Lymphoma & Plasma Cell Disorders

Hydrogels

Credit: Kathy Atkinson

Researchers have devised a novel way to deliver chemotherapy drugs “on demand,” according to a paper published in Proceedings of the National Academy of Sciences.

The team loaded a biocompatible hydrogel with a chemotherapy drug and used ultrasound to trigger the gel to release the drug.

Like many other injectable gels, this one gradually releases a low level of the drug by diffusion over time. But the new hydrogel differs from others in a key way.

Researchers previously applied ultrasound to gels to temporarily increase doses of drug, but that approach was a one-shot deal, as the ultrasound was used to destroy those gels.

In the current study, the researchers used ultrasound to temporarily disrupt the gel so that it released short, high-dose bursts of the drug. But when they stopped the ultrasound, the hydrogels self-healed.

By closing back up, they were ready to go for the next “on demand” drug burst, providing a way to administer drugs with a greater level of control than was possible before.

The researchers also demonstrated in lab cultures and in mouse models of breast cancer that the pulsed, ultrasound-triggered hydrogel approach to drug delivery was more effective at stopping the growth of tumor cells than traditional, sustained-release drug therapy.

“Our approach counters the whole idea of sustained drug release and offers a double whammy,” said study author David J. Mooney, PhD, of the Harvard School of Engineering and Applied Sciences in Boston.

“We have shown that we can use the hydrogels repeatedly and turn the drug pulses on and off at will, and that the drug bursts in concert with the baseline low-level drug delivery seems to be particularly effective in killing cancer cells.”

Self-healing hydrogel

Key to the researchers’ success in designing a hydrogel that self-heals was choosing the right kind of hydrogel with the right kind of drug and applying the right intensity of ultrasound.

“We were able to trigger our system with a level of ultrasound that was much lower than high-intensity focused ultrasound that is used clinically to heat and destroy tumors,” said study author Cathal Kearney, PhD, of the Royal College of Surgeons in Ireland. “The careful selection of materials and properties make it a reversible process.”

The team carried out the majority of their work for this study with a gel made out of alginate, a natural polysaccharide from algae that is held together with calcium ions.

In a series of tests, they found that, with the right level of ultrasound, the bonds break up and enable the gel to release its drug cargo. But as long as the gel is in the presence of more calcium, the bonds reform and the gel self-heals.

Drug testing

Once the researchers knew the gel would self-heal, they tested out a drug they suspected it would hold well: the chemotherapy drug mitoxantrone.

Sure enough, the ultrasound triggered the gel to release the blue-colored drug, as indicated by the newly blue color of the surrounding medium. Just a single ultrasound dose was effective, and the gel reformed after it was disrupted, making multiple cycles possible.

Next, the team tested the treatment in mouse models of breast cancer. They injected the drug-laden gel close to the tumors.

Over the course of 6 months, the mice that received a low-level, sustained release of the drug with a daily concentrated pulse of ultrasound (2.5 minutes) fared significantly better than mice treated the same but without ultrasound.

In contrast to controls, the tumors in the ultrasound-treated mice did not grow substantially. And the mice survived for an additional 80 days.

Potential applications

The researchers believe their technique could help improve cancer treatment and other therapies requiring drugs to be delivered at the right place and the right time—from post-surgery pain medications to protein-based drugs that require daily injections.

It requires an initial injection of the hydrogel, but the approach could be a much less traumatic, minimally invasive, and more effective method of drug delivery than current methods, Dr Mooney said.

The researchers also found their hydrogel can release cargo other than drugs, including proteins and condensed plasmid DNA. This lays the groundwork for using these hydrogels for tissue regeneration and gene therapy.

Dr Mooney said he and his colleagues plan to explore these potential applications, as well as the possibility of unleashing 2 different drugs independently from the same hydrogel.

Hydrogels

Credit: Kathy Atkinson

Researchers have devised a novel way to deliver chemotherapy drugs “on demand,” according to a paper published in Proceedings of the National Academy of Sciences.

The team loaded a biocompatible hydrogel with a chemotherapy drug and used ultrasound to trigger the gel to release the drug.

Like many other injectable gels, this one gradually releases a low level of the drug by diffusion over time. But the new hydrogel differs from others in a key way.

Researchers previously applied ultrasound to gels to temporarily increase doses of drug, but that approach was a one-shot deal, as the ultrasound was used to destroy those gels.

In the current study, the researchers used ultrasound to temporarily disrupt the gel so that it released short, high-dose bursts of the drug. But when they stopped the ultrasound, the hydrogels self-healed.

By closing back up, they were ready to go for the next “on demand” drug burst, providing a way to administer drugs with a greater level of control than was possible before.

The researchers also demonstrated in lab cultures and in mouse models of breast cancer that the pulsed, ultrasound-triggered hydrogel approach to drug delivery was more effective at stopping the growth of tumor cells than traditional, sustained-release drug therapy.

“Our approach counters the whole idea of sustained drug release and offers a double whammy,” said study author David J. Mooney, PhD, of the Harvard School of Engineering and Applied Sciences in Boston.

“We have shown that we can use the hydrogels repeatedly and turn the drug pulses on and off at will, and that the drug bursts in concert with the baseline low-level drug delivery seems to be particularly effective in killing cancer cells.”

Self-healing hydrogel

Key to the researchers’ success in designing a hydrogel that self-heals was choosing the right kind of hydrogel with the right kind of drug and applying the right intensity of ultrasound.

“We were able to trigger our system with a level of ultrasound that was much lower than high-intensity focused ultrasound that is used clinically to heat and destroy tumors,” said study author Cathal Kearney, PhD, of the Royal College of Surgeons in Ireland. “The careful selection of materials and properties make it a reversible process.”

The team carried out the majority of their work for this study with a gel made out of alginate, a natural polysaccharide from algae that is held together with calcium ions.

In a series of tests, they found that, with the right level of ultrasound, the bonds break up and enable the gel to release its drug cargo. But as long as the gel is in the presence of more calcium, the bonds reform and the gel self-heals.

Drug testing

Once the researchers knew the gel would self-heal, they tested out a drug they suspected it would hold well: the chemotherapy drug mitoxantrone.

Sure enough, the ultrasound triggered the gel to release the blue-colored drug, as indicated by the newly blue color of the surrounding medium. Just a single ultrasound dose was effective, and the gel reformed after it was disrupted, making multiple cycles possible.

Next, the team tested the treatment in mouse models of breast cancer. They injected the drug-laden gel close to the tumors.

Over the course of 6 months, the mice that received a low-level, sustained release of the drug with a daily concentrated pulse of ultrasound (2.5 minutes) fared significantly better than mice treated the same but without ultrasound.

In contrast to controls, the tumors in the ultrasound-treated mice did not grow substantially. And the mice survived for an additional 80 days.

Potential applications

The researchers believe their technique could help improve cancer treatment and other therapies requiring drugs to be delivered at the right place and the right time—from post-surgery pain medications to protein-based drugs that require daily injections.

It requires an initial injection of the hydrogel, but the approach could be a much less traumatic, minimally invasive, and more effective method of drug delivery than current methods, Dr Mooney said.

The researchers also found their hydrogel can release cargo other than drugs, including proteins and condensed plasmid DNA. This lays the groundwork for using these hydrogels for tissue regeneration and gene therapy.

Dr Mooney said he and his colleagues plan to explore these potential applications, as well as the possibility of unleashing 2 different drugs independently from the same hydrogel.

Hydrogels

Credit: Kathy Atkinson

Researchers have devised a novel way to deliver chemotherapy drugs “on demand,” according to a paper published in Proceedings of the National Academy of Sciences.

The team loaded a biocompatible hydrogel with a chemotherapy drug and used ultrasound to trigger the gel to release the drug.

Like many other injectable gels, this one gradually releases a low level of the drug by diffusion over time. But the new hydrogel differs from others in a key way.

Researchers previously applied ultrasound to gels to temporarily increase doses of drug, but that approach was a one-shot deal, as the ultrasound was used to destroy those gels.

In the current study, the researchers used ultrasound to temporarily disrupt the gel so that it released short, high-dose bursts of the drug. But when they stopped the ultrasound, the hydrogels self-healed.

By closing back up, they were ready to go for the next “on demand” drug burst, providing a way to administer drugs with a greater level of control than was possible before.

The researchers also demonstrated in lab cultures and in mouse models of breast cancer that the pulsed, ultrasound-triggered hydrogel approach to drug delivery was more effective at stopping the growth of tumor cells than traditional, sustained-release drug therapy.

“Our approach counters the whole idea of sustained drug release and offers a double whammy,” said study author David J. Mooney, PhD, of the Harvard School of Engineering and Applied Sciences in Boston.

“We have shown that we can use the hydrogels repeatedly and turn the drug pulses on and off at will, and that the drug bursts in concert with the baseline low-level drug delivery seems to be particularly effective in killing cancer cells.”

Self-healing hydrogel

Key to the researchers’ success in designing a hydrogel that self-heals was choosing the right kind of hydrogel with the right kind of drug and applying the right intensity of ultrasound.

“We were able to trigger our system with a level of ultrasound that was much lower than high-intensity focused ultrasound that is used clinically to heat and destroy tumors,” said study author Cathal Kearney, PhD, of the Royal College of Surgeons in Ireland. “The careful selection of materials and properties make it a reversible process.”

The team carried out the majority of their work for this study with a gel made out of alginate, a natural polysaccharide from algae that is held together with calcium ions.

In a series of tests, they found that, with the right level of ultrasound, the bonds break up and enable the gel to release its drug cargo. But as long as the gel is in the presence of more calcium, the bonds reform and the gel self-heals.

Drug testing

Once the researchers knew the gel would self-heal, they tested out a drug they suspected it would hold well: the chemotherapy drug mitoxantrone.

Sure enough, the ultrasound triggered the gel to release the blue-colored drug, as indicated by the newly blue color of the surrounding medium. Just a single ultrasound dose was effective, and the gel reformed after it was disrupted, making multiple cycles possible.

Next, the team tested the treatment in mouse models of breast cancer. They injected the drug-laden gel close to the tumors.

Over the course of 6 months, the mice that received a low-level, sustained release of the drug with a daily concentrated pulse of ultrasound (2.5 minutes) fared significantly better than mice treated the same but without ultrasound.

In contrast to controls, the tumors in the ultrasound-treated mice did not grow substantially. And the mice survived for an additional 80 days.

Potential applications

The researchers believe their technique could help improve cancer treatment and other therapies requiring drugs to be delivered at the right place and the right time—from post-surgery pain medications to protein-based drugs that require daily injections.

It requires an initial injection of the hydrogel, but the approach could be a much less traumatic, minimally invasive, and more effective method of drug delivery than current methods, Dr Mooney said.

The researchers also found their hydrogel can release cargo other than drugs, including proteins and condensed plasmid DNA. This lays the groundwork for using these hydrogels for tissue regeneration and gene therapy.

Dr Mooney said he and his colleagues plan to explore these potential applications, as well as the possibility of unleashing 2 different drugs independently from the same hydrogel.

Doctor consults with a family

Credit: Rhoda Baer

A new analysis suggests family dysfunction is the greatest predictor of emotional and behavioral problems among children who have a parent with cancer.

Other variables, such as the child’s age, did not predict the risk as accurately.

And illness-related factors, such as the parent’s prognosis, did not appear to have an impact at all.

Birgit Möller, PhD, of the University Medical Center Hamburg-Eppendorf in Germany, and her colleagues reported these findings in Cancer.

The researchers evaluated 235 families in which at least 1 parent was diagnosed with cancer. This included 402 parents and 324 children aged 11 to 21 years. Parents and children completed questionnaires that assessed emotional and behavioral health.

Responses suggested that children of cancer patients have higher-than-average levels of emotional and behavioral symptoms.

The overall mean values for emotional and behavioral problems—from both the parents’ and children’s perspectives—were significantly higher in the study population than the average values from a representative non-cancer population.

General family functioning was the strongest predictor of children’s symptom status from both the parents’ and child’s perspectives.

The effects of the child’s age and gender on behavioral and emotional symptoms varied according to the subject asked. But none of the respondents reported an association between child adjustment and illness-related factors such as poor prognoses or recurrent illness.

Dr Möller noted that screening for child mental health problems, family dysfunction, and parental depression can be easily adopted into cancer care so that families in need of support can be identified.

“Additional training of oncologists, interdisciplinary approaches, and family-based mental health liaison services are recommended to meet the needs of minor

children and their families and to minimize negative long-term effects in children,” she said.

Dr Möller and her team have developed a preventive counseling program—called the Children of Somatically Ill Parents (COSIP) program—that focuses on family communication, involvement of family members, flexible problem solving, mutual support, and parenting issues.

Doctor consults with a family

Credit: Rhoda Baer

A new analysis suggests family dysfunction is the greatest predictor of emotional and behavioral problems among children who have a parent with cancer.

Other variables, such as the child’s age, did not predict the risk as accurately.

And illness-related factors, such as the parent’s prognosis, did not appear to have an impact at all.

Birgit Möller, PhD, of the University Medical Center Hamburg-Eppendorf in Germany, and her colleagues reported these findings in Cancer.

The researchers evaluated 235 families in which at least 1 parent was diagnosed with cancer. This included 402 parents and 324 children aged 11 to 21 years. Parents and children completed questionnaires that assessed emotional and behavioral health.

Responses suggested that children of cancer patients have higher-than-average levels of emotional and behavioral symptoms.

The overall mean values for emotional and behavioral problems—from both the parents’ and children’s perspectives—were significantly higher in the study population than the average values from a representative non-cancer population.

General family functioning was the strongest predictor of children’s symptom status from both the parents’ and child’s perspectives.

The effects of the child’s age and gender on behavioral and emotional symptoms varied according to the subject asked. But none of the respondents reported an association between child adjustment and illness-related factors such as poor prognoses or recurrent illness.

Dr Möller noted that screening for child mental health problems, family dysfunction, and parental depression can be easily adopted into cancer care so that families in need of support can be identified.

“Additional training of oncologists, interdisciplinary approaches, and family-based mental health liaison services are recommended to meet the needs of minor

children and their families and to minimize negative long-term effects in children,” she said.

Dr Möller and her team have developed a preventive counseling program—called the Children of Somatically Ill Parents (COSIP) program—that focuses on family communication, involvement of family members, flexible problem solving, mutual support, and parenting issues.

Doctor consults with a family

Credit: Rhoda Baer

A new analysis suggests family dysfunction is the greatest predictor of emotional and behavioral problems among children who have a parent with cancer.

Other variables, such as the child’s age, did not predict the risk as accurately.

And illness-related factors, such as the parent’s prognosis, did not appear to have an impact at all.

Birgit Möller, PhD, of the University Medical Center Hamburg-Eppendorf in Germany, and her colleagues reported these findings in Cancer.

The researchers evaluated 235 families in which at least 1 parent was diagnosed with cancer. This included 402 parents and 324 children aged 11 to 21 years. Parents and children completed questionnaires that assessed emotional and behavioral health.

Responses suggested that children of cancer patients have higher-than-average levels of emotional and behavioral symptoms.

The overall mean values for emotional and behavioral problems—from both the parents’ and children’s perspectives—were significantly higher in the study population than the average values from a representative non-cancer population.

General family functioning was the strongest predictor of children’s symptom status from both the parents’ and child’s perspectives.

The effects of the child’s age and gender on behavioral and emotional symptoms varied according to the subject asked. But none of the respondents reported an association between child adjustment and illness-related factors such as poor prognoses or recurrent illness.

Dr Möller noted that screening for child mental health problems, family dysfunction, and parental depression can be easily adopted into cancer care so that families in need of support can be identified.

“Additional training of oncologists, interdisciplinary approaches, and family-based mental health liaison services are recommended to meet the needs of minor

children and their families and to minimize negative long-term effects in children,” she said.

Dr Möller and her team have developed a preventive counseling program—called the Children of Somatically Ill Parents (COSIP) program—that focuses on family communication, involvement of family members, flexible problem solving, mutual support, and parenting issues.

Burkitt lymphoma cells

Credit: Ed Uthman

Preclinical research suggests a newly engineered protein can suppress tumor growth and extend survival in a mouse model of lymphoma.

The molecule, called BINDI (BHRF1-inhibiting design acting intracellularly), was designed to trigger the self-destruction of cancer cells infected with the Epstein-Barr virus (EBV).

EBV can disrupt the body’s clearance of old, abnormal, infected, and damaged cells. And BINDI works by overriding this interference.

Erik Procko, PhD, of the University of Washington in Seattle, and his colleagues described results observed with BINDI in Cell.

The researchers used computational design and experimental optimization to generate BINDI. The protein was designed to recognize and attach itself to an EBV protein called BHRF1 and to ignore similar proteins. BHRF1 keeps cancer cells alive, but, when bound to BINDI, it can no longer fend off cell death.

By examining the crystal structure of BINDI, the researchers saw that it nearly matched their computationally designed architecture for the protein molecule.

Furthermore, experiments showed that BINDI could prompt EBV-infected cancer cell lines to shrivel, disassemble their components, and burst into small pieces.

The researchers also tested BINDI in a mouse model of EBV-positive lymphoma. They delivered BINDI into cancer cells via an antibody-targeted nanocarrier designed to deliver protein cargo to intracellular cancer targets.

And BINDI behaved as ordered. It suppressed tumor growth and enabled the mice to live longer than control mice.

The researchers said this work demonstrates the potential to develop new classes of more effective, intracellular protein drugs, as current protein therapeutics are limited to extracellular targets.

Burkitt lymphoma cells

Credit: Ed Uthman

Preclinical research suggests a newly engineered protein can suppress tumor growth and extend survival in a mouse model of lymphoma.

The molecule, called BINDI (BHRF1-inhibiting design acting intracellularly), was designed to trigger the self-destruction of cancer cells infected with the Epstein-Barr virus (EBV).

EBV can disrupt the body’s clearance of old, abnormal, infected, and damaged cells. And BINDI works by overriding this interference.

Erik Procko, PhD, of the University of Washington in Seattle, and his colleagues described results observed with BINDI in Cell.

The researchers used computational design and experimental optimization to generate BINDI. The protein was designed to recognize and attach itself to an EBV protein called BHRF1 and to ignore similar proteins. BHRF1 keeps cancer cells alive, but, when bound to BINDI, it can no longer fend off cell death.

By examining the crystal structure of BINDI, the researchers saw that it nearly matched their computationally designed architecture for the protein molecule.

Furthermore, experiments showed that BINDI could prompt EBV-infected cancer cell lines to shrivel, disassemble their components, and burst into small pieces.

The researchers also tested BINDI in a mouse model of EBV-positive lymphoma. They delivered BINDI into cancer cells via an antibody-targeted nanocarrier designed to deliver protein cargo to intracellular cancer targets.

And BINDI behaved as ordered. It suppressed tumor growth and enabled the mice to live longer than control mice.

The researchers said this work demonstrates the potential to develop new classes of more effective, intracellular protein drugs, as current protein therapeutics are limited to extracellular targets.

Burkitt lymphoma cells

Credit: Ed Uthman

Preclinical research suggests a newly engineered protein can suppress tumor growth and extend survival in a mouse model of lymphoma.

The molecule, called BINDI (BHRF1-inhibiting design acting intracellularly), was designed to trigger the self-destruction of cancer cells infected with the Epstein-Barr virus (EBV).

EBV can disrupt the body’s clearance of old, abnormal, infected, and damaged cells. And BINDI works by overriding this interference.

Erik Procko, PhD, of the University of Washington in Seattle, and his colleagues described results observed with BINDI in Cell.

The researchers used computational design and experimental optimization to generate BINDI. The protein was designed to recognize and attach itself to an EBV protein called BHRF1 and to ignore similar proteins. BHRF1 keeps cancer cells alive, but, when bound to BINDI, it can no longer fend off cell death.

By examining the crystal structure of BINDI, the researchers saw that it nearly matched their computationally designed architecture for the protein molecule.

Furthermore, experiments showed that BINDI could prompt EBV-infected cancer cell lines to shrivel, disassemble their components, and burst into small pieces.

The researchers also tested BINDI in a mouse model of EBV-positive lymphoma. They delivered BINDI into cancer cells via an antibody-targeted nanocarrier designed to deliver protein cargo to intracellular cancer targets.

And BINDI behaved as ordered. It suppressed tumor growth and enabled the mice to live longer than control mice.

The researchers said this work demonstrates the potential to develop new classes of more effective, intracellular protein drugs, as current protein therapeutics are limited to extracellular targets.

Doctor consults with a cancer

patient and her father

Credit: Rhoda Baer

A new questionnaire can measure a cancer patient’s risk for financial stress, according to a paper published in Cancer.

Researchers developed the 11-item questionnaire, called the COmprehensive Score for financial Toxicity (COST), through conversations with more than 150 cancer patients.

The team used the term “financial toxicity” to describe the expense, anxiety, and loss of confidence confronting patients who face big, unpredictable costs of cancer treatment.

And the researchers said financial toxicity can be considered another side effect of cancer care.

“Few physicians discuss this increasingly significant side effect with their patients,” said study author Jonas de Souza, MD, of the University of Chicago Medicine in Illinois.

“Physicians aren’t trained to do this. It makes them, as well as patients, feel uncomfortable. [However,] we believe that a thoughtful, concise tool that could help predict a patient’s risk for financial toxicity might open the lines of communication. This gives us a way to launch that discussion.”

Development of the COST questionnaire began with a literature review and a series of extensive interviews. Dr de Souza and his colleagues spoke with 20 patients and 6 cancer professionals, as well as nurses and social workers, and this produced a list of 147 questions.

The researchers pared the list down to 58 questions. Then, they asked 35 patients to help them decide which of the remaining questions were the most important. And the patients narrowed the list down to 30.

“In the end, 155 patients led us, with some judicious editing, to a set of 11 statements,” Dr de Souza said. “This was sufficiently brief to prevent annoying those responding to the questions but thorough enough to get us the information we need.”

All 11 entries are short and easy to understand, according to the researchers. For example, item 2 states, “My out-of-pocket medical expenses are more than I thought they would be.” And item 7 states, “I am able to meet my monthly expenses.”

For each question, patients choose from 5 potential responses: “not at all”, “a little bit,” “somewhat,” “quite a bit,” or “very much.”

Learning how a patient responds may help caregivers determine who is likely to need education, financial counseling, or referral to a support network. The quiz may also predict who is likely to have problems and require interventions.

All patients who helped develop the study had been in treatment for at least 2 months and had received bills. Excluding the top 10% and the bottom 10%, patients in the study earned between $37,000 and $111,000. The median annual income for these patients was about $63,000.

The researchers expected that financial toxicity would correlate with income.

“But, in our small sample, that did not hold up,” Dr de Souza said. “People with less education seemed to have more financial distress, but variations in income did not make much difference. We need bigger studies to confirm that, but at least we now have a tool we can use to study this.”

The researchers are now conducting a larger study to validate these findings and correlate the newly developed scale with quality of life and anxiety in cancer patients.

“We need to assess outcomes that are important for patients,” Dr de Souza said. “[T]his is another important piece of information in the shared-decision-making process.”

Doctor consults with a cancer

patient and her father

Credit: Rhoda Baer

A new questionnaire can measure a cancer patient’s risk for financial stress, according to a paper published in Cancer.

Researchers developed the 11-item questionnaire, called the COmprehensive Score for financial Toxicity (COST), through conversations with more than 150 cancer patients.

The team used the term “financial toxicity” to describe the expense, anxiety, and loss of confidence confronting patients who face big, unpredictable costs of cancer treatment.

And the researchers said financial toxicity can be considered another side effect of cancer care.

“Few physicians discuss this increasingly significant side effect with their patients,” said study author Jonas de Souza, MD, of the University of Chicago Medicine in Illinois.

“Physicians aren’t trained to do this. It makes them, as well as patients, feel uncomfortable. [However,] we believe that a thoughtful, concise tool that could help predict a patient’s risk for financial toxicity might open the lines of communication. This gives us a way to launch that discussion.”

Development of the COST questionnaire began with a literature review and a series of extensive interviews. Dr de Souza and his colleagues spoke with 20 patients and 6 cancer professionals, as well as nurses and social workers, and this produced a list of 147 questions.

The researchers pared the list down to 58 questions. Then, they asked 35 patients to help them decide which of the remaining questions were the most important. And the patients narrowed the list down to 30.

“In the end, 155 patients led us, with some judicious editing, to a set of 11 statements,” Dr de Souza said. “This was sufficiently brief to prevent annoying those responding to the questions but thorough enough to get us the information we need.”

All 11 entries are short and easy to understand, according to the researchers. For example, item 2 states, “My out-of-pocket medical expenses are more than I thought they would be.” And item 7 states, “I am able to meet my monthly expenses.”

For each question, patients choose from 5 potential responses: “not at all”, “a little bit,” “somewhat,” “quite a bit,” or “very much.”

Learning how a patient responds may help caregivers determine who is likely to need education, financial counseling, or referral to a support network. The quiz may also predict who is likely to have problems and require interventions.

All patients who helped develop the study had been in treatment for at least 2 months and had received bills. Excluding the top 10% and the bottom 10%, patients in the study earned between $37,000 and $111,000. The median annual income for these patients was about $63,000.

The researchers expected that financial toxicity would correlate with income.

“But, in our small sample, that did not hold up,” Dr de Souza said. “People with less education seemed to have more financial distress, but variations in income did not make much difference. We need bigger studies to confirm that, but at least we now have a tool we can use to study this.”

The researchers are now conducting a larger study to validate these findings and correlate the newly developed scale with quality of life and anxiety in cancer patients.

“We need to assess outcomes that are important for patients,” Dr de Souza said. “[T]his is another important piece of information in the shared-decision-making process.”

Doctor consults with a cancer

patient and her father

Credit: Rhoda Baer

A new questionnaire can measure a cancer patient’s risk for financial stress, according to a paper published in Cancer.

Researchers developed the 11-item questionnaire, called the COmprehensive Score for financial Toxicity (COST), through conversations with more than 150 cancer patients.

The team used the term “financial toxicity” to describe the expense, anxiety, and loss of confidence confronting patients who face big, unpredictable costs of cancer treatment.

And the researchers said financial toxicity can be considered another side effect of cancer care.

“Few physicians discuss this increasingly significant side effect with their patients,” said study author Jonas de Souza, MD, of the University of Chicago Medicine in Illinois.

“Physicians aren’t trained to do this. It makes them, as well as patients, feel uncomfortable. [However,] we believe that a thoughtful, concise tool that could help predict a patient’s risk for financial toxicity might open the lines of communication. This gives us a way to launch that discussion.”

Development of the COST questionnaire began with a literature review and a series of extensive interviews. Dr de Souza and his colleagues spoke with 20 patients and 6 cancer professionals, as well as nurses and social workers, and this produced a list of 147 questions.

The researchers pared the list down to 58 questions. Then, they asked 35 patients to help them decide which of the remaining questions were the most important. And the patients narrowed the list down to 30.

“In the end, 155 patients led us, with some judicious editing, to a set of 11 statements,” Dr de Souza said. “This was sufficiently brief to prevent annoying those responding to the questions but thorough enough to get us the information we need.”

All 11 entries are short and easy to understand, according to the researchers. For example, item 2 states, “My out-of-pocket medical expenses are more than I thought they would be.” And item 7 states, “I am able to meet my monthly expenses.”

For each question, patients choose from 5 potential responses: “not at all”, “a little bit,” “somewhat,” “quite a bit,” or “very much.”

Learning how a patient responds may help caregivers determine who is likely to need education, financial counseling, or referral to a support network. The quiz may also predict who is likely to have problems and require interventions.

All patients who helped develop the study had been in treatment for at least 2 months and had received bills. Excluding the top 10% and the bottom 10%, patients in the study earned between $37,000 and $111,000. The median annual income for these patients was about $63,000.

The researchers expected that financial toxicity would correlate with income.

“But, in our small sample, that did not hold up,” Dr de Souza said. “People with less education seemed to have more financial distress, but variations in income did not make much difference. We need bigger studies to confirm that, but at least we now have a tool we can use to study this.”

The researchers are now conducting a larger study to validate these findings and correlate the newly developed scale with quality of life and anxiety in cancer patients.

“We need to assess outcomes that are important for patients,” Dr de Souza said. “[T]his is another important piece of information in the shared-decision-making process.”

Attendees at ASCO 2014

©ASCO/Brian Powers

CHICAGO—Hepatitis C reactivation does not worsen survival outcomes for HIV-positive patients diagnosed with lymphoma, new research indicates.

The study showed these patients can tolerate chemotherapy without adverse outcomes and are therefore eligible for aggressive treatment.

They should be closely monitored, however, according to study investigator Stefan K. Barta, MD, of Fox Chase Cancer Center in Philadelphia, Pennsylvania.

Dr Barta and his colleagues presented results observed in HIV-positive lymphoma patients at the 2014 ASCO Annual Meeting as abstract 8578.

The team noted that more than a quarter of HIV-positive patients are also infected with the hepatitis C virus (HCV), which may complicate treatment and care decisions after a cancer diagnosis.

“Patients undergoing chemotherapy can experience reactivation of the hepatitis C virus, which, in turn, can lead to liver failure,” Dr Barta said. “This means we have to dose-reduce chemotherapy, which could negatively affect outcomes.”

In addition, HIV-positive patients often take a host of other medications, including anti-retrovirals, which makes them especially vulnerable to side effects.

However, Dr Barta said these potential risks shouldn’t deter oncologists from treating these patients with chemotherapy because he and his colleagues found that reactivation of HCV did not worsen survival outcomes in this population.

The researchers analyzed the medical records of 190 HIV-positive patients who had been diagnosed with lymphoma at the Albert Einstein Cancer Center in Bronx, New York, from 1997 to 2013. Patients with primary central nervous system lymphomas were excluded.

Fifty-three (28%) eligible patients were also infected with HCV. The virus reactivated in 17 of those patients, or about one-third of the patient population infected with HCV, during treatment.

Patients infected with HCV had an overall survival of 59.7 months, compared to 88.6 months for patients with neither HCV nor hepatitis B virus (HBV).

However, that survival advantage vanished when the researchers adjusted for variables including age, sex, race, CD4 count, the presence of cirrhosis, type of lymphoma, and levels of lactate dehydrogenase (LDH).

The multivariate analysis showed that co-infection with HCV was not associated with lower overall survival in lymphoma patients.

At the same time, the researchers did find worse overall survival outcomes associated with low CD4 count (below 100 cells/cubic millimeter), a diagnosis of non-Hodgkin lymphoma, advanced stage disease, LDH levels over 190, or cirrhosis.

Dr Barta said he hopes this research will open cancer trials up to an understudied patient population. HIV-positive patients with HCV are often excluded from these trials because of concerns about liver failure and toxicity arising from the interaction of retroviral medications with chemotherapy.

“This is really important for a large proportion of patients,” he said. “We want to assure researchers that these patients, as long as they have adequate liver function, should also be enrolled in clinical trials.”

Attendees at ASCO 2014

©ASCO/Brian Powers

CHICAGO—Hepatitis C reactivation does not worsen survival outcomes for HIV-positive patients diagnosed with lymphoma, new research indicates.

The study showed these patients can tolerate chemotherapy without adverse outcomes and are therefore eligible for aggressive treatment.

They should be closely monitored, however, according to study investigator Stefan K. Barta, MD, of Fox Chase Cancer Center in Philadelphia, Pennsylvania.

Dr Barta and his colleagues presented results observed in HIV-positive lymphoma patients at the 2014 ASCO Annual Meeting as abstract 8578.

The team noted that more than a quarter of HIV-positive patients are also infected with the hepatitis C virus (HCV), which may complicate treatment and care decisions after a cancer diagnosis.

“Patients undergoing chemotherapy can experience reactivation of the hepatitis C virus, which, in turn, can lead to liver failure,” Dr Barta said. “This means we have to dose-reduce chemotherapy, which could negatively affect outcomes.”

In addition, HIV-positive patients often take a host of other medications, including anti-retrovirals, which makes them especially vulnerable to side effects.

However, Dr Barta said these potential risks shouldn’t deter oncologists from treating these patients with chemotherapy because he and his colleagues found that reactivation of HCV did not worsen survival outcomes in this population.

The researchers analyzed the medical records of 190 HIV-positive patients who had been diagnosed with lymphoma at the Albert Einstein Cancer Center in Bronx, New York, from 1997 to 2013. Patients with primary central nervous system lymphomas were excluded.

Fifty-three (28%) eligible patients were also infected with HCV. The virus reactivated in 17 of those patients, or about one-third of the patient population infected with HCV, during treatment.

Patients infected with HCV had an overall survival of 59.7 months, compared to 88.6 months for patients with neither HCV nor hepatitis B virus (HBV).

However, that survival advantage vanished when the researchers adjusted for variables including age, sex, race, CD4 count, the presence of cirrhosis, type of lymphoma, and levels of lactate dehydrogenase (LDH).

The multivariate analysis showed that co-infection with HCV was not associated with lower overall survival in lymphoma patients.

At the same time, the researchers did find worse overall survival outcomes associated with low CD4 count (below 100 cells/cubic millimeter), a diagnosis of non-Hodgkin lymphoma, advanced stage disease, LDH levels over 190, or cirrhosis.

Dr Barta said he hopes this research will open cancer trials up to an understudied patient population. HIV-positive patients with HCV are often excluded from these trials because of concerns about liver failure and toxicity arising from the interaction of retroviral medications with chemotherapy.

“This is really important for a large proportion of patients,” he said. “We want to assure researchers that these patients, as long as they have adequate liver function, should also be enrolled in clinical trials.”

Attendees at ASCO 2014

©ASCO/Brian Powers

CHICAGO—Hepatitis C reactivation does not worsen survival outcomes for HIV-positive patients diagnosed with lymphoma, new research indicates.

The study showed these patients can tolerate chemotherapy without adverse outcomes and are therefore eligible for aggressive treatment.

They should be closely monitored, however, according to study investigator Stefan K. Barta, MD, of Fox Chase Cancer Center in Philadelphia, Pennsylvania.

Dr Barta and his colleagues presented results observed in HIV-positive lymphoma patients at the 2014 ASCO Annual Meeting as abstract 8578.

The team noted that more than a quarter of HIV-positive patients are also infected with the hepatitis C virus (HCV), which may complicate treatment and care decisions after a cancer diagnosis.

“Patients undergoing chemotherapy can experience reactivation of the hepatitis C virus, which, in turn, can lead to liver failure,” Dr Barta said. “This means we have to dose-reduce chemotherapy, which could negatively affect outcomes.”

In addition, HIV-positive patients often take a host of other medications, including anti-retrovirals, which makes them especially vulnerable to side effects.

However, Dr Barta said these potential risks shouldn’t deter oncologists from treating these patients with chemotherapy because he and his colleagues found that reactivation of HCV did not worsen survival outcomes in this population.

The researchers analyzed the medical records of 190 HIV-positive patients who had been diagnosed with lymphoma at the Albert Einstein Cancer Center in Bronx, New York, from 1997 to 2013. Patients with primary central nervous system lymphomas were excluded.

Fifty-three (28%) eligible patients were also infected with HCV. The virus reactivated in 17 of those patients, or about one-third of the patient population infected with HCV, during treatment.

Patients infected with HCV had an overall survival of 59.7 months, compared to 88.6 months for patients with neither HCV nor hepatitis B virus (HBV).

However, that survival advantage vanished when the researchers adjusted for variables including age, sex, race, CD4 count, the presence of cirrhosis, type of lymphoma, and levels of lactate dehydrogenase (LDH).

The multivariate analysis showed that co-infection with HCV was not associated with lower overall survival in lymphoma patients.

At the same time, the researchers did find worse overall survival outcomes associated with low CD4 count (below 100 cells/cubic millimeter), a diagnosis of non-Hodgkin lymphoma, advanced stage disease, LDH levels over 190, or cirrhosis.

Dr Barta said he hopes this research will open cancer trials up to an understudied patient population. HIV-positive patients with HCV are often excluded from these trials because of concerns about liver failure and toxicity arising from the interaction of retroviral medications with chemotherapy.

“This is really important for a large proportion of patients,” he said. “We want to assure researchers that these patients, as long as they have adequate liver function, should also be enrolled in clinical trials.”

Attendees at ASCO 2014

©ASCO/Phil McCarten

CHICAGO—Elderly males with non-Hodgkin lymphoma (NHL) may require one-third higher doses of rituximab than the current standard to attain optimal responses to rituximab-containing chemotherapy, a new study suggests.

Increasing the rituximab dose eliminated any gender-related differences in survival among elderly patients with aggressive, CD20+, B-cell lymphomas, said investigator Michael Pfreundschuh, MD, of Saarland University Medical Center in Germany.

He presented this finding at the 2014 ASCO Annual Meeting (abstract 8501).

Although rituximab has been used in NHL for nearly 2 decades, standard dosing of the drug is still largely empiric. Only recently have researchers examined whether responses to the drug may vary by gender and age.

New data show that rituximab clears the body more rapidly in elderly males than elderly females, suggesting that rituximab dosing may need to be increased in older men to maintain adequate drug exposure.

Dr Pfreundschuh noted that the RICOVER-60 trial established 6 cycles of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone every 14 days (R-CHOP-14), followed by 2 additional cycles of rituximab, as the new standard of care for elderly patients with NHL in Germany.

Further analysis of the trial’s results indicates that rituximab dosing may be inadequate in males older than 60, since they fare much worse than elderly females in terms of progression-free survival (PFS).

To test this gender difference, the German High-grade Non-Hodgkin Lymphoma Study Group designed the SEXIE-R-CHOP-14 trial.

The group tested 2 different rituximab doses in patients aged 61 to 80 with stage I to IV, CD20+, diffuse large B-cell lymphoma (DLBCL). A group of 120 females received rituximab at 375 mg/m² per treatment cycle, and a group of 148 males received 500 mg/m² per treatment cycle.

The increased rituximab dose in males resulted in slightly higher trough serum levels than in females. However, rituximab levels dropped faster in males, resulting in nearly identical serum levels thereafter and a very similar overall rituximab exposure time, Dr Pfreundschuh said.

The higher dose of rituximab given to elderly males did not result in increased toxicity.

Survival rates were similar between the male and female groups. The 3-year PFS was 74% in males and 68% in females, and 3-year overall survival was 82% in males and 72% in females.

A multivariate analysis that evaluated gender as a risk factor revealed that the male-vs-female hazard ratio for PFS was 0.8 in SEXIE-R-CHOP-14, compared to 1.6 in RICOVER-60. Similarly, the male-vs-female hazard ratio for overall survival was 0.7 in SEXIE-R-CHOP-14 and 1.4 in RICOVER-60.

“Increasing the rituximab dose by one-third eliminated the increased risk [of death and progression in]  elderly males,” Dr Pfreundschuh concluded.

He also noted that younger males and females have faster rituximab clearance than elderly females. So increasing the dose in these populations should also result in a better outcome.

Attendees at ASCO 2014

©ASCO/Phil McCarten

CHICAGO—Elderly males with non-Hodgkin lymphoma (NHL) may require one-third higher doses of rituximab than the current standard to attain optimal responses to rituximab-containing chemotherapy, a new study suggests.

Increasing the rituximab dose eliminated any gender-related differences in survival among elderly patients with aggressive, CD20+, B-cell lymphomas, said investigator Michael Pfreundschuh, MD, of Saarland University Medical Center in Germany.

He presented this finding at the 2014 ASCO Annual Meeting (abstract 8501).

Although rituximab has been used in NHL for nearly 2 decades, standard dosing of the drug is still largely empiric. Only recently have researchers examined whether responses to the drug may vary by gender and age.

New data show that rituximab clears the body more rapidly in elderly males than elderly females, suggesting that rituximab dosing may need to be increased in older men to maintain adequate drug exposure.

Dr Pfreundschuh noted that the RICOVER-60 trial established 6 cycles of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone every 14 days (R-CHOP-14), followed by 2 additional cycles of rituximab, as the new standard of care for elderly patients with NHL in Germany.

Further analysis of the trial’s results indicates that rituximab dosing may be inadequate in males older than 60, since they fare much worse than elderly females in terms of progression-free survival (PFS).

To test this gender difference, the German High-grade Non-Hodgkin Lymphoma Study Group designed the SEXIE-R-CHOP-14 trial.

The group tested 2 different rituximab doses in patients aged 61 to 80 with stage I to IV, CD20+, diffuse large B-cell lymphoma (DLBCL). A group of 120 females received rituximab at 375 mg/m² per treatment cycle, and a group of 148 males received 500 mg/m² per treatment cycle.

The increased rituximab dose in males resulted in slightly higher trough serum levels than in females. However, rituximab levels dropped faster in males, resulting in nearly identical serum levels thereafter and a very similar overall rituximab exposure time, Dr Pfreundschuh said.

The higher dose of rituximab given to elderly males did not result in increased toxicity.

Survival rates were similar between the male and female groups. The 3-year PFS was 74% in males and 68% in females, and 3-year overall survival was 82% in males and 72% in females.

A multivariate analysis that evaluated gender as a risk factor revealed that the male-vs-female hazard ratio for PFS was 0.8 in SEXIE-R-CHOP-14, compared to 1.6 in RICOVER-60. Similarly, the male-vs-female hazard ratio for overall survival was 0.7 in SEXIE-R-CHOP-14 and 1.4 in RICOVER-60.

“Increasing the rituximab dose by one-third eliminated the increased risk [of death and progression in]  elderly males,” Dr Pfreundschuh concluded.

He also noted that younger males and females have faster rituximab clearance than elderly females. So increasing the dose in these populations should also result in a better outcome.

Attendees at ASCO 2014

©ASCO/Phil McCarten

CHICAGO—Elderly males with non-Hodgkin lymphoma (NHL) may require one-third higher doses of rituximab than the current standard to attain optimal responses to rituximab-containing chemotherapy, a new study suggests.

Increasing the rituximab dose eliminated any gender-related differences in survival among elderly patients with aggressive, CD20+, B-cell lymphomas, said investigator Michael Pfreundschuh, MD, of Saarland University Medical Center in Germany.

He presented this finding at the 2014 ASCO Annual Meeting (abstract 8501).

Although rituximab has been used in NHL for nearly 2 decades, standard dosing of the drug is still largely empiric. Only recently have researchers examined whether responses to the drug may vary by gender and age.

New data show that rituximab clears the body more rapidly in elderly males than elderly females, suggesting that rituximab dosing may need to be increased in older men to maintain adequate drug exposure.

Dr Pfreundschuh noted that the RICOVER-60 trial established 6 cycles of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone every 14 days (R-CHOP-14), followed by 2 additional cycles of rituximab, as the new standard of care for elderly patients with NHL in Germany.

Further analysis of the trial’s results indicates that rituximab dosing may be inadequate in males older than 60, since they fare much worse than elderly females in terms of progression-free survival (PFS).

To test this gender difference, the German High-grade Non-Hodgkin Lymphoma Study Group designed the SEXIE-R-CHOP-14 trial.

The group tested 2 different rituximab doses in patients aged 61 to 80 with stage I to IV, CD20+, diffuse large B-cell lymphoma (DLBCL). A group of 120 females received rituximab at 375 mg/m² per treatment cycle, and a group of 148 males received 500 mg/m² per treatment cycle.

The increased rituximab dose in males resulted in slightly higher trough serum levels than in females. However, rituximab levels dropped faster in males, resulting in nearly identical serum levels thereafter and a very similar overall rituximab exposure time, Dr Pfreundschuh said.

The higher dose of rituximab given to elderly males did not result in increased toxicity.

Survival rates were similar between the male and female groups. The 3-year PFS was 74% in males and 68% in females, and 3-year overall survival was 82% in males and 72% in females.

A multivariate analysis that evaluated gender as a risk factor revealed that the male-vs-female hazard ratio for PFS was 0.8 in SEXIE-R-CHOP-14, compared to 1.6 in RICOVER-60. Similarly, the male-vs-female hazard ratio for overall survival was 0.7 in SEXIE-R-CHOP-14 and 1.4 in RICOVER-60.

“Increasing the rituximab dose by one-third eliminated the increased risk [of death and progression in]  elderly males,” Dr Pfreundschuh concluded.

He also noted that younger males and females have faster rituximab clearance than elderly females. So increasing the dose in these populations should also result in a better outcome.

Session at EHA 2014

Photo courtesy of EHA

MILAN—The BCL-2 inhibitor ABT-199 may be a feasible treatment option for patients with chronic lymphocyctic leukemia/small lymphocytic lymphoma (CLL/SLL), according to research presented at the 19th Congress of the European Hematology Association (EHA).

Previous results showed that ABT-199 can elicit responses in patients with CLL/SLL, but it can also induce tumor lysis syndrome (TLS).

In fact, 2 TLS-related deaths prompted the temporary suspension of enrollment in trials of ABT-199.

But now, researchers have reported that a modified dosing schedule, prophylaxis, and patient monitoring can reduce, and perhaps even eliminate, the risk of TLS.

And ABT-199 can produce solid responses, even in high-risk CLL/SLL patients.

John Seymour, MBBS, PhD, of the Peter MacCallum Cancer Center in Victoria, Australia, and his colleagues presented results observed with a TLS prophylactic regimen at the EHA Congress as abstract P868.

Dr Seymour also presented data from a phase 1 study of ABT-199 monotherapy as abstract S702. Both studies were supported by AbbVie and Genentech, the companies developing ABT-199.

Assessing the risk of TLS

To identify pre-treatment risk factors for TLS and appropriate prophylactic measures, Dr Seymour and his colleagues analyzed 77 CLL/SLL patients who were treated with ABT-199 prior to the identification of TLS (from June 2011 to March 2013).

Twenty-four of these patients had values meeting Cairo-Bishop criteria for TLS, and medical adjudication suggested 19 (25%) of them had TLS.

Comparing these patients to those who did not develop TLS, the researchers found that patients were at low risk of developing TLS if they had a nodal mass measuring less than 5 cm and an absolute lymphocyte count (ALC) less than 25,000.

Patients were at medium risk of TLS if they had a nodal mass of 5 cm to 9 cm or an ALC of at least 25,000. And patients were at high risk of TLS if they had a nodal mass of 10 cm or greater or a nodal mass of 5 cm to 9 cm and an ALC of 25,000 or greater.

Dose modification

The researchers also found that TLS events tended to occur within 24 hours of the first dose of ABT-199. And the initial exposure (median Cmax value) for patients who had a TLS incident was higher than patients without TLS (0.49 μg/mL vs 0.23 μg/mL).

However, simulations suggested that, at a 20 mg starting dose, 98% of patients will achieve initial peak exposures similar to patients without TLS (Cmax below 0.23 ug/mL).

So the researchers modified the dosing schedule of ABT-199 in subsequently treated patients. The patients received a 20 mg starting dose, then 50 mg for the rest of week 1, 100 mg in week 2, 200 mg in week 3, and 400 mg in week 4.

However, if 1 or more electrolytes met Cairo-Bishop criteria and/or there was a 30% or greater decrease in ALC with the first dose, patients received the drug at 20 mg in week 1, 50 mg in week 2, 100 mg in week 3, 200 mg in week 4, and 400 mg in week 5.

Prophylactic measures

Dr Seymour and his colleagues also recommended several other steps to minimize the risk of TLS. They said their findings support hospitalizing and monitoring patients for the first dose of 20 mg and 50 mg, regardless of their risk of TLS.

High-risk patients should be hospitalized for all subsequent dose escalations until they are re-categorized to medium- or low-risk groups. The researchers also said hospitalization should be considered at subsequent dose escalation for medium-risk patients with creatinine clearance of 80 mL/min or less.

All patients should receive oral hydration prior to receiving ABT-199, and hospitalized patients should receive intravenous hydration (150-200 cc/hour, as tolerated).

All patients should receive a uric-acid-reducing agent at least 72 hours before their first dose of ABT-199. Rasburicase is strongly suggested for high-risk patients with high baseline uric acid and for patients who develop rapid rises in uric acid values.

The researchers also recommended laboratory assessment at 8 hours and 24 hours in an outpatient setting and at 4, 8, 12, and 24 hours in hospitalized patients.

Approach reduces TLS risk

Lastly, Dr Seymour and his colleagues analyzed the effect of the modified dosing schedule and the aforementioned prophylactic measures on a cohort of 58 CLL/SLL patients treated with ABT-199.

The TLS risk stratification was similar in this cohort and the pre-modification cohort of 77 patients. There was, however, a higher proportion of patients in the post-modification cohort who fell into the high-risk category.

According to Cairo-Bishop criteria, 3 patients (3.9%) had clinical TLS in the pre-modification cohort and 16 (20.8%) had laboratory TLS. In the post-modification cohort, none of the patients had clinical TLS, and 8 (13.8%) had laboratory TLS.

According to the Howard definition of TLS, 3 patients (3.9%) in the pre-modification cohort had clinical TLS, and 7 (9.1%) had laboratory TLS. But none of the patients in the post-modification cohort had clinical or laboratory TLS.

Phase 1 trial of ABT-199 monotherapy

In another presentation at the EHA Congress, Dr Seymour reported results from a phase 1 study of ABT-199 monotherapy in 105 patients with high-risk CLL/SLL.

Following the identification of TLS, patients received treatment according to the modified schedule, as well as TLS prophylaxis.

In all, 7 patients developed TLS. One of these patients died, and 1 required dialysis. As of April 9, 2014, there were no cases of TLS among the 49 patients who received ABT-199 according to the modified dosing schedule, as well as TLS prophylaxis.

Other common treatment-emergent adverse events included diarrhea (40%), neutropenia (36%), and nausea (35%). Grade 3/4 neutropenia occurred in 33% of patients, and febrile neutropenia occurred in 4%.

Thirty-seven patients discontinued treatment—22 due to progressive disease, 12 due to adverse events, and 3 for other reasons (1 required warfarin, and 2 proceeded to transplant).

Seventy-eight patients were evaluable for treatment response. Nineteen of these patients had del (17p), 41 were fludarabine-refractory, and 24 had unmutated IGHV.

The response rate was 77% overall, 79% among patients with del (17p), 76% in those who were fludarabine-refractory, and 75% in those with unmutated IGHV. The complete response rates were 23% 26%, 22%, and 29%, respectively.

As of April 9, the median progression-free survival was about 18 months. The median progression-free survival had not been reached for patients treated at or above 400 mg.

Session at EHA 2014

Photo courtesy of EHA

MILAN—The BCL-2 inhibitor ABT-199 may be a feasible treatment option for patients with chronic lymphocyctic leukemia/small lymphocytic lymphoma (CLL/SLL), according to research presented at the 19th Congress of the European Hematology Association (EHA).

Previous results showed that ABT-199 can elicit responses in patients with CLL/SLL, but it can also induce tumor lysis syndrome (TLS).

In fact, 2 TLS-related deaths prompted the temporary suspension of enrollment in trials of ABT-199.

But now, researchers have reported that a modified dosing schedule, prophylaxis, and patient monitoring can reduce, and perhaps even eliminate, the risk of TLS.

And ABT-199 can produce solid responses, even in high-risk CLL/SLL patients.

John Seymour, MBBS, PhD, of the Peter MacCallum Cancer Center in Victoria, Australia, and his colleagues presented results observed with a TLS prophylactic regimen at the EHA Congress as abstract P868.

Dr Seymour also presented data from a phase 1 study of ABT-199 monotherapy as abstract S702. Both studies were supported by AbbVie and Genentech, the companies developing ABT-199.

Assessing the risk of TLS

To identify pre-treatment risk factors for TLS and appropriate prophylactic measures, Dr Seymour and his colleagues analyzed 77 CLL/SLL patients who were treated with ABT-199 prior to the identification of TLS (from June 2011 to March 2013).

Twenty-four of these patients had values meeting Cairo-Bishop criteria for TLS, and medical adjudication suggested 19 (25%) of them had TLS.

Comparing these patients to those who did not develop TLS, the researchers found that patients were at low risk of developing TLS if they had a nodal mass measuring less than 5 cm and an absolute lymphocyte count (ALC) less than 25,000.

Patients were at medium risk of TLS if they had a nodal mass of 5 cm to 9 cm or an ALC of at least 25,000. And patients were at high risk of TLS if they had a nodal mass of 10 cm or greater or a nodal mass of 5 cm to 9 cm and an ALC of 25,000 or greater.

Dose modification

The researchers also found that TLS events tended to occur within 24 hours of the first dose of ABT-199. And the initial exposure (median Cmax value) for patients who had a TLS incident was higher than patients without TLS (0.49 μg/mL vs 0.23 μg/mL).

However, simulations suggested that, at a 20 mg starting dose, 98% of patients will achieve initial peak exposures similar to patients without TLS (Cmax below 0.23 ug/mL).

So the researchers modified the dosing schedule of ABT-199 in subsequently treated patients. The patients received a 20 mg starting dose, then 50 mg for the rest of week 1, 100 mg in week 2, 200 mg in week 3, and 400 mg in week 4.

However, if 1 or more electrolytes met Cairo-Bishop criteria and/or there was a 30% or greater decrease in ALC with the first dose, patients received the drug at 20 mg in week 1, 50 mg in week 2, 100 mg in week 3, 200 mg in week 4, and 400 mg in week 5.

Prophylactic measures

Dr Seymour and his colleagues also recommended several other steps to minimize the risk of TLS. They said their findings support hospitalizing and monitoring patients for the first dose of 20 mg and 50 mg, regardless of their risk of TLS.

High-risk patients should be hospitalized for all subsequent dose escalations until they are re-categorized to medium- or low-risk groups. The researchers also said hospitalization should be considered at subsequent dose escalation for medium-risk patients with creatinine clearance of 80 mL/min or less.

All patients should receive oral hydration prior to receiving ABT-199, and hospitalized patients should receive intravenous hydration (150-200 cc/hour, as tolerated).

All patients should receive a uric-acid-reducing agent at least 72 hours before their first dose of ABT-199. Rasburicase is strongly suggested for high-risk patients with high baseline uric acid and for patients who develop rapid rises in uric acid values.

The researchers also recommended laboratory assessment at 8 hours and 24 hours in an outpatient setting and at 4, 8, 12, and 24 hours in hospitalized patients.

Approach reduces TLS risk

Lastly, Dr Seymour and his colleagues analyzed the effect of the modified dosing schedule and the aforementioned prophylactic measures on a cohort of 58 CLL/SLL patients treated with ABT-199.

The TLS risk stratification was similar in this cohort and the pre-modification cohort of 77 patients. There was, however, a higher proportion of patients in the post-modification cohort who fell into the high-risk category.

According to Cairo-Bishop criteria, 3 patients (3.9%) had clinical TLS in the pre-modification cohort and 16 (20.8%) had laboratory TLS. In the post-modification cohort, none of the patients had clinical TLS, and 8 (13.8%) had laboratory TLS.

According to the Howard definition of TLS, 3 patients (3.9%) in the pre-modification cohort had clinical TLS, and 7 (9.1%) had laboratory TLS. But none of the patients in the post-modification cohort had clinical or laboratory TLS.

Phase 1 trial of ABT-199 monotherapy

In another presentation at the EHA Congress, Dr Seymour reported results from a phase 1 study of ABT-199 monotherapy in 105 patients with high-risk CLL/SLL.

Following the identification of TLS, patients received treatment according to the modified schedule, as well as TLS prophylaxis.

In all, 7 patients developed TLS. One of these patients died, and 1 required dialysis. As of April 9, 2014, there were no cases of TLS among the 49 patients who received ABT-199 according to the modified dosing schedule, as well as TLS prophylaxis.

Other common treatment-emergent adverse events included diarrhea (40%), neutropenia (36%), and nausea (35%). Grade 3/4 neutropenia occurred in 33% of patients, and febrile neutropenia occurred in 4%.

Thirty-seven patients discontinued treatment—22 due to progressive disease, 12 due to adverse events, and 3 for other reasons (1 required warfarin, and 2 proceeded to transplant).

Seventy-eight patients were evaluable for treatment response. Nineteen of these patients had del (17p), 41 were fludarabine-refractory, and 24 had unmutated IGHV.

The response rate was 77% overall, 79% among patients with del (17p), 76% in those who were fludarabine-refractory, and 75% in those with unmutated IGHV. The complete response rates were 23% 26%, 22%, and 29%, respectively.

As of April 9, the median progression-free survival was about 18 months. The median progression-free survival had not been reached for patients treated at or above 400 mg.

Session at EHA 2014

Photo courtesy of EHA

MILAN—The BCL-2 inhibitor ABT-199 may be a feasible treatment option for patients with chronic lymphocyctic leukemia/small lymphocytic lymphoma (CLL/SLL), according to research presented at the 19th Congress of the European Hematology Association (EHA).

Previous results showed that ABT-199 can elicit responses in patients with CLL/SLL, but it can also induce tumor lysis syndrome (TLS).

In fact, 2 TLS-related deaths prompted the temporary suspension of enrollment in trials of ABT-199.

But now, researchers have reported that a modified dosing schedule, prophylaxis, and patient monitoring can reduce, and perhaps even eliminate, the risk of TLS.

And ABT-199 can produce solid responses, even in high-risk CLL/SLL patients.

John Seymour, MBBS, PhD, of the Peter MacCallum Cancer Center in Victoria, Australia, and his colleagues presented results observed with a TLS prophylactic regimen at the EHA Congress as abstract P868.

Dr Seymour also presented data from a phase 1 study of ABT-199 monotherapy as abstract S702. Both studies were supported by AbbVie and Genentech, the companies developing ABT-199.

Assessing the risk of TLS

To identify pre-treatment risk factors for TLS and appropriate prophylactic measures, Dr Seymour and his colleagues analyzed 77 CLL/SLL patients who were treated with ABT-199 prior to the identification of TLS (from June 2011 to March 2013).

Twenty-four of these patients had values meeting Cairo-Bishop criteria for TLS, and medical adjudication suggested 19 (25%) of them had TLS.

Comparing these patients to those who did not develop TLS, the researchers found that patients were at low risk of developing TLS if they had a nodal mass measuring less than 5 cm and an absolute lymphocyte count (ALC) less than 25,000.

Patients were at medium risk of TLS if they had a nodal mass of 5 cm to 9 cm or an ALC of at least 25,000. And patients were at high risk of TLS if they had a nodal mass of 10 cm or greater or a nodal mass of 5 cm to 9 cm and an ALC of 25,000 or greater.

Dose modification

The researchers also found that TLS events tended to occur within 24 hours of the first dose of ABT-199. And the initial exposure (median Cmax value) for patients who had a TLS incident was higher than patients without TLS (0.49 μg/mL vs 0.23 μg/mL).

However, simulations suggested that, at a 20 mg starting dose, 98% of patients will achieve initial peak exposures similar to patients without TLS (Cmax below 0.23 ug/mL).

So the researchers modified the dosing schedule of ABT-199 in subsequently treated patients. The patients received a 20 mg starting dose, then 50 mg for the rest of week 1, 100 mg in week 2, 200 mg in week 3, and 400 mg in week 4.

However, if 1 or more electrolytes met Cairo-Bishop criteria and/or there was a 30% or greater decrease in ALC with the first dose, patients received the drug at 20 mg in week 1, 50 mg in week 2, 100 mg in week 3, 200 mg in week 4, and 400 mg in week 5.

Prophylactic measures

Dr Seymour and his colleagues also recommended several other steps to minimize the risk of TLS. They said their findings support hospitalizing and monitoring patients for the first dose of 20 mg and 50 mg, regardless of their risk of TLS.

High-risk patients should be hospitalized for all subsequent dose escalations until they are re-categorized to medium- or low-risk groups. The researchers also said hospitalization should be considered at subsequent dose escalation for medium-risk patients with creatinine clearance of 80 mL/min or less.

All patients should receive oral hydration prior to receiving ABT-199, and hospitalized patients should receive intravenous hydration (150-200 cc/hour, as tolerated).

All patients should receive a uric-acid-reducing agent at least 72 hours before their first dose of ABT-199. Rasburicase is strongly suggested for high-risk patients with high baseline uric acid and for patients who develop rapid rises in uric acid values.

The researchers also recommended laboratory assessment at 8 hours and 24 hours in an outpatient setting and at 4, 8, 12, and 24 hours in hospitalized patients.

Approach reduces TLS risk

Lastly, Dr Seymour and his colleagues analyzed the effect of the modified dosing schedule and the aforementioned prophylactic measures on a cohort of 58 CLL/SLL patients treated with ABT-199.

The TLS risk stratification was similar in this cohort and the pre-modification cohort of 77 patients. There was, however, a higher proportion of patients in the post-modification cohort who fell into the high-risk category.

According to Cairo-Bishop criteria, 3 patients (3.9%) had clinical TLS in the pre-modification cohort and 16 (20.8%) had laboratory TLS. In the post-modification cohort, none of the patients had clinical TLS, and 8 (13.8%) had laboratory TLS.

According to the Howard definition of TLS, 3 patients (3.9%) in the pre-modification cohort had clinical TLS, and 7 (9.1%) had laboratory TLS. But none of the patients in the post-modification cohort had clinical or laboratory TLS.

Phase 1 trial of ABT-199 monotherapy

In another presentation at the EHA Congress, Dr Seymour reported results from a phase 1 study of ABT-199 monotherapy in 105 patients with high-risk CLL/SLL.

Following the identification of TLS, patients received treatment according to the modified schedule, as well as TLS prophylaxis.

In all, 7 patients developed TLS. One of these patients died, and 1 required dialysis. As of April 9, 2014, there were no cases of TLS among the 49 patients who received ABT-199 according to the modified dosing schedule, as well as TLS prophylaxis.

Other common treatment-emergent adverse events included diarrhea (40%), neutropenia (36%), and nausea (35%). Grade 3/4 neutropenia occurred in 33% of patients, and febrile neutropenia occurred in 4%.

Thirty-seven patients discontinued treatment—22 due to progressive disease, 12 due to adverse events, and 3 for other reasons (1 required warfarin, and 2 proceeded to transplant).

Seventy-eight patients were evaluable for treatment response. Nineteen of these patients had del (17p), 41 were fludarabine-refractory, and 24 had unmutated IGHV.

The response rate was 77% overall, 79% among patients with del (17p), 76% in those who were fludarabine-refractory, and 75% in those with unmutated IGHV. The complete response rates were 23% 26%, 22%, and 29%, respectively.

As of April 9, the median progression-free survival was about 18 months. The median progression-free survival had not been reached for patients treated at or above 400 mg.

CHICAGO—Investigators have found evidence to suggest that identifying central nervous system (CNS) involvement at diagnosis does not impact overall survival for patients with AIDS-related lymphoma (ARL).

The research showed that ARL patients with CNS involvement at diagnosis were nearly 3 times as likely as their peers to have CNS relapse during cancer treatment.

But there was no significant difference between the 2 groups with regard to survival.

This may be due to the low overall incidence of CNS relapse, the use of insufficient treatments, and/or inadequate methods for identifying patients with CNS involvement, according to the investigators.

Stefan K. Barta, MD, of the Fox Chase Cancer Center in Philadelphia, Pennsylvania, and his colleagues conducted this research and presented the results at the 2014 ASCO Annual Meeting (abstract 8570).

In 2013, Dr Barta led the assembly of a database containing medical data from more than 1500 patients newly diagnosed with ARL who participated in clinical trials in Europe and the US from 1990 through 2010.

In the new study, he and his colleagues used the database to identify 880 patients with ARL whose data included complete information on CNS involvement at diagnosis and CNS relapse.

The team set out to find associations between CNS relapse and patient characteristics, including age, sex, CD4 count, lymphoma subtype, treatment history with combination antiretroviral therapies (cART), rituximab use, and the type of initial chemotherapy.

All of the patients had received either intrathecal therapy for CNS involvement or intrathecal prophylaxis with single-agent or 3-agent regimens. Sixty-nine percent of patients (n=607) had received cART, and 31% (n=276) had received rituximab-containing induction chemoimmunotherapy.

CNS involvement was identified in 13% of patients at diagnosis, including 27% of patients with Burkitt lymphoma or Burkitt-like lymphoma and 6% of patients with diffuse large B-cell lymphoma.

There was no difference in the prevalence of baseline CNS involvement between patients treated before and after the introduction of cART (13% each).

In all, 5.3% of patients experienced CNS relapse at a median of 4.2 months after diagnosis (range, 0.3-19.3 months). This included 12% of patients diagnosed with CNS involvement at baseline and 4% of patients who were not.

The median overall survival after CNS relapse was 1.6 months (range, 0-86.4 months). There was no significant difference in overall survival between patients with CNS involvement at diagnosis and those without it. The hazard ratio was 0.85 (P=0.32).

Multivariate analysis showed the only baseline characteristic significantly associated with the frequency of CNS relapse was CNS involvement, with a hazard ratio of 2.9 (P=0.01). None of the treatments had a significant impact on CNS relapse.

Dr Barta said these results suggest that current treatments are insufficient, and the approaches used to identify CNS involvement may be missing many patients who are at risk of CNS relapse.

“A lot of patients who relapsed probably had undetected CNS involvement at diagnosis,” he said. “We want to figure out if there are better strategies to identify patients at risk.”

CHICAGO—Investigators have found evidence to suggest that identifying central nervous system (CNS) involvement at diagnosis does not impact overall survival for patients with AIDS-related lymphoma (ARL).

The research showed that ARL patients with CNS involvement at diagnosis were nearly 3 times as likely as their peers to have CNS relapse during cancer treatment.

But there was no significant difference between the 2 groups with regard to survival.

This may be due to the low overall incidence of CNS relapse, the use of insufficient treatments, and/or inadequate methods for identifying patients with CNS involvement, according to the investigators.

Stefan K. Barta, MD, of the Fox Chase Cancer Center in Philadelphia, Pennsylvania, and his colleagues conducted this research and presented the results at the 2014 ASCO Annual Meeting (abstract 8570).

In 2013, Dr Barta led the assembly of a database containing medical data from more than 1500 patients newly diagnosed with ARL who participated in clinical trials in Europe and the US from 1990 through 2010.

In the new study, he and his colleagues used the database to identify 880 patients with ARL whose data included complete information on CNS involvement at diagnosis and CNS relapse.

The team set out to find associations between CNS relapse and patient characteristics, including age, sex, CD4 count, lymphoma subtype, treatment history with combination antiretroviral therapies (cART), rituximab use, and the type of initial chemotherapy.

All of the patients had received either intrathecal therapy for CNS involvement or intrathecal prophylaxis with single-agent or 3-agent regimens. Sixty-nine percent of patients (n=607) had received cART, and 31% (n=276) had received rituximab-containing induction chemoimmunotherapy.

CNS involvement was identified in 13% of patients at diagnosis, including 27% of patients with Burkitt lymphoma or Burkitt-like lymphoma and 6% of patients with diffuse large B-cell lymphoma.

There was no difference in the prevalence of baseline CNS involvement between patients treated before and after the introduction of cART (13% each).

In all, 5.3% of patients experienced CNS relapse at a median of 4.2 months after diagnosis (range, 0.3-19.3 months). This included 12% of patients diagnosed with CNS involvement at baseline and 4% of patients who were not.

The median overall survival after CNS relapse was 1.6 months (range, 0-86.4 months). There was no significant difference in overall survival between patients with CNS involvement at diagnosis and those without it. The hazard ratio was 0.85 (P=0.32).

Multivariate analysis showed the only baseline characteristic significantly associated with the frequency of CNS relapse was CNS involvement, with a hazard ratio of 2.9 (P=0.01). None of the treatments had a significant impact on CNS relapse.

Dr Barta said these results suggest that current treatments are insufficient, and the approaches used to identify CNS involvement may be missing many patients who are at risk of CNS relapse.

“A lot of patients who relapsed probably had undetected CNS involvement at diagnosis,” he said. “We want to figure out if there are better strategies to identify patients at risk.”

CHICAGO—Investigators have found evidence to suggest that identifying central nervous system (CNS) involvement at diagnosis does not impact overall survival for patients with AIDS-related lymphoma (ARL).

The research showed that ARL patients with CNS involvement at diagnosis were nearly 3 times as likely as their peers to have CNS relapse during cancer treatment.

But there was no significant difference between the 2 groups with regard to survival.

This may be due to the low overall incidence of CNS relapse, the use of insufficient treatments, and/or inadequate methods for identifying patients with CNS involvement, according to the investigators.

Stefan K. Barta, MD, of the Fox Chase Cancer Center in Philadelphia, Pennsylvania, and his colleagues conducted this research and presented the results at the 2014 ASCO Annual Meeting (abstract 8570).

In 2013, Dr Barta led the assembly of a database containing medical data from more than 1500 patients newly diagnosed with ARL who participated in clinical trials in Europe and the US from 1990 through 2010.

In the new study, he and his colleagues used the database to identify 880 patients with ARL whose data included complete information on CNS involvement at diagnosis and CNS relapse.

The team set out to find associations between CNS relapse and patient characteristics, including age, sex, CD4 count, lymphoma subtype, treatment history with combination antiretroviral therapies (cART), rituximab use, and the type of initial chemotherapy.

All of the patients had received either intrathecal therapy for CNS involvement or intrathecal prophylaxis with single-agent or 3-agent regimens. Sixty-nine percent of patients (n=607) had received cART, and 31% (n=276) had received rituximab-containing induction chemoimmunotherapy.

CNS involvement was identified in 13% of patients at diagnosis, including 27% of patients with Burkitt lymphoma or Burkitt-like lymphoma and 6% of patients with diffuse large B-cell lymphoma.

There was no difference in the prevalence of baseline CNS involvement between patients treated before and after the introduction of cART (13% each).

In all, 5.3% of patients experienced CNS relapse at a median of 4.2 months after diagnosis (range, 0.3-19.3 months). This included 12% of patients diagnosed with CNS involvement at baseline and 4% of patients who were not.

The median overall survival after CNS relapse was 1.6 months (range, 0-86.4 months). There was no significant difference in overall survival between patients with CNS involvement at diagnosis and those without it. The hazard ratio was 0.85 (P=0.32).

Multivariate analysis showed the only baseline characteristic significantly associated with the frequency of CNS relapse was CNS involvement, with a hazard ratio of 2.9 (P=0.01). None of the treatments had a significant impact on CNS relapse.

Dr Barta said these results suggest that current treatments are insufficient, and the approaches used to identify CNS involvement may be missing many patients who are at risk of CNS relapse.

“A lot of patients who relapsed probably had undetected CNS involvement at diagnosis,” he said. “We want to figure out if there are better strategies to identify patients at risk.”