Lymphoma & Plasma Cell Disorders

SAN DIEGO—Preclinical research has revealed a mechanism of rituximab resistance in chronic lymphocytic leukemia (CLL), as well as a possible new treatment approach.

The study suggests the TNF-family member BAFF contributes to CLL cells’ resistance to direct and rituximab-induced natural killer (NK) cell reactivity.

However, the BAFF-specific antibody belimumab can overcome this resistance and restore CLL cells’ sensitivity to chemotherapy.

Julia Wild, a PhD student at Eberhard Karls University in Tuebingen, Germany, and her colleagues presented these findings at the AACR Annual Meeting 2014 as abstract 148.

“It is widely known that NK cells’ ability to react against lymphoblastic leukemia is impaired, as compared to myeloid leukemia,” Wild said. “And we now think we’ve identified a factor involved in this—a member of the tumor necrosis factor family called BAFF.”

Previous research showed that NK cells’ ability to target malignant cells and mediate antibody-dependent cellular cytotoxicity (ADCC) is compromised in CLL, but the underlying mechanisms were not clear. Wild and her colleagues therefore speculated that BAFF, which regulates B-cell proliferation and survival, plays a role.

The researchers’ initial experiments revealed that NK cells express BAFF at the mRNA level and release the protein in a soluble form, with levels depending on the state of activation.

The team then assessed BAFF expression in primary CLL cells. They collected cells from 17 CLL patients and analyzed surface expression of the 3 BAFF receptors. All 17 samples were positive for BAFF-R and TACI, and about 53% (9/17) were positive for BCMA.

Additional experiments revealed that BAFF enhances the metabolic activity of primary CLL cells. To uncover this result, the researchers incubated the cells with increasing concentrations of BAFF. And they compared untreated cells to cells treated with belimumab, isotype control, BAFF, BAFF plus belimumab, and BAFF plus isotype control.

The team then compared untreated CLL cells to cells treated with fludarabine and cyclophosphamide (Flu/Cy); Flu/Cy plus BAFF; and Flu/Cy, BAFF, and belimumab.

They found that BAFF protects CLL cells from chemotherapy-induced death. However, belimumab inhibits the protective effects of BAFF and restores CLL cells’ sensitivity to chemotherapy.

The researchers then performed cytotoxicity assays in primary CLL cells, comparing untreated cells to cells exposed to BAFF alone; rituximab alone; BAFF and rituximab; BAFF and belimumab; and rituximab, BAFF, and belimumab.

They found that lysis was highest among cells treated with rituximab alone or rituximab, BAFF, and belimumab, with comparable results in these 2 groups.

The team also evaluated CLL cell lysis due to ADCC induction. They analyzed peripheral blood mononuclear cells from CLL patients, comparing untreated cells to cells exposed to rituximab alone; rituximab and BAFF; rituximab, belimumab, and BAFF; and rituximab, bevacizumab, and BAFF.

Results showed that CLL cell survival was lowest (and comparable) in cells treated with rituximab alone or rituximab, belimumab, and BAFF.

“When CLL cells are cultured in the presence of BAFF, cytotoxicity is decreased as compared to untreated cells, and this is not only for direct NK-cell activity, but also for ADCC-mediated activity,” Wild summarized.

“But we can block this effect with belimumab, which suggests we could use this antibody for CLL treatment.”

SAN DIEGO—Preclinical research has revealed a mechanism of rituximab resistance in chronic lymphocytic leukemia (CLL), as well as a possible new treatment approach.

The study suggests the TNF-family member BAFF contributes to CLL cells’ resistance to direct and rituximab-induced natural killer (NK) cell reactivity.

However, the BAFF-specific antibody belimumab can overcome this resistance and restore CLL cells’ sensitivity to chemotherapy.

Julia Wild, a PhD student at Eberhard Karls University in Tuebingen, Germany, and her colleagues presented these findings at the AACR Annual Meeting 2014 as abstract 148.

“It is widely known that NK cells’ ability to react against lymphoblastic leukemia is impaired, as compared to myeloid leukemia,” Wild said. “And we now think we’ve identified a factor involved in this—a member of the tumor necrosis factor family called BAFF.”

Previous research showed that NK cells’ ability to target malignant cells and mediate antibody-dependent cellular cytotoxicity (ADCC) is compromised in CLL, but the underlying mechanisms were not clear. Wild and her colleagues therefore speculated that BAFF, which regulates B-cell proliferation and survival, plays a role.

The researchers’ initial experiments revealed that NK cells express BAFF at the mRNA level and release the protein in a soluble form, with levels depending on the state of activation.

The team then assessed BAFF expression in primary CLL cells. They collected cells from 17 CLL patients and analyzed surface expression of the 3 BAFF receptors. All 17 samples were positive for BAFF-R and TACI, and about 53% (9/17) were positive for BCMA.

Additional experiments revealed that BAFF enhances the metabolic activity of primary CLL cells. To uncover this result, the researchers incubated the cells with increasing concentrations of BAFF. And they compared untreated cells to cells treated with belimumab, isotype control, BAFF, BAFF plus belimumab, and BAFF plus isotype control.

The team then compared untreated CLL cells to cells treated with fludarabine and cyclophosphamide (Flu/Cy); Flu/Cy plus BAFF; and Flu/Cy, BAFF, and belimumab.

They found that BAFF protects CLL cells from chemotherapy-induced death. However, belimumab inhibits the protective effects of BAFF and restores CLL cells’ sensitivity to chemotherapy.

The researchers then performed cytotoxicity assays in primary CLL cells, comparing untreated cells to cells exposed to BAFF alone; rituximab alone; BAFF and rituximab; BAFF and belimumab; and rituximab, BAFF, and belimumab.

They found that lysis was highest among cells treated with rituximab alone or rituximab, BAFF, and belimumab, with comparable results in these 2 groups.

The team also evaluated CLL cell lysis due to ADCC induction. They analyzed peripheral blood mononuclear cells from CLL patients, comparing untreated cells to cells exposed to rituximab alone; rituximab and BAFF; rituximab, belimumab, and BAFF; and rituximab, bevacizumab, and BAFF.

Results showed that CLL cell survival was lowest (and comparable) in cells treated with rituximab alone or rituximab, belimumab, and BAFF.

“When CLL cells are cultured in the presence of BAFF, cytotoxicity is decreased as compared to untreated cells, and this is not only for direct NK-cell activity, but also for ADCC-mediated activity,” Wild summarized.

“But we can block this effect with belimumab, which suggests we could use this antibody for CLL treatment.”

SAN DIEGO—Preclinical research has revealed a mechanism of rituximab resistance in chronic lymphocytic leukemia (CLL), as well as a possible new treatment approach.

The study suggests the TNF-family member BAFF contributes to CLL cells’ resistance to direct and rituximab-induced natural killer (NK) cell reactivity.

However, the BAFF-specific antibody belimumab can overcome this resistance and restore CLL cells’ sensitivity to chemotherapy.

Julia Wild, a PhD student at Eberhard Karls University in Tuebingen, Germany, and her colleagues presented these findings at the AACR Annual Meeting 2014 as abstract 148.

“It is widely known that NK cells’ ability to react against lymphoblastic leukemia is impaired, as compared to myeloid leukemia,” Wild said. “And we now think we’ve identified a factor involved in this—a member of the tumor necrosis factor family called BAFF.”

Previous research showed that NK cells’ ability to target malignant cells and mediate antibody-dependent cellular cytotoxicity (ADCC) is compromised in CLL, but the underlying mechanisms were not clear. Wild and her colleagues therefore speculated that BAFF, which regulates B-cell proliferation and survival, plays a role.

The researchers’ initial experiments revealed that NK cells express BAFF at the mRNA level and release the protein in a soluble form, with levels depending on the state of activation.

The team then assessed BAFF expression in primary CLL cells. They collected cells from 17 CLL patients and analyzed surface expression of the 3 BAFF receptors. All 17 samples were positive for BAFF-R and TACI, and about 53% (9/17) were positive for BCMA.

Additional experiments revealed that BAFF enhances the metabolic activity of primary CLL cells. To uncover this result, the researchers incubated the cells with increasing concentrations of BAFF. And they compared untreated cells to cells treated with belimumab, isotype control, BAFF, BAFF plus belimumab, and BAFF plus isotype control.

The team then compared untreated CLL cells to cells treated with fludarabine and cyclophosphamide (Flu/Cy); Flu/Cy plus BAFF; and Flu/Cy, BAFF, and belimumab.

They found that BAFF protects CLL cells from chemotherapy-induced death. However, belimumab inhibits the protective effects of BAFF and restores CLL cells’ sensitivity to chemotherapy.

The researchers then performed cytotoxicity assays in primary CLL cells, comparing untreated cells to cells exposed to BAFF alone; rituximab alone; BAFF and rituximab; BAFF and belimumab; and rituximab, BAFF, and belimumab.

They found that lysis was highest among cells treated with rituximab alone or rituximab, BAFF, and belimumab, with comparable results in these 2 groups.

The team also evaluated CLL cell lysis due to ADCC induction. They analyzed peripheral blood mononuclear cells from CLL patients, comparing untreated cells to cells exposed to rituximab alone; rituximab and BAFF; rituximab, belimumab, and BAFF; and rituximab, bevacizumab, and BAFF.

Results showed that CLL cell survival was lowest (and comparable) in cells treated with rituximab alone or rituximab, belimumab, and BAFF.

“When CLL cells are cultured in the presence of BAFF, cytotoxicity is decreased as compared to untreated cells, and this is not only for direct NK-cell activity, but also for ADCC-mediated activity,” Wild summarized.

“But we can block this effect with belimumab, which suggests we could use this antibody for CLL treatment.”

Doctor consults with a cancer

patient and her father

Credit: Rhoda Baer

Feeling as though they play an active role in their treatment decisions increases satisfaction among cancer patients undergoing radiotherapy (RT), according to research published in Cancer.

In a study of more than 300 RT patients, those who were involved in their treatment decisions—or perceived they had some control over their treatment—were more satisfied than their peers.

On the other hand, patients who wanted control over their treatment but did not feel they had any were more likely than their peers to experience anxiety, depression, and fatigue.

“Our findings emphasize the value of patient-physician relationships and communication, specifically in radiation oncology, and their impact on patient experience in a way that hasn’t been shown before,” said study author Neha Vapiwala, MD, of the Perelman School of Medicine at the University of Pennsylvania.

Dr Vapiwala and her colleagues noted that past studies of shared decision-making (SDM)—in which patients and providers make healthcare decisions together, taking into account scientific evidence and patient preferences—have shown an association between patient satisfaction and quality of life.

However, none of these studies has evaluated the impact of SDM on patients undergoing RT. Often, radiation oncology is seen as a treatment avenue that is ultimately left to the physician to dictate. But there are tailored options, decisions, and discussions that can apply to individual patients.

With this in mind, the researchers conducted a survey of SDM in 305 patients undergoing RT. In all, 31% of patients said they experienced SDM, 32% perceived control in their treatment decisions, and 76% reported feeling very satisfied with their radiation treatment course overall.

Patient satisfaction was significantly higher among those who perceived SDM than among those who did not—84.4% and 71.4%, respectively (P<0.02).

And satisfaction was higher among patients who perceived control over their treatment than among those who did not—89.7% and 69.2%, respectively (P<0.001).

Patients who expressed a desire for control over their treatment decisions but did not perceive having any control were significantly more likely than their peers to experience symptoms tied to psychological distress.

Anxiety was reported in 44% and 20% of patients, respectively (P<0.02). Depression was reported in 44% and 15%, respectively (P<0.01). And fatigue was reported in 68% and 39.2%, respectively (P<0.01).

The researchers said one of this study’s strengths is the diverse group of patients enrolled. Ages ranged from 18 to 87 years, and a variety of ethnic/racial groups were represented. Patients had a range of cancers at all stages, and could participate in the study as long as they were well enough.

The team said the next step for this research is to determine both physician and patient barriers to SDM and identify methods to break down these barriers.

“As providers, it doesn’t matter what treatment you are offering, or how complicated it is, or how busy you may be,” Dr Vapiwala said. “It’s worth taking even a few minutes to talk to patients about seemingly minor decisions in which they can provide some input.”

“It’s not only critical in today’s healthcare setting, where both information and misinformation are rampant, but will very likely lead to the patient feeling positively about the encounter.”

Doctor consults with a cancer

patient and her father

Credit: Rhoda Baer

Feeling as though they play an active role in their treatment decisions increases satisfaction among cancer patients undergoing radiotherapy (RT), according to research published in Cancer.

In a study of more than 300 RT patients, those who were involved in their treatment decisions—or perceived they had some control over their treatment—were more satisfied than their peers.

On the other hand, patients who wanted control over their treatment but did not feel they had any were more likely than their peers to experience anxiety, depression, and fatigue.

“Our findings emphasize the value of patient-physician relationships and communication, specifically in radiation oncology, and their impact on patient experience in a way that hasn’t been shown before,” said study author Neha Vapiwala, MD, of the Perelman School of Medicine at the University of Pennsylvania.

Dr Vapiwala and her colleagues noted that past studies of shared decision-making (SDM)—in which patients and providers make healthcare decisions together, taking into account scientific evidence and patient preferences—have shown an association between patient satisfaction and quality of life.

However, none of these studies has evaluated the impact of SDM on patients undergoing RT. Often, radiation oncology is seen as a treatment avenue that is ultimately left to the physician to dictate. But there are tailored options, decisions, and discussions that can apply to individual patients.

With this in mind, the researchers conducted a survey of SDM in 305 patients undergoing RT. In all, 31% of patients said they experienced SDM, 32% perceived control in their treatment decisions, and 76% reported feeling very satisfied with their radiation treatment course overall.

Patient satisfaction was significantly higher among those who perceived SDM than among those who did not—84.4% and 71.4%, respectively (P<0.02).

And satisfaction was higher among patients who perceived control over their treatment than among those who did not—89.7% and 69.2%, respectively (P<0.001).

Patients who expressed a desire for control over their treatment decisions but did not perceive having any control were significantly more likely than their peers to experience symptoms tied to psychological distress.

Anxiety was reported in 44% and 20% of patients, respectively (P<0.02). Depression was reported in 44% and 15%, respectively (P<0.01). And fatigue was reported in 68% and 39.2%, respectively (P<0.01).

The researchers said one of this study’s strengths is the diverse group of patients enrolled. Ages ranged from 18 to 87 years, and a variety of ethnic/racial groups were represented. Patients had a range of cancers at all stages, and could participate in the study as long as they were well enough.

The team said the next step for this research is to determine both physician and patient barriers to SDM and identify methods to break down these barriers.

“As providers, it doesn’t matter what treatment you are offering, or how complicated it is, or how busy you may be,” Dr Vapiwala said. “It’s worth taking even a few minutes to talk to patients about seemingly minor decisions in which they can provide some input.”

“It’s not only critical in today’s healthcare setting, where both information and misinformation are rampant, but will very likely lead to the patient feeling positively about the encounter.”

Doctor consults with a cancer

patient and her father

Credit: Rhoda Baer

Feeling as though they play an active role in their treatment decisions increases satisfaction among cancer patients undergoing radiotherapy (RT), according to research published in Cancer.

In a study of more than 300 RT patients, those who were involved in their treatment decisions—or perceived they had some control over their treatment—were more satisfied than their peers.

On the other hand, patients who wanted control over their treatment but did not feel they had any were more likely than their peers to experience anxiety, depression, and fatigue.

“Our findings emphasize the value of patient-physician relationships and communication, specifically in radiation oncology, and their impact on patient experience in a way that hasn’t been shown before,” said study author Neha Vapiwala, MD, of the Perelman School of Medicine at the University of Pennsylvania.

Dr Vapiwala and her colleagues noted that past studies of shared decision-making (SDM)—in which patients and providers make healthcare decisions together, taking into account scientific evidence and patient preferences—have shown an association between patient satisfaction and quality of life.

However, none of these studies has evaluated the impact of SDM on patients undergoing RT. Often, radiation oncology is seen as a treatment avenue that is ultimately left to the physician to dictate. But there are tailored options, decisions, and discussions that can apply to individual patients.

With this in mind, the researchers conducted a survey of SDM in 305 patients undergoing RT. In all, 31% of patients said they experienced SDM, 32% perceived control in their treatment decisions, and 76% reported feeling very satisfied with their radiation treatment course overall.

Patient satisfaction was significantly higher among those who perceived SDM than among those who did not—84.4% and 71.4%, respectively (P<0.02).

And satisfaction was higher among patients who perceived control over their treatment than among those who did not—89.7% and 69.2%, respectively (P<0.001).

Patients who expressed a desire for control over their treatment decisions but did not perceive having any control were significantly more likely than their peers to experience symptoms tied to psychological distress.

Anxiety was reported in 44% and 20% of patients, respectively (P<0.02). Depression was reported in 44% and 15%, respectively (P<0.01). And fatigue was reported in 68% and 39.2%, respectively (P<0.01).

The researchers said one of this study’s strengths is the diverse group of patients enrolled. Ages ranged from 18 to 87 years, and a variety of ethnic/racial groups were represented. Patients had a range of cancers at all stages, and could participate in the study as long as they were well enough.

The team said the next step for this research is to determine both physician and patient barriers to SDM and identify methods to break down these barriers.

“As providers, it doesn’t matter what treatment you are offering, or how complicated it is, or how busy you may be,” Dr Vapiwala said. “It’s worth taking even a few minutes to talk to patients about seemingly minor decisions in which they can provide some input.”

“It’s not only critical in today’s healthcare setting, where both information and misinformation are rampant, but will very likely lead to the patient feeling positively about the encounter.”

Doctor consulting

with a cancer patient

NCI/Mathews Media Group

The American Society of Clinical Oncology (ASCO) has issued 3 practice guidelines for preventing and managing symptoms that can affect adult cancer survivors—neuropathy, fatigue, and depression/anxiety.

The guideline on chemotherapy-induced peripheral neuropathy (CIPN) lists a few options for treating the condition but discourages interventions to prevent CIPN, as there is insufficient evidence that these interventions benefit patients.

The guideline on fatigue recommends that healthcare providers start screening cancer patients for the condition at diagnosis and emphasizes the importance of educating patients about fatigue.

The guideline on depression and anxiety recommends periodic evaluations for symptoms of depression and anxiety in all cancer patients. It also suggests that all patients be offered supportive care services.

All 3 of these guidelines are published in the Journal of Clinical Oncology.

Treating and preventing CIPN

ASCO’s guideline on CIPN lists a handful of drugs that may be helpful in diminishing the symptoms of CIPN, but it does not recommend any agents for preventing the condition.

In fact, the guideline provides a list of agents that should not be offered for the prevention of CIPN, including acetyl-L-carnitine, amifostine, amitriptyline, CaMg, diethyldithio-carbamate, glutathione, nimodipine, Org 2766, all-trans retinoic acid, rhuLIF, and vitamin E.

“There is no clear panacea for neuropathy,” said Gary Lyman, MD, MPH, co-chair of the ASCO Survivorship Guidelines Advisory Group.

“Some of the drugs used for prevention or treatment of neuropathy may cause side effects or interfere with other drugs. We want to be clear that if there is no evidence of benefit from those drugs, it’s probably best not to take them.”

As for treatment, the guideline states that data support a “moderate” recommendation for duloxetine.

It also notes that there is no strong evidence of benefit for the use of tricyclic antidepressants, gabapentin, and a topical gel containing baclofen, amitriptyline, and ketamine. However, it may be reasonable to try those agents in select patients.

To develop this guideline, an ASCO panel conducted a systematic review of relevant medical literature. They analyzed data from 48 randomized, clinical trials focused on managing CIPN.

Screening and managing fatigue

ASCO’s guideline on fatigue recommends that all patients be screened for fatigue from the point of diagnosis onward. Healthcare providers should assess fatigue history, disease status, and treatable contributing factors.

All patients should be educated about the differences between normal and cancer-related fatigue, causes of fatigue, and contributing factors.

Healthcare providers should discuss with patients strategies to manage fatigue, including physical activity, psychosocial interventions (such as cognitive and behavioral therapies or psycho-educational therapies), and mind-body interventions (such as yoga or acupuncture).

To develop this guideline, an ASCO panel conducted a systematic review of clinical practice guideline databases and relevant medical literature. The adaptation is based on a Pan-Canadian guideline on fatigue and 2 National Comprehensive Cancer Network guidelines on cancer-related fatigue and survivorship.

Handling anxiety and depression

ASCO’s guideline on anxiety and depression recommends that healthcare providers periodically evaluate all cancer patients for symptoms of depression and anxiety. The assessments should be performed using validated, published measures and procedures.

All patients should have the option of receiving supportive care services, such as education about the normalcy of stress in the context of cancer, signs and symptoms of distress, and stress reduction strategies.

Patients who display moderate or severe symptoms of anxiety and depression should be referred for the appropriate psychological, psychosocial, or psychiatric interventions.

“Doctors sometimes don’t give these symptoms much attention because they think it’s normal that their patients are a little anxious or depressed about their disease,” Dr Lyman said. “But it’s important to keep an eye on the symptoms and step in when they start to interfere with the patients’ quality of life.”

To develop this guideline, an ASCO panel conducted a systematic review of clinical practice guideline databases and relevant medical literature. The adaptation is based on a Pan-Canadian practice guideline on psychological distress in adults with cancer.

Doctor consulting

with a cancer patient

NCI/Mathews Media Group

The American Society of Clinical Oncology (ASCO) has issued 3 practice guidelines for preventing and managing symptoms that can affect adult cancer survivors—neuropathy, fatigue, and depression/anxiety.

The guideline on chemotherapy-induced peripheral neuropathy (CIPN) lists a few options for treating the condition but discourages interventions to prevent CIPN, as there is insufficient evidence that these interventions benefit patients.

The guideline on fatigue recommends that healthcare providers start screening cancer patients for the condition at diagnosis and emphasizes the importance of educating patients about fatigue.

The guideline on depression and anxiety recommends periodic evaluations for symptoms of depression and anxiety in all cancer patients. It also suggests that all patients be offered supportive care services.

All 3 of these guidelines are published in the Journal of Clinical Oncology.

Treating and preventing CIPN

ASCO’s guideline on CIPN lists a handful of drugs that may be helpful in diminishing the symptoms of CIPN, but it does not recommend any agents for preventing the condition.

In fact, the guideline provides a list of agents that should not be offered for the prevention of CIPN, including acetyl-L-carnitine, amifostine, amitriptyline, CaMg, diethyldithio-carbamate, glutathione, nimodipine, Org 2766, all-trans retinoic acid, rhuLIF, and vitamin E.

“There is no clear panacea for neuropathy,” said Gary Lyman, MD, MPH, co-chair of the ASCO Survivorship Guidelines Advisory Group.

“Some of the drugs used for prevention or treatment of neuropathy may cause side effects or interfere with other drugs. We want to be clear that if there is no evidence of benefit from those drugs, it’s probably best not to take them.”

As for treatment, the guideline states that data support a “moderate” recommendation for duloxetine.

It also notes that there is no strong evidence of benefit for the use of tricyclic antidepressants, gabapentin, and a topical gel containing baclofen, amitriptyline, and ketamine. However, it may be reasonable to try those agents in select patients.

To develop this guideline, an ASCO panel conducted a systematic review of relevant medical literature. They analyzed data from 48 randomized, clinical trials focused on managing CIPN.

Screening and managing fatigue

ASCO’s guideline on fatigue recommends that all patients be screened for fatigue from the point of diagnosis onward. Healthcare providers should assess fatigue history, disease status, and treatable contributing factors.

All patients should be educated about the differences between normal and cancer-related fatigue, causes of fatigue, and contributing factors.

Healthcare providers should discuss with patients strategies to manage fatigue, including physical activity, psychosocial interventions (such as cognitive and behavioral therapies or psycho-educational therapies), and mind-body interventions (such as yoga or acupuncture).

To develop this guideline, an ASCO panel conducted a systematic review of clinical practice guideline databases and relevant medical literature. The adaptation is based on a Pan-Canadian guideline on fatigue and 2 National Comprehensive Cancer Network guidelines on cancer-related fatigue and survivorship.

Handling anxiety and depression

ASCO’s guideline on anxiety and depression recommends that healthcare providers periodically evaluate all cancer patients for symptoms of depression and anxiety. The assessments should be performed using validated, published measures and procedures.

All patients should have the option of receiving supportive care services, such as education about the normalcy of stress in the context of cancer, signs and symptoms of distress, and stress reduction strategies.

Patients who display moderate or severe symptoms of anxiety and depression should be referred for the appropriate psychological, psychosocial, or psychiatric interventions.

“Doctors sometimes don’t give these symptoms much attention because they think it’s normal that their patients are a little anxious or depressed about their disease,” Dr Lyman said. “But it’s important to keep an eye on the symptoms and step in when they start to interfere with the patients’ quality of life.”

To develop this guideline, an ASCO panel conducted a systematic review of clinical practice guideline databases and relevant medical literature. The adaptation is based on a Pan-Canadian practice guideline on psychological distress in adults with cancer.

Doctor consulting

with a cancer patient

NCI/Mathews Media Group

The American Society of Clinical Oncology (ASCO) has issued 3 practice guidelines for preventing and managing symptoms that can affect adult cancer survivors—neuropathy, fatigue, and depression/anxiety.

The guideline on chemotherapy-induced peripheral neuropathy (CIPN) lists a few options for treating the condition but discourages interventions to prevent CIPN, as there is insufficient evidence that these interventions benefit patients.

The guideline on fatigue recommends that healthcare providers start screening cancer patients for the condition at diagnosis and emphasizes the importance of educating patients about fatigue.

The guideline on depression and anxiety recommends periodic evaluations for symptoms of depression and anxiety in all cancer patients. It also suggests that all patients be offered supportive care services.

All 3 of these guidelines are published in the Journal of Clinical Oncology.

Treating and preventing CIPN

ASCO’s guideline on CIPN lists a handful of drugs that may be helpful in diminishing the symptoms of CIPN, but it does not recommend any agents for preventing the condition.

In fact, the guideline provides a list of agents that should not be offered for the prevention of CIPN, including acetyl-L-carnitine, amifostine, amitriptyline, CaMg, diethyldithio-carbamate, glutathione, nimodipine, Org 2766, all-trans retinoic acid, rhuLIF, and vitamin E.

“There is no clear panacea for neuropathy,” said Gary Lyman, MD, MPH, co-chair of the ASCO Survivorship Guidelines Advisory Group.

“Some of the drugs used for prevention or treatment of neuropathy may cause side effects or interfere with other drugs. We want to be clear that if there is no evidence of benefit from those drugs, it’s probably best not to take them.”

As for treatment, the guideline states that data support a “moderate” recommendation for duloxetine.

It also notes that there is no strong evidence of benefit for the use of tricyclic antidepressants, gabapentin, and a topical gel containing baclofen, amitriptyline, and ketamine. However, it may be reasonable to try those agents in select patients.

To develop this guideline, an ASCO panel conducted a systematic review of relevant medical literature. They analyzed data from 48 randomized, clinical trials focused on managing CIPN.

Screening and managing fatigue

ASCO’s guideline on fatigue recommends that all patients be screened for fatigue from the point of diagnosis onward. Healthcare providers should assess fatigue history, disease status, and treatable contributing factors.

All patients should be educated about the differences between normal and cancer-related fatigue, causes of fatigue, and contributing factors.

Healthcare providers should discuss with patients strategies to manage fatigue, including physical activity, psychosocial interventions (such as cognitive and behavioral therapies or psycho-educational therapies), and mind-body interventions (such as yoga or acupuncture).

To develop this guideline, an ASCO panel conducted a systematic review of clinical practice guideline databases and relevant medical literature. The adaptation is based on a Pan-Canadian guideline on fatigue and 2 National Comprehensive Cancer Network guidelines on cancer-related fatigue and survivorship.

Handling anxiety and depression

ASCO’s guideline on anxiety and depression recommends that healthcare providers periodically evaluate all cancer patients for symptoms of depression and anxiety. The assessments should be performed using validated, published measures and procedures.

All patients should have the option of receiving supportive care services, such as education about the normalcy of stress in the context of cancer, signs and symptoms of distress, and stress reduction strategies.

Patients who display moderate or severe symptoms of anxiety and depression should be referred for the appropriate psychological, psychosocial, or psychiatric interventions.

“Doctors sometimes don’t give these symptoms much attention because they think it’s normal that their patients are a little anxious or depressed about their disease,” Dr Lyman said. “But it’s important to keep an eye on the symptoms and step in when they start to interfere with the patients’ quality of life.”

To develop this guideline, an ASCO panel conducted a systematic review of clinical practice guideline databases and relevant medical literature. The adaptation is based on a Pan-Canadian practice guideline on psychological distress in adults with cancer.

Doctor examining patient

Logan Tuttle

Factors other than cancer treatment or chronic health conditions can influence the risk of death among survivors of childhood cancers, according to a study published in the Journal of Cancer Survivorship.

The researchers found an increased risk of death among cancer survivors who rarely exercised, were underweight, visited the doctor 5 or more times a year, considered themselves in “fair” or “poor” health, and had concerns about their future health.

Cheryl Cox, PhD, of the St Jude Children’s Research Hospital in Memphis, Tennessee, and her colleagues conducted this research using data from the Childhood Cancer Survivor Study.

The team compared 7162 childhood cancer survivors to 445 subjects who survived childhood cancer but ultimately died from causes other than cancer or non-health-related events (such as accidents).

The researchers matched subjects according to their primary diagnosis, age at the time of baseline questionnaire, and the time from diagnosis to baseline questionnaire.

Among the 445 subjects who died, the median age at death was 37.6 years. Malignant neoplasms (42%), cardiac conditions (20%), and pulmonary conditions (7%) caused the most deaths.

Subjects who died were slightly older than living subjects and more often of black race (vs white, Hispanic, or “other”). They were less likely to have a post-high school education or to be married. And they were more likely to have a household income below $20,000 or have an existing grade 3 or 4 chronic health condition.

When the researchers adjusted their analyses for sociodemographic characteristics, exposure to chemotherapy and/or radiation, and the number and severity of chronic health conditions, they identified a number of factors associated with an increased risk for all-cause mortality.

One of these factors was a lack of exercise—specifically, not exercising at all (odds ratio [OR]=1.72, P<0.001) or exercising 1 to 2 days a week (OR=1.65, P=0.004), compared to exercising 3 or more days a week.

On the other hand, being overweight or obese did not significantly increase a subject’s risk of death, but being underweight did (OR=2.58, P<0.001).

As one might expect, increased use of medical care was associated with an increased risk of mortality.

Subjects who reported 5 to 6 doctor visits per year had twice the risk of death as subjects who reported 1 to 2 visits (OR=2.07, P<0.001). And subjects who reported more than 20 annual doctor visits had a nearly 4-fold greater risk of death than subjects who reported 1 to 2 visits (OR=3.87, P<0.001).

Similarly, subjects had an increased risk of mortality if they described their general health as being “poor” or “fair” (OR=1.98, P<0.001). And being “concerned” or “very concerned” about future health was associated with an increased risk of mortality as well (OR=1.54, P=0.01)

On the other hand, smoking did not have a significant impact on the risk of death, and alcohol consumption appeared to have a positive impact on life expectancy.

Subjects who reported consuming 5 or more drinks per month had a lower risk of mortality than subjects who said they did not consume alcohol at all (OR=0.75, P=0.05).

Dr Cox and her colleagues said this research has revealed novel predictors of mortality not associated with a cancer survivor’s primary disease, treatment, or late effects. And continued observation could point to interventions for reducing the risk of death in these patients.

Doctor examining patient

Logan Tuttle

Factors other than cancer treatment or chronic health conditions can influence the risk of death among survivors of childhood cancers, according to a study published in the Journal of Cancer Survivorship.

The researchers found an increased risk of death among cancer survivors who rarely exercised, were underweight, visited the doctor 5 or more times a year, considered themselves in “fair” or “poor” health, and had concerns about their future health.

Cheryl Cox, PhD, of the St Jude Children’s Research Hospital in Memphis, Tennessee, and her colleagues conducted this research using data from the Childhood Cancer Survivor Study.

The team compared 7162 childhood cancer survivors to 445 subjects who survived childhood cancer but ultimately died from causes other than cancer or non-health-related events (such as accidents).

The researchers matched subjects according to their primary diagnosis, age at the time of baseline questionnaire, and the time from diagnosis to baseline questionnaire.

Among the 445 subjects who died, the median age at death was 37.6 years. Malignant neoplasms (42%), cardiac conditions (20%), and pulmonary conditions (7%) caused the most deaths.

Subjects who died were slightly older than living subjects and more often of black race (vs white, Hispanic, or “other”). They were less likely to have a post-high school education or to be married. And they were more likely to have a household income below $20,000 or have an existing grade 3 or 4 chronic health condition.

When the researchers adjusted their analyses for sociodemographic characteristics, exposure to chemotherapy and/or radiation, and the number and severity of chronic health conditions, they identified a number of factors associated with an increased risk for all-cause mortality.

One of these factors was a lack of exercise—specifically, not exercising at all (odds ratio [OR]=1.72, P<0.001) or exercising 1 to 2 days a week (OR=1.65, P=0.004), compared to exercising 3 or more days a week.

On the other hand, being overweight or obese did not significantly increase a subject’s risk of death, but being underweight did (OR=2.58, P<0.001).

As one might expect, increased use of medical care was associated with an increased risk of mortality.

Subjects who reported 5 to 6 doctor visits per year had twice the risk of death as subjects who reported 1 to 2 visits (OR=2.07, P<0.001). And subjects who reported more than 20 annual doctor visits had a nearly 4-fold greater risk of death than subjects who reported 1 to 2 visits (OR=3.87, P<0.001).

Similarly, subjects had an increased risk of mortality if they described their general health as being “poor” or “fair” (OR=1.98, P<0.001). And being “concerned” or “very concerned” about future health was associated with an increased risk of mortality as well (OR=1.54, P=0.01)

On the other hand, smoking did not have a significant impact on the risk of death, and alcohol consumption appeared to have a positive impact on life expectancy.

Subjects who reported consuming 5 or more drinks per month had a lower risk of mortality than subjects who said they did not consume alcohol at all (OR=0.75, P=0.05).

Dr Cox and her colleagues said this research has revealed novel predictors of mortality not associated with a cancer survivor’s primary disease, treatment, or late effects. And continued observation could point to interventions for reducing the risk of death in these patients.

Doctor examining patient

Logan Tuttle

Factors other than cancer treatment or chronic health conditions can influence the risk of death among survivors of childhood cancers, according to a study published in the Journal of Cancer Survivorship.

The researchers found an increased risk of death among cancer survivors who rarely exercised, were underweight, visited the doctor 5 or more times a year, considered themselves in “fair” or “poor” health, and had concerns about their future health.

Cheryl Cox, PhD, of the St Jude Children’s Research Hospital in Memphis, Tennessee, and her colleagues conducted this research using data from the Childhood Cancer Survivor Study.

The team compared 7162 childhood cancer survivors to 445 subjects who survived childhood cancer but ultimately died from causes other than cancer or non-health-related events (such as accidents).

The researchers matched subjects according to their primary diagnosis, age at the time of baseline questionnaire, and the time from diagnosis to baseline questionnaire.

Among the 445 subjects who died, the median age at death was 37.6 years. Malignant neoplasms (42%), cardiac conditions (20%), and pulmonary conditions (7%) caused the most deaths.

Subjects who died were slightly older than living subjects and more often of black race (vs white, Hispanic, or “other”). They were less likely to have a post-high school education or to be married. And they were more likely to have a household income below $20,000 or have an existing grade 3 or 4 chronic health condition.

When the researchers adjusted their analyses for sociodemographic characteristics, exposure to chemotherapy and/or radiation, and the number and severity of chronic health conditions, they identified a number of factors associated with an increased risk for all-cause mortality.

One of these factors was a lack of exercise—specifically, not exercising at all (odds ratio [OR]=1.72, P<0.001) or exercising 1 to 2 days a week (OR=1.65, P=0.004), compared to exercising 3 or more days a week.

On the other hand, being overweight or obese did not significantly increase a subject’s risk of death, but being underweight did (OR=2.58, P<0.001).

As one might expect, increased use of medical care was associated with an increased risk of mortality.

Subjects who reported 5 to 6 doctor visits per year had twice the risk of death as subjects who reported 1 to 2 visits (OR=2.07, P<0.001). And subjects who reported more than 20 annual doctor visits had a nearly 4-fold greater risk of death than subjects who reported 1 to 2 visits (OR=3.87, P<0.001).

Similarly, subjects had an increased risk of mortality if they described their general health as being “poor” or “fair” (OR=1.98, P<0.001). And being “concerned” or “very concerned” about future health was associated with an increased risk of mortality as well (OR=1.54, P=0.01)

On the other hand, smoking did not have a significant impact on the risk of death, and alcohol consumption appeared to have a positive impact on life expectancy.

Subjects who reported consuming 5 or more drinks per month had a lower risk of mortality than subjects who said they did not consume alcohol at all (OR=0.75, P=0.05).

Dr Cox and her colleagues said this research has revealed novel predictors of mortality not associated with a cancer survivor’s primary disease, treatment, or late effects. And continued observation could point to interventions for reducing the risk of death in these patients.

SAN DIEGO—Results of a pilot study suggest an experimental molecule can increase hemoglobin levels in patients with hematologic malignancies who are suffering from anemia.

The molecule, lexaptepid pegol (NOX-H94), is a pegylated L-stereoisomer RNA aptamer that binds and neutralizes hepcidin.

In this phase 2 study, 5 of 12 patients who received lexaptepid pegol experienced a hemoglobin increase of 1 g/dL or greater and qualified as responders.

Researchers presented these results at the AACR Annual Meeting 2014 as abstract 3847. The study was supported by NOXXON Pharma AG, the Berlin, Germany-based company developing lexaptepid pegol.

“Our concept is to treat anemia by inhibiting the activity of hepcidin,” said study investigator Kai Riecke, MD, of NOXXON Pharma.

“Hepcidin regulates iron in the blood. The problem is that, in quite a few tumors, hepcidin reduces iron in the circulation, and, over a long period of time, that leads to iron-restricted anemia.”

So Dr Riecke and his colleagues tested their antihepcidin molecule, lexaptepid pegol, in anemic cancer patients. The team enrolled patients with hemoglobin levels less than 10 g/dL who had been diagnosed with multiple myeloma, chronic lymphocytic leukemia, Hodgkin lymphoma, or non-Hodgkin lymphoma.

The patients had a median age of 64 years (range, 35-77). At baseline, the mean hemoglobin was 9.5 ± 0.2 g/dL, the mean serum ferritin was 1067 ± 297 μg/L, the mean serum iron was 34 ± 6 μg/dL, and the mean transferrin saturation was 16.7 ± 3.4%.

The patients received twice-weekly intravenous infusions of lexaptepid pegol for 4 weeks, and the researchers observed patients for 1 month after treatment. Patients were not allowed to receive erythropoiesis-stimulating agents or iron products during the study period.

The results showed increases in hemoglobin of 1 g/dL or greater, which qualified as a response, in 5 of the 12 patients (42%). Three patients achieved a response within 2 weeks of treatment initiation. All 5 patients maintained the increase in hemoglobin throughout the follow-up period.

There was no clear difference in response among the different malignancies, Dr Reike said. But he also noted that, as the study included a small number of patients, it wasn’t really possible for the researchers to make a fair comparison.

In addition to increasing hemoglobin levels, lexaptepid pegol decreased the mean serum ferritin from 1067 μg/L to 815 μg/L in the entire cohort of patients (P=0.014) and from 772 μg/L to 462 μg/L in responders (but this was not significant).

Reticulocyte hemoglobin increased from 22.7 pg to 24.9 pg (P=0.019) in responding patients, but there was no increase in non-responders. (Data for this measurement were only available for 3 of the responders—but all 7 of the non-responders—due to differences in measurement capabilities at the different research sites).

“During the treatment, we saw a very nice increase in reticulocyte hemoglobin, which shows, in these patients, the red blood cells were able to take up iron and build up more hemoglobin,” Dr Riecke said.

The researchers also observed an increase in the mean reticulocyte index in responding patients, from 0.9 to 1.2, although the increase was not significant.

“So this shows that, not only do you have an increase in hemoglobin within each reticulocyte, but you have an increase in the number of reticulocytes—something that we didn’t really expect in the beginning,” Dr Riecke said. “And this may be a sign that the efficacy of erythropoiesis is improved.”

Additionally, responding patients experienced a decrease in soluble transferrin receptor levels, from 10.0 mg/L to 8.6 mg/L, although this was not significant. Soluble transferrin receptor levels remained unchanged in non-responders. (Data for this measurement were only available for 3 of the responders and 4 of the non-responders.)

“The decrease in soluble transferrin receptor levels is a sign that, in the beginning, the cells were very iron-hungry, and then their hunger was satisfied—at least to a certain extent—during the treatment with our drug,” Dr Reike said. “This is a sign that, by reducing hepcidin, more iron is being released into the circulation, and this iron can effectively be used for erythropoiesis.”

Dr Reike added that, although the researchers did observe some adverse effects in the patients, none of these could be clearly attributed to lexaptepid pegol.

Some of the patients did have low blood pressure shortly after treatment, but that may have been influenced by factors other than treatment, he said. Furthermore, in the phase 1 study of lexaptepid pegol in healthy subjects, the only adverse effect that occurred in the treatment arm (and not in the placebo arm) was headache.

Based on these results, NOXXON is now planning—and recruiting for—a study of lexaptepid pegol in dialysis patients.

SAN DIEGO—Results of a pilot study suggest an experimental molecule can increase hemoglobin levels in patients with hematologic malignancies who are suffering from anemia.

The molecule, lexaptepid pegol (NOX-H94), is a pegylated L-stereoisomer RNA aptamer that binds and neutralizes hepcidin.

In this phase 2 study, 5 of 12 patients who received lexaptepid pegol experienced a hemoglobin increase of 1 g/dL or greater and qualified as responders.

Researchers presented these results at the AACR Annual Meeting 2014 as abstract 3847. The study was supported by NOXXON Pharma AG, the Berlin, Germany-based company developing lexaptepid pegol.

“Our concept is to treat anemia by inhibiting the activity of hepcidin,” said study investigator Kai Riecke, MD, of NOXXON Pharma.

“Hepcidin regulates iron in the blood. The problem is that, in quite a few tumors, hepcidin reduces iron in the circulation, and, over a long period of time, that leads to iron-restricted anemia.”

So Dr Riecke and his colleagues tested their antihepcidin molecule, lexaptepid pegol, in anemic cancer patients. The team enrolled patients with hemoglobin levels less than 10 g/dL who had been diagnosed with multiple myeloma, chronic lymphocytic leukemia, Hodgkin lymphoma, or non-Hodgkin lymphoma.

The patients had a median age of 64 years (range, 35-77). At baseline, the mean hemoglobin was 9.5 ± 0.2 g/dL, the mean serum ferritin was 1067 ± 297 μg/L, the mean serum iron was 34 ± 6 μg/dL, and the mean transferrin saturation was 16.7 ± 3.4%.

The patients received twice-weekly intravenous infusions of lexaptepid pegol for 4 weeks, and the researchers observed patients for 1 month after treatment. Patients were not allowed to receive erythropoiesis-stimulating agents or iron products during the study period.

The results showed increases in hemoglobin of 1 g/dL or greater, which qualified as a response, in 5 of the 12 patients (42%). Three patients achieved a response within 2 weeks of treatment initiation. All 5 patients maintained the increase in hemoglobin throughout the follow-up period.

There was no clear difference in response among the different malignancies, Dr Reike said. But he also noted that, as the study included a small number of patients, it wasn’t really possible for the researchers to make a fair comparison.

In addition to increasing hemoglobin levels, lexaptepid pegol decreased the mean serum ferritin from 1067 μg/L to 815 μg/L in the entire cohort of patients (P=0.014) and from 772 μg/L to 462 μg/L in responders (but this was not significant).

Reticulocyte hemoglobin increased from 22.7 pg to 24.9 pg (P=0.019) in responding patients, but there was no increase in non-responders. (Data for this measurement were only available for 3 of the responders—but all 7 of the non-responders—due to differences in measurement capabilities at the different research sites).

“During the treatment, we saw a very nice increase in reticulocyte hemoglobin, which shows, in these patients, the red blood cells were able to take up iron and build up more hemoglobin,” Dr Riecke said.

The researchers also observed an increase in the mean reticulocyte index in responding patients, from 0.9 to 1.2, although the increase was not significant.

“So this shows that, not only do you have an increase in hemoglobin within each reticulocyte, but you have an increase in the number of reticulocytes—something that we didn’t really expect in the beginning,” Dr Riecke said. “And this may be a sign that the efficacy of erythropoiesis is improved.”

Additionally, responding patients experienced a decrease in soluble transferrin receptor levels, from 10.0 mg/L to 8.6 mg/L, although this was not significant. Soluble transferrin receptor levels remained unchanged in non-responders. (Data for this measurement were only available for 3 of the responders and 4 of the non-responders.)

“The decrease in soluble transferrin receptor levels is a sign that, in the beginning, the cells were very iron-hungry, and then their hunger was satisfied—at least to a certain extent—during the treatment with our drug,” Dr Reike said. “This is a sign that, by reducing hepcidin, more iron is being released into the circulation, and this iron can effectively be used for erythropoiesis.”

Dr Reike added that, although the researchers did observe some adverse effects in the patients, none of these could be clearly attributed to lexaptepid pegol.

Some of the patients did have low blood pressure shortly after treatment, but that may have been influenced by factors other than treatment, he said. Furthermore, in the phase 1 study of lexaptepid pegol in healthy subjects, the only adverse effect that occurred in the treatment arm (and not in the placebo arm) was headache.

Based on these results, NOXXON is now planning—and recruiting for—a study of lexaptepid pegol in dialysis patients.

SAN DIEGO—Results of a pilot study suggest an experimental molecule can increase hemoglobin levels in patients with hematologic malignancies who are suffering from anemia.

The molecule, lexaptepid pegol (NOX-H94), is a pegylated L-stereoisomer RNA aptamer that binds and neutralizes hepcidin.

In this phase 2 study, 5 of 12 patients who received lexaptepid pegol experienced a hemoglobin increase of 1 g/dL or greater and qualified as responders.

Researchers presented these results at the AACR Annual Meeting 2014 as abstract 3847. The study was supported by NOXXON Pharma AG, the Berlin, Germany-based company developing lexaptepid pegol.

“Our concept is to treat anemia by inhibiting the activity of hepcidin,” said study investigator Kai Riecke, MD, of NOXXON Pharma.

“Hepcidin regulates iron in the blood. The problem is that, in quite a few tumors, hepcidin reduces iron in the circulation, and, over a long period of time, that leads to iron-restricted anemia.”

So Dr Riecke and his colleagues tested their antihepcidin molecule, lexaptepid pegol, in anemic cancer patients. The team enrolled patients with hemoglobin levels less than 10 g/dL who had been diagnosed with multiple myeloma, chronic lymphocytic leukemia, Hodgkin lymphoma, or non-Hodgkin lymphoma.

The patients had a median age of 64 years (range, 35-77). At baseline, the mean hemoglobin was 9.5 ± 0.2 g/dL, the mean serum ferritin was 1067 ± 297 μg/L, the mean serum iron was 34 ± 6 μg/dL, and the mean transferrin saturation was 16.7 ± 3.4%.

The patients received twice-weekly intravenous infusions of lexaptepid pegol for 4 weeks, and the researchers observed patients for 1 month after treatment. Patients were not allowed to receive erythropoiesis-stimulating agents or iron products during the study period.

The results showed increases in hemoglobin of 1 g/dL or greater, which qualified as a response, in 5 of the 12 patients (42%). Three patients achieved a response within 2 weeks of treatment initiation. All 5 patients maintained the increase in hemoglobin throughout the follow-up period.

There was no clear difference in response among the different malignancies, Dr Reike said. But he also noted that, as the study included a small number of patients, it wasn’t really possible for the researchers to make a fair comparison.

In addition to increasing hemoglobin levels, lexaptepid pegol decreased the mean serum ferritin from 1067 μg/L to 815 μg/L in the entire cohort of patients (P=0.014) and from 772 μg/L to 462 μg/L in responders (but this was not significant).

Reticulocyte hemoglobin increased from 22.7 pg to 24.9 pg (P=0.019) in responding patients, but there was no increase in non-responders. (Data for this measurement were only available for 3 of the responders—but all 7 of the non-responders—due to differences in measurement capabilities at the different research sites).

“During the treatment, we saw a very nice increase in reticulocyte hemoglobin, which shows, in these patients, the red blood cells were able to take up iron and build up more hemoglobin,” Dr Riecke said.

The researchers also observed an increase in the mean reticulocyte index in responding patients, from 0.9 to 1.2, although the increase was not significant.

“So this shows that, not only do you have an increase in hemoglobin within each reticulocyte, but you have an increase in the number of reticulocytes—something that we didn’t really expect in the beginning,” Dr Riecke said. “And this may be a sign that the efficacy of erythropoiesis is improved.”

Additionally, responding patients experienced a decrease in soluble transferrin receptor levels, from 10.0 mg/L to 8.6 mg/L, although this was not significant. Soluble transferrin receptor levels remained unchanged in non-responders. (Data for this measurement were only available for 3 of the responders and 4 of the non-responders.)

“The decrease in soluble transferrin receptor levels is a sign that, in the beginning, the cells were very iron-hungry, and then their hunger was satisfied—at least to a certain extent—during the treatment with our drug,” Dr Reike said. “This is a sign that, by reducing hepcidin, more iron is being released into the circulation, and this iron can effectively be used for erythropoiesis.”

Dr Reike added that, although the researchers did observe some adverse effects in the patients, none of these could be clearly attributed to lexaptepid pegol.

Some of the patients did have low blood pressure shortly after treatment, but that may have been influenced by factors other than treatment, he said. Furthermore, in the phase 1 study of lexaptepid pegol in healthy subjects, the only adverse effect that occurred in the treatment arm (and not in the placebo arm) was headache.

Based on these results, NOXXON is now planning—and recruiting for—a study of lexaptepid pegol in dialysis patients.

SAN DIEGO—Preclinical research suggests that combining a BET inhibitor with lenalidomide may overcome resistance to bortezomib in mantle cell lymphoma (MCL).

Experiments in MCL cell lines and mouse models of the disease showed that lenalidomide alone is active in bortezomib-resistant cells and tumors.

But the anticancer effects are more pronounced with the addition of the BET inhibitor CPI203.

“So we think that this new combination based on BET inhibition and lenalidomide may be helpful for the design of new therapies in the subset of MCL patients resistant to bortezomib,” said study investigator Gael Roue, PhD, of IDIBAPS in Barcelona, Spain.

Dr Roue and his colleagues presented this research in a poster at the AACR Annual Meeting 2014 (abstract 1691*). The team included researchers from Constellation Pharmaceuticals, the company developing CPI203.

With this research, the investigators wanted to assess the possibility of targeting IRF4 and MYC signaling and overcoming bortezomib resistance with lenalidomide-based therapies.

To that end, they tested lenalidomide in 9 MCL cell lines. They found the drug’s antitumor activity is mediated by inhibition of the plasmacytic differentiation program in bortezomib-resistant MCL.

The team then evaluated the effects of lenalidomide on REC-1 cells injected into SCID mice. And they found that lenalidomide significantly reduced tumor growth compared to vehicle control (P=0.04).

The researchers next injected mice with REC-1 cells and treated them with 50 mg/kg of lenalidomide, 0.15 mg/kg of bortezomib, both agents, or vehicle control. The mice received lenalidomide 5 days a week and bortezomib twice a week for up to 18 days.

Lenalidomide alone significantly reduced tumor volume when compared to control (P=0.04). The same was true of the combination treatment compared to control (P=0.02).

The investigators also noted a 25% increase in MYC expression in cells and tumors that were resistant to bortezomib. So they speculated that inhibiting MYC could increase lenalidomide activity.

“This was the rationale for combining lenalidomide with a BET inhibitor,” Dr Roue said. “BET inhibitors are known to inhibit MYC transcription, to inhibit MYC signaling, in multiple myeloma and lymphoma cells.”

The researchers first evaluated the effects of CPI203 alone. They cultured 9 MCL cell lines and peripheral blood mononuclear cells from 2 healthy donors with increasing concentrations of CPI203 and assessed cytotoxicity, MYC levels, and cell viability.

They found that CPI203 was active in all the cell lines tested, but it didn’t affect the proliferation or viability of the healthy cells. And CPI203 activity was linked to the downregulation of MYC.

The team then tested CPI203 in combination with lenalidomide. They treated REC-1 cells for 72 hours with 0.1 μM to 0.5 μM of CPI203 and/or 1 μM to 5 μM of lenalidomide.

“[W]e observed synergistic activity in vitro, linked to a complete disappearance of MYC and also of IRF4,” Dr Roue said.

Finally, the investigators tested the 2 agents in mice with bortezomib-resistant MCL. The mice were injected with REC-1 cells and randomized to treatment with lenalidomide at 50 mg/kg/day, CPI203 at 2.5 mg/kg BID, both agents, or vehicle control.

“We found that by treating mice with [both agents] for 3 weeks, we reached 80% tumor remission, which was linked to inhibition of mitosis, complete disappearance of MYC and IRF4 protein levels, and induction of apoptosis in about 30% to 40% of the tumors.”

The researchers said these results suggest the lenalidomide-BET inhibitor combination warrants investigation in MCL patients who are refractory to bortezomib.

*Information in the abstract differs from that presented at the meeting.

SAN DIEGO—Preclinical research suggests that combining a BET inhibitor with lenalidomide may overcome resistance to bortezomib in mantle cell lymphoma (MCL).

Experiments in MCL cell lines and mouse models of the disease showed that lenalidomide alone is active in bortezomib-resistant cells and tumors.

But the anticancer effects are more pronounced with the addition of the BET inhibitor CPI203.

“So we think that this new combination based on BET inhibition and lenalidomide may be helpful for the design of new therapies in the subset of MCL patients resistant to bortezomib,” said study investigator Gael Roue, PhD, of IDIBAPS in Barcelona, Spain.

Dr Roue and his colleagues presented this research in a poster at the AACR Annual Meeting 2014 (abstract 1691*). The team included researchers from Constellation Pharmaceuticals, the company developing CPI203.

With this research, the investigators wanted to assess the possibility of targeting IRF4 and MYC signaling and overcoming bortezomib resistance with lenalidomide-based therapies.

To that end, they tested lenalidomide in 9 MCL cell lines. They found the drug’s antitumor activity is mediated by inhibition of the plasmacytic differentiation program in bortezomib-resistant MCL.

The team then evaluated the effects of lenalidomide on REC-1 cells injected into SCID mice. And they found that lenalidomide significantly reduced tumor growth compared to vehicle control (P=0.04).

The researchers next injected mice with REC-1 cells and treated them with 50 mg/kg of lenalidomide, 0.15 mg/kg of bortezomib, both agents, or vehicle control. The mice received lenalidomide 5 days a week and bortezomib twice a week for up to 18 days.

Lenalidomide alone significantly reduced tumor volume when compared to control (P=0.04). The same was true of the combination treatment compared to control (P=0.02).

The investigators also noted a 25% increase in MYC expression in cells and tumors that were resistant to bortezomib. So they speculated that inhibiting MYC could increase lenalidomide activity.

“This was the rationale for combining lenalidomide with a BET inhibitor,” Dr Roue said. “BET inhibitors are known to inhibit MYC transcription, to inhibit MYC signaling, in multiple myeloma and lymphoma cells.”

The researchers first evaluated the effects of CPI203 alone. They cultured 9 MCL cell lines and peripheral blood mononuclear cells from 2 healthy donors with increasing concentrations of CPI203 and assessed cytotoxicity, MYC levels, and cell viability.

They found that CPI203 was active in all the cell lines tested, but it didn’t affect the proliferation or viability of the healthy cells. And CPI203 activity was linked to the downregulation of MYC.

The team then tested CPI203 in combination with lenalidomide. They treated REC-1 cells for 72 hours with 0.1 μM to 0.5 μM of CPI203 and/or 1 μM to 5 μM of lenalidomide.

“[W]e observed synergistic activity in vitro, linked to a complete disappearance of MYC and also of IRF4,” Dr Roue said.

Finally, the investigators tested the 2 agents in mice with bortezomib-resistant MCL. The mice were injected with REC-1 cells and randomized to treatment with lenalidomide at 50 mg/kg/day, CPI203 at 2.5 mg/kg BID, both agents, or vehicle control.

“We found that by treating mice with [both agents] for 3 weeks, we reached 80% tumor remission, which was linked to inhibition of mitosis, complete disappearance of MYC and IRF4 protein levels, and induction of apoptosis in about 30% to 40% of the tumors.”

The researchers said these results suggest the lenalidomide-BET inhibitor combination warrants investigation in MCL patients who are refractory to bortezomib.

*Information in the abstract differs from that presented at the meeting.

SAN DIEGO—Preclinical research suggests that combining a BET inhibitor with lenalidomide may overcome resistance to bortezomib in mantle cell lymphoma (MCL).

Experiments in MCL cell lines and mouse models of the disease showed that lenalidomide alone is active in bortezomib-resistant cells and tumors.

But the anticancer effects are more pronounced with the addition of the BET inhibitor CPI203.

“So we think that this new combination based on BET inhibition and lenalidomide may be helpful for the design of new therapies in the subset of MCL patients resistant to bortezomib,” said study investigator Gael Roue, PhD, of IDIBAPS in Barcelona, Spain.

Dr Roue and his colleagues presented this research in a poster at the AACR Annual Meeting 2014 (abstract 1691*). The team included researchers from Constellation Pharmaceuticals, the company developing CPI203.

With this research, the investigators wanted to assess the possibility of targeting IRF4 and MYC signaling and overcoming bortezomib resistance with lenalidomide-based therapies.

To that end, they tested lenalidomide in 9 MCL cell lines. They found the drug’s antitumor activity is mediated by inhibition of the plasmacytic differentiation program in bortezomib-resistant MCL.

The team then evaluated the effects of lenalidomide on REC-1 cells injected into SCID mice. And they found that lenalidomide significantly reduced tumor growth compared to vehicle control (P=0.04).

The researchers next injected mice with REC-1 cells and treated them with 50 mg/kg of lenalidomide, 0.15 mg/kg of bortezomib, both agents, or vehicle control. The mice received lenalidomide 5 days a week and bortezomib twice a week for up to 18 days.

Lenalidomide alone significantly reduced tumor volume when compared to control (P=0.04). The same was true of the combination treatment compared to control (P=0.02).

The investigators also noted a 25% increase in MYC expression in cells and tumors that were resistant to bortezomib. So they speculated that inhibiting MYC could increase lenalidomide activity.

“This was the rationale for combining lenalidomide with a BET inhibitor,” Dr Roue said. “BET inhibitors are known to inhibit MYC transcription, to inhibit MYC signaling, in multiple myeloma and lymphoma cells.”

The researchers first evaluated the effects of CPI203 alone. They cultured 9 MCL cell lines and peripheral blood mononuclear cells from 2 healthy donors with increasing concentrations of CPI203 and assessed cytotoxicity, MYC levels, and cell viability.

They found that CPI203 was active in all the cell lines tested, but it didn’t affect the proliferation or viability of the healthy cells. And CPI203 activity was linked to the downregulation of MYC.

The team then tested CPI203 in combination with lenalidomide. They treated REC-1 cells for 72 hours with 0.1 μM to 0.5 μM of CPI203 and/or 1 μM to 5 μM of lenalidomide.

“[W]e observed synergistic activity in vitro, linked to a complete disappearance of MYC and also of IRF4,” Dr Roue said.

Finally, the investigators tested the 2 agents in mice with bortezomib-resistant MCL. The mice were injected with REC-1 cells and randomized to treatment with lenalidomide at 50 mg/kg/day, CPI203 at 2.5 mg/kg BID, both agents, or vehicle control.

“We found that by treating mice with [both agents] for 3 weeks, we reached 80% tumor remission, which was linked to inhibition of mitosis, complete disappearance of MYC and IRF4 protein levels, and induction of apoptosis in about 30% to 40% of the tumors.”

The researchers said these results suggest the lenalidomide-BET inhibitor combination warrants investigation in MCL patients who are refractory to bortezomib.

*Information in the abstract differs from that presented at the meeting.

An NK cell in action

Credit: Bjorn Onfelt/Dan Davis

New research provides additional insight into how natural killer (NK) cells eliminate abnormal hematopoietic cells.

The investigators evaluated 2 molecules that are known to play important roles in this process.

Ewing’s sarcoma-associated transcript 2 (EAT-2) and signaling lymphocytic activation molecule (SLAM)–associated protein (SAP) are expressed in NK cells, and their combined expression is essential for NK cells to kill abnormal hematopoietic cells.

“We knew that EAT-2 cooperates with SAP, and, with this research project, we wanted to better understand why they are both required for the proper functioning of NK cells,” said study author André Veillette, PhD, of the Institut de Recherches Cliniques de Montréal (IRCM) in Canada.

Dr Veillette and his colleagues described this research in the Journal of Experimental Medicine.

“We identified the molecular chain of events that occur and showed that EAT-2 and SAP perform different functions using distinct mechanisms,” Dr Veillette said. “These findings explain the cooperative and essential function of these 2 molecules in activating NK cells, thereby allowing them to kill abnormal blood cells.”

The investigators noted that SAP couples SLAM family receptors to the protein tyrosine kinase Fyn and the exchange factor Vav, thereby promoting conjugate formation between NK cells and target hematopoietic cells.

EAT-2, on the other hand, works by accelerating the polarization and exocytosis of cytotoxic granules toward hematopoietic cells.

EAT-2 mediates its effects in NK cells by linking SLAM family receptors to phospholipase Cγ, calcium fluxes, and Erk kinase. These signals are triggered by 1 or 2 tyrosines that are located in the carboxyl-terminal tail of EAT-2.

Dr Veillete pointed out that, although EAT-2 and SAP behave differently, both are linked to receptors of the SLAM family on the cell surface.

“Because they can make better drug targets, our future work will focus on these receptors,” he said, “which could eventually lead to identifying new potential treatment avenues for blood cancers such as leukemia and lymphoma.”

An NK cell in action

Credit: Bjorn Onfelt/Dan Davis

New research provides additional insight into how natural killer (NK) cells eliminate abnormal hematopoietic cells.

The investigators evaluated 2 molecules that are known to play important roles in this process.

Ewing’s sarcoma-associated transcript 2 (EAT-2) and signaling lymphocytic activation molecule (SLAM)–associated protein (SAP) are expressed in NK cells, and their combined expression is essential for NK cells to kill abnormal hematopoietic cells.

“We knew that EAT-2 cooperates with SAP, and, with this research project, we wanted to better understand why they are both required for the proper functioning of NK cells,” said study author André Veillette, PhD, of the Institut de Recherches Cliniques de Montréal (IRCM) in Canada.

Dr Veillette and his colleagues described this research in the Journal of Experimental Medicine.

“We identified the molecular chain of events that occur and showed that EAT-2 and SAP perform different functions using distinct mechanisms,” Dr Veillette said. “These findings explain the cooperative and essential function of these 2 molecules in activating NK cells, thereby allowing them to kill abnormal blood cells.”

The investigators noted that SAP couples SLAM family receptors to the protein tyrosine kinase Fyn and the exchange factor Vav, thereby promoting conjugate formation between NK cells and target hematopoietic cells.

EAT-2, on the other hand, works by accelerating the polarization and exocytosis of cytotoxic granules toward hematopoietic cells.

EAT-2 mediates its effects in NK cells by linking SLAM family receptors to phospholipase Cγ, calcium fluxes, and Erk kinase. These signals are triggered by 1 or 2 tyrosines that are located in the carboxyl-terminal tail of EAT-2.

Dr Veillete pointed out that, although EAT-2 and SAP behave differently, both are linked to receptors of the SLAM family on the cell surface.

“Because they can make better drug targets, our future work will focus on these receptors,” he said, “which could eventually lead to identifying new potential treatment avenues for blood cancers such as leukemia and lymphoma.”

An NK cell in action

Credit: Bjorn Onfelt/Dan Davis

New research provides additional insight into how natural killer (NK) cells eliminate abnormal hematopoietic cells.

The investigators evaluated 2 molecules that are known to play important roles in this process.

Ewing’s sarcoma-associated transcript 2 (EAT-2) and signaling lymphocytic activation molecule (SLAM)–associated protein (SAP) are expressed in NK cells, and their combined expression is essential for NK cells to kill abnormal hematopoietic cells.

“We knew that EAT-2 cooperates with SAP, and, with this research project, we wanted to better understand why they are both required for the proper functioning of NK cells,” said study author André Veillette, PhD, of the Institut de Recherches Cliniques de Montréal (IRCM) in Canada.

Dr Veillette and his colleagues described this research in the Journal of Experimental Medicine.

“We identified the molecular chain of events that occur and showed that EAT-2 and SAP perform different functions using distinct mechanisms,” Dr Veillette said. “These findings explain the cooperative and essential function of these 2 molecules in activating NK cells, thereby allowing them to kill abnormal blood cells.”

The investigators noted that SAP couples SLAM family receptors to the protein tyrosine kinase Fyn and the exchange factor Vav, thereby promoting conjugate formation between NK cells and target hematopoietic cells.

EAT-2, on the other hand, works by accelerating the polarization and exocytosis of cytotoxic granules toward hematopoietic cells.

EAT-2 mediates its effects in NK cells by linking SLAM family receptors to phospholipase Cγ, calcium fluxes, and Erk kinase. These signals are triggered by 1 or 2 tyrosines that are located in the carboxyl-terminal tail of EAT-2.

Dr Veillete pointed out that, although EAT-2 and SAP behave differently, both are linked to receptors of the SLAM family on the cell surface.

“Because they can make better drug targets, our future work will focus on these receptors,” he said, “which could eventually lead to identifying new potential treatment avenues for blood cancers such as leukemia and lymphoma.”

AACR Annual Meeting 2014

SAN DIEGO—The use of hormone therapy may lower the risk of B-cell non-Hodgkin lymphoma (NHL) in menopausal women, according to a presentation at the AACR Annual Meeting 2014.

Researchers found that menopausal women who used hormone therapy were about 30% less likely than their untreated peers to develop NHL.

And the risk of NHL decreased further if a woman began receiving hormone therapy at a younger age and used it for a longer period of time.

Sophia Wang, PhD, of City of Hope National Medical Center in Duarte, California, presented these findings at the meeting as abstract 2918.

“The connection between lymphomas and menopausal hormone therapy use hinges on understanding the disease’s biology and the window of susceptibility,” Dr Wang said. “Hormone therapy is of interest because the loss of estrogen coupled with aging in women result in decreased immune function, which can elevate the risk of non-Hodgkin lymphoma.”

For this study, Dr Wang and her colleagues examined data from the Los Angeles Cancer Surveillance Program. They compared 685 postmenopausal women diagnosed with B-cell NHL to 685 postmenopausal women without lymphoma.

The researchers assessed the women’s use of menopausal hormone therapy, which included estrogen alone or estrogen with progestin in pill, patch, topical cream, or injected forms.

After controlling for factors such as age, race, and socioeconomic status, Dr Wang and her colleagues found that women who reported using any form of menopausal hormone therapy were approximately 30% less likely to be diagnosed with B-cell NHL, compared to women who reported never using hormone therapy.

An additional analysis showed that the risk reduction was even greater for women who initiated menopausal hormone therapy at 45 years of age or younger and used it for at least 5 years.

This group was approximately 40% less likely to be diagnosed with B-cell NHL compared to those who had never used hormone therapy.

Dr Wang said further research is needed to determine the exact biological mechanisms that might be linked to a lower NHL risk. These mechanisms could include supporting a healthy immune system or reducing inflammation.

She also cautioned that these findings are preliminary and should not change current recommendations and guidelines for menopausal hormone therapy use.

Due to well-established evidence tying menopausal hormone therapy to elevated risks of breast and endometrial cancers, the American Cancer Society recommends that women considering or using this therapy do so at the lowest effective dose for the shortest amount of time needed and that they discuss with their physicians other treatments to alleviate menopausal symptoms.

AACR Annual Meeting 2014

SAN DIEGO—The use of hormone therapy may lower the risk of B-cell non-Hodgkin lymphoma (NHL) in menopausal women, according to a presentation at the AACR Annual Meeting 2014.

Researchers found that menopausal women who used hormone therapy were about 30% less likely than their untreated peers to develop NHL.

And the risk of NHL decreased further if a woman began receiving hormone therapy at a younger age and used it for a longer period of time.

Sophia Wang, PhD, of City of Hope National Medical Center in Duarte, California, presented these findings at the meeting as abstract 2918.

“The connection between lymphomas and menopausal hormone therapy use hinges on understanding the disease’s biology and the window of susceptibility,” Dr Wang said. “Hormone therapy is of interest because the loss of estrogen coupled with aging in women result in decreased immune function, which can elevate the risk of non-Hodgkin lymphoma.”

For this study, Dr Wang and her colleagues examined data from the Los Angeles Cancer Surveillance Program. They compared 685 postmenopausal women diagnosed with B-cell NHL to 685 postmenopausal women without lymphoma.

The researchers assessed the women’s use of menopausal hormone therapy, which included estrogen alone or estrogen with progestin in pill, patch, topical cream, or injected forms.

After controlling for factors such as age, race, and socioeconomic status, Dr Wang and her colleagues found that women who reported using any form of menopausal hormone therapy were approximately 30% less likely to be diagnosed with B-cell NHL, compared to women who reported never using hormone therapy.

An additional analysis showed that the risk reduction was even greater for women who initiated menopausal hormone therapy at 45 years of age or younger and used it for at least 5 years.

This group was approximately 40% less likely to be diagnosed with B-cell NHL compared to those who had never used hormone therapy.

Dr Wang said further research is needed to determine the exact biological mechanisms that might be linked to a lower NHL risk. These mechanisms could include supporting a healthy immune system or reducing inflammation.

She also cautioned that these findings are preliminary and should not change current recommendations and guidelines for menopausal hormone therapy use.

Due to well-established evidence tying menopausal hormone therapy to elevated risks of breast and endometrial cancers, the American Cancer Society recommends that women considering or using this therapy do so at the lowest effective dose for the shortest amount of time needed and that they discuss with their physicians other treatments to alleviate menopausal symptoms.

AACR Annual Meeting 2014

SAN DIEGO—The use of hormone therapy may lower the risk of B-cell non-Hodgkin lymphoma (NHL) in menopausal women, according to a presentation at the AACR Annual Meeting 2014.

Researchers found that menopausal women who used hormone therapy were about 30% less likely than their untreated peers to develop NHL.

And the risk of NHL decreased further if a woman began receiving hormone therapy at a younger age and used it for a longer period of time.

Sophia Wang, PhD, of City of Hope National Medical Center in Duarte, California, presented these findings at the meeting as abstract 2918.

“The connection between lymphomas and menopausal hormone therapy use hinges on understanding the disease’s biology and the window of susceptibility,” Dr Wang said. “Hormone therapy is of interest because the loss of estrogen coupled with aging in women result in decreased immune function, which can elevate the risk of non-Hodgkin lymphoma.”

For this study, Dr Wang and her colleagues examined data from the Los Angeles Cancer Surveillance Program. They compared 685 postmenopausal women diagnosed with B-cell NHL to 685 postmenopausal women without lymphoma.

The researchers assessed the women’s use of menopausal hormone therapy, which included estrogen alone or estrogen with progestin in pill, patch, topical cream, or injected forms.

After controlling for factors such as age, race, and socioeconomic status, Dr Wang and her colleagues found that women who reported using any form of menopausal hormone therapy were approximately 30% less likely to be diagnosed with B-cell NHL, compared to women who reported never using hormone therapy.

An additional analysis showed that the risk reduction was even greater for women who initiated menopausal hormone therapy at 45 years of age or younger and used it for at least 5 years.

This group was approximately 40% less likely to be diagnosed with B-cell NHL compared to those who had never used hormone therapy.

Dr Wang said further research is needed to determine the exact biological mechanisms that might be linked to a lower NHL risk. These mechanisms could include supporting a healthy immune system or reducing inflammation.

She also cautioned that these findings are preliminary and should not change current recommendations and guidelines for menopausal hormone therapy use.

Due to well-established evidence tying menopausal hormone therapy to elevated risks of breast and endometrial cancers, the American Cancer Society recommends that women considering or using this therapy do so at the lowest effective dose for the shortest amount of time needed and that they discuss with their physicians other treatments to alleviate menopausal symptoms.

BALB/c mice

Credit: Aaron Logan

SAN DIEGO—Researchers have found evidence to suggest there may be little difference between an immune response that kills cancer cells and one that stimulates tumor growth.

The team set out to determine whether the immune responses that mediate cancer immunosurveillance and those responsible for inflammatory facilitation are qualitatively or quantitatively distinct.

They tested antibodies in mouse models of a few different cancers, including rituximab in Burkitt lymphoma.

And they found that lower antibody concentrations stimulated tumor growth, while higher concentrations inhibited growth, and the dose range was “surprisingly narrow.”

The researchers reported these findings in a paper published in PNAS and a poster presentation at the AACR Annual Meeting 2014 (abstract 1063).

“We have found that the intensity difference between an immune response that stimulates cancer and one that kills it may not be very much,” said principal investigator Ajit Varki, MD, of the University of California, San Diego School of Medicine.

“This may come as a surprise to researchers exploring two areas typically considered distinct: the role of the immune system in preventing and killing cancers and the role of chronic inflammation in stimulating cancers. As always, it turns out that the immune system is a double-edged sword.”

The concept of naturally occurring immunosurveillance against malignancies is not new, and there is compelling evidence for it. But understanding this process is confounded by the fact that some types of immune reaction promote tumor development.

Dr Varki and his colleagues looked specifically at a non-human sialic acid sugar molecule called Neu5Gc. Previous research showed that Neu5Gc accumulates in human tumors from dietary sources, despite an ongoing antibody response against it.

The researchers deployed antibodies against Neu5Gc in a mouse tumor model to determine whether and to what degree the antibodies altered tumor progression. The team found that low antibody doses stimulated growth, but high doses inhibited it.

The effect occurred over a “linear and remarkably narrow range,” according to Dr Varki, generating an immune response curve or “inverse hormesis.” Moreover, this curve could be shifted to the left or right simply by modifying the quality of the immune response.

The researchers uncovered similar findings in experiments with mouse models of colon and lung cancer, as well as when they used rituximab in a model of Burkitt lymphoma.

Dr Varki said these results could have implications for all aspects of cancer research. The immune response can have multiple roles in the genesis of cancers, in altering the progress of established tumors and in anticancer therapies that use antibodies as drugs.

Dr Varki is a co-founder of the company Sialix, Inc., which has licensed UC San Diego technologies related to anti-Neu5Gc antibodies in cancer.

BALB/c mice

Credit: Aaron Logan

SAN DIEGO—Researchers have found evidence to suggest there may be little difference between an immune response that kills cancer cells and one that stimulates tumor growth.

The team set out to determine whether the immune responses that mediate cancer immunosurveillance and those responsible for inflammatory facilitation are qualitatively or quantitatively distinct.

They tested antibodies in mouse models of a few different cancers, including rituximab in Burkitt lymphoma.

And they found that lower antibody concentrations stimulated tumor growth, while higher concentrations inhibited growth, and the dose range was “surprisingly narrow.”

The researchers reported these findings in a paper published in PNAS and a poster presentation at the AACR Annual Meeting 2014 (abstract 1063).

“We have found that the intensity difference between an immune response that stimulates cancer and one that kills it may not be very much,” said principal investigator Ajit Varki, MD, of the University of California, San Diego School of Medicine.

“This may come as a surprise to researchers exploring two areas typically considered distinct: the role of the immune system in preventing and killing cancers and the role of chronic inflammation in stimulating cancers. As always, it turns out that the immune system is a double-edged sword.”

The concept of naturally occurring immunosurveillance against malignancies is not new, and there is compelling evidence for it. But understanding this process is confounded by the fact that some types of immune reaction promote tumor development.

Dr Varki and his colleagues looked specifically at a non-human sialic acid sugar molecule called Neu5Gc. Previous research showed that Neu5Gc accumulates in human tumors from dietary sources, despite an ongoing antibody response against it.

The researchers deployed antibodies against Neu5Gc in a mouse tumor model to determine whether and to what degree the antibodies altered tumor progression. The team found that low antibody doses stimulated growth, but high doses inhibited it.

The effect occurred over a “linear and remarkably narrow range,” according to Dr Varki, generating an immune response curve or “inverse hormesis.” Moreover, this curve could be shifted to the left or right simply by modifying the quality of the immune response.

The researchers uncovered similar findings in experiments with mouse models of colon and lung cancer, as well as when they used rituximab in a model of Burkitt lymphoma.

Dr Varki said these results could have implications for all aspects of cancer research. The immune response can have multiple roles in the genesis of cancers, in altering the progress of established tumors and in anticancer therapies that use antibodies as drugs.

Dr Varki is a co-founder of the company Sialix, Inc., which has licensed UC San Diego technologies related to anti-Neu5Gc antibodies in cancer.

BALB/c mice

Credit: Aaron Logan

SAN DIEGO—Researchers have found evidence to suggest there may be little difference between an immune response that kills cancer cells and one that stimulates tumor growth.

The team set out to determine whether the immune responses that mediate cancer immunosurveillance and those responsible for inflammatory facilitation are qualitatively or quantitatively distinct.

They tested antibodies in mouse models of a few different cancers, including rituximab in Burkitt lymphoma.

And they found that lower antibody concentrations stimulated tumor growth, while higher concentrations inhibited growth, and the dose range was “surprisingly narrow.”

The researchers reported these findings in a paper published in PNAS and a poster presentation at the AACR Annual Meeting 2014 (abstract 1063).

“We have found that the intensity difference between an immune response that stimulates cancer and one that kills it may not be very much,” said principal investigator Ajit Varki, MD, of the University of California, San Diego School of Medicine.

“This may come as a surprise to researchers exploring two areas typically considered distinct: the role of the immune system in preventing and killing cancers and the role of chronic inflammation in stimulating cancers. As always, it turns out that the immune system is a double-edged sword.”

The concept of naturally occurring immunosurveillance against malignancies is not new, and there is compelling evidence for it. But understanding this process is confounded by the fact that some types of immune reaction promote tumor development.

Dr Varki and his colleagues looked specifically at a non-human sialic acid sugar molecule called Neu5Gc. Previous research showed that Neu5Gc accumulates in human tumors from dietary sources, despite an ongoing antibody response against it.

The researchers deployed antibodies against Neu5Gc in a mouse tumor model to determine whether and to what degree the antibodies altered tumor progression. The team found that low antibody doses stimulated growth, but high doses inhibited it.

The effect occurred over a “linear and remarkably narrow range,” according to Dr Varki, generating an immune response curve or “inverse hormesis.” Moreover, this curve could be shifted to the left or right simply by modifying the quality of the immune response.

The researchers uncovered similar findings in experiments with mouse models of colon and lung cancer, as well as when they used rituximab in a model of Burkitt lymphoma.

Dr Varki said these results could have implications for all aspects of cancer research. The immune response can have multiple roles in the genesis of cancers, in altering the progress of established tumors and in anticancer therapies that use antibodies as drugs.

Dr Varki is a co-founder of the company Sialix, Inc., which has licensed UC San Diego technologies related to anti-Neu5Gc antibodies in cancer.

Cells undergoing autophagy

Credit: Sarah Pfau

SAN DIEGO—New research suggests that autophagy may allow cancer cells to recover and divide, rather than die, when faced with chemotherapy.

“What we showed is that if this mechanism doesn’t work right—for example, if autophagy is too high or if the target regulated by autophagy isn’t around—cancer cells may be able to rescue themselves from death caused by chemotherapies,” said study author Andrew Thorburn, PhD, of the University of Colorado Denver.

He and his colleagues believe this finding has important implications. It demonstrates a mechanism whereby autophagy controls cell death, and it further reinforces the clinical potential of inhibiting autophagy to sensitize cancer cells to chemotherapy.

Dr Thorburn and his colleagues recounted their research in Cell Reports and presented it in an education session at the AACR Annual Meeting 2014.

The researchers had set out to examine how autophagy affects canonical death receptor-induced mitochondrial outer membrane permeabilization (MOMP) and apoptosis. They found that MOMP occurs at variable times in cells, and it’s delayed by autophagy.

Furthermore, autophagy leads to inefficient MOMP. This causes some cells to die via a slower process than typical apoptosis, which allows them to eventually recover and divide.

Specifically, the researchers found that, as a cancer cell begins to die, mitochondrial cell walls break down. And the cell’s mitochondria release proteins via MOMP.

But then, high autophagy allows the cell to encapsulate and “digest” these released proteins before MOMP can keep the cell well and truly dead. The cell recovers and goes on to divide.

“The implication here is that if you inhibit autophagy, you’d make this less likely to happen; ie, when you kill cancer cells, they would stay dead,” Dr Thorburn said.

He and his colleagues also found that autophagy depends on the target PUMA to regulate cell death. When PUMA is absent, it doesn’t matter if autophagy is inhibited. Without the communicating action of PUMA, cancer cells evade apoptosis and continue to survive.

The researchers said this suggests autophagy can control apoptosis via a regulator that makes MOMP faster and more efficient, thus ensuring the rapid completion of apoptosis.

“Autophagy is complex and, as yet, not fully understood,” Dr Thorburn said. “But now that we see a molecular mechanism whereby cell fate can be determined by autophagy, we hope to discover patient populations that could benefit from drugs that inhibit this action.”

Cells undergoing autophagy

Credit: Sarah Pfau

SAN DIEGO—New research suggests that autophagy may allow cancer cells to recover and divide, rather than die, when faced with chemotherapy.

“What we showed is that if this mechanism doesn’t work right—for example, if autophagy is too high or if the target regulated by autophagy isn’t around—cancer cells may be able to rescue themselves from death caused by chemotherapies,” said study author Andrew Thorburn, PhD, of the University of Colorado Denver.

He and his colleagues believe this finding has important implications. It demonstrates a mechanism whereby autophagy controls cell death, and it further reinforces the clinical potential of inhibiting autophagy to sensitize cancer cells to chemotherapy.

Dr Thorburn and his colleagues recounted their research in Cell Reports and presented it in an education session at the AACR Annual Meeting 2014.

The researchers had set out to examine how autophagy affects canonical death receptor-induced mitochondrial outer membrane permeabilization (MOMP) and apoptosis. They found that MOMP occurs at variable times in cells, and it’s delayed by autophagy.

Furthermore, autophagy leads to inefficient MOMP. This causes some cells to die via a slower process than typical apoptosis, which allows them to eventually recover and divide.

Specifically, the researchers found that, as a cancer cell begins to die, mitochondrial cell walls break down. And the cell’s mitochondria release proteins via MOMP.

But then, high autophagy allows the cell to encapsulate and “digest” these released proteins before MOMP can keep the cell well and truly dead. The cell recovers and goes on to divide.

“The implication here is that if you inhibit autophagy, you’d make this less likely to happen; ie, when you kill cancer cells, they would stay dead,” Dr Thorburn said.

He and his colleagues also found that autophagy depends on the target PUMA to regulate cell death. When PUMA is absent, it doesn’t matter if autophagy is inhibited. Without the communicating action of PUMA, cancer cells evade apoptosis and continue to survive.

The researchers said this suggests autophagy can control apoptosis via a regulator that makes MOMP faster and more efficient, thus ensuring the rapid completion of apoptosis.

“Autophagy is complex and, as yet, not fully understood,” Dr Thorburn said. “But now that we see a molecular mechanism whereby cell fate can be determined by autophagy, we hope to discover patient populations that could benefit from drugs that inhibit this action.”

Cells undergoing autophagy

Credit: Sarah Pfau

SAN DIEGO—New research suggests that autophagy may allow cancer cells to recover and divide, rather than die, when faced with chemotherapy.

“What we showed is that if this mechanism doesn’t work right—for example, if autophagy is too high or if the target regulated by autophagy isn’t around—cancer cells may be able to rescue themselves from death caused by chemotherapies,” said study author Andrew Thorburn, PhD, of the University of Colorado Denver.

He and his colleagues believe this finding has important implications. It demonstrates a mechanism whereby autophagy controls cell death, and it further reinforces the clinical potential of inhibiting autophagy to sensitize cancer cells to chemotherapy.

Dr Thorburn and his colleagues recounted their research in Cell Reports and presented it in an education session at the AACR Annual Meeting 2014.

The researchers had set out to examine how autophagy affects canonical death receptor-induced mitochondrial outer membrane permeabilization (MOMP) and apoptosis. They found that MOMP occurs at variable times in cells, and it’s delayed by autophagy.

Furthermore, autophagy leads to inefficient MOMP. This causes some cells to die via a slower process than typical apoptosis, which allows them to eventually recover and divide.

Specifically, the researchers found that, as a cancer cell begins to die, mitochondrial cell walls break down. And the cell’s mitochondria release proteins via MOMP.

But then, high autophagy allows the cell to encapsulate and “digest” these released proteins before MOMP can keep the cell well and truly dead. The cell recovers and goes on to divide.

“The implication here is that if you inhibit autophagy, you’d make this less likely to happen; ie, when you kill cancer cells, they would stay dead,” Dr Thorburn said.

He and his colleagues also found that autophagy depends on the target PUMA to regulate cell death. When PUMA is absent, it doesn’t matter if autophagy is inhibited. Without the communicating action of PUMA, cancer cells evade apoptosis and continue to survive.

The researchers said this suggests autophagy can control apoptosis via a regulator that makes MOMP faster and more efficient, thus ensuring the rapid completion of apoptosis.

“Autophagy is complex and, as yet, not fully understood,” Dr Thorburn said. “But now that we see a molecular mechanism whereby cell fate can be determined by autophagy, we hope to discover patient populations that could benefit from drugs that inhibit this action.”