P falciparum gametocytes

Credit: Swiss TPH

Malaria parasites exploit the epigenetic regulator HP1 to promote their survival and transmission between human hosts, a new study suggests.

It appears that Plasmodium falciparum uses HP1 to control the expression of surface antigens and escape the body’s immune responses. This prolongs the parasite’s survival and enables its transmission.

Researchers believe this discovery paves the way for new strategies to prevent malaria transmission.

Till Voss, PhD, of the Swiss Tropical and Public Health Institute in Basel, and his colleagues detailed the discovery in Cell Host & Microbe.

The team knew that HP1 induces heritable condensation of chromosomal regions. As a result, genes located within these regions are not expressed.

Since this conformation is reversible, HP1-controlled genes can become activated without requiring changes in the underlying DNA sequence.

With this in mind, the researchers engineered a mutant P falciparum parasite in which HP1 expression can be shut down. And the team observed that, in HP1-depleted parasites, all of the 60 var genes became highly active.

Each var gene encodes a distinct variant of the virulence factor PfEMP1, which is displayed on the surface of the parasite-infected red blood cell. PfEMP1 is a major target of the immune system in infected humans.

Individual parasites normally express only 1 of the 60 var/PfEMP1 proteins, while keeping all other members silenced. By switching to another var/PfEMP1 variant, the parasite is able to escape existing immune responses raised against previous variants.

Dr Voss and his colleagues found that HP1 protects the PfEMP1 antigenic repertoire from being exposed to the immune system all at once.

“This finding is a major step forward in understanding the complex mechanisms responsible for antigenic variation,” Dr Voss said. “Furthermore, the tools generated in our study may be relevant for future research on malaria vaccines and immunity.”

The researchers also found that parasites lacking HP1 fail to copy their genomes and are therefore unable to proliferate. Initially, this led the team to believe that all the parasites they had cultured were dead.

However, more than 50% of these parasites turned out to be fully viable and differentiated into gametocytes, the sexual form of the malaria parasite. Gametocytes are the only form of the parasite capable of infecting a mosquito and are a prerequisite to transmit malaria between humans.

“Such a high sexual conversion rate is unprecedented,” Dr Voss said. “Usually, only around 1% of parasites undergo this switch.”

Further experiments revealed that a master transcription factor triggering sexual differentiation—AP2-G—is expressed at much higher levels in parasites lacking HP1. Under normal conditions, HP1 silences the expression of AP2-G and therefore prevents sexual conversion in most parasites.

“The switch from parasite proliferation to gametocyte differentiation is controlled epigenetically by an HP1-dependent mechanism,” Dr Voss said.

“With this knowledge in hand, and with the identification of another epigenetic regulator involved in the same process [also published in Cell Host & Microbe], we are now able to specifically track the sexual conversion pathway in molecular detail.”

This may enable the development of new drugs to prevent sexual conversion and, consequently, malaria transmission.

P falciparum gametocytes

Credit: Swiss TPH

Malaria parasites exploit the epigenetic regulator HP1 to promote their survival and transmission between human hosts, a new study suggests.

It appears that Plasmodium falciparum uses HP1 to control the expression of surface antigens and escape the body’s immune responses. This prolongs the parasite’s survival and enables its transmission.

Researchers believe this discovery paves the way for new strategies to prevent malaria transmission.

Till Voss, PhD, of the Swiss Tropical and Public Health Institute in Basel, and his colleagues detailed the discovery in Cell Host & Microbe.

The team knew that HP1 induces heritable condensation of chromosomal regions. As a result, genes located within these regions are not expressed.

Since this conformation is reversible, HP1-controlled genes can become activated without requiring changes in the underlying DNA sequence.

With this in mind, the researchers engineered a mutant P falciparum parasite in which HP1 expression can be shut down. And the team observed that, in HP1-depleted parasites, all of the 60 var genes became highly active.

Each var gene encodes a distinct variant of the virulence factor PfEMP1, which is displayed on the surface of the parasite-infected red blood cell. PfEMP1 is a major target of the immune system in infected humans.

Individual parasites normally express only 1 of the 60 var/PfEMP1 proteins, while keeping all other members silenced. By switching to another var/PfEMP1 variant, the parasite is able to escape existing immune responses raised against previous variants.

Dr Voss and his colleagues found that HP1 protects the PfEMP1 antigenic repertoire from being exposed to the immune system all at once.

“This finding is a major step forward in understanding the complex mechanisms responsible for antigenic variation,” Dr Voss said. “Furthermore, the tools generated in our study may be relevant for future research on malaria vaccines and immunity.”

The researchers also found that parasites lacking HP1 fail to copy their genomes and are therefore unable to proliferate. Initially, this led the team to believe that all the parasites they had cultured were dead.

However, more than 50% of these parasites turned out to be fully viable and differentiated into gametocytes, the sexual form of the malaria parasite. Gametocytes are the only form of the parasite capable of infecting a mosquito and are a prerequisite to transmit malaria between humans.

“Such a high sexual conversion rate is unprecedented,” Dr Voss said. “Usually, only around 1% of parasites undergo this switch.”

Further experiments revealed that a master transcription factor triggering sexual differentiation—AP2-G—is expressed at much higher levels in parasites lacking HP1. Under normal conditions, HP1 silences the expression of AP2-G and therefore prevents sexual conversion in most parasites.

“The switch from parasite proliferation to gametocyte differentiation is controlled epigenetically by an HP1-dependent mechanism,” Dr Voss said.

“With this knowledge in hand, and with the identification of another epigenetic regulator involved in the same process [also published in Cell Host & Microbe], we are now able to specifically track the sexual conversion pathway in molecular detail.”

This may enable the development of new drugs to prevent sexual conversion and, consequently, malaria transmission.

P falciparum gametocytes

Credit: Swiss TPH

Malaria parasites exploit the epigenetic regulator HP1 to promote their survival and transmission between human hosts, a new study suggests.

It appears that Plasmodium falciparum uses HP1 to control the expression of surface antigens and escape the body’s immune responses. This prolongs the parasite’s survival and enables its transmission.

Researchers believe this discovery paves the way for new strategies to prevent malaria transmission.

Till Voss, PhD, of the Swiss Tropical and Public Health Institute in Basel, and his colleagues detailed the discovery in Cell Host & Microbe.

The team knew that HP1 induces heritable condensation of chromosomal regions. As a result, genes located within these regions are not expressed.

Since this conformation is reversible, HP1-controlled genes can become activated without requiring changes in the underlying DNA sequence.

With this in mind, the researchers engineered a mutant P falciparum parasite in which HP1 expression can be shut down. And the team observed that, in HP1-depleted parasites, all of the 60 var genes became highly active.

Each var gene encodes a distinct variant of the virulence factor PfEMP1, which is displayed on the surface of the parasite-infected red blood cell. PfEMP1 is a major target of the immune system in infected humans.

Individual parasites normally express only 1 of the 60 var/PfEMP1 proteins, while keeping all other members silenced. By switching to another var/PfEMP1 variant, the parasite is able to escape existing immune responses raised against previous variants.

Dr Voss and his colleagues found that HP1 protects the PfEMP1 antigenic repertoire from being exposed to the immune system all at once.

“This finding is a major step forward in understanding the complex mechanisms responsible for antigenic variation,” Dr Voss said. “Furthermore, the tools generated in our study may be relevant for future research on malaria vaccines and immunity.”

The researchers also found that parasites lacking HP1 fail to copy their genomes and are therefore unable to proliferate. Initially, this led the team to believe that all the parasites they had cultured were dead.

However, more than 50% of these parasites turned out to be fully viable and differentiated into gametocytes, the sexual form of the malaria parasite. Gametocytes are the only form of the parasite capable of infecting a mosquito and are a prerequisite to transmit malaria between humans.

“Such a high sexual conversion rate is unprecedented,” Dr Voss said. “Usually, only around 1% of parasites undergo this switch.”

Further experiments revealed that a master transcription factor triggering sexual differentiation—AP2-G—is expressed at much higher levels in parasites lacking HP1. Under normal conditions, HP1 silences the expression of AP2-G and therefore prevents sexual conversion in most parasites.

“The switch from parasite proliferation to gametocyte differentiation is controlled epigenetically by an HP1-dependent mechanism,” Dr Voss said.

“With this knowledge in hand, and with the identification of another epigenetic regulator involved in the same process [also published in Cell Host & Microbe], we are now able to specifically track the sexual conversion pathway in molecular detail.”

This may enable the development of new drugs to prevent sexual conversion and, consequently, malaria transmission.

Nick Huntington, PhD

Credit: Walter and Eliza Hall

Institute of Medical Research

New research suggests the Mcl-1 protein is crucial for the survival of natural killer (NK) cells and, therefore, innate immune responses.

Researchers deleted Mcl-1 from NK cells in mice and observed a loss of the cells from all tissues.

This made the mice more receptive to allogeneic hematopoietic stem cell transplants and resistant to toxic shock following a sepsis challenge, but it also made the mice susceptible to melanoma metastases.

The researchers believe their findings, published in Nature Communications, will help to determine how NK cells can be manipulated to treat a range of disorders.

They said Mcl-1 could be a target for boosting or depleting NK cell populations when necessary.

The researchers first discovered that Mcl-1 is highly expressed in NK cells. And Mcl-1 is regulated by IL-15 in a dose-dependent manner via STAT5 phosphorylation and subsequent binding to the 3′-UTR of Mcl-1.

“We showed Mcl-1 levels inside the cell increase in response to [IL-15],” said study author Nick Huntington, PhD, of the Walter and Eliza Hall Institute of Medical Research in Victoria, Australia.

“We previously knew IL-15 boosted production and survival of natural killer cells, and we have shown that IL-15 does this by initiating a cascade of signals that tell the natural killer cell to produce Mcl-1 to keep it alive.”

To further explore this phenomenon, the researchers deleted Mcl-1 from NK cells in mice and observed depletion of the cells in all tissues. The team said this was the result of a failure to antagonize pro-apoptotic proteins in the outer mitochondrial membrane.

Additional experiments showed that the mice needed the NK cells to fight off invading melanoma cells that had spread past the original cancer site.

“Without natural killer cells, the body was unable to destroy melanoma metastases that had spread throughout the body, and the cancers overwhelmed the lungs,” Dr Huntington said.

However, the loss of NK cells also made mice more receptive to allogeneic stem cell transplants and resistant to toxic shock after polymicrobial sepsis challenge.

“Natural killer cells led the response that caused rejection of donor stem cells in bone marrow transplantations,” Dr Huntington said. “They also produced inflammatory signals that can result in toxic shock syndrome, a potentially fatal illness caused by bacterial toxins that causes a whole-body inflammatory reaction.”

The researchers said these results clearly show a non-redundant pathway linking IL-15 to Mcl-1 in the maintenance of NK cells and innate immune responses.

Dr Huntington said the discovery provides a solid lead to look for ways of boosting or depleting NK cells when necessary.

“Now that we know the critical importance of Mcl-1 in the survival of natural killer cells,” he said, “we are investigating how we might manipulate this protein, or other proteins in the pathway, to treat disease.”

Nick Huntington, PhD

Credit: Walter and Eliza Hall

Institute of Medical Research

New research suggests the Mcl-1 protein is crucial for the survival of natural killer (NK) cells and, therefore, innate immune responses.

Researchers deleted Mcl-1 from NK cells in mice and observed a loss of the cells from all tissues.

This made the mice more receptive to allogeneic hematopoietic stem cell transplants and resistant to toxic shock following a sepsis challenge, but it also made the mice susceptible to melanoma metastases.

The researchers believe their findings, published in Nature Communications, will help to determine how NK cells can be manipulated to treat a range of disorders.

They said Mcl-1 could be a target for boosting or depleting NK cell populations when necessary.

The researchers first discovered that Mcl-1 is highly expressed in NK cells. And Mcl-1 is regulated by IL-15 in a dose-dependent manner via STAT5 phosphorylation and subsequent binding to the 3′-UTR of Mcl-1.

“We showed Mcl-1 levels inside the cell increase in response to [IL-15],” said study author Nick Huntington, PhD, of the Walter and Eliza Hall Institute of Medical Research in Victoria, Australia.

“We previously knew IL-15 boosted production and survival of natural killer cells, and we have shown that IL-15 does this by initiating a cascade of signals that tell the natural killer cell to produce Mcl-1 to keep it alive.”

To further explore this phenomenon, the researchers deleted Mcl-1 from NK cells in mice and observed depletion of the cells in all tissues. The team said this was the result of a failure to antagonize pro-apoptotic proteins in the outer mitochondrial membrane.

Additional experiments showed that the mice needed the NK cells to fight off invading melanoma cells that had spread past the original cancer site.

“Without natural killer cells, the body was unable to destroy melanoma metastases that had spread throughout the body, and the cancers overwhelmed the lungs,” Dr Huntington said.

However, the loss of NK cells also made mice more receptive to allogeneic stem cell transplants and resistant to toxic shock after polymicrobial sepsis challenge.

“Natural killer cells led the response that caused rejection of donor stem cells in bone marrow transplantations,” Dr Huntington said. “They also produced inflammatory signals that can result in toxic shock syndrome, a potentially fatal illness caused by bacterial toxins that causes a whole-body inflammatory reaction.”

The researchers said these results clearly show a non-redundant pathway linking IL-15 to Mcl-1 in the maintenance of NK cells and innate immune responses.

Dr Huntington said the discovery provides a solid lead to look for ways of boosting or depleting NK cells when necessary.

“Now that we know the critical importance of Mcl-1 in the survival of natural killer cells,” he said, “we are investigating how we might manipulate this protein, or other proteins in the pathway, to treat disease.”

Nick Huntington, PhD

Credit: Walter and Eliza Hall

Institute of Medical Research

New research suggests the Mcl-1 protein is crucial for the survival of natural killer (NK) cells and, therefore, innate immune responses.

Researchers deleted Mcl-1 from NK cells in mice and observed a loss of the cells from all tissues.

This made the mice more receptive to allogeneic hematopoietic stem cell transplants and resistant to toxic shock following a sepsis challenge, but it also made the mice susceptible to melanoma metastases.

The researchers believe their findings, published in Nature Communications, will help to determine how NK cells can be manipulated to treat a range of disorders.

They said Mcl-1 could be a target for boosting or depleting NK cell populations when necessary.

The researchers first discovered that Mcl-1 is highly expressed in NK cells. And Mcl-1 is regulated by IL-15 in a dose-dependent manner via STAT5 phosphorylation and subsequent binding to the 3′-UTR of Mcl-1.

“We showed Mcl-1 levels inside the cell increase in response to [IL-15],” said study author Nick Huntington, PhD, of the Walter and Eliza Hall Institute of Medical Research in Victoria, Australia.

“We previously knew IL-15 boosted production and survival of natural killer cells, and we have shown that IL-15 does this by initiating a cascade of signals that tell the natural killer cell to produce Mcl-1 to keep it alive.”

To further explore this phenomenon, the researchers deleted Mcl-1 from NK cells in mice and observed depletion of the cells in all tissues. The team said this was the result of a failure to antagonize pro-apoptotic proteins in the outer mitochondrial membrane.

Additional experiments showed that the mice needed the NK cells to fight off invading melanoma cells that had spread past the original cancer site.

“Without natural killer cells, the body was unable to destroy melanoma metastases that had spread throughout the body, and the cancers overwhelmed the lungs,” Dr Huntington said.

However, the loss of NK cells also made mice more receptive to allogeneic stem cell transplants and resistant to toxic shock after polymicrobial sepsis challenge.

“Natural killer cells led the response that caused rejection of donor stem cells in bone marrow transplantations,” Dr Huntington said. “They also produced inflammatory signals that can result in toxic shock syndrome, a potentially fatal illness caused by bacterial toxins that causes a whole-body inflammatory reaction.”

The researchers said these results clearly show a non-redundant pathway linking IL-15 to Mcl-1 in the maintenance of NK cells and innate immune responses.

Dr Huntington said the discovery provides a solid lead to look for ways of boosting or depleting NK cells when necessary.

“Now that we know the critical importance of Mcl-1 in the survival of natural killer cells,” he said, “we are investigating how we might manipulate this protein, or other proteins in the pathway, to treat disease.”

Last year, when the Physician Payment Sunshine Act became law, I recommended that all physicians involved in any sort of financial relationship with the pharmaceutical industry review the data reported about them prior to public posting of the information. Since that posting is due to occur at the end of this month, a reminder is in order.

Under a new bureaucracy created by the Affordable Care Act – formally called the Open Payments program – all manufacturers of drugs, devices, and medical supplies covered by federal health care programs must report any financial interactions with physicians and teaching hospitals to the Centers for Medicare & Medicaid Services (CMS).

Reportable interactions include consulting; food; ownership or investment interest; direct compensation for speakers at education programs; and research. Compensation for conducting clinical trials must be reported, but will not be posted on the website until the product receives approval from the Food and Drug Administration or until 4 years after the payment, whichever is earlier. Payments for trials involving a new indication for an approved drug will be posted immediately.

There are a number of specific exclusions, such as certified and accredited continuing medical education activities funded by manufacturers, and product samples for patient use. Medical students and residents are excluded entirely.

Under the law, you are allowed to review your data and seek corrections before it is published. Publication is scheduled to occur on Sept. 30, so if you have not yet done this, there is no time to waste. Although you will have an additional 2 years to pursue corrections after the online content goes live, any erroneous information will remain on the site until corrections can be made, so the best time to find and fix errors is now.

If you don’t see drug reps, accept sponsored lunches, or give sponsored talks, don’t assume that you won’t be on the website. Check anyway; you might be indirectly involved in a compensation situation that you were not aware of, or you may have been reported in error.

To review your data, register at the CMS Enterprise Portal, and request access to the Open Payments system.

Once you are satisfied that your interactions have been reported accurately, the question of what effect the law will have on research, continuing education, and private practice remains. The short answer is that no one knows. Much will depend on how the public interprets the data – if they take notice at all.

Sunshine laws have been in effect for several years in six states: California, Colorado, Massachusetts, Minnesota, Vermont, and West Virginia; plus the District of Columbia. (Maine repealed its law in 2011.) Observers disagree on their impact. Studies in Maine and West Virginia showed no significant public reaction or changes in prescribing patterns, according to a 2012 article in Archives of Internal Medicine (Arch. Intern. Med. 2012;172:819-21).

Potential effects on physician-patient interactions are equally unclear. Do patients think less of doctors who accept the occasional industry-sponsored lunch for their employees? Do they think more of doctors who speak at meetings or conduct industry-sponsored clinical research? There are no objective data, as far as I know.

My guess is that attorneys, activists, and the occasional reporter will data-mine the website on a regular basis, and perhaps use their findings as ammunition in any agenda that they might be pushing, but few patients will ever bother to visit. Nevertheless, you should review each year’s reportage to ensure the accuracy of anything posted about you.

The data must be reported to CMS by March 31 each year, so you will need to set aside time each April or May to review it. If you have many or complex industry relationships, you should probably contact each company in January or February and ask to see the data before it is submitted. Then, review it again once CMS gets it, to be sure nothing was changed. A free app is available to help physicians track payments and other reportable industry interactions; search for "Open Payments" at your favorite app store.

Maintaining accurate financial records has always been important, but it will be even more so now, to effectively dispute any inconsistencies. While the extra work may turn out to have been unnecessary, it is still a prudent precaution, given the possible consequences of any increased government or public scrutiny that may (or may not) result.

Dr. Eastern practices dermatology and dermatologic surgery in Belleville, N.J. He is the author of numerous articles and textbook chapters, and is a long-time monthly columnist for Skin & Allergy News.

Last year, when the Physician Payment Sunshine Act became law, I recommended that all physicians involved in any sort of financial relationship with the pharmaceutical industry review the data reported about them prior to public posting of the information. Since that posting is due to occur at the end of this month, a reminder is in order.

Under a new bureaucracy created by the Affordable Care Act – formally called the Open Payments program – all manufacturers of drugs, devices, and medical supplies covered by federal health care programs must report any financial interactions with physicians and teaching hospitals to the Centers for Medicare & Medicaid Services (CMS).

Reportable interactions include consulting; food; ownership or investment interest; direct compensation for speakers at education programs; and research. Compensation for conducting clinical trials must be reported, but will not be posted on the website until the product receives approval from the Food and Drug Administration or until 4 years after the payment, whichever is earlier. Payments for trials involving a new indication for an approved drug will be posted immediately.

There are a number of specific exclusions, such as certified and accredited continuing medical education activities funded by manufacturers, and product samples for patient use. Medical students and residents are excluded entirely.

Under the law, you are allowed to review your data and seek corrections before it is published. Publication is scheduled to occur on Sept. 30, so if you have not yet done this, there is no time to waste. Although you will have an additional 2 years to pursue corrections after the online content goes live, any erroneous information will remain on the site until corrections can be made, so the best time to find and fix errors is now.

If you don’t see drug reps, accept sponsored lunches, or give sponsored talks, don’t assume that you won’t be on the website. Check anyway; you might be indirectly involved in a compensation situation that you were not aware of, or you may have been reported in error.

To review your data, register at the CMS Enterprise Portal, and request access to the Open Payments system.

Once you are satisfied that your interactions have been reported accurately, the question of what effect the law will have on research, continuing education, and private practice remains. The short answer is that no one knows. Much will depend on how the public interprets the data – if they take notice at all.

Sunshine laws have been in effect for several years in six states: California, Colorado, Massachusetts, Minnesota, Vermont, and West Virginia; plus the District of Columbia. (Maine repealed its law in 2011.) Observers disagree on their impact. Studies in Maine and West Virginia showed no significant public reaction or changes in prescribing patterns, according to a 2012 article in Archives of Internal Medicine (Arch. Intern. Med. 2012;172:819-21).

Potential effects on physician-patient interactions are equally unclear. Do patients think less of doctors who accept the occasional industry-sponsored lunch for their employees? Do they think more of doctors who speak at meetings or conduct industry-sponsored clinical research? There are no objective data, as far as I know.

My guess is that attorneys, activists, and the occasional reporter will data-mine the website on a regular basis, and perhaps use their findings as ammunition in any agenda that they might be pushing, but few patients will ever bother to visit. Nevertheless, you should review each year’s reportage to ensure the accuracy of anything posted about you.

The data must be reported to CMS by March 31 each year, so you will need to set aside time each April or May to review it. If you have many or complex industry relationships, you should probably contact each company in January or February and ask to see the data before it is submitted. Then, review it again once CMS gets it, to be sure nothing was changed. A free app is available to help physicians track payments and other reportable industry interactions; search for "Open Payments" at your favorite app store.

Maintaining accurate financial records has always been important, but it will be even more so now, to effectively dispute any inconsistencies. While the extra work may turn out to have been unnecessary, it is still a prudent precaution, given the possible consequences of any increased government or public scrutiny that may (or may not) result.

Dr. Eastern practices dermatology and dermatologic surgery in Belleville, N.J. He is the author of numerous articles and textbook chapters, and is a long-time monthly columnist for Skin & Allergy News.

Last year, when the Physician Payment Sunshine Act became law, I recommended that all physicians involved in any sort of financial relationship with the pharmaceutical industry review the data reported about them prior to public posting of the information. Since that posting is due to occur at the end of this month, a reminder is in order.

Under a new bureaucracy created by the Affordable Care Act – formally called the Open Payments program – all manufacturers of drugs, devices, and medical supplies covered by federal health care programs must report any financial interactions with physicians and teaching hospitals to the Centers for Medicare & Medicaid Services (CMS).

Reportable interactions include consulting; food; ownership or investment interest; direct compensation for speakers at education programs; and research. Compensation for conducting clinical trials must be reported, but will not be posted on the website until the product receives approval from the Food and Drug Administration or until 4 years after the payment, whichever is earlier. Payments for trials involving a new indication for an approved drug will be posted immediately.

There are a number of specific exclusions, such as certified and accredited continuing medical education activities funded by manufacturers, and product samples for patient use. Medical students and residents are excluded entirely.

Under the law, you are allowed to review your data and seek corrections before it is published. Publication is scheduled to occur on Sept. 30, so if you have not yet done this, there is no time to waste. Although you will have an additional 2 years to pursue corrections after the online content goes live, any erroneous information will remain on the site until corrections can be made, so the best time to find and fix errors is now.

If you don’t see drug reps, accept sponsored lunches, or give sponsored talks, don’t assume that you won’t be on the website. Check anyway; you might be indirectly involved in a compensation situation that you were not aware of, or you may have been reported in error.

To review your data, register at the CMS Enterprise Portal, and request access to the Open Payments system.

Once you are satisfied that your interactions have been reported accurately, the question of what effect the law will have on research, continuing education, and private practice remains. The short answer is that no one knows. Much will depend on how the public interprets the data – if they take notice at all.

Sunshine laws have been in effect for several years in six states: California, Colorado, Massachusetts, Minnesota, Vermont, and West Virginia; plus the District of Columbia. (Maine repealed its law in 2011.) Observers disagree on their impact. Studies in Maine and West Virginia showed no significant public reaction or changes in prescribing patterns, according to a 2012 article in Archives of Internal Medicine (Arch. Intern. Med. 2012;172:819-21).

Potential effects on physician-patient interactions are equally unclear. Do patients think less of doctors who accept the occasional industry-sponsored lunch for their employees? Do they think more of doctors who speak at meetings or conduct industry-sponsored clinical research? There are no objective data, as far as I know.

My guess is that attorneys, activists, and the occasional reporter will data-mine the website on a regular basis, and perhaps use their findings as ammunition in any agenda that they might be pushing, but few patients will ever bother to visit. Nevertheless, you should review each year’s reportage to ensure the accuracy of anything posted about you.

The data must be reported to CMS by March 31 each year, so you will need to set aside time each April or May to review it. If you have many or complex industry relationships, you should probably contact each company in January or February and ask to see the data before it is submitted. Then, review it again once CMS gets it, to be sure nothing was changed. A free app is available to help physicians track payments and other reportable industry interactions; search for "Open Payments" at your favorite app store.

Maintaining accurate financial records has always been important, but it will be even more so now, to effectively dispute any inconsistencies. While the extra work may turn out to have been unnecessary, it is still a prudent precaution, given the possible consequences of any increased government or public scrutiny that may (or may not) result.

Dr. Eastern practices dermatology and dermatologic surgery in Belleville, N.J. He is the author of numerous articles and textbook chapters, and is a long-time monthly columnist for Skin & Allergy News.

In my last column, I addressed the question of whether or not to outsource your practice’s social media efforts. While some medical practices do their own social media, others simply don’t have the time, resources, or desire to do it themselves. That’s where social media consultants come in. Hiring the right consultant offers numerous benefits such as devising a strategic plan that aligns with your practice’s unique goals, as well helping you develop and market your personal brand.

Last time, I offered guidelines to help you choose the right consultant for your practice. This time, I’ll offer some pitfalls to avoid when choosing a social media consultant or agency. If a consultant promises any of the following, be skeptical:

• Thousands of followers in just a few weeks! Authentic social media takes time because it’s about building relationships. There are digital programs that let you buy followers, but I don’t recommend them. It’s much better to have a smaller, genuine, truly engaged target audience than a huge, inauthentic one. Building a genuine target audience takes longer to cultivate, but it is far more effective in the long run.

• Your videos will go viral! We’ve all seen videos that have gone viral (many involve grumpy cats, which I don’t recommend using for your brand). Chances are if you’re making a 2-minute video on how to treat rosacea or ringworm, it won’t go viral. (Unless it involves a grumpy cat.) Instead, focus on realistic expectations. Your consultant should offer creative ways to market your brand, whether it’s video or text. But getting hung up on going viral is like waiting to win the lottery. It’s better to regularly create and share high-quality content that over time will garner an audience.

• You’ll double your patients in weeks! The number one way physicians acquire new patients is through word of mouth. Social media is word of mouth enhanced by technology, so it has the potential to grow your patient base. But it takes time. If acquiring new patients is one of your goals, then be certain that your consultant creates a realistic plan to achieve that goal.

• We’re your one-stop shop! Although I advocate using social media to market your practice, I believe it should be only one spoke in your marketing wheel. Traditional forms of marketing, such as newspaper and magazine advertisements, newsletters, and local radio and television appearances, still offer real benefits for many practices. If someone is trying to convince you to abandon all your other marketing efforts, be cautious.

• We’ve had 100% success with all of our clients! Would you believe your fellow doctor if he said he hadn’t had a patient complaint in 3 years? I didn’t think so. Don’t believe a consultant who tells you he’s never made mistakes or had an unhappy client. Ask what a consultant has learned from negative and positive experiences. What insight have they gleaned from that unsuccessful experience? How can these insights help when devising your strategy?

With these guidelines in place, you’re putting your practice and your reputation in safer hands.

Dr. Benabio is a partner physician in the department of dermatology of the Southern California Permanente Group in San Diego and a volunteer clinical assistant professor at the University of California, San Diego. Dr. Benabio is @dermdoc on Twitter.

In my last column, I addressed the question of whether or not to outsource your practice’s social media efforts. While some medical practices do their own social media, others simply don’t have the time, resources, or desire to do it themselves. That’s where social media consultants come in. Hiring the right consultant offers numerous benefits such as devising a strategic plan that aligns with your practice’s unique goals, as well helping you develop and market your personal brand.

Last time, I offered guidelines to help you choose the right consultant for your practice. This time, I’ll offer some pitfalls to avoid when choosing a social media consultant or agency. If a consultant promises any of the following, be skeptical:

• Thousands of followers in just a few weeks! Authentic social media takes time because it’s about building relationships. There are digital programs that let you buy followers, but I don’t recommend them. It’s much better to have a smaller, genuine, truly engaged target audience than a huge, inauthentic one. Building a genuine target audience takes longer to cultivate, but it is far more effective in the long run.

• Your videos will go viral! We’ve all seen videos that have gone viral (many involve grumpy cats, which I don’t recommend using for your brand). Chances are if you’re making a 2-minute video on how to treat rosacea or ringworm, it won’t go viral. (Unless it involves a grumpy cat.) Instead, focus on realistic expectations. Your consultant should offer creative ways to market your brand, whether it’s video or text. But getting hung up on going viral is like waiting to win the lottery. It’s better to regularly create and share high-quality content that over time will garner an audience.

• You’ll double your patients in weeks! The number one way physicians acquire new patients is through word of mouth. Social media is word of mouth enhanced by technology, so it has the potential to grow your patient base. But it takes time. If acquiring new patients is one of your goals, then be certain that your consultant creates a realistic plan to achieve that goal.

• We’re your one-stop shop! Although I advocate using social media to market your practice, I believe it should be only one spoke in your marketing wheel. Traditional forms of marketing, such as newspaper and magazine advertisements, newsletters, and local radio and television appearances, still offer real benefits for many practices. If someone is trying to convince you to abandon all your other marketing efforts, be cautious.

• We’ve had 100% success with all of our clients! Would you believe your fellow doctor if he said he hadn’t had a patient complaint in 3 years? I didn’t think so. Don’t believe a consultant who tells you he’s never made mistakes or had an unhappy client. Ask what a consultant has learned from negative and positive experiences. What insight have they gleaned from that unsuccessful experience? How can these insights help when devising your strategy?

With these guidelines in place, you’re putting your practice and your reputation in safer hands.

Dr. Benabio is a partner physician in the department of dermatology of the Southern California Permanente Group in San Diego and a volunteer clinical assistant professor at the University of California, San Diego. Dr. Benabio is @dermdoc on Twitter.

In my last column, I addressed the question of whether or not to outsource your practice’s social media efforts. While some medical practices do their own social media, others simply don’t have the time, resources, or desire to do it themselves. That’s where social media consultants come in. Hiring the right consultant offers numerous benefits such as devising a strategic plan that aligns with your practice’s unique goals, as well helping you develop and market your personal brand.

Last time, I offered guidelines to help you choose the right consultant for your practice. This time, I’ll offer some pitfalls to avoid when choosing a social media consultant or agency. If a consultant promises any of the following, be skeptical:

• Thousands of followers in just a few weeks! Authentic social media takes time because it’s about building relationships. There are digital programs that let you buy followers, but I don’t recommend them. It’s much better to have a smaller, genuine, truly engaged target audience than a huge, inauthentic one. Building a genuine target audience takes longer to cultivate, but it is far more effective in the long run.

• Your videos will go viral! We’ve all seen videos that have gone viral (many involve grumpy cats, which I don’t recommend using for your brand). Chances are if you’re making a 2-minute video on how to treat rosacea or ringworm, it won’t go viral. (Unless it involves a grumpy cat.) Instead, focus on realistic expectations. Your consultant should offer creative ways to market your brand, whether it’s video or text. But getting hung up on going viral is like waiting to win the lottery. It’s better to regularly create and share high-quality content that over time will garner an audience.

• You’ll double your patients in weeks! The number one way physicians acquire new patients is through word of mouth. Social media is word of mouth enhanced by technology, so it has the potential to grow your patient base. But it takes time. If acquiring new patients is one of your goals, then be certain that your consultant creates a realistic plan to achieve that goal.

• We’re your one-stop shop! Although I advocate using social media to market your practice, I believe it should be only one spoke in your marketing wheel. Traditional forms of marketing, such as newspaper and magazine advertisements, newsletters, and local radio and television appearances, still offer real benefits for many practices. If someone is trying to convince you to abandon all your other marketing efforts, be cautious.

• We’ve had 100% success with all of our clients! Would you believe your fellow doctor if he said he hadn’t had a patient complaint in 3 years? I didn’t think so. Don’t believe a consultant who tells you he’s never made mistakes or had an unhappy client. Ask what a consultant has learned from negative and positive experiences. What insight have they gleaned from that unsuccessful experience? How can these insights help when devising your strategy?

With these guidelines in place, you’re putting your practice and your reputation in safer hands.

Dr. Benabio is a partner physician in the department of dermatology of the Southern California Permanente Group in San Diego and a volunteer clinical assistant professor at the University of California, San Diego. Dr. Benabio is @dermdoc on Twitter.

Recently, Federal Practitioner talked with Benjamin Powers, MD, and Suman Kambhampati, MD, about factors that come into play when treating patients with chronic myelogenous leukemia (CML) and the dramatic improvements in treatment that have been made. To find out more about these factors and improvements, read Blast Phase Chronic Myelogenous Leukemia from the August 2014 issue.

Dr. Powers is a fellow and Dr. Kambhampati is an associate professor of medicine, both in the Department of Internal Medicine, Division of Hematology/Oncology, at the University of Kansas Medical Center in Kansas City, Kansas. Dr. Kambhampati is also a staff physician in the Hematology/Oncology Division at the Kansas City VAMC in Kansas City, Missouri.

Recently, Federal Practitioner talked with Benjamin Powers, MD, and Suman Kambhampati, MD, about factors that come into play when treating patients with chronic myelogenous leukemia (CML) and the dramatic improvements in treatment that have been made. To find out more about these factors and improvements, read Blast Phase Chronic Myelogenous Leukemia from the August 2014 issue.

Dr. Powers is a fellow and Dr. Kambhampati is an associate professor of medicine, both in the Department of Internal Medicine, Division of Hematology/Oncology, at the University of Kansas Medical Center in Kansas City, Kansas. Dr. Kambhampati is also a staff physician in the Hematology/Oncology Division at the Kansas City VAMC in Kansas City, Missouri.

Recently, Federal Practitioner talked with Benjamin Powers, MD, and Suman Kambhampati, MD, about factors that come into play when treating patients with chronic myelogenous leukemia (CML) and the dramatic improvements in treatment that have been made. To find out more about these factors and improvements, read Blast Phase Chronic Myelogenous Leukemia from the August 2014 issue.

Dr. Powers is a fellow and Dr. Kambhampati is an associate professor of medicine, both in the Department of Internal Medicine, Division of Hematology/Oncology, at the University of Kansas Medical Center in Kansas City, Kansas. Dr. Kambhampati is also a staff physician in the Hematology/Oncology Division at the Kansas City VAMC in Kansas City, Missouri.

Sickled and normal red cells

Credit: Graham Beards

Scientists have discovered that manipulating gene regulation can cause red blood cells to produce fetal hemoglobin, a finding that may have implications for sickle cell disease (SCD) and other hemoglobinopathies.

The researchers used protein-engineering techniques to force chromatin fiber into looped structures that contact DNA at specific sites to preferentially activate genes that regulate hemoglobin.

The team described the work in Cell. The research was previously presented at the 2013 ASH Annual Meeting.

Key to the researcher’s method is a developmental transition that normally occurs in the blood of newborns. A biological switch regulates a changeover from fetal hemoglobin to adult hemoglobin as it begins to silence the genes that produce fetal hemoglobin.

Hematologists have long known that SCD patients with elevated levels of fetal hemoglobin have a milder form of the disease.

“This observation has been a major driver in the field to understand the molecular basis of the mechanisms that control the biological switch, with the ultimate goal to reverse it,” said study author Gerd A. Blobel, MD, PhD, of The Children’s Hospital of Philadelphia in Pennsylvania.

In previous research, his team used bioengineering techniques to adapt zinc-finger proteins to latch onto specific DNA sites far apart on a chromosome. The chromatin loop that results transmits regulatory signals for specific genes.

In their current work, the researchers custom-designed zinc fingers to flip the biological switch in hematopoietic stem cells, reactivating the genes expressing fetal hemoglobin at the expense of the genes expressing adult hemoglobin.

The team achieved these results in cultured blood cells from adult mice and adult humans.

The researchers are now planning to test the approach in animal models of SCD. If this strategy corrects the disease in animals, it may set the stage to move to human trials.

Dr Blobel also noted that, in principle, the forced chromatin looping approach could be applied to other hemoglobin-related disorders, such as certain forms of thalassemia.

Sickled and normal red cells

Credit: Graham Beards

Scientists have discovered that manipulating gene regulation can cause red blood cells to produce fetal hemoglobin, a finding that may have implications for sickle cell disease (SCD) and other hemoglobinopathies.

The researchers used protein-engineering techniques to force chromatin fiber into looped structures that contact DNA at specific sites to preferentially activate genes that regulate hemoglobin.

The team described the work in Cell. The research was previously presented at the 2013 ASH Annual Meeting.

Key to the researcher’s method is a developmental transition that normally occurs in the blood of newborns. A biological switch regulates a changeover from fetal hemoglobin to adult hemoglobin as it begins to silence the genes that produce fetal hemoglobin.

Hematologists have long known that SCD patients with elevated levels of fetal hemoglobin have a milder form of the disease.

“This observation has been a major driver in the field to understand the molecular basis of the mechanisms that control the biological switch, with the ultimate goal to reverse it,” said study author Gerd A. Blobel, MD, PhD, of The Children’s Hospital of Philadelphia in Pennsylvania.

In previous research, his team used bioengineering techniques to adapt zinc-finger proteins to latch onto specific DNA sites far apart on a chromosome. The chromatin loop that results transmits regulatory signals for specific genes.

In their current work, the researchers custom-designed zinc fingers to flip the biological switch in hematopoietic stem cells, reactivating the genes expressing fetal hemoglobin at the expense of the genes expressing adult hemoglobin.

The team achieved these results in cultured blood cells from adult mice and adult humans.

The researchers are now planning to test the approach in animal models of SCD. If this strategy corrects the disease in animals, it may set the stage to move to human trials.

Dr Blobel also noted that, in principle, the forced chromatin looping approach could be applied to other hemoglobin-related disorders, such as certain forms of thalassemia.

Sickled and normal red cells

Credit: Graham Beards

Scientists have discovered that manipulating gene regulation can cause red blood cells to produce fetal hemoglobin, a finding that may have implications for sickle cell disease (SCD) and other hemoglobinopathies.

The researchers used protein-engineering techniques to force chromatin fiber into looped structures that contact DNA at specific sites to preferentially activate genes that regulate hemoglobin.

The team described the work in Cell. The research was previously presented at the 2013 ASH Annual Meeting.

Key to the researcher’s method is a developmental transition that normally occurs in the blood of newborns. A biological switch regulates a changeover from fetal hemoglobin to adult hemoglobin as it begins to silence the genes that produce fetal hemoglobin.

Hematologists have long known that SCD patients with elevated levels of fetal hemoglobin have a milder form of the disease.

“This observation has been a major driver in the field to understand the molecular basis of the mechanisms that control the biological switch, with the ultimate goal to reverse it,” said study author Gerd A. Blobel, MD, PhD, of The Children’s Hospital of Philadelphia in Pennsylvania.

In previous research, his team used bioengineering techniques to adapt zinc-finger proteins to latch onto specific DNA sites far apart on a chromosome. The chromatin loop that results transmits regulatory signals for specific genes.

In their current work, the researchers custom-designed zinc fingers to flip the biological switch in hematopoietic stem cells, reactivating the genes expressing fetal hemoglobin at the expense of the genes expressing adult hemoglobin.

The team achieved these results in cultured blood cells from adult mice and adult humans.

The researchers are now planning to test the approach in animal models of SCD. If this strategy corrects the disease in animals, it may set the stage to move to human trials.

Dr Blobel also noted that, in principle, the forced chromatin looping approach could be applied to other hemoglobin-related disorders, such as certain forms of thalassemia.

The proteasome inhibitor carfilzomib (Kyprolis) did not meet its primary endpoint in the phase 3 FOCUS trial, according to the drug’s developers.

Single-agent carfilzomib did not improve overall survival compared to an active control regimen of corticosteroids plus optional cyclophosphamide in patients with relapsed and refractory multiple myeloma (MM).

This result raises questions about carfilzomib’s chances for regulatory approval around the world.

However, the companies developing the drug, Amgen and its subsidiary Onyx Pharmaceuticals, Inc., said results of the phase 3 ASPIRE trial should be sufficient to support carfilzomib’s approval.

At present, carfilzomib has accelerated approval from the US Food and Drug Administration for the treatment of MM patients who have received at least 2 prior therapies, including bortezomib and an immunomodulatory agent, and have demonstrated disease progression on or within 60 days of completing their last therapy.

That approval was based on response rates observed with carfilzomib. For the drug to gain full approval, it must demonstrate a clinical benefit.

The FOCUS trial

For the FOCUS trial, researchers enrolled 315 patients with relapsed and advanced refractory MM.

Patients were randomized to receive carfilzomib or an active control regimen consisting of low-dose dexamethasone, or equivalent corticosteroids, plus optional cyclophosphamide.

Nearly all patients in the control arm received cyclophosphamide. Patients were heavily pretreated and had received a median of 5 treatment regimens prior to study entry.

The trial’s primary endpoint was overall survival, and there was no significant difference between the 2 treatment arms. The hazard ratio was 0.975.

Treatment discontinuation due to adverse events and on-study deaths were comparable between the treatment arms. The rate of cardiac events in the carfilzomib arm was consistent with the current US label.

However, there was an increase in the incidence of renal adverse events of all grades observed in the carfilzomib arm compared to the active control arm and the label.

Full prescribing information for carfilzomib is available at www.kyprolis.com.

Amgen and Onyx said detailed results from the FOCUS trial will be submitted for presentation at an upcoming scientific meeting.

The proteasome inhibitor carfilzomib (Kyprolis) did not meet its primary endpoint in the phase 3 FOCUS trial, according to the drug’s developers.

Single-agent carfilzomib did not improve overall survival compared to an active control regimen of corticosteroids plus optional cyclophosphamide in patients with relapsed and refractory multiple myeloma (MM).

This result raises questions about carfilzomib’s chances for regulatory approval around the world.

However, the companies developing the drug, Amgen and its subsidiary Onyx Pharmaceuticals, Inc., said results of the phase 3 ASPIRE trial should be sufficient to support carfilzomib’s approval.

At present, carfilzomib has accelerated approval from the US Food and Drug Administration for the treatment of MM patients who have received at least 2 prior therapies, including bortezomib and an immunomodulatory agent, and have demonstrated disease progression on or within 60 days of completing their last therapy.

That approval was based on response rates observed with carfilzomib. For the drug to gain full approval, it must demonstrate a clinical benefit.

The FOCUS trial

For the FOCUS trial, researchers enrolled 315 patients with relapsed and advanced refractory MM.

Patients were randomized to receive carfilzomib or an active control regimen consisting of low-dose dexamethasone, or equivalent corticosteroids, plus optional cyclophosphamide.

Nearly all patients in the control arm received cyclophosphamide. Patients were heavily pretreated and had received a median of 5 treatment regimens prior to study entry.

The trial’s primary endpoint was overall survival, and there was no significant difference between the 2 treatment arms. The hazard ratio was 0.975.

Treatment discontinuation due to adverse events and on-study deaths were comparable between the treatment arms. The rate of cardiac events in the carfilzomib arm was consistent with the current US label.

However, there was an increase in the incidence of renal adverse events of all grades observed in the carfilzomib arm compared to the active control arm and the label.

Full prescribing information for carfilzomib is available at www.kyprolis.com.

Amgen and Onyx said detailed results from the FOCUS trial will be submitted for presentation at an upcoming scientific meeting.

The proteasome inhibitor carfilzomib (Kyprolis) did not meet its primary endpoint in the phase 3 FOCUS trial, according to the drug’s developers.

Single-agent carfilzomib did not improve overall survival compared to an active control regimen of corticosteroids plus optional cyclophosphamide in patients with relapsed and refractory multiple myeloma (MM).

This result raises questions about carfilzomib’s chances for regulatory approval around the world.

However, the companies developing the drug, Amgen and its subsidiary Onyx Pharmaceuticals, Inc., said results of the phase 3 ASPIRE trial should be sufficient to support carfilzomib’s approval.

At present, carfilzomib has accelerated approval from the US Food and Drug Administration for the treatment of MM patients who have received at least 2 prior therapies, including bortezomib and an immunomodulatory agent, and have demonstrated disease progression on or within 60 days of completing their last therapy.

That approval was based on response rates observed with carfilzomib. For the drug to gain full approval, it must demonstrate a clinical benefit.

The FOCUS trial

For the FOCUS trial, researchers enrolled 315 patients with relapsed and advanced refractory MM.

Patients were randomized to receive carfilzomib or an active control regimen consisting of low-dose dexamethasone, or equivalent corticosteroids, plus optional cyclophosphamide.

Nearly all patients in the control arm received cyclophosphamide. Patients were heavily pretreated and had received a median of 5 treatment regimens prior to study entry.

The trial’s primary endpoint was overall survival, and there was no significant difference between the 2 treatment arms. The hazard ratio was 0.975.

Treatment discontinuation due to adverse events and on-study deaths were comparable between the treatment arms. The rate of cardiac events in the carfilzomib arm was consistent with the current US label.

However, there was an increase in the incidence of renal adverse events of all grades observed in the carfilzomib arm compared to the active control arm and the label.

Full prescribing information for carfilzomib is available at www.kyprolis.com.

Amgen and Onyx said detailed results from the FOCUS trial will be submitted for presentation at an upcoming scientific meeting.

ALL cells in the bone marrow

Two genes appear to play a key role in acute lymphoblastic leukemia (ALL), particularly for patients who also have Down syndrome.

Researchers found evidence suggesting that 2 in 3 cases of ALL among patients with Down syndrome may be caused by mutations in RAS or JAK2, but the mutations tend not to occur together.

The group therefore believes that if we can begin to identify which of the genes is mutated in ALL patients, we can tailor therapy accordingly.

“We believe our findings are a breakthrough in understanding the underlying causes of leukemia, and, eventually, we hope to design more tailored and effective treatment for this cancer, with less toxic drugs and less side effects,” said study author Dean Nizetic, MD, PhD, a professor at both Queen Mary University of London in the UK and Lee Kong Chian School of Medicine in Singapore.

He and his colleagues reported their findings in Nature Communications.

The researchers conducted full-exome or targeted sequencing in 42 samples from 39 patients with ALL and Down syndrome. The team found similar recurrence rates for driver mutations in RAS (15/42), JAK2 mutations (12/42), and P2RY8-CRLF2 fusions (14/42).

Together, RAS and JAK2 mutations drove two-thirds of the ALL cases, though the mutations were almost completely mutually exclusive (P=0.016).

The researchers also noted that, in two-thirds of patients with relapsed ALL, there was a switch from a primary JAK2- or PTPN11-mutated subclone to a RAS-mutated subclone in relapse.

Moving forward, the team plans to conduct more studies to determine how else RAS and JAK2 might affect children who have ALL, with or without Down syndrome.

ALL cells in the bone marrow

Two genes appear to play a key role in acute lymphoblastic leukemia (ALL), particularly for patients who also have Down syndrome.

Researchers found evidence suggesting that 2 in 3 cases of ALL among patients with Down syndrome may be caused by mutations in RAS or JAK2, but the mutations tend not to occur together.

The group therefore believes that if we can begin to identify which of the genes is mutated in ALL patients, we can tailor therapy accordingly.

“We believe our findings are a breakthrough in understanding the underlying causes of leukemia, and, eventually, we hope to design more tailored and effective treatment for this cancer, with less toxic drugs and less side effects,” said study author Dean Nizetic, MD, PhD, a professor at both Queen Mary University of London in the UK and Lee Kong Chian School of Medicine in Singapore.

He and his colleagues reported their findings in Nature Communications.

The researchers conducted full-exome or targeted sequencing in 42 samples from 39 patients with ALL and Down syndrome. The team found similar recurrence rates for driver mutations in RAS (15/42), JAK2 mutations (12/42), and P2RY8-CRLF2 fusions (14/42).

Together, RAS and JAK2 mutations drove two-thirds of the ALL cases, though the mutations were almost completely mutually exclusive (P=0.016).

The researchers also noted that, in two-thirds of patients with relapsed ALL, there was a switch from a primary JAK2- or PTPN11-mutated subclone to a RAS-mutated subclone in relapse.

Moving forward, the team plans to conduct more studies to determine how else RAS and JAK2 might affect children who have ALL, with or without Down syndrome.

ALL cells in the bone marrow

Two genes appear to play a key role in acute lymphoblastic leukemia (ALL), particularly for patients who also have Down syndrome.

Researchers found evidence suggesting that 2 in 3 cases of ALL among patients with Down syndrome may be caused by mutations in RAS or JAK2, but the mutations tend not to occur together.

The group therefore believes that if we can begin to identify which of the genes is mutated in ALL patients, we can tailor therapy accordingly.

“We believe our findings are a breakthrough in understanding the underlying causes of leukemia, and, eventually, we hope to design more tailored and effective treatment for this cancer, with less toxic drugs and less side effects,” said study author Dean Nizetic, MD, PhD, a professor at both Queen Mary University of London in the UK and Lee Kong Chian School of Medicine in Singapore.

He and his colleagues reported their findings in Nature Communications.

The researchers conducted full-exome or targeted sequencing in 42 samples from 39 patients with ALL and Down syndrome. The team found similar recurrence rates for driver mutations in RAS (15/42), JAK2 mutations (12/42), and P2RY8-CRLF2 fusions (14/42).

Together, RAS and JAK2 mutations drove two-thirds of the ALL cases, though the mutations were almost completely mutually exclusive (P=0.016).

The researchers also noted that, in two-thirds of patients with relapsed ALL, there was a switch from a primary JAK2- or PTPN11-mutated subclone to a RAS-mutated subclone in relapse.

Moving forward, the team plans to conduct more studies to determine how else RAS and JAK2 might affect children who have ALL, with or without Down syndrome.

Preparing pills for a trial

Credit: Esther Dyson

The US Food and Drug Administration (FDA) has granted fast track designation for AG-221 to treat acute myelogenous leukemia (AML) patients with mutated isocitrate dehydrogenase-2 (IDH2).

AG-221 is an IDH2 inhibitor under evaluation in a phase 1 trial of patients with advanced hematologic malignancies.

Results from this trial were presented at the 19th Congress of the European Hematology Association, which took place in Milan in June.

The FDA’s fast track drug development program is designed to expedite clinical development and submission of a new drug application (NDA) for drugs with the potential to treat serious or life-threatening conditions and address unmet medical needs.

Fast track designation facilitates meetings between the FDA and the company developing a drug to discuss all aspects of development to support approval. It also affords the developer the opportunity to submit sections of an NDA on a rolling basis as data become available, so the FDA does not have wait for the entire NDA submission before beginning its review.

AG-221 also recently received orphan designation as a treatment for AML. The FDA grants orphan status to support the development of drugs for underserved patient populations or rare disorders that affect fewer than 200,000 people in the US.

Orphan designation affords the drug’s developer certain benefits, including market exclusivity upon regulatory approval, exemption of FDA application fees, and tax credits for qualified clinical trials.

Phase 1 trial results

Thus far in the phase 1 study, AG-221 has proven active and well-tolerated in patients with AML, myelodysplastic syndromes (MDS), and chronic myelomonocytic leukemia (CMML).

The trial included 35 patients with a median age of 68 years (range, 48-81).

Twenty-seven patients had relapsed/refractory AML, 4 had relapsed/refractory MDS, 2 had untreated AML, 1 had CMML, and 1 had granulocytic sarcoma. Thirty-one patients had R140Q IDH2 mutations, and 4 had R172K IDH2 mutations.

The patients received AG-221 at doses ranging from 30 mg BID to 150 mg QD. Patients completed a median of 1 cycle of treatment (range, <1-5+) and a mean of 2 cycles.

The drug was generally well-tolerated, largely prompting grade 1 or 2 adverse events. Grade 3 or higher events included thrombocytopenia (n=3), anemia (n=1), febrile neutropenia (n=3), sepsis (n=3), diarrhea (n=1), fatigue (n=1), leukocytosis (n=2), neutropenia (n=1), and rash (n=1).

Four patients had serious events possibly related to treatment. One patient had grade 3 confusion and grade 5 respiratory failure. One patient had grade 3 leukocytosis, grade 3 anorexia, and grade 1 nausea. One patient had grade 3 diarrhea. And 1 patient had grade 3 leukocytosis.

Twenty-five patients were evaluable for response. There were 6 complete responses (CRs), 2 CRs with incomplete platelet recovery, 1 CR with incomplete hematologic recovery, and 5 partial responses. Five patients had stable disease, and 6 had progressive disease.

The most responses occurred among patients who received AG-221 at 50 mg BID, and most responses occurred in cycle 1.

Twelve of the 14 responses are ongoing. Of the 8 patients who achieved a CR or CR with incomplete platelet recovery, 5 have lasted more than 2.5 months (range, 1-4+ months). And the 5 patients with stable disease remain on study.

This study is sponsored by Agios Pharmaceuticals Inc., the company developing AG-221 in collaboration with Celgene.

Preparing pills for a trial

Credit: Esther Dyson

The US Food and Drug Administration (FDA) has granted fast track designation for AG-221 to treat acute myelogenous leukemia (AML) patients with mutated isocitrate dehydrogenase-2 (IDH2).

AG-221 is an IDH2 inhibitor under evaluation in a phase 1 trial of patients with advanced hematologic malignancies.

Results from this trial were presented at the 19th Congress of the European Hematology Association, which took place in Milan in June.

The FDA’s fast track drug development program is designed to expedite clinical development and submission of a new drug application (NDA) for drugs with the potential to treat serious or life-threatening conditions and address unmet medical needs.

Fast track designation facilitates meetings between the FDA and the company developing a drug to discuss all aspects of development to support approval. It also affords the developer the opportunity to submit sections of an NDA on a rolling basis as data become available, so the FDA does not have wait for the entire NDA submission before beginning its review.

AG-221 also recently received orphan designation as a treatment for AML. The FDA grants orphan status to support the development of drugs for underserved patient populations or rare disorders that affect fewer than 200,000 people in the US.

Orphan designation affords the drug’s developer certain benefits, including market exclusivity upon regulatory approval, exemption of FDA application fees, and tax credits for qualified clinical trials.

Phase 1 trial results

Thus far in the phase 1 study, AG-221 has proven active and well-tolerated in patients with AML, myelodysplastic syndromes (MDS), and chronic myelomonocytic leukemia (CMML).

The trial included 35 patients with a median age of 68 years (range, 48-81).

Twenty-seven patients had relapsed/refractory AML, 4 had relapsed/refractory MDS, 2 had untreated AML, 1 had CMML, and 1 had granulocytic sarcoma. Thirty-one patients had R140Q IDH2 mutations, and 4 had R172K IDH2 mutations.

The patients received AG-221 at doses ranging from 30 mg BID to 150 mg QD. Patients completed a median of 1 cycle of treatment (range, <1-5+) and a mean of 2 cycles.

The drug was generally well-tolerated, largely prompting grade 1 or 2 adverse events. Grade 3 or higher events included thrombocytopenia (n=3), anemia (n=1), febrile neutropenia (n=3), sepsis (n=3), diarrhea (n=1), fatigue (n=1), leukocytosis (n=2), neutropenia (n=1), and rash (n=1).

Four patients had serious events possibly related to treatment. One patient had grade 3 confusion and grade 5 respiratory failure. One patient had grade 3 leukocytosis, grade 3 anorexia, and grade 1 nausea. One patient had grade 3 diarrhea. And 1 patient had grade 3 leukocytosis.

Twenty-five patients were evaluable for response. There were 6 complete responses (CRs), 2 CRs with incomplete platelet recovery, 1 CR with incomplete hematologic recovery, and 5 partial responses. Five patients had stable disease, and 6 had progressive disease.

The most responses occurred among patients who received AG-221 at 50 mg BID, and most responses occurred in cycle 1.

Twelve of the 14 responses are ongoing. Of the 8 patients who achieved a CR or CR with incomplete platelet recovery, 5 have lasted more than 2.5 months (range, 1-4+ months). And the 5 patients with stable disease remain on study.

This study is sponsored by Agios Pharmaceuticals Inc., the company developing AG-221 in collaboration with Celgene.

Preparing pills for a trial

Credit: Esther Dyson

The US Food and Drug Administration (FDA) has granted fast track designation for AG-221 to treat acute myelogenous leukemia (AML) patients with mutated isocitrate dehydrogenase-2 (IDH2).

AG-221 is an IDH2 inhibitor under evaluation in a phase 1 trial of patients with advanced hematologic malignancies.

Results from this trial were presented at the 19th Congress of the European Hematology Association, which took place in Milan in June.

The FDA’s fast track drug development program is designed to expedite clinical development and submission of a new drug application (NDA) for drugs with the potential to treat serious or life-threatening conditions and address unmet medical needs.

Fast track designation facilitates meetings between the FDA and the company developing a drug to discuss all aspects of development to support approval. It also affords the developer the opportunity to submit sections of an NDA on a rolling basis as data become available, so the FDA does not have wait for the entire NDA submission before beginning its review.

AG-221 also recently received orphan designation as a treatment for AML. The FDA grants orphan status to support the development of drugs for underserved patient populations or rare disorders that affect fewer than 200,000 people in the US.

Orphan designation affords the drug’s developer certain benefits, including market exclusivity upon regulatory approval, exemption of FDA application fees, and tax credits for qualified clinical trials.

Phase 1 trial results

Thus far in the phase 1 study, AG-221 has proven active and well-tolerated in patients with AML, myelodysplastic syndromes (MDS), and chronic myelomonocytic leukemia (CMML).

The trial included 35 patients with a median age of 68 years (range, 48-81).

Twenty-seven patients had relapsed/refractory AML, 4 had relapsed/refractory MDS, 2 had untreated AML, 1 had CMML, and 1 had granulocytic sarcoma. Thirty-one patients had R140Q IDH2 mutations, and 4 had R172K IDH2 mutations.

The patients received AG-221 at doses ranging from 30 mg BID to 150 mg QD. Patients completed a median of 1 cycle of treatment (range, <1-5+) and a mean of 2 cycles.

The drug was generally well-tolerated, largely prompting grade 1 or 2 adverse events. Grade 3 or higher events included thrombocytopenia (n=3), anemia (n=1), febrile neutropenia (n=3), sepsis (n=3), diarrhea (n=1), fatigue (n=1), leukocytosis (n=2), neutropenia (n=1), and rash (n=1).

Four patients had serious events possibly related to treatment. One patient had grade 3 confusion and grade 5 respiratory failure. One patient had grade 3 leukocytosis, grade 3 anorexia, and grade 1 nausea. One patient had grade 3 diarrhea. And 1 patient had grade 3 leukocytosis.

Twenty-five patients were evaluable for response. There were 6 complete responses (CRs), 2 CRs with incomplete platelet recovery, 1 CR with incomplete hematologic recovery, and 5 partial responses. Five patients had stable disease, and 6 had progressive disease.

The most responses occurred among patients who received AG-221 at 50 mg BID, and most responses occurred in cycle 1.

Twelve of the 14 responses are ongoing. Of the 8 patients who achieved a CR or CR with incomplete platelet recovery, 5 have lasted more than 2.5 months (range, 1-4+ months). And the 5 patients with stable disease remain on study.

This study is sponsored by Agios Pharmaceuticals Inc., the company developing AG-221 in collaboration with Celgene.