Lymphoma & Plasma Cell Disorders

DURBAN, SOUTH AFRICA – The good news about non-Hodgkin lymphoma in the setting of HIV infection is that the risk drops dramatically after several years of antiretroviral therapy. The bad news? The risk still remains extraordinarily high, compared with the risk seen in the general population, Mathias Egger, MD, reported at the 21st International AIDS Conference.

That was a key finding in a new analysis of lymphoma trends in more than 210,000 HIV-positive adults on combination antiretroviral therapy (ART) during more than 1.1 million person-years of follow-up in North America, Europe, Latin America, and South Africa.

Bruce Jancin/Frontline Medical News

The non-Hodgkin lymphoma (NHL) incidence rate standardized to 40 years of age was 287 cases per 100,000 person-years. From a pre-ART baseline of about 500 cases per 100,000 person-years, it dropped “massively” within a year after going on ART. Even after 5 years of ART, however, the rate remained in the range of 60-200 cases per 100,000 person-years, depending upon geographic location and HIV transmission route. In contrast, the incidence rate among the general population of the U.S. and Canada, which is among the world’s highest, is less than 10 per 100,000 person-years, according to Dr. Egger, professor of epidemiology and public health at the University of Bern, Switzerland.

The risk of developing NHL in the setting of HIV infection varied by continent. It was slightly higher in HIV-infected patients in North America than in Europe or South Africa, although the South African data are considered unreliable due to underascertainment of cancers.

In Latin American HIV-infected adults the NHL rate was lowest of all, fully 54% lower than in Europe after adjustment for current CD4 cell count, ART regimen and duration, and transmission risk group. The low NHL rate in Latin America was driven by a very low risk in HIV-infected women.

Across the world, NHL rates in patients on ART were consistently lowest in women, intermediate in heterosexual men, and highest in men who have sex with men.

The explanation for the regional variation in NHL trends might plausibly involve differing prevalences of Epstein-Barr virus–2 and other oncogenic viruses as well as differences in the completeness of cancer ascertainment, Dr. Egger said.

While NHL is categorized as an AIDS-defining condition, Hodgkin lymphoma is not. Nonetheless, the risk of Hodgkin lymphoma is markedly increased in the setting of HIV infection. In one classic meta-analysis, it was increased by 11-fold, compared with that seen in the general population (Lancet. 2007 Jul 7;370(9581):59-67).

In a study of more than 41,000 HIV-infected European adults by Dr. Egger and his coworkers, the incidence of Hodgkin lymphoma was 49 cases per 100,000 person-years. Importantly, unlike in NHL, the cumulative incidence and mortality of Hodgkin lymphoma were unaffected by ART (Blood. 2011 Jun 9;117(23):6100-8).

The clinical implication of these trends in HIV-related lymphomas is clear: with more than 2 million new cases of HIV infection occurring annually worldwide, and with infected patients living far longer as ART transforms HIV infection into a chronic manageable condition, physicians can anticipate encountering a steadily growing number of patients with NHL and Hodgkin lymphoma, he said.

The NHL study was funded by the European Union and the U.S. National Institutes of Health. The analysis utilized data collected by the Collaboration of Observational HIV Epidemiology and Research Europe (COHERE) and the International Epidemiologic Databases to Evaluate AIDS (IeDEA). Dr. Egger reported having no financial conflicts of interest.

bjancin@frontlinemedcom.com

DURBAN, SOUTH AFRICA – The good news about non-Hodgkin lymphoma in the setting of HIV infection is that the risk drops dramatically after several years of antiretroviral therapy. The bad news? The risk still remains extraordinarily high, compared with the risk seen in the general population, Mathias Egger, MD, reported at the 21st International AIDS Conference.

That was a key finding in a new analysis of lymphoma trends in more than 210,000 HIV-positive adults on combination antiretroviral therapy (ART) during more than 1.1 million person-years of follow-up in North America, Europe, Latin America, and South Africa.

Bruce Jancin/Frontline Medical News

The non-Hodgkin lymphoma (NHL) incidence rate standardized to 40 years of age was 287 cases per 100,000 person-years. From a pre-ART baseline of about 500 cases per 100,000 person-years, it dropped “massively” within a year after going on ART. Even after 5 years of ART, however, the rate remained in the range of 60-200 cases per 100,000 person-years, depending upon geographic location and HIV transmission route. In contrast, the incidence rate among the general population of the U.S. and Canada, which is among the world’s highest, is less than 10 per 100,000 person-years, according to Dr. Egger, professor of epidemiology and public health at the University of Bern, Switzerland.

The risk of developing NHL in the setting of HIV infection varied by continent. It was slightly higher in HIV-infected patients in North America than in Europe or South Africa, although the South African data are considered unreliable due to underascertainment of cancers.

In Latin American HIV-infected adults the NHL rate was lowest of all, fully 54% lower than in Europe after adjustment for current CD4 cell count, ART regimen and duration, and transmission risk group. The low NHL rate in Latin America was driven by a very low risk in HIV-infected women.

Across the world, NHL rates in patients on ART were consistently lowest in women, intermediate in heterosexual men, and highest in men who have sex with men.

The explanation for the regional variation in NHL trends might plausibly involve differing prevalences of Epstein-Barr virus–2 and other oncogenic viruses as well as differences in the completeness of cancer ascertainment, Dr. Egger said.

While NHL is categorized as an AIDS-defining condition, Hodgkin lymphoma is not. Nonetheless, the risk of Hodgkin lymphoma is markedly increased in the setting of HIV infection. In one classic meta-analysis, it was increased by 11-fold, compared with that seen in the general population (Lancet. 2007 Jul 7;370(9581):59-67).

In a study of more than 41,000 HIV-infected European adults by Dr. Egger and his coworkers, the incidence of Hodgkin lymphoma was 49 cases per 100,000 person-years. Importantly, unlike in NHL, the cumulative incidence and mortality of Hodgkin lymphoma were unaffected by ART (Blood. 2011 Jun 9;117(23):6100-8).

The clinical implication of these trends in HIV-related lymphomas is clear: with more than 2 million new cases of HIV infection occurring annually worldwide, and with infected patients living far longer as ART transforms HIV infection into a chronic manageable condition, physicians can anticipate encountering a steadily growing number of patients with NHL and Hodgkin lymphoma, he said.

The NHL study was funded by the European Union and the U.S. National Institutes of Health. The analysis utilized data collected by the Collaboration of Observational HIV Epidemiology and Research Europe (COHERE) and the International Epidemiologic Databases to Evaluate AIDS (IeDEA). Dr. Egger reported having no financial conflicts of interest.

bjancin@frontlinemedcom.com

DURBAN, SOUTH AFRICA – The good news about non-Hodgkin lymphoma in the setting of HIV infection is that the risk drops dramatically after several years of antiretroviral therapy. The bad news? The risk still remains extraordinarily high, compared with the risk seen in the general population, Mathias Egger, MD, reported at the 21st International AIDS Conference.

That was a key finding in a new analysis of lymphoma trends in more than 210,000 HIV-positive adults on combination antiretroviral therapy (ART) during more than 1.1 million person-years of follow-up in North America, Europe, Latin America, and South Africa.

Bruce Jancin/Frontline Medical News

The non-Hodgkin lymphoma (NHL) incidence rate standardized to 40 years of age was 287 cases per 100,000 person-years. From a pre-ART baseline of about 500 cases per 100,000 person-years, it dropped “massively” within a year after going on ART. Even after 5 years of ART, however, the rate remained in the range of 60-200 cases per 100,000 person-years, depending upon geographic location and HIV transmission route. In contrast, the incidence rate among the general population of the U.S. and Canada, which is among the world’s highest, is less than 10 per 100,000 person-years, according to Dr. Egger, professor of epidemiology and public health at the University of Bern, Switzerland.

The risk of developing NHL in the setting of HIV infection varied by continent. It was slightly higher in HIV-infected patients in North America than in Europe or South Africa, although the South African data are considered unreliable due to underascertainment of cancers.

In Latin American HIV-infected adults the NHL rate was lowest of all, fully 54% lower than in Europe after adjustment for current CD4 cell count, ART regimen and duration, and transmission risk group. The low NHL rate in Latin America was driven by a very low risk in HIV-infected women.

Across the world, NHL rates in patients on ART were consistently lowest in women, intermediate in heterosexual men, and highest in men who have sex with men.

The explanation for the regional variation in NHL trends might plausibly involve differing prevalences of Epstein-Barr virus–2 and other oncogenic viruses as well as differences in the completeness of cancer ascertainment, Dr. Egger said.

While NHL is categorized as an AIDS-defining condition, Hodgkin lymphoma is not. Nonetheless, the risk of Hodgkin lymphoma is markedly increased in the setting of HIV infection. In one classic meta-analysis, it was increased by 11-fold, compared with that seen in the general population (Lancet. 2007 Jul 7;370(9581):59-67).

In a study of more than 41,000 HIV-infected European adults by Dr. Egger and his coworkers, the incidence of Hodgkin lymphoma was 49 cases per 100,000 person-years. Importantly, unlike in NHL, the cumulative incidence and mortality of Hodgkin lymphoma were unaffected by ART (Blood. 2011 Jun 9;117(23):6100-8).

The clinical implication of these trends in HIV-related lymphomas is clear: with more than 2 million new cases of HIV infection occurring annually worldwide, and with infected patients living far longer as ART transforms HIV infection into a chronic manageable condition, physicians can anticipate encountering a steadily growing number of patients with NHL and Hodgkin lymphoma, he said.

The NHL study was funded by the European Union and the U.S. National Institutes of Health. The analysis utilized data collected by the Collaboration of Observational HIV Epidemiology and Research Europe (COHERE) and the International Epidemiologic Databases to Evaluate AIDS (IeDEA). Dr. Egger reported having no financial conflicts of interest.

bjancin@frontlinemedcom.com

Venous thromboembolism may occur later in the disease process of multiple myeloma than has historically been reported, based on data reported by Brea Lipe, MD, of the University of Kansas Medical Center, Kansas City, and her colleagues.

The risk for VTE appears to change over time. Patients with multiple myeloma should be assessed for VTE risk and thromboprophylaxis on an ongoing basis throughout the disease course, the researchers recommended at the annual meeting of the American Society of Clinical Oncology.

In a study originally designed to examine the adoption and utility of the International Myeloma Working Group thromboprophylaxis guidelines, the researchers used the Healthcare Enterprise Repository for Ontological Narration (HERON) database to identify case patients with multiple myeloma and a venous thromboembolism. Patients who had multiple myeloma and had not experienced a VTE were matched to the cases based on gender, age, and time of diagnosis. Patient charts were manually extracted to identify treatment history, disease history, risk factors for VTE, and guideline adherence regarding use of prophylactic anticoagulation for the matched patients at the time of diagnosis and at the time of the VTE.

There were 86 cases and 211 controls in the final cohort. The median time from diagnosis to VTE was 952 days. In accordance with the guidelines, patients with a higher risk of VTE were more likely to be on low-molecular-weight heparin (LMWH) or warfarin versus patients with a lower risk of VTE on aspirin or no prophylaxis (P less than .001). Risk category or prophylactic medication were not associated with the rate of VTE when considering baseline risk factors. Over time, however, the risk category of case patients changed to a higher risk group and this was associated with a higher risk of VTE (P = .06).

“While we were unable to validate the IMWG recommendations for thromboprophylaxis at diagnosis, our data suggest that VTE in multiple myeloma may occur later in the disease process than has historically been reported,” the researchers concluded.

Dr. Lipe has been an adviser to Takeda.

mdales@frontlinemedcom.com

On Twitter @maryjodales

Venous thromboembolism may occur later in the disease process of multiple myeloma than has historically been reported, based on data reported by Brea Lipe, MD, of the University of Kansas Medical Center, Kansas City, and her colleagues.

The risk for VTE appears to change over time. Patients with multiple myeloma should be assessed for VTE risk and thromboprophylaxis on an ongoing basis throughout the disease course, the researchers recommended at the annual meeting of the American Society of Clinical Oncology.

In a study originally designed to examine the adoption and utility of the International Myeloma Working Group thromboprophylaxis guidelines, the researchers used the Healthcare Enterprise Repository for Ontological Narration (HERON) database to identify case patients with multiple myeloma and a venous thromboembolism. Patients who had multiple myeloma and had not experienced a VTE were matched to the cases based on gender, age, and time of diagnosis. Patient charts were manually extracted to identify treatment history, disease history, risk factors for VTE, and guideline adherence regarding use of prophylactic anticoagulation for the matched patients at the time of diagnosis and at the time of the VTE.

There were 86 cases and 211 controls in the final cohort. The median time from diagnosis to VTE was 952 days. In accordance with the guidelines, patients with a higher risk of VTE were more likely to be on low-molecular-weight heparin (LMWH) or warfarin versus patients with a lower risk of VTE on aspirin or no prophylaxis (P less than .001). Risk category or prophylactic medication were not associated with the rate of VTE when considering baseline risk factors. Over time, however, the risk category of case patients changed to a higher risk group and this was associated with a higher risk of VTE (P = .06).

“While we were unable to validate the IMWG recommendations for thromboprophylaxis at diagnosis, our data suggest that VTE in multiple myeloma may occur later in the disease process than has historically been reported,” the researchers concluded.

Dr. Lipe has been an adviser to Takeda.

mdales@frontlinemedcom.com

On Twitter @maryjodales

Venous thromboembolism may occur later in the disease process of multiple myeloma than has historically been reported, based on data reported by Brea Lipe, MD, of the University of Kansas Medical Center, Kansas City, and her colleagues.

The risk for VTE appears to change over time. Patients with multiple myeloma should be assessed for VTE risk and thromboprophylaxis on an ongoing basis throughout the disease course, the researchers recommended at the annual meeting of the American Society of Clinical Oncology.

In a study originally designed to examine the adoption and utility of the International Myeloma Working Group thromboprophylaxis guidelines, the researchers used the Healthcare Enterprise Repository for Ontological Narration (HERON) database to identify case patients with multiple myeloma and a venous thromboembolism. Patients who had multiple myeloma and had not experienced a VTE were matched to the cases based on gender, age, and time of diagnosis. Patient charts were manually extracted to identify treatment history, disease history, risk factors for VTE, and guideline adherence regarding use of prophylactic anticoagulation for the matched patients at the time of diagnosis and at the time of the VTE.

There were 86 cases and 211 controls in the final cohort. The median time from diagnosis to VTE was 952 days. In accordance with the guidelines, patients with a higher risk of VTE were more likely to be on low-molecular-weight heparin (LMWH) or warfarin versus patients with a lower risk of VTE on aspirin or no prophylaxis (P less than .001). Risk category or prophylactic medication were not associated with the rate of VTE when considering baseline risk factors. Over time, however, the risk category of case patients changed to a higher risk group and this was associated with a higher risk of VTE (P = .06).

“While we were unable to validate the IMWG recommendations for thromboprophylaxis at diagnosis, our data suggest that VTE in multiple myeloma may occur later in the disease process than has historically been reported,” the researchers concluded.

Dr. Lipe has been an adviser to Takeda.

mdales@frontlinemedcom.com

On Twitter @maryjodales

Pregnant woman

Photo by Nina Matthews

Preclinical research suggests the chemotherapy drug etoposide may have adverse effects on the developing ovaries of female fetuses.

Researchers found that etoposide can damage the development of mouse ovary tissue in vitro.

However, if the drug is given after ovarian follicles have developed, the damage is not significant.

The researchers said further study is needed to assess whether etoposide has similar effects on human tissue.

“In a study involving mouse tissue, we have shown that etoposide can damage the development of the ovaries while a fetus is in the womb,” said study author Norah Spears, DPhil, of the University of Edinburgh in the UK.

“The drug affects the germ cells in the ovaries, which are the cells that give rise to eggs. This is important because it could mean that the fertility of the offspring could be affected in later life.”

Dr Spears and her colleagues reported these findings in BMC Cancer.

The researchers noted that etoposide is considered safe for use in the second and third trimester of pregnancy because it has a low risk of miscarriage and birth defects. However, little is known about the effects of the drug on the unborn baby in later life.

A woman’s reproductive lifespan is determined before birth, while the ovaries are developing in the womb. The second and third trimesters are particularly important, as that’s when female germ cells form ovarian follicles, which determine how many eggs a woman will be able to release in her lifetime.

Ovarian follicles each contain an oocyte. The process by which oocytes become enclosed in follicles starts about 17 weeks into fetal development and is only completed in late pregnancy.

Dr Spears and her colleagues found that exposing mouse ovaries to etoposide before follicles had formed caused the death of most germ cells. The few remaining germ cells went on to form unhealthy follicles. Once oocytes were enclosed in follicles, however, etoposide had no significant adverse effects.

The researchers collected fetal and neonatal ovaries from mice and cultured them in the lab. The team then exposed groups of 6 ovaries each to different doses of etoposide.

When fetal ovaries were treated with etoposide prior to follicle formation, this resulted in dose-dependent damage. Total follicle numbers declined by 72% to 90% in response to medium and high doses of etoposide, respectively.

In neonatal ovaries after follicle formation, etoposide only had minor effects, even at doses higher than those used to treat fetal ovaries.

“Our work indicates that female mouse germ cells are particularly susceptible to damage by etoposide at a specific early developmental stage, immediately prior to follicle formation, and that there could be possible consequences to the fertility of females born to women who were treated with etoposide during the second trimester of their pregnancy,” Dr Spears said.

She and her colleagues noted that additional research is needed to determine if these effects might occur in humans. And research is needed to determine whether the adverse effects of etoposide in germ cells are caused by damage to the DNA or because etoposide affects other processes such as transcription.

Pregnant woman

Photo by Nina Matthews

Preclinical research suggests the chemotherapy drug etoposide may have adverse effects on the developing ovaries of female fetuses.

Researchers found that etoposide can damage the development of mouse ovary tissue in vitro.

However, if the drug is given after ovarian follicles have developed, the damage is not significant.

The researchers said further study is needed to assess whether etoposide has similar effects on human tissue.

“In a study involving mouse tissue, we have shown that etoposide can damage the development of the ovaries while a fetus is in the womb,” said study author Norah Spears, DPhil, of the University of Edinburgh in the UK.

“The drug affects the germ cells in the ovaries, which are the cells that give rise to eggs. This is important because it could mean that the fertility of the offspring could be affected in later life.”

Dr Spears and her colleagues reported these findings in BMC Cancer.

The researchers noted that etoposide is considered safe for use in the second and third trimester of pregnancy because it has a low risk of miscarriage and birth defects. However, little is known about the effects of the drug on the unborn baby in later life.

A woman’s reproductive lifespan is determined before birth, while the ovaries are developing in the womb. The second and third trimesters are particularly important, as that’s when female germ cells form ovarian follicles, which determine how many eggs a woman will be able to release in her lifetime.

Ovarian follicles each contain an oocyte. The process by which oocytes become enclosed in follicles starts about 17 weeks into fetal development and is only completed in late pregnancy.

Dr Spears and her colleagues found that exposing mouse ovaries to etoposide before follicles had formed caused the death of most germ cells. The few remaining germ cells went on to form unhealthy follicles. Once oocytes were enclosed in follicles, however, etoposide had no significant adverse effects.

The researchers collected fetal and neonatal ovaries from mice and cultured them in the lab. The team then exposed groups of 6 ovaries each to different doses of etoposide.

When fetal ovaries were treated with etoposide prior to follicle formation, this resulted in dose-dependent damage. Total follicle numbers declined by 72% to 90% in response to medium and high doses of etoposide, respectively.

In neonatal ovaries after follicle formation, etoposide only had minor effects, even at doses higher than those used to treat fetal ovaries.

“Our work indicates that female mouse germ cells are particularly susceptible to damage by etoposide at a specific early developmental stage, immediately prior to follicle formation, and that there could be possible consequences to the fertility of females born to women who were treated with etoposide during the second trimester of their pregnancy,” Dr Spears said.

She and her colleagues noted that additional research is needed to determine if these effects might occur in humans. And research is needed to determine whether the adverse effects of etoposide in germ cells are caused by damage to the DNA or because etoposide affects other processes such as transcription.

Pregnant woman

Photo by Nina Matthews

Preclinical research suggests the chemotherapy drug etoposide may have adverse effects on the developing ovaries of female fetuses.

Researchers found that etoposide can damage the development of mouse ovary tissue in vitro.

However, if the drug is given after ovarian follicles have developed, the damage is not significant.

The researchers said further study is needed to assess whether etoposide has similar effects on human tissue.

“In a study involving mouse tissue, we have shown that etoposide can damage the development of the ovaries while a fetus is in the womb,” said study author Norah Spears, DPhil, of the University of Edinburgh in the UK.

“The drug affects the germ cells in the ovaries, which are the cells that give rise to eggs. This is important because it could mean that the fertility of the offspring could be affected in later life.”

Dr Spears and her colleagues reported these findings in BMC Cancer.

The researchers noted that etoposide is considered safe for use in the second and third trimester of pregnancy because it has a low risk of miscarriage and birth defects. However, little is known about the effects of the drug on the unborn baby in later life.

A woman’s reproductive lifespan is determined before birth, while the ovaries are developing in the womb. The second and third trimesters are particularly important, as that’s when female germ cells form ovarian follicles, which determine how many eggs a woman will be able to release in her lifetime.

Ovarian follicles each contain an oocyte. The process by which oocytes become enclosed in follicles starts about 17 weeks into fetal development and is only completed in late pregnancy.

Dr Spears and her colleagues found that exposing mouse ovaries to etoposide before follicles had formed caused the death of most germ cells. The few remaining germ cells went on to form unhealthy follicles. Once oocytes were enclosed in follicles, however, etoposide had no significant adverse effects.

The researchers collected fetal and neonatal ovaries from mice and cultured them in the lab. The team then exposed groups of 6 ovaries each to different doses of etoposide.

When fetal ovaries were treated with etoposide prior to follicle formation, this resulted in dose-dependent damage. Total follicle numbers declined by 72% to 90% in response to medium and high doses of etoposide, respectively.

In neonatal ovaries after follicle formation, etoposide only had minor effects, even at doses higher than those used to treat fetal ovaries.

“Our work indicates that female mouse germ cells are particularly susceptible to damage by etoposide at a specific early developmental stage, immediately prior to follicle formation, and that there could be possible consequences to the fertility of females born to women who were treated with etoposide during the second trimester of their pregnancy,” Dr Spears said.

She and her colleagues noted that additional research is needed to determine if these effects might occur in humans. And research is needed to determine whether the adverse effects of etoposide in germ cells are caused by damage to the DNA or because etoposide affects other processes such as transcription.

 

 

T cells

Photo courtesy of NIAID

 

The US Food and Drug Administration (FDA) has granted orphan drug designation for a CD4-directed chimeric antigen receptor (CD4CAR) T-cell therapy to treat peripheral T-cell lymphoma (PTCL).

The CD4CAR therapy, also known as ICG122, consists of properly matched allogeneic T cells engineered to express an anti-CD4 single-chain variable fragment antibody domain.

ICG122 is being developed by iCell Gene Therapeutics.

The company is planning a phase 1 trial of ICG122 in cooperation with the National Institutes of Health, Indiana Clinical and Translational Sciences Institute, Stony Brook Hospital, and the James Graham Brown Cancer Center at University of Louisville.

“CD4CAR could significantly enhance currently available treatment options for [PTCL] patients,” said Yupo Ma, MD, PhD, a professor at Stony Brook University and chairman and chief scientific officer at iCell Gene Therapeutics.

“The orphan drug designation is an important achievement as we advance our development plans for this promising treatment in T-cell hematologic cancers.”

The FDA grants orphan designation to drugs and biologics intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the drug is approved.

 

 

T cells

Photo courtesy of NIAID

 

The US Food and Drug Administration (FDA) has granted orphan drug designation for a CD4-directed chimeric antigen receptor (CD4CAR) T-cell therapy to treat peripheral T-cell lymphoma (PTCL).

The CD4CAR therapy, also known as ICG122, consists of properly matched allogeneic T cells engineered to express an anti-CD4 single-chain variable fragment antibody domain.

ICG122 is being developed by iCell Gene Therapeutics.

The company is planning a phase 1 trial of ICG122 in cooperation with the National Institutes of Health, Indiana Clinical and Translational Sciences Institute, Stony Brook Hospital, and the James Graham Brown Cancer Center at University of Louisville.

“CD4CAR could significantly enhance currently available treatment options for [PTCL] patients,” said Yupo Ma, MD, PhD, a professor at Stony Brook University and chairman and chief scientific officer at iCell Gene Therapeutics.

“The orphan drug designation is an important achievement as we advance our development plans for this promising treatment in T-cell hematologic cancers.”

The FDA grants orphan designation to drugs and biologics intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the drug is approved.

 

 

T cells

Photo courtesy of NIAID

 

The US Food and Drug Administration (FDA) has granted orphan drug designation for a CD4-directed chimeric antigen receptor (CD4CAR) T-cell therapy to treat peripheral T-cell lymphoma (PTCL).

The CD4CAR therapy, also known as ICG122, consists of properly matched allogeneic T cells engineered to express an anti-CD4 single-chain variable fragment antibody domain.

ICG122 is being developed by iCell Gene Therapeutics.

The company is planning a phase 1 trial of ICG122 in cooperation with the National Institutes of Health, Indiana Clinical and Translational Sciences Institute, Stony Brook Hospital, and the James Graham Brown Cancer Center at University of Louisville.

“CD4CAR could significantly enhance currently available treatment options for [PTCL] patients,” said Yupo Ma, MD, PhD, a professor at Stony Brook University and chairman and chief scientific officer at iCell Gene Therapeutics.

“The orphan drug designation is an important achievement as we advance our development plans for this promising treatment in T-cell hematologic cancers.”

The FDA grants orphan designation to drugs and biologics intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the drug is approved.

Quality of life measures were comparable for multiple myeloma patients whether they received panobinostat or placebo in combination with bortezomib and dexamethasone, Paul G. Richardson, MD, of Dana-Farber Cancer Institute, Boston, and his associates in the PANORAMA-1 trial reported at the annual meeting of the American Society of Clinical Oncology.

Symptoms, function, and health-related quality of life were measured using the EORTC-QLQ-30, QLQ-MY20, and FACT/GOG-Ntx scales at screening, the first day of the first therapy cycle, and every 6 weeks thereafter in multiple myeloma patients randomly assigned to receive 21-day cycles of either the triple regimen or a placebo plus bortezomib and dexamethasone.

Panobinostat, in combination with bortezomib and dexamethasone, is approved for multiple myeloma patients who have received at least two prior regimens, including bortezomib and an immunomodulatory drug

In the U.S.-label population of the PANORAMA-1 study, patient-reported outcomes data were available at baseline for 94 and 92 patients based on the EORTC QLQ-C30, Global Health Status/QoL scale and for 91 and 95 patients based on the QLQMY20, Disease Symptoms (DS) subscale and FACT/GOG-Ntx Neurotoxicity subscale.

After 24 weeks of therapy, FACT-GOG-Ntx scores were similar (32.03 vs. 33.92, respectively), suggesting no difference in neurotoxicity symptoms. In the QLQ-MY20 DS subscale, scores initially improved and stabilized, with no difference between the two groups of patients (20.65 vs. 15.85). After initially declining, EORTC QLQ-C30 Global Health Status/QoL scores were also comparable (54.84 vs. 58.55).

The study was sponsored by Novartis Pharmaceuticals, the maker of panobinostat. Dr. Richardson is an adviser to Novartis as well as several other drug companies.

mdales@frontlinemedcom.com

On Twitter @maryjodales

Quality of life measures were comparable for multiple myeloma patients whether they received panobinostat or placebo in combination with bortezomib and dexamethasone, Paul G. Richardson, MD, of Dana-Farber Cancer Institute, Boston, and his associates in the PANORAMA-1 trial reported at the annual meeting of the American Society of Clinical Oncology.

Symptoms, function, and health-related quality of life were measured using the EORTC-QLQ-30, QLQ-MY20, and FACT/GOG-Ntx scales at screening, the first day of the first therapy cycle, and every 6 weeks thereafter in multiple myeloma patients randomly assigned to receive 21-day cycles of either the triple regimen or a placebo plus bortezomib and dexamethasone.

Panobinostat, in combination with bortezomib and dexamethasone, is approved for multiple myeloma patients who have received at least two prior regimens, including bortezomib and an immunomodulatory drug

In the U.S.-label population of the PANORAMA-1 study, patient-reported outcomes data were available at baseline for 94 and 92 patients based on the EORTC QLQ-C30, Global Health Status/QoL scale and for 91 and 95 patients based on the QLQMY20, Disease Symptoms (DS) subscale and FACT/GOG-Ntx Neurotoxicity subscale.

After 24 weeks of therapy, FACT-GOG-Ntx scores were similar (32.03 vs. 33.92, respectively), suggesting no difference in neurotoxicity symptoms. In the QLQ-MY20 DS subscale, scores initially improved and stabilized, with no difference between the two groups of patients (20.65 vs. 15.85). After initially declining, EORTC QLQ-C30 Global Health Status/QoL scores were also comparable (54.84 vs. 58.55).

The study was sponsored by Novartis Pharmaceuticals, the maker of panobinostat. Dr. Richardson is an adviser to Novartis as well as several other drug companies.

mdales@frontlinemedcom.com

On Twitter @maryjodales

Quality of life measures were comparable for multiple myeloma patients whether they received panobinostat or placebo in combination with bortezomib and dexamethasone, Paul G. Richardson, MD, of Dana-Farber Cancer Institute, Boston, and his associates in the PANORAMA-1 trial reported at the annual meeting of the American Society of Clinical Oncology.

Symptoms, function, and health-related quality of life were measured using the EORTC-QLQ-30, QLQ-MY20, and FACT/GOG-Ntx scales at screening, the first day of the first therapy cycle, and every 6 weeks thereafter in multiple myeloma patients randomly assigned to receive 21-day cycles of either the triple regimen or a placebo plus bortezomib and dexamethasone.

Panobinostat, in combination with bortezomib and dexamethasone, is approved for multiple myeloma patients who have received at least two prior regimens, including bortezomib and an immunomodulatory drug

In the U.S.-label population of the PANORAMA-1 study, patient-reported outcomes data were available at baseline for 94 and 92 patients based on the EORTC QLQ-C30, Global Health Status/QoL scale and for 91 and 95 patients based on the QLQMY20, Disease Symptoms (DS) subscale and FACT/GOG-Ntx Neurotoxicity subscale.

After 24 weeks of therapy, FACT-GOG-Ntx scores were similar (32.03 vs. 33.92, respectively), suggesting no difference in neurotoxicity symptoms. In the QLQ-MY20 DS subscale, scores initially improved and stabilized, with no difference between the two groups of patients (20.65 vs. 15.85). After initially declining, EORTC QLQ-C30 Global Health Status/QoL scores were also comparable (54.84 vs. 58.55).

The study was sponsored by Novartis Pharmaceuticals, the maker of panobinostat. Dr. Richardson is an adviser to Novartis as well as several other drug companies.

mdales@frontlinemedcom.com

On Twitter @maryjodales

Patient receiving chemotherapy

Photo by Rhoda Baer

The US Food and Drug Administration (FDA) has approved granisetron extended-release injection (Sustol®) for the prevention of chemotherapy-induced nausea and vomiting (CINV) in adults.

Extended-release granisetron is a serotonin-3 (5-HT3) receptor antagonist that utilizes Biochronomer® polymer-based drug delivery technology to maintain therapeutic levels of granisetron for at least 5 days, covering both the acute and delayed phases of CINV.

The product is intended for use in combination with other anti-emetics to prevent acute and delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic chemotherapy (MEC) or anthracycline and cyclophosphamide (AC) combination chemotherapy regimens.

“Despite advances in the management of CINV, up to half of patients receiving chemotherapy can still experience CINV, with delayed CINV being particularly challenging to control,” said Ralph V. Boccia, MD, of the Center for Cancer and Blood Disorders in Bethesda, Maryland.

“In our experience, other 5-HT3 receptor antagonists, including palonosetron, are generally effective for 48 hours or less. Sustol, due to its extended-release profile, represents a novel option that can protect patients from CINV for a full 5 days.”

Extended-release granisetron (formerly known as APF530) is a product of Heron Therapeutics, Inc. The US commercial launch of the drug is planned for the fourth quarter of 2016.

Phase 3 trials

The global phase 3 development program of extended-release granisetron consisted of 2 large, guideline-based clinical trials of more than 2000 cancer patients.

In one trial, researchers compared extended-release granisetron to palonosetron for the prevention of acute and delayed CINV after MEC or highly emetogenic chemotherapy (HEC).

Results suggested extended-release granisetron was non-inferior to palonosetron. The most common adverse events observed in patients receiving granisetron were injection-site reactions and constipation.

In another trial, researchers compared extended-release granisetron to ondansetron for control of delayed CINV after HEC. Patients received extended-release granisetron, dexamethasone, and fosaprepitant or ondansetron, dexamethasone, and fosaprepitant.

A higher percentage of patients in the granisetron arm had delayed-phase complete response. The incidence of treatment-emergent adverse events was similar between the treatment arms.

“The Sustol clinical trial populations and results are highly representative of cancer patients in our real-world clinical practice,” said Jeffrey Vacirca, MD, of North Shore Hematology Oncology Associates in East Setauket, New York.

“Use of MEC regimens is widespread, and AC-based regimens are among the most commonly prescribed highly emetogenic chemotherapy regimens. The most significant challenge for my breast cancer patients receiving AC is chemotherapy-induced nausea and vomiting. Sustol represents a better option to manage this devastating side effect of therapy.”

For more details on the drug, access the full prescribing information at www.SUSTOL.com.

Patient receiving chemotherapy

Photo by Rhoda Baer

The US Food and Drug Administration (FDA) has approved granisetron extended-release injection (Sustol®) for the prevention of chemotherapy-induced nausea and vomiting (CINV) in adults.

Extended-release granisetron is a serotonin-3 (5-HT3) receptor antagonist that utilizes Biochronomer® polymer-based drug delivery technology to maintain therapeutic levels of granisetron for at least 5 days, covering both the acute and delayed phases of CINV.

The product is intended for use in combination with other anti-emetics to prevent acute and delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic chemotherapy (MEC) or anthracycline and cyclophosphamide (AC) combination chemotherapy regimens.

“Despite advances in the management of CINV, up to half of patients receiving chemotherapy can still experience CINV, with delayed CINV being particularly challenging to control,” said Ralph V. Boccia, MD, of the Center for Cancer and Blood Disorders in Bethesda, Maryland.

“In our experience, other 5-HT3 receptor antagonists, including palonosetron, are generally effective for 48 hours or less. Sustol, due to its extended-release profile, represents a novel option that can protect patients from CINV for a full 5 days.”

Extended-release granisetron (formerly known as APF530) is a product of Heron Therapeutics, Inc. The US commercial launch of the drug is planned for the fourth quarter of 2016.

Phase 3 trials

The global phase 3 development program of extended-release granisetron consisted of 2 large, guideline-based clinical trials of more than 2000 cancer patients.

In one trial, researchers compared extended-release granisetron to palonosetron for the prevention of acute and delayed CINV after MEC or highly emetogenic chemotherapy (HEC).

Results suggested extended-release granisetron was non-inferior to palonosetron. The most common adverse events observed in patients receiving granisetron were injection-site reactions and constipation.

In another trial, researchers compared extended-release granisetron to ondansetron for control of delayed CINV after HEC. Patients received extended-release granisetron, dexamethasone, and fosaprepitant or ondansetron, dexamethasone, and fosaprepitant.

A higher percentage of patients in the granisetron arm had delayed-phase complete response. The incidence of treatment-emergent adverse events was similar between the treatment arms.

“The Sustol clinical trial populations and results are highly representative of cancer patients in our real-world clinical practice,” said Jeffrey Vacirca, MD, of North Shore Hematology Oncology Associates in East Setauket, New York.

“Use of MEC regimens is widespread, and AC-based regimens are among the most commonly prescribed highly emetogenic chemotherapy regimens. The most significant challenge for my breast cancer patients receiving AC is chemotherapy-induced nausea and vomiting. Sustol represents a better option to manage this devastating side effect of therapy.”

For more details on the drug, access the full prescribing information at www.SUSTOL.com.

Patient receiving chemotherapy

Photo by Rhoda Baer

The US Food and Drug Administration (FDA) has approved granisetron extended-release injection (Sustol®) for the prevention of chemotherapy-induced nausea and vomiting (CINV) in adults.

Extended-release granisetron is a serotonin-3 (5-HT3) receptor antagonist that utilizes Biochronomer® polymer-based drug delivery technology to maintain therapeutic levels of granisetron for at least 5 days, covering both the acute and delayed phases of CINV.

The product is intended for use in combination with other anti-emetics to prevent acute and delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic chemotherapy (MEC) or anthracycline and cyclophosphamide (AC) combination chemotherapy regimens.

“Despite advances in the management of CINV, up to half of patients receiving chemotherapy can still experience CINV, with delayed CINV being particularly challenging to control,” said Ralph V. Boccia, MD, of the Center for Cancer and Blood Disorders in Bethesda, Maryland.

“In our experience, other 5-HT3 receptor antagonists, including palonosetron, are generally effective for 48 hours or less. Sustol, due to its extended-release profile, represents a novel option that can protect patients from CINV for a full 5 days.”

Extended-release granisetron (formerly known as APF530) is a product of Heron Therapeutics, Inc. The US commercial launch of the drug is planned for the fourth quarter of 2016.

Phase 3 trials

The global phase 3 development program of extended-release granisetron consisted of 2 large, guideline-based clinical trials of more than 2000 cancer patients.

In one trial, researchers compared extended-release granisetron to palonosetron for the prevention of acute and delayed CINV after MEC or highly emetogenic chemotherapy (HEC).

Results suggested extended-release granisetron was non-inferior to palonosetron. The most common adverse events observed in patients receiving granisetron were injection-site reactions and constipation.

In another trial, researchers compared extended-release granisetron to ondansetron for control of delayed CINV after HEC. Patients received extended-release granisetron, dexamethasone, and fosaprepitant or ondansetron, dexamethasone, and fosaprepitant.

A higher percentage of patients in the granisetron arm had delayed-phase complete response. The incidence of treatment-emergent adverse events was similar between the treatment arms.

“The Sustol clinical trial populations and results are highly representative of cancer patients in our real-world clinical practice,” said Jeffrey Vacirca, MD, of North Shore Hematology Oncology Associates in East Setauket, New York.

“Use of MEC regimens is widespread, and AC-based regimens are among the most commonly prescribed highly emetogenic chemotherapy regimens. The most significant challenge for my breast cancer patients receiving AC is chemotherapy-induced nausea and vomiting. Sustol represents a better option to manage this devastating side effect of therapy.”

For more details on the drug, access the full prescribing information at www.SUSTOL.com.

The incidence of Kaposi’s sarcoma among HIV patients has declined in the antiretroviral era, but the cancers are now presenting in older patients, after treatment starts, and in patients who have undetectable levels of HIV RNA.

Changes were also seen in the appearance of non-Hodgkin lymphoma, which is now occurring in patients with higher CD4 counts and lower HIV viral loads.

Although the findings of this large database study were largely driven by the fact that more patients are on antiretroviral therapy (ART) and in active clinical care, biological forces may also be at work, wrote Elizabeth L. Yanik, PhD, of the National Cancer Institute, Rockville, Md., and her associates (Am J Clin Oncol. 2016 Aug 9. doi: 10.1200/JCO.2016.67.6999).

“For example, cancers that develop in patients with HIV infection after immune recovery may manifest genetic or epigenetic changes that facilitate evasion from the immune system … [and] given that human herpesvirus-8 and Epstein-Barr virus are genetically heterogeneous, another possibility is that patients in whom Kaposi’s or non-Hodgkin lymphoma develops after immune reconstitution may be infected with more pathogenic strains.”

Dr. Yanik and her colleagues mined data from the Centers for AIDS Research Network of Integrated Clinical Systems (CNICS). The 24,901 patients have been followed from 1996-2011. Among them, 446 cases of Kaposi’s sarcoma (KS) and 258 cases of non-Hodgkin lymphoma (NHL) developed. Overall, KS and NHL incidence rates decreased 5% and 8% per year, respectively.

The proportion of KS diagnosed during routine care increased significantly, from 32% to 49%, reflecting the fact that more HIV patients continue to enter active clinical settings. The diagnostic setting of NHL did not change significantly over the study period, with 64% of cases being diagnosed in routine care in the latter years. From the beginning to the end of the study period, patient median age at diagnosis increased for both KS (from 37 to 42 years) and NHL (from 40 to 46 years).

The authors said this is a direct result of changing care patterns. “The proportion of KS cases diagnosed among patients who received ART increased not because KS incidence increased in patients who received ART but because of the growing fraction of the HIV population administered ART.”

As the study period progressed, more cases of KS appeared 6 months or longer after ART initiation, from 26% in the early years to 60% in the latter years. This change didn’t occur with NHL cases; 68% of them were diagnosed at least 6 months after ART began.

The mean CD4 count at diagnosis increased with time for both KS and NHL. During 2007-2011, 15% of KS cases and 24% of NHL cases were diagnosed at CD4 counts of 500 cells/mL or more, whereas less than half were diagnosed at CD4 counts less than 200 cells/mL, the authors observed.

Both cancers began to appear during periods of decreased viral load as the study progressed, although the decrease was only significant for NHL. However, from 2007 to 2011, 29% of KS cases and 51% of NHL cases were diagnosed when HIV RNA was suppressed to 500 copies/mL or lower.

Again, the authors related this to improved clinical care. “These clinical characteristics and the changes in the underlying HIV population are inherently related. Improvements in ART access and earlier initiation lead to earlier suppression of HIV RNA and, ultimately, higher CD4 counts,” they said.

msullivan@frontlinemedcom.com

On Twitter @Alz_Gal

The incidence of Kaposi’s sarcoma among HIV patients has declined in the antiretroviral era, but the cancers are now presenting in older patients, after treatment starts, and in patients who have undetectable levels of HIV RNA.

Changes were also seen in the appearance of non-Hodgkin lymphoma, which is now occurring in patients with higher CD4 counts and lower HIV viral loads.

Although the findings of this large database study were largely driven by the fact that more patients are on antiretroviral therapy (ART) and in active clinical care, biological forces may also be at work, wrote Elizabeth L. Yanik, PhD, of the National Cancer Institute, Rockville, Md., and her associates (Am J Clin Oncol. 2016 Aug 9. doi: 10.1200/JCO.2016.67.6999).

“For example, cancers that develop in patients with HIV infection after immune recovery may manifest genetic or epigenetic changes that facilitate evasion from the immune system … [and] given that human herpesvirus-8 and Epstein-Barr virus are genetically heterogeneous, another possibility is that patients in whom Kaposi’s or non-Hodgkin lymphoma develops after immune reconstitution may be infected with more pathogenic strains.”

Dr. Yanik and her colleagues mined data from the Centers for AIDS Research Network of Integrated Clinical Systems (CNICS). The 24,901 patients have been followed from 1996-2011. Among them, 446 cases of Kaposi’s sarcoma (KS) and 258 cases of non-Hodgkin lymphoma (NHL) developed. Overall, KS and NHL incidence rates decreased 5% and 8% per year, respectively.

The proportion of KS diagnosed during routine care increased significantly, from 32% to 49%, reflecting the fact that more HIV patients continue to enter active clinical settings. The diagnostic setting of NHL did not change significantly over the study period, with 64% of cases being diagnosed in routine care in the latter years. From the beginning to the end of the study period, patient median age at diagnosis increased for both KS (from 37 to 42 years) and NHL (from 40 to 46 years).

The authors said this is a direct result of changing care patterns. “The proportion of KS cases diagnosed among patients who received ART increased not because KS incidence increased in patients who received ART but because of the growing fraction of the HIV population administered ART.”

As the study period progressed, more cases of KS appeared 6 months or longer after ART initiation, from 26% in the early years to 60% in the latter years. This change didn’t occur with NHL cases; 68% of them were diagnosed at least 6 months after ART began.

The mean CD4 count at diagnosis increased with time for both KS and NHL. During 2007-2011, 15% of KS cases and 24% of NHL cases were diagnosed at CD4 counts of 500 cells/mL or more, whereas less than half were diagnosed at CD4 counts less than 200 cells/mL, the authors observed.

Both cancers began to appear during periods of decreased viral load as the study progressed, although the decrease was only significant for NHL. However, from 2007 to 2011, 29% of KS cases and 51% of NHL cases were diagnosed when HIV RNA was suppressed to 500 copies/mL or lower.

Again, the authors related this to improved clinical care. “These clinical characteristics and the changes in the underlying HIV population are inherently related. Improvements in ART access and earlier initiation lead to earlier suppression of HIV RNA and, ultimately, higher CD4 counts,” they said.

msullivan@frontlinemedcom.com

On Twitter @Alz_Gal

The incidence of Kaposi’s sarcoma among HIV patients has declined in the antiretroviral era, but the cancers are now presenting in older patients, after treatment starts, and in patients who have undetectable levels of HIV RNA.

Changes were also seen in the appearance of non-Hodgkin lymphoma, which is now occurring in patients with higher CD4 counts and lower HIV viral loads.

Although the findings of this large database study were largely driven by the fact that more patients are on antiretroviral therapy (ART) and in active clinical care, biological forces may also be at work, wrote Elizabeth L. Yanik, PhD, of the National Cancer Institute, Rockville, Md., and her associates (Am J Clin Oncol. 2016 Aug 9. doi: 10.1200/JCO.2016.67.6999).

“For example, cancers that develop in patients with HIV infection after immune recovery may manifest genetic or epigenetic changes that facilitate evasion from the immune system … [and] given that human herpesvirus-8 and Epstein-Barr virus are genetically heterogeneous, another possibility is that patients in whom Kaposi’s or non-Hodgkin lymphoma develops after immune reconstitution may be infected with more pathogenic strains.”

Dr. Yanik and her colleagues mined data from the Centers for AIDS Research Network of Integrated Clinical Systems (CNICS). The 24,901 patients have been followed from 1996-2011. Among them, 446 cases of Kaposi’s sarcoma (KS) and 258 cases of non-Hodgkin lymphoma (NHL) developed. Overall, KS and NHL incidence rates decreased 5% and 8% per year, respectively.

The proportion of KS diagnosed during routine care increased significantly, from 32% to 49%, reflecting the fact that more HIV patients continue to enter active clinical settings. The diagnostic setting of NHL did not change significantly over the study period, with 64% of cases being diagnosed in routine care in the latter years. From the beginning to the end of the study period, patient median age at diagnosis increased for both KS (from 37 to 42 years) and NHL (from 40 to 46 years).

The authors said this is a direct result of changing care patterns. “The proportion of KS cases diagnosed among patients who received ART increased not because KS incidence increased in patients who received ART but because of the growing fraction of the HIV population administered ART.”

As the study period progressed, more cases of KS appeared 6 months or longer after ART initiation, from 26% in the early years to 60% in the latter years. This change didn’t occur with NHL cases; 68% of them were diagnosed at least 6 months after ART began.

The mean CD4 count at diagnosis increased with time for both KS and NHL. During 2007-2011, 15% of KS cases and 24% of NHL cases were diagnosed at CD4 counts of 500 cells/mL or more, whereas less than half were diagnosed at CD4 counts less than 200 cells/mL, the authors observed.

Both cancers began to appear during periods of decreased viral load as the study progressed, although the decrease was only significant for NHL. However, from 2007 to 2011, 29% of KS cases and 51% of NHL cases were diagnosed when HIV RNA was suppressed to 500 copies/mL or lower.

Again, the authors related this to improved clinical care. “These clinical characteristics and the changes in the underlying HIV population are inherently related. Improvements in ART access and earlier initiation lead to earlier suppression of HIV RNA and, ultimately, higher CD4 counts,” they said.

msullivan@frontlinemedcom.com

On Twitter @Alz_Gal

Lab mouse

Preclinical research suggests a novel antibody can inhibit the migration of lymphoma cells and stop the cells from proliferating.

“Since they cannot survive in the blood for long, [lymphoma] cells are compelled to find a more accommodating environment—such as the lymphatic system—where they can proliferate,” explained Thomas Matthes, MD, of the University of Geneva in Switzerland.

“We decided to focus on this Achilles’ heel by containing them in the blood so as to prevent any resulting harm.”

Dr Matthes and his colleagues described this approach in the Journal of Leukocyte Biology.

The team noted that the inner wall of blood vessels is formed by a layer of endothelial cells that act as a barrier, which prevents the blood cells from leaving the circulation.

Yet, some lymphoma cells are equipped with a surface marker, the JAM-C protein, that is also present on the surface of endothelial cells. JAM-C’s presence on the surface of lymphoma cells facilitates their migration through the vessel walls between adjacent endothelial cells.

To block the effect of this protein, Dr Matthes and his colleagues developed an antibody targeting JAM-C.

This antibody, H225, was designed to bind solely to JAM-C. In doing so, H225 was able to prevent lymphoma cells from migrating out of the blood vessels.

In fact, H225 decreased the transit of lymphoma cells into the organs of the lymphatic system by over 50%.

“This is not its only effect,” Dr Matthes noted. “H225 also significantly limited cell proliferation, even when tumor cells had already settled in the lymphatic system. In our mice, we observed the nearly complete disappearance of already present tumor cells in the organs.”

Specifically, H225 reduced tumor growth of JAM-C+ mantle cell lymphoma cells in the bone marrow, spleen, liver, and lymph nodes.

The researchers believe this work has laid the foundation for a new therapeutic strategy against lymphoma. The team is now focusing its efforts on the quest for an efficient treatment that could be offered to patients.

Lab mouse

Preclinical research suggests a novel antibody can inhibit the migration of lymphoma cells and stop the cells from proliferating.

“Since they cannot survive in the blood for long, [lymphoma] cells are compelled to find a more accommodating environment—such as the lymphatic system—where they can proliferate,” explained Thomas Matthes, MD, of the University of Geneva in Switzerland.

“We decided to focus on this Achilles’ heel by containing them in the blood so as to prevent any resulting harm.”

Dr Matthes and his colleagues described this approach in the Journal of Leukocyte Biology.

The team noted that the inner wall of blood vessels is formed by a layer of endothelial cells that act as a barrier, which prevents the blood cells from leaving the circulation.

Yet, some lymphoma cells are equipped with a surface marker, the JAM-C protein, that is also present on the surface of endothelial cells. JAM-C’s presence on the surface of lymphoma cells facilitates their migration through the vessel walls between adjacent endothelial cells.

To block the effect of this protein, Dr Matthes and his colleagues developed an antibody targeting JAM-C.

This antibody, H225, was designed to bind solely to JAM-C. In doing so, H225 was able to prevent lymphoma cells from migrating out of the blood vessels.

In fact, H225 decreased the transit of lymphoma cells into the organs of the lymphatic system by over 50%.

“This is not its only effect,” Dr Matthes noted. “H225 also significantly limited cell proliferation, even when tumor cells had already settled in the lymphatic system. In our mice, we observed the nearly complete disappearance of already present tumor cells in the organs.”

Specifically, H225 reduced tumor growth of JAM-C+ mantle cell lymphoma cells in the bone marrow, spleen, liver, and lymph nodes.

The researchers believe this work has laid the foundation for a new therapeutic strategy against lymphoma. The team is now focusing its efforts on the quest for an efficient treatment that could be offered to patients.

Lab mouse

Preclinical research suggests a novel antibody can inhibit the migration of lymphoma cells and stop the cells from proliferating.

“Since they cannot survive in the blood for long, [lymphoma] cells are compelled to find a more accommodating environment—such as the lymphatic system—where they can proliferate,” explained Thomas Matthes, MD, of the University of Geneva in Switzerland.

“We decided to focus on this Achilles’ heel by containing them in the blood so as to prevent any resulting harm.”

Dr Matthes and his colleagues described this approach in the Journal of Leukocyte Biology.

The team noted that the inner wall of blood vessels is formed by a layer of endothelial cells that act as a barrier, which prevents the blood cells from leaving the circulation.

Yet, some lymphoma cells are equipped with a surface marker, the JAM-C protein, that is also present on the surface of endothelial cells. JAM-C’s presence on the surface of lymphoma cells facilitates their migration through the vessel walls between adjacent endothelial cells.

To block the effect of this protein, Dr Matthes and his colleagues developed an antibody targeting JAM-C.

This antibody, H225, was designed to bind solely to JAM-C. In doing so, H225 was able to prevent lymphoma cells from migrating out of the blood vessels.

In fact, H225 decreased the transit of lymphoma cells into the organs of the lymphatic system by over 50%.

“This is not its only effect,” Dr Matthes noted. “H225 also significantly limited cell proliferation, even when tumor cells had already settled in the lymphatic system. In our mice, we observed the nearly complete disappearance of already present tumor cells in the organs.”

Specifically, H225 reduced tumor growth of JAM-C+ mantle cell lymphoma cells in the bone marrow, spleen, liver, and lymph nodes.

The researchers believe this work has laid the foundation for a new therapeutic strategy against lymphoma. The team is now focusing its efforts on the quest for an efficient treatment that could be offered to patients.

The European Commission has granted orphan drug designation for the T-cell therapy product candidate BPX-501 and the small molecule rimiducid.

BPX-501 consists of genetically modified donor T cells incorporating the CaspaCIDe safety switch, which is designed to eliminate the T cells in the event of toxicity.

Rimiducid is used to activate the CaspaCIDe safety switch, which consists of the CID-binding domain coupled to the signaling domain of caspase-9, an enzyme that is part of the apoptotic pathway.

The goal of this therapy is to allow physicians to more safely perform haploidentical hematopoietic stem cell transplant (haplo-HSCT).

Haplo-HSCT recipients receive BPX-501 to speed immune reconstitution and provide control over viral infections. And rimiducid is used to eliminate BPX-501 alloreactive T cells if severe graft-vs-host disease (GVHD) occurs.

If a patient develops severe GVHD, rimiducid is used to trigger activation of the domain of caspase-9, which leads to selective apoptosis of the CaspaCIDe-containing cells.

About orphan designation

Orphan drug designation from the European Commission provides regulatory and financial incentives for companies to develop and market therapies that treat serious or life-threatening conditions that affect no more than 5 in 10,000 people in the European Union (EU), and where no treatment is currently approved.

In addition to a 10-year period of marketing exclusivity in the EU upon product approval, orphan drug designation provides fee waivers, protocol assistance, and marketing authorization under the centralized procedure granting approval in all EU countries.

BPX-501/rimiducid development

BPX-501 and rimiducid are being developed by Bellicum Pharmaceuticals.

The company has met with regulatory authorities in Europe to discuss the potential approval pathway for BPX-501 and rimiducid for the treatment of immunodeficiency and GVHD following haplo-HSCT in pediatric patients with leukemias, lymphomas, and rare inherited blood diseases who do not have a matched donor.

These discussions have resulted in an initial agreement regarding the company’s development plans, subject to further refinement in a formal protocol assistance process that is available for orphan drug products.

Based on regulatory discussions, Bellicum believes that data from the European arm of its BP-004 trial, with a 6-month follow-up time and expanded to enroll additional patients, could form the basis of marketing authorization applications for BPX-501 and rimiducid.

The European Medicines Agency’s Committee for Medicinal Products for Human Use has agreed that review and approval under “exceptional circumstances” may be suitable, recognizing that a randomized trial may not be feasible in the pediatric setting. In place of a randomized trial, Bellicum intends to collect data from a concurrent observational study of allogeneic HSCT outcomes in the pediatric setting.

The European Medicines Agency can grant early market authorization to orphan drug products under exceptional circumstances. Exceptional circumstances can be granted for medicines that treat very rare diseases or where controlled studies are impractical or not consistent with accepted principles of medical ethics.

BP-004 trial

BP-004 is a phase 1/2 dose-escalation trial of BPX-501 and rimiducid in pediatric patients with malignant and nonmalignant diseases. Interim results from this trial were reported in 2 presentations at the 42nd Annual Meeting of the European Society for Blood and Marrow Transplantation in April 2016.

One presentation involved patients with acute leukemia who received BPX-501 after haplo-HSCT. At a median follow-up of 7 months, 16 of the 17 patients were alive and disease-free. There were several cases of GVHD, but nearly all were resolved.

The other presentation covered patients with nonmalignant disorders who received BPX-501 after haplo-HSCT. At a median follow-up of 7 months, all 24 patients studied were still alive and disease-free. The incidence of GVHD was considered “very low.” 

The European Commission has granted orphan drug designation for the T-cell therapy product candidate BPX-501 and the small molecule rimiducid.

BPX-501 consists of genetically modified donor T cells incorporating the CaspaCIDe safety switch, which is designed to eliminate the T cells in the event of toxicity.

Rimiducid is used to activate the CaspaCIDe safety switch, which consists of the CID-binding domain coupled to the signaling domain of caspase-9, an enzyme that is part of the apoptotic pathway.

The goal of this therapy is to allow physicians to more safely perform haploidentical hematopoietic stem cell transplant (haplo-HSCT).

Haplo-HSCT recipients receive BPX-501 to speed immune reconstitution and provide control over viral infections. And rimiducid is used to eliminate BPX-501 alloreactive T cells if severe graft-vs-host disease (GVHD) occurs.

If a patient develops severe GVHD, rimiducid is used to trigger activation of the domain of caspase-9, which leads to selective apoptosis of the CaspaCIDe-containing cells.

About orphan designation

Orphan drug designation from the European Commission provides regulatory and financial incentives for companies to develop and market therapies that treat serious or life-threatening conditions that affect no more than 5 in 10,000 people in the European Union (EU), and where no treatment is currently approved.

In addition to a 10-year period of marketing exclusivity in the EU upon product approval, orphan drug designation provides fee waivers, protocol assistance, and marketing authorization under the centralized procedure granting approval in all EU countries.

BPX-501/rimiducid development

BPX-501 and rimiducid are being developed by Bellicum Pharmaceuticals.

The company has met with regulatory authorities in Europe to discuss the potential approval pathway for BPX-501 and rimiducid for the treatment of immunodeficiency and GVHD following haplo-HSCT in pediatric patients with leukemias, lymphomas, and rare inherited blood diseases who do not have a matched donor.

These discussions have resulted in an initial agreement regarding the company’s development plans, subject to further refinement in a formal protocol assistance process that is available for orphan drug products.

Based on regulatory discussions, Bellicum believes that data from the European arm of its BP-004 trial, with a 6-month follow-up time and expanded to enroll additional patients, could form the basis of marketing authorization applications for BPX-501 and rimiducid.

The European Medicines Agency’s Committee for Medicinal Products for Human Use has agreed that review and approval under “exceptional circumstances” may be suitable, recognizing that a randomized trial may not be feasible in the pediatric setting. In place of a randomized trial, Bellicum intends to collect data from a concurrent observational study of allogeneic HSCT outcomes in the pediatric setting.

The European Medicines Agency can grant early market authorization to orphan drug products under exceptional circumstances. Exceptional circumstances can be granted for medicines that treat very rare diseases or where controlled studies are impractical or not consistent with accepted principles of medical ethics.

BP-004 trial

BP-004 is a phase 1/2 dose-escalation trial of BPX-501 and rimiducid in pediatric patients with malignant and nonmalignant diseases. Interim results from this trial were reported in 2 presentations at the 42nd Annual Meeting of the European Society for Blood and Marrow Transplantation in April 2016.

One presentation involved patients with acute leukemia who received BPX-501 after haplo-HSCT. At a median follow-up of 7 months, 16 of the 17 patients were alive and disease-free. There were several cases of GVHD, but nearly all were resolved.

The other presentation covered patients with nonmalignant disorders who received BPX-501 after haplo-HSCT. At a median follow-up of 7 months, all 24 patients studied were still alive and disease-free. The incidence of GVHD was considered “very low.” 

The European Commission has granted orphan drug designation for the T-cell therapy product candidate BPX-501 and the small molecule rimiducid.

BPX-501 consists of genetically modified donor T cells incorporating the CaspaCIDe safety switch, which is designed to eliminate the T cells in the event of toxicity.

Rimiducid is used to activate the CaspaCIDe safety switch, which consists of the CID-binding domain coupled to the signaling domain of caspase-9, an enzyme that is part of the apoptotic pathway.

The goal of this therapy is to allow physicians to more safely perform haploidentical hematopoietic stem cell transplant (haplo-HSCT).

Haplo-HSCT recipients receive BPX-501 to speed immune reconstitution and provide control over viral infections. And rimiducid is used to eliminate BPX-501 alloreactive T cells if severe graft-vs-host disease (GVHD) occurs.

If a patient develops severe GVHD, rimiducid is used to trigger activation of the domain of caspase-9, which leads to selective apoptosis of the CaspaCIDe-containing cells.

About orphan designation

Orphan drug designation from the European Commission provides regulatory and financial incentives for companies to develop and market therapies that treat serious or life-threatening conditions that affect no more than 5 in 10,000 people in the European Union (EU), and where no treatment is currently approved.

In addition to a 10-year period of marketing exclusivity in the EU upon product approval, orphan drug designation provides fee waivers, protocol assistance, and marketing authorization under the centralized procedure granting approval in all EU countries.

BPX-501/rimiducid development

BPX-501 and rimiducid are being developed by Bellicum Pharmaceuticals.

The company has met with regulatory authorities in Europe to discuss the potential approval pathway for BPX-501 and rimiducid for the treatment of immunodeficiency and GVHD following haplo-HSCT in pediatric patients with leukemias, lymphomas, and rare inherited blood diseases who do not have a matched donor.

These discussions have resulted in an initial agreement regarding the company’s development plans, subject to further refinement in a formal protocol assistance process that is available for orphan drug products.

Based on regulatory discussions, Bellicum believes that data from the European arm of its BP-004 trial, with a 6-month follow-up time and expanded to enroll additional patients, could form the basis of marketing authorization applications for BPX-501 and rimiducid.

The European Medicines Agency’s Committee for Medicinal Products for Human Use has agreed that review and approval under “exceptional circumstances” may be suitable, recognizing that a randomized trial may not be feasible in the pediatric setting. In place of a randomized trial, Bellicum intends to collect data from a concurrent observational study of allogeneic HSCT outcomes in the pediatric setting.

The European Medicines Agency can grant early market authorization to orphan drug products under exceptional circumstances. Exceptional circumstances can be granted for medicines that treat very rare diseases or where controlled studies are impractical or not consistent with accepted principles of medical ethics.

BP-004 trial

BP-004 is a phase 1/2 dose-escalation trial of BPX-501 and rimiducid in pediatric patients with malignant and nonmalignant diseases. Interim results from this trial were reported in 2 presentations at the 42nd Annual Meeting of the European Society for Blood and Marrow Transplantation in April 2016.

One presentation involved patients with acute leukemia who received BPX-501 after haplo-HSCT. At a median follow-up of 7 months, 16 of the 17 patients were alive and disease-free. There were several cases of GVHD, but nearly all were resolved.

The other presentation covered patients with nonmalignant disorders who received BPX-501 after haplo-HSCT. At a median follow-up of 7 months, all 24 patients studied were still alive and disease-free. The incidence of GVHD was considered “very low.” 

T cells

Image by NIAID

Researchers have reported “favorable” long-term results from a pair of phase 1 trials in which they used the non-viral Sleeping Beauty (SB) transposon/transposase system to create CD19-specific chimeric antigen receptor (CAR) T cells.

These CAR T cells appeared to be safe, and results suggested they can provide additional control of leukemia and lymphoma when given after autologous or allogeneic hematopoietic stem cell transplant (HSCT).

In addition, the researchers said use of the SB transposon/transposase platform could reduce the costs and complexity associated with recombinant viral vector-based immunotherapy.

The team described their results with the SB system in The Journal of Clinical Investigation. Results from these trials were previously reported at the inaugural CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference.

The trials were sponsored by MD Anderson Cancer Center in collaboration with the National Cancer Institute, National Center for Research Resources, Intrexon Corporation, and Ziopharm Oncology.

The trials included 26 patients with multiply relapsed B-lineage acute lymphoblastic leukemia (ALL, n=17) or B-cell non-Hodgkin lymphoma (NHL, n=9).

The patients received SB-modified T cells after autologous (n=7) or allogeneic (n=19) HSCT.

The researchers said SB-mediated gene transfer and stimulation resulted in large ex vivo expansion of T cells while retaining CAR expression and without integration hotspots.

Autologous and allogeneic T cells survived after infusion an average of 201 days and 51 days, respectively.

Safety

The researchers said there were no unexpected acute infusion or delayed toxicities. Mild elevations in cytokines were observed but not cytokine storm.

Three allogeneic HSCT recipients developed graft-vs-host disease (GVHD). One patient developed grade 1 acute skin GVHD that resolved with topical steroids, and 1 developed chronic skin GVHD that responded to systemic steroids.

The third patient, who had a history of drug-induced liver toxicity, developed recurrent liver toxicity with a component of liver GVHD 1 month after T-cell infusion. This patient died of liver failure.

There were 5 other deaths, all of them due to disease relapse.

Efficacy: Autologous HSCT

Seven patients with advanced NHL were treated with autologous HSCT, followed by the administration of patient-derived CAR T cells.

Six of the 7 patients were in complete remission (CR) at a median follow-up of 25.5 months (range, 6.4 to 32.7 months).

The 30-month progression-free survival (PFS) rate was 83%, and the overall survival (OS) rate was 100%.

Efficacy: Allogeneic HSCT

Nineteen patients (ALL n=17, NHL n=2) received donor-derived CAR T cells after allogeneic HSCT. The patients had advanced disease at the time of HSCT, and CAR T cells were administered without additional lymphodepletion.

Eleven of 19 patients were still in CR at a median follow-up of 7.5 months (range, 2.7 to 17.9 months). The 1-year PFS rate was 53%, and the OS rate was 63%.

The researchers also looked at the subset of allogeneic HSCT recipients who received haplo-identical CAR T cells. These 8 patients had a 1-year PFS rate of 75% and an OS rate of 100%.

“By following these patients over an extended duration, as we do in these studies, we can better understand the added benefit of CAR-T over HSCT alone,” said Francois Lebel, MD, of Ziopharm Oncology.

“Although the primary objective of these trials was not to establish efficacy, the recipients’ outcomes are encouraging, with apparent doubling of survivals compared to historical controls. We are encouraged by these clinical data and look forward to results from our phase 1 study infusing our next-generation CD19-specific CAR T cells in patients with advanced lymphoid malignancies.”

T cells

Image by NIAID

Researchers have reported “favorable” long-term results from a pair of phase 1 trials in which they used the non-viral Sleeping Beauty (SB) transposon/transposase system to create CD19-specific chimeric antigen receptor (CAR) T cells.

These CAR T cells appeared to be safe, and results suggested they can provide additional control of leukemia and lymphoma when given after autologous or allogeneic hematopoietic stem cell transplant (HSCT).

In addition, the researchers said use of the SB transposon/transposase platform could reduce the costs and complexity associated with recombinant viral vector-based immunotherapy.

The team described their results with the SB system in The Journal of Clinical Investigation. Results from these trials were previously reported at the inaugural CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference.

The trials were sponsored by MD Anderson Cancer Center in collaboration with the National Cancer Institute, National Center for Research Resources, Intrexon Corporation, and Ziopharm Oncology.

The trials included 26 patients with multiply relapsed B-lineage acute lymphoblastic leukemia (ALL, n=17) or B-cell non-Hodgkin lymphoma (NHL, n=9).

The patients received SB-modified T cells after autologous (n=7) or allogeneic (n=19) HSCT.

The researchers said SB-mediated gene transfer and stimulation resulted in large ex vivo expansion of T cells while retaining CAR expression and without integration hotspots.

Autologous and allogeneic T cells survived after infusion an average of 201 days and 51 days, respectively.

Safety

The researchers said there were no unexpected acute infusion or delayed toxicities. Mild elevations in cytokines were observed but not cytokine storm.

Three allogeneic HSCT recipients developed graft-vs-host disease (GVHD). One patient developed grade 1 acute skin GVHD that resolved with topical steroids, and 1 developed chronic skin GVHD that responded to systemic steroids.

The third patient, who had a history of drug-induced liver toxicity, developed recurrent liver toxicity with a component of liver GVHD 1 month after T-cell infusion. This patient died of liver failure.

There were 5 other deaths, all of them due to disease relapse.

Efficacy: Autologous HSCT

Seven patients with advanced NHL were treated with autologous HSCT, followed by the administration of patient-derived CAR T cells.

Six of the 7 patients were in complete remission (CR) at a median follow-up of 25.5 months (range, 6.4 to 32.7 months).

The 30-month progression-free survival (PFS) rate was 83%, and the overall survival (OS) rate was 100%.

Efficacy: Allogeneic HSCT

Nineteen patients (ALL n=17, NHL n=2) received donor-derived CAR T cells after allogeneic HSCT. The patients had advanced disease at the time of HSCT, and CAR T cells were administered without additional lymphodepletion.

Eleven of 19 patients were still in CR at a median follow-up of 7.5 months (range, 2.7 to 17.9 months). The 1-year PFS rate was 53%, and the OS rate was 63%.

The researchers also looked at the subset of allogeneic HSCT recipients who received haplo-identical CAR T cells. These 8 patients had a 1-year PFS rate of 75% and an OS rate of 100%.

“By following these patients over an extended duration, as we do in these studies, we can better understand the added benefit of CAR-T over HSCT alone,” said Francois Lebel, MD, of Ziopharm Oncology.

“Although the primary objective of these trials was not to establish efficacy, the recipients’ outcomes are encouraging, with apparent doubling of survivals compared to historical controls. We are encouraged by these clinical data and look forward to results from our phase 1 study infusing our next-generation CD19-specific CAR T cells in patients with advanced lymphoid malignancies.”

T cells

Image by NIAID

Researchers have reported “favorable” long-term results from a pair of phase 1 trials in which they used the non-viral Sleeping Beauty (SB) transposon/transposase system to create CD19-specific chimeric antigen receptor (CAR) T cells.

These CAR T cells appeared to be safe, and results suggested they can provide additional control of leukemia and lymphoma when given after autologous or allogeneic hematopoietic stem cell transplant (HSCT).

In addition, the researchers said use of the SB transposon/transposase platform could reduce the costs and complexity associated with recombinant viral vector-based immunotherapy.

The team described their results with the SB system in The Journal of Clinical Investigation. Results from these trials were previously reported at the inaugural CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference.

The trials were sponsored by MD Anderson Cancer Center in collaboration with the National Cancer Institute, National Center for Research Resources, Intrexon Corporation, and Ziopharm Oncology.

The trials included 26 patients with multiply relapsed B-lineage acute lymphoblastic leukemia (ALL, n=17) or B-cell non-Hodgkin lymphoma (NHL, n=9).

The patients received SB-modified T cells after autologous (n=7) or allogeneic (n=19) HSCT.

The researchers said SB-mediated gene transfer and stimulation resulted in large ex vivo expansion of T cells while retaining CAR expression and without integration hotspots.

Autologous and allogeneic T cells survived after infusion an average of 201 days and 51 days, respectively.

Safety

The researchers said there were no unexpected acute infusion or delayed toxicities. Mild elevations in cytokines were observed but not cytokine storm.

Three allogeneic HSCT recipients developed graft-vs-host disease (GVHD). One patient developed grade 1 acute skin GVHD that resolved with topical steroids, and 1 developed chronic skin GVHD that responded to systemic steroids.

The third patient, who had a history of drug-induced liver toxicity, developed recurrent liver toxicity with a component of liver GVHD 1 month after T-cell infusion. This patient died of liver failure.

There were 5 other deaths, all of them due to disease relapse.

Efficacy: Autologous HSCT

Seven patients with advanced NHL were treated with autologous HSCT, followed by the administration of patient-derived CAR T cells.

Six of the 7 patients were in complete remission (CR) at a median follow-up of 25.5 months (range, 6.4 to 32.7 months).

The 30-month progression-free survival (PFS) rate was 83%, and the overall survival (OS) rate was 100%.

Efficacy: Allogeneic HSCT

Nineteen patients (ALL n=17, NHL n=2) received donor-derived CAR T cells after allogeneic HSCT. The patients had advanced disease at the time of HSCT, and CAR T cells were administered without additional lymphodepletion.

Eleven of 19 patients were still in CR at a median follow-up of 7.5 months (range, 2.7 to 17.9 months). The 1-year PFS rate was 53%, and the OS rate was 63%.

The researchers also looked at the subset of allogeneic HSCT recipients who received haplo-identical CAR T cells. These 8 patients had a 1-year PFS rate of 75% and an OS rate of 100%.

“By following these patients over an extended duration, as we do in these studies, we can better understand the added benefit of CAR-T over HSCT alone,” said Francois Lebel, MD, of Ziopharm Oncology.

“Although the primary objective of these trials was not to establish efficacy, the recipients’ outcomes are encouraging, with apparent doubling of survivals compared to historical controls. We are encouraged by these clinical data and look forward to results from our phase 1 study infusing our next-generation CD19-specific CAR T cells in patients with advanced lymphoid malignancies.”