COPENHAGEN – It’s early days yet, but results look highly promising for the ability of an experimental gene-transfer therapy to improve coagulation parameters in patients with severe hemophilia B.

In a phase I/II dose-escalation study, a single 1-hour infusion of the gene-transfer product, labeled SPK-9001, resulted in factor IX activity levels ranging from 25% to 39% of normal in four men with severe or moderately severe hemophilia B, reported Dr. Katherine A High, president and chief scientific officer of Spark Therapeutics, maker of the product.

©Kativ/iStockphoto

“One of the most remarkable features of the data in my mind has been a very consistent performance,” she said at a briefing at the annual congress of the European Hematology Association.

The product consists of a vector containing a novel bio-engineered adeno-associated virus (AAV) capsid with tropism for liver, and a factor IX cassette that carries a strong liver-specific promoter to drive the expression of the factor IX variant, dubbed factor IX Padua.

“The hypothesis of the work was that if we could engineer a vector efficient enough, we would be able to infuse it at a dose low enough that it would drive loads of expression greater than 12% of normal, which in previous work has been shown to be associated with an absence of joint bleeds in natural history studies of people with mild disease, and that infusion at a low dose would eliminate the need for any type of immune suppression with steroids,” Dr. High said.

Other attempts at genetic engineering in patients with hemophilia B have been hampered by the need to use high doses of vector that can induce an immune response, thereby negating the benefit of therapy.

In this ongoing study, conducted in Mississippi, Pennsylvania, and California, males 18 and older with a confirmed diagnosis of hemophilia B (defined as equal to or less than 2 IU/dL or 2% endogenous factor IX) who have received 50 or more days of exposure to factor IX products are enrolled. The patients must have a minimum average of four bleeding events per year requiring episodic treatment of factor IX infusions or prophylactic factor IX infusions, no measurable factor IX inhibitor as assessed by the central laboratory, and no prior history of inhibitors to factor IX protein.

In an oral session at the congress, Dr. Spencer Sullivan, assistant professor of pediatrics and medicine at the University of Mississippi Medical Center in Jackson, presented data on four men whose age ranges from 18 to 47 years.

In the dose-escalation phase of the study, the patients received single infusions of SPK-9001 at an initial starting dose of 5 x 1011 vector genomes of body weight. They were followed for 7-26 weeks after gene transfer for factor IX activity levels, liver enzymes, bleeding episode, and factor usage. As of May 22, 2016, the first four patients showed factor IX activity levels of 32%, 39%, 25%, and 27% of normal, respectively.

All subjects are currently off prophylactic factor IX infusions. During the course of follow-up, one patient infused himself with factor IX once, treating himself 2 days after vector infusion for a suspected ankle bleed.

Asked by a reporter how durable the effect was, Dr. High replied that in dog models of hemophilia B the effect of the gene transfer has been durable.

The best evidence to date of durability in humans, she said, comes from investigators at University College in London (England), who found that if patients can make it past the first 8-10 weeks without developing an immune response to the transfer product, they are likely to do well, and to have a durable effect, she said.

Dr. Anton Hagenbeek, from the Academic Medical Center, University of Amsterdam, who moderated the briefing but was not involved in the study, said that Dr. High was “to be congratulated for these best data ever seen.”

He asked, facetiously, whether she thought that “thousands of patients would buy a ticket to Philadelphia.” The “City of Brotherly Love” is home to one of the trial sites and to Spark headquarters.

The study is sponsored by Spark Therapeutics and Pfizer. Dr. High is president and chief scientific officer of Spark. Dr. Sullivan and Dr. Hagenbeek reported no relevant disclosures.

COPENHAGEN – It’s early days yet, but results look highly promising for the ability of an experimental gene-transfer therapy to improve coagulation parameters in patients with severe hemophilia B.

In a phase I/II dose-escalation study, a single 1-hour infusion of the gene-transfer product, labeled SPK-9001, resulted in factor IX activity levels ranging from 25% to 39% of normal in four men with severe or moderately severe hemophilia B, reported Dr. Katherine A High, president and chief scientific officer of Spark Therapeutics, maker of the product.

©Kativ/iStockphoto

“One of the most remarkable features of the data in my mind has been a very consistent performance,” she said at a briefing at the annual congress of the European Hematology Association.

The product consists of a vector containing a novel bio-engineered adeno-associated virus (AAV) capsid with tropism for liver, and a factor IX cassette that carries a strong liver-specific promoter to drive the expression of the factor IX variant, dubbed factor IX Padua.

“The hypothesis of the work was that if we could engineer a vector efficient enough, we would be able to infuse it at a dose low enough that it would drive loads of expression greater than 12% of normal, which in previous work has been shown to be associated with an absence of joint bleeds in natural history studies of people with mild disease, and that infusion at a low dose would eliminate the need for any type of immune suppression with steroids,” Dr. High said.

Other attempts at genetic engineering in patients with hemophilia B have been hampered by the need to use high doses of vector that can induce an immune response, thereby negating the benefit of therapy.

In this ongoing study, conducted in Mississippi, Pennsylvania, and California, males 18 and older with a confirmed diagnosis of hemophilia B (defined as equal to or less than 2 IU/dL or 2% endogenous factor IX) who have received 50 or more days of exposure to factor IX products are enrolled. The patients must have a minimum average of four bleeding events per year requiring episodic treatment of factor IX infusions or prophylactic factor IX infusions, no measurable factor IX inhibitor as assessed by the central laboratory, and no prior history of inhibitors to factor IX protein.

In an oral session at the congress, Dr. Spencer Sullivan, assistant professor of pediatrics and medicine at the University of Mississippi Medical Center in Jackson, presented data on four men whose age ranges from 18 to 47 years.

In the dose-escalation phase of the study, the patients received single infusions of SPK-9001 at an initial starting dose of 5 x 1011 vector genomes of body weight. They were followed for 7-26 weeks after gene transfer for factor IX activity levels, liver enzymes, bleeding episode, and factor usage. As of May 22, 2016, the first four patients showed factor IX activity levels of 32%, 39%, 25%, and 27% of normal, respectively.

All subjects are currently off prophylactic factor IX infusions. During the course of follow-up, one patient infused himself with factor IX once, treating himself 2 days after vector infusion for a suspected ankle bleed.

Asked by a reporter how durable the effect was, Dr. High replied that in dog models of hemophilia B the effect of the gene transfer has been durable.

The best evidence to date of durability in humans, she said, comes from investigators at University College in London (England), who found that if patients can make it past the first 8-10 weeks without developing an immune response to the transfer product, they are likely to do well, and to have a durable effect, she said.

Dr. Anton Hagenbeek, from the Academic Medical Center, University of Amsterdam, who moderated the briefing but was not involved in the study, said that Dr. High was “to be congratulated for these best data ever seen.”

He asked, facetiously, whether she thought that “thousands of patients would buy a ticket to Philadelphia.” The “City of Brotherly Love” is home to one of the trial sites and to Spark headquarters.

The study is sponsored by Spark Therapeutics and Pfizer. Dr. High is president and chief scientific officer of Spark. Dr. Sullivan and Dr. Hagenbeek reported no relevant disclosures.

COPENHAGEN – It’s early days yet, but results look highly promising for the ability of an experimental gene-transfer therapy to improve coagulation parameters in patients with severe hemophilia B.

In a phase I/II dose-escalation study, a single 1-hour infusion of the gene-transfer product, labeled SPK-9001, resulted in factor IX activity levels ranging from 25% to 39% of normal in four men with severe or moderately severe hemophilia B, reported Dr. Katherine A High, president and chief scientific officer of Spark Therapeutics, maker of the product.

©Kativ/iStockphoto

“One of the most remarkable features of the data in my mind has been a very consistent performance,” she said at a briefing at the annual congress of the European Hematology Association.

The product consists of a vector containing a novel bio-engineered adeno-associated virus (AAV) capsid with tropism for liver, and a factor IX cassette that carries a strong liver-specific promoter to drive the expression of the factor IX variant, dubbed factor IX Padua.

“The hypothesis of the work was that if we could engineer a vector efficient enough, we would be able to infuse it at a dose low enough that it would drive loads of expression greater than 12% of normal, which in previous work has been shown to be associated with an absence of joint bleeds in natural history studies of people with mild disease, and that infusion at a low dose would eliminate the need for any type of immune suppression with steroids,” Dr. High said.

Other attempts at genetic engineering in patients with hemophilia B have been hampered by the need to use high doses of vector that can induce an immune response, thereby negating the benefit of therapy.

In this ongoing study, conducted in Mississippi, Pennsylvania, and California, males 18 and older with a confirmed diagnosis of hemophilia B (defined as equal to or less than 2 IU/dL or 2% endogenous factor IX) who have received 50 or more days of exposure to factor IX products are enrolled. The patients must have a minimum average of four bleeding events per year requiring episodic treatment of factor IX infusions or prophylactic factor IX infusions, no measurable factor IX inhibitor as assessed by the central laboratory, and no prior history of inhibitors to factor IX protein.

In an oral session at the congress, Dr. Spencer Sullivan, assistant professor of pediatrics and medicine at the University of Mississippi Medical Center in Jackson, presented data on four men whose age ranges from 18 to 47 years.

In the dose-escalation phase of the study, the patients received single infusions of SPK-9001 at an initial starting dose of 5 x 1011 vector genomes of body weight. They were followed for 7-26 weeks after gene transfer for factor IX activity levels, liver enzymes, bleeding episode, and factor usage. As of May 22, 2016, the first four patients showed factor IX activity levels of 32%, 39%, 25%, and 27% of normal, respectively.

All subjects are currently off prophylactic factor IX infusions. During the course of follow-up, one patient infused himself with factor IX once, treating himself 2 days after vector infusion for a suspected ankle bleed.

Asked by a reporter how durable the effect was, Dr. High replied that in dog models of hemophilia B the effect of the gene transfer has been durable.

The best evidence to date of durability in humans, she said, comes from investigators at University College in London (England), who found that if patients can make it past the first 8-10 weeks without developing an immune response to the transfer product, they are likely to do well, and to have a durable effect, she said.

Dr. Anton Hagenbeek, from the Academic Medical Center, University of Amsterdam, who moderated the briefing but was not involved in the study, said that Dr. High was “to be congratulated for these best data ever seen.”

He asked, facetiously, whether she thought that “thousands of patients would buy a ticket to Philadelphia.” The “City of Brotherly Love” is home to one of the trial sites and to Spark headquarters.

The study is sponsored by Spark Therapeutics and Pfizer. Dr. High is president and chief scientific officer of Spark. Dr. Sullivan and Dr. Hagenbeek reported no relevant disclosures.

CHICAGO – Artificially prolonging the platinum-free interval by introducing a non–platinum-based chemotherapy before re-treatment with platinum-based chemotherapy in patients with partially platinum-sensitive recurrent ovarian cancer did not improve efficacy, and actually worsened the outcomes in patients in the randomized, open-label, phase III Multicentre Italian Trials in Ovarian Cancer 8 (MITO8) trial.

Based on the findings, immediate re-treatment with platinum-based chemotherapy remains the standard treatment strategy in such patients, Dr. Sandro Pignata reported at the annual meeting of the American Society of Clinical Oncology.

The idea that a non-platinum therapy might artificially extend the platinum-free interval, thereby improving outcomes in ovarian cancer patients who experience recurrence between 6 and 12 months after responding to platinum-based therapy, was first proposed more than 20 years ago. Despite a lack of prospective data with respect to this non–platinum-therapy approach, the idea has been used successfully to market non-platinum chemotherapy agents such as paclitaxel, topotecan, pegylated liposomal doxorubicin (PLD), and more recently, PLD-trabectedin for use before reinitiating platinum chemotherapy, explained Dr. Pignata of S.C. Oncologia Medica Ginecologica, Istituto Nazionale Tumori, Napoli.

In fact, a 2007 retrospective analysis (SOCRATES) showed that 35% of patients with recurrence at 6-12 months after platinum-based therapy were treated with a non-platinum single agent before re-treatment with a platinum-based therapy, and that the approach has been used as the control arm in multiple phase III trials that included patients with a platinum-free interval of 6-12 months. The findings indicate that the unproven hypothesis has been adapted into clinical practice, but the investigators were unable to demonstrate an advantage with the approach and concluded that further investigation was warranted.

MITO8, a multi-organization collaborative effort, was designed to test whether artificial prolongation of the platinum-free interval with a single-agent non-platinum treatment would improve overall survival in recurrent partially platinum-sensitive ovarian cancer patients.

In 107 such patients randomized to the experimental arm – receiving a non–platinum-based chemotherapy first to prolong the platinum-free interval, followed by platinum-based chemotherapy after progression – the median time from previous platinum to randomization was 8 months, and from randomization to platinum, 7.8 months. Median overall survival, the primary endpoint of the study, was 21.8 months.

In 108 patients randomized to immediate standard therapy with platinum-based chemotherapy followed by non-platinum therapy, median time from previous platinum to randomization was 8 months, and overall survival was 24.5 months (hazard ratio favoring platinum chemotherapy, 1.38), Dr. Pignata said, noting that the difference in overall survival approached but did not reach statistical significance.

A secondary endpoint of progression-free survival after the second treatment was 12.8 months in the experimental arm, vs. 16.4 months in the platinum-based chemotherapy arm (adjusted HR, 1.41). This difference was statistically significant.

No differences with respect to safety or toxicity were seen between the groups.

MITO8 subjects were women with ovarian cancer recurring between 6 and 12 months after previous platinum-based chemotherapy. The patients had received no more than two prior lines of chemotherapy, had good performance status, and had normal organ function.

Non–platinum-based therapy used in the study included pegylated liposomal doxorubicin, except during a period of the study when the agent was in short supply and other single agents were used, including gemcitabine and topotecan. Most patients, however, received PLD.

Platinum-based therapy was carboplatin plus paclitaxel or, in patients with neurotoxicity at baseline, carboplatin plus gemcitabine.

The shortage of PLD was just one of numerous challenges encountered during the course of the beleaguered study. Enrollment began in 2009, but was temporarily suspended in 2011 because of the PLD shortage. In 2012, the amendment to allow other non–platinum-based chemotherapies to be used was approved at most sites and enrollment resumed. However, accrual slowed and enrollment was closed in 2015. The study was stopped early, and the final analysis was conducted in March 2016 when events plateaued. The investigators, in conjunction with the independent data monitoring committee, determined that the results “still had to be presented early because they still may affect clinical practice.”

Dr. Pignata said that the hypothesis “was based on the fact that there were more responses in the patients treated with a platinum after a non-platinum, but this was not the case ... Responses were more frequent in the patients who received platinum first and then non-platinum later,” he said. The response rates for the experimental vs. standard approaches, respectively, were 43% vs. 56% among RECIST responders, and 70% vs. 75% among CA125 responders.

The findings of MITO8, one of the first clinical trials in ovarian cancer to evaluate two different sequences of chemotherapy, send “a strong message that even in the presence of a very nice hypothesis, we have to await the results of prospective clinical trials before changing clinical practice,” he said.

Dr. Maurie Markman of Cancer Treatment Centers of America in Boca Raton, Fla., the invited discussant, praised the work of Dr. Pignata and his colleagues, calling their study “elegant,” and “an extraordinary effort.”

“In this unbelievably important analysis, the hypothesis was flat-out wrong,” he said.

The study is an example of “a simple, provocative, and potentially highly clinically relevant hypothesis that should be able to be quickly tested in either a cooperative group setting, in multiple institutions interested in gynecologic malignancies ... when or very shortly after it is initially proposed,” he said.

Waiting 20 years is unacceptable, he said, adding: “This is tragic, this length of time to get an answer. And I must ask ... how many ovarian cancer patients over this many-year period have received second-line chemotherapy based on this conceptual approach, and may have actually been harmed?”

To prevent such outcomes in the future, Dr. Markman proposed heavier reliance on “nonrandomized population-based studies including real-world patients managed by a variety of approaches with securely privacy-protected data included within a public database,” to test noninvestigational approaches to disease management.

“And for this database, I would propose ASCO’s CancerLinq,” he said.

Dr. Pignata reported receiving honoraria from, and serving as a consultant or adviser for AstraZeneca, PharmaMar, and Roche, and receiving research funding from Roche. Dr. Markman is a consultant or advisor for Amgen, Celgene, CritiTech, and Pfizer; is on the speakers bureau for AstraZeneca and Genentech/Roche, and has provided expert testimony for several entities

[email protected]

CHICAGO – Artificially prolonging the platinum-free interval by introducing a non–platinum-based chemotherapy before re-treatment with platinum-based chemotherapy in patients with partially platinum-sensitive recurrent ovarian cancer did not improve efficacy, and actually worsened the outcomes in patients in the randomized, open-label, phase III Multicentre Italian Trials in Ovarian Cancer 8 (MITO8) trial.

Based on the findings, immediate re-treatment with platinum-based chemotherapy remains the standard treatment strategy in such patients, Dr. Sandro Pignata reported at the annual meeting of the American Society of Clinical Oncology.

The idea that a non-platinum therapy might artificially extend the platinum-free interval, thereby improving outcomes in ovarian cancer patients who experience recurrence between 6 and 12 months after responding to platinum-based therapy, was first proposed more than 20 years ago. Despite a lack of prospective data with respect to this non–platinum-therapy approach, the idea has been used successfully to market non-platinum chemotherapy agents such as paclitaxel, topotecan, pegylated liposomal doxorubicin (PLD), and more recently, PLD-trabectedin for use before reinitiating platinum chemotherapy, explained Dr. Pignata of S.C. Oncologia Medica Ginecologica, Istituto Nazionale Tumori, Napoli.

In fact, a 2007 retrospective analysis (SOCRATES) showed that 35% of patients with recurrence at 6-12 months after platinum-based therapy were treated with a non-platinum single agent before re-treatment with a platinum-based therapy, and that the approach has been used as the control arm in multiple phase III trials that included patients with a platinum-free interval of 6-12 months. The findings indicate that the unproven hypothesis has been adapted into clinical practice, but the investigators were unable to demonstrate an advantage with the approach and concluded that further investigation was warranted.

MITO8, a multi-organization collaborative effort, was designed to test whether artificial prolongation of the platinum-free interval with a single-agent non-platinum treatment would improve overall survival in recurrent partially platinum-sensitive ovarian cancer patients.

In 107 such patients randomized to the experimental arm – receiving a non–platinum-based chemotherapy first to prolong the platinum-free interval, followed by platinum-based chemotherapy after progression – the median time from previous platinum to randomization was 8 months, and from randomization to platinum, 7.8 months. Median overall survival, the primary endpoint of the study, was 21.8 months.

In 108 patients randomized to immediate standard therapy with platinum-based chemotherapy followed by non-platinum therapy, median time from previous platinum to randomization was 8 months, and overall survival was 24.5 months (hazard ratio favoring platinum chemotherapy, 1.38), Dr. Pignata said, noting that the difference in overall survival approached but did not reach statistical significance.

A secondary endpoint of progression-free survival after the second treatment was 12.8 months in the experimental arm, vs. 16.4 months in the platinum-based chemotherapy arm (adjusted HR, 1.41). This difference was statistically significant.

No differences with respect to safety or toxicity were seen between the groups.

MITO8 subjects were women with ovarian cancer recurring between 6 and 12 months after previous platinum-based chemotherapy. The patients had received no more than two prior lines of chemotherapy, had good performance status, and had normal organ function.

Non–platinum-based therapy used in the study included pegylated liposomal doxorubicin, except during a period of the study when the agent was in short supply and other single agents were used, including gemcitabine and topotecan. Most patients, however, received PLD.

Platinum-based therapy was carboplatin plus paclitaxel or, in patients with neurotoxicity at baseline, carboplatin plus gemcitabine.

The shortage of PLD was just one of numerous challenges encountered during the course of the beleaguered study. Enrollment began in 2009, but was temporarily suspended in 2011 because of the PLD shortage. In 2012, the amendment to allow other non–platinum-based chemotherapies to be used was approved at most sites and enrollment resumed. However, accrual slowed and enrollment was closed in 2015. The study was stopped early, and the final analysis was conducted in March 2016 when events plateaued. The investigators, in conjunction with the independent data monitoring committee, determined that the results “still had to be presented early because they still may affect clinical practice.”

Dr. Pignata said that the hypothesis “was based on the fact that there were more responses in the patients treated with a platinum after a non-platinum, but this was not the case ... Responses were more frequent in the patients who received platinum first and then non-platinum later,” he said. The response rates for the experimental vs. standard approaches, respectively, were 43% vs. 56% among RECIST responders, and 70% vs. 75% among CA125 responders.

The findings of MITO8, one of the first clinical trials in ovarian cancer to evaluate two different sequences of chemotherapy, send “a strong message that even in the presence of a very nice hypothesis, we have to await the results of prospective clinical trials before changing clinical practice,” he said.

Dr. Maurie Markman of Cancer Treatment Centers of America in Boca Raton, Fla., the invited discussant, praised the work of Dr. Pignata and his colleagues, calling their study “elegant,” and “an extraordinary effort.”

“In this unbelievably important analysis, the hypothesis was flat-out wrong,” he said.

The study is an example of “a simple, provocative, and potentially highly clinically relevant hypothesis that should be able to be quickly tested in either a cooperative group setting, in multiple institutions interested in gynecologic malignancies ... when or very shortly after it is initially proposed,” he said.

Waiting 20 years is unacceptable, he said, adding: “This is tragic, this length of time to get an answer. And I must ask ... how many ovarian cancer patients over this many-year period have received second-line chemotherapy based on this conceptual approach, and may have actually been harmed?”

To prevent such outcomes in the future, Dr. Markman proposed heavier reliance on “nonrandomized population-based studies including real-world patients managed by a variety of approaches with securely privacy-protected data included within a public database,” to test noninvestigational approaches to disease management.

“And for this database, I would propose ASCO’s CancerLinq,” he said.

Dr. Pignata reported receiving honoraria from, and serving as a consultant or adviser for AstraZeneca, PharmaMar, and Roche, and receiving research funding from Roche. Dr. Markman is a consultant or advisor for Amgen, Celgene, CritiTech, and Pfizer; is on the speakers bureau for AstraZeneca and Genentech/Roche, and has provided expert testimony for several entities

[email protected]

CHICAGO – Artificially prolonging the platinum-free interval by introducing a non–platinum-based chemotherapy before re-treatment with platinum-based chemotherapy in patients with partially platinum-sensitive recurrent ovarian cancer did not improve efficacy, and actually worsened the outcomes in patients in the randomized, open-label, phase III Multicentre Italian Trials in Ovarian Cancer 8 (MITO8) trial.

Based on the findings, immediate re-treatment with platinum-based chemotherapy remains the standard treatment strategy in such patients, Dr. Sandro Pignata reported at the annual meeting of the American Society of Clinical Oncology.

The idea that a non-platinum therapy might artificially extend the platinum-free interval, thereby improving outcomes in ovarian cancer patients who experience recurrence between 6 and 12 months after responding to platinum-based therapy, was first proposed more than 20 years ago. Despite a lack of prospective data with respect to this non–platinum-therapy approach, the idea has been used successfully to market non-platinum chemotherapy agents such as paclitaxel, topotecan, pegylated liposomal doxorubicin (PLD), and more recently, PLD-trabectedin for use before reinitiating platinum chemotherapy, explained Dr. Pignata of S.C. Oncologia Medica Ginecologica, Istituto Nazionale Tumori, Napoli.

In fact, a 2007 retrospective analysis (SOCRATES) showed that 35% of patients with recurrence at 6-12 months after platinum-based therapy were treated with a non-platinum single agent before re-treatment with a platinum-based therapy, and that the approach has been used as the control arm in multiple phase III trials that included patients with a platinum-free interval of 6-12 months. The findings indicate that the unproven hypothesis has been adapted into clinical practice, but the investigators were unable to demonstrate an advantage with the approach and concluded that further investigation was warranted.

MITO8, a multi-organization collaborative effort, was designed to test whether artificial prolongation of the platinum-free interval with a single-agent non-platinum treatment would improve overall survival in recurrent partially platinum-sensitive ovarian cancer patients.

In 107 such patients randomized to the experimental arm – receiving a non–platinum-based chemotherapy first to prolong the platinum-free interval, followed by platinum-based chemotherapy after progression – the median time from previous platinum to randomization was 8 months, and from randomization to platinum, 7.8 months. Median overall survival, the primary endpoint of the study, was 21.8 months.

In 108 patients randomized to immediate standard therapy with platinum-based chemotherapy followed by non-platinum therapy, median time from previous platinum to randomization was 8 months, and overall survival was 24.5 months (hazard ratio favoring platinum chemotherapy, 1.38), Dr. Pignata said, noting that the difference in overall survival approached but did not reach statistical significance.

A secondary endpoint of progression-free survival after the second treatment was 12.8 months in the experimental arm, vs. 16.4 months in the platinum-based chemotherapy arm (adjusted HR, 1.41). This difference was statistically significant.

No differences with respect to safety or toxicity were seen between the groups.

MITO8 subjects were women with ovarian cancer recurring between 6 and 12 months after previous platinum-based chemotherapy. The patients had received no more than two prior lines of chemotherapy, had good performance status, and had normal organ function.

Non–platinum-based therapy used in the study included pegylated liposomal doxorubicin, except during a period of the study when the agent was in short supply and other single agents were used, including gemcitabine and topotecan. Most patients, however, received PLD.

Platinum-based therapy was carboplatin plus paclitaxel or, in patients with neurotoxicity at baseline, carboplatin plus gemcitabine.

The shortage of PLD was just one of numerous challenges encountered during the course of the beleaguered study. Enrollment began in 2009, but was temporarily suspended in 2011 because of the PLD shortage. In 2012, the amendment to allow other non–platinum-based chemotherapies to be used was approved at most sites and enrollment resumed. However, accrual slowed and enrollment was closed in 2015. The study was stopped early, and the final analysis was conducted in March 2016 when events plateaued. The investigators, in conjunction with the independent data monitoring committee, determined that the results “still had to be presented early because they still may affect clinical practice.”

Dr. Pignata said that the hypothesis “was based on the fact that there were more responses in the patients treated with a platinum after a non-platinum, but this was not the case ... Responses were more frequent in the patients who received platinum first and then non-platinum later,” he said. The response rates for the experimental vs. standard approaches, respectively, were 43% vs. 56% among RECIST responders, and 70% vs. 75% among CA125 responders.

The findings of MITO8, one of the first clinical trials in ovarian cancer to evaluate two different sequences of chemotherapy, send “a strong message that even in the presence of a very nice hypothesis, we have to await the results of prospective clinical trials before changing clinical practice,” he said.

Dr. Maurie Markman of Cancer Treatment Centers of America in Boca Raton, Fla., the invited discussant, praised the work of Dr. Pignata and his colleagues, calling their study “elegant,” and “an extraordinary effort.”

“In this unbelievably important analysis, the hypothesis was flat-out wrong,” he said.

The study is an example of “a simple, provocative, and potentially highly clinically relevant hypothesis that should be able to be quickly tested in either a cooperative group setting, in multiple institutions interested in gynecologic malignancies ... when or very shortly after it is initially proposed,” he said.

Waiting 20 years is unacceptable, he said, adding: “This is tragic, this length of time to get an answer. And I must ask ... how many ovarian cancer patients over this many-year period have received second-line chemotherapy based on this conceptual approach, and may have actually been harmed?”

To prevent such outcomes in the future, Dr. Markman proposed heavier reliance on “nonrandomized population-based studies including real-world patients managed by a variety of approaches with securely privacy-protected data included within a public database,” to test noninvestigational approaches to disease management.

“And for this database, I would propose ASCO’s CancerLinq,” he said.

Dr. Pignata reported receiving honoraria from, and serving as a consultant or adviser for AstraZeneca, PharmaMar, and Roche, and receiving research funding from Roche. Dr. Markman is a consultant or advisor for Amgen, Celgene, CritiTech, and Pfizer; is on the speakers bureau for AstraZeneca and Genentech/Roche, and has provided expert testimony for several entities

[email protected]

COPENHAGEN – A study from seven Nordic and Baltic countries adds to the growing body of evidence that young adults with acute lymphoblastic leukemia do better when they are treated like children – that is, with a standard pediatric chemotherapy regimen.

In a study of 221 patients from the age of 18 to 45 with acute lymphoblastic leukemia (ALL) treated with a pediatric regimen and followed for a median of 4 years, the event-free survival rate was 73%, compared with 42% for historical controls, reported Dr. Nina Toft from Herlev (Denmark) University Hospital.

“We have improved the survival for ALL patients 18 to 45 years, and we show that the cure rates are close to those of children. If you compare an adult in the standard-risk group with a child in the standard-risk group, there’s no difference,” she said at a briefing at the annual congress of the European Hematology Association (EHA).

The findings support those from an earlier study reported at the 2014 annual meeting of the American Society of Hematology. That study, conducted by Dr. Wendy Stock of the University of Chicago Medical Center and her colleagues showed that among 296 adolescents and young adults with ALL treated with an intensive pediatric chemotherapy combination regimen rather than a less-intensive adult regimen, the rate of overall survival (OS) at 2 years was 78%, and the event-free survival (EFS) rate was 66%.

In the current study, Dr. Toft and her colleagues looked at event-free survival among 1,509 children and adults (up to age 45) diagnosed with Philadelphia chromosome-negative ALL from July 2008 through December 2014.

The patients were treated in Sweden, Norway, Iceland, Finland Denmark, Lithuania, and Estonia, and all received the Nordic Society for Pediatric Hematology and Oncology (NOPHO)–ALL 2008 protocol, consisting of induction with prednisolone, vincristine, doxorubicin, and pegylated (PEG) asparaginase; consolidation for patients with standard- and intermediate-risk disease, with mercaptopurine, vincristine, PEG asparaginase, and methotrexate; and additional intensive combination chemotherapy for patients with high-risk disease, followed by maintenance with mercaptopurine and/or methotrexate, PEG asparaginase, vincristine, and dexamethasone.

Of the 1,509 patients, 1,022 were children from 1 to 9 years, 266 were preteens/adolescents (10-17 years), and 221 were adults up to age 45.

All patients were stratified by clinical, cytogenetic, and other factors into one of four risk groups: standard, intermediate, high risk, or high risk in first remission after a hematopoietic stem cell transplant, and all were treated with the NOPHO-ALL 2008 protocol.

The investigators found that in general older patients had higher-risk disease. Nonetheless, treatment intervals and severe toxicities, with the exception of osteonecrosis and thrombosis, were “almost identical” between adults and children, Dr. Toft said.

After a median of 4 years of follow-up, 16 patients, 3 of whom were adults, had died during the induction phase, and 50 patients (12 adults) had died in first remission.

There were a total of 123 relapses (36 among adults), and 1 adult and 12 children were diagnosed with a second malignancy.

Overall 5-year EFS rates were 88% for patients aged 1-9 years, 79% for those 10-17 years, and 73% for those 18-45, and these differences were significant (P less than .001). However, when EFS was stratified by risk group, EFS rates were lower only for adults with intermediate-risk disease (78% vs. 90% for 1- to 9-year-olds and 82% for 10- to 17-year-olds, P = .002).

Although the investigators did not formally report overall survival data, it was approximately 95% among all children in the cohort, and approximately 76% among the adults, Dr. Toft said in response to a reporter.

“What we need now is further cooperation, because we need to unite and get more patients so that we can show new developments faster. We also need to find new risk criteria, because of the intermediate-risk group; something is missing for the adults. We need more cytogenetics, we need something to define the patients as high risk or not,” Dr. Toft said.

“We also need new drugs, because with this method we’ve reached the limit of toxicity,” she added.

The study was sponsored by health authorities in the participating countries. Dr. Toft reported no relevant financial disclosures.

COPENHAGEN – A study from seven Nordic and Baltic countries adds to the growing body of evidence that young adults with acute lymphoblastic leukemia do better when they are treated like children – that is, with a standard pediatric chemotherapy regimen.

In a study of 221 patients from the age of 18 to 45 with acute lymphoblastic leukemia (ALL) treated with a pediatric regimen and followed for a median of 4 years, the event-free survival rate was 73%, compared with 42% for historical controls, reported Dr. Nina Toft from Herlev (Denmark) University Hospital.

“We have improved the survival for ALL patients 18 to 45 years, and we show that the cure rates are close to those of children. If you compare an adult in the standard-risk group with a child in the standard-risk group, there’s no difference,” she said at a briefing at the annual congress of the European Hematology Association (EHA).

The findings support those from an earlier study reported at the 2014 annual meeting of the American Society of Hematology. That study, conducted by Dr. Wendy Stock of the University of Chicago Medical Center and her colleagues showed that among 296 adolescents and young adults with ALL treated with an intensive pediatric chemotherapy combination regimen rather than a less-intensive adult regimen, the rate of overall survival (OS) at 2 years was 78%, and the event-free survival (EFS) rate was 66%.

In the current study, Dr. Toft and her colleagues looked at event-free survival among 1,509 children and adults (up to age 45) diagnosed with Philadelphia chromosome-negative ALL from July 2008 through December 2014.

The patients were treated in Sweden, Norway, Iceland, Finland Denmark, Lithuania, and Estonia, and all received the Nordic Society for Pediatric Hematology and Oncology (NOPHO)–ALL 2008 protocol, consisting of induction with prednisolone, vincristine, doxorubicin, and pegylated (PEG) asparaginase; consolidation for patients with standard- and intermediate-risk disease, with mercaptopurine, vincristine, PEG asparaginase, and methotrexate; and additional intensive combination chemotherapy for patients with high-risk disease, followed by maintenance with mercaptopurine and/or methotrexate, PEG asparaginase, vincristine, and dexamethasone.

Of the 1,509 patients, 1,022 were children from 1 to 9 years, 266 were preteens/adolescents (10-17 years), and 221 were adults up to age 45.

All patients were stratified by clinical, cytogenetic, and other factors into one of four risk groups: standard, intermediate, high risk, or high risk in first remission after a hematopoietic stem cell transplant, and all were treated with the NOPHO-ALL 2008 protocol.

The investigators found that in general older patients had higher-risk disease. Nonetheless, treatment intervals and severe toxicities, with the exception of osteonecrosis and thrombosis, were “almost identical” between adults and children, Dr. Toft said.

After a median of 4 years of follow-up, 16 patients, 3 of whom were adults, had died during the induction phase, and 50 patients (12 adults) had died in first remission.

There were a total of 123 relapses (36 among adults), and 1 adult and 12 children were diagnosed with a second malignancy.

Overall 5-year EFS rates were 88% for patients aged 1-9 years, 79% for those 10-17 years, and 73% for those 18-45, and these differences were significant (P less than .001). However, when EFS was stratified by risk group, EFS rates were lower only for adults with intermediate-risk disease (78% vs. 90% for 1- to 9-year-olds and 82% for 10- to 17-year-olds, P = .002).

Although the investigators did not formally report overall survival data, it was approximately 95% among all children in the cohort, and approximately 76% among the adults, Dr. Toft said in response to a reporter.

“What we need now is further cooperation, because we need to unite and get more patients so that we can show new developments faster. We also need to find new risk criteria, because of the intermediate-risk group; something is missing for the adults. We need more cytogenetics, we need something to define the patients as high risk or not,” Dr. Toft said.

“We also need new drugs, because with this method we’ve reached the limit of toxicity,” she added.

The study was sponsored by health authorities in the participating countries. Dr. Toft reported no relevant financial disclosures.

COPENHAGEN – A study from seven Nordic and Baltic countries adds to the growing body of evidence that young adults with acute lymphoblastic leukemia do better when they are treated like children – that is, with a standard pediatric chemotherapy regimen.

In a study of 221 patients from the age of 18 to 45 with acute lymphoblastic leukemia (ALL) treated with a pediatric regimen and followed for a median of 4 years, the event-free survival rate was 73%, compared with 42% for historical controls, reported Dr. Nina Toft from Herlev (Denmark) University Hospital.

“We have improved the survival for ALL patients 18 to 45 years, and we show that the cure rates are close to those of children. If you compare an adult in the standard-risk group with a child in the standard-risk group, there’s no difference,” she said at a briefing at the annual congress of the European Hematology Association (EHA).

The findings support those from an earlier study reported at the 2014 annual meeting of the American Society of Hematology. That study, conducted by Dr. Wendy Stock of the University of Chicago Medical Center and her colleagues showed that among 296 adolescents and young adults with ALL treated with an intensive pediatric chemotherapy combination regimen rather than a less-intensive adult regimen, the rate of overall survival (OS) at 2 years was 78%, and the event-free survival (EFS) rate was 66%.

In the current study, Dr. Toft and her colleagues looked at event-free survival among 1,509 children and adults (up to age 45) diagnosed with Philadelphia chromosome-negative ALL from July 2008 through December 2014.

The patients were treated in Sweden, Norway, Iceland, Finland Denmark, Lithuania, and Estonia, and all received the Nordic Society for Pediatric Hematology and Oncology (NOPHO)–ALL 2008 protocol, consisting of induction with prednisolone, vincristine, doxorubicin, and pegylated (PEG) asparaginase; consolidation for patients with standard- and intermediate-risk disease, with mercaptopurine, vincristine, PEG asparaginase, and methotrexate; and additional intensive combination chemotherapy for patients with high-risk disease, followed by maintenance with mercaptopurine and/or methotrexate, PEG asparaginase, vincristine, and dexamethasone.

Of the 1,509 patients, 1,022 were children from 1 to 9 years, 266 were preteens/adolescents (10-17 years), and 221 were adults up to age 45.

All patients were stratified by clinical, cytogenetic, and other factors into one of four risk groups: standard, intermediate, high risk, or high risk in first remission after a hematopoietic stem cell transplant, and all were treated with the NOPHO-ALL 2008 protocol.

The investigators found that in general older patients had higher-risk disease. Nonetheless, treatment intervals and severe toxicities, with the exception of osteonecrosis and thrombosis, were “almost identical” between adults and children, Dr. Toft said.

After a median of 4 years of follow-up, 16 patients, 3 of whom were adults, had died during the induction phase, and 50 patients (12 adults) had died in first remission.

There were a total of 123 relapses (36 among adults), and 1 adult and 12 children were diagnosed with a second malignancy.

Overall 5-year EFS rates were 88% for patients aged 1-9 years, 79% for those 10-17 years, and 73% for those 18-45, and these differences were significant (P less than .001). However, when EFS was stratified by risk group, EFS rates were lower only for adults with intermediate-risk disease (78% vs. 90% for 1- to 9-year-olds and 82% for 10- to 17-year-olds, P = .002).

Although the investigators did not formally report overall survival data, it was approximately 95% among all children in the cohort, and approximately 76% among the adults, Dr. Toft said in response to a reporter.

“What we need now is further cooperation, because we need to unite and get more patients so that we can show new developments faster. We also need to find new risk criteria, because of the intermediate-risk group; something is missing for the adults. We need more cytogenetics, we need something to define the patients as high risk or not,” Dr. Toft said.

“We also need new drugs, because with this method we’ve reached the limit of toxicity,” she added.

The study was sponsored by health authorities in the participating countries. Dr. Toft reported no relevant financial disclosures.

CHICAGO – An inadequately designed medical practice website can pose serious legal dangers, said Michael J. Sacopulos, a medical malpractice defense attorney based in Terre Haute, Ind.

Here is a list of website to-dos that can reduce your legal risks:

• Post emergency information on the website contact page. Unlike the practice’s phone system, the website may fail to include a disclaimer that the patient should call 911 if experiencing a medical emergency.

• Provide disclaimers about doctor-patient relationship. In addition, it’s important that the website includes a warning that communications through the website do not constitute a doctor-patient relationship, Mr. Sacopulos said during an American Bar Association conference. “Most [websites] have a box where you can leave comments. [People need to be told] that it does not create a physician-patient relationship when they describe their medical condition, sometimes even posting photographs.”

• Advise regarding comment security. Under the Health Information Technology for Economic and Clinical Health (HITECH) Act, medical information sent through electronic channels must be encrypted unless a patient consents otherwise. If information can be transmitted through a website’s comment box, patients should be advised that the transmission is not secure before they send their information, Mr. Sacopulos said.

• Secure any online appointment scheduling. Make sure that patients’ names and personal information are not visible to other patients when they schedule appointments, he said. A cardiology practice in Phoenix learned this the hard way when it had to pay the U.S. Department of Health & Human Services $100,000 for lack of HIPAA safeguards online. An investigation by the Office for Civil Rights found the practice was posting clinical and surgical appointments for patients on an Internet-based calendar that was publicly accessible.

• Ensure patient anonymity. The accidental release of private medical information occurred on the website of a St. Louis physician who obtained consent from her patients to include their before and after photos. No names were posted with the photos, but the computer file names of the photos included the patients’ names, and when a person scrolled over a photo with a cursor, the file name popped up. This allowed the public to view the patient name associated with each photo and caused serious problems for the practice, including litigation, he noted.

• Be aware of state board requirements that pertain to physician practice websites. Several state boards do not allow testimonials to be posted on websites. States also differ on the inclusion of before and after photos. New Jersey, for example, allows before and after photos on websites, while New York does not. Some state boards allow doctors to cite that they are board certified on a website without specifics, while states such as Louisiana require that physicians announce the specific certifying board.

“These are ethical and affirmative duties on behalf of physicians that oftentimes come up in websites,” he said.

• Adhere to the Americans With Disabilities Act (ADA). A website is considered real estate for purposes of the ADA, meaning it must include an accessible format to patients with disabilities, Mr. Sacupulos said. Problems arise when certain website features make sites difficult or incompatible with assistance devices that disabled patients require, such as a screen reader or voice interactive software. The National Federation for the Blind has been active in this area and has filed multiple class action lawsuits against companies that did not have compliant websites, he said. An ADA tool kit for best website practices can be found online.

• Hire an experienced Web designer to create the practice’s website. Too often, practices use a family member or friend to set up the company’s page, Mr. Sacupulos said. In one such instance, a young designer became angry at his doctor employer and set up a false website in his name, alleging abuses against patients. “Work with someone credible,” he advised. “Make sure you own your own domain. Many of these Web designers will purchase the domain name and build a site around it, which is great until you want to move to the next Web designer, and then you have to buy your domain back.”

[email protected]

On Twitter @legal_med

CHICAGO – An inadequately designed medical practice website can pose serious legal dangers, said Michael J. Sacopulos, a medical malpractice defense attorney based in Terre Haute, Ind.

Here is a list of website to-dos that can reduce your legal risks:

• Post emergency information on the website contact page. Unlike the practice’s phone system, the website may fail to include a disclaimer that the patient should call 911 if experiencing a medical emergency.

• Provide disclaimers about doctor-patient relationship. In addition, it’s important that the website includes a warning that communications through the website do not constitute a doctor-patient relationship, Mr. Sacopulos said during an American Bar Association conference. “Most [websites] have a box where you can leave comments. [People need to be told] that it does not create a physician-patient relationship when they describe their medical condition, sometimes even posting photographs.”

• Advise regarding comment security. Under the Health Information Technology for Economic and Clinical Health (HITECH) Act, medical information sent through electronic channels must be encrypted unless a patient consents otherwise. If information can be transmitted through a website’s comment box, patients should be advised that the transmission is not secure before they send their information, Mr. Sacopulos said.

• Secure any online appointment scheduling. Make sure that patients’ names and personal information are not visible to other patients when they schedule appointments, he said. A cardiology practice in Phoenix learned this the hard way when it had to pay the U.S. Department of Health & Human Services $100,000 for lack of HIPAA safeguards online. An investigation by the Office for Civil Rights found the practice was posting clinical and surgical appointments for patients on an Internet-based calendar that was publicly accessible.

• Ensure patient anonymity. The accidental release of private medical information occurred on the website of a St. Louis physician who obtained consent from her patients to include their before and after photos. No names were posted with the photos, but the computer file names of the photos included the patients’ names, and when a person scrolled over a photo with a cursor, the file name popped up. This allowed the public to view the patient name associated with each photo and caused serious problems for the practice, including litigation, he noted.

• Be aware of state board requirements that pertain to physician practice websites. Several state boards do not allow testimonials to be posted on websites. States also differ on the inclusion of before and after photos. New Jersey, for example, allows before and after photos on websites, while New York does not. Some state boards allow doctors to cite that they are board certified on a website without specifics, while states such as Louisiana require that physicians announce the specific certifying board.

“These are ethical and affirmative duties on behalf of physicians that oftentimes come up in websites,” he said.

• Adhere to the Americans With Disabilities Act (ADA). A website is considered real estate for purposes of the ADA, meaning it must include an accessible format to patients with disabilities, Mr. Sacupulos said. Problems arise when certain website features make sites difficult or incompatible with assistance devices that disabled patients require, such as a screen reader or voice interactive software. The National Federation for the Blind has been active in this area and has filed multiple class action lawsuits against companies that did not have compliant websites, he said. An ADA tool kit for best website practices can be found online.

• Hire an experienced Web designer to create the practice’s website. Too often, practices use a family member or friend to set up the company’s page, Mr. Sacupulos said. In one such instance, a young designer became angry at his doctor employer and set up a false website in his name, alleging abuses against patients. “Work with someone credible,” he advised. “Make sure you own your own domain. Many of these Web designers will purchase the domain name and build a site around it, which is great until you want to move to the next Web designer, and then you have to buy your domain back.”

[email protected]

On Twitter @legal_med

CHICAGO – An inadequately designed medical practice website can pose serious legal dangers, said Michael J. Sacopulos, a medical malpractice defense attorney based in Terre Haute, Ind.

Here is a list of website to-dos that can reduce your legal risks:

• Post emergency information on the website contact page. Unlike the practice’s phone system, the website may fail to include a disclaimer that the patient should call 911 if experiencing a medical emergency.

• Provide disclaimers about doctor-patient relationship. In addition, it’s important that the website includes a warning that communications through the website do not constitute a doctor-patient relationship, Mr. Sacopulos said during an American Bar Association conference. “Most [websites] have a box where you can leave comments. [People need to be told] that it does not create a physician-patient relationship when they describe their medical condition, sometimes even posting photographs.”

• Advise regarding comment security. Under the Health Information Technology for Economic and Clinical Health (HITECH) Act, medical information sent through electronic channels must be encrypted unless a patient consents otherwise. If information can be transmitted through a website’s comment box, patients should be advised that the transmission is not secure before they send their information, Mr. Sacopulos said.

• Secure any online appointment scheduling. Make sure that patients’ names and personal information are not visible to other patients when they schedule appointments, he said. A cardiology practice in Phoenix learned this the hard way when it had to pay the U.S. Department of Health & Human Services $100,000 for lack of HIPAA safeguards online. An investigation by the Office for Civil Rights found the practice was posting clinical and surgical appointments for patients on an Internet-based calendar that was publicly accessible.

• Ensure patient anonymity. The accidental release of private medical information occurred on the website of a St. Louis physician who obtained consent from her patients to include their before and after photos. No names were posted with the photos, but the computer file names of the photos included the patients’ names, and when a person scrolled over a photo with a cursor, the file name popped up. This allowed the public to view the patient name associated with each photo and caused serious problems for the practice, including litigation, he noted.

• Be aware of state board requirements that pertain to physician practice websites. Several state boards do not allow testimonials to be posted on websites. States also differ on the inclusion of before and after photos. New Jersey, for example, allows before and after photos on websites, while New York does not. Some state boards allow doctors to cite that they are board certified on a website without specifics, while states such as Louisiana require that physicians announce the specific certifying board.

“These are ethical and affirmative duties on behalf of physicians that oftentimes come up in websites,” he said.

• Adhere to the Americans With Disabilities Act (ADA). A website is considered real estate for purposes of the ADA, meaning it must include an accessible format to patients with disabilities, Mr. Sacupulos said. Problems arise when certain website features make sites difficult or incompatible with assistance devices that disabled patients require, such as a screen reader or voice interactive software. The National Federation for the Blind has been active in this area and has filed multiple class action lawsuits against companies that did not have compliant websites, he said. An ADA tool kit for best website practices can be found online.

• Hire an experienced Web designer to create the practice’s website. Too often, practices use a family member or friend to set up the company’s page, Mr. Sacupulos said. In one such instance, a young designer became angry at his doctor employer and set up a false website in his name, alleging abuses against patients. “Work with someone credible,” he advised. “Make sure you own your own domain. Many of these Web designers will purchase the domain name and build a site around it, which is great until you want to move to the next Web designer, and then you have to buy your domain back.”

[email protected]

On Twitter @legal_med

The gene BIRC5 is an “important player” in chondrosarcoma survival, say researchers from Leiden University, The Netherlands, and Athens University, Greece. They propose that targeting survivin, a protein encoded by BIRC5, could lead to a potential avenue for treating the tumor that accounts for 20% of all malignant bone cancers.

Chondrosarcomas are “intrinsically resistant” to chemo- and radiotherapy,” the researchers say, leaving surgery as the only curative option. So they aimed to identify genes that could be used in targeted drug treatment.

Related: Using a Multiplex of Biomarkers to Detect Prostate Cancer

They screened for 51 apoptosis-related genes. When the screening pinpointed survivin as essential for chondrosarcoma survival, the researchers used immunohistochemistry to analyze cytoplasmic survivin expression in 207 chondrosarcomas of different subtypes. Survivin is highly expressed, they found, in tumor tissue and cell lines of conventional as well as rare subtypes of chondrosarcoma.

Related: A Team Approach to Nonmelanotic Skin Cancer Procedures

The researchers also tested sensitivity to YM155 (a survivin-inhibiting compound) and found chondrosarcoma cells lines were highly sensitive. They say their findings suggest that YM155, which is already in phase I and II clinical trials for other tumors, could be readily applicable in clinical trials for chondrosarcoma patients. Although some larger phase II studies have not shown promising antitumor activity in diffuse large B-cell lymphoma, non-small cell lung cancer, melanoma, or prostate cancer, that doesn’t mean YM155 can’t help in chondrosarcoma patients, they say. Especially, they note, because in chondrosarcoma,YM155 does not induce apoptosis but blocks the cell cycle.

Related: Using a Multiplex of Biomarkers to Detect Prostate Cancer

In particular TP53 mutant cell lines were sensitive; thus, TP53 mutation may be a biomarker that can allow preselecting patients for treatment.

Source:
de Jong Y, van Oosterwijk JG, Kruisselbrink AB. Targeting survivin as a potential new treatment for chondrosarcoma of bone. Oncogenesis. 2016;5:e222.
doi: 10.1038/oncsis.2016.33.

The gene BIRC5 is an “important player” in chondrosarcoma survival, say researchers from Leiden University, The Netherlands, and Athens University, Greece. They propose that targeting survivin, a protein encoded by BIRC5, could lead to a potential avenue for treating the tumor that accounts for 20% of all malignant bone cancers.

Chondrosarcomas are “intrinsically resistant” to chemo- and radiotherapy,” the researchers say, leaving surgery as the only curative option. So they aimed to identify genes that could be used in targeted drug treatment.

Related: Using a Multiplex of Biomarkers to Detect Prostate Cancer

They screened for 51 apoptosis-related genes. When the screening pinpointed survivin as essential for chondrosarcoma survival, the researchers used immunohistochemistry to analyze cytoplasmic survivin expression in 207 chondrosarcomas of different subtypes. Survivin is highly expressed, they found, in tumor tissue and cell lines of conventional as well as rare subtypes of chondrosarcoma.

Related: A Team Approach to Nonmelanotic Skin Cancer Procedures

The researchers also tested sensitivity to YM155 (a survivin-inhibiting compound) and found chondrosarcoma cells lines were highly sensitive. They say their findings suggest that YM155, which is already in phase I and II clinical trials for other tumors, could be readily applicable in clinical trials for chondrosarcoma patients. Although some larger phase II studies have not shown promising antitumor activity in diffuse large B-cell lymphoma, non-small cell lung cancer, melanoma, or prostate cancer, that doesn’t mean YM155 can’t help in chondrosarcoma patients, they say. Especially, they note, because in chondrosarcoma,YM155 does not induce apoptosis but blocks the cell cycle.

Related: Using a Multiplex of Biomarkers to Detect Prostate Cancer

In particular TP53 mutant cell lines were sensitive; thus, TP53 mutation may be a biomarker that can allow preselecting patients for treatment.

Source:
de Jong Y, van Oosterwijk JG, Kruisselbrink AB. Targeting survivin as a potential new treatment for chondrosarcoma of bone. Oncogenesis. 2016;5:e222.
doi: 10.1038/oncsis.2016.33.

The gene BIRC5 is an “important player” in chondrosarcoma survival, say researchers from Leiden University, The Netherlands, and Athens University, Greece. They propose that targeting survivin, a protein encoded by BIRC5, could lead to a potential avenue for treating the tumor that accounts for 20% of all malignant bone cancers.

Chondrosarcomas are “intrinsically resistant” to chemo- and radiotherapy,” the researchers say, leaving surgery as the only curative option. So they aimed to identify genes that could be used in targeted drug treatment.

Related: Using a Multiplex of Biomarkers to Detect Prostate Cancer

They screened for 51 apoptosis-related genes. When the screening pinpointed survivin as essential for chondrosarcoma survival, the researchers used immunohistochemistry to analyze cytoplasmic survivin expression in 207 chondrosarcomas of different subtypes. Survivin is highly expressed, they found, in tumor tissue and cell lines of conventional as well as rare subtypes of chondrosarcoma.

Related: A Team Approach to Nonmelanotic Skin Cancer Procedures

The researchers also tested sensitivity to YM155 (a survivin-inhibiting compound) and found chondrosarcoma cells lines were highly sensitive. They say their findings suggest that YM155, which is already in phase I and II clinical trials for other tumors, could be readily applicable in clinical trials for chondrosarcoma patients. Although some larger phase II studies have not shown promising antitumor activity in diffuse large B-cell lymphoma, non-small cell lung cancer, melanoma, or prostate cancer, that doesn’t mean YM155 can’t help in chondrosarcoma patients, they say. Especially, they note, because in chondrosarcoma,YM155 does not induce apoptosis but blocks the cell cycle.

Related: Using a Multiplex of Biomarkers to Detect Prostate Cancer

In particular TP53 mutant cell lines were sensitive; thus, TP53 mutation may be a biomarker that can allow preselecting patients for treatment.

Source:
de Jong Y, van Oosterwijk JG, Kruisselbrink AB. Targeting survivin as a potential new treatment for chondrosarcoma of bone. Oncogenesis. 2016;5:e222.
doi: 10.1038/oncsis.2016.33.

SAN DIEGO – Statin therapy was independently associated with a substantial survival benefit in women with ovarian cancer in an analysis of the linked Surveillance, Epidemiology and End Results and Medicare databases.

“This is the largest series ever reported supporting the anticancer effect of statin therapy on epithelial ovarian cancer with a concomitant improvement in overall survival. A prospective study in ovarian cancer patients is warranted. Identification of biomarkers that may predict response to statins would help further select patient populations and guide therapy,” Dr. Tilley Jenkins Vogel said in presenting the study results at the annual meeting of the Society of Gynecologic Oncology.

Bruce Jancin/Frontline Medical News

She and her coinvestigators at Cedars-Sinai Medical Center in Los Angeles identified 1,510 women in the SEER registry who were diagnosed with epithelial ovarian cancer during 2007-2009, underwent primary surgical resection, and survived for at least 60 days post surgery. Forty-nine percent were stage III, 25% stage IV. Forty-two percent of the women were on a statin.

Mean overall survival in the statin users was 32.2 months compared to 28.7 months in nonusers. In the stage III cohort, mean overall survival in statin users versus nonusers was 31.7 and 25.9 months.

In a multivariate analysis adjusted for potential confounders of age, race, heart disease and other comorbid conditions prior to cancer diagnosis, and the use of platinum-based chemotherapy, statin therapy was independently associated with a 34% reduction in the risk of mortality. In women whose ovarian cancer histology was serous, statin use was associated with a 31% reduction in death; in those with a nonserous histology, it was a 48% reduction, Dr. Vogel continued.

Diving deeper into the dataset, she found that the overall survival benefit was present only in the 89% of statin users who were on lipophilic statins, such as atorvastatin or simvastatin. This is consistent with other investigators’ reports that the noncardiovascular benefits of statin therapy are largely restricted to the lipophilic class of the LDL-lowering agents.

An anti–ovarian cancer benefit for statin therapy appears to have biologic plausibility, according to Dr. Vogel. She and her coworkers have previously shown synergistic cytotoxicity in vitro when statins are administered concurrently with platinum chemotherapy.

“This effect is believed to be mediated by greater inhibition of cell proliferation, increased apoptosis, and modification of proteins in the RAS pathway,” she said.

Rapidly growing cells, such as cancer cells, require cholesterol to synthesize cell membrane. It’s hypothesized that one mechanism for statins’ anticancer effect is that by reducing intracellular cholesterol levels the drugs interfere with this process, Dr. Vogel noted.

She reported having no financial conflicts regarding this study, conducted without commercial support.

[email protected]

SAN DIEGO – Statin therapy was independently associated with a substantial survival benefit in women with ovarian cancer in an analysis of the linked Surveillance, Epidemiology and End Results and Medicare databases.

“This is the largest series ever reported supporting the anticancer effect of statin therapy on epithelial ovarian cancer with a concomitant improvement in overall survival. A prospective study in ovarian cancer patients is warranted. Identification of biomarkers that may predict response to statins would help further select patient populations and guide therapy,” Dr. Tilley Jenkins Vogel said in presenting the study results at the annual meeting of the Society of Gynecologic Oncology.

Bruce Jancin/Frontline Medical News

She and her coinvestigators at Cedars-Sinai Medical Center in Los Angeles identified 1,510 women in the SEER registry who were diagnosed with epithelial ovarian cancer during 2007-2009, underwent primary surgical resection, and survived for at least 60 days post surgery. Forty-nine percent were stage III, 25% stage IV. Forty-two percent of the women were on a statin.

Mean overall survival in the statin users was 32.2 months compared to 28.7 months in nonusers. In the stage III cohort, mean overall survival in statin users versus nonusers was 31.7 and 25.9 months.

In a multivariate analysis adjusted for potential confounders of age, race, heart disease and other comorbid conditions prior to cancer diagnosis, and the use of platinum-based chemotherapy, statin therapy was independently associated with a 34% reduction in the risk of mortality. In women whose ovarian cancer histology was serous, statin use was associated with a 31% reduction in death; in those with a nonserous histology, it was a 48% reduction, Dr. Vogel continued.

Diving deeper into the dataset, she found that the overall survival benefit was present only in the 89% of statin users who were on lipophilic statins, such as atorvastatin or simvastatin. This is consistent with other investigators’ reports that the noncardiovascular benefits of statin therapy are largely restricted to the lipophilic class of the LDL-lowering agents.

An anti–ovarian cancer benefit for statin therapy appears to have biologic plausibility, according to Dr. Vogel. She and her coworkers have previously shown synergistic cytotoxicity in vitro when statins are administered concurrently with platinum chemotherapy.

“This effect is believed to be mediated by greater inhibition of cell proliferation, increased apoptosis, and modification of proteins in the RAS pathway,” she said.

Rapidly growing cells, such as cancer cells, require cholesterol to synthesize cell membrane. It’s hypothesized that one mechanism for statins’ anticancer effect is that by reducing intracellular cholesterol levels the drugs interfere with this process, Dr. Vogel noted.

She reported having no financial conflicts regarding this study, conducted without commercial support.

[email protected]

SAN DIEGO – Statin therapy was independently associated with a substantial survival benefit in women with ovarian cancer in an analysis of the linked Surveillance, Epidemiology and End Results and Medicare databases.

“This is the largest series ever reported supporting the anticancer effect of statin therapy on epithelial ovarian cancer with a concomitant improvement in overall survival. A prospective study in ovarian cancer patients is warranted. Identification of biomarkers that may predict response to statins would help further select patient populations and guide therapy,” Dr. Tilley Jenkins Vogel said in presenting the study results at the annual meeting of the Society of Gynecologic Oncology.

Bruce Jancin/Frontline Medical News

She and her coinvestigators at Cedars-Sinai Medical Center in Los Angeles identified 1,510 women in the SEER registry who were diagnosed with epithelial ovarian cancer during 2007-2009, underwent primary surgical resection, and survived for at least 60 days post surgery. Forty-nine percent were stage III, 25% stage IV. Forty-two percent of the women were on a statin.

Mean overall survival in the statin users was 32.2 months compared to 28.7 months in nonusers. In the stage III cohort, mean overall survival in statin users versus nonusers was 31.7 and 25.9 months.

In a multivariate analysis adjusted for potential confounders of age, race, heart disease and other comorbid conditions prior to cancer diagnosis, and the use of platinum-based chemotherapy, statin therapy was independently associated with a 34% reduction in the risk of mortality. In women whose ovarian cancer histology was serous, statin use was associated with a 31% reduction in death; in those with a nonserous histology, it was a 48% reduction, Dr. Vogel continued.

Diving deeper into the dataset, she found that the overall survival benefit was present only in the 89% of statin users who were on lipophilic statins, such as atorvastatin or simvastatin. This is consistent with other investigators’ reports that the noncardiovascular benefits of statin therapy are largely restricted to the lipophilic class of the LDL-lowering agents.

An anti–ovarian cancer benefit for statin therapy appears to have biologic plausibility, according to Dr. Vogel. She and her coworkers have previously shown synergistic cytotoxicity in vitro when statins are administered concurrently with platinum chemotherapy.

“This effect is believed to be mediated by greater inhibition of cell proliferation, increased apoptosis, and modification of proteins in the RAS pathway,” she said.

Rapidly growing cells, such as cancer cells, require cholesterol to synthesize cell membrane. It’s hypothesized that one mechanism for statins’ anticancer effect is that by reducing intracellular cholesterol levels the drugs interfere with this process, Dr. Vogel noted.

She reported having no financial conflicts regarding this study, conducted without commercial support.

[email protected]

Chicago – A newly developed heat shock protein peptide vaccination appears to be safe and effective in treating patients with newly diagnosed glioblastoma (GBM), according to the results of a phase II single arm study.

In adding the vaccine to standard therapy for 46 patients with newly diagnosed GBM, median overall survival was 23.8 months, and there were no grade 3 or 4 adverse events associated with the vaccine, lead author Dr. Orin Bloch of Northwestern University, Chicago, reported at the annual meeting of the American Society of Clinical Oncology.

Standard therapy typically results in a median survival of 16 months, he said.

“There is a lot of information out there right now regarding CNS and other solid organ tumors particularly in the area of checkpoint modulation and its ability to stimulate an innate immune response against a tumor. I think in GBM we are facing a bit of a different scenario, however, because the tumor exists in a very privileged area behind the blood brain barrier and doesn’t regularly metastasize beyond the CNS,” Dr. Bloch said.

Therefore, only modulating checkpoints without stimulating and educating the immune system may not be the most effective approach. Adaptive immunity through vaccination or some other form of stimulation might be more successful, Dr. Bloch said.

“As a way of inducing immune stimulation and education using tumor-autologous peptides, one can capitalize on the native system of heat shock stimulation. Heat shock proteins are chaperone proteins that are ubiquitously expressed in cells and they’re bound to any number of intracellular peptides at any one time including, in tumor cells, neoantigens. If you extract these heat shock proteins with their bound antigens and deliver them in a naked form into the systemic circulation, their uptake into antigen-presenting cells through the CD91 receptor [will result in] the peptide [being] cleaved and presented on MHC class one and two for stimulation of CD8- and CD4-positive T cell response,” he said.

Heat shock proteins also interact with toll-like receptors and stimulate the secretion of pro-inflammatory cytokines, “acting as their own adjuvant,” Dr. Bloch further explained. Utilizing heat shock proteins activates both the innate and adaptive immune responses.

“This is an ideal platform for developing an immunotherapy for glioblastoma,” Dr. Bloch said.

In this phase II study, 46 adult patients with GBM underwent surgical resection of their tumors followed by chemoradiotherapy. At least four 25-microgram doses of vaccine were generated from tissue obtained during surgery. Within 5 weeks of completing radiotherapy, patients began receiving weekly vaccinations in combination with adjuvant temozolomide. Patients continued receiving vaccines until depletion or until tumor progression.

Median progression-free survival was 17.8 months (95% confidence interval, 11.3-21.6) and median overall survival was 23.8 months (95% CI, 19.8-30.2).

PD-L1 expression on circulating monocytes was also measured from peripheral blood samples obtained during surgery. Patients were classified as having either high PD-L1 expression (54.5% or more of monocytes) or low PD-L1 expression. Among patients classified as having high PD-L1 expression, the median overall survival was 18.0 months (95% CI, 10.0-23.3). Patients who had low PD-L1 expression had a significantly longer median overall survival time of 44.7 months with a confidence interval not calculable (hazard ratio, 3.35; 95% CI, 1.36-8.23; P = .003).

Finally, a multivariate proportional hazards model showed the MGMT methylation status and PD-L1 expression were the two greatest independent predictors of survival.

“Survival among patients who received the HSPPV-96 was greater than expected compared to historical controls... These results certainly, we feel, provide rationale for a phase III trial of vaccine plus standard of care versus standard of care alone,” Dr. Bloch said.

“PD-L1 expression on circulating myeloid cells is independently predictive of clinical response to vaccination, and it suggests that the low PD-L1 expressing population will most benefit from this anti-tumor vaccination scheme, but it also suggests that high PD-L1 expressing patients may benefit from combined checkpoint inhibition. Systemic immunosuppression driven by peripheral monocyte expression of PD-L1 is a previously unidentified factor that may mitigate vaccine efficacy,” Dr. Bloch further commented.

This study was funded by the National Cancer Institute, the National Institute of Neurological Disorders and Stroke, the National Brain Tumor Society, the American Brain Tumor Association, and Accelerated Brain Cancer Cure. Dr. Bloch reporting having no relevant disclosures.

[email protected]

On Twitter @jessnicolecraig

Chicago – A newly developed heat shock protein peptide vaccination appears to be safe and effective in treating patients with newly diagnosed glioblastoma (GBM), according to the results of a phase II single arm study.

In adding the vaccine to standard therapy for 46 patients with newly diagnosed GBM, median overall survival was 23.8 months, and there were no grade 3 or 4 adverse events associated with the vaccine, lead author Dr. Orin Bloch of Northwestern University, Chicago, reported at the annual meeting of the American Society of Clinical Oncology.

Standard therapy typically results in a median survival of 16 months, he said.

“There is a lot of information out there right now regarding CNS and other solid organ tumors particularly in the area of checkpoint modulation and its ability to stimulate an innate immune response against a tumor. I think in GBM we are facing a bit of a different scenario, however, because the tumor exists in a very privileged area behind the blood brain barrier and doesn’t regularly metastasize beyond the CNS,” Dr. Bloch said.

Therefore, only modulating checkpoints without stimulating and educating the immune system may not be the most effective approach. Adaptive immunity through vaccination or some other form of stimulation might be more successful, Dr. Bloch said.

“As a way of inducing immune stimulation and education using tumor-autologous peptides, one can capitalize on the native system of heat shock stimulation. Heat shock proteins are chaperone proteins that are ubiquitously expressed in cells and they’re bound to any number of intracellular peptides at any one time including, in tumor cells, neoantigens. If you extract these heat shock proteins with their bound antigens and deliver them in a naked form into the systemic circulation, their uptake into antigen-presenting cells through the CD91 receptor [will result in] the peptide [being] cleaved and presented on MHC class one and two for stimulation of CD8- and CD4-positive T cell response,” he said.

Heat shock proteins also interact with toll-like receptors and stimulate the secretion of pro-inflammatory cytokines, “acting as their own adjuvant,” Dr. Bloch further explained. Utilizing heat shock proteins activates both the innate and adaptive immune responses.

“This is an ideal platform for developing an immunotherapy for glioblastoma,” Dr. Bloch said.

In this phase II study, 46 adult patients with GBM underwent surgical resection of their tumors followed by chemoradiotherapy. At least four 25-microgram doses of vaccine were generated from tissue obtained during surgery. Within 5 weeks of completing radiotherapy, patients began receiving weekly vaccinations in combination with adjuvant temozolomide. Patients continued receiving vaccines until depletion or until tumor progression.

Median progression-free survival was 17.8 months (95% confidence interval, 11.3-21.6) and median overall survival was 23.8 months (95% CI, 19.8-30.2).

PD-L1 expression on circulating monocytes was also measured from peripheral blood samples obtained during surgery. Patients were classified as having either high PD-L1 expression (54.5% or more of monocytes) or low PD-L1 expression. Among patients classified as having high PD-L1 expression, the median overall survival was 18.0 months (95% CI, 10.0-23.3). Patients who had low PD-L1 expression had a significantly longer median overall survival time of 44.7 months with a confidence interval not calculable (hazard ratio, 3.35; 95% CI, 1.36-8.23; P = .003).

Finally, a multivariate proportional hazards model showed the MGMT methylation status and PD-L1 expression were the two greatest independent predictors of survival.

“Survival among patients who received the HSPPV-96 was greater than expected compared to historical controls... These results certainly, we feel, provide rationale for a phase III trial of vaccine plus standard of care versus standard of care alone,” Dr. Bloch said.

“PD-L1 expression on circulating myeloid cells is independently predictive of clinical response to vaccination, and it suggests that the low PD-L1 expressing population will most benefit from this anti-tumor vaccination scheme, but it also suggests that high PD-L1 expressing patients may benefit from combined checkpoint inhibition. Systemic immunosuppression driven by peripheral monocyte expression of PD-L1 is a previously unidentified factor that may mitigate vaccine efficacy,” Dr. Bloch further commented.

This study was funded by the National Cancer Institute, the National Institute of Neurological Disorders and Stroke, the National Brain Tumor Society, the American Brain Tumor Association, and Accelerated Brain Cancer Cure. Dr. Bloch reporting having no relevant disclosures.

[email protected]

On Twitter @jessnicolecraig

Chicago – A newly developed heat shock protein peptide vaccination appears to be safe and effective in treating patients with newly diagnosed glioblastoma (GBM), according to the results of a phase II single arm study.

In adding the vaccine to standard therapy for 46 patients with newly diagnosed GBM, median overall survival was 23.8 months, and there were no grade 3 or 4 adverse events associated with the vaccine, lead author Dr. Orin Bloch of Northwestern University, Chicago, reported at the annual meeting of the American Society of Clinical Oncology.

Standard therapy typically results in a median survival of 16 months, he said.

“There is a lot of information out there right now regarding CNS and other solid organ tumors particularly in the area of checkpoint modulation and its ability to stimulate an innate immune response against a tumor. I think in GBM we are facing a bit of a different scenario, however, because the tumor exists in a very privileged area behind the blood brain barrier and doesn’t regularly metastasize beyond the CNS,” Dr. Bloch said.

Therefore, only modulating checkpoints without stimulating and educating the immune system may not be the most effective approach. Adaptive immunity through vaccination or some other form of stimulation might be more successful, Dr. Bloch said.

“As a way of inducing immune stimulation and education using tumor-autologous peptides, one can capitalize on the native system of heat shock stimulation. Heat shock proteins are chaperone proteins that are ubiquitously expressed in cells and they’re bound to any number of intracellular peptides at any one time including, in tumor cells, neoantigens. If you extract these heat shock proteins with their bound antigens and deliver them in a naked form into the systemic circulation, their uptake into antigen-presenting cells through the CD91 receptor [will result in] the peptide [being] cleaved and presented on MHC class one and two for stimulation of CD8- and CD4-positive T cell response,” he said.

Heat shock proteins also interact with toll-like receptors and stimulate the secretion of pro-inflammatory cytokines, “acting as their own adjuvant,” Dr. Bloch further explained. Utilizing heat shock proteins activates both the innate and adaptive immune responses.

“This is an ideal platform for developing an immunotherapy for glioblastoma,” Dr. Bloch said.

In this phase II study, 46 adult patients with GBM underwent surgical resection of their tumors followed by chemoradiotherapy. At least four 25-microgram doses of vaccine were generated from tissue obtained during surgery. Within 5 weeks of completing radiotherapy, patients began receiving weekly vaccinations in combination with adjuvant temozolomide. Patients continued receiving vaccines until depletion or until tumor progression.

Median progression-free survival was 17.8 months (95% confidence interval, 11.3-21.6) and median overall survival was 23.8 months (95% CI, 19.8-30.2).

PD-L1 expression on circulating monocytes was also measured from peripheral blood samples obtained during surgery. Patients were classified as having either high PD-L1 expression (54.5% or more of monocytes) or low PD-L1 expression. Among patients classified as having high PD-L1 expression, the median overall survival was 18.0 months (95% CI, 10.0-23.3). Patients who had low PD-L1 expression had a significantly longer median overall survival time of 44.7 months with a confidence interval not calculable (hazard ratio, 3.35; 95% CI, 1.36-8.23; P = .003).

Finally, a multivariate proportional hazards model showed the MGMT methylation status and PD-L1 expression were the two greatest independent predictors of survival.

“Survival among patients who received the HSPPV-96 was greater than expected compared to historical controls... These results certainly, we feel, provide rationale for a phase III trial of vaccine plus standard of care versus standard of care alone,” Dr. Bloch said.

“PD-L1 expression on circulating myeloid cells is independently predictive of clinical response to vaccination, and it suggests that the low PD-L1 expressing population will most benefit from this anti-tumor vaccination scheme, but it also suggests that high PD-L1 expressing patients may benefit from combined checkpoint inhibition. Systemic immunosuppression driven by peripheral monocyte expression of PD-L1 is a previously unidentified factor that may mitigate vaccine efficacy,” Dr. Bloch further commented.

This study was funded by the National Cancer Institute, the National Institute of Neurological Disorders and Stroke, the National Brain Tumor Society, the American Brain Tumor Association, and Accelerated Brain Cancer Cure. Dr. Bloch reporting having no relevant disclosures.

[email protected]

On Twitter @jessnicolecraig

Editor’s note: “Everything We Say and Do” is an informational series developed by SHM’s Patient Experience Committee to provide readers with thoughtful and actionable communication tactics that have great potential to positively impact patients’ experience of care. Each article will focus on how the contributor applies one or more of the “key communication” tactics in practice to maintain provider accountability for “everything we say and do that affects our patients’ thoughts, feelings, and well-being.”

View a chart outlining key communication tactics

What I Say and Do

I use the teach-back method to confirm my patients’ understanding.

Why I Do It

Teach-back allows me to address my patients’ uncertainty about the plan and clarify any misunderstandings.

As doctors, one of our most important jobs is explaining in ways our patients understand. It doesn’t matter how brilliant our treatment plan is if our patients do not understand it. We all want to feel like we’re making a difference in our patients’ lives. Yet it’s hard for our patients to do what we recommend if they don’t understand.

Unfortunately, many patients are too embarrassed to ask questions, or they simply do not know what to ask. Patients will also say they understand everything even when they do not because they fear appearing uneducated.

This is why the teach-back method is so valuable. The teach-back method allows you to better assess your patients’ understanding of their medical problems. It allows you to uncover and clarify any misunderstandings your patients may have about the plan. It also helps you to engage in a more collaborative relationship with your patients.

How I Do It

Teach-back helps me to test my effectiveness as a teacher by allowing me to assess whether my patient understands; if not, I explain in a different way.

One of the common mistakes clinicians make when assessing for understanding is asking, “Do you have any questions?” or “Does this make sense?” The problem with these questions is that they are closed-ended. The only responses are yes or no. Your patients may say they understand even when they do not. In reality, it does not matter how brilliant your treatment plans are if patients do not follow them because they do not understand.

Teach-back encourages the doctor to check for understanding by using open-ended instead of closed-ended questions.

Example one: “This is a new diagnosis for you, so I want to make sure you understand. Will you tell me in your own words what congestive heart failure is?”

Example two: “I want to make sure I explained this clearly. I know your daughter helps you manage your health. What will you tell her about the changes we made to your blood pressure medication?”

Teach-back steps:

1. I explain the concept to my patients, avoiding medical jargon.
2. I assess my patients’ understanding by asking them to explain the concept in their own words.
3. I clarify anything my patients did not understand and reassess their understanding.
4. If my patients still do not understand, I find a new way to explain the concept.
5. I repeat the process of explaining and assessing for understanding until my patients are able to accurately state their understanding.

There are a few key things to remember as you perform teach-back. The first is to ensure you use a caring tone when speaking with your patients. Next, if you have several concepts you want to teach, break it into small pieces. Use teach-back for the first concept before moving on to the next. Finally, one of the most common questions I get from other doctors about teach-back is how to assess patients’ understanding without sounding condescending. I address this by making it about me and my effectiveness as a teacher. I tell my patients it is my responsibility to explain things in a way they understand, so if they do not, I will explain it in a different way. When I frame it this way, patients are not offended by my asking them to perform teach-back because they realize I’m doing it as a test of my effectiveness as a teacher.

Example: “Mr. Johnson, as your doctor, one of my top priorities is to ensure I’m explaining things in a way you understand. I want to make sure my instructions about how to take your new medication are clear. Would you mind telling me in your own words how you will take this new medication?”

Now that you know what teach-back is and understand how helpful it can be, start incorporating it into your practice. Think about a few concepts that you teach again and again, such as disease management, medication changes, and self-care instructions. Next, think about how you could use teach-back in these scenarios. Practice what you will say when you ask patients to engage in teach-back. Finally, commit to using teach-back with your next few patients. The more you practice, the easier it becomes.

For more information on teach-back, visit www.teachbacktraining.org.

Dr. Dorrah is regional medical director for quality and the patient experience, Baylor Scott & White Health, Round Rock, Texas.

Editor’s note: “Everything We Say and Do” is an informational series developed by SHM’s Patient Experience Committee to provide readers with thoughtful and actionable communication tactics that have great potential to positively impact patients’ experience of care. Each article will focus on how the contributor applies one or more of the “key communication” tactics in practice to maintain provider accountability for “everything we say and do that affects our patients’ thoughts, feelings, and well-being.”

View a chart outlining key communication tactics

What I Say and Do

I use the teach-back method to confirm my patients’ understanding.

Why I Do It

Teach-back allows me to address my patients’ uncertainty about the plan and clarify any misunderstandings.

As doctors, one of our most important jobs is explaining in ways our patients understand. It doesn’t matter how brilliant our treatment plan is if our patients do not understand it. We all want to feel like we’re making a difference in our patients’ lives. Yet it’s hard for our patients to do what we recommend if they don’t understand.

Unfortunately, many patients are too embarrassed to ask questions, or they simply do not know what to ask. Patients will also say they understand everything even when they do not because they fear appearing uneducated.

This is why the teach-back method is so valuable. The teach-back method allows you to better assess your patients’ understanding of their medical problems. It allows you to uncover and clarify any misunderstandings your patients may have about the plan. It also helps you to engage in a more collaborative relationship with your patients.

How I Do It

Teach-back helps me to test my effectiveness as a teacher by allowing me to assess whether my patient understands; if not, I explain in a different way.

One of the common mistakes clinicians make when assessing for understanding is asking, “Do you have any questions?” or “Does this make sense?” The problem with these questions is that they are closed-ended. The only responses are yes or no. Your patients may say they understand even when they do not. In reality, it does not matter how brilliant your treatment plans are if patients do not follow them because they do not understand.

Teach-back encourages the doctor to check for understanding by using open-ended instead of closed-ended questions.

Example one: “This is a new diagnosis for you, so I want to make sure you understand. Will you tell me in your own words what congestive heart failure is?”

Example two: “I want to make sure I explained this clearly. I know your daughter helps you manage your health. What will you tell her about the changes we made to your blood pressure medication?”

Teach-back steps:

1. I explain the concept to my patients, avoiding medical jargon.
2. I assess my patients’ understanding by asking them to explain the concept in their own words.
3. I clarify anything my patients did not understand and reassess their understanding.
4. If my patients still do not understand, I find a new way to explain the concept.
5. I repeat the process of explaining and assessing for understanding until my patients are able to accurately state their understanding.

There are a few key things to remember as you perform teach-back. The first is to ensure you use a caring tone when speaking with your patients. Next, if you have several concepts you want to teach, break it into small pieces. Use teach-back for the first concept before moving on to the next. Finally, one of the most common questions I get from other doctors about teach-back is how to assess patients’ understanding without sounding condescending. I address this by making it about me and my effectiveness as a teacher. I tell my patients it is my responsibility to explain things in a way they understand, so if they do not, I will explain it in a different way. When I frame it this way, patients are not offended by my asking them to perform teach-back because they realize I’m doing it as a test of my effectiveness as a teacher.

Example: “Mr. Johnson, as your doctor, one of my top priorities is to ensure I’m explaining things in a way you understand. I want to make sure my instructions about how to take your new medication are clear. Would you mind telling me in your own words how you will take this new medication?”

Now that you know what teach-back is and understand how helpful it can be, start incorporating it into your practice. Think about a few concepts that you teach again and again, such as disease management, medication changes, and self-care instructions. Next, think about how you could use teach-back in these scenarios. Practice what you will say when you ask patients to engage in teach-back. Finally, commit to using teach-back with your next few patients. The more you practice, the easier it becomes.

For more information on teach-back, visit www.teachbacktraining.org.

Dr. Dorrah is regional medical director for quality and the patient experience, Baylor Scott & White Health, Round Rock, Texas.

Editor’s note: “Everything We Say and Do” is an informational series developed by SHM’s Patient Experience Committee to provide readers with thoughtful and actionable communication tactics that have great potential to positively impact patients’ experience of care. Each article will focus on how the contributor applies one or more of the “key communication” tactics in practice to maintain provider accountability for “everything we say and do that affects our patients’ thoughts, feelings, and well-being.”

View a chart outlining key communication tactics

What I Say and Do

I use the teach-back method to confirm my patients’ understanding.

Why I Do It

Teach-back allows me to address my patients’ uncertainty about the plan and clarify any misunderstandings.

As doctors, one of our most important jobs is explaining in ways our patients understand. It doesn’t matter how brilliant our treatment plan is if our patients do not understand it. We all want to feel like we’re making a difference in our patients’ lives. Yet it’s hard for our patients to do what we recommend if they don’t understand.

Unfortunately, many patients are too embarrassed to ask questions, or they simply do not know what to ask. Patients will also say they understand everything even when they do not because they fear appearing uneducated.

This is why the teach-back method is so valuable. The teach-back method allows you to better assess your patients’ understanding of their medical problems. It allows you to uncover and clarify any misunderstandings your patients may have about the plan. It also helps you to engage in a more collaborative relationship with your patients.

How I Do It

Teach-back helps me to test my effectiveness as a teacher by allowing me to assess whether my patient understands; if not, I explain in a different way.

One of the common mistakes clinicians make when assessing for understanding is asking, “Do you have any questions?” or “Does this make sense?” The problem with these questions is that they are closed-ended. The only responses are yes or no. Your patients may say they understand even when they do not. In reality, it does not matter how brilliant your treatment plans are if patients do not follow them because they do not understand.

Teach-back encourages the doctor to check for understanding by using open-ended instead of closed-ended questions.

Example one: “This is a new diagnosis for you, so I want to make sure you understand. Will you tell me in your own words what congestive heart failure is?”

Example two: “I want to make sure I explained this clearly. I know your daughter helps you manage your health. What will you tell her about the changes we made to your blood pressure medication?”

Teach-back steps:

1. I explain the concept to my patients, avoiding medical jargon.
2. I assess my patients’ understanding by asking them to explain the concept in their own words.
3. I clarify anything my patients did not understand and reassess their understanding.
4. If my patients still do not understand, I find a new way to explain the concept.
5. I repeat the process of explaining and assessing for understanding until my patients are able to accurately state their understanding.

There are a few key things to remember as you perform teach-back. The first is to ensure you use a caring tone when speaking with your patients. Next, if you have several concepts you want to teach, break it into small pieces. Use teach-back for the first concept before moving on to the next. Finally, one of the most common questions I get from other doctors about teach-back is how to assess patients’ understanding without sounding condescending. I address this by making it about me and my effectiveness as a teacher. I tell my patients it is my responsibility to explain things in a way they understand, so if they do not, I will explain it in a different way. When I frame it this way, patients are not offended by my asking them to perform teach-back because they realize I’m doing it as a test of my effectiveness as a teacher.

Example: “Mr. Johnson, as your doctor, one of my top priorities is to ensure I’m explaining things in a way you understand. I want to make sure my instructions about how to take your new medication are clear. Would you mind telling me in your own words how you will take this new medication?”

Now that you know what teach-back is and understand how helpful it can be, start incorporating it into your practice. Think about a few concepts that you teach again and again, such as disease management, medication changes, and self-care instructions. Next, think about how you could use teach-back in these scenarios. Practice what you will say when you ask patients to engage in teach-back. Finally, commit to using teach-back with your next few patients. The more you practice, the easier it becomes.

For more information on teach-back, visit www.teachbacktraining.org.

Dr. Dorrah is regional medical director for quality and the patient experience, Baylor Scott & White Health, Round Rock, Texas.

 

 

Max S. Topp, MD

 

COPENHAGEN—Interim results from the phase 3 TOWER trial suggest blinatumomab can prolong overall survival (OS) when compared to standard care in adults with Ph-negative, relapsed/refractory B-cell precursor acute lymphoblastic leukemia (B-ALL).

The median OS for patients treated with blinatumomab was nearly double the median OS of patients who received standard chemotherapy (investigator’s choice of 4 different regimens).

Based on these results, Amgen, the company sponsoring the trial, decided to stop it early.

“This was the first study to show that immunotherapy can outcompete chemotherapy,” said Max S. Topp, MD, of University Hospital of Wuerzburg in Germany.

Dr Topp presented results from this study at the 21st Congress of the European Hematology Association (abstract S149).

Patients and treatment

The TOWER trial enrolled and randomized 405 patients with Ph-negative, relapsed/refractory B-ALL, and 376 of them ultimately received treatment.

The patients received blinatumomab (n=267) or investigator’s choice of 1 of 4 protocol-defined standard chemotherapy regimens (n=109):

• FLAG (fludarabine, high-dose cytarabine, and granulocyte-colony stimulating factor), with or without an anthracycline (n=49, 45%)
• A high-dose cytarabine-based regimen (n=19, 17%)
• A high-dose methotrexate-based regimen (n=22, 20%)
• A clofarabine-based regimen (n=19, 17%).

Patients who received blinatumomab received it as a continuous infusion, 4 weeks on and 2 weeks off, at 9 µg/day for 7 days, then 28 µg/day on weeks 2-4. They received 2 cycles of induction, which was followed by 3 cycles of consolidation if they had ≤5% blasts.

If patients still had ≤5% blasts after consolidation, they received up to 12 months of blinatumomab maintenance. Maintenance was a continuous infusion, 4 weeks on and 8 weeks off, at 28 µg/day.

Patient characteristics were similar between the treatment arms. The median age was 37 in both arms (overall range, 18-80). About 40% of patients in the blinatumomab arm and 50% in the chemotherapy arm had not received any prior salvage regimens.

More than 30% of patients in both arms had undergone an allogeneic hematopoietic stem cell transplant (allo-HSCT), and about 20% were primary refractory. Roughly 30% of blinatumomab-treated patients were refractory to salvage therapy, as were more than 20% of chemotherapy-treated patients.

Response and survival

During induction, in the intent-to-treat population (n=271 in the blinatumomab arm and 134 in the chemotherapy arm), the overall response rate was 44% in the blinatumomab arm and 25% in the chemotherapy arm (P<0.001). The complete response rates were 34% and 16%, respectively.

Among patients who received their assigned treatment (n=267 in the blinatumomab arm and 109 in the chemotherapy arm), the overall response rates were 45% and 30%, respectively (P=0.007).

In the intent-to-treat population, the median OS was 7.7 months (95% CI, 5.6-9.6) in the blinatumomab arm and 4 months (95% CI, 2.9-5.3) in the chemotherapy arm (hazard ratio=0.71, P=0.012). The survival curves were similar in the as-treated population.

Dr Topp noted that the improvement in OS with blinatumomab was consistent across subgroups, regardless of age, prior salvage therapy, or prior allo-HSCT.

Dr Topp and his colleagues also considered the effect post-treatment allo-HSCT might have on OS. Sixty-five patients in the blinatumomab arm and 32 in the chemotherapy arm went on to receive an allo-HSCT (24% of patients in both arms).

When the researchers censored for post-treatment allo-HSCT, the median OS was 6.9 months in the blinatumomab arm and 3.9 months in the chemotherapy arm (hazard ratio=0.66, P=0.004).

Safety

In the as-treated population, 99% of patients in both arms experienced adverse events (AEs).


The incidence of grade 3 AEs was 37% in the blinatumomab arm and 30% in the chemotherapy arm. The incidence of grade 4 AEs was 31% and 44%, respectively. The incidence of grade 5 AEs was 19% and 17%, respectively.

Grade 3 or higher AEs of interest, according to Dr Topp, were infection (34% with blinatumomab and 52% with chemotherapy), neutropenia (38% and 58%, respectively), neurologic events (9% and 8%, respectively), and cytokine release syndrome (5% and 0%, respectively).

Seven patients—5 in the blinatumomab arm and 2 in the chemotherapy arm—who did not undergo allo-HSCT died during the study without documented relapse.

 

 

Max S. Topp, MD

 

COPENHAGEN—Interim results from the phase 3 TOWER trial suggest blinatumomab can prolong overall survival (OS) when compared to standard care in adults with Ph-negative, relapsed/refractory B-cell precursor acute lymphoblastic leukemia (B-ALL).

The median OS for patients treated with blinatumomab was nearly double the median OS of patients who received standard chemotherapy (investigator’s choice of 4 different regimens).

Based on these results, Amgen, the company sponsoring the trial, decided to stop it early.

“This was the first study to show that immunotherapy can outcompete chemotherapy,” said Max S. Topp, MD, of University Hospital of Wuerzburg in Germany.

Dr Topp presented results from this study at the 21st Congress of the European Hematology Association (abstract S149).

Patients and treatment

The TOWER trial enrolled and randomized 405 patients with Ph-negative, relapsed/refractory B-ALL, and 376 of them ultimately received treatment.

The patients received blinatumomab (n=267) or investigator’s choice of 1 of 4 protocol-defined standard chemotherapy regimens (n=109):

• FLAG (fludarabine, high-dose cytarabine, and granulocyte-colony stimulating factor), with or without an anthracycline (n=49, 45%)
• A high-dose cytarabine-based regimen (n=19, 17%)
• A high-dose methotrexate-based regimen (n=22, 20%)
• A clofarabine-based regimen (n=19, 17%).

Patients who received blinatumomab received it as a continuous infusion, 4 weeks on and 2 weeks off, at 9 µg/day for 7 days, then 28 µg/day on weeks 2-4. They received 2 cycles of induction, which was followed by 3 cycles of consolidation if they had ≤5% blasts.

If patients still had ≤5% blasts after consolidation, they received up to 12 months of blinatumomab maintenance. Maintenance was a continuous infusion, 4 weeks on and 8 weeks off, at 28 µg/day.

Patient characteristics were similar between the treatment arms. The median age was 37 in both arms (overall range, 18-80). About 40% of patients in the blinatumomab arm and 50% in the chemotherapy arm had not received any prior salvage regimens.

More than 30% of patients in both arms had undergone an allogeneic hematopoietic stem cell transplant (allo-HSCT), and about 20% were primary refractory. Roughly 30% of blinatumomab-treated patients were refractory to salvage therapy, as were more than 20% of chemotherapy-treated patients.

Response and survival

During induction, in the intent-to-treat population (n=271 in the blinatumomab arm and 134 in the chemotherapy arm), the overall response rate was 44% in the blinatumomab arm and 25% in the chemotherapy arm (P<0.001). The complete response rates were 34% and 16%, respectively.

Among patients who received their assigned treatment (n=267 in the blinatumomab arm and 109 in the chemotherapy arm), the overall response rates were 45% and 30%, respectively (P=0.007).

In the intent-to-treat population, the median OS was 7.7 months (95% CI, 5.6-9.6) in the blinatumomab arm and 4 months (95% CI, 2.9-5.3) in the chemotherapy arm (hazard ratio=0.71, P=0.012). The survival curves were similar in the as-treated population.

Dr Topp noted that the improvement in OS with blinatumomab was consistent across subgroups, regardless of age, prior salvage therapy, or prior allo-HSCT.

Dr Topp and his colleagues also considered the effect post-treatment allo-HSCT might have on OS. Sixty-five patients in the blinatumomab arm and 32 in the chemotherapy arm went on to receive an allo-HSCT (24% of patients in both arms).

When the researchers censored for post-treatment allo-HSCT, the median OS was 6.9 months in the blinatumomab arm and 3.9 months in the chemotherapy arm (hazard ratio=0.66, P=0.004).

Safety

In the as-treated population, 99% of patients in both arms experienced adverse events (AEs).


The incidence of grade 3 AEs was 37% in the blinatumomab arm and 30% in the chemotherapy arm. The incidence of grade 4 AEs was 31% and 44%, respectively. The incidence of grade 5 AEs was 19% and 17%, respectively.

Grade 3 or higher AEs of interest, according to Dr Topp, were infection (34% with blinatumomab and 52% with chemotherapy), neutropenia (38% and 58%, respectively), neurologic events (9% and 8%, respectively), and cytokine release syndrome (5% and 0%, respectively).

Seven patients—5 in the blinatumomab arm and 2 in the chemotherapy arm—who did not undergo allo-HSCT died during the study without documented relapse.

 

 

Max S. Topp, MD

 

COPENHAGEN—Interim results from the phase 3 TOWER trial suggest blinatumomab can prolong overall survival (OS) when compared to standard care in adults with Ph-negative, relapsed/refractory B-cell precursor acute lymphoblastic leukemia (B-ALL).

The median OS for patients treated with blinatumomab was nearly double the median OS of patients who received standard chemotherapy (investigator’s choice of 4 different regimens).

Based on these results, Amgen, the company sponsoring the trial, decided to stop it early.

“This was the first study to show that immunotherapy can outcompete chemotherapy,” said Max S. Topp, MD, of University Hospital of Wuerzburg in Germany.

Dr Topp presented results from this study at the 21st Congress of the European Hematology Association (abstract S149).

Patients and treatment

The TOWER trial enrolled and randomized 405 patients with Ph-negative, relapsed/refractory B-ALL, and 376 of them ultimately received treatment.

The patients received blinatumomab (n=267) or investigator’s choice of 1 of 4 protocol-defined standard chemotherapy regimens (n=109):

• FLAG (fludarabine, high-dose cytarabine, and granulocyte-colony stimulating factor), with or without an anthracycline (n=49, 45%)
• A high-dose cytarabine-based regimen (n=19, 17%)
• A high-dose methotrexate-based regimen (n=22, 20%)
• A clofarabine-based regimen (n=19, 17%).

Patients who received blinatumomab received it as a continuous infusion, 4 weeks on and 2 weeks off, at 9 µg/day for 7 days, then 28 µg/day on weeks 2-4. They received 2 cycles of induction, which was followed by 3 cycles of consolidation if they had ≤5% blasts.

If patients still had ≤5% blasts after consolidation, they received up to 12 months of blinatumomab maintenance. Maintenance was a continuous infusion, 4 weeks on and 8 weeks off, at 28 µg/day.

Patient characteristics were similar between the treatment arms. The median age was 37 in both arms (overall range, 18-80). About 40% of patients in the blinatumomab arm and 50% in the chemotherapy arm had not received any prior salvage regimens.

More than 30% of patients in both arms had undergone an allogeneic hematopoietic stem cell transplant (allo-HSCT), and about 20% were primary refractory. Roughly 30% of blinatumomab-treated patients were refractory to salvage therapy, as were more than 20% of chemotherapy-treated patients.

Response and survival

During induction, in the intent-to-treat population (n=271 in the blinatumomab arm and 134 in the chemotherapy arm), the overall response rate was 44% in the blinatumomab arm and 25% in the chemotherapy arm (P<0.001). The complete response rates were 34% and 16%, respectively.

Among patients who received their assigned treatment (n=267 in the blinatumomab arm and 109 in the chemotherapy arm), the overall response rates were 45% and 30%, respectively (P=0.007).

In the intent-to-treat population, the median OS was 7.7 months (95% CI, 5.6-9.6) in the blinatumomab arm and 4 months (95% CI, 2.9-5.3) in the chemotherapy arm (hazard ratio=0.71, P=0.012). The survival curves were similar in the as-treated population.

Dr Topp noted that the improvement in OS with blinatumomab was consistent across subgroups, regardless of age, prior salvage therapy, or prior allo-HSCT.

Dr Topp and his colleagues also considered the effect post-treatment allo-HSCT might have on OS. Sixty-five patients in the blinatumomab arm and 32 in the chemotherapy arm went on to receive an allo-HSCT (24% of patients in both arms).

When the researchers censored for post-treatment allo-HSCT, the median OS was 6.9 months in the blinatumomab arm and 3.9 months in the chemotherapy arm (hazard ratio=0.66, P=0.004).

Safety

In the as-treated population, 99% of patients in both arms experienced adverse events (AEs).


The incidence of grade 3 AEs was 37% in the blinatumomab arm and 30% in the chemotherapy arm. The incidence of grade 4 AEs was 31% and 44%, respectively. The incidence of grade 5 AEs was 19% and 17%, respectively.

Grade 3 or higher AEs of interest, according to Dr Topp, were infection (34% with blinatumomab and 52% with chemotherapy), neutropenia (38% and 58%, respectively), neurologic events (9% and 8%, respectively), and cytokine release syndrome (5% and 0%, respectively).

Seven patients—5 in the blinatumomab arm and 2 in the chemotherapy arm—who did not undergo allo-HSCT died during the study without documented relapse.

Uwe Platzbecker, MD

COPENHAGEN—The erythropoiesis-stimulating agent (ESA) darbepoetin alfa can provide a clinical benefit in patients with lower-risk myelodysplastic syndromes (MDS), a phase 3 trial suggests.

In the ARCADE trial, darbepoetin alfa significantly reduced the incidence of red blood cell (RBC) transfusions in patients with low- and intermediate-1 risk myelodysplastic syndrome (MDS), when compared to placebo.

The ESA also significantly improved erythroid response.

In addition, researchers said adverse events (AEs) were generally balanced between the darbepoetin alfa and placebo arms.

Uwe Platzbecker, MD, of University Hospital Carl Gustav Carus Dresden in Germany, presented these results at the 21st Congress of the European Hematology Association (abstract S128). The ARCADE trial was sponsored by Amgen.

Dr Platzbecker noted that, although ESAs are recommended in clinical guidelines to treat anemia in patients with lower-risk MDS, the drugs are not widely approved for this indication.

So, in the ARCADE trial, he and his colleagues assessed darbepoetin alfa in patients with low- or intermediate-1 risk MDS who had not previously taken ESAs or biologic response modifiers.

The patients had hemoglobin levels ≤10 g/dL, endogenous erythropoietin levels ≤500 mU/mL, and low transfusion burden (<4 RBC units in each of 2 consecutive 8-week periods prior to randomization).

During a 24-week period, 147 patients received either darbepoetin alfa at 500 μg (n=97) or placebo (n=49) every 3 weeks. The ESA dose was withheld if patients’ hemoglobin was >12.0 g/dL and decreased if hemoglobin increased by >1.5 g/dL in 3 weeks without transfusion.

At week 25, when the primary and key secondary endpoints were assessed, patients underwent an end-of-treatment period visit. They could then enter a 48-week active treatment period and cross over to receive darbepoetin alfa, with dose escalation allowed beginning on week 31. Treatment continued until week 72 or 73, and patients continue to be assessed every 26 weeks, for a minimum of 3 years.

Patient characteristics

Dr Platzbecker said baseline demographic and disease characteristics were generally similar between the treatment arms. All patients were Caucasian, and about 55% were male. The median age was 74 (range, 67-79). About half of patients in each treatment arm belonged to the low-risk IPSS category.

In both arms, most patients had refractory cytopenia with multilineage dysplasia (38.8% in the placebo arm and 46.4% in the darbepoetin alfa arm). Patients also had refractory anemia with excess blasts-1 (20.4% and 13.4%, respectively), refractory anemia (26.5% and 9.3%), refractory anemia with ring sideroblasts (8.2% and 17.5%), 5q deletion (4.1% and 11.3%), unclassifiable MDS (2.0% and 1.0%), and MDS of an unknown type (0% and 1.0%).

In the 16 weeks before randomization, 58.2% of all patients—53.1% in the placebo arm and 60.8% in the darbepoetin alfa arm—did not have any RBC transfusions. About 25% (24.7%)—22.4% in the placebo arm and 25.8% in the darbepoetin alfa arm—received 1 to 3 RBC units. And 17.1%—24.5% in the placebo arm and 13.4% in the darbepoetin alfa arm—received 4 or more RBC units.

Dosing

During the 24-week double-blind period of the study, 77% (37/48) of patients in the placebo arm and 79% (77/98) in the darbepoetin alfa arm received all 8 doses of treatment.

Sixteen percent (n=16) of patients in the darbepoetin alfa arm had a single dose reduction, and 2% (n=2) had 2 dose reductions. None of the patients in the placebo arm had a dose reduction.

Eleven percent of patients in the darbepoetin alfa arm had doses withheld due to increased hemoglobin. The dose was withheld once for 6 patients, twice for 4 patients, and 3 times for 1 patient. None of the placebo-treated patients had a dose withheld for this reason.

Ten percent (n=5) of placebo-treated patients and 2% (n=2) of darbepoetin alfa-treated patients had a dose withheld due to an AE. Two percent (n=1) and 3% (n=3) of patients, respectively, had a dose withheld for “other” reasons (noncompliance, investigator decision, and no investigational product on site).

During the 48-week open-label period of the study, 81% (102/126) of patients who received darbepoetin alfa increased their dose frequency from every 3 weeks to every 2 weeks. Dr Platzbecker said this suggests the optimal dose of the drug was not achieved during the 24-week double-blind period of the study.

Efficacy

During the 24-week double-blind period, there was a significant difference between the treatment arms with regard to RBC transfusions. The transfusion incidence was 59.2% (29/49) in the placebo arm and 36.1% (35/97) in the darbepoetin alfa arm (P=0.008).

During the 48-week open-label period, the incidence of RBC transfusion was 50.8% (64/126) among patients receiving darbepoetin alfa.

During the 24-week double-blind period, 11 patients (14.7%) in the darbepoetin alfa arm had an erythroid hematologic improvement (HI-E), but none of the patients in the placebo arm had such an improvement.

All 11 patients with HI-E had a baseline serum erythropoietin level less than 100 mU/mL, 1 of the patients had 2 RBC units transfused in the 16 weeks prior to randomization, but none had transfusions in the 8 weeks prior to randomization. Four of the patients had a dose withheld due to having hemoglobin levels greater than 12 g/dL.

During the 48-week open-label period, the HI-E rate was 34.7% (34/98) among patients receiving darbepoetin alfa.

Dr Platzbecker said the nature of the HI-E criteria likely underestimated the clinical benefit of darbepoetin alfa in this trial, and this was further complicated by the trial design. Specifically, hemoglobin was measured every 3 weeks, some patients may have had their doses reduced even if they were still anemic, and the optimal dose of darbepoetin alfa was likely not given during the double-blind period (as evidenced by the increase in doses during the open-label period).

For these reasons, Dr Platzbecker and his colleagues are exploring alternative response analyses to determine if there were additional patients who received a clinical benefit from darbepoetin alfa but did not meet HI-E criteria.

Safety

During the 24-week double-blind period, 4.2% (n=2) of patients in the placebo arm and 3.1% (n=3) in the darbepoetin alfa arm had AEs that led to treatment discontinuation. In the placebo arm, these events were pulmonary hypertension and renal failure. In the darbepoetin alfa arm, the events were pulmonary thrombosis, thrombocytopenia, and increased blast cell count.

The incidence of grade 3 or higher AEs was 27.1% (n=13) in the placebo arm and 15.3% (n=15) in the darbepoetin alfa arm. The incidence of grade 4 or higher AEs was 12.5% (n=6) and 5.1% (n=5), respectively. And the incidence of serious AEs was 16.7% (n=8) and 11.2% (n=11), respectively.

The incidence of fatal AEs was 4.2% (n=2) and 1% (n=1), respectively, but none of these were treatment-related. The deaths in the placebo arm were due to cardiac failure and cerebral hemorrhage, while the death in the darbepoetin alfa arm was due to hemorrhagic proctitis.

One patient in the darbepoetin alfa arm experienced a treatment-related serious AE.

AEs occurring at least 5% more frequently in the darbepoetin alfa arm than the placebo arm were fatigue (17.3% and 8.3%), pyrexia (9.2% and 2.1%), headache (7.1% and 2.1%), and myalgia (5.1% and 0%).

During the 48-week double-blind period, 7.9% (n=3) of patients formerly in the placebo arm and 3.4% (n=3) of patients formerly in the darbepoetin alfa arm had AEs that led to treatment discontinuation.

The incidence of grade 3 or higher AEs was 23.7% (n=9) and 31.0% (n=27), respectively. The incidence of grade 4 or higher AEs was 10.5% (n=4) and 10.3% (n=9), respectively. And the incidence of serious AEs was 18.4% (n=7) and 25.3% (n=22), respectively.

The incidence of fatal AEs was 2.6% (n=1) and 1.1% (n=1), respectively, but none of these were treatment-related. Two patients experienced a treatment-related serious AE—1 from each of the former treatment arms.

Uwe Platzbecker, MD

COPENHAGEN—The erythropoiesis-stimulating agent (ESA) darbepoetin alfa can provide a clinical benefit in patients with lower-risk myelodysplastic syndromes (MDS), a phase 3 trial suggests.

In the ARCADE trial, darbepoetin alfa significantly reduced the incidence of red blood cell (RBC) transfusions in patients with low- and intermediate-1 risk myelodysplastic syndrome (MDS), when compared to placebo.

The ESA also significantly improved erythroid response.

In addition, researchers said adverse events (AEs) were generally balanced between the darbepoetin alfa and placebo arms.

Uwe Platzbecker, MD, of University Hospital Carl Gustav Carus Dresden in Germany, presented these results at the 21st Congress of the European Hematology Association (abstract S128). The ARCADE trial was sponsored by Amgen.

Dr Platzbecker noted that, although ESAs are recommended in clinical guidelines to treat anemia in patients with lower-risk MDS, the drugs are not widely approved for this indication.

So, in the ARCADE trial, he and his colleagues assessed darbepoetin alfa in patients with low- or intermediate-1 risk MDS who had not previously taken ESAs or biologic response modifiers.

The patients had hemoglobin levels ≤10 g/dL, endogenous erythropoietin levels ≤500 mU/mL, and low transfusion burden (<4 RBC units in each of 2 consecutive 8-week periods prior to randomization).

During a 24-week period, 147 patients received either darbepoetin alfa at 500 μg (n=97) or placebo (n=49) every 3 weeks. The ESA dose was withheld if patients’ hemoglobin was >12.0 g/dL and decreased if hemoglobin increased by >1.5 g/dL in 3 weeks without transfusion.

At week 25, when the primary and key secondary endpoints were assessed, patients underwent an end-of-treatment period visit. They could then enter a 48-week active treatment period and cross over to receive darbepoetin alfa, with dose escalation allowed beginning on week 31. Treatment continued until week 72 or 73, and patients continue to be assessed every 26 weeks, for a minimum of 3 years.

Patient characteristics

Dr Platzbecker said baseline demographic and disease characteristics were generally similar between the treatment arms. All patients were Caucasian, and about 55% were male. The median age was 74 (range, 67-79). About half of patients in each treatment arm belonged to the low-risk IPSS category.

In both arms, most patients had refractory cytopenia with multilineage dysplasia (38.8% in the placebo arm and 46.4% in the darbepoetin alfa arm). Patients also had refractory anemia with excess blasts-1 (20.4% and 13.4%, respectively), refractory anemia (26.5% and 9.3%), refractory anemia with ring sideroblasts (8.2% and 17.5%), 5q deletion (4.1% and 11.3%), unclassifiable MDS (2.0% and 1.0%), and MDS of an unknown type (0% and 1.0%).

In the 16 weeks before randomization, 58.2% of all patients—53.1% in the placebo arm and 60.8% in the darbepoetin alfa arm—did not have any RBC transfusions. About 25% (24.7%)—22.4% in the placebo arm and 25.8% in the darbepoetin alfa arm—received 1 to 3 RBC units. And 17.1%—24.5% in the placebo arm and 13.4% in the darbepoetin alfa arm—received 4 or more RBC units.

Dosing

During the 24-week double-blind period of the study, 77% (37/48) of patients in the placebo arm and 79% (77/98) in the darbepoetin alfa arm received all 8 doses of treatment.

Sixteen percent (n=16) of patients in the darbepoetin alfa arm had a single dose reduction, and 2% (n=2) had 2 dose reductions. None of the patients in the placebo arm had a dose reduction.

Eleven percent of patients in the darbepoetin alfa arm had doses withheld due to increased hemoglobin. The dose was withheld once for 6 patients, twice for 4 patients, and 3 times for 1 patient. None of the placebo-treated patients had a dose withheld for this reason.

Ten percent (n=5) of placebo-treated patients and 2% (n=2) of darbepoetin alfa-treated patients had a dose withheld due to an AE. Two percent (n=1) and 3% (n=3) of patients, respectively, had a dose withheld for “other” reasons (noncompliance, investigator decision, and no investigational product on site).

During the 48-week open-label period of the study, 81% (102/126) of patients who received darbepoetin alfa increased their dose frequency from every 3 weeks to every 2 weeks. Dr Platzbecker said this suggests the optimal dose of the drug was not achieved during the 24-week double-blind period of the study.

Efficacy

During the 24-week double-blind period, there was a significant difference between the treatment arms with regard to RBC transfusions. The transfusion incidence was 59.2% (29/49) in the placebo arm and 36.1% (35/97) in the darbepoetin alfa arm (P=0.008).

During the 48-week open-label period, the incidence of RBC transfusion was 50.8% (64/126) among patients receiving darbepoetin alfa.

During the 24-week double-blind period, 11 patients (14.7%) in the darbepoetin alfa arm had an erythroid hematologic improvement (HI-E), but none of the patients in the placebo arm had such an improvement.

All 11 patients with HI-E had a baseline serum erythropoietin level less than 100 mU/mL, 1 of the patients had 2 RBC units transfused in the 16 weeks prior to randomization, but none had transfusions in the 8 weeks prior to randomization. Four of the patients had a dose withheld due to having hemoglobin levels greater than 12 g/dL.

During the 48-week open-label period, the HI-E rate was 34.7% (34/98) among patients receiving darbepoetin alfa.

Dr Platzbecker said the nature of the HI-E criteria likely underestimated the clinical benefit of darbepoetin alfa in this trial, and this was further complicated by the trial design. Specifically, hemoglobin was measured every 3 weeks, some patients may have had their doses reduced even if they were still anemic, and the optimal dose of darbepoetin alfa was likely not given during the double-blind period (as evidenced by the increase in doses during the open-label period).

For these reasons, Dr Platzbecker and his colleagues are exploring alternative response analyses to determine if there were additional patients who received a clinical benefit from darbepoetin alfa but did not meet HI-E criteria.

Safety

During the 24-week double-blind period, 4.2% (n=2) of patients in the placebo arm and 3.1% (n=3) in the darbepoetin alfa arm had AEs that led to treatment discontinuation. In the placebo arm, these events were pulmonary hypertension and renal failure. In the darbepoetin alfa arm, the events were pulmonary thrombosis, thrombocytopenia, and increased blast cell count.

The incidence of grade 3 or higher AEs was 27.1% (n=13) in the placebo arm and 15.3% (n=15) in the darbepoetin alfa arm. The incidence of grade 4 or higher AEs was 12.5% (n=6) and 5.1% (n=5), respectively. And the incidence of serious AEs was 16.7% (n=8) and 11.2% (n=11), respectively.

The incidence of fatal AEs was 4.2% (n=2) and 1% (n=1), respectively, but none of these were treatment-related. The deaths in the placebo arm were due to cardiac failure and cerebral hemorrhage, while the death in the darbepoetin alfa arm was due to hemorrhagic proctitis.

One patient in the darbepoetin alfa arm experienced a treatment-related serious AE.

AEs occurring at least 5% more frequently in the darbepoetin alfa arm than the placebo arm were fatigue (17.3% and 8.3%), pyrexia (9.2% and 2.1%), headache (7.1% and 2.1%), and myalgia (5.1% and 0%).

During the 48-week double-blind period, 7.9% (n=3) of patients formerly in the placebo arm and 3.4% (n=3) of patients formerly in the darbepoetin alfa arm had AEs that led to treatment discontinuation.

The incidence of grade 3 or higher AEs was 23.7% (n=9) and 31.0% (n=27), respectively. The incidence of grade 4 or higher AEs was 10.5% (n=4) and 10.3% (n=9), respectively. And the incidence of serious AEs was 18.4% (n=7) and 25.3% (n=22), respectively.

The incidence of fatal AEs was 2.6% (n=1) and 1.1% (n=1), respectively, but none of these were treatment-related. Two patients experienced a treatment-related serious AE—1 from each of the former treatment arms.

Uwe Platzbecker, MD

COPENHAGEN—The erythropoiesis-stimulating agent (ESA) darbepoetin alfa can provide a clinical benefit in patients with lower-risk myelodysplastic syndromes (MDS), a phase 3 trial suggests.

In the ARCADE trial, darbepoetin alfa significantly reduced the incidence of red blood cell (RBC) transfusions in patients with low- and intermediate-1 risk myelodysplastic syndrome (MDS), when compared to placebo.

The ESA also significantly improved erythroid response.

In addition, researchers said adverse events (AEs) were generally balanced between the darbepoetin alfa and placebo arms.

Uwe Platzbecker, MD, of University Hospital Carl Gustav Carus Dresden in Germany, presented these results at the 21st Congress of the European Hematology Association (abstract S128). The ARCADE trial was sponsored by Amgen.

Dr Platzbecker noted that, although ESAs are recommended in clinical guidelines to treat anemia in patients with lower-risk MDS, the drugs are not widely approved for this indication.

So, in the ARCADE trial, he and his colleagues assessed darbepoetin alfa in patients with low- or intermediate-1 risk MDS who had not previously taken ESAs or biologic response modifiers.

The patients had hemoglobin levels ≤10 g/dL, endogenous erythropoietin levels ≤500 mU/mL, and low transfusion burden (<4 RBC units in each of 2 consecutive 8-week periods prior to randomization).

During a 24-week period, 147 patients received either darbepoetin alfa at 500 μg (n=97) or placebo (n=49) every 3 weeks. The ESA dose was withheld if patients’ hemoglobin was >12.0 g/dL and decreased if hemoglobin increased by >1.5 g/dL in 3 weeks without transfusion.

At week 25, when the primary and key secondary endpoints were assessed, patients underwent an end-of-treatment period visit. They could then enter a 48-week active treatment period and cross over to receive darbepoetin alfa, with dose escalation allowed beginning on week 31. Treatment continued until week 72 or 73, and patients continue to be assessed every 26 weeks, for a minimum of 3 years.

Patient characteristics

Dr Platzbecker said baseline demographic and disease characteristics were generally similar between the treatment arms. All patients were Caucasian, and about 55% were male. The median age was 74 (range, 67-79). About half of patients in each treatment arm belonged to the low-risk IPSS category.

In both arms, most patients had refractory cytopenia with multilineage dysplasia (38.8% in the placebo arm and 46.4% in the darbepoetin alfa arm). Patients also had refractory anemia with excess blasts-1 (20.4% and 13.4%, respectively), refractory anemia (26.5% and 9.3%), refractory anemia with ring sideroblasts (8.2% and 17.5%), 5q deletion (4.1% and 11.3%), unclassifiable MDS (2.0% and 1.0%), and MDS of an unknown type (0% and 1.0%).

In the 16 weeks before randomization, 58.2% of all patients—53.1% in the placebo arm and 60.8% in the darbepoetin alfa arm—did not have any RBC transfusions. About 25% (24.7%)—22.4% in the placebo arm and 25.8% in the darbepoetin alfa arm—received 1 to 3 RBC units. And 17.1%—24.5% in the placebo arm and 13.4% in the darbepoetin alfa arm—received 4 or more RBC units.

Dosing

During the 24-week double-blind period of the study, 77% (37/48) of patients in the placebo arm and 79% (77/98) in the darbepoetin alfa arm received all 8 doses of treatment.

Sixteen percent (n=16) of patients in the darbepoetin alfa arm had a single dose reduction, and 2% (n=2) had 2 dose reductions. None of the patients in the placebo arm had a dose reduction.

Eleven percent of patients in the darbepoetin alfa arm had doses withheld due to increased hemoglobin. The dose was withheld once for 6 patients, twice for 4 patients, and 3 times for 1 patient. None of the placebo-treated patients had a dose withheld for this reason.

Ten percent (n=5) of placebo-treated patients and 2% (n=2) of darbepoetin alfa-treated patients had a dose withheld due to an AE. Two percent (n=1) and 3% (n=3) of patients, respectively, had a dose withheld for “other” reasons (noncompliance, investigator decision, and no investigational product on site).

During the 48-week open-label period of the study, 81% (102/126) of patients who received darbepoetin alfa increased their dose frequency from every 3 weeks to every 2 weeks. Dr Platzbecker said this suggests the optimal dose of the drug was not achieved during the 24-week double-blind period of the study.

Efficacy

During the 24-week double-blind period, there was a significant difference between the treatment arms with regard to RBC transfusions. The transfusion incidence was 59.2% (29/49) in the placebo arm and 36.1% (35/97) in the darbepoetin alfa arm (P=0.008).

During the 48-week open-label period, the incidence of RBC transfusion was 50.8% (64/126) among patients receiving darbepoetin alfa.

During the 24-week double-blind period, 11 patients (14.7%) in the darbepoetin alfa arm had an erythroid hematologic improvement (HI-E), but none of the patients in the placebo arm had such an improvement.

All 11 patients with HI-E had a baseline serum erythropoietin level less than 100 mU/mL, 1 of the patients had 2 RBC units transfused in the 16 weeks prior to randomization, but none had transfusions in the 8 weeks prior to randomization. Four of the patients had a dose withheld due to having hemoglobin levels greater than 12 g/dL.

During the 48-week open-label period, the HI-E rate was 34.7% (34/98) among patients receiving darbepoetin alfa.

Dr Platzbecker said the nature of the HI-E criteria likely underestimated the clinical benefit of darbepoetin alfa in this trial, and this was further complicated by the trial design. Specifically, hemoglobin was measured every 3 weeks, some patients may have had their doses reduced even if they were still anemic, and the optimal dose of darbepoetin alfa was likely not given during the double-blind period (as evidenced by the increase in doses during the open-label period).

For these reasons, Dr Platzbecker and his colleagues are exploring alternative response analyses to determine if there were additional patients who received a clinical benefit from darbepoetin alfa but did not meet HI-E criteria.

Safety

During the 24-week double-blind period, 4.2% (n=2) of patients in the placebo arm and 3.1% (n=3) in the darbepoetin alfa arm had AEs that led to treatment discontinuation. In the placebo arm, these events were pulmonary hypertension and renal failure. In the darbepoetin alfa arm, the events were pulmonary thrombosis, thrombocytopenia, and increased blast cell count.

The incidence of grade 3 or higher AEs was 27.1% (n=13) in the placebo arm and 15.3% (n=15) in the darbepoetin alfa arm. The incidence of grade 4 or higher AEs was 12.5% (n=6) and 5.1% (n=5), respectively. And the incidence of serious AEs was 16.7% (n=8) and 11.2% (n=11), respectively.

The incidence of fatal AEs was 4.2% (n=2) and 1% (n=1), respectively, but none of these were treatment-related. The deaths in the placebo arm were due to cardiac failure and cerebral hemorrhage, while the death in the darbepoetin alfa arm was due to hemorrhagic proctitis.

One patient in the darbepoetin alfa arm experienced a treatment-related serious AE.

AEs occurring at least 5% more frequently in the darbepoetin alfa arm than the placebo arm were fatigue (17.3% and 8.3%), pyrexia (9.2% and 2.1%), headache (7.1% and 2.1%), and myalgia (5.1% and 0%).

During the 48-week double-blind period, 7.9% (n=3) of patients formerly in the placebo arm and 3.4% (n=3) of patients formerly in the darbepoetin alfa arm had AEs that led to treatment discontinuation.

The incidence of grade 3 or higher AEs was 23.7% (n=9) and 31.0% (n=27), respectively. The incidence of grade 4 or higher AEs was 10.5% (n=4) and 10.3% (n=9), respectively. And the incidence of serious AEs was 18.4% (n=7) and 25.3% (n=22), respectively.

The incidence of fatal AEs was 2.6% (n=1) and 1.1% (n=1), respectively, but none of these were treatment-related. Two patients experienced a treatment-related serious AE—1 from each of the former treatment arms.