleomorphic sarcoma. The metastatic work-up confirmed locoregional right inguinal and retroperitoneal lymph node disease, with 2 lung nodules that were too small to characterize. She also had a paraneoplastic leukocytosis with a white blood cell count of 45,500 cells/ml (normal 10,500 cells/ml).

Discussion

Surgery remains the primary treatment modality for localized soft tissue sarcoma. Obtaining a margin-free resection, while maintaining optimal function, is the objective with extremity sarcoma. In addition to surgical resection, doxorubicin-based adjuvant chemotherapy remains the standard of care with modest improvement in overall survival and disease-free survival, especially in sarcomas of the extremities.^5,6 Gemcitabine also has activity in soft tissue sarcomas⁷ and might synergize with docetaxel. High response rates of 53% with fixed dose infusion rates of these agents in uterine leiomyosarcoma led the Sarcoma Alliance for Research through Collaboration investigators to consider this regimen for other STS.⁸ An overall response rate of 16% was noted across all sarcoma subtypes, and undifferentiated pleomorphic sarcoma had a response rate of 32%.

In our experience, a modified schedule of gemcitabine and docetaxel is better tolerated than the standard every 3 weeks regimen or doxorubicin-based chemotherapies. As previously described, gemcitabine and docetaxel were administered to this patient every 2 weeks.⁹ This regimen, in our experience, is less toxic and preserves the dose intensity of the regimen. A complete pathologic necrosis of the primary tumor and regional nodal basin was observed, as well as pulmonary nodule regression, enabling an R0-wide excision and regional lymphadenectomy. The colonic recurrence was surprising, but easily managed with surgical resection.

Pathologic complete response after neoadjuvant chemotherapy is a rare event, observed in about 10% of patients. However, when observed, complete pathologic necrosis (>95%) provided a distant recurrence-free survival of 100% at 3 years.^10-12

Our patient, despite achieving a complete pathologic response and excellent initial local control, ultimately experienced an isolated metastatic recurrence in the colon within 1 year of therapy. Data supports performing metastatectomy for stage IV extremity sarcoma for isolated pulmonary or hepatic burden in selected patients with improved survival rates.^13,14 As far as we know, there is no published literature describing isolated colon metastases in the absence of liver burden from lower extremity soft tissue sarcomas, or the outcome of surgical resection and adjuvant therapy in these cases.

In conclusion, high-grade pleomorphic sarcoma often follows an aggressive clinical course with ultimately local and distant recurrence. Use of multimodal therapy may have a role in improving local control. Complete pathologic necrosis is a rare event that is predictive of improved outcome. Our case represents an unusual pattern of recurrence among patients with a complete pathologic response to neoadjuvant therapy with isolated colon metastases. Timely, comprehensive management together with vigilant surveillance remain key priorities in the long-term management of high-risk sarcoma.

Soft tissue sarcomas (STS) are a heterogeneous group of tumors of mesenchymal origin that represent a rare form of adult malignancy. According to the World Health Organization classification system, there are more than 100 histologic subtypes of sarcoma based on tissue of origin. Staging criteria most commonly use the American Joint Committee on Cancer’s TNM Classification of Malignant Tumours. About 50% of soft tissue sarcomas originate in the lower extremity.¹ Advancements in the use of multimodal therapy have reduced the need for amputation and allowed for equally effective treatment strategies that use limb-sparing surgical resections.

Although most sarcoma metastases spread in a hematogenous fashion, nodal spread is underestimated. Certain histologic subtypes carry a higher predilection for nodal involvement: these include rhabdomyosarcoma, synovial sarcoma, epithelioid sarcoma, vascular sarcoma, and clear-cell sarcoma.^2-4 Fong and colleagues have reported that 2.6% of sarcomas have lymphatic spread.³ In the current report, we describe a rare observation of locoregional pelvic nodal metastases from a large undifferentiated pleomorphic sarcoma of the right thigh.

Case presentation and summary

A 63-year-old white woman had a 1-year history of a right thigh mass and an unintentional weight loss of 40 lb. After a year of chiropractic care, she was referred to a physician because of palpable inguinal adenopathy and a 20-cm mass in the medial compartment of the right thigh, with heterogeneous appearance on a magnetic-resonance imaging scan (Figure 1). The patient was referred to the sarcoma transdisciplinary team for evaluation. She was diagnosed by core needle biopsy with a high-grade malignant epithelioid and spindle-cell neoplasm, favoring pleomorphic sarcoma. The metastatic work-up confirmed locoregional right inguinal and retroperitoneal lymph node disease, with 2 lung nodules that were too small to characterize. She also had a paraneoplastic leukocytosis with a white blood cell count of 45,500 cells/ml (normal 10,500 cells/ml).

Discussion

Surgery remains the primary treatment modality for localized soft tissue sarcoma. Obtaining a margin-free resection, while maintaining optimal function, is the objective with extremity sarcoma. In addition to surgical resection, doxorubicin-based adjuvant chemotherapy remains the standard of care with modest improvement in overall survival and disease-free survival, especially in sarcomas of the extremities.^5,6 Gemcitabine also has activity in soft tissue sarcomas⁷ and might synergize with docetaxel. High response rates of 53% with fixed dose infusion rates of these agents in uterine leiomyosarcoma led the Sarcoma Alliance for Research through Collaboration investigators to consider this regimen for other STS.⁸ An overall response rate of 16% was noted across all sarcoma subtypes, and undifferentiated pleomorphic sarcoma had a response rate of 32%.

In our experience, a modified schedule of gemcitabine and docetaxel is better tolerated than the standard every 3 weeks regimen or doxorubicin-based chemotherapies. As previously described, gemcitabine and docetaxel were administered to this patient every 2 weeks.⁹ This regimen, in our experience, is less toxic and preserves the dose intensity of the regimen. A complete pathologic necrosis of the primary tumor and regional nodal basin was observed, as well as pulmonary nodule regression, enabling an R0-wide excision and regional lymphadenectomy. The colonic recurrence was surprising, but easily managed with surgical resection.

Pathologic complete response after neoadjuvant chemotherapy is a rare event, observed in about 10% of patients. However, when observed, complete pathologic necrosis (>95%) provided a distant recurrence-free survival of 100% at 3 years.^10-12

Our patient, despite achieving a complete pathologic response and excellent initial local control, ultimately experienced an isolated metastatic recurrence in the colon within 1 year of therapy. Data supports performing metastatectomy for stage IV extremity sarcoma for isolated pulmonary or hepatic burden in selected patients with improved survival rates.^13,14 As far as we know, there is no published literature describing isolated colon metastases in the absence of liver burden from lower extremity soft tissue sarcomas, or the outcome of surgical resection and adjuvant therapy in these cases.

In conclusion, high-grade pleomorphic sarcoma often follows an aggressive clinical course with ultimately local and distant recurrence. Use of multimodal therapy may have a role in improving local control. Complete pathologic necrosis is a rare event that is predictive of improved outcome. Our case represents an unusual pattern of recurrence among patients with a complete pathologic response to neoadjuvant therapy with isolated colon metastases. Timely, comprehensive management together with vigilant surveillance remain key priorities in the long-term management of high-risk sarcoma.

A recent increase in the death rate from stroke resulted in more than 32,000 more deaths than would have occurred had the previous long-term decline continued, according to the Centers for Disease Control and Prevention.

The overall age-standardized stroke death rate among adults aged 35 years and older declined from 118.4 per 100,000 in 2000 to 73.3 per 100,000 in 2015, for an average annual percent change of –3.1%. That long-term rate, however, includes a more recent, but statistically nonsignificant, increase of 2.5% a year in 2013-2015, which produced an estimated 32,593 excess deaths based on the previous rate of decline, the CDC investigators said (MMWR 2017 Sep 6;66[early release]:1-7).

rfranki@frontlinemedcom.com

A recent increase in the death rate from stroke resulted in more than 32,000 more deaths than would have occurred had the previous long-term decline continued, according to the Centers for Disease Control and Prevention.

The overall age-standardized stroke death rate among adults aged 35 years and older declined from 118.4 per 100,000 in 2000 to 73.3 per 100,000 in 2015, for an average annual percent change of –3.1%. That long-term rate, however, includes a more recent, but statistically nonsignificant, increase of 2.5% a year in 2013-2015, which produced an estimated 32,593 excess deaths based on the previous rate of decline, the CDC investigators said (MMWR 2017 Sep 6;66[early release]:1-7).

rfranki@frontlinemedcom.com

A recent increase in the death rate from stroke resulted in more than 32,000 more deaths than would have occurred had the previous long-term decline continued, according to the Centers for Disease Control and Prevention.

The overall age-standardized stroke death rate among adults aged 35 years and older declined from 118.4 per 100,000 in 2000 to 73.3 per 100,000 in 2015, for an average annual percent change of –3.1%. That long-term rate, however, includes a more recent, but statistically nonsignificant, increase of 2.5% a year in 2013-2015, which produced an estimated 32,593 excess deaths based on the previous rate of decline, the CDC investigators said (MMWR 2017 Sep 6;66[early release]:1-7).

rfranki@frontlinemedcom.com

The incidence of malignant melanoma has been rising in the United States, especially among non-Hispanic white men and women. Death rates have increased for those aged 65 years or older, and incidence rates have increased for all age groups.¹ It is a serious public health issue.

Given the unique biology of melanoma, metastatic disease can present in a variety of ways. In most cases, the lymph nodes and lungs are involved.² The incidence of brain metastases is 10%-40%, however the percentage may be even higher based on reported incidence of autopsy reports.³ The most common forms of metastatic melanoma to the spine are vertebral and intramedullary.⁴ Specifically, leptomeningeal involvement can be found in 20% of patients in clinical studies and 44%-70% in autopsy series of patients with central nervous system (CNS) metastatic disease.⁵ Despite its incidence, leptomeningeal disease (LMD) from melanoma is rarely discussed in the literature and the diagnosis may be difficult. Even rarer is the documented presentation of intramedullary spinal cord metastases, or “drop metastases.”⁶ In our review of the literature, we found no published case reports to date of drop metastases from melanoma causing cauda equina syndrome.

The prognosis of patients with metastatic melanoma with brain metastases is very poor, with a median overall survival of about 4 months reported in several studies.^7-9 Prognosis is even worse for patients with leptomeningeal involvement, and median survival without therapy is about 4-6 weeks.¹⁰ A combination of intrathecal and systemic chemotherapy can be used to treat LMD.¹¹

Case presentation and summary

This is the case of a 56-year-old man with history of metastatic melanoma that had been initially diagnosed about 4 years before the current case presentation. Original sites of disease were a supraclavicular lymph node and solitary liver metastasis, both of which were resected. The patient then developed biopsy-proven lung involvement that required left and right wedge resections. Mutation testing for BRAF V600E and BRAF V600K was sent and not detected. Therefore the patient did not receive any BRAF-targeted therapies. Subsequently, recurrent metastatic disease to the brain with 2 dominant lesions in the cerebellum and the occiput as well as numerous small lesions at the gray-white matter junction was identified (Figure 1 and Figure 2).

The patient received whole-brain radiation (30 Gy in 10 fractions of 3 Gy each). There was no evidence of disease in his spine at that time. About 2 weeks after completing whole-brain radiation, the patient presented to the hospital with left lower extremity weakness, urinary retention, bowel incontinence, saddle anesthesia, and malaise. The symptoms had begun after he had finished whole-brain radiation and weakness progressed to the point at which he need a cane to be able to walk. A physical examination was significant for hyporreflexia, decreased strength and sensitivity on left lower extremity, saddle anesthesia, and lumbar spinal tenderness to palpation. The results of magnetic-resonance imaging (MRI) of the spine revealed multiple soft-tissue nodules extending from the conus medullaris throughout the cauda equina, consistent with intramedullary metastases, as well as concomitant leptomeningeal involvement (Figure 3).

Conclusions

Although metastatic melanoma to the brain is not uncommon, leptomeningeal and intramedullary drop metastases are an infrequent presentation. Even more rare are intramedullary drop metastasis that are significant enough to cause cauda equina syndrome, as with our patient. The incidence of LMD has increased over the years and may continue to increase, likely because of the improved overall survival and a prolonged control of extracranial disease with newly approved systemic therapeutic drugs, such as molecularly targeted therapy and immunotherapy.¹² Intramedullary metastases are extremely rare, but reported incidence has seemed to be increasing due to detection with MRI. Currently there are fewer than 100 case reports of intramedullary spinal cord metastasis.⁶ In one retrospective study, 40 patients with intramedullary metastatic disease secondary to systemic cancer were identified during 1980-1993.⁶ About half of those cases were from lung cancer, the second most common was breast cancer.

CNS involvement by melanoma can have debilitating complications and confers a poor prognosis. In another retrospective study, several patient characteristics were found to be associated with significantly shorter survival in patients with known brain metastases, including presence of neurologic symptoms and leptomeningeal involvement.³

Malignant cells can reach the CSF by several routes: direct extension, hematogenous, venous access, venous drainage from bone marrow and cranial and peripheral nerves. Once the tumor has reached the CSF, it can seed any portion of the nervous system that has contact with the CSF and become entangled among the cauda equine.¹³

Given the rarity of leptomeningeal and intramedullary involvement of melanoma, there are no standard treatment guidelines. Treatment for LMD usually consists of intrathecal and systemic chemotherapy. Commonly used intrathecal agents are methotrexate, liposomal cytarabine, and thiopeta.¹¹ The goals of treatment are to improve or stabilize neurologic status of the patient and ideally prolong survival. The choice of agent for intrathecal chemotherapy is guided by the primary tumor, however, there is no strong evidence to choose one agent over the other.^12,14 Methotrexate or cytarabine are generally recommended in the National Comprehensive Cancer Network (NCCN) guidelines. Targeted therapy toward the primary tumor is occasionally used for treatment of LMD, for example rituximab can be given intrathecally for lymphoma,¹⁵ and trastuzumab has been given intrathecally for breast cancer.¹⁶ No intrathecal targeted agents are currently available for melanoma. Administration of intrathecal chemotherapy is given via lumbar puncture or Ommaya reservoir. Induction intrathecal chemotherapy is recommended by NCCN to be given for 4-6 weeks. The schedule of administration varies based on the agent used. Most systemic chemotherapy has poor CSF penetration, which is the basis behind using chemotherapy intrathecally in these patients.¹⁴ However, novel therapies for melanoma, such as ipilimumab, have shown activity in the CNS, and it is not known if intrathecal chemotherapy will continue to play role in the management of LMD.¹⁷

Systemic therapy for metastatic melanoma has changed with the development of novel agents, which have shown better efficacy than traditional chemotherapy. The recommendation for first-line systemic therapy of metastatic unresectable melanoma is based on several factors: BRAF mutation status, tempo of disease, and presence or absence of cancer-related symptoms. Immunotherapy for metastatic melanoma that is unresectable includes anti-programmed cell death protein-1 (PD-1) monotherapy (nivolumab or pembrolizumab) or combination therapy with nivolumab plus ipilimumab. Targeted therapy is preferred in cases with an identified BRAF mutation. Combination therapy with dabrafenib plus trametinib or with vemurafenib plus cobimetinib is recommended. Single-agent therapy may also be used with dabrafenib or vemurafenib.¹⁸

Ipilimumab is a monoclonal antibody that blocks cytotoxic T-lymphocyte antigen-4 to potentiate an anti-tumor T-cell response that was approved in 2011 by the US Food and Drug Administration for the treatment of melanoma. A randomized, phase 3 clinical trial showed an increase in overall survival in patients with unresectable metastatic disease who had received previous treatment.¹⁹ Before that, no therapy had been shown to improve overall survival in patients with metastatic melanoma. Patients with CNS metastases were included in this study.¹⁹

The activity of ipilimumab specifically in patients with brain metastasis was further studied in a phase 2 trial that enrolled 72 patients, 1 cohort with symptomatic brain metastases and the other cohort with asymptomatic brain metastases.²⁰ After 12 weeks of therapy, response was assessed by modified World Health Organization criteria for disease control (complete response plus partial response plus stable disease). In all, 18% of patients with asymptomatic brain metastasis achieved disease control, compared with 10% of patients with symptomatic brain metastases. When the brain alone was assessed, 24% of asymptomatic patients and 10% of symptomatic patients achieved disease control. No unexpected toxic effects occurred during the study. Anti-PD1 therapy such as nivolumab, which has shown durable responses in metastatic melanoma, has no published results specifically in patients with active brain metastases.

Of the BRAF-targeted therapy, dabrafenib and vemurafenib have also been studied in patients with brain metastases. For darafenib, 172 patients with BRAF-mutated metastatic melanoma were included in a phase 2 clinical trial that showed an intracranial response of 39% in previously untreated patients and 31% in patients whose brain metastases had progressed after previous local treatment.²¹ Vemurafenib has also shown intracranial response in a phase 2 clinical trial.²²

The role of the aforementioned therapies in patients with metastatic melanoma with CNS disease should not be overlooked because these patients are typically excluded from clinical trials. As already noted, agents such as ipilimumab and the dabrafenib–vemurafenib combination have been studied in patients with brain metastases and have shown disease control, but more studies are needed to truly assess whether there is an improvement in overall survival and whether that will change treatment guidelines. Although patients with parenchymal brain metastases were included in these studies, it is not clear how patients with LMD and intramedullary spinal cord metastases, such as our patient, would be affected. It is also not clear whether intrathecal chemotherapy will continue to play a role in management of metastatic melanoma with LMD, especially if these newer agents have CNS activity in addition to controlling extracranial disease. Although rarely documented, leptomeningeal and intramedullary metastatic disease will likely become increasingly recognized as patients with cancer live longer and diagnostic studies improve. These initial studies showing intracranial disease control show compelling evidence to continue enrolling patients with active CNS disease in clinical trials.

The incidence of malignant melanoma has been rising in the United States, especially among non-Hispanic white men and women. Death rates have increased for those aged 65 years or older, and incidence rates have increased for all age groups.¹ It is a serious public health issue.

Given the unique biology of melanoma, metastatic disease can present in a variety of ways. In most cases, the lymph nodes and lungs are involved.² The incidence of brain metastases is 10%-40%, however the percentage may be even higher based on reported incidence of autopsy reports.³ The most common forms of metastatic melanoma to the spine are vertebral and intramedullary.⁴ Specifically, leptomeningeal involvement can be found in 20% of patients in clinical studies and 44%-70% in autopsy series of patients with central nervous system (CNS) metastatic disease.⁵ Despite its incidence, leptomeningeal disease (LMD) from melanoma is rarely discussed in the literature and the diagnosis may be difficult. Even rarer is the documented presentation of intramedullary spinal cord metastases, or “drop metastases.”⁶ In our review of the literature, we found no published case reports to date of drop metastases from melanoma causing cauda equina syndrome.

The prognosis of patients with metastatic melanoma with brain metastases is very poor, with a median overall survival of about 4 months reported in several studies.^7-9 Prognosis is even worse for patients with leptomeningeal involvement, and median survival without therapy is about 4-6 weeks.¹⁰ A combination of intrathecal and systemic chemotherapy can be used to treat LMD.¹¹

Case presentation and summary

This is the case of a 56-year-old man with history of metastatic melanoma that had been initially diagnosed about 4 years before the current case presentation. Original sites of disease were a supraclavicular lymph node and solitary liver metastasis, both of which were resected. The patient then developed biopsy-proven lung involvement that required left and right wedge resections. Mutation testing for BRAF V600E and BRAF V600K was sent and not detected. Therefore the patient did not receive any BRAF-targeted therapies. Subsequently, recurrent metastatic disease to the brain with 2 dominant lesions in the cerebellum and the occiput as well as numerous small lesions at the gray-white matter junction was identified (Figure 1 and Figure 2).

The patient received whole-brain radiation (30 Gy in 10 fractions of 3 Gy each). There was no evidence of disease in his spine at that time. About 2 weeks after completing whole-brain radiation, the patient presented to the hospital with left lower extremity weakness, urinary retention, bowel incontinence, saddle anesthesia, and malaise. The symptoms had begun after he had finished whole-brain radiation and weakness progressed to the point at which he need a cane to be able to walk. A physical examination was significant for hyporreflexia, decreased strength and sensitivity on left lower extremity, saddle anesthesia, and lumbar spinal tenderness to palpation. The results of magnetic-resonance imaging (MRI) of the spine revealed multiple soft-tissue nodules extending from the conus medullaris throughout the cauda equina, consistent with intramedullary metastases, as well as concomitant leptomeningeal involvement (Figure 3).

Conclusions

Although metastatic melanoma to the brain is not uncommon, leptomeningeal and intramedullary drop metastases are an infrequent presentation. Even more rare are intramedullary drop metastasis that are significant enough to cause cauda equina syndrome, as with our patient. The incidence of LMD has increased over the years and may continue to increase, likely because of the improved overall survival and a prolonged control of extracranial disease with newly approved systemic therapeutic drugs, such as molecularly targeted therapy and immunotherapy.¹² Intramedullary metastases are extremely rare, but reported incidence has seemed to be increasing due to detection with MRI. Currently there are fewer than 100 case reports of intramedullary spinal cord metastasis.⁶ In one retrospective study, 40 patients with intramedullary metastatic disease secondary to systemic cancer were identified during 1980-1993.⁶ About half of those cases were from lung cancer, the second most common was breast cancer.

CNS involvement by melanoma can have debilitating complications and confers a poor prognosis. In another retrospective study, several patient characteristics were found to be associated with significantly shorter survival in patients with known brain metastases, including presence of neurologic symptoms and leptomeningeal involvement.³

Malignant cells can reach the CSF by several routes: direct extension, hematogenous, venous access, venous drainage from bone marrow and cranial and peripheral nerves. Once the tumor has reached the CSF, it can seed any portion of the nervous system that has contact with the CSF and become entangled among the cauda equine.¹³

Given the rarity of leptomeningeal and intramedullary involvement of melanoma, there are no standard treatment guidelines. Treatment for LMD usually consists of intrathecal and systemic chemotherapy. Commonly used intrathecal agents are methotrexate, liposomal cytarabine, and thiopeta.¹¹ The goals of treatment are to improve or stabilize neurologic status of the patient and ideally prolong survival. The choice of agent for intrathecal chemotherapy is guided by the primary tumor, however, there is no strong evidence to choose one agent over the other.^12,14 Methotrexate or cytarabine are generally recommended in the National Comprehensive Cancer Network (NCCN) guidelines. Targeted therapy toward the primary tumor is occasionally used for treatment of LMD, for example rituximab can be given intrathecally for lymphoma,¹⁵ and trastuzumab has been given intrathecally for breast cancer.¹⁶ No intrathecal targeted agents are currently available for melanoma. Administration of intrathecal chemotherapy is given via lumbar puncture or Ommaya reservoir. Induction intrathecal chemotherapy is recommended by NCCN to be given for 4-6 weeks. The schedule of administration varies based on the agent used. Most systemic chemotherapy has poor CSF penetration, which is the basis behind using chemotherapy intrathecally in these patients.¹⁴ However, novel therapies for melanoma, such as ipilimumab, have shown activity in the CNS, and it is not known if intrathecal chemotherapy will continue to play role in the management of LMD.¹⁷

Systemic therapy for metastatic melanoma has changed with the development of novel agents, which have shown better efficacy than traditional chemotherapy. The recommendation for first-line systemic therapy of metastatic unresectable melanoma is based on several factors: BRAF mutation status, tempo of disease, and presence or absence of cancer-related symptoms. Immunotherapy for metastatic melanoma that is unresectable includes anti-programmed cell death protein-1 (PD-1) monotherapy (nivolumab or pembrolizumab) or combination therapy with nivolumab plus ipilimumab. Targeted therapy is preferred in cases with an identified BRAF mutation. Combination therapy with dabrafenib plus trametinib or with vemurafenib plus cobimetinib is recommended. Single-agent therapy may also be used with dabrafenib or vemurafenib.¹⁸

Ipilimumab is a monoclonal antibody that blocks cytotoxic T-lymphocyte antigen-4 to potentiate an anti-tumor T-cell response that was approved in 2011 by the US Food and Drug Administration for the treatment of melanoma. A randomized, phase 3 clinical trial showed an increase in overall survival in patients with unresectable metastatic disease who had received previous treatment.¹⁹ Before that, no therapy had been shown to improve overall survival in patients with metastatic melanoma. Patients with CNS metastases were included in this study.¹⁹

The activity of ipilimumab specifically in patients with brain metastasis was further studied in a phase 2 trial that enrolled 72 patients, 1 cohort with symptomatic brain metastases and the other cohort with asymptomatic brain metastases.²⁰ After 12 weeks of therapy, response was assessed by modified World Health Organization criteria for disease control (complete response plus partial response plus stable disease). In all, 18% of patients with asymptomatic brain metastasis achieved disease control, compared with 10% of patients with symptomatic brain metastases. When the brain alone was assessed, 24% of asymptomatic patients and 10% of symptomatic patients achieved disease control. No unexpected toxic effects occurred during the study. Anti-PD1 therapy such as nivolumab, which has shown durable responses in metastatic melanoma, has no published results specifically in patients with active brain metastases.

Of the BRAF-targeted therapy, dabrafenib and vemurafenib have also been studied in patients with brain metastases. For darafenib, 172 patients with BRAF-mutated metastatic melanoma were included in a phase 2 clinical trial that showed an intracranial response of 39% in previously untreated patients and 31% in patients whose brain metastases had progressed after previous local treatment.²¹ Vemurafenib has also shown intracranial response in a phase 2 clinical trial.²²

The role of the aforementioned therapies in patients with metastatic melanoma with CNS disease should not be overlooked because these patients are typically excluded from clinical trials. As already noted, agents such as ipilimumab and the dabrafenib–vemurafenib combination have been studied in patients with brain metastases and have shown disease control, but more studies are needed to truly assess whether there is an improvement in overall survival and whether that will change treatment guidelines. Although patients with parenchymal brain metastases were included in these studies, it is not clear how patients with LMD and intramedullary spinal cord metastases, such as our patient, would be affected. It is also not clear whether intrathecal chemotherapy will continue to play a role in management of metastatic melanoma with LMD, especially if these newer agents have CNS activity in addition to controlling extracranial disease. Although rarely documented, leptomeningeal and intramedullary metastatic disease will likely become increasingly recognized as patients with cancer live longer and diagnostic studies improve. These initial studies showing intracranial disease control show compelling evidence to continue enrolling patients with active CNS disease in clinical trials.

The incidence of malignant melanoma has been rising in the United States, especially among non-Hispanic white men and women. Death rates have increased for those aged 65 years or older, and incidence rates have increased for all age groups.¹ It is a serious public health issue.

Given the unique biology of melanoma, metastatic disease can present in a variety of ways. In most cases, the lymph nodes and lungs are involved.² The incidence of brain metastases is 10%-40%, however the percentage may be even higher based on reported incidence of autopsy reports.³ The most common forms of metastatic melanoma to the spine are vertebral and intramedullary.⁴ Specifically, leptomeningeal involvement can be found in 20% of patients in clinical studies and 44%-70% in autopsy series of patients with central nervous system (CNS) metastatic disease.⁵ Despite its incidence, leptomeningeal disease (LMD) from melanoma is rarely discussed in the literature and the diagnosis may be difficult. Even rarer is the documented presentation of intramedullary spinal cord metastases, or “drop metastases.”⁶ In our review of the literature, we found no published case reports to date of drop metastases from melanoma causing cauda equina syndrome.

The prognosis of patients with metastatic melanoma with brain metastases is very poor, with a median overall survival of about 4 months reported in several studies.^7-9 Prognosis is even worse for patients with leptomeningeal involvement, and median survival without therapy is about 4-6 weeks.¹⁰ A combination of intrathecal and systemic chemotherapy can be used to treat LMD.¹¹

Case presentation and summary

This is the case of a 56-year-old man with history of metastatic melanoma that had been initially diagnosed about 4 years before the current case presentation. Original sites of disease were a supraclavicular lymph node and solitary liver metastasis, both of which were resected. The patient then developed biopsy-proven lung involvement that required left and right wedge resections. Mutation testing for BRAF V600E and BRAF V600K was sent and not detected. Therefore the patient did not receive any BRAF-targeted therapies. Subsequently, recurrent metastatic disease to the brain with 2 dominant lesions in the cerebellum and the occiput as well as numerous small lesions at the gray-white matter junction was identified (Figure 1 and Figure 2).

The patient received whole-brain radiation (30 Gy in 10 fractions of 3 Gy each). There was no evidence of disease in his spine at that time. About 2 weeks after completing whole-brain radiation, the patient presented to the hospital with left lower extremity weakness, urinary retention, bowel incontinence, saddle anesthesia, and malaise. The symptoms had begun after he had finished whole-brain radiation and weakness progressed to the point at which he need a cane to be able to walk. A physical examination was significant for hyporreflexia, decreased strength and sensitivity on left lower extremity, saddle anesthesia, and lumbar spinal tenderness to palpation. The results of magnetic-resonance imaging (MRI) of the spine revealed multiple soft-tissue nodules extending from the conus medullaris throughout the cauda equina, consistent with intramedullary metastases, as well as concomitant leptomeningeal involvement (Figure 3).

Conclusions

Although metastatic melanoma to the brain is not uncommon, leptomeningeal and intramedullary drop metastases are an infrequent presentation. Even more rare are intramedullary drop metastasis that are significant enough to cause cauda equina syndrome, as with our patient. The incidence of LMD has increased over the years and may continue to increase, likely because of the improved overall survival and a prolonged control of extracranial disease with newly approved systemic therapeutic drugs, such as molecularly targeted therapy and immunotherapy.¹² Intramedullary metastases are extremely rare, but reported incidence has seemed to be increasing due to detection with MRI. Currently there are fewer than 100 case reports of intramedullary spinal cord metastasis.⁶ In one retrospective study, 40 patients with intramedullary metastatic disease secondary to systemic cancer were identified during 1980-1993.⁶ About half of those cases were from lung cancer, the second most common was breast cancer.

CNS involvement by melanoma can have debilitating complications and confers a poor prognosis. In another retrospective study, several patient characteristics were found to be associated with significantly shorter survival in patients with known brain metastases, including presence of neurologic symptoms and leptomeningeal involvement.³

Malignant cells can reach the CSF by several routes: direct extension, hematogenous, venous access, venous drainage from bone marrow and cranial and peripheral nerves. Once the tumor has reached the CSF, it can seed any portion of the nervous system that has contact with the CSF and become entangled among the cauda equine.¹³

Given the rarity of leptomeningeal and intramedullary involvement of melanoma, there are no standard treatment guidelines. Treatment for LMD usually consists of intrathecal and systemic chemotherapy. Commonly used intrathecal agents are methotrexate, liposomal cytarabine, and thiopeta.¹¹ The goals of treatment are to improve or stabilize neurologic status of the patient and ideally prolong survival. The choice of agent for intrathecal chemotherapy is guided by the primary tumor, however, there is no strong evidence to choose one agent over the other.^12,14 Methotrexate or cytarabine are generally recommended in the National Comprehensive Cancer Network (NCCN) guidelines. Targeted therapy toward the primary tumor is occasionally used for treatment of LMD, for example rituximab can be given intrathecally for lymphoma,¹⁵ and trastuzumab has been given intrathecally for breast cancer.¹⁶ No intrathecal targeted agents are currently available for melanoma. Administration of intrathecal chemotherapy is given via lumbar puncture or Ommaya reservoir. Induction intrathecal chemotherapy is recommended by NCCN to be given for 4-6 weeks. The schedule of administration varies based on the agent used. Most systemic chemotherapy has poor CSF penetration, which is the basis behind using chemotherapy intrathecally in these patients.¹⁴ However, novel therapies for melanoma, such as ipilimumab, have shown activity in the CNS, and it is not known if intrathecal chemotherapy will continue to play role in the management of LMD.¹⁷

Systemic therapy for metastatic melanoma has changed with the development of novel agents, which have shown better efficacy than traditional chemotherapy. The recommendation for first-line systemic therapy of metastatic unresectable melanoma is based on several factors: BRAF mutation status, tempo of disease, and presence or absence of cancer-related symptoms. Immunotherapy for metastatic melanoma that is unresectable includes anti-programmed cell death protein-1 (PD-1) monotherapy (nivolumab or pembrolizumab) or combination therapy with nivolumab plus ipilimumab. Targeted therapy is preferred in cases with an identified BRAF mutation. Combination therapy with dabrafenib plus trametinib or with vemurafenib plus cobimetinib is recommended. Single-agent therapy may also be used with dabrafenib or vemurafenib.¹⁸

Ipilimumab is a monoclonal antibody that blocks cytotoxic T-lymphocyte antigen-4 to potentiate an anti-tumor T-cell response that was approved in 2011 by the US Food and Drug Administration for the treatment of melanoma. A randomized, phase 3 clinical trial showed an increase in overall survival in patients with unresectable metastatic disease who had received previous treatment.¹⁹ Before that, no therapy had been shown to improve overall survival in patients with metastatic melanoma. Patients with CNS metastases were included in this study.¹⁹

The activity of ipilimumab specifically in patients with brain metastasis was further studied in a phase 2 trial that enrolled 72 patients, 1 cohort with symptomatic brain metastases and the other cohort with asymptomatic brain metastases.²⁰ After 12 weeks of therapy, response was assessed by modified World Health Organization criteria for disease control (complete response plus partial response plus stable disease). In all, 18% of patients with asymptomatic brain metastasis achieved disease control, compared with 10% of patients with symptomatic brain metastases. When the brain alone was assessed, 24% of asymptomatic patients and 10% of symptomatic patients achieved disease control. No unexpected toxic effects occurred during the study. Anti-PD1 therapy such as nivolumab, which has shown durable responses in metastatic melanoma, has no published results specifically in patients with active brain metastases.

Of the BRAF-targeted therapy, dabrafenib and vemurafenib have also been studied in patients with brain metastases. For darafenib, 172 patients with BRAF-mutated metastatic melanoma were included in a phase 2 clinical trial that showed an intracranial response of 39% in previously untreated patients and 31% in patients whose brain metastases had progressed after previous local treatment.²¹ Vemurafenib has also shown intracranial response in a phase 2 clinical trial.²²

The role of the aforementioned therapies in patients with metastatic melanoma with CNS disease should not be overlooked because these patients are typically excluded from clinical trials. As already noted, agents such as ipilimumab and the dabrafenib–vemurafenib combination have been studied in patients with brain metastases and have shown disease control, but more studies are needed to truly assess whether there is an improvement in overall survival and whether that will change treatment guidelines. Although patients with parenchymal brain metastases were included in these studies, it is not clear how patients with LMD and intramedullary spinal cord metastases, such as our patient, would be affected. It is also not clear whether intrathecal chemotherapy will continue to play a role in management of metastatic melanoma with LMD, especially if these newer agents have CNS activity in addition to controlling extracranial disease. Although rarely documented, leptomeningeal and intramedullary metastatic disease will likely become increasingly recognized as patients with cancer live longer and diagnostic studies improve. These initial studies showing intracranial disease control show compelling evidence to continue enrolling patients with active CNS disease in clinical trials.