Leukemia, Myelodysplasia, Transplantation

Lab mouse

Preclinical research suggests high-dose vitamin C may be effective against TET2-mutant leukemias.

Investigators found that vitamin C mimics TET2 restoration, thereby suppressing leukemic colony formation, inhibiting leukemia progression in mice, and enhancing leukemia cells’ sensitivity to treatment with a PARP inhibitor.

“We’re excited by the prospect that high-dose vitamin C might become a safe treatment for blood diseases caused by TET2-deficient leukemia stem cells, most likely in combination with other targeted therapies,” said study author Benjamin G. Neel, MD, PhD, of NYU School of Medicine in New York, New York.

Dr Neel and his colleagues reported their findings in Cell.

Previous research had shown that vitamin C could stimulate the activity of TET2 as well as TET1 and TET3.

Because only 1 copy of the TET2 gene in each stem cell is usually affected in TET2-mutant blood diseases, the investigators hypothesized that high doses of vitamin C might reverse the effects of TET2 deficiency by turning up the action of the remaining functional gene.

Indeed, the team found that vitamin C had the same effect as restoring TET2 function genetically. By promoting DNA demethylation, high-dose vitamin C induced stem cells to mature and suppressed the growth of leukemic stem cells (LSCs) implanted in mice.

“Interestingly, we also found that vitamin C treatment had an effect on leukemic stem cells that resembled damage to their DNA,” said study author Luisa Cimmino, PhD, of NYU School of Medicine.

“For this reason, we decided to combine vitamin C with a PARP inhibitor, a drug type known to cause cancer cell death by blocking the repair of DNA damage, and already approved for treating certain patients with ovarian cancer.”

The combination had an enhanced effect on LSCs, further shifting them from self-renewal back toward maturity and cell death.

Dr Cimmino said these results suggest vitamin C might also be effective against leukemias without TET2 mutations. As vitamin C turns up any TET2 activity normally in place, it might drive LSCs without TET2 mutations toward death as well.

Lab mouse

Preclinical research suggests high-dose vitamin C may be effective against TET2-mutant leukemias.

Investigators found that vitamin C mimics TET2 restoration, thereby suppressing leukemic colony formation, inhibiting leukemia progression in mice, and enhancing leukemia cells’ sensitivity to treatment with a PARP inhibitor.

“We’re excited by the prospect that high-dose vitamin C might become a safe treatment for blood diseases caused by TET2-deficient leukemia stem cells, most likely in combination with other targeted therapies,” said study author Benjamin G. Neel, MD, PhD, of NYU School of Medicine in New York, New York.

Dr Neel and his colleagues reported their findings in Cell.

Previous research had shown that vitamin C could stimulate the activity of TET2 as well as TET1 and TET3.

Because only 1 copy of the TET2 gene in each stem cell is usually affected in TET2-mutant blood diseases, the investigators hypothesized that high doses of vitamin C might reverse the effects of TET2 deficiency by turning up the action of the remaining functional gene.

Indeed, the team found that vitamin C had the same effect as restoring TET2 function genetically. By promoting DNA demethylation, high-dose vitamin C induced stem cells to mature and suppressed the growth of leukemic stem cells (LSCs) implanted in mice.

“Interestingly, we also found that vitamin C treatment had an effect on leukemic stem cells that resembled damage to their DNA,” said study author Luisa Cimmino, PhD, of NYU School of Medicine.

“For this reason, we decided to combine vitamin C with a PARP inhibitor, a drug type known to cause cancer cell death by blocking the repair of DNA damage, and already approved for treating certain patients with ovarian cancer.”

The combination had an enhanced effect on LSCs, further shifting them from self-renewal back toward maturity and cell death.

Dr Cimmino said these results suggest vitamin C might also be effective against leukemias without TET2 mutations. As vitamin C turns up any TET2 activity normally in place, it might drive LSCs without TET2 mutations toward death as well.

Lab mouse

Preclinical research suggests high-dose vitamin C may be effective against TET2-mutant leukemias.

Investigators found that vitamin C mimics TET2 restoration, thereby suppressing leukemic colony formation, inhibiting leukemia progression in mice, and enhancing leukemia cells’ sensitivity to treatment with a PARP inhibitor.

“We’re excited by the prospect that high-dose vitamin C might become a safe treatment for blood diseases caused by TET2-deficient leukemia stem cells, most likely in combination with other targeted therapies,” said study author Benjamin G. Neel, MD, PhD, of NYU School of Medicine in New York, New York.

Dr Neel and his colleagues reported their findings in Cell.

Previous research had shown that vitamin C could stimulate the activity of TET2 as well as TET1 and TET3.

Because only 1 copy of the TET2 gene in each stem cell is usually affected in TET2-mutant blood diseases, the investigators hypothesized that high doses of vitamin C might reverse the effects of TET2 deficiency by turning up the action of the remaining functional gene.

Indeed, the team found that vitamin C had the same effect as restoring TET2 function genetically. By promoting DNA demethylation, high-dose vitamin C induced stem cells to mature and suppressed the growth of leukemic stem cells (LSCs) implanted in mice.

“Interestingly, we also found that vitamin C treatment had an effect on leukemic stem cells that resembled damage to their DNA,” said study author Luisa Cimmino, PhD, of NYU School of Medicine.

“For this reason, we decided to combine vitamin C with a PARP inhibitor, a drug type known to cause cancer cell death by blocking the repair of DNA damage, and already approved for treating certain patients with ovarian cancer.”

The combination had an enhanced effect on LSCs, further shifting them from self-renewal back toward maturity and cell death.

Dr Cimmino said these results suggest vitamin C might also be effective against leukemias without TET2 mutations. As vitamin C turns up any TET2 activity normally in place, it might drive LSCs without TET2 mutations toward death as well.

Photo by Bill Branson

The US Food and Drug Administration (FDA) has approved inotuzumab ozogamicin (Besponsa®) for the treatment of adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL).

The labeling for inotuzumab ozogamicin includes a boxed warning stating that the drug poses a risk of hepatotoxicity, including hepatic veno-occlusive disease (or sinusoidal obstruction syndrome), as well as an increased risk of post-transplant non-relapse mortality.

The full prescribing information for inotuzumab ozogamicin is available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/761040s000lbl.pdf.

Inotuzumab ozogamicin is an antibody-drug conjugate that consists of a monoclonal antibody targeting CD22 and a cytotoxic agent known as calicheamicin.

The product originates from a collaboration between Pfizer and Celltech (now UCB), but Pfizer has sole responsibility for all manufacturing and clinical development activities.

Inotuzumab ozogamicin was reviewed and approved under the FDA’s breakthrough therapy designation and priority review programs.

The application for inotuzumab ozogamicin was supported by results from the phase 3 INO-VATE trial, which were published in NEJM in June 2016.

The trial enrolled 326 adults with relapsed or refractory B-cell ALL. Patients received inotuzumab ozogamicin or 1 of 3 chemotherapy regimens (high-dose cytarabine, cytarabine plus mitoxantrone, or fludarabine, cytarabine, and granulocyte colony-stimulating factor).

The rate of complete remission, including incomplete hematologic recovery, was 80.7% in the inotuzumab arm and 29.4% in the chemotherapy arm (P<0.001). The median duration of remission was 4.6 months and 3.1 months, respectively (P=0.03).

Forty-one percent of patients treated with inotuzumab and 11% of those who received chemotherapy proceeded to stem cell transplant directly after treatment (P<0.001).

The median progression-free survival was 5.0 months in the inotuzumab arm and 1.8 months in the chemotherapy arm (P<0.001).

The median overall survival was 7.7 months and 6.7 months, respectively (P=0.04). This did not meet the prespecified boundary of significance (P=0.0208).

Liver-related adverse events were more common in the inotuzumab arm than the chemotherapy arm. The most frequent of these were increased aspartate aminotransferase level (20% vs 10%), hyperbilirubinemia (15% vs 10%), and increased alanine aminotransferase level (14% vs 11%).

Veno-occlusive liver disease occurred in 11% of patients in the inotuzumab arm and 1% in the chemotherapy arm.

There were 17 deaths during treatment in the inotuzumab arm and 11 in the chemotherapy arm. Four deaths were considered related to inotuzumab, and 2 were thought to be related to chemotherapy.

Photo by Bill Branson

The US Food and Drug Administration (FDA) has approved inotuzumab ozogamicin (Besponsa®) for the treatment of adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL).

The labeling for inotuzumab ozogamicin includes a boxed warning stating that the drug poses a risk of hepatotoxicity, including hepatic veno-occlusive disease (or sinusoidal obstruction syndrome), as well as an increased risk of post-transplant non-relapse mortality.

The full prescribing information for inotuzumab ozogamicin is available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/761040s000lbl.pdf.

Inotuzumab ozogamicin is an antibody-drug conjugate that consists of a monoclonal antibody targeting CD22 and a cytotoxic agent known as calicheamicin.

The product originates from a collaboration between Pfizer and Celltech (now UCB), but Pfizer has sole responsibility for all manufacturing and clinical development activities.

Inotuzumab ozogamicin was reviewed and approved under the FDA’s breakthrough therapy designation and priority review programs.

The application for inotuzumab ozogamicin was supported by results from the phase 3 INO-VATE trial, which were published in NEJM in June 2016.

The trial enrolled 326 adults with relapsed or refractory B-cell ALL. Patients received inotuzumab ozogamicin or 1 of 3 chemotherapy regimens (high-dose cytarabine, cytarabine plus mitoxantrone, or fludarabine, cytarabine, and granulocyte colony-stimulating factor).

The rate of complete remission, including incomplete hematologic recovery, was 80.7% in the inotuzumab arm and 29.4% in the chemotherapy arm (P<0.001). The median duration of remission was 4.6 months and 3.1 months, respectively (P=0.03).

Forty-one percent of patients treated with inotuzumab and 11% of those who received chemotherapy proceeded to stem cell transplant directly after treatment (P<0.001).

The median progression-free survival was 5.0 months in the inotuzumab arm and 1.8 months in the chemotherapy arm (P<0.001).

The median overall survival was 7.7 months and 6.7 months, respectively (P=0.04). This did not meet the prespecified boundary of significance (P=0.0208).

Liver-related adverse events were more common in the inotuzumab arm than the chemotherapy arm. The most frequent of these were increased aspartate aminotransferase level (20% vs 10%), hyperbilirubinemia (15% vs 10%), and increased alanine aminotransferase level (14% vs 11%).

Veno-occlusive liver disease occurred in 11% of patients in the inotuzumab arm and 1% in the chemotherapy arm.

There were 17 deaths during treatment in the inotuzumab arm and 11 in the chemotherapy arm. Four deaths were considered related to inotuzumab, and 2 were thought to be related to chemotherapy.

Photo by Bill Branson

The US Food and Drug Administration (FDA) has approved inotuzumab ozogamicin (Besponsa®) for the treatment of adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL).

The labeling for inotuzumab ozogamicin includes a boxed warning stating that the drug poses a risk of hepatotoxicity, including hepatic veno-occlusive disease (or sinusoidal obstruction syndrome), as well as an increased risk of post-transplant non-relapse mortality.

The full prescribing information for inotuzumab ozogamicin is available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/761040s000lbl.pdf.

Inotuzumab ozogamicin is an antibody-drug conjugate that consists of a monoclonal antibody targeting CD22 and a cytotoxic agent known as calicheamicin.

The product originates from a collaboration between Pfizer and Celltech (now UCB), but Pfizer has sole responsibility for all manufacturing and clinical development activities.

Inotuzumab ozogamicin was reviewed and approved under the FDA’s breakthrough therapy designation and priority review programs.

The application for inotuzumab ozogamicin was supported by results from the phase 3 INO-VATE trial, which were published in NEJM in June 2016.

The trial enrolled 326 adults with relapsed or refractory B-cell ALL. Patients received inotuzumab ozogamicin or 1 of 3 chemotherapy regimens (high-dose cytarabine, cytarabine plus mitoxantrone, or fludarabine, cytarabine, and granulocyte colony-stimulating factor).

The rate of complete remission, including incomplete hematologic recovery, was 80.7% in the inotuzumab arm and 29.4% in the chemotherapy arm (P<0.001). The median duration of remission was 4.6 months and 3.1 months, respectively (P=0.03).

Forty-one percent of patients treated with inotuzumab and 11% of those who received chemotherapy proceeded to stem cell transplant directly after treatment (P<0.001).

The median progression-free survival was 5.0 months in the inotuzumab arm and 1.8 months in the chemotherapy arm (P<0.001).

The median overall survival was 7.7 months and 6.7 months, respectively (P=0.04). This did not meet the prespecified boundary of significance (P=0.0208).

Liver-related adverse events were more common in the inotuzumab arm than the chemotherapy arm. The most frequent of these were increased aspartate aminotransferase level (20% vs 10%), hyperbilirubinemia (15% vs 10%), and increased alanine aminotransferase level (14% vs 11%).

Veno-occlusive liver disease occurred in 11% of patients in the inotuzumab arm and 1% in the chemotherapy arm.

There were 17 deaths during treatment in the inotuzumab arm and 11 in the chemotherapy arm. Four deaths were considered related to inotuzumab, and 2 were thought to be related to chemotherapy.

Photo by Darren Baker

A new study indicates that survivors of the Holocaust have experienced a small but consistent increase in the risk of developing cancer.

The findings, published in the journal Cancer, offer an example of how extreme population-level tragedies can have an impact on health.

Holocaust survivors were exposed to a variety of factors that have been linked with cancer.

So researchers set out to investigate whether the starvation, overcrowding, infectious diseases, and psychological stress that survivors endured might have contributed to the development of cancer in some individuals.

The team studied 152,622 Holocaust survivors who were followed for more than 45 years.

The researchers used 2 definitions of exposure to classify the survivors.

One definition was based on an individual’s entitlement for compensation for suffering persecution during the war. The other was based on the country of origin, dividing countries into those that were directly governed by Nazi Germany and those that were not occupied by Nazis.

The cancer incidence was significantly higher in survivors who were granted compensation than in those who were not—21.9% and 16.1%, respectively (P<0.0001).

However, the difference between survivors from occupied and non-occupied countries was not significant—22.7% and 21.4%, respectively.

On the other hand, when the researchers adjusted for confounding factors, survivors who had been exposed by either definition had a significantly increased risk of cancer.

For survivors who were granted compensation, the hazard ratio (HR) was 1.06 (P<0.001). For survivors born in occupied countries, the HR was 1.08 (P<0.001).

There was no increased risk of acute or chronic leukemia among patients who received compensation. And there was no increased risk of acute leukemia for survivors born in occupied countries.

However, there was a significantly increased risk of chronic leukemia among survivors born in occupied countries (HR=1.33, P=0.001)

“The data emphasize the importance of learning about the combined effect of several exposures occurring intensely and contemporaneously on cancer risk, such as those that unfortunately occurred during World War II,” said study author Siegal Sadetzki, MD, of the Chaim Sheba Medical Center in Tel HaShomer, Israel.

An editorial related to this study noted that the association between cancer and the extreme deprivation experienced by Holocaust survivors may also have parallels with other extreme population-level events, including in racial/ethnic minority groups experiencing severe social deprivation over time.

Photo by Darren Baker

A new study indicates that survivors of the Holocaust have experienced a small but consistent increase in the risk of developing cancer.

The findings, published in the journal Cancer, offer an example of how extreme population-level tragedies can have an impact on health.

Holocaust survivors were exposed to a variety of factors that have been linked with cancer.

So researchers set out to investigate whether the starvation, overcrowding, infectious diseases, and psychological stress that survivors endured might have contributed to the development of cancer in some individuals.

The team studied 152,622 Holocaust survivors who were followed for more than 45 years.

The researchers used 2 definitions of exposure to classify the survivors.

One definition was based on an individual’s entitlement for compensation for suffering persecution during the war. The other was based on the country of origin, dividing countries into those that were directly governed by Nazi Germany and those that were not occupied by Nazis.

The cancer incidence was significantly higher in survivors who were granted compensation than in those who were not—21.9% and 16.1%, respectively (P<0.0001).

However, the difference between survivors from occupied and non-occupied countries was not significant—22.7% and 21.4%, respectively.

On the other hand, when the researchers adjusted for confounding factors, survivors who had been exposed by either definition had a significantly increased risk of cancer.

For survivors who were granted compensation, the hazard ratio (HR) was 1.06 (P<0.001). For survivors born in occupied countries, the HR was 1.08 (P<0.001).

There was no increased risk of acute or chronic leukemia among patients who received compensation. And there was no increased risk of acute leukemia for survivors born in occupied countries.

However, there was a significantly increased risk of chronic leukemia among survivors born in occupied countries (HR=1.33, P=0.001)

“The data emphasize the importance of learning about the combined effect of several exposures occurring intensely and contemporaneously on cancer risk, such as those that unfortunately occurred during World War II,” said study author Siegal Sadetzki, MD, of the Chaim Sheba Medical Center in Tel HaShomer, Israel.

An editorial related to this study noted that the association between cancer and the extreme deprivation experienced by Holocaust survivors may also have parallels with other extreme population-level events, including in racial/ethnic minority groups experiencing severe social deprivation over time.

Photo by Darren Baker

A new study indicates that survivors of the Holocaust have experienced a small but consistent increase in the risk of developing cancer.

The findings, published in the journal Cancer, offer an example of how extreme population-level tragedies can have an impact on health.

Holocaust survivors were exposed to a variety of factors that have been linked with cancer.

So researchers set out to investigate whether the starvation, overcrowding, infectious diseases, and psychological stress that survivors endured might have contributed to the development of cancer in some individuals.

The team studied 152,622 Holocaust survivors who were followed for more than 45 years.

The researchers used 2 definitions of exposure to classify the survivors.

One definition was based on an individual’s entitlement for compensation for suffering persecution during the war. The other was based on the country of origin, dividing countries into those that were directly governed by Nazi Germany and those that were not occupied by Nazis.

The cancer incidence was significantly higher in survivors who were granted compensation than in those who were not—21.9% and 16.1%, respectively (P<0.0001).

However, the difference between survivors from occupied and non-occupied countries was not significant—22.7% and 21.4%, respectively.

On the other hand, when the researchers adjusted for confounding factors, survivors who had been exposed by either definition had a significantly increased risk of cancer.

For survivors who were granted compensation, the hazard ratio (HR) was 1.06 (P<0.001). For survivors born in occupied countries, the HR was 1.08 (P<0.001).

There was no increased risk of acute or chronic leukemia among patients who received compensation. And there was no increased risk of acute leukemia for survivors born in occupied countries.

However, there was a significantly increased risk of chronic leukemia among survivors born in occupied countries (HR=1.33, P=0.001)

“The data emphasize the importance of learning about the combined effect of several exposures occurring intensely and contemporaneously on cancer risk, such as those that unfortunately occurred during World War II,” said study author Siegal Sadetzki, MD, of the Chaim Sheba Medical Center in Tel HaShomer, Israel.

An editorial related to this study noted that the association between cancer and the extreme deprivation experienced by Holocaust survivors may also have parallels with other extreme population-level events, including in racial/ethnic minority groups experiencing severe social deprivation over time.

The Food and Drug Administration has approved the antibody drug conjugate inotuzumab ozogamicin for the treatment of adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL).

The treatment, to be marketed by Pfizer as Besponsa, won approval based on the results of the INO-VATE ALL trial, which randomized 326 patients to receive either inotuzumab ozogamicin (164 patients) or a chemotherapy regimen of the investigator’s choice (162 patients). To be considered for inclusion in the trial, patients with Philadelphia chromosome–negative or –positive relapsed or refractory B-cell precursor ALL were required to have at least 5% bone marrow blasts and have received one or two induction chemotherapy regimens.

[email protected]

On Twitter @denisefulton

The Food and Drug Administration has approved the antibody drug conjugate inotuzumab ozogamicin for the treatment of adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL).

The treatment, to be marketed by Pfizer as Besponsa, won approval based on the results of the INO-VATE ALL trial, which randomized 326 patients to receive either inotuzumab ozogamicin (164 patients) or a chemotherapy regimen of the investigator’s choice (162 patients). To be considered for inclusion in the trial, patients with Philadelphia chromosome–negative or –positive relapsed or refractory B-cell precursor ALL were required to have at least 5% bone marrow blasts and have received one or two induction chemotherapy regimens.

[email protected]

On Twitter @denisefulton

The Food and Drug Administration has approved the antibody drug conjugate inotuzumab ozogamicin for the treatment of adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL).

The treatment, to be marketed by Pfizer as Besponsa, won approval based on the results of the INO-VATE ALL trial, which randomized 326 patients to receive either inotuzumab ozogamicin (164 patients) or a chemotherapy regimen of the investigator’s choice (162 patients). To be considered for inclusion in the trial, patients with Philadelphia chromosome–negative or –positive relapsed or refractory B-cell precursor ALL were required to have at least 5% bone marrow blasts and have received one or two induction chemotherapy regimens.

[email protected]

On Twitter @denisefulton

Photo by Steven Harbour

New research has revealed shortcomings of post-approval studies for drugs granted accelerated approval in the US.

Researchers found that, for drugs granted accelerated approval from 2009 to 2013, both pre-approval and post-approval trials had limitations in their design and the endpoints used.

“One might expect accelerated approval confirmatory trials to be much more rigorous than the pre-approval trials,” said study author Aaron S. Kesselheim, MD, of Brigham and Women’s Hospital in Boston, Massachusetts.

“But we found that there were few differences in these key design features of the trials conducted before or after approval.”

Dr Kesselheim and his colleagues reported these findings in JAMA.

The researchers examined pre- and post-approval clinical trials of drugs granted accelerated approval by the US Food and Drug Administration (FDA) between 2009 and 2013.

During that time, the FDA granted 22 drugs accelerated approval for 24 indications (15 of them for hematologic disorders).

Fourteen of the indications were approved on the basis of single-intervention-group studies that enrolled a median of 132 patients.

The FDA ordered 38 post-approval studies to confirm the safety and efficacy of the drugs.

Three years after the last drug’s approval, half of those studies (n=19) were not complete. Eight (42%) of the incomplete studies were either terminated or delayed by more than 1 year.

For 14 of the 24 indications (58%), results from the post-approval studies were not available after a median of 5 years of follow-up.

Study comparison

Published reports were available for 18 of the 19 completed post-approval studies. The characteristics of these studies did not differ much from the 30 pre-approval studies.

There were no statistically significant differences with regard to median patient enrollment (P=0.17), the use of randomized (P=0.31) or double-blind trials (P=0.17), the use of placebo as a comparator (P=0.17), or the lack of a comparator (P=0.21).

However, there was a significant difference in the use of an active comparator (P=0.02), with more post-approval studies using an active comparator.

The researchers also found that 17 of the 18 post-approval trials still used surrogate measures of effect as primary endpoints.

There was no significant difference between pre- and post-approval trials when it came to the use of disease response (P=0.17) or most other surrogate measures (P=0.21) as the trials’ primary endpoint.

The same was true for overall survival (P=0.20), although significantly more post-approval studies used progression-free survival (P=0.001) as a primary endpoint.

“It is important to use clinical endpoints in testing investigational drugs whenever possible because there are numerous cases of drugs approved on the basis of a surrogate measure that turn out to later not effect actual clinical outcomes—or even make them worse,” Dr Kesselheim said.

To address these issues and improve the quality of confirmatory studies, Dr Kesselheim suggested the FDA clearly describe the limitations in the pre-approval data that will need to be addressed in post-approval studies.

He also suggested the agency work with manufacturers to ensure that post-approval studies are conducted using design features that will be optimally useful for confirming the efficacy of the drug.

Photo by Steven Harbour

New research has revealed shortcomings of post-approval studies for drugs granted accelerated approval in the US.

Researchers found that, for drugs granted accelerated approval from 2009 to 2013, both pre-approval and post-approval trials had limitations in their design and the endpoints used.

“One might expect accelerated approval confirmatory trials to be much more rigorous than the pre-approval trials,” said study author Aaron S. Kesselheim, MD, of Brigham and Women’s Hospital in Boston, Massachusetts.

“But we found that there were few differences in these key design features of the trials conducted before or after approval.”

Dr Kesselheim and his colleagues reported these findings in JAMA.

The researchers examined pre- and post-approval clinical trials of drugs granted accelerated approval by the US Food and Drug Administration (FDA) between 2009 and 2013.

During that time, the FDA granted 22 drugs accelerated approval for 24 indications (15 of them for hematologic disorders).

Fourteen of the indications were approved on the basis of single-intervention-group studies that enrolled a median of 132 patients.

The FDA ordered 38 post-approval studies to confirm the safety and efficacy of the drugs.

Three years after the last drug’s approval, half of those studies (n=19) were not complete. Eight (42%) of the incomplete studies were either terminated or delayed by more than 1 year.

For 14 of the 24 indications (58%), results from the post-approval studies were not available after a median of 5 years of follow-up.

Study comparison

Published reports were available for 18 of the 19 completed post-approval studies. The characteristics of these studies did not differ much from the 30 pre-approval studies.

There were no statistically significant differences with regard to median patient enrollment (P=0.17), the use of randomized (P=0.31) or double-blind trials (P=0.17), the use of placebo as a comparator (P=0.17), or the lack of a comparator (P=0.21).

However, there was a significant difference in the use of an active comparator (P=0.02), with more post-approval studies using an active comparator.

The researchers also found that 17 of the 18 post-approval trials still used surrogate measures of effect as primary endpoints.

There was no significant difference between pre- and post-approval trials when it came to the use of disease response (P=0.17) or most other surrogate measures (P=0.21) as the trials’ primary endpoint.

The same was true for overall survival (P=0.20), although significantly more post-approval studies used progression-free survival (P=0.001) as a primary endpoint.

“It is important to use clinical endpoints in testing investigational drugs whenever possible because there are numerous cases of drugs approved on the basis of a surrogate measure that turn out to later not effect actual clinical outcomes—or even make them worse,” Dr Kesselheim said.

To address these issues and improve the quality of confirmatory studies, Dr Kesselheim suggested the FDA clearly describe the limitations in the pre-approval data that will need to be addressed in post-approval studies.

He also suggested the agency work with manufacturers to ensure that post-approval studies are conducted using design features that will be optimally useful for confirming the efficacy of the drug.

Photo by Steven Harbour

New research has revealed shortcomings of post-approval studies for drugs granted accelerated approval in the US.

Researchers found that, for drugs granted accelerated approval from 2009 to 2013, both pre-approval and post-approval trials had limitations in their design and the endpoints used.

“One might expect accelerated approval confirmatory trials to be much more rigorous than the pre-approval trials,” said study author Aaron S. Kesselheim, MD, of Brigham and Women’s Hospital in Boston, Massachusetts.

“But we found that there were few differences in these key design features of the trials conducted before or after approval.”

Dr Kesselheim and his colleagues reported these findings in JAMA.

The researchers examined pre- and post-approval clinical trials of drugs granted accelerated approval by the US Food and Drug Administration (FDA) between 2009 and 2013.

During that time, the FDA granted 22 drugs accelerated approval for 24 indications (15 of them for hematologic disorders).

Fourteen of the indications were approved on the basis of single-intervention-group studies that enrolled a median of 132 patients.

The FDA ordered 38 post-approval studies to confirm the safety and efficacy of the drugs.

Three years after the last drug’s approval, half of those studies (n=19) were not complete. Eight (42%) of the incomplete studies were either terminated or delayed by more than 1 year.

For 14 of the 24 indications (58%), results from the post-approval studies were not available after a median of 5 years of follow-up.

Study comparison

Published reports were available for 18 of the 19 completed post-approval studies. The characteristics of these studies did not differ much from the 30 pre-approval studies.

There were no statistically significant differences with regard to median patient enrollment (P=0.17), the use of randomized (P=0.31) or double-blind trials (P=0.17), the use of placebo as a comparator (P=0.17), or the lack of a comparator (P=0.21).

However, there was a significant difference in the use of an active comparator (P=0.02), with more post-approval studies using an active comparator.

The researchers also found that 17 of the 18 post-approval trials still used surrogate measures of effect as primary endpoints.

There was no significant difference between pre- and post-approval trials when it came to the use of disease response (P=0.17) or most other surrogate measures (P=0.21) as the trials’ primary endpoint.

The same was true for overall survival (P=0.20), although significantly more post-approval studies used progression-free survival (P=0.001) as a primary endpoint.

“It is important to use clinical endpoints in testing investigational drugs whenever possible because there are numerous cases of drugs approved on the basis of a surrogate measure that turn out to later not effect actual clinical outcomes—or even make them worse,” Dr Kesselheim said.

To address these issues and improve the quality of confirmatory studies, Dr Kesselheim suggested the FDA clearly describe the limitations in the pre-approval data that will need to be addressed in post-approval studies.

He also suggested the agency work with manufacturers to ensure that post-approval studies are conducted using design features that will be optimally useful for confirming the efficacy of the drug.

AML cells

The US Food and Drug Administration (FDA) has granted orphan drug designation to H3B-8800 as a treatment for patients with acute myelogenous leukemia (AML) or chronic myelomonocytic leukemia (CMML).

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

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

About H3B-8800

H3B-8800 is an orally bioavailable small-molecule modulator of wild-type and mutant SF3b complexes. The SF3b complex is a key component of the spliceosome that is found in the cell nucleus and is responsible for the removal of noncoding introns from a transcribed pre-messenger RNA.

Recurrent heterozygous mutations in several core members of the spliceosome (SF3B1, U2AF1, SRSF2, and ZRSR2) have been identified in solid tumor and hematologic malignancies. Mutations in the core spliceosome components lead to aberrant mRNA splicing that may contribute to disease pathogenesis.

Preclinical data have suggested that H3B-8800 modulates RNA splicing and shows preferential antitumor activity in spliceosome-mutant cancer models, including models of AML and CMML. H3B-8800 showed dose-dependent modulation of canonical and aberrant splicing when administered at tolerated doses.

Results from this research were presented at the 2017 AACR Annual Meeting (abstract 1185).

H3B-8800 is currently under investigation in a phase 1 trial of patients with AML, CMML, and myelodysplastic syndromes that may carry mutations in the core spliceosome genes.

H3B-8800 is being developed by H3 Biomedicine Inc.

AML cells

The US Food and Drug Administration (FDA) has granted orphan drug designation to H3B-8800 as a treatment for patients with acute myelogenous leukemia (AML) or chronic myelomonocytic leukemia (CMML).

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

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

About H3B-8800

H3B-8800 is an orally bioavailable small-molecule modulator of wild-type and mutant SF3b complexes. The SF3b complex is a key component of the spliceosome that is found in the cell nucleus and is responsible for the removal of noncoding introns from a transcribed pre-messenger RNA.

Recurrent heterozygous mutations in several core members of the spliceosome (SF3B1, U2AF1, SRSF2, and ZRSR2) have been identified in solid tumor and hematologic malignancies. Mutations in the core spliceosome components lead to aberrant mRNA splicing that may contribute to disease pathogenesis.

Preclinical data have suggested that H3B-8800 modulates RNA splicing and shows preferential antitumor activity in spliceosome-mutant cancer models, including models of AML and CMML. H3B-8800 showed dose-dependent modulation of canonical and aberrant splicing when administered at tolerated doses.

Results from this research were presented at the 2017 AACR Annual Meeting (abstract 1185).

H3B-8800 is currently under investigation in a phase 1 trial of patients with AML, CMML, and myelodysplastic syndromes that may carry mutations in the core spliceosome genes.

H3B-8800 is being developed by H3 Biomedicine Inc.

AML cells

The US Food and Drug Administration (FDA) has granted orphan drug designation to H3B-8800 as a treatment for patients with acute myelogenous leukemia (AML) or chronic myelomonocytic leukemia (CMML).

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

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

About H3B-8800

H3B-8800 is an orally bioavailable small-molecule modulator of wild-type and mutant SF3b complexes. The SF3b complex is a key component of the spliceosome that is found in the cell nucleus and is responsible for the removal of noncoding introns from a transcribed pre-messenger RNA.

Recurrent heterozygous mutations in several core members of the spliceosome (SF3B1, U2AF1, SRSF2, and ZRSR2) have been identified in solid tumor and hematologic malignancies. Mutations in the core spliceosome components lead to aberrant mRNA splicing that may contribute to disease pathogenesis.

Preclinical data have suggested that H3B-8800 modulates RNA splicing and shows preferential antitumor activity in spliceosome-mutant cancer models, including models of AML and CMML. H3B-8800 showed dose-dependent modulation of canonical and aberrant splicing when administered at tolerated doses.

Results from this research were presented at the 2017 AACR Annual Meeting (abstract 1185).

H3B-8800 is currently under investigation in a phase 1 trial of patients with AML, CMML, and myelodysplastic syndromes that may carry mutations in the core spliceosome genes.

H3B-8800 is being developed by H3 Biomedicine Inc.

Mast cells

Stem cell factor (SCF) and KIT signaling are not necessary for early mast cell development, according to research published in Blood.

It has been assumed that the differentiation of hematopoietic progenitors to mast cells requires SCF and KIT signaling.

However, researchers found that mast cell progenitors can survive, mature, and proliferate in the absence of SCF and KIT signaling.

The researchers began this work by analyzing mast cell progenitor populations in samples from healthy subjects, patients with chronic myeloid leukemia (CML) or gastrointestinal stromal tumors (GIST) who were treated with imatinib, and patients with systemic mastocytosis carrying the D816V KIT mutation.

Imatinib inhibits KIT signaling, and the D816V KIT mutation causes KIT signaling to be constitutively active.

The researchers found the imatinib-treated CML and GIST patients and the patients with systemic mastocytosis all had mast cell progenitor populations similar to those observed in healthy subjects.

The team therefore concluded that dysfunctional KIT signaling does not affect the frequency of circulating mast cell progenitors in vivo.

On the other hand, the researchers also found that circulating mast cells were sensitive to imatinib in patients with CML. The patients had higher numbers of peripheral blood mast cells at diagnosis than they did after treatment with imatinib.

“When the patients were treated with the drug imatinib, which blocks the effect of stem cell factor, the number of mature mast cells dropped, while the number of progenitor cells did not change,” said study author Gunnar Nilsson, PhD, of Karolinska Institutet in Stockholm, Sweden.

Subsequent experiments showed that mast cell progenitors can survive in vitro without KIT signaling and without SCF. In addition, mast cell progenitors were able to mature and proliferate in vitro without SCF.

In fact, the researchers said they found that interleukin 3 was sufficient to promote the survival of mast cell progenitors in vitro.

“The study increases our understanding of how mast cells are formed and could be important in the development of new therapies, for example, for mastocytosis . . . ,” said study author Joakim Dahlin, PhD, of the University of Cambridge in the UK.

“One hypothesis that we will now test is whether interleukin 3 can be a new target in the treatment of mast cell-driven diseases.”

Mast cells

Stem cell factor (SCF) and KIT signaling are not necessary for early mast cell development, according to research published in Blood.

It has been assumed that the differentiation of hematopoietic progenitors to mast cells requires SCF and KIT signaling.

However, researchers found that mast cell progenitors can survive, mature, and proliferate in the absence of SCF and KIT signaling.

The researchers began this work by analyzing mast cell progenitor populations in samples from healthy subjects, patients with chronic myeloid leukemia (CML) or gastrointestinal stromal tumors (GIST) who were treated with imatinib, and patients with systemic mastocytosis carrying the D816V KIT mutation.

Imatinib inhibits KIT signaling, and the D816V KIT mutation causes KIT signaling to be constitutively active.

The researchers found the imatinib-treated CML and GIST patients and the patients with systemic mastocytosis all had mast cell progenitor populations similar to those observed in healthy subjects.

The team therefore concluded that dysfunctional KIT signaling does not affect the frequency of circulating mast cell progenitors in vivo.

On the other hand, the researchers also found that circulating mast cells were sensitive to imatinib in patients with CML. The patients had higher numbers of peripheral blood mast cells at diagnosis than they did after treatment with imatinib.

“When the patients were treated with the drug imatinib, which blocks the effect of stem cell factor, the number of mature mast cells dropped, while the number of progenitor cells did not change,” said study author Gunnar Nilsson, PhD, of Karolinska Institutet in Stockholm, Sweden.

Subsequent experiments showed that mast cell progenitors can survive in vitro without KIT signaling and without SCF. In addition, mast cell progenitors were able to mature and proliferate in vitro without SCF.

In fact, the researchers said they found that interleukin 3 was sufficient to promote the survival of mast cell progenitors in vitro.

“The study increases our understanding of how mast cells are formed and could be important in the development of new therapies, for example, for mastocytosis . . . ,” said study author Joakim Dahlin, PhD, of the University of Cambridge in the UK.

“One hypothesis that we will now test is whether interleukin 3 can be a new target in the treatment of mast cell-driven diseases.”

Mast cells

Stem cell factor (SCF) and KIT signaling are not necessary for early mast cell development, according to research published in Blood.

It has been assumed that the differentiation of hematopoietic progenitors to mast cells requires SCF and KIT signaling.

However, researchers found that mast cell progenitors can survive, mature, and proliferate in the absence of SCF and KIT signaling.

The researchers began this work by analyzing mast cell progenitor populations in samples from healthy subjects, patients with chronic myeloid leukemia (CML) or gastrointestinal stromal tumors (GIST) who were treated with imatinib, and patients with systemic mastocytosis carrying the D816V KIT mutation.

Imatinib inhibits KIT signaling, and the D816V KIT mutation causes KIT signaling to be constitutively active.

The researchers found the imatinib-treated CML and GIST patients and the patients with systemic mastocytosis all had mast cell progenitor populations similar to those observed in healthy subjects.

The team therefore concluded that dysfunctional KIT signaling does not affect the frequency of circulating mast cell progenitors in vivo.

On the other hand, the researchers also found that circulating mast cells were sensitive to imatinib in patients with CML. The patients had higher numbers of peripheral blood mast cells at diagnosis than they did after treatment with imatinib.

“When the patients were treated with the drug imatinib, which blocks the effect of stem cell factor, the number of mature mast cells dropped, while the number of progenitor cells did not change,” said study author Gunnar Nilsson, PhD, of Karolinska Institutet in Stockholm, Sweden.

Subsequent experiments showed that mast cell progenitors can survive in vitro without KIT signaling and without SCF. In addition, mast cell progenitors were able to mature and proliferate in vitro without SCF.

In fact, the researchers said they found that interleukin 3 was sufficient to promote the survival of mast cell progenitors in vitro.

“The study increases our understanding of how mast cells are formed and could be important in the development of new therapies, for example, for mastocytosis . . . ,” said study author Joakim Dahlin, PhD, of the University of Cambridge in the UK.

“One hypothesis that we will now test is whether interleukin 3 can be a new target in the treatment of mast cell-driven diseases.”

Photo by Rhoda Baer

New research suggests older cancer patients and their caregivers often differ in their assessment of the patients’ abilities.

In this study, patients generally rated their physical and mental function higher than caregivers did.

The study also showed the differences in assessment of patients’ physical abilities were associated with greater caregiver burden.

This research was published in The Oncologist.

“Caregivers are such an important part of our healthcare system, particularly for older adults with cancer,” said study author Arti Hurria, MD, of City of Hope National Medical Center in Duarte, California.

“We wanted to further understand the factors that are associated with caregiver burden.”

One factor Dr Hurria and her colleagues thought might be important is differences in assessments of patient health and physical abilities between patients and their caregivers.

“In daily practice, we sometimes see a disconnect between what the patient perceives their general health and abilities to be in comparison to what the caregiver thinks,” Dr Hurria said. “We wanted to see whether this disconnect impacted caregiver burden.”

To do this, Dr Hurria and her colleagues questioned 100 older cancer patients and their caregivers.

Subjects were asked about the patients’ general health and physical function, meaning their ability to perform everyday activities. The researchers then compared the answers given by the patients and their respective caregivers.

The researchers also assessed the level of caregiver burden (defined as a subjective feeling of stress caused by being overwhelmed by the demands of caring) by administering a standard questionnaire on topics such as sleep disturbance, physical effort, and patient behavior.

The 100 cancer patients, ages 65 to 91, were suffering from a variety of cancers. The most common were lymphoma (n=26), breast cancer (n=19), and gastrointestinal cancers (n=15). Twelve patients had leukemia, and 10 had myeloma.

The ages of the caregivers ranged from 28 to 85, and the majority were female (73%). They were mainly either the spouse of the patient (68%) or an adult child (18%).

Results

There was no significant difference in patient and caregiver accounts of the patients’ comorbidities (P=0.68), falls in the last 6 months (P=0.71), or percent weight change in the last 6 months (P=0.21).

However, caregivers consistently rated patients as having poorer physical function and mental health and requiring more social support than the patients themselves did.

There was a significant difference (P<0.05) in caregiver and patient accounts when it came to the following measures:

• Need for help with instrumental activities of daily living
• Karnofsky Performance Status
• Medical Outcomes Study-Physical Function
• Medical Outcomes Study-Social Support Survey
• Mental Health Inventory.

Only the disparity in the assessment of physical function was significantly associated with greater caregiver burden (P<0.001). What is still unclear is the cause of this disparity.

“I think there are 2 possible explanations,” said study author Tina Hsu, MD, of the University of Ottawa in Ontario, Canada.

“One is that older adults with cancer either don’t appreciate how much help they require or, more likely, they are able preserve their sense of independence and dignity through a perception that they feel they can do more than they really can.”

“Alternatively, it is possible that caregivers who are more stressed out perceive their loved one to require more help than they actually do need. Most likely, the truth of how much help the patient actually needs lies somewhere between what patients and caregivers report.”

Based on their findings, Drs Hsu and Hurria and their colleagues advise that clinicians consider assessing caregiver burden in those caregivers who report the patient as being more dependent than the patient does themselves.

“Caregivers play an essential role in supporting older adults with cancer,” Dr Hsu said. “We plan to further explore factors associated with caregiver burden in this population, particularly in those who are frailer and thus require even more hands-on support. We also hope to explore what resources caregivers of older adults with cancer feel they need to better help them with their role.”

Photo by Rhoda Baer

New research suggests older cancer patients and their caregivers often differ in their assessment of the patients’ abilities.

In this study, patients generally rated their physical and mental function higher than caregivers did.

The study also showed the differences in assessment of patients’ physical abilities were associated with greater caregiver burden.

This research was published in The Oncologist.

“Caregivers are such an important part of our healthcare system, particularly for older adults with cancer,” said study author Arti Hurria, MD, of City of Hope National Medical Center in Duarte, California.

“We wanted to further understand the factors that are associated with caregiver burden.”

One factor Dr Hurria and her colleagues thought might be important is differences in assessments of patient health and physical abilities between patients and their caregivers.

“In daily practice, we sometimes see a disconnect between what the patient perceives their general health and abilities to be in comparison to what the caregiver thinks,” Dr Hurria said. “We wanted to see whether this disconnect impacted caregiver burden.”

To do this, Dr Hurria and her colleagues questioned 100 older cancer patients and their caregivers.

Subjects were asked about the patients’ general health and physical function, meaning their ability to perform everyday activities. The researchers then compared the answers given by the patients and their respective caregivers.

The researchers also assessed the level of caregiver burden (defined as a subjective feeling of stress caused by being overwhelmed by the demands of caring) by administering a standard questionnaire on topics such as sleep disturbance, physical effort, and patient behavior.

The 100 cancer patients, ages 65 to 91, were suffering from a variety of cancers. The most common were lymphoma (n=26), breast cancer (n=19), and gastrointestinal cancers (n=15). Twelve patients had leukemia, and 10 had myeloma.

The ages of the caregivers ranged from 28 to 85, and the majority were female (73%). They were mainly either the spouse of the patient (68%) or an adult child (18%).

Results

There was no significant difference in patient and caregiver accounts of the patients’ comorbidities (P=0.68), falls in the last 6 months (P=0.71), or percent weight change in the last 6 months (P=0.21).

However, caregivers consistently rated patients as having poorer physical function and mental health and requiring more social support than the patients themselves did.

There was a significant difference (P<0.05) in caregiver and patient accounts when it came to the following measures:

• Need for help with instrumental activities of daily living
• Karnofsky Performance Status
• Medical Outcomes Study-Physical Function
• Medical Outcomes Study-Social Support Survey
• Mental Health Inventory.

Only the disparity in the assessment of physical function was significantly associated with greater caregiver burden (P<0.001). What is still unclear is the cause of this disparity.

“I think there are 2 possible explanations,” said study author Tina Hsu, MD, of the University of Ottawa in Ontario, Canada.

“One is that older adults with cancer either don’t appreciate how much help they require or, more likely, they are able preserve their sense of independence and dignity through a perception that they feel they can do more than they really can.”

“Alternatively, it is possible that caregivers who are more stressed out perceive their loved one to require more help than they actually do need. Most likely, the truth of how much help the patient actually needs lies somewhere between what patients and caregivers report.”

Based on their findings, Drs Hsu and Hurria and their colleagues advise that clinicians consider assessing caregiver burden in those caregivers who report the patient as being more dependent than the patient does themselves.

“Caregivers play an essential role in supporting older adults with cancer,” Dr Hsu said. “We plan to further explore factors associated with caregiver burden in this population, particularly in those who are frailer and thus require even more hands-on support. We also hope to explore what resources caregivers of older adults with cancer feel they need to better help them with their role.”

Photo by Rhoda Baer

New research suggests older cancer patients and their caregivers often differ in their assessment of the patients’ abilities.

In this study, patients generally rated their physical and mental function higher than caregivers did.

The study also showed the differences in assessment of patients’ physical abilities were associated with greater caregiver burden.

This research was published in The Oncologist.

“Caregivers are such an important part of our healthcare system, particularly for older adults with cancer,” said study author Arti Hurria, MD, of City of Hope National Medical Center in Duarte, California.

“We wanted to further understand the factors that are associated with caregiver burden.”

One factor Dr Hurria and her colleagues thought might be important is differences in assessments of patient health and physical abilities between patients and their caregivers.

“In daily practice, we sometimes see a disconnect between what the patient perceives their general health and abilities to be in comparison to what the caregiver thinks,” Dr Hurria said. “We wanted to see whether this disconnect impacted caregiver burden.”

To do this, Dr Hurria and her colleagues questioned 100 older cancer patients and their caregivers.

Subjects were asked about the patients’ general health and physical function, meaning their ability to perform everyday activities. The researchers then compared the answers given by the patients and their respective caregivers.

The researchers also assessed the level of caregiver burden (defined as a subjective feeling of stress caused by being overwhelmed by the demands of caring) by administering a standard questionnaire on topics such as sleep disturbance, physical effort, and patient behavior.

The 100 cancer patients, ages 65 to 91, were suffering from a variety of cancers. The most common were lymphoma (n=26), breast cancer (n=19), and gastrointestinal cancers (n=15). Twelve patients had leukemia, and 10 had myeloma.

The ages of the caregivers ranged from 28 to 85, and the majority were female (73%). They were mainly either the spouse of the patient (68%) or an adult child (18%).

Results

There was no significant difference in patient and caregiver accounts of the patients’ comorbidities (P=0.68), falls in the last 6 months (P=0.71), or percent weight change in the last 6 months (P=0.21).

However, caregivers consistently rated patients as having poorer physical function and mental health and requiring more social support than the patients themselves did.

There was a significant difference (P<0.05) in caregiver and patient accounts when it came to the following measures:

• Need for help with instrumental activities of daily living
• Karnofsky Performance Status
• Medical Outcomes Study-Physical Function
• Medical Outcomes Study-Social Support Survey
• Mental Health Inventory.

Only the disparity in the assessment of physical function was significantly associated with greater caregiver burden (P<0.001). What is still unclear is the cause of this disparity.

“I think there are 2 possible explanations,” said study author Tina Hsu, MD, of the University of Ottawa in Ontario, Canada.

“One is that older adults with cancer either don’t appreciate how much help they require or, more likely, they are able preserve their sense of independence and dignity through a perception that they feel they can do more than they really can.”

“Alternatively, it is possible that caregivers who are more stressed out perceive their loved one to require more help than they actually do need. Most likely, the truth of how much help the patient actually needs lies somewhere between what patients and caregivers report.”

Based on their findings, Drs Hsu and Hurria and their colleagues advise that clinicians consider assessing caregiver burden in those caregivers who report the patient as being more dependent than the patient does themselves.

“Caregivers play an essential role in supporting older adults with cancer,” Dr Hsu said. “We plan to further explore factors associated with caregiver burden in this population, particularly in those who are frailer and thus require even more hands-on support. We also hope to explore what resources caregivers of older adults with cancer feel they need to better help them with their role.”

Although adults older than 65 newly diagnosed with acute myeloid leukemia (AML) have a generally poor prognosis and short life expectancy, fewer than half were enrolled in hospice, and of those patients who were enrolled, two-thirds entered hospice within the last week of life, results of a retrospective cohort study show.

The findings suggest that there is substantial room for improvement in the care of older patients with AML in their last days of life, said investigators led by Rong Wang, PhD, and colleagues from Yale University in New Haven, Connecticut.

“[We] found that the current end-of-life care for older patients with AML is suboptimal, as reflected by low hospice enrollment and high use of potentially aggressive treatment. Transfer in and out of hospice was associated with the receipt of transfusions. Changes to current hospice services, such as enabling the provision of transfusion support, and improvements in physician-patient communications, may help facilitate better end-of-life care in this patient population,” they wrote (J Clin Oncol. 2017 Aug 7. doi: 10.1200/JCO.2017.72.7149)

Patients aged 65 and over with AML have a median overall survival (OS) of only about 2 months, and the older the patient, the worse the survival, with patients 85 and older having a median OS of just 1 month, the investigators noted.

“Hence, end-of-life care is particularly relevant for this patient population,” they wrote.

To get a better idea of how clinicians prescribe hospice and palliative care for older patients with AML, Dr. Wang and colleagues conducted a population-based, retrospective cohort study of patients with AML who were 66 or older at diagnosis, received a diagnosis from 1999 through 2011, and died before the end of 2012.

They reviewed Medicare claims data on 13,156 patients to see whether patients were receiving aggressive care such as chemotherapy and whether and when they were enrolled in hospice.

The investigators found that the proportion of patients who were enrolled in hospice after an AML diagnosis increased from 31.3% in 1999 to 56.4% in 2012 (P for trend less than .01).

They also discovered, however, that most of the increase was attributable to patients who were enrolled within the last week of life.

When they compared patients who died within 30 days of diagnosis to those who lived longer than 30 days after diagnosis, they found that the longer-lived patients were significantly more likely to have been enrolled in hospice (48.1% vs. 30.7%, P less than .01). Additionally, of those patients who were enrolled in hospice, 51.2% of those who died within 30 days of entering hospice had been enrolled in the last 3 days of life, compared with 24.9% of those who survived for more than a month after entering hospice (P value not shown).

Over the course of the study 1,528 patients (11.6%) had chemotherapy within their last two weeks of life. The proportion of patients undergoing chemotherapy within their last 14 days increased from 7.7% in 1999 to 18.8% in 2012 (P for trend less than .01).

Patients who had end-of-life chemotherapy were significantly more likely to have had an ICU stay in the last month of life (43.0% vs. 28.4%; P less than .01) and were significantly more likely to be enrolled in hospice (22.1% vs. 47.4%, P less than .01) than patients who did not get chemotherapy with the last 14 days of life.

Predictors for end-of-life chemotherapy were male sex, being married, and dying in more recent years. Patients who were older, had state Medicaid buy-in (an optional program for workers with disabilities), or who lived outside the Northeast or major metropolitan areas were less likely to be subjected to chemotherapy in their final days.

Overall, 3,956 patients (30.1%) were admitted to the ICU within 30 days of their deaths. The percentage of ICU admissions just before death increased from 25.2% in 1999 to 31.3% in 2012 (P for trend .01).

Predictors for late-life ICU admission were similar to those for chemotherapy, except that patients with state Medicaid buy-in had 19% greater odds of being admitted to an ICU within 30 days of death (P less than .01).

The study was funded by the National Cancer Institute. Dr. Wang reported no relevant conflicts of interests. Multiple coauthors reported financial relationships with various companies.

[email protected]

Although adults older than 65 newly diagnosed with acute myeloid leukemia (AML) have a generally poor prognosis and short life expectancy, fewer than half were enrolled in hospice, and of those patients who were enrolled, two-thirds entered hospice within the last week of life, results of a retrospective cohort study show.

The findings suggest that there is substantial room for improvement in the care of older patients with AML in their last days of life, said investigators led by Rong Wang, PhD, and colleagues from Yale University in New Haven, Connecticut.

“[We] found that the current end-of-life care for older patients with AML is suboptimal, as reflected by low hospice enrollment and high use of potentially aggressive treatment. Transfer in and out of hospice was associated with the receipt of transfusions. Changes to current hospice services, such as enabling the provision of transfusion support, and improvements in physician-patient communications, may help facilitate better end-of-life care in this patient population,” they wrote (J Clin Oncol. 2017 Aug 7. doi: 10.1200/JCO.2017.72.7149)

Patients aged 65 and over with AML have a median overall survival (OS) of only about 2 months, and the older the patient, the worse the survival, with patients 85 and older having a median OS of just 1 month, the investigators noted.

“Hence, end-of-life care is particularly relevant for this patient population,” they wrote.

To get a better idea of how clinicians prescribe hospice and palliative care for older patients with AML, Dr. Wang and colleagues conducted a population-based, retrospective cohort study of patients with AML who were 66 or older at diagnosis, received a diagnosis from 1999 through 2011, and died before the end of 2012.

They reviewed Medicare claims data on 13,156 patients to see whether patients were receiving aggressive care such as chemotherapy and whether and when they were enrolled in hospice.

The investigators found that the proportion of patients who were enrolled in hospice after an AML diagnosis increased from 31.3% in 1999 to 56.4% in 2012 (P for trend less than .01).

They also discovered, however, that most of the increase was attributable to patients who were enrolled within the last week of life.

When they compared patients who died within 30 days of diagnosis to those who lived longer than 30 days after diagnosis, they found that the longer-lived patients were significantly more likely to have been enrolled in hospice (48.1% vs. 30.7%, P less than .01). Additionally, of those patients who were enrolled in hospice, 51.2% of those who died within 30 days of entering hospice had been enrolled in the last 3 days of life, compared with 24.9% of those who survived for more than a month after entering hospice (P value not shown).

Over the course of the study 1,528 patients (11.6%) had chemotherapy within their last two weeks of life. The proportion of patients undergoing chemotherapy within their last 14 days increased from 7.7% in 1999 to 18.8% in 2012 (P for trend less than .01).

Patients who had end-of-life chemotherapy were significantly more likely to have had an ICU stay in the last month of life (43.0% vs. 28.4%; P less than .01) and were significantly more likely to be enrolled in hospice (22.1% vs. 47.4%, P less than .01) than patients who did not get chemotherapy with the last 14 days of life.

Predictors for end-of-life chemotherapy were male sex, being married, and dying in more recent years. Patients who were older, had state Medicaid buy-in (an optional program for workers with disabilities), or who lived outside the Northeast or major metropolitan areas were less likely to be subjected to chemotherapy in their final days.

Overall, 3,956 patients (30.1%) were admitted to the ICU within 30 days of their deaths. The percentage of ICU admissions just before death increased from 25.2% in 1999 to 31.3% in 2012 (P for trend .01).

Predictors for late-life ICU admission were similar to those for chemotherapy, except that patients with state Medicaid buy-in had 19% greater odds of being admitted to an ICU within 30 days of death (P less than .01).

The study was funded by the National Cancer Institute. Dr. Wang reported no relevant conflicts of interests. Multiple coauthors reported financial relationships with various companies.

[email protected]

Although adults older than 65 newly diagnosed with acute myeloid leukemia (AML) have a generally poor prognosis and short life expectancy, fewer than half were enrolled in hospice, and of those patients who were enrolled, two-thirds entered hospice within the last week of life, results of a retrospective cohort study show.

The findings suggest that there is substantial room for improvement in the care of older patients with AML in their last days of life, said investigators led by Rong Wang, PhD, and colleagues from Yale University in New Haven, Connecticut.

“[We] found that the current end-of-life care for older patients with AML is suboptimal, as reflected by low hospice enrollment and high use of potentially aggressive treatment. Transfer in and out of hospice was associated with the receipt of transfusions. Changes to current hospice services, such as enabling the provision of transfusion support, and improvements in physician-patient communications, may help facilitate better end-of-life care in this patient population,” they wrote (J Clin Oncol. 2017 Aug 7. doi: 10.1200/JCO.2017.72.7149)

Patients aged 65 and over with AML have a median overall survival (OS) of only about 2 months, and the older the patient, the worse the survival, with patients 85 and older having a median OS of just 1 month, the investigators noted.

“Hence, end-of-life care is particularly relevant for this patient population,” they wrote.

To get a better idea of how clinicians prescribe hospice and palliative care for older patients with AML, Dr. Wang and colleagues conducted a population-based, retrospective cohort study of patients with AML who were 66 or older at diagnosis, received a diagnosis from 1999 through 2011, and died before the end of 2012.

They reviewed Medicare claims data on 13,156 patients to see whether patients were receiving aggressive care such as chemotherapy and whether and when they were enrolled in hospice.

The investigators found that the proportion of patients who were enrolled in hospice after an AML diagnosis increased from 31.3% in 1999 to 56.4% in 2012 (P for trend less than .01).

They also discovered, however, that most of the increase was attributable to patients who were enrolled within the last week of life.

When they compared patients who died within 30 days of diagnosis to those who lived longer than 30 days after diagnosis, they found that the longer-lived patients were significantly more likely to have been enrolled in hospice (48.1% vs. 30.7%, P less than .01). Additionally, of those patients who were enrolled in hospice, 51.2% of those who died within 30 days of entering hospice had been enrolled in the last 3 days of life, compared with 24.9% of those who survived for more than a month after entering hospice (P value not shown).

Over the course of the study 1,528 patients (11.6%) had chemotherapy within their last two weeks of life. The proportion of patients undergoing chemotherapy within their last 14 days increased from 7.7% in 1999 to 18.8% in 2012 (P for trend less than .01).

Patients who had end-of-life chemotherapy were significantly more likely to have had an ICU stay in the last month of life (43.0% vs. 28.4%; P less than .01) and were significantly more likely to be enrolled in hospice (22.1% vs. 47.4%, P less than .01) than patients who did not get chemotherapy with the last 14 days of life.

Predictors for end-of-life chemotherapy were male sex, being married, and dying in more recent years. Patients who were older, had state Medicaid buy-in (an optional program for workers with disabilities), or who lived outside the Northeast or major metropolitan areas were less likely to be subjected to chemotherapy in their final days.

Overall, 3,956 patients (30.1%) were admitted to the ICU within 30 days of their deaths. The percentage of ICU admissions just before death increased from 25.2% in 1999 to 31.3% in 2012 (P for trend .01).

Predictors for late-life ICU admission were similar to those for chemotherapy, except that patients with state Medicaid buy-in had 19% greater odds of being admitted to an ICU within 30 days of death (P less than .01).

The study was funded by the National Cancer Institute. Dr. Wang reported no relevant conflicts of interests. Multiple coauthors reported financial relationships with various companies.

[email protected]

College of Medicine

New research suggests virus-specific T cells (VSTs) can protect patients from severe viral infections that sometimes occur after hematopoietic stem cell transplant (HSCT).

The VSTs proved effective against 5 different viruses—Epstein-Barr virus (EBV), adenovirus (AdV), cytomegalovirus (CMV), BK virus (BKV), and human herpesvirus 6 (HHV-6).

Ifigeneia Tzannou, MD, of Baylor College of Medicine in Houston, Texas, and her colleagues reported these findings in the Journal of Clinical Oncology.

“In this study, we continued our previous work . . . in which we showed that patients who had developed an Epstein-Barr virus infection after a transplant . . . could be helped by receiving immune cells specialized in eliminating that particular virus,” Dr Tzannou said. “Then, we and others successfully targeted other viruses—namely, adenoviruses and cytomegalovirus.”

“The novel contribution of this study is that we have targeted additional viruses, the BK virus and the HHV-6 virus, which had not been targeted this way before,” added study author Bilal Omer, MD, of Baylor College of Medicine.

“This is important because the BK virus does not have an effective treatment, and the complications are significant, including severe pain and bleeding. These patients are in the hospital for weeks, months sometimes, and, now, we have a treatment option.”

The researchers tested their VSTs in a phase 2 trial of 38 HSCT recipients with at least 1 of the aforementioned viruses.

“[To prepare the VSTs,] we take blood from healthy donors who have already been exposed to these viruses and who we have confirmed have immune cells that can fight the infections,” Dr Tzannou said.

“We isolate the cells and let them multiply in culture. The final product is a mixture of cells that, together, can target all 5 viruses. We prepared 59 sets of virus-specific cells from different donors following this procedure.”

“Our strategy is to prepare a number of sets of virus-specific cells ahead of time and store them in a freezer, ready to use when a patient needs them,” Dr Omer noted. “To match patient and donor, we use elaborate matching algorithms.”

Patients

The trial included 38 patients who had undergone HSCT to treat acute myeloid leukemia/myelodysplastic syndromes (n=20), acute lymphoblastic leukemia (n=9), lymphoma/myeloma (n=3), or nonmalignant disorders (n=6).

These 38 patients had a total of 45 infections—CMV (n=17), EBV (n=2), AdV (n=7), BKV (n=16), and HHV-6 (n=3).

Response

The researchers monitored virus levels and other clinical responses in the 37 evaluable patients.

Six weeks after the first VST infusion, the overall response rate was 91.9%.

Seventeen patients received VSTs for persistent CMV. Sixteen of these patients (94.1%) responded, 6 with complete responses (CRs) and 10 with partial responses (PRs).

Two patients received VSTs for EBV, and both achieved a virologic CR.

Seven patients received VSTs for persistent AdV. The response rate was 71.4%. Four patients achieved a CR, 1 had a PR, and 2 patients did not respond.

Three patients received VSTs to treat HHV-6 reactivations. The response rate was 67%. Two patients had a PR, and 1 was not evaluable.

Sixteen patients received VSTs for BKV-associated hemorrhagic cystitis (n= 14) or BKV-associated nephritis (n=2).

All 16 patients responded. One had a clinical and virologic CR. Six had a clinical CR but a virologic PR. Seven had a virologic and clinical PR. And 2 patients had only a virologic PR.

A total of 15 patients received a second VST infusion—1 due to lack of response, 7 who had a PR, and 7 due to recurrence. Ten of these patients responded to the second infusion—1 with a CR and 9 with a PR.

Four patients received a third infusion of VSTs. Two achieved a CR, 1 had a PR, and 1 did not respond.

Toxicity

One patient developed an isolated fever within 24 hours of VST infusion, but the researchers did not observe any other immediate toxicities.

One of the patients with BKV-associated hemorrhagic cystitis experienced transient hydronephrosis and a decrease in renal function associated with a concomitant bacterial urinary tract infection.

Nineteen patients had prior grade 2 to 4 graft-versus-host disease (GVHD)—15 with grade 2 and 4 with grade 3. All GVHD was quiescent at the time of VST infusion.

One patient developed recurrent grade 3 gastrointestinal GVHD after VST infusion and rapid corticosteroid taper. Five patients developed recurrent (n=3) or de novo (n=2) grade 1 to 2 skin GVHD, which resolved with topical treatment (n=4) and reinitiation of corticosteroid treatment (n=1).

Two patients had a flare of upper-gastrointestinal GVHD, which resolved after a brief corticosteroid course.

“We didn’t have any significant toxicities,” Dr Tzannou said. “Taken together, the results of this trial suggest that it is reasonable to consider this treatment as an early option for these patients. We hope that the results of a future multicenter, phase 3 clinical trial will help raise awareness in both physicians and patients that this treatment, which is safe and effective, is available.”

College of Medicine

New research suggests virus-specific T cells (VSTs) can protect patients from severe viral infections that sometimes occur after hematopoietic stem cell transplant (HSCT).

The VSTs proved effective against 5 different viruses—Epstein-Barr virus (EBV), adenovirus (AdV), cytomegalovirus (CMV), BK virus (BKV), and human herpesvirus 6 (HHV-6).

Ifigeneia Tzannou, MD, of Baylor College of Medicine in Houston, Texas, and her colleagues reported these findings in the Journal of Clinical Oncology.

“In this study, we continued our previous work . . . in which we showed that patients who had developed an Epstein-Barr virus infection after a transplant . . . could be helped by receiving immune cells specialized in eliminating that particular virus,” Dr Tzannou said. “Then, we and others successfully targeted other viruses—namely, adenoviruses and cytomegalovirus.”

“The novel contribution of this study is that we have targeted additional viruses, the BK virus and the HHV-6 virus, which had not been targeted this way before,” added study author Bilal Omer, MD, of Baylor College of Medicine.

“This is important because the BK virus does not have an effective treatment, and the complications are significant, including severe pain and bleeding. These patients are in the hospital for weeks, months sometimes, and, now, we have a treatment option.”

The researchers tested their VSTs in a phase 2 trial of 38 HSCT recipients with at least 1 of the aforementioned viruses.

“[To prepare the VSTs,] we take blood from healthy donors who have already been exposed to these viruses and who we have confirmed have immune cells that can fight the infections,” Dr Tzannou said.

“We isolate the cells and let them multiply in culture. The final product is a mixture of cells that, together, can target all 5 viruses. We prepared 59 sets of virus-specific cells from different donors following this procedure.”

“Our strategy is to prepare a number of sets of virus-specific cells ahead of time and store them in a freezer, ready to use when a patient needs them,” Dr Omer noted. “To match patient and donor, we use elaborate matching algorithms.”

Patients

The trial included 38 patients who had undergone HSCT to treat acute myeloid leukemia/myelodysplastic syndromes (n=20), acute lymphoblastic leukemia (n=9), lymphoma/myeloma (n=3), or nonmalignant disorders (n=6).

These 38 patients had a total of 45 infections—CMV (n=17), EBV (n=2), AdV (n=7), BKV (n=16), and HHV-6 (n=3).

Response

The researchers monitored virus levels and other clinical responses in the 37 evaluable patients.

Six weeks after the first VST infusion, the overall response rate was 91.9%.

Seventeen patients received VSTs for persistent CMV. Sixteen of these patients (94.1%) responded, 6 with complete responses (CRs) and 10 with partial responses (PRs).

Two patients received VSTs for EBV, and both achieved a virologic CR.

Seven patients received VSTs for persistent AdV. The response rate was 71.4%. Four patients achieved a CR, 1 had a PR, and 2 patients did not respond.

Three patients received VSTs to treat HHV-6 reactivations. The response rate was 67%. Two patients had a PR, and 1 was not evaluable.

Sixteen patients received VSTs for BKV-associated hemorrhagic cystitis (n= 14) or BKV-associated nephritis (n=2).

All 16 patients responded. One had a clinical and virologic CR. Six had a clinical CR but a virologic PR. Seven had a virologic and clinical PR. And 2 patients had only a virologic PR.

A total of 15 patients received a second VST infusion—1 due to lack of response, 7 who had a PR, and 7 due to recurrence. Ten of these patients responded to the second infusion—1 with a CR and 9 with a PR.

Four patients received a third infusion of VSTs. Two achieved a CR, 1 had a PR, and 1 did not respond.

Toxicity

One patient developed an isolated fever within 24 hours of VST infusion, but the researchers did not observe any other immediate toxicities.

One of the patients with BKV-associated hemorrhagic cystitis experienced transient hydronephrosis and a decrease in renal function associated with a concomitant bacterial urinary tract infection.

Nineteen patients had prior grade 2 to 4 graft-versus-host disease (GVHD)—15 with grade 2 and 4 with grade 3. All GVHD was quiescent at the time of VST infusion.

One patient developed recurrent grade 3 gastrointestinal GVHD after VST infusion and rapid corticosteroid taper. Five patients developed recurrent (n=3) or de novo (n=2) grade 1 to 2 skin GVHD, which resolved with topical treatment (n=4) and reinitiation of corticosteroid treatment (n=1).

Two patients had a flare of upper-gastrointestinal GVHD, which resolved after a brief corticosteroid course.

“We didn’t have any significant toxicities,” Dr Tzannou said. “Taken together, the results of this trial suggest that it is reasonable to consider this treatment as an early option for these patients. We hope that the results of a future multicenter, phase 3 clinical trial will help raise awareness in both physicians and patients that this treatment, which is safe and effective, is available.”

College of Medicine

New research suggests virus-specific T cells (VSTs) can protect patients from severe viral infections that sometimes occur after hematopoietic stem cell transplant (HSCT).

The VSTs proved effective against 5 different viruses—Epstein-Barr virus (EBV), adenovirus (AdV), cytomegalovirus (CMV), BK virus (BKV), and human herpesvirus 6 (HHV-6).

Ifigeneia Tzannou, MD, of Baylor College of Medicine in Houston, Texas, and her colleagues reported these findings in the Journal of Clinical Oncology.

“In this study, we continued our previous work . . . in which we showed that patients who had developed an Epstein-Barr virus infection after a transplant . . . could be helped by receiving immune cells specialized in eliminating that particular virus,” Dr Tzannou said. “Then, we and others successfully targeted other viruses—namely, adenoviruses and cytomegalovirus.”

“The novel contribution of this study is that we have targeted additional viruses, the BK virus and the HHV-6 virus, which had not been targeted this way before,” added study author Bilal Omer, MD, of Baylor College of Medicine.

“This is important because the BK virus does not have an effective treatment, and the complications are significant, including severe pain and bleeding. These patients are in the hospital for weeks, months sometimes, and, now, we have a treatment option.”

The researchers tested their VSTs in a phase 2 trial of 38 HSCT recipients with at least 1 of the aforementioned viruses.

“[To prepare the VSTs,] we take blood from healthy donors who have already been exposed to these viruses and who we have confirmed have immune cells that can fight the infections,” Dr Tzannou said.

“We isolate the cells and let them multiply in culture. The final product is a mixture of cells that, together, can target all 5 viruses. We prepared 59 sets of virus-specific cells from different donors following this procedure.”

“Our strategy is to prepare a number of sets of virus-specific cells ahead of time and store them in a freezer, ready to use when a patient needs them,” Dr Omer noted. “To match patient and donor, we use elaborate matching algorithms.”

Patients

The trial included 38 patients who had undergone HSCT to treat acute myeloid leukemia/myelodysplastic syndromes (n=20), acute lymphoblastic leukemia (n=9), lymphoma/myeloma (n=3), or nonmalignant disorders (n=6).

These 38 patients had a total of 45 infections—CMV (n=17), EBV (n=2), AdV (n=7), BKV (n=16), and HHV-6 (n=3).

Response

The researchers monitored virus levels and other clinical responses in the 37 evaluable patients.

Six weeks after the first VST infusion, the overall response rate was 91.9%.

Seventeen patients received VSTs for persistent CMV. Sixteen of these patients (94.1%) responded, 6 with complete responses (CRs) and 10 with partial responses (PRs).

Two patients received VSTs for EBV, and both achieved a virologic CR.

Seven patients received VSTs for persistent AdV. The response rate was 71.4%. Four patients achieved a CR, 1 had a PR, and 2 patients did not respond.

Three patients received VSTs to treat HHV-6 reactivations. The response rate was 67%. Two patients had a PR, and 1 was not evaluable.

Sixteen patients received VSTs for BKV-associated hemorrhagic cystitis (n= 14) or BKV-associated nephritis (n=2).

All 16 patients responded. One had a clinical and virologic CR. Six had a clinical CR but a virologic PR. Seven had a virologic and clinical PR. And 2 patients had only a virologic PR.

A total of 15 patients received a second VST infusion—1 due to lack of response, 7 who had a PR, and 7 due to recurrence. Ten of these patients responded to the second infusion—1 with a CR and 9 with a PR.

Four patients received a third infusion of VSTs. Two achieved a CR, 1 had a PR, and 1 did not respond.

Toxicity

One patient developed an isolated fever within 24 hours of VST infusion, but the researchers did not observe any other immediate toxicities.

One of the patients with BKV-associated hemorrhagic cystitis experienced transient hydronephrosis and a decrease in renal function associated with a concomitant bacterial urinary tract infection.

Nineteen patients had prior grade 2 to 4 graft-versus-host disease (GVHD)—15 with grade 2 and 4 with grade 3. All GVHD was quiescent at the time of VST infusion.

One patient developed recurrent grade 3 gastrointestinal GVHD after VST infusion and rapid corticosteroid taper. Five patients developed recurrent (n=3) or de novo (n=2) grade 1 to 2 skin GVHD, which resolved with topical treatment (n=4) and reinitiation of corticosteroid treatment (n=1).

Two patients had a flare of upper-gastrointestinal GVHD, which resolved after a brief corticosteroid course.

“We didn’t have any significant toxicities,” Dr Tzannou said. “Taken together, the results of this trial suggest that it is reasonable to consider this treatment as an early option for these patients. We hope that the results of a future multicenter, phase 3 clinical trial will help raise awareness in both physicians and patients that this treatment, which is safe and effective, is available.”