Multiple Myeloma

Drug production

Photo courtesy of the FDA

Despite recent progress in the fight against cancers, these diseases continue to exert “an immense toll” in the US, according to the AACR Cancer Progress Report 2015.

The report highlights the recent approval by the US Food and Drug Administration (FDA) of several anticancer therapies, a vaccine, and 2 diagnostic aids.

But the report also includes data suggesting that cancer cases, and costs related to cancer care, are on the rise.

The report states that, between Aug. 1, 2014, and July 31, 2015, the FDA approved 9 anticancer therapies, either for the first time or for new indications.

During the same period, the FDA approved a new cancer vaccine, a new cancer screening test, and a new use for a previously approved imaging agent.

Despite these advances, cancers continue to exert personal and economic tolls, according to the report.

It states that cancer is the number 1 cause of disease-related death among US children. And more than 589,000 people in the US are projected to die from cancer in 2015.

The number of new cancer cases in the US is predicted to rise from 1.7 million in 2015 to 2.4 million in 2035.

In addition, estimates suggest the direct medical costs of cancer care in the US in 2010 were nearly $125 billion, and these costs are predicted to rise to $156 billion in 2020.

These data underscore the need for more research to develop new approaches to cancer prevention and treatment, according to the report.

Its authors call for Congress and the administration to provide the National Institutes of Health, National Cancer Institute, and FDA with annual funding increases.

“We have made spectacular progress against cancer, which has saved the lives of millions of individuals in the United States and around the world,” said Margaret Foti, PhD, MD, chief executive officer of the AACR.

“However, without increased federal funding for cancer research, we will not be able to realize the promise of recent discoveries and technological advances.”

Drug production

Photo courtesy of the FDA

Despite recent progress in the fight against cancers, these diseases continue to exert “an immense toll” in the US, according to the AACR Cancer Progress Report 2015.

The report highlights the recent approval by the US Food and Drug Administration (FDA) of several anticancer therapies, a vaccine, and 2 diagnostic aids.

But the report also includes data suggesting that cancer cases, and costs related to cancer care, are on the rise.

The report states that, between Aug. 1, 2014, and July 31, 2015, the FDA approved 9 anticancer therapies, either for the first time or for new indications.

During the same period, the FDA approved a new cancer vaccine, a new cancer screening test, and a new use for a previously approved imaging agent.

Despite these advances, cancers continue to exert personal and economic tolls, according to the report.

It states that cancer is the number 1 cause of disease-related death among US children. And more than 589,000 people in the US are projected to die from cancer in 2015.

The number of new cancer cases in the US is predicted to rise from 1.7 million in 2015 to 2.4 million in 2035.

In addition, estimates suggest the direct medical costs of cancer care in the US in 2010 were nearly $125 billion, and these costs are predicted to rise to $156 billion in 2020.

These data underscore the need for more research to develop new approaches to cancer prevention and treatment, according to the report.

Its authors call for Congress and the administration to provide the National Institutes of Health, National Cancer Institute, and FDA with annual funding increases.

“We have made spectacular progress against cancer, which has saved the lives of millions of individuals in the United States and around the world,” said Margaret Foti, PhD, MD, chief executive officer of the AACR.

“However, without increased federal funding for cancer research, we will not be able to realize the promise of recent discoveries and technological advances.”

Drug production

Photo courtesy of the FDA

Despite recent progress in the fight against cancers, these diseases continue to exert “an immense toll” in the US, according to the AACR Cancer Progress Report 2015.

The report highlights the recent approval by the US Food and Drug Administration (FDA) of several anticancer therapies, a vaccine, and 2 diagnostic aids.

But the report also includes data suggesting that cancer cases, and costs related to cancer care, are on the rise.

The report states that, between Aug. 1, 2014, and July 31, 2015, the FDA approved 9 anticancer therapies, either for the first time or for new indications.

During the same period, the FDA approved a new cancer vaccine, a new cancer screening test, and a new use for a previously approved imaging agent.

Despite these advances, cancers continue to exert personal and economic tolls, according to the report.

It states that cancer is the number 1 cause of disease-related death among US children. And more than 589,000 people in the US are projected to die from cancer in 2015.

The number of new cancer cases in the US is predicted to rise from 1.7 million in 2015 to 2.4 million in 2035.

In addition, estimates suggest the direct medical costs of cancer care in the US in 2010 were nearly $125 billion, and these costs are predicted to rise to $156 billion in 2020.

These data underscore the need for more research to develop new approaches to cancer prevention and treatment, according to the report.

Its authors call for Congress and the administration to provide the National Institutes of Health, National Cancer Institute, and FDA with annual funding increases.

“We have made spectacular progress against cancer, which has saved the lives of millions of individuals in the United States and around the world,” said Margaret Foti, PhD, MD, chief executive officer of the AACR.

“However, without increased federal funding for cancer research, we will not be able to realize the promise of recent discoveries and technological advances.”

US dollars

Photo by Petr Kratochvil

Results of a small survey suggest patients with multiple myeloma (MM) are vulnerable to “financial toxicity,” due to costly treatments, even if they have health insurance and well-paying jobs.

All of the 100 patients surveyed had health insurance and a median household income above the US average.

Yet 46% of respondents said they tapped into their savings to pay for treatment, and 21% borrowed money to pay for care.

Seventeen percent of patients reported delays in treatment due to costs, and 11% said excessive costs caused them to stop treatment altogether.

Results of this survey appear in The Lancet Haematology.

Risk of financial toxicity

Financial toxicity is described as the burden of out-of-pocket costs that can affect patients’ wellbeing and become an adverse effect of treatment.

Previous studies have suggested that patients frequently employ coping mechanisms to help defray out-of-pocket costs, some of which compromise treatment adherence. Financial toxicity may also negatively impact quality of life, and some reports suggest it may contribute to increased mortality.

“While advances in multiple myeloma therapy have contributed to significant improvements in patient outcomes, the clinical gains have come with rising costs,” said Scott Huntington, MD, of Yale University in New Haven, Connecticut.

Costs of newly approved drugs for hematologic malignancies have increased 10-fold in the past 15 years, with many agents costing $10,000 or more a month.

“And today . . . , most patients are on a new drug, compared to a decade ago when less than 5% were,” Dr Huntington said. “So we’re not talking about a select group of patients faced with this burden. Many are facing the financial challenges of treatment.”

Survey population

To investigate the effects of treatment costs in MM, Dr Huntington and his colleagues surveyed 100 patients treated at the Abramson Cancer Center in Philadelphia, Pennsylvania. The median age of the patients was 64, and 53% were female.

The researchers used the COST (Comprehensive Score for Financial Toxicity) questionnaire and other survey questions. The COST tool measures various aspects of financial circumstances, such as income, education, marital status, ability to work, and overall opinions about additional expenses and a person’s current financial situation.

All survey respondents were insured, and all of the patients with Medicare fee-for-service coverage (39%) had additional supplemental insurance to assist with out-of-pocket costs.

The respondents also had a median household income and education level above the national average. The median annual household income

was reported between $60,000 and $79,999, and 70% of respondents reported having some college education.

At the time of the survey, 62% of respondents were receiving first-line (35%) or second-line (27%) treatment. All patients were receiving or had received at least 1 novel drug for MM.

Seventy-five percent of patients had received both lenalidomide and bortezomib since their diagnosis, and 58% had undergone an autologous stem cell transplant. Forty-four percent of patients had received 3 to 4 treatment regimens, and 25% had received 5 or more.

Survey results

Of the 100 patients surveyed, 59% said MM treatment costs were higher than expected, and 71% indicated at least minor financial burden. Fifty-five percent of patients said they had to reduce spending on basic goods since their diagnosis, and 64% said they had to reduce spending on leisure activities.

Thirty-six percent of respondents reported applying for financial assistance to pay for treatment, including 18% who reported incomes over $100,000. Forty-six percent of respondents said they used their savings to pay for treatment, and 21% borrowed money.

The high cost of MM therapy prompted treatment delays for 17% of patients, caused 12% of patients to fill only part of a prescription, and made 11% of patients stop treatment altogether.

Adding to the financial burden, more than half of respondents said they had to reduce their hours at work or quit their job after being diagnosed with MM.

The researchers said these results suggest a need to “acknowledge the untenable rise in treatment costs and its impact on patients.” And “strengthened collaboration” between patients and healthcare stakeholders is needed to promote reforms that lead to more affordable cancer care.

US dollars

Photo by Petr Kratochvil

Results of a small survey suggest patients with multiple myeloma (MM) are vulnerable to “financial toxicity,” due to costly treatments, even if they have health insurance and well-paying jobs.

All of the 100 patients surveyed had health insurance and a median household income above the US average.

Yet 46% of respondents said they tapped into their savings to pay for treatment, and 21% borrowed money to pay for care.

Seventeen percent of patients reported delays in treatment due to costs, and 11% said excessive costs caused them to stop treatment altogether.

Results of this survey appear in The Lancet Haematology.

Risk of financial toxicity

Financial toxicity is described as the burden of out-of-pocket costs that can affect patients’ wellbeing and become an adverse effect of treatment.

Previous studies have suggested that patients frequently employ coping mechanisms to help defray out-of-pocket costs, some of which compromise treatment adherence. Financial toxicity may also negatively impact quality of life, and some reports suggest it may contribute to increased mortality.

“While advances in multiple myeloma therapy have contributed to significant improvements in patient outcomes, the clinical gains have come with rising costs,” said Scott Huntington, MD, of Yale University in New Haven, Connecticut.

Costs of newly approved drugs for hematologic malignancies have increased 10-fold in the past 15 years, with many agents costing $10,000 or more a month.

“And today . . . , most patients are on a new drug, compared to a decade ago when less than 5% were,” Dr Huntington said. “So we’re not talking about a select group of patients faced with this burden. Many are facing the financial challenges of treatment.”

Survey population

To investigate the effects of treatment costs in MM, Dr Huntington and his colleagues surveyed 100 patients treated at the Abramson Cancer Center in Philadelphia, Pennsylvania. The median age of the patients was 64, and 53% were female.

The researchers used the COST (Comprehensive Score for Financial Toxicity) questionnaire and other survey questions. The COST tool measures various aspects of financial circumstances, such as income, education, marital status, ability to work, and overall opinions about additional expenses and a person’s current financial situation.

All survey respondents were insured, and all of the patients with Medicare fee-for-service coverage (39%) had additional supplemental insurance to assist with out-of-pocket costs.

The respondents also had a median household income and education level above the national average. The median annual household income

was reported between $60,000 and $79,999, and 70% of respondents reported having some college education.

At the time of the survey, 62% of respondents were receiving first-line (35%) or second-line (27%) treatment. All patients were receiving or had received at least 1 novel drug for MM.

Seventy-five percent of patients had received both lenalidomide and bortezomib since their diagnosis, and 58% had undergone an autologous stem cell transplant. Forty-four percent of patients had received 3 to 4 treatment regimens, and 25% had received 5 or more.

Survey results

Of the 100 patients surveyed, 59% said MM treatment costs were higher than expected, and 71% indicated at least minor financial burden. Fifty-five percent of patients said they had to reduce spending on basic goods since their diagnosis, and 64% said they had to reduce spending on leisure activities.

Thirty-six percent of respondents reported applying for financial assistance to pay for treatment, including 18% who reported incomes over $100,000. Forty-six percent of respondents said they used their savings to pay for treatment, and 21% borrowed money.

The high cost of MM therapy prompted treatment delays for 17% of patients, caused 12% of patients to fill only part of a prescription, and made 11% of patients stop treatment altogether.

Adding to the financial burden, more than half of respondents said they had to reduce their hours at work or quit their job after being diagnosed with MM.

The researchers said these results suggest a need to “acknowledge the untenable rise in treatment costs and its impact on patients.” And “strengthened collaboration” between patients and healthcare stakeholders is needed to promote reforms that lead to more affordable cancer care.

US dollars

Photo by Petr Kratochvil

Results of a small survey suggest patients with multiple myeloma (MM) are vulnerable to “financial toxicity,” due to costly treatments, even if they have health insurance and well-paying jobs.

All of the 100 patients surveyed had health insurance and a median household income above the US average.

Yet 46% of respondents said they tapped into their savings to pay for treatment, and 21% borrowed money to pay for care.

Seventeen percent of patients reported delays in treatment due to costs, and 11% said excessive costs caused them to stop treatment altogether.

Results of this survey appear in The Lancet Haematology.

Risk of financial toxicity

Financial toxicity is described as the burden of out-of-pocket costs that can affect patients’ wellbeing and become an adverse effect of treatment.

Previous studies have suggested that patients frequently employ coping mechanisms to help defray out-of-pocket costs, some of which compromise treatment adherence. Financial toxicity may also negatively impact quality of life, and some reports suggest it may contribute to increased mortality.

“While advances in multiple myeloma therapy have contributed to significant improvements in patient outcomes, the clinical gains have come with rising costs,” said Scott Huntington, MD, of Yale University in New Haven, Connecticut.

Costs of newly approved drugs for hematologic malignancies have increased 10-fold in the past 15 years, with many agents costing $10,000 or more a month.

“And today . . . , most patients are on a new drug, compared to a decade ago when less than 5% were,” Dr Huntington said. “So we’re not talking about a select group of patients faced with this burden. Many are facing the financial challenges of treatment.”

Survey population

To investigate the effects of treatment costs in MM, Dr Huntington and his colleagues surveyed 100 patients treated at the Abramson Cancer Center in Philadelphia, Pennsylvania. The median age of the patients was 64, and 53% were female.

The researchers used the COST (Comprehensive Score for Financial Toxicity) questionnaire and other survey questions. The COST tool measures various aspects of financial circumstances, such as income, education, marital status, ability to work, and overall opinions about additional expenses and a person’s current financial situation.

All survey respondents were insured, and all of the patients with Medicare fee-for-service coverage (39%) had additional supplemental insurance to assist with out-of-pocket costs.

The respondents also had a median household income and education level above the national average. The median annual household income

was reported between $60,000 and $79,999, and 70% of respondents reported having some college education.

At the time of the survey, 62% of respondents were receiving first-line (35%) or second-line (27%) treatment. All patients were receiving or had received at least 1 novel drug for MM.

Seventy-five percent of patients had received both lenalidomide and bortezomib since their diagnosis, and 58% had undergone an autologous stem cell transplant. Forty-four percent of patients had received 3 to 4 treatment regimens, and 25% had received 5 or more.

Survey results

Of the 100 patients surveyed, 59% said MM treatment costs were higher than expected, and 71% indicated at least minor financial burden. Fifty-five percent of patients said they had to reduce spending on basic goods since their diagnosis, and 64% said they had to reduce spending on leisure activities.

Thirty-six percent of respondents reported applying for financial assistance to pay for treatment, including 18% who reported incomes over $100,000. Forty-six percent of respondents said they used their savings to pay for treatment, and 21% borrowed money.

The high cost of MM therapy prompted treatment delays for 17% of patients, caused 12% of patients to fill only part of a prescription, and made 11% of patients stop treatment altogether.

Adding to the financial burden, more than half of respondents said they had to reduce their hours at work or quit their job after being diagnosed with MM.

The researchers said these results suggest a need to “acknowledge the untenable rise in treatment costs and its impact on patients.” And “strengthened collaboration” between patients and healthcare stakeholders is needed to promote reforms that lead to more affordable cancer care.

Nicotiana benthamiana plants

Scientists have reported a new way to produce the chemotherapeutic agent etoposide, and they believe this discovery could lead to a more stable supply of the drug.

Currently, producing etoposide requires isolating one of its precursors, (–)-podophyllotoxin, from the endangered, slow-growing, Himalayan Mayapple plant (Podophyllum hexandrum).

But researchers found they could generate the immediate precursor to etoposide—(–)-4’-desmethyl-epipodophyllotoxin—in a more easily accessible, faster-growing tobacco plant (Nicotiana benthamiana).

Elizabeth Sattely, PhD, of Stanford University in California, and her graduate student, Warren Lau, described this work in Science.

The pair noted that there are 4 known genes behind (–)-podophyllotoxin production, but the full recipe for this compound has eluded researchers, in part because of the Mayapple’s immense genome.

To tap into the Mayapple’s chemotherapeutic potential, Lau and Dr Sattely first focused on the 4 known genes—PLR, SDH, CYP719A23, and DIR. Then, they analyzed RNA sequencing data from the Mayapple to identify similar genes.

Next, the pair manipulated the tobacco plant to express multiple gene candidates at once and identified the resulting compounds in leaf tissue using mass spectrometry.

Dr Sattely and Lau identified 6 new genes—OMT3, CYP71CU1, OMT1, 2-ODD, CYP71BE54, and CYP82D61.

These genes, when expressed with the original 4, produce the immediate etoposide precursor (–)-4′-desmethyl-epipodophyllotoxin, which outperforms (–)-podophyllotoxin as a chemotherapy ingredient.

The researchers said this work has revealed a simpler and more direct route to etoposide that circumvents the semisynthetic epimerization and demethylation required to produce etoposide from (–)-podophyllotoxin.

However, Dr Sattely said the eventual goal is to use yeast instead of plants to produce etoposide. Yeast can be grown in large vats and may therefore provide a more stable source of drugs.

In addition, yeast provides the opportunity to modify genes to produce proteins with slightly different functions. And it may be possible to feed the yeast a slightly different starting product, thereby changing the chemical a molecular assembly line churns out.

These approaches could provide a way of tweaking existing drugs in an effort to improve them.

Nicotiana benthamiana plants

Scientists have reported a new way to produce the chemotherapeutic agent etoposide, and they believe this discovery could lead to a more stable supply of the drug.

Currently, producing etoposide requires isolating one of its precursors, (–)-podophyllotoxin, from the endangered, slow-growing, Himalayan Mayapple plant (Podophyllum hexandrum).

But researchers found they could generate the immediate precursor to etoposide—(–)-4’-desmethyl-epipodophyllotoxin—in a more easily accessible, faster-growing tobacco plant (Nicotiana benthamiana).

Elizabeth Sattely, PhD, of Stanford University in California, and her graduate student, Warren Lau, described this work in Science.

The pair noted that there are 4 known genes behind (–)-podophyllotoxin production, but the full recipe for this compound has eluded researchers, in part because of the Mayapple’s immense genome.

To tap into the Mayapple’s chemotherapeutic potential, Lau and Dr Sattely first focused on the 4 known genes—PLR, SDH, CYP719A23, and DIR. Then, they analyzed RNA sequencing data from the Mayapple to identify similar genes.

Next, the pair manipulated the tobacco plant to express multiple gene candidates at once and identified the resulting compounds in leaf tissue using mass spectrometry.

Dr Sattely and Lau identified 6 new genes—OMT3, CYP71CU1, OMT1, 2-ODD, CYP71BE54, and CYP82D61.

These genes, when expressed with the original 4, produce the immediate etoposide precursor (–)-4′-desmethyl-epipodophyllotoxin, which outperforms (–)-podophyllotoxin as a chemotherapy ingredient.

The researchers said this work has revealed a simpler and more direct route to etoposide that circumvents the semisynthetic epimerization and demethylation required to produce etoposide from (–)-podophyllotoxin.

However, Dr Sattely said the eventual goal is to use yeast instead of plants to produce etoposide. Yeast can be grown in large vats and may therefore provide a more stable source of drugs.

In addition, yeast provides the opportunity to modify genes to produce proteins with slightly different functions. And it may be possible to feed the yeast a slightly different starting product, thereby changing the chemical a molecular assembly line churns out.

These approaches could provide a way of tweaking existing drugs in an effort to improve them.

Nicotiana benthamiana plants

Scientists have reported a new way to produce the chemotherapeutic agent etoposide, and they believe this discovery could lead to a more stable supply of the drug.

Currently, producing etoposide requires isolating one of its precursors, (–)-podophyllotoxin, from the endangered, slow-growing, Himalayan Mayapple plant (Podophyllum hexandrum).

But researchers found they could generate the immediate precursor to etoposide—(–)-4’-desmethyl-epipodophyllotoxin—in a more easily accessible, faster-growing tobacco plant (Nicotiana benthamiana).

Elizabeth Sattely, PhD, of Stanford University in California, and her graduate student, Warren Lau, described this work in Science.

The pair noted that there are 4 known genes behind (–)-podophyllotoxin production, but the full recipe for this compound has eluded researchers, in part because of the Mayapple’s immense genome.

To tap into the Mayapple’s chemotherapeutic potential, Lau and Dr Sattely first focused on the 4 known genes—PLR, SDH, CYP719A23, and DIR. Then, they analyzed RNA sequencing data from the Mayapple to identify similar genes.

Next, the pair manipulated the tobacco plant to express multiple gene candidates at once and identified the resulting compounds in leaf tissue using mass spectrometry.

Dr Sattely and Lau identified 6 new genes—OMT3, CYP71CU1, OMT1, 2-ODD, CYP71BE54, and CYP82D61.

These genes, when expressed with the original 4, produce the immediate etoposide precursor (–)-4′-desmethyl-epipodophyllotoxin, which outperforms (–)-podophyllotoxin as a chemotherapy ingredient.

The researchers said this work has revealed a simpler and more direct route to etoposide that circumvents the semisynthetic epimerization and demethylation required to produce etoposide from (–)-podophyllotoxin.

However, Dr Sattely said the eventual goal is to use yeast instead of plants to produce etoposide. Yeast can be grown in large vats and may therefore provide a more stable source of drugs.

In addition, yeast provides the opportunity to modify genes to produce proteins with slightly different functions. And it may be possible to feed the yeast a slightly different starting product, thereby changing the chemical a molecular assembly line churns out.

These approaches could provide a way of tweaking existing drugs in an effort to improve them.

There was a 2.4-fold increased risk for monoclonal gammopathy of undetermined significance (MGUS), a precursor to multiple myeloma (MM), for Air Force veterans exposed to Agent Orange, according to a study reported in JAMA Oncology. Already, veterans who develop MM and were exposed to Agent Orange during military service are eligible to receive benefits, but the study further highlights the relationship.

Related: Management of Myeloma and Its Precursor Syndromes

The Agent Orange used during aerial spray missions of herbicides in the Vietnam War contained 2, 4-dichlorophenoxyacetic acid (2,4-D) and 2,4,5-trichlorophenoxyacetic acid (2,4,5-T), as well as human carcinogen 2,3,7,8-tetrachlorodibenzo-p-doxin in variable amounts. After obtaining the laboratory data from 958 serum samples from Air Force personnel, the Air Force Health Studies questionnaire, and results from the physical exam from all participants, researchers were able to compare their findings with control group veterans.

Related: Nephrotic Syndrome Is a Marker for Occult Cancer

The researchers created 2 test groups from Air Force veterans. The first were 777 participants of Operation Ranch Hand, who conducted aerial herbicidal missions from 1962 to 1971, and the second group was made up of 1,174 participants, who had similar duties but did not participate in the missions.

The risk of MGUS was more pronounced in veterans aged > 70 years (odds ratio [OR], 3.4; 95% confidence interval [CI], 1.27-4.44; P = .007). Among veterans aged > 70 years, there was not a significant increase in risk (OR, 1.4%; 95% CI, 0.55-3.63; P = .63). The crude prevalence of overall MGUS was 7.1% (34 of 479) in the exposed veterans, compared with 3.1% (15 of 479) in the comparison group.

Source
Landgren O, Shim YK, Michalek J, et al. JAMA Oncol. [Published online ahead of print September 3, 2015.]
doi: 10.1001/jamaoncol.2015.2938.

There was a 2.4-fold increased risk for monoclonal gammopathy of undetermined significance (MGUS), a precursor to multiple myeloma (MM), for Air Force veterans exposed to Agent Orange, according to a study reported in JAMA Oncology. Already, veterans who develop MM and were exposed to Agent Orange during military service are eligible to receive benefits, but the study further highlights the relationship.

Related: Management of Myeloma and Its Precursor Syndromes

The Agent Orange used during aerial spray missions of herbicides in the Vietnam War contained 2, 4-dichlorophenoxyacetic acid (2,4-D) and 2,4,5-trichlorophenoxyacetic acid (2,4,5-T), as well as human carcinogen 2,3,7,8-tetrachlorodibenzo-p-doxin in variable amounts. After obtaining the laboratory data from 958 serum samples from Air Force personnel, the Air Force Health Studies questionnaire, and results from the physical exam from all participants, researchers were able to compare their findings with control group veterans.

Related: Nephrotic Syndrome Is a Marker for Occult Cancer

The researchers created 2 test groups from Air Force veterans. The first were 777 participants of Operation Ranch Hand, who conducted aerial herbicidal missions from 1962 to 1971, and the second group was made up of 1,174 participants, who had similar duties but did not participate in the missions.

The risk of MGUS was more pronounced in veterans aged > 70 years (odds ratio [OR], 3.4; 95% confidence interval [CI], 1.27-4.44; P = .007). Among veterans aged > 70 years, there was not a significant increase in risk (OR, 1.4%; 95% CI, 0.55-3.63; P = .63). The crude prevalence of overall MGUS was 7.1% (34 of 479) in the exposed veterans, compared with 3.1% (15 of 479) in the comparison group.

Source
Landgren O, Shim YK, Michalek J, et al. JAMA Oncol. [Published online ahead of print September 3, 2015.]
doi: 10.1001/jamaoncol.2015.2938.

There was a 2.4-fold increased risk for monoclonal gammopathy of undetermined significance (MGUS), a precursor to multiple myeloma (MM), for Air Force veterans exposed to Agent Orange, according to a study reported in JAMA Oncology. Already, veterans who develop MM and were exposed to Agent Orange during military service are eligible to receive benefits, but the study further highlights the relationship.

Related: Management of Myeloma and Its Precursor Syndromes

The Agent Orange used during aerial spray missions of herbicides in the Vietnam War contained 2, 4-dichlorophenoxyacetic acid (2,4-D) and 2,4,5-trichlorophenoxyacetic acid (2,4,5-T), as well as human carcinogen 2,3,7,8-tetrachlorodibenzo-p-doxin in variable amounts. After obtaining the laboratory data from 958 serum samples from Air Force personnel, the Air Force Health Studies questionnaire, and results from the physical exam from all participants, researchers were able to compare their findings with control group veterans.

Related: Nephrotic Syndrome Is a Marker for Occult Cancer

The researchers created 2 test groups from Air Force veterans. The first were 777 participants of Operation Ranch Hand, who conducted aerial herbicidal missions from 1962 to 1971, and the second group was made up of 1,174 participants, who had similar duties but did not participate in the missions.

The risk of MGUS was more pronounced in veterans aged > 70 years (odds ratio [OR], 3.4; 95% confidence interval [CI], 1.27-4.44; P = .007). Among veterans aged > 70 years, there was not a significant increase in risk (OR, 1.4%; 95% CI, 0.55-3.63; P = .63). The crude prevalence of overall MGUS was 7.1% (34 of 479) in the exposed veterans, compared with 3.1% (15 of 479) in the comparison group.

Source
Landgren O, Shim YK, Michalek J, et al. JAMA Oncol. [Published online ahead of print September 3, 2015.]
doi: 10.1001/jamaoncol.2015.2938.

CTL019 preparation

Photo from Penn Medicine

Investigators have described a 3-pronged treatment approach that induced sustained remission in a patient with advanced multiple myeloma (MM).

The treatment combined chemotherapy, autologous stem cell transplant, and the chimeric antigen receptor T-cell therapy CTL019.

The patient, who had received 9 prior lines of therapy, responded to this combination despite the fact that 99.95% of her neoplastic plasma cells did not express CD19.

“There was some skepticism about whether a CD19-directed therapy would work in this disease, since nearly all of these patients’ cancerous plasma cells do not express CD19,” said study author Edward Stadtmauer, MD, of the University of Pennsylvania in Philadelphia.

“Since there was data showing that the possible stem cells can be CD19-positive, our hypothesis was that we may be able to devise a therapy targeted at early precursors of those cells.”

Dr Stadtmauer and his colleagues described this case, which is part of a larger trial, in NEJM.

Prior to receiving the combination therapy, the MM patient had received 9 different treatment regimens in the 5 years since her diagnosis (at age 43).

The patient had received regimens containing lenalidomide, bortezomib, dexamethasone, carfilzomib, pomalidomide, vorinostat, clarithromycin, and elotuzumab. She also received a previous autologous stem cell transplant, which had only controlled her disease for a few months.

For this study, the patient received high-dose melphalan (140 mg/m²), reinfusion of autologous stem cells (≥2.1×10⁶ cells per kg of body weight), and a CTL019 infusion 12 days later.

Response and adverse effects

The patient experienced transplant-related side effects prior to receiving CTL019, including grade 4 neutropenia and thrombocytopenia, grade 2 nausea and anorexia, neutropenic fever, and Staphylococcus aureus bacteremia. By day 100 after transplant, all transplant-related adverse effects had resolved.

The patient had hypogammaglobulinemia before transplant that persisted at day 100 after transplant and was attributed to the effects of CTL019 on normal B cells and plasma cells. There were no other adverse events attributable to CTL019.

On day 130 after transplant, the patient began to receive lenalidomide maintenance at 5 mg daily (an optional part of the protocol). Her dose was later reduced to 5 mg twice weekly because of gastrointestinal side effects.

At day 130 after CTL019 infusion, tests revealed no evidence of disease. The patient—who was the first to be treated as part of this trial—remains in remission more than 12 months after receiving this therapy.

“We couldn’t be more pleased with this patient’s response,” said study author Alfred Garfall, MD, of the University of Pennsylvania.

“We believe her CTL019 cells made the difference, since we would not have expected such a durable remission with a transplant alone, considering the very transient response this patient had to her first transplant several years ago.”

Dr Garfall and his colleagues also reported on the trial’s overall progress. Of the 10 patients who have received this combination therapy to date, 6 remain progression-free, although 2 patients have been treated very recently.

The additional CTL019-attributable side effects have been grade 1 cytokine release syndrome (n=1) and grade 3 enterocolitis due to autologous graft-vs-host disease (n=1).

This trial is sponsored by Novartis, the company developing CTL019, and others. CTL019 was originally developed at the University of Pennsylvania, but the university licensed the technology to Novartis.

CTL019 preparation

Photo from Penn Medicine

Investigators have described a 3-pronged treatment approach that induced sustained remission in a patient with advanced multiple myeloma (MM).

The treatment combined chemotherapy, autologous stem cell transplant, and the chimeric antigen receptor T-cell therapy CTL019.

The patient, who had received 9 prior lines of therapy, responded to this combination despite the fact that 99.95% of her neoplastic plasma cells did not express CD19.

“There was some skepticism about whether a CD19-directed therapy would work in this disease, since nearly all of these patients’ cancerous plasma cells do not express CD19,” said study author Edward Stadtmauer, MD, of the University of Pennsylvania in Philadelphia.

“Since there was data showing that the possible stem cells can be CD19-positive, our hypothesis was that we may be able to devise a therapy targeted at early precursors of those cells.”

Dr Stadtmauer and his colleagues described this case, which is part of a larger trial, in NEJM.

Prior to receiving the combination therapy, the MM patient had received 9 different treatment regimens in the 5 years since her diagnosis (at age 43).

The patient had received regimens containing lenalidomide, bortezomib, dexamethasone, carfilzomib, pomalidomide, vorinostat, clarithromycin, and elotuzumab. She also received a previous autologous stem cell transplant, which had only controlled her disease for a few months.

For this study, the patient received high-dose melphalan (140 mg/m²), reinfusion of autologous stem cells (≥2.1×10⁶ cells per kg of body weight), and a CTL019 infusion 12 days later.

Response and adverse effects

The patient experienced transplant-related side effects prior to receiving CTL019, including grade 4 neutropenia and thrombocytopenia, grade 2 nausea and anorexia, neutropenic fever, and Staphylococcus aureus bacteremia. By day 100 after transplant, all transplant-related adverse effects had resolved.

The patient had hypogammaglobulinemia before transplant that persisted at day 100 after transplant and was attributed to the effects of CTL019 on normal B cells and plasma cells. There were no other adverse events attributable to CTL019.

On day 130 after transplant, the patient began to receive lenalidomide maintenance at 5 mg daily (an optional part of the protocol). Her dose was later reduced to 5 mg twice weekly because of gastrointestinal side effects.

At day 130 after CTL019 infusion, tests revealed no evidence of disease. The patient—who was the first to be treated as part of this trial—remains in remission more than 12 months after receiving this therapy.

“We couldn’t be more pleased with this patient’s response,” said study author Alfred Garfall, MD, of the University of Pennsylvania.

“We believe her CTL019 cells made the difference, since we would not have expected such a durable remission with a transplant alone, considering the very transient response this patient had to her first transplant several years ago.”

Dr Garfall and his colleagues also reported on the trial’s overall progress. Of the 10 patients who have received this combination therapy to date, 6 remain progression-free, although 2 patients have been treated very recently.

The additional CTL019-attributable side effects have been grade 1 cytokine release syndrome (n=1) and grade 3 enterocolitis due to autologous graft-vs-host disease (n=1).

This trial is sponsored by Novartis, the company developing CTL019, and others. CTL019 was originally developed at the University of Pennsylvania, but the university licensed the technology to Novartis.

CTL019 preparation

Photo from Penn Medicine

Investigators have described a 3-pronged treatment approach that induced sustained remission in a patient with advanced multiple myeloma (MM).

The treatment combined chemotherapy, autologous stem cell transplant, and the chimeric antigen receptor T-cell therapy CTL019.

The patient, who had received 9 prior lines of therapy, responded to this combination despite the fact that 99.95% of her neoplastic plasma cells did not express CD19.

“There was some skepticism about whether a CD19-directed therapy would work in this disease, since nearly all of these patients’ cancerous plasma cells do not express CD19,” said study author Edward Stadtmauer, MD, of the University of Pennsylvania in Philadelphia.

“Since there was data showing that the possible stem cells can be CD19-positive, our hypothesis was that we may be able to devise a therapy targeted at early precursors of those cells.”

Dr Stadtmauer and his colleagues described this case, which is part of a larger trial, in NEJM.

Prior to receiving the combination therapy, the MM patient had received 9 different treatment regimens in the 5 years since her diagnosis (at age 43).

The patient had received regimens containing lenalidomide, bortezomib, dexamethasone, carfilzomib, pomalidomide, vorinostat, clarithromycin, and elotuzumab. She also received a previous autologous stem cell transplant, which had only controlled her disease for a few months.

For this study, the patient received high-dose melphalan (140 mg/m²), reinfusion of autologous stem cells (≥2.1×10⁶ cells per kg of body weight), and a CTL019 infusion 12 days later.

Response and adverse effects

The patient experienced transplant-related side effects prior to receiving CTL019, including grade 4 neutropenia and thrombocytopenia, grade 2 nausea and anorexia, neutropenic fever, and Staphylococcus aureus bacteremia. By day 100 after transplant, all transplant-related adverse effects had resolved.

The patient had hypogammaglobulinemia before transplant that persisted at day 100 after transplant and was attributed to the effects of CTL019 on normal B cells and plasma cells. There were no other adverse events attributable to CTL019.

On day 130 after transplant, the patient began to receive lenalidomide maintenance at 5 mg daily (an optional part of the protocol). Her dose was later reduced to 5 mg twice weekly because of gastrointestinal side effects.

At day 130 after CTL019 infusion, tests revealed no evidence of disease. The patient—who was the first to be treated as part of this trial—remains in remission more than 12 months after receiving this therapy.

“We couldn’t be more pleased with this patient’s response,” said study author Alfred Garfall, MD, of the University of Pennsylvania.

“We believe her CTL019 cells made the difference, since we would not have expected such a durable remission with a transplant alone, considering the very transient response this patient had to her first transplant several years ago.”

Dr Garfall and his colleagues also reported on the trial’s overall progress. Of the 10 patients who have received this combination therapy to date, 6 remain progression-free, although 2 patients have been treated very recently.

The additional CTL019-attributable side effects have been grade 1 cytokine release syndrome (n=1) and grade 3 enterocolitis due to autologous graft-vs-host disease (n=1).

This trial is sponsored by Novartis, the company developing CTL019, and others. CTL019 was originally developed at the University of Pennsylvania, but the university licensed the technology to Novartis.

The first recipient of CTL019 for advanced refractory multiple myeloma achieved a durable complete response without developing cytokine release syndrome, according to a study published Sept. 9 in the New England Journal of Medicine.

“Twelve months after transplantation, the patient had no evidence of monoclonal immunoglobulin on serum and urine immunofixation and no clinical signs or symptoms of multiple myeloma,” said Dr. Alfred Garfall and his associates at the University of Pennsylvania in Philadelphia. “This response was achieved despite the absence of CD19 expression in 99.95% of the patient’s neoplastic plasma cells.”

Courtesy Wikimedia Commons/KGH/Creative Commons License

CTL019 consists of autologous T cells modified to express an anti-CD19 chimeric antigen receptor (CAR) from a lentiviral vector. The cell therapy has yielded promising results in relapsed/refractory CLL and ALL,but was overlooked in MM because it was thought to infrequently express CD19, the researchers said.

“Several reports, however, have suggested that a minor component of the MM clone with drug-resistant, disease-propagating properties has a B-cell (i.e., CD19-positive) phenotype,” they noted. “In addition, our unpublished observations suggest that neoplastic plasma cells express low levels of CD19” (N Engl J Med. 2015 Sep 9;373:1040-7).

In response, they designed a pilot trial of adults whose MM relapsed or progressed within a year after initial autologous stem cell transplant. The first participant, a 43-year-old woman with IgA kappa MM, partially responded to lenalidomide, bortezomib, and dexamethasone but progressed when therapy was paused to collect stem cells for transplant. She then partially responded to cisplatin, doxorubicin, cyclophosphamide, and etoposide followed by high-dose melphalan and ASCT, but progressed again and continued to worsen despite a total of nine lines of therapy. A bone marrow sample revealed more than 95% plasma cells when the patient began the CTL019 trial, the researchers said.

For the study, the patient received a lower melphalan dose (140 mg/m² of body surface area), followed by ASCT, CTL019 starting 2 weeks later, and maintenance lenalidomide. On day 100, her tumor burden had dropped by 5-log10, the researchers said. She also did not develop cytokine release syndrome, they added.

So far, 10 patients have been treated on study, of whom six remain progression free, according to the investigators. “The only additional CTL019-attributable toxic effects observed have been one instance of grade 1 cytokine release syndrome and one instance of grade 3 enterocolitis due to autologous graft-versus-host disease,” they reported.

Novartis supported the study and approved the manuscript. The work was also funded by the National Institutes of Health, the International Society for Advancement of Cytometry, the University of Pennsylvania Institute or Translational Medicine and Therapeutics, and a Conquer Cancer Foundation Young Investigator Award. The University of Pennsylvania has licensed technologies involved in this trial to Novartis. Several scientists involved in this trial hold patents for these technologies. As a result of the licensing relationship with Novartis, the University of Pennsylvania receives significant financial benefit, and these inventors have benefited financially or may benefit in the future.

The first recipient of CTL019 for advanced refractory multiple myeloma achieved a durable complete response without developing cytokine release syndrome, according to a study published Sept. 9 in the New England Journal of Medicine.

“Twelve months after transplantation, the patient had no evidence of monoclonal immunoglobulin on serum and urine immunofixation and no clinical signs or symptoms of multiple myeloma,” said Dr. Alfred Garfall and his associates at the University of Pennsylvania in Philadelphia. “This response was achieved despite the absence of CD19 expression in 99.95% of the patient’s neoplastic plasma cells.”

Courtesy Wikimedia Commons/KGH/Creative Commons License

CTL019 consists of autologous T cells modified to express an anti-CD19 chimeric antigen receptor (CAR) from a lentiviral vector. The cell therapy has yielded promising results in relapsed/refractory CLL and ALL,but was overlooked in MM because it was thought to infrequently express CD19, the researchers said.

“Several reports, however, have suggested that a minor component of the MM clone with drug-resistant, disease-propagating properties has a B-cell (i.e., CD19-positive) phenotype,” they noted. “In addition, our unpublished observations suggest that neoplastic plasma cells express low levels of CD19” (N Engl J Med. 2015 Sep 9;373:1040-7).

In response, they designed a pilot trial of adults whose MM relapsed or progressed within a year after initial autologous stem cell transplant. The first participant, a 43-year-old woman with IgA kappa MM, partially responded to lenalidomide, bortezomib, and dexamethasone but progressed when therapy was paused to collect stem cells for transplant. She then partially responded to cisplatin, doxorubicin, cyclophosphamide, and etoposide followed by high-dose melphalan and ASCT, but progressed again and continued to worsen despite a total of nine lines of therapy. A bone marrow sample revealed more than 95% plasma cells when the patient began the CTL019 trial, the researchers said.

For the study, the patient received a lower melphalan dose (140 mg/m² of body surface area), followed by ASCT, CTL019 starting 2 weeks later, and maintenance lenalidomide. On day 100, her tumor burden had dropped by 5-log10, the researchers said. She also did not develop cytokine release syndrome, they added.

So far, 10 patients have been treated on study, of whom six remain progression free, according to the investigators. “The only additional CTL019-attributable toxic effects observed have been one instance of grade 1 cytokine release syndrome and one instance of grade 3 enterocolitis due to autologous graft-versus-host disease,” they reported.

Novartis supported the study and approved the manuscript. The work was also funded by the National Institutes of Health, the International Society for Advancement of Cytometry, the University of Pennsylvania Institute or Translational Medicine and Therapeutics, and a Conquer Cancer Foundation Young Investigator Award. The University of Pennsylvania has licensed technologies involved in this trial to Novartis. Several scientists involved in this trial hold patents for these technologies. As a result of the licensing relationship with Novartis, the University of Pennsylvania receives significant financial benefit, and these inventors have benefited financially or may benefit in the future.

The first recipient of CTL019 for advanced refractory multiple myeloma achieved a durable complete response without developing cytokine release syndrome, according to a study published Sept. 9 in the New England Journal of Medicine.

“Twelve months after transplantation, the patient had no evidence of monoclonal immunoglobulin on serum and urine immunofixation and no clinical signs or symptoms of multiple myeloma,” said Dr. Alfred Garfall and his associates at the University of Pennsylvania in Philadelphia. “This response was achieved despite the absence of CD19 expression in 99.95% of the patient’s neoplastic plasma cells.”

Courtesy Wikimedia Commons/KGH/Creative Commons License

CTL019 consists of autologous T cells modified to express an anti-CD19 chimeric antigen receptor (CAR) from a lentiviral vector. The cell therapy has yielded promising results in relapsed/refractory CLL and ALL,but was overlooked in MM because it was thought to infrequently express CD19, the researchers said.

“Several reports, however, have suggested that a minor component of the MM clone with drug-resistant, disease-propagating properties has a B-cell (i.e., CD19-positive) phenotype,” they noted. “In addition, our unpublished observations suggest that neoplastic plasma cells express low levels of CD19” (N Engl J Med. 2015 Sep 9;373:1040-7).

In response, they designed a pilot trial of adults whose MM relapsed or progressed within a year after initial autologous stem cell transplant. The first participant, a 43-year-old woman with IgA kappa MM, partially responded to lenalidomide, bortezomib, and dexamethasone but progressed when therapy was paused to collect stem cells for transplant. She then partially responded to cisplatin, doxorubicin, cyclophosphamide, and etoposide followed by high-dose melphalan and ASCT, but progressed again and continued to worsen despite a total of nine lines of therapy. A bone marrow sample revealed more than 95% plasma cells when the patient began the CTL019 trial, the researchers said.

For the study, the patient received a lower melphalan dose (140 mg/m² of body surface area), followed by ASCT, CTL019 starting 2 weeks later, and maintenance lenalidomide. On day 100, her tumor burden had dropped by 5-log10, the researchers said. She also did not develop cytokine release syndrome, they added.

So far, 10 patients have been treated on study, of whom six remain progression free, according to the investigators. “The only additional CTL019-attributable toxic effects observed have been one instance of grade 1 cytokine release syndrome and one instance of grade 3 enterocolitis due to autologous graft-versus-host disease,” they reported.

Novartis supported the study and approved the manuscript. The work was also funded by the National Institutes of Health, the International Society for Advancement of Cytometry, the University of Pennsylvania Institute or Translational Medicine and Therapeutics, and a Conquer Cancer Foundation Young Investigator Award. The University of Pennsylvania has licensed technologies involved in this trial to Novartis. Several scientists involved in this trial hold patents for these technologies. As a result of the licensing relationship with Novartis, the University of Pennsylvania receives significant financial benefit, and these inventors have benefited financially or may benefit in the future.

Researcher in the lab

Photo by Darren Baker

Researchers say they have created a model that can show how nearly any drug behaves in P-glycoprotein (P-gp), a protein associated with chemotherapy failure.

The team developed this computer-generated model to overcome the problem of relying on static images for the structure of P-gp.

When the researchers introduced drugs into the model, the drugs responded the way they do in real life and behaved according to predictions.

John G. Wise, PhD, of Southern Methodist University in Dallas, Texas, and his colleagues described the model in Biochemistry.

“The value of this fundamental research is that it generates dynamic mechanisms that let us understand something in biochemistry, in biology,” Dr Wise said. “And by understanding P-gp in such detail, we can now think of ways to better and more specifically inhibit it.”

Dr Wise and his colleagues noted that P-gp protects cells by pumping out toxins, but that can include chemotherapy drugs. So inhibiting P-gp’s pumping action might circumvent chemotherapy failure.

With than in mind, the team tested tariquidar, a P-gp inhibitor in clinical trials, in their model.

It hasn’t been clear exactly where tariquidar binds in P-gp. But the model showed the drug prefers to bind high in the protein. Tariquidar also behaved as expected. It wasn’t effectively pumped from the cell.

“Now we have more details on how tariquidar inhibits P-gp, where it inhibits, and what it’s actually binding to,” Dr Wise said.

He and his colleagues also used their model to uncover additional details about the behavior of other drugs in P-gp.

“For a long time, it’s been thought that there are at least a couple of distinct binding sites for drugs,” Dr Wise said.

“Sure enough, with our models, we found that [the chemotherapeutic agent] daunorubicin, at least, prefers to bind on one side of the P-gp model, while verapamil—a commonly prescribed blood pressure medicine—prefers the other side.”

Not only did the researchers show computationally that there are 2 different starting points for drugs, they also showed that there are 2 different pathways to get the drugs through.

“The 2 different drugs start at different sites, and they’re funneled to the outside by being pushed by the protein,” Dr Wise said. “But the actual parts of the protein that are pushing the drugs out are different.”

Drug discovery

Being able to watch molecular machinery up close, while it is doing its job the way it does in real life, may spark new drug discoveries to fight cancer, Dr Wise said.

“Having an accurate model that actually moves—that shows the dynamics of the thing—is incredibly helpful in developing therapies against a molecular target to inhibit it,” Dr Wise said. “The only other ways to do it are blind, and the chances of success using blind methods are very low.”

“Scientists have tried for 30 years to find inhibitors of this pump and have done it without knowing the structure and with only little knowledge about the mechanism, screening more or less blindly for compounds that inhibit the thing.”

“They found drugs that worked in the test tube and that worked in cultured cells but that didn’t work in the patient. With our model, because we can see the pump moving, we can probably predict better what’s going to make an inhibitor actually work well.”

Dr Wise and his colleagues used the P-gp model to virtually screen millions of publicly available compounds. They discovered 3 new drug leads that could ultimately inhibit P-gp and offer better odds of survival to prostate cancer patients.

The researchers reported these findings in Pharmacology Research & Perspectives.

Creating the model

To build the P-gp model, Dr Wise and his colleagues used static structures from the US Protein Data Bank repository. They used structures showing various stages of transport to simulate 4 points of reference.

From there, the team fed a supercomputer parameters and characteristics of the protein, as well as how it should behave physically, including when kinetic energy was added to bring the protein and its surrounding membrane and water up to body temperature.

The animated model resulted from calculating differences between 2 structures and using targeted molecular dynamics programs to slightly nudge the model to the next step.

“You do that several million times and make several trillion calculations, and you arrive at the next structure,” Dr Wise said. “In this way, we can nudge P-gp through a full catalytic transport cycle.”

Finally, using a docking program, the researchers individually introduced daunorubicin and other drugs into the protein and watched the drugs move through P-gp’s catalytic cycle.

“What happened was: the drugs moved,” Dr Wise said. “And they moved the way they should move, clinically, biochemically, physiologically, to pump the compounds out of the cell.”

Challenging the model

The researchers ran a critical control to further test if the model worked.

“We thought maybe anything you put in the protein, relevant or not, would get pumped through,” Dr Wise said. “So we put in something that is not a transport substrate of P-gp, something that, biochemically, would never be transported by P-gp.”

“We put it in, starting where daunorubicin is effectively pumped out, and, very quickly, the compound left the protein. But it left the opposite way, back into the cell. This experiment gave us more confidence that what we are seeing in these models is reflecting what happens in the cell.”

Dr Wise admitted that, until he saw it for himself, he had doubts the virtual P-gp model would behave like real-life P-gp.

“It’s a crude approximation of a complex, sophisticated human protein, but it’s so much better than the static images available now,” Dr Wise said.

“I’ve got to emphasize for all the disbelievers, for the ‘culture of doubters’ out there, that this model works. It moves the drugs through the membrane. That speaks for itself. What P-gp does in the cell, cancerous or normal, it does in our simulations.”

Researcher in the lab

Photo by Darren Baker

Researchers say they have created a model that can show how nearly any drug behaves in P-glycoprotein (P-gp), a protein associated with chemotherapy failure.

The team developed this computer-generated model to overcome the problem of relying on static images for the structure of P-gp.

When the researchers introduced drugs into the model, the drugs responded the way they do in real life and behaved according to predictions.

John G. Wise, PhD, of Southern Methodist University in Dallas, Texas, and his colleagues described the model in Biochemistry.

“The value of this fundamental research is that it generates dynamic mechanisms that let us understand something in biochemistry, in biology,” Dr Wise said. “And by understanding P-gp in such detail, we can now think of ways to better and more specifically inhibit it.”

Dr Wise and his colleagues noted that P-gp protects cells by pumping out toxins, but that can include chemotherapy drugs. So inhibiting P-gp’s pumping action might circumvent chemotherapy failure.

With than in mind, the team tested tariquidar, a P-gp inhibitor in clinical trials, in their model.

It hasn’t been clear exactly where tariquidar binds in P-gp. But the model showed the drug prefers to bind high in the protein. Tariquidar also behaved as expected. It wasn’t effectively pumped from the cell.

“Now we have more details on how tariquidar inhibits P-gp, where it inhibits, and what it’s actually binding to,” Dr Wise said.

He and his colleagues also used their model to uncover additional details about the behavior of other drugs in P-gp.

“For a long time, it’s been thought that there are at least a couple of distinct binding sites for drugs,” Dr Wise said.

“Sure enough, with our models, we found that [the chemotherapeutic agent] daunorubicin, at least, prefers to bind on one side of the P-gp model, while verapamil—a commonly prescribed blood pressure medicine—prefers the other side.”

Not only did the researchers show computationally that there are 2 different starting points for drugs, they also showed that there are 2 different pathways to get the drugs through.

“The 2 different drugs start at different sites, and they’re funneled to the outside by being pushed by the protein,” Dr Wise said. “But the actual parts of the protein that are pushing the drugs out are different.”

Drug discovery

Being able to watch molecular machinery up close, while it is doing its job the way it does in real life, may spark new drug discoveries to fight cancer, Dr Wise said.

“Having an accurate model that actually moves—that shows the dynamics of the thing—is incredibly helpful in developing therapies against a molecular target to inhibit it,” Dr Wise said. “The only other ways to do it are blind, and the chances of success using blind methods are very low.”

“Scientists have tried for 30 years to find inhibitors of this pump and have done it without knowing the structure and with only little knowledge about the mechanism, screening more or less blindly for compounds that inhibit the thing.”

“They found drugs that worked in the test tube and that worked in cultured cells but that didn’t work in the patient. With our model, because we can see the pump moving, we can probably predict better what’s going to make an inhibitor actually work well.”

Dr Wise and his colleagues used the P-gp model to virtually screen millions of publicly available compounds. They discovered 3 new drug leads that could ultimately inhibit P-gp and offer better odds of survival to prostate cancer patients.

The researchers reported these findings in Pharmacology Research & Perspectives.

Creating the model

To build the P-gp model, Dr Wise and his colleagues used static structures from the US Protein Data Bank repository. They used structures showing various stages of transport to simulate 4 points of reference.

From there, the team fed a supercomputer parameters and characteristics of the protein, as well as how it should behave physically, including when kinetic energy was added to bring the protein and its surrounding membrane and water up to body temperature.

The animated model resulted from calculating differences between 2 structures and using targeted molecular dynamics programs to slightly nudge the model to the next step.

“You do that several million times and make several trillion calculations, and you arrive at the next structure,” Dr Wise said. “In this way, we can nudge P-gp through a full catalytic transport cycle.”

Finally, using a docking program, the researchers individually introduced daunorubicin and other drugs into the protein and watched the drugs move through P-gp’s catalytic cycle.

“What happened was: the drugs moved,” Dr Wise said. “And they moved the way they should move, clinically, biochemically, physiologically, to pump the compounds out of the cell.”

Challenging the model

The researchers ran a critical control to further test if the model worked.

“We thought maybe anything you put in the protein, relevant or not, would get pumped through,” Dr Wise said. “So we put in something that is not a transport substrate of P-gp, something that, biochemically, would never be transported by P-gp.”

“We put it in, starting where daunorubicin is effectively pumped out, and, very quickly, the compound left the protein. But it left the opposite way, back into the cell. This experiment gave us more confidence that what we are seeing in these models is reflecting what happens in the cell.”

Dr Wise admitted that, until he saw it for himself, he had doubts the virtual P-gp model would behave like real-life P-gp.

“It’s a crude approximation of a complex, sophisticated human protein, but it’s so much better than the static images available now,” Dr Wise said.

“I’ve got to emphasize for all the disbelievers, for the ‘culture of doubters’ out there, that this model works. It moves the drugs through the membrane. That speaks for itself. What P-gp does in the cell, cancerous or normal, it does in our simulations.”

Researcher in the lab

Photo by Darren Baker

Researchers say they have created a model that can show how nearly any drug behaves in P-glycoprotein (P-gp), a protein associated with chemotherapy failure.

The team developed this computer-generated model to overcome the problem of relying on static images for the structure of P-gp.

When the researchers introduced drugs into the model, the drugs responded the way they do in real life and behaved according to predictions.

John G. Wise, PhD, of Southern Methodist University in Dallas, Texas, and his colleagues described the model in Biochemistry.

“The value of this fundamental research is that it generates dynamic mechanisms that let us understand something in biochemistry, in biology,” Dr Wise said. “And by understanding P-gp in such detail, we can now think of ways to better and more specifically inhibit it.”

Dr Wise and his colleagues noted that P-gp protects cells by pumping out toxins, but that can include chemotherapy drugs. So inhibiting P-gp’s pumping action might circumvent chemotherapy failure.

With than in mind, the team tested tariquidar, a P-gp inhibitor in clinical trials, in their model.

It hasn’t been clear exactly where tariquidar binds in P-gp. But the model showed the drug prefers to bind high in the protein. Tariquidar also behaved as expected. It wasn’t effectively pumped from the cell.

“Now we have more details on how tariquidar inhibits P-gp, where it inhibits, and what it’s actually binding to,” Dr Wise said.

He and his colleagues also used their model to uncover additional details about the behavior of other drugs in P-gp.

“For a long time, it’s been thought that there are at least a couple of distinct binding sites for drugs,” Dr Wise said.

“Sure enough, with our models, we found that [the chemotherapeutic agent] daunorubicin, at least, prefers to bind on one side of the P-gp model, while verapamil—a commonly prescribed blood pressure medicine—prefers the other side.”

Not only did the researchers show computationally that there are 2 different starting points for drugs, they also showed that there are 2 different pathways to get the drugs through.

“The 2 different drugs start at different sites, and they’re funneled to the outside by being pushed by the protein,” Dr Wise said. “But the actual parts of the protein that are pushing the drugs out are different.”

Drug discovery

Being able to watch molecular machinery up close, while it is doing its job the way it does in real life, may spark new drug discoveries to fight cancer, Dr Wise said.

“Having an accurate model that actually moves—that shows the dynamics of the thing—is incredibly helpful in developing therapies against a molecular target to inhibit it,” Dr Wise said. “The only other ways to do it are blind, and the chances of success using blind methods are very low.”

“Scientists have tried for 30 years to find inhibitors of this pump and have done it without knowing the structure and with only little knowledge about the mechanism, screening more or less blindly for compounds that inhibit the thing.”

“They found drugs that worked in the test tube and that worked in cultured cells but that didn’t work in the patient. With our model, because we can see the pump moving, we can probably predict better what’s going to make an inhibitor actually work well.”

Dr Wise and his colleagues used the P-gp model to virtually screen millions of publicly available compounds. They discovered 3 new drug leads that could ultimately inhibit P-gp and offer better odds of survival to prostate cancer patients.

The researchers reported these findings in Pharmacology Research & Perspectives.

Creating the model

To build the P-gp model, Dr Wise and his colleagues used static structures from the US Protein Data Bank repository. They used structures showing various stages of transport to simulate 4 points of reference.

From there, the team fed a supercomputer parameters and characteristics of the protein, as well as how it should behave physically, including when kinetic energy was added to bring the protein and its surrounding membrane and water up to body temperature.

The animated model resulted from calculating differences between 2 structures and using targeted molecular dynamics programs to slightly nudge the model to the next step.

“You do that several million times and make several trillion calculations, and you arrive at the next structure,” Dr Wise said. “In this way, we can nudge P-gp through a full catalytic transport cycle.”

Finally, using a docking program, the researchers individually introduced daunorubicin and other drugs into the protein and watched the drugs move through P-gp’s catalytic cycle.

“What happened was: the drugs moved,” Dr Wise said. “And they moved the way they should move, clinically, biochemically, physiologically, to pump the compounds out of the cell.”

Challenging the model

The researchers ran a critical control to further test if the model worked.

“We thought maybe anything you put in the protein, relevant or not, would get pumped through,” Dr Wise said. “So we put in something that is not a transport substrate of P-gp, something that, biochemically, would never be transported by P-gp.”

“We put it in, starting where daunorubicin is effectively pumped out, and, very quickly, the compound left the protein. But it left the opposite way, back into the cell. This experiment gave us more confidence that what we are seeing in these models is reflecting what happens in the cell.”

Dr Wise admitted that, until he saw it for himself, he had doubts the virtual P-gp model would behave like real-life P-gp.

“It’s a crude approximation of a complex, sophisticated human protein, but it’s so much better than the static images available now,” Dr Wise said.

“I’ve got to emphasize for all the disbelievers, for the ‘culture of doubters’ out there, that this model works. It moves the drugs through the membrane. That speaks for itself. What P-gp does in the cell, cancerous or normal, it does in our simulations.”

Prescription drugs

Photo courtesy of CDC

England’s National Health Service (NHS) plans to remove several drugs used to treat hematologic malignancies from the Cancer Drugs Fund (CDF).

The plan is that, as of November 4, 2015, pomalidomide, lenalidomide, ibrutinib, dasatinib, brentuximab, bosutinib, and bendamustine will no longer be funded via the CDF for certain indications.

Ofatumumab was removed from the CDF list yesterday but is now available through the NHS.

Drugs used to treat solid tumor malignancies are set to be de-funded through CDF in November as well.

However, the NHS said the proposal to remove a drug from the CDF is not necessarily a final decision.

In cases where a drug offers enough clinical benefit, the pharmaceutical company developing that drug has the opportunity to reduce the price they are asking the NHS to pay to ensure that it achieves a satisfactory level of value for money. The NHS said a number of such negotiations are underway.

In addition, patients who are currently receiving the drugs set to be removed from the CDF will continue to have access to those drugs.

About the CDF and the NHS

The CDF—set up in 2010 and currently due to run until March 2016—is money the government has set aside to pay for cancer drugs that haven’t been approved by the National Institute for Health and Care Excellence (NICE) and aren’t available within the NHS in England. Most cancer drugs are routinely funded outside of the CDF.

NHS England and NICE are planning to consult on a proposed new system for commissioning cancer drugs. The NHS said the new system will be designed to provide the agency with a more systematic approach to getting the best price for cancer drugs.

Reason for drug removals

The NHS previously increased the budget for the CDF from £200 million in 2013/14, to £280 million in 2014/15, and £340 million from April 2015. This represents a total increase of 70% since August 2014.

However, current projections suggest that spending would rise to around £410 million for this year, an over-spend of £70 million, in the absence of further prioritization. The NHS said this money could be used for other aspects of cancer treatment or NHS services for other patient groups.

Therefore, some drugs are set to be removed from the CDF. The NHS said all decisions on drugs to be maintained in the CDF were based on the advice of clinicians, the best available evidence, and the cost of the treatment.

“There is no escaping the fact that we face a difficult set of choices, but it is our duty to ensure we get maximum value from every penny available on behalf of patients,” said Peter Clark, chair of the CDF.

“We must ensure we invest in those treatments that offer the most benefit, based on rigorous evidence-based clinical analysis and an assessment of the cost of those treatments.”

While de-funding certain drugs will reduce costs, the CDF is not expected to be back on budget this financial year. The NHS does expect the CDF will be operating within its budget during 2016/17.

Blood cancer drugs to be removed

The following drugs are currently on the CDF list for the following indications, but they are set to be de-listed on November 4, 2015.

Bendamustine

For the treatment of chronic lymphocytic leukemia (CLL) where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• CLL (not licensed in this indication)
• Second-line indication, third-line indication, or fourth-line indication
• To be used within the treating Trust’s governance framework, as bendamustine is not licensed in this indication

For the treatment of relapsed mantle cell lymphoma (MCL) where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• MCL
• Option for second- or subsequent-line chemotherapy
• No previous treatment with bendamustine
• To be used within the treating Trust’s governance framework, as bendamustine is not licensed in this indication

*Bendamustine will remain on the CDF for other indications.

Bosutinib

For the treatment of refractory, chronic phase chronic myeloid leukemia (CML) where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Chronic phase CML
• Refractory to nilotinib or dasatinib (if dasatinib accessed via a clinical trial or via its current approved CDF indication)

For the treatment of refractory, accelerated phase CML where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Accelerated phase CML
• Refractory to nilotinib or dasatinib (if dasatinib accessed via a clinical trial or via its current approved CDF indication)
• Significant intolerance to nilotinib (grade 3 or 4 events)

For the treatment of accelerated phase CML where there is intolerance of treatments and where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Accelerated phase CML
• Significant intolerance to dasatinib (grade 3 or 4 adverse events; if dasatinib accessed via its current approved CDF indication)
• Significant intolerance to nilotinib (grade 3 or 4 events)

*Bosutinib will still be available through the CDF for patients with chronic phase CML that is intolerant of other treatments.

Brentuximab

For the treatment of refractory, systemic anaplastic lymphoma where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Relapsed or refractory systemic anaplastic large-cell lymphoma

For the treatment of relapsed or refractory CD30+ Hodgkin lymphoma where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Relapsed or refractory CD30+ Hodgkin lymphoma
• Following autologous stem cell transplant or following at least 2 prior therapies when autologous stem cell transplant or multi-agent chemotherapy is not an option

Dasatinib

For the treatment of Philadelphia-chromosome-positive (Ph+) acute lymphoblastic leukemia where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Refractory or significant intolerance or resistance to prior therapy including imatinib (grade 3 or 4 adverse events)
• Second-line indication or third-line indication

*Dasatinib will still be available for chronic phase and accelerated phase CML.

Ibrutinib

For the treatment of relapsed/refractory CLL where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Confirmed CLL
• Must have received at least 1 prior therapy for CLL
• Considered not appropriate for treatment or retreatment with purine-analogue-based therapy due to:

  • Failure to respond to chemo-immunotherapy or
  • A progression-free interval of less than 3 years or
  • Age of 70 years or more or
  • Age of 65 years or more plus the presence of comorbidities or
  • A 17p or TP53 deletion

• ECOG performance status of 0-2
• A neutrophil count of ≥0.75 x 10⁹/L
• A platelet count of ≥30 x 10⁹/L
• Patient not on warfarin or CYP3A4/5 inhibitors
• No prior treatment with idelalisib

For the treatment of relapsed/refractory MCL where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Confirmed MCL with cyclin D1 overexpression or translocation breakpoints at t(11;14)
• Failure to achieve at least partial response with, or documented disease progression disease after, the most recent treatment regimen
• ECOG performance status of 0-2
• At least 1 but no more than 5 previous lines of treatment

Lenalidomide

For the second-line treatment of multiple myeloma (MM) where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• MM
• Second-line indication
• Contraindication to bortezomib or previously received bortezomib in the first-line setting

*Lenalidomide will still be available for patients with myelodysplastic syndromes with 5q deletion.

Pomalidomide

For the treatment of relapsed and refractory MM where the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically
• MM
• Performance status of 0-2
• Previously received treatment with adequate trials of at least all of the following options of therapy: bortezomib, lenalidomide, and alkylating agents
• Failed treatment with bortezomib or lenalidomide, as defined by: progression on or before 60 days of treatment, progressive disease 6 months or less after achieving a partial response, or intolerance to bortezomib
• Refractory disease to previous treatment
• No resistance to high-dose dexamethasone used in the last line of therapy
• No peripheral neuropathy of grade 2 or more

A complete list of proposed changes to the CDF, as well as the drugs that were de-listed on March 12, 2015, is available on the NHS website.

Prescription drugs

Photo courtesy of CDC

England’s National Health Service (NHS) plans to remove several drugs used to treat hematologic malignancies from the Cancer Drugs Fund (CDF).

The plan is that, as of November 4, 2015, pomalidomide, lenalidomide, ibrutinib, dasatinib, brentuximab, bosutinib, and bendamustine will no longer be funded via the CDF for certain indications.

Ofatumumab was removed from the CDF list yesterday but is now available through the NHS.

Drugs used to treat solid tumor malignancies are set to be de-funded through CDF in November as well.

However, the NHS said the proposal to remove a drug from the CDF is not necessarily a final decision.

In cases where a drug offers enough clinical benefit, the pharmaceutical company developing that drug has the opportunity to reduce the price they are asking the NHS to pay to ensure that it achieves a satisfactory level of value for money. The NHS said a number of such negotiations are underway.

In addition, patients who are currently receiving the drugs set to be removed from the CDF will continue to have access to those drugs.

About the CDF and the NHS

The CDF—set up in 2010 and currently due to run until March 2016—is money the government has set aside to pay for cancer drugs that haven’t been approved by the National Institute for Health and Care Excellence (NICE) and aren’t available within the NHS in England. Most cancer drugs are routinely funded outside of the CDF.

NHS England and NICE are planning to consult on a proposed new system for commissioning cancer drugs. The NHS said the new system will be designed to provide the agency with a more systematic approach to getting the best price for cancer drugs.

Reason for drug removals

The NHS previously increased the budget for the CDF from £200 million in 2013/14, to £280 million in 2014/15, and £340 million from April 2015. This represents a total increase of 70% since August 2014.

However, current projections suggest that spending would rise to around £410 million for this year, an over-spend of £70 million, in the absence of further prioritization. The NHS said this money could be used for other aspects of cancer treatment or NHS services for other patient groups.

Therefore, some drugs are set to be removed from the CDF. The NHS said all decisions on drugs to be maintained in the CDF were based on the advice of clinicians, the best available evidence, and the cost of the treatment.

“There is no escaping the fact that we face a difficult set of choices, but it is our duty to ensure we get maximum value from every penny available on behalf of patients,” said Peter Clark, chair of the CDF.

“We must ensure we invest in those treatments that offer the most benefit, based on rigorous evidence-based clinical analysis and an assessment of the cost of those treatments.”

While de-funding certain drugs will reduce costs, the CDF is not expected to be back on budget this financial year. The NHS does expect the CDF will be operating within its budget during 2016/17.

Blood cancer drugs to be removed

The following drugs are currently on the CDF list for the following indications, but they are set to be de-listed on November 4, 2015.

Bendamustine

For the treatment of chronic lymphocytic leukemia (CLL) where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• CLL (not licensed in this indication)
• Second-line indication, third-line indication, or fourth-line indication
• To be used within the treating Trust’s governance framework, as bendamustine is not licensed in this indication

For the treatment of relapsed mantle cell lymphoma (MCL) where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• MCL
• Option for second- or subsequent-line chemotherapy
• No previous treatment with bendamustine
• To be used within the treating Trust’s governance framework, as bendamustine is not licensed in this indication

*Bendamustine will remain on the CDF for other indications.

Bosutinib

For the treatment of refractory, chronic phase chronic myeloid leukemia (CML) where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Chronic phase CML
• Refractory to nilotinib or dasatinib (if dasatinib accessed via a clinical trial or via its current approved CDF indication)

For the treatment of refractory, accelerated phase CML where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Accelerated phase CML
• Refractory to nilotinib or dasatinib (if dasatinib accessed via a clinical trial or via its current approved CDF indication)
• Significant intolerance to nilotinib (grade 3 or 4 events)

For the treatment of accelerated phase CML where there is intolerance of treatments and where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Accelerated phase CML
• Significant intolerance to dasatinib (grade 3 or 4 adverse events; if dasatinib accessed via its current approved CDF indication)
• Significant intolerance to nilotinib (grade 3 or 4 events)

*Bosutinib will still be available through the CDF for patients with chronic phase CML that is intolerant of other treatments.

Brentuximab

For the treatment of refractory, systemic anaplastic lymphoma where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Relapsed or refractory systemic anaplastic large-cell lymphoma

For the treatment of relapsed or refractory CD30+ Hodgkin lymphoma where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Relapsed or refractory CD30+ Hodgkin lymphoma
• Following autologous stem cell transplant or following at least 2 prior therapies when autologous stem cell transplant or multi-agent chemotherapy is not an option

Dasatinib

For the treatment of Philadelphia-chromosome-positive (Ph+) acute lymphoblastic leukemia where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Refractory or significant intolerance or resistance to prior therapy including imatinib (grade 3 or 4 adverse events)
• Second-line indication or third-line indication

*Dasatinib will still be available for chronic phase and accelerated phase CML.

Ibrutinib

For the treatment of relapsed/refractory CLL where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Confirmed CLL
• Must have received at least 1 prior therapy for CLL
• Considered not appropriate for treatment or retreatment with purine-analogue-based therapy due to:

  • Failure to respond to chemo-immunotherapy or
  • A progression-free interval of less than 3 years or
  • Age of 70 years or more or
  • Age of 65 years or more plus the presence of comorbidities or
  • A 17p or TP53 deletion

• ECOG performance status of 0-2
• A neutrophil count of ≥0.75 x 10⁹/L
• A platelet count of ≥30 x 10⁹/L
• Patient not on warfarin or CYP3A4/5 inhibitors
• No prior treatment with idelalisib

For the treatment of relapsed/refractory MCL where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Confirmed MCL with cyclin D1 overexpression or translocation breakpoints at t(11;14)
• Failure to achieve at least partial response with, or documented disease progression disease after, the most recent treatment regimen
• ECOG performance status of 0-2
• At least 1 but no more than 5 previous lines of treatment

Lenalidomide

For the second-line treatment of multiple myeloma (MM) where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• MM
• Second-line indication
• Contraindication to bortezomib or previously received bortezomib in the first-line setting

*Lenalidomide will still be available for patients with myelodysplastic syndromes with 5q deletion.

Pomalidomide

For the treatment of relapsed and refractory MM where the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically
• MM
• Performance status of 0-2
• Previously received treatment with adequate trials of at least all of the following options of therapy: bortezomib, lenalidomide, and alkylating agents
• Failed treatment with bortezomib or lenalidomide, as defined by: progression on or before 60 days of treatment, progressive disease 6 months or less after achieving a partial response, or intolerance to bortezomib
• Refractory disease to previous treatment
• No resistance to high-dose dexamethasone used in the last line of therapy
• No peripheral neuropathy of grade 2 or more

A complete list of proposed changes to the CDF, as well as the drugs that were de-listed on March 12, 2015, is available on the NHS website.

Prescription drugs

Photo courtesy of CDC

England’s National Health Service (NHS) plans to remove several drugs used to treat hematologic malignancies from the Cancer Drugs Fund (CDF).

The plan is that, as of November 4, 2015, pomalidomide, lenalidomide, ibrutinib, dasatinib, brentuximab, bosutinib, and bendamustine will no longer be funded via the CDF for certain indications.

Ofatumumab was removed from the CDF list yesterday but is now available through the NHS.

Drugs used to treat solid tumor malignancies are set to be de-funded through CDF in November as well.

However, the NHS said the proposal to remove a drug from the CDF is not necessarily a final decision.

In cases where a drug offers enough clinical benefit, the pharmaceutical company developing that drug has the opportunity to reduce the price they are asking the NHS to pay to ensure that it achieves a satisfactory level of value for money. The NHS said a number of such negotiations are underway.

In addition, patients who are currently receiving the drugs set to be removed from the CDF will continue to have access to those drugs.

About the CDF and the NHS

The CDF—set up in 2010 and currently due to run until March 2016—is money the government has set aside to pay for cancer drugs that haven’t been approved by the National Institute for Health and Care Excellence (NICE) and aren’t available within the NHS in England. Most cancer drugs are routinely funded outside of the CDF.

NHS England and NICE are planning to consult on a proposed new system for commissioning cancer drugs. The NHS said the new system will be designed to provide the agency with a more systematic approach to getting the best price for cancer drugs.

Reason for drug removals

The NHS previously increased the budget for the CDF from £200 million in 2013/14, to £280 million in 2014/15, and £340 million from April 2015. This represents a total increase of 70% since August 2014.

However, current projections suggest that spending would rise to around £410 million for this year, an over-spend of £70 million, in the absence of further prioritization. The NHS said this money could be used for other aspects of cancer treatment or NHS services for other patient groups.

Therefore, some drugs are set to be removed from the CDF. The NHS said all decisions on drugs to be maintained in the CDF were based on the advice of clinicians, the best available evidence, and the cost of the treatment.

“There is no escaping the fact that we face a difficult set of choices, but it is our duty to ensure we get maximum value from every penny available on behalf of patients,” said Peter Clark, chair of the CDF.

“We must ensure we invest in those treatments that offer the most benefit, based on rigorous evidence-based clinical analysis and an assessment of the cost of those treatments.”

While de-funding certain drugs will reduce costs, the CDF is not expected to be back on budget this financial year. The NHS does expect the CDF will be operating within its budget during 2016/17.

Blood cancer drugs to be removed

The following drugs are currently on the CDF list for the following indications, but they are set to be de-listed on November 4, 2015.

Bendamustine

For the treatment of chronic lymphocytic leukemia (CLL) where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• CLL (not licensed in this indication)
• Second-line indication, third-line indication, or fourth-line indication
• To be used within the treating Trust’s governance framework, as bendamustine is not licensed in this indication

For the treatment of relapsed mantle cell lymphoma (MCL) where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• MCL
• Option for second- or subsequent-line chemotherapy
• No previous treatment with bendamustine
• To be used within the treating Trust’s governance framework, as bendamustine is not licensed in this indication

*Bendamustine will remain on the CDF for other indications.

Bosutinib

For the treatment of refractory, chronic phase chronic myeloid leukemia (CML) where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Chronic phase CML
• Refractory to nilotinib or dasatinib (if dasatinib accessed via a clinical trial or via its current approved CDF indication)

For the treatment of refractory, accelerated phase CML where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Accelerated phase CML
• Refractory to nilotinib or dasatinib (if dasatinib accessed via a clinical trial or via its current approved CDF indication)
• Significant intolerance to nilotinib (grade 3 or 4 events)

For the treatment of accelerated phase CML where there is intolerance of treatments and where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Accelerated phase CML
• Significant intolerance to dasatinib (grade 3 or 4 adverse events; if dasatinib accessed via its current approved CDF indication)
• Significant intolerance to nilotinib (grade 3 or 4 events)

*Bosutinib will still be available through the CDF for patients with chronic phase CML that is intolerant of other treatments.

Brentuximab

For the treatment of refractory, systemic anaplastic lymphoma where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Relapsed or refractory systemic anaplastic large-cell lymphoma

For the treatment of relapsed or refractory CD30+ Hodgkin lymphoma where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Relapsed or refractory CD30+ Hodgkin lymphoma
• Following autologous stem cell transplant or following at least 2 prior therapies when autologous stem cell transplant or multi-agent chemotherapy is not an option

Dasatinib

For the treatment of Philadelphia-chromosome-positive (Ph+) acute lymphoblastic leukemia where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Refractory or significant intolerance or resistance to prior therapy including imatinib (grade 3 or 4 adverse events)
• Second-line indication or third-line indication

*Dasatinib will still be available for chronic phase and accelerated phase CML.

Ibrutinib

For the treatment of relapsed/refractory CLL where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Confirmed CLL
• Must have received at least 1 prior therapy for CLL
• Considered not appropriate for treatment or retreatment with purine-analogue-based therapy due to:

  • Failure to respond to chemo-immunotherapy or
  • A progression-free interval of less than 3 years or
  • Age of 70 years or more or
  • Age of 65 years or more plus the presence of comorbidities or
  • A 17p or TP53 deletion

• ECOG performance status of 0-2
• A neutrophil count of ≥0.75 x 10⁹/L
• A platelet count of ≥30 x 10⁹/L
• Patient not on warfarin or CYP3A4/5 inhibitors
• No prior treatment with idelalisib

For the treatment of relapsed/refractory MCL where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Confirmed MCL with cyclin D1 overexpression or translocation breakpoints at t(11;14)
• Failure to achieve at least partial response with, or documented disease progression disease after, the most recent treatment regimen
• ECOG performance status of 0-2
• At least 1 but no more than 5 previous lines of treatment

Lenalidomide

For the second-line treatment of multiple myeloma (MM) where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• MM
• Second-line indication
• Contraindication to bortezomib or previously received bortezomib in the first-line setting

*Lenalidomide will still be available for patients with myelodysplastic syndromes with 5q deletion.

Pomalidomide

For the treatment of relapsed and refractory MM where the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically
• MM
• Performance status of 0-2
• Previously received treatment with adequate trials of at least all of the following options of therapy: bortezomib, lenalidomide, and alkylating agents
• Failed treatment with bortezomib or lenalidomide, as defined by: progression on or before 60 days of treatment, progressive disease 6 months or less after achieving a partial response, or intolerance to bortezomib
• Refractory disease to previous treatment
• No resistance to high-dose dexamethasone used in the last line of therapy
• No peripheral neuropathy of grade 2 or more

A complete list of proposed changes to the CDF, as well as the drugs that were de-listed on March 12, 2015, is available on the NHS website.