SAN FRANCISCO – Delaying initiation of renal replacement therapy in critically ill patients with severe acute kidney injury appears to be not only safe but beneficial, according to a randomized controlled trial conducted in France.

The trial, known as Artificial Kidney Initiation in Kidney Injury (AKIKI), was conducted among 620 adult patients from 31 intensive care units. The investigators were led by Dr. Stéphane Gaudry of Assistance Publique–Hôpitaux de Paris.

The death rate did not differ significantly between groups assigned to an early versus a late initiation strategy, according to results presented at an international conference of the American Thoracic Society and simultaneously published (N Engl J Med. 2016 May 15. doi: 10.1056/NEJMoa1603017).

Moreover, nearly half of the patients in the delayed initiation group were able to avoid renal replacement therapy. And they were less likely to develop bloodstream infections and had more rapid onset of diuresis (heralding recovery of renal function) than did peers in whom the therapy was initiated early.

“Our study should not be interpreted as suggesting that a ‘wait and see’ approach is safe for all patients. Indeed, careful surveillance is mandatory when deciding to delay renal-replacement therapy in patients with severe acute kidney injury so that any complications will be detected and renal-replacement therapy initiated without delay,” the investigators concluded. “In our trial, delaying the initiation of therapy allowed many patients to recover from acute kidney injury without embarking on such a treatment course.”

Further, the “findings may not be generalizable, because more than 50% of the patients in our trial received intermittent hemodialysis as the first method of therapy and only 30% of the patients received continuous renal-replacement therapy as the sole method (with no intermittent dialysis at any time).”

The author of an accompanying editorial, Dr. Ravindra L. Mehta of the University of California, San Diego, lists some caveats in interpreting the trial’s findings as support for the delayed initiation strategy.

For example, he notes, the longer time to initiation with the delayed strategy contributed to worsening of metabolic and clinical status in the patients who ultimately did need therapy; the study did not assess the development of chronic kidney disease; and the types of renal replacement therapy selected for patients seem “surprising” as the majority put on this therapy needed vasopressors.

“The findings highlight a need for dynamic risk-stratification tools to identify patients who will not need renal-replacement therapy for management of their acute kidney injury,” Dr. Mehta concluded, noting that ongoing studies should help inform management in this area. “Meanwhile, we should focus on the timely application of renal-replacement therapy while considering individual patient characteristics, process-of-care elements, and logistics to achieve therapeutic goals …”

Patients were eligible for the trial if they had severe acute kidney injury, defined as Kidney Disease: Improving Global Outcomes (KDIGO) stage 3; required mechanical ventilation, catecholamine infusion, or both; and did not have a potentially life-threatening complication directly related to renal failure.

In those assigned to the early strategy, renal replacement therapy was started immediately after randomization. In those assigned to the delayed strategy, it was started if any of several criteria was met: severe hyperkalemia, metabolic acidosis, pulmonary edema, blood urea nitrogen level higher than 112 mg/dL, or oliguria for more than 72 hours after randomization. The specific type of renal replacement therapy was left up to each study site.

The median time between randomization and initiation of renal replacement therapy was 2 hours in the early strategy group and 57 hours in the delayed strategy group.

The estimated 60-day mortality rate – the trial’s primary outcome – was 48.5% with early initiation of therapy and 49.7% with delayed initiation, a nonsignificant difference.

Fully 49% of patients in the delayed strategy group never received renal replacement therapy. In addition, patients in this group were half as likely as were peers in the early initiation group to develop a bloodstream infection (5% vs. 10%), and they had more rapid onset of diuresis (P less than .001).

The groups were essentially the same with respect to the rate of gastrointestinal bleeding and the lengths of stay in the intensive care unit and in the hospital.

Dr. Gaudry disclosed that he received grant support from the French Ministry of Health during the study, and from XENIOS France outside the research. The trial was supported by a grant from Programme Hospitalier de Recherche Clinique National, 2012 (AOM12456), funded by the French Ministry of Health..

SAN FRANCISCO – Delaying initiation of renal replacement therapy in critically ill patients with severe acute kidney injury appears to be not only safe but beneficial, according to a randomized controlled trial conducted in France.

The trial, known as Artificial Kidney Initiation in Kidney Injury (AKIKI), was conducted among 620 adult patients from 31 intensive care units. The investigators were led by Dr. Stéphane Gaudry of Assistance Publique–Hôpitaux de Paris.

The death rate did not differ significantly between groups assigned to an early versus a late initiation strategy, according to results presented at an international conference of the American Thoracic Society and simultaneously published (N Engl J Med. 2016 May 15. doi: 10.1056/NEJMoa1603017).

Moreover, nearly half of the patients in the delayed initiation group were able to avoid renal replacement therapy. And they were less likely to develop bloodstream infections and had more rapid onset of diuresis (heralding recovery of renal function) than did peers in whom the therapy was initiated early.

“Our study should not be interpreted as suggesting that a ‘wait and see’ approach is safe for all patients. Indeed, careful surveillance is mandatory when deciding to delay renal-replacement therapy in patients with severe acute kidney injury so that any complications will be detected and renal-replacement therapy initiated without delay,” the investigators concluded. “In our trial, delaying the initiation of therapy allowed many patients to recover from acute kidney injury without embarking on such a treatment course.”

Further, the “findings may not be generalizable, because more than 50% of the patients in our trial received intermittent hemodialysis as the first method of therapy and only 30% of the patients received continuous renal-replacement therapy as the sole method (with no intermittent dialysis at any time).”

The author of an accompanying editorial, Dr. Ravindra L. Mehta of the University of California, San Diego, lists some caveats in interpreting the trial’s findings as support for the delayed initiation strategy.

For example, he notes, the longer time to initiation with the delayed strategy contributed to worsening of metabolic and clinical status in the patients who ultimately did need therapy; the study did not assess the development of chronic kidney disease; and the types of renal replacement therapy selected for patients seem “surprising” as the majority put on this therapy needed vasopressors.

“The findings highlight a need for dynamic risk-stratification tools to identify patients who will not need renal-replacement therapy for management of their acute kidney injury,” Dr. Mehta concluded, noting that ongoing studies should help inform management in this area. “Meanwhile, we should focus on the timely application of renal-replacement therapy while considering individual patient characteristics, process-of-care elements, and logistics to achieve therapeutic goals …”

Patients were eligible for the trial if they had severe acute kidney injury, defined as Kidney Disease: Improving Global Outcomes (KDIGO) stage 3; required mechanical ventilation, catecholamine infusion, or both; and did not have a potentially life-threatening complication directly related to renal failure.

In those assigned to the early strategy, renal replacement therapy was started immediately after randomization. In those assigned to the delayed strategy, it was started if any of several criteria was met: severe hyperkalemia, metabolic acidosis, pulmonary edema, blood urea nitrogen level higher than 112 mg/dL, or oliguria for more than 72 hours after randomization. The specific type of renal replacement therapy was left up to each study site.

The median time between randomization and initiation of renal replacement therapy was 2 hours in the early strategy group and 57 hours in the delayed strategy group.

The estimated 60-day mortality rate – the trial’s primary outcome – was 48.5% with early initiation of therapy and 49.7% with delayed initiation, a nonsignificant difference.

Fully 49% of patients in the delayed strategy group never received renal replacement therapy. In addition, patients in this group were half as likely as were peers in the early initiation group to develop a bloodstream infection (5% vs. 10%), and they had more rapid onset of diuresis (P less than .001).

The groups were essentially the same with respect to the rate of gastrointestinal bleeding and the lengths of stay in the intensive care unit and in the hospital.

Dr. Gaudry disclosed that he received grant support from the French Ministry of Health during the study, and from XENIOS France outside the research. The trial was supported by a grant from Programme Hospitalier de Recherche Clinique National, 2012 (AOM12456), funded by the French Ministry of Health..

SAN FRANCISCO – Delaying initiation of renal replacement therapy in critically ill patients with severe acute kidney injury appears to be not only safe but beneficial, according to a randomized controlled trial conducted in France.

The trial, known as Artificial Kidney Initiation in Kidney Injury (AKIKI), was conducted among 620 adult patients from 31 intensive care units. The investigators were led by Dr. Stéphane Gaudry of Assistance Publique–Hôpitaux de Paris.

The death rate did not differ significantly between groups assigned to an early versus a late initiation strategy, according to results presented at an international conference of the American Thoracic Society and simultaneously published (N Engl J Med. 2016 May 15. doi: 10.1056/NEJMoa1603017).

Moreover, nearly half of the patients in the delayed initiation group were able to avoid renal replacement therapy. And they were less likely to develop bloodstream infections and had more rapid onset of diuresis (heralding recovery of renal function) than did peers in whom the therapy was initiated early.

“Our study should not be interpreted as suggesting that a ‘wait and see’ approach is safe for all patients. Indeed, careful surveillance is mandatory when deciding to delay renal-replacement therapy in patients with severe acute kidney injury so that any complications will be detected and renal-replacement therapy initiated without delay,” the investigators concluded. “In our trial, delaying the initiation of therapy allowed many patients to recover from acute kidney injury without embarking on such a treatment course.”

Further, the “findings may not be generalizable, because more than 50% of the patients in our trial received intermittent hemodialysis as the first method of therapy and only 30% of the patients received continuous renal-replacement therapy as the sole method (with no intermittent dialysis at any time).”

The author of an accompanying editorial, Dr. Ravindra L. Mehta of the University of California, San Diego, lists some caveats in interpreting the trial’s findings as support for the delayed initiation strategy.

For example, he notes, the longer time to initiation with the delayed strategy contributed to worsening of metabolic and clinical status in the patients who ultimately did need therapy; the study did not assess the development of chronic kidney disease; and the types of renal replacement therapy selected for patients seem “surprising” as the majority put on this therapy needed vasopressors.

“The findings highlight a need for dynamic risk-stratification tools to identify patients who will not need renal-replacement therapy for management of their acute kidney injury,” Dr. Mehta concluded, noting that ongoing studies should help inform management in this area. “Meanwhile, we should focus on the timely application of renal-replacement therapy while considering individual patient characteristics, process-of-care elements, and logistics to achieve therapeutic goals …”

Patients were eligible for the trial if they had severe acute kidney injury, defined as Kidney Disease: Improving Global Outcomes (KDIGO) stage 3; required mechanical ventilation, catecholamine infusion, or both; and did not have a potentially life-threatening complication directly related to renal failure.

In those assigned to the early strategy, renal replacement therapy was started immediately after randomization. In those assigned to the delayed strategy, it was started if any of several criteria was met: severe hyperkalemia, metabolic acidosis, pulmonary edema, blood urea nitrogen level higher than 112 mg/dL, or oliguria for more than 72 hours after randomization. The specific type of renal replacement therapy was left up to each study site.

The median time between randomization and initiation of renal replacement therapy was 2 hours in the early strategy group and 57 hours in the delayed strategy group.

The estimated 60-day mortality rate – the trial’s primary outcome – was 48.5% with early initiation of therapy and 49.7% with delayed initiation, a nonsignificant difference.

Fully 49% of patients in the delayed strategy group never received renal replacement therapy. In addition, patients in this group were half as likely as were peers in the early initiation group to develop a bloodstream infection (5% vs. 10%), and they had more rapid onset of diuresis (P less than .001).

The groups were essentially the same with respect to the rate of gastrointestinal bleeding and the lengths of stay in the intensive care unit and in the hospital.

Dr. Gaudry disclosed that he received grant support from the French Ministry of Health during the study, and from XENIOS France outside the research. The trial was supported by a grant from Programme Hospitalier de Recherche Clinique National, 2012 (AOM12456), funded by the French Ministry of Health..

Health care is changing. For some, this is cause for celebration: A safer, convenient, more efficient system is upon us. For others, the end is nigh: impossibly demanding patients, crushing bureaucracy, and a once sacred relationship desecrated by invasive technology.

The ascent of digital health technologies is an important driver of health care change, yet its impact is still indeterminate. Any technology that empowers patients as well as physicians will improve patients’ health outcomes. Or so it might seem. The truth is more nuanced: Some services will improve outcomes, others won’t. Fitting Fitbits into our current system is like inserting the wrong key into a lock: It might go in, but it doesn’t open anything. Fortunately, some keys are opening doors to better care – doors that that we’ve never entered – but finding the right ones is laborious. Dr. Joe Kvedar is here to help.

As a physician leader who straddles the gap between physician-centered and consumer-centered health care, Dr. Kvedar has spent his career leveraging technology to improve care delivery for both. In his new book, “The Internet of Healthy Things,” he shares what he has learned. He uses numerous examples from his experience as a physician and pioneer in digital health care with Partners HealthCare, Boston, delving deeply into the business of health care and the behavioral habits of patients.

As he notes, Partners was “prescient” in the health care landscape, introducing video conferencing in the 1990s, second opinions on the Internet in 2001, and texting as a tool for health messaging in 2008. He asks now: “What are the connected health devices and applications that our clinicians will be using in 5-10 years?” Then he uses his acumen and research to answer his own question. The ensuing chapters are more prescriptive than predictive, however. None of us knows where health care will be in 10 years, but we should think about where it ought to be.

Whether you chart on an Apple Watch or on paper, this discussion is important to you. Physicians are key players in determining where and how medicine is practiced, and we need to understand relevant risks and benefits to make the right decisions.

Confusing the matter is that desired outcomes are not absolute but relative. It depends on the frame of reference. Patients measure outcomes with service, payers with cost, and we physicians with quality. Which measurement is correct? How can we know if a remote monitoring device is worthwhile if we can’t agree on what it delivers? Is it simply sending home “the sicker even quicker?” Does a Big Pharma beyond-the-pill app really only increase consumption of the costliest medications or create more affordable alternatives?

Technologies that increase access to services such as live chat, messaging, and monitoring may be preferred by patients, but physicians see them as piling on to backbreaking loads. More artificial intelligence is needed to enable these services without requiring physician work. We need driverless health care.

Keeping patients involved has a whole other set of requirements. The tools must be easy, the information personal, the data actionable, and its use Candy-Crush-Saga addictive. This is no small feat, but there is hope.

Partner’s Text 2 Move program, which Dr. Kvedar describes as the “gold standard of what learning about your consumer means,” showed that highly personalized, targeted text messages could have a significant impact on patients’ behavior and health. It is just this type of technology that many are relentlessly pursuing to deliver care more effectively.

Dr. Kvedar devotes significant attention to the patient/consumer experience in a thoughtful, complex manner. Rather than elevate or denigrate the rise of the engaged patient, he examines this phenomenon through several lenses, addressing equally the concerns of practicing physicians and health care entrepreneurs. Nearly 20 years ago, Regina Herzlinger of Harvard Business School, Boston, predicted the rise of health care consumerism. Retail clinics, direct-to-consumer services, and the “Yelpification” of health care are signals that we’ve arrived.

It’s tough to make predictions, especially about the future, Yogi Berra warned us. The book’s mention of Theranos, the failing pinprick blood lab company founded by celebrity Stanford student Elizabeth Holmes, is an example of how risky it is to place bets on where we are headed and how quickly we will get there. DIY at-home labs are further off than they appeared, and that is the hazard of any such books: it is difficult to see more than what’s just in front of us.

Ultimately, Dr. Kvedar’s message is as realistic as it is optimistic: “The same information that could help drive healthcare costs down can be used to create highly individualized programs that will help people stay healthier and happier.” But we should resist the urge to ask “Are we there yet?” No. We’ve a ways to go.

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. Write to him at [email protected].

Health care is changing. For some, this is cause for celebration: A safer, convenient, more efficient system is upon us. For others, the end is nigh: impossibly demanding patients, crushing bureaucracy, and a once sacred relationship desecrated by invasive technology.

The ascent of digital health technologies is an important driver of health care change, yet its impact is still indeterminate. Any technology that empowers patients as well as physicians will improve patients’ health outcomes. Or so it might seem. The truth is more nuanced: Some services will improve outcomes, others won’t. Fitting Fitbits into our current system is like inserting the wrong key into a lock: It might go in, but it doesn’t open anything. Fortunately, some keys are opening doors to better care – doors that that we’ve never entered – but finding the right ones is laborious. Dr. Joe Kvedar is here to help.

As a physician leader who straddles the gap between physician-centered and consumer-centered health care, Dr. Kvedar has spent his career leveraging technology to improve care delivery for both. In his new book, “The Internet of Healthy Things,” he shares what he has learned. He uses numerous examples from his experience as a physician and pioneer in digital health care with Partners HealthCare, Boston, delving deeply into the business of health care and the behavioral habits of patients.

As he notes, Partners was “prescient” in the health care landscape, introducing video conferencing in the 1990s, second opinions on the Internet in 2001, and texting as a tool for health messaging in 2008. He asks now: “What are the connected health devices and applications that our clinicians will be using in 5-10 years?” Then he uses his acumen and research to answer his own question. The ensuing chapters are more prescriptive than predictive, however. None of us knows where health care will be in 10 years, but we should think about where it ought to be.

Whether you chart on an Apple Watch or on paper, this discussion is important to you. Physicians are key players in determining where and how medicine is practiced, and we need to understand relevant risks and benefits to make the right decisions.

Confusing the matter is that desired outcomes are not absolute but relative. It depends on the frame of reference. Patients measure outcomes with service, payers with cost, and we physicians with quality. Which measurement is correct? How can we know if a remote monitoring device is worthwhile if we can’t agree on what it delivers? Is it simply sending home “the sicker even quicker?” Does a Big Pharma beyond-the-pill app really only increase consumption of the costliest medications or create more affordable alternatives?

Technologies that increase access to services such as live chat, messaging, and monitoring may be preferred by patients, but physicians see them as piling on to backbreaking loads. More artificial intelligence is needed to enable these services without requiring physician work. We need driverless health care.

Keeping patients involved has a whole other set of requirements. The tools must be easy, the information personal, the data actionable, and its use Candy-Crush-Saga addictive. This is no small feat, but there is hope.

Partner’s Text 2 Move program, which Dr. Kvedar describes as the “gold standard of what learning about your consumer means,” showed that highly personalized, targeted text messages could have a significant impact on patients’ behavior and health. It is just this type of technology that many are relentlessly pursuing to deliver care more effectively.

Dr. Kvedar devotes significant attention to the patient/consumer experience in a thoughtful, complex manner. Rather than elevate or denigrate the rise of the engaged patient, he examines this phenomenon through several lenses, addressing equally the concerns of practicing physicians and health care entrepreneurs. Nearly 20 years ago, Regina Herzlinger of Harvard Business School, Boston, predicted the rise of health care consumerism. Retail clinics, direct-to-consumer services, and the “Yelpification” of health care are signals that we’ve arrived.

It’s tough to make predictions, especially about the future, Yogi Berra warned us. The book’s mention of Theranos, the failing pinprick blood lab company founded by celebrity Stanford student Elizabeth Holmes, is an example of how risky it is to place bets on where we are headed and how quickly we will get there. DIY at-home labs are further off than they appeared, and that is the hazard of any such books: it is difficult to see more than what’s just in front of us.

Ultimately, Dr. Kvedar’s message is as realistic as it is optimistic: “The same information that could help drive healthcare costs down can be used to create highly individualized programs that will help people stay healthier and happier.” But we should resist the urge to ask “Are we there yet?” No. We’ve a ways to go.

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. Write to him at [email protected].

Health care is changing. For some, this is cause for celebration: A safer, convenient, more efficient system is upon us. For others, the end is nigh: impossibly demanding patients, crushing bureaucracy, and a once sacred relationship desecrated by invasive technology.

The ascent of digital health technologies is an important driver of health care change, yet its impact is still indeterminate. Any technology that empowers patients as well as physicians will improve patients’ health outcomes. Or so it might seem. The truth is more nuanced: Some services will improve outcomes, others won’t. Fitting Fitbits into our current system is like inserting the wrong key into a lock: It might go in, but it doesn’t open anything. Fortunately, some keys are opening doors to better care – doors that that we’ve never entered – but finding the right ones is laborious. Dr. Joe Kvedar is here to help.

As a physician leader who straddles the gap between physician-centered and consumer-centered health care, Dr. Kvedar has spent his career leveraging technology to improve care delivery for both. In his new book, “The Internet of Healthy Things,” he shares what he has learned. He uses numerous examples from his experience as a physician and pioneer in digital health care with Partners HealthCare, Boston, delving deeply into the business of health care and the behavioral habits of patients.

As he notes, Partners was “prescient” in the health care landscape, introducing video conferencing in the 1990s, second opinions on the Internet in 2001, and texting as a tool for health messaging in 2008. He asks now: “What are the connected health devices and applications that our clinicians will be using in 5-10 years?” Then he uses his acumen and research to answer his own question. The ensuing chapters are more prescriptive than predictive, however. None of us knows where health care will be in 10 years, but we should think about where it ought to be.

Whether you chart on an Apple Watch or on paper, this discussion is important to you. Physicians are key players in determining where and how medicine is practiced, and we need to understand relevant risks and benefits to make the right decisions.

Confusing the matter is that desired outcomes are not absolute but relative. It depends on the frame of reference. Patients measure outcomes with service, payers with cost, and we physicians with quality. Which measurement is correct? How can we know if a remote monitoring device is worthwhile if we can’t agree on what it delivers? Is it simply sending home “the sicker even quicker?” Does a Big Pharma beyond-the-pill app really only increase consumption of the costliest medications or create more affordable alternatives?

Technologies that increase access to services such as live chat, messaging, and monitoring may be preferred by patients, but physicians see them as piling on to backbreaking loads. More artificial intelligence is needed to enable these services without requiring physician work. We need driverless health care.

Keeping patients involved has a whole other set of requirements. The tools must be easy, the information personal, the data actionable, and its use Candy-Crush-Saga addictive. This is no small feat, but there is hope.

Partner’s Text 2 Move program, which Dr. Kvedar describes as the “gold standard of what learning about your consumer means,” showed that highly personalized, targeted text messages could have a significant impact on patients’ behavior and health. It is just this type of technology that many are relentlessly pursuing to deliver care more effectively.

Dr. Kvedar devotes significant attention to the patient/consumer experience in a thoughtful, complex manner. Rather than elevate or denigrate the rise of the engaged patient, he examines this phenomenon through several lenses, addressing equally the concerns of practicing physicians and health care entrepreneurs. Nearly 20 years ago, Regina Herzlinger of Harvard Business School, Boston, predicted the rise of health care consumerism. Retail clinics, direct-to-consumer services, and the “Yelpification” of health care are signals that we’ve arrived.

It’s tough to make predictions, especially about the future, Yogi Berra warned us. The book’s mention of Theranos, the failing pinprick blood lab company founded by celebrity Stanford student Elizabeth Holmes, is an example of how risky it is to place bets on where we are headed and how quickly we will get there. DIY at-home labs are further off than they appeared, and that is the hazard of any such books: it is difficult to see more than what’s just in front of us.

Ultimately, Dr. Kvedar’s message is as realistic as it is optimistic: “The same information that could help drive healthcare costs down can be used to create highly individualized programs that will help people stay healthier and happier.” But we should resist the urge to ask “Are we there yet?” No. We’ve a ways to go.

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. Write to him at [email protected].

Meletios A. Dimopoulos, MD

COPENHAGEN—The combination of daratumumab, lenalidomide, and dexamethasone (DRd) could become a new standard of care for patients with relapsed or refractory multiple myeloma (MM), according to a speaker at the 21st Congress of the European Hematology Association.

In the phase 3 POLLUX study, DRd conferred the highest response rate reported to date in the treatment of relapsed/refractory MM.

DRd also significantly improved progression free survival (PFS) when compared to treatment with lenalidomide and dexamethasone (Rd).

In addition, the safety profile of DRd was manageable and consistent with results observed in previous studies, according to Meletios A. Dimopoulos, MD, of the National and Kapodistrian University of Athens in Greece.

Dr Dimopoulos presented these results at the congress as abstract LB2238. The POLLUX study was funded by Janssen Research & Development, LLC.

Treatment and patients

POLLUX was a randomized, double-blind study that enrolled 569 patients with relapsed or refractory MM. Patients had received 1 or more prior lines of therapy and had progressive disease.

The patients were randomized to receive DRd (n=286) or Rd (n=283). All patients received lenalidomide at 25 mg on days 1-21 of each cycle until disease progression. They also received dexamethasone at 40 mg weekly until disease progression.

Patients in the daratumumab arm also received daratumumab at 16 mg/kg once a week in cycles 1-2, every other week in cycles 3-6, and once every 4 weeks until disease progression.

Dr Dimopoulos noted that patient and disease features were equally distributed between the treatment arms. The median age was 65 in both arms (overall range, 34-89). About half of patients in each arm had ISS stage I disease, and patients were, roughly, a median of 4 years from diagnosis.

In both arms, patients had a median of 1 prior lines of therapy (overall range, 1-11). Roughly 60% of patients in both arms had received a prior transplant, 86% had received a proteasome inhibitor, 55% had received an immunomodulatory agent, 18% had prior lenalidomide, and 44% had received a proteasome inhibitor and an immunomodulatory agent.

Roughly 28% of patients in each arm were refractory to a proteasome inhibitor, and nearly 30% were refractory to their last line of therapy.

Results

At a median follow-up of 13.5 months, about 35% of patients had discontinued treatment—23% in the DRd arm and 47% in the Rd arm.

Reasons for discontinuation included disease progression (14% and 34%, respectively), adverse events (7% and 8%, respectively), non-compliance with study drug (0.4% and 2%, respectively), withdrawal by patient (0.4% and 2%, respectively), physician decision (1% and 0.7%, respectively), and death (0.7% and 0.4%, respectively).

The study’s primary endpoint was PFS. The median PFS has not been reached in the DRd arm and was 18.4 months in the Rd arm. The 12-month PFS was 83% and 60%, respectively, and the 18-month PFS was 78% and 52%, respectively.

“There is an unprecedented improvement of progression-free survival in favor of daratumumab with lenalidomide and dexamethasone, with a hazard ratio of 0.37 [95% CI, 0.27-0.52; P<0.0001], which corresponds to a 63% reduction in the risk of progressive disease or death in favor of DRd,” Dr Dimopoulos said.

He also pointed out that the improvement in PFS for the DRd arm was seen across all patient subgroups, regardless of age, ISS stage, prior treatment, and type of MM.

Furthermore, response rates were significantly higher in the DRd arm than in the Rd arm. The overall response rates were 93% and 76%, respectively (P<0.0001). And the complete response rates were 43% and 19%, respectively (P<0.0001).

“This trial was associated with the highest response ever reported—so far, at least—in the treatment of relapsed/refractory myeloma,” Dr Dimopoulos noted.

The median duration of response was not reached in the DRd arm and was 17.4 months in the Rd arm.

In addition, there was an overall survival advantage with DRd. The 18-month overall survival was 86% in the DRd arm and 76% in the Rd arm. The hazard ratio was 0.64 (95% CI, 0.40-1.01; P=0.0534).

As for safety, the most common hematologic adverse events (in the DRd and Rd arms, respectively) were neutropenia (59% and 43%), anemia (31% and 35%), thrombocytopenia (27% for both), lymphopenia (6% and 5%), and febrile neutropenia (6% and 3%).

The most common non-hematologic adverse events (in the DRd and Rd arms, respectively) were diarrhea (43% and 25%), fatigue (35% and 28%), upper respiratory tract infection (32% and 21%), constipation (29% and 25%), cough (29% and 13%), muscle spasms (26% and 19%), and pneumonia (14% and 13%).

“DRd has a manageable safety profile consistent with the known safety profile of daratumumab or Rd alone,” Dr Dimopoulos said. “And we believe the combination of daratumumab with lenalidomide and dexamethasone potentially represents a new standard of care for myeloma patients after 1 or more prior lines of therapy.”

Meletios A. Dimopoulos, MD

COPENHAGEN—The combination of daratumumab, lenalidomide, and dexamethasone (DRd) could become a new standard of care for patients with relapsed or refractory multiple myeloma (MM), according to a speaker at the 21st Congress of the European Hematology Association.

In the phase 3 POLLUX study, DRd conferred the highest response rate reported to date in the treatment of relapsed/refractory MM.

DRd also significantly improved progression free survival (PFS) when compared to treatment with lenalidomide and dexamethasone (Rd).

In addition, the safety profile of DRd was manageable and consistent with results observed in previous studies, according to Meletios A. Dimopoulos, MD, of the National and Kapodistrian University of Athens in Greece.

Dr Dimopoulos presented these results at the congress as abstract LB2238. The POLLUX study was funded by Janssen Research & Development, LLC.

Treatment and patients

POLLUX was a randomized, double-blind study that enrolled 569 patients with relapsed or refractory MM. Patients had received 1 or more prior lines of therapy and had progressive disease.

The patients were randomized to receive DRd (n=286) or Rd (n=283). All patients received lenalidomide at 25 mg on days 1-21 of each cycle until disease progression. They also received dexamethasone at 40 mg weekly until disease progression.

Patients in the daratumumab arm also received daratumumab at 16 mg/kg once a week in cycles 1-2, every other week in cycles 3-6, and once every 4 weeks until disease progression.

Dr Dimopoulos noted that patient and disease features were equally distributed between the treatment arms. The median age was 65 in both arms (overall range, 34-89). About half of patients in each arm had ISS stage I disease, and patients were, roughly, a median of 4 years from diagnosis.

In both arms, patients had a median of 1 prior lines of therapy (overall range, 1-11). Roughly 60% of patients in both arms had received a prior transplant, 86% had received a proteasome inhibitor, 55% had received an immunomodulatory agent, 18% had prior lenalidomide, and 44% had received a proteasome inhibitor and an immunomodulatory agent.

Roughly 28% of patients in each arm were refractory to a proteasome inhibitor, and nearly 30% were refractory to their last line of therapy.

Results

At a median follow-up of 13.5 months, about 35% of patients had discontinued treatment—23% in the DRd arm and 47% in the Rd arm.

Reasons for discontinuation included disease progression (14% and 34%, respectively), adverse events (7% and 8%, respectively), non-compliance with study drug (0.4% and 2%, respectively), withdrawal by patient (0.4% and 2%, respectively), physician decision (1% and 0.7%, respectively), and death (0.7% and 0.4%, respectively).

The study’s primary endpoint was PFS. The median PFS has not been reached in the DRd arm and was 18.4 months in the Rd arm. The 12-month PFS was 83% and 60%, respectively, and the 18-month PFS was 78% and 52%, respectively.

“There is an unprecedented improvement of progression-free survival in favor of daratumumab with lenalidomide and dexamethasone, with a hazard ratio of 0.37 [95% CI, 0.27-0.52; P<0.0001], which corresponds to a 63% reduction in the risk of progressive disease or death in favor of DRd,” Dr Dimopoulos said.

He also pointed out that the improvement in PFS for the DRd arm was seen across all patient subgroups, regardless of age, ISS stage, prior treatment, and type of MM.

Furthermore, response rates were significantly higher in the DRd arm than in the Rd arm. The overall response rates were 93% and 76%, respectively (P<0.0001). And the complete response rates were 43% and 19%, respectively (P<0.0001).

“This trial was associated with the highest response ever reported—so far, at least—in the treatment of relapsed/refractory myeloma,” Dr Dimopoulos noted.

The median duration of response was not reached in the DRd arm and was 17.4 months in the Rd arm.

In addition, there was an overall survival advantage with DRd. The 18-month overall survival was 86% in the DRd arm and 76% in the Rd arm. The hazard ratio was 0.64 (95% CI, 0.40-1.01; P=0.0534).

As for safety, the most common hematologic adverse events (in the DRd and Rd arms, respectively) were neutropenia (59% and 43%), anemia (31% and 35%), thrombocytopenia (27% for both), lymphopenia (6% and 5%), and febrile neutropenia (6% and 3%).

The most common non-hematologic adverse events (in the DRd and Rd arms, respectively) were diarrhea (43% and 25%), fatigue (35% and 28%), upper respiratory tract infection (32% and 21%), constipation (29% and 25%), cough (29% and 13%), muscle spasms (26% and 19%), and pneumonia (14% and 13%).

“DRd has a manageable safety profile consistent with the known safety profile of daratumumab or Rd alone,” Dr Dimopoulos said. “And we believe the combination of daratumumab with lenalidomide and dexamethasone potentially represents a new standard of care for myeloma patients after 1 or more prior lines of therapy.”

Meletios A. Dimopoulos, MD

COPENHAGEN—The combination of daratumumab, lenalidomide, and dexamethasone (DRd) could become a new standard of care for patients with relapsed or refractory multiple myeloma (MM), according to a speaker at the 21st Congress of the European Hematology Association.

In the phase 3 POLLUX study, DRd conferred the highest response rate reported to date in the treatment of relapsed/refractory MM.

DRd also significantly improved progression free survival (PFS) when compared to treatment with lenalidomide and dexamethasone (Rd).

In addition, the safety profile of DRd was manageable and consistent with results observed in previous studies, according to Meletios A. Dimopoulos, MD, of the National and Kapodistrian University of Athens in Greece.

Dr Dimopoulos presented these results at the congress as abstract LB2238. The POLLUX study was funded by Janssen Research & Development, LLC.

Treatment and patients

POLLUX was a randomized, double-blind study that enrolled 569 patients with relapsed or refractory MM. Patients had received 1 or more prior lines of therapy and had progressive disease.

The patients were randomized to receive DRd (n=286) or Rd (n=283). All patients received lenalidomide at 25 mg on days 1-21 of each cycle until disease progression. They also received dexamethasone at 40 mg weekly until disease progression.

Patients in the daratumumab arm also received daratumumab at 16 mg/kg once a week in cycles 1-2, every other week in cycles 3-6, and once every 4 weeks until disease progression.

Dr Dimopoulos noted that patient and disease features were equally distributed between the treatment arms. The median age was 65 in both arms (overall range, 34-89). About half of patients in each arm had ISS stage I disease, and patients were, roughly, a median of 4 years from diagnosis.

In both arms, patients had a median of 1 prior lines of therapy (overall range, 1-11). Roughly 60% of patients in both arms had received a prior transplant, 86% had received a proteasome inhibitor, 55% had received an immunomodulatory agent, 18% had prior lenalidomide, and 44% had received a proteasome inhibitor and an immunomodulatory agent.

Roughly 28% of patients in each arm were refractory to a proteasome inhibitor, and nearly 30% were refractory to their last line of therapy.

Results

At a median follow-up of 13.5 months, about 35% of patients had discontinued treatment—23% in the DRd arm and 47% in the Rd arm.

Reasons for discontinuation included disease progression (14% and 34%, respectively), adverse events (7% and 8%, respectively), non-compliance with study drug (0.4% and 2%, respectively), withdrawal by patient (0.4% and 2%, respectively), physician decision (1% and 0.7%, respectively), and death (0.7% and 0.4%, respectively).

The study’s primary endpoint was PFS. The median PFS has not been reached in the DRd arm and was 18.4 months in the Rd arm. The 12-month PFS was 83% and 60%, respectively, and the 18-month PFS was 78% and 52%, respectively.

“There is an unprecedented improvement of progression-free survival in favor of daratumumab with lenalidomide and dexamethasone, with a hazard ratio of 0.37 [95% CI, 0.27-0.52; P<0.0001], which corresponds to a 63% reduction in the risk of progressive disease or death in favor of DRd,” Dr Dimopoulos said.

He also pointed out that the improvement in PFS for the DRd arm was seen across all patient subgroups, regardless of age, ISS stage, prior treatment, and type of MM.

Furthermore, response rates were significantly higher in the DRd arm than in the Rd arm. The overall response rates were 93% and 76%, respectively (P<0.0001). And the complete response rates were 43% and 19%, respectively (P<0.0001).

“This trial was associated with the highest response ever reported—so far, at least—in the treatment of relapsed/refractory myeloma,” Dr Dimopoulos noted.

The median duration of response was not reached in the DRd arm and was 17.4 months in the Rd arm.

In addition, there was an overall survival advantage with DRd. The 18-month overall survival was 86% in the DRd arm and 76% in the Rd arm. The hazard ratio was 0.64 (95% CI, 0.40-1.01; P=0.0534).

As for safety, the most common hematologic adverse events (in the DRd and Rd arms, respectively) were neutropenia (59% and 43%), anemia (31% and 35%), thrombocytopenia (27% for both), lymphopenia (6% and 5%), and febrile neutropenia (6% and 3%).

The most common non-hematologic adverse events (in the DRd and Rd arms, respectively) were diarrhea (43% and 25%), fatigue (35% and 28%), upper respiratory tract infection (32% and 21%), constipation (29% and 25%), cough (29% and 13%), muscle spasms (26% and 19%), and pneumonia (14% and 13%).

“DRd has a manageable safety profile consistent with the known safety profile of daratumumab or Rd alone,” Dr Dimopoulos said. “And we believe the combination of daratumumab with lenalidomide and dexamethasone potentially represents a new standard of care for myeloma patients after 1 or more prior lines of therapy.”

Genome testing

Photo courtesy of NIGMS

Using patient samples from 3 prospective multicenter clinical trials of the German-Austrian AML Study Group, researchers have identified 5234 driver mutations involving 76 genes or regions in 1540 patients with acute myeloid leukemia (AML).

They say the sample size afforded a more comprehensive analysis than previously conducted, and as a result, they found patients were divided into at least 11 subgroups of AML.

They also identified 3 genomic categories beyond the existing World Health Organization (WHO) subgroups. These genomic categories are chromatin–spliceosome mutations, TP53–aneuploidy, and provisionally, IDH2^R172 mutations.

Their study, led by scientists at the Wellcome Trust Sanger Institute and international collaborators, could have an impact on clinical trial design and improve the way patients are diagnosed and treated in the future.

The scientists stated in their published paper that 736 patients (48%) in their study would not have fit into the molecular groups included in the 2008 WHO classification of adult AML. This prompted them to reevaluate genomic classification of AML from the beginning.

“We have shown that AML is an umbrella term for a group of at least 11 different types of leukemia,” said Peter Campbell, MBChB, PhD, co-leader of the study. “We can now start to decode these genetics to shape clinical trials and develop diagnostics.”

The scientists found NPM1-mutated AML to be the largest class in their cohort, accounting for 27% of the patients.

The second largest subgroup--the chromatin-spliceosome group—accounted for 18% of patients, the TP53-aneuploidy group accounted for 13%, and the IDH2^R172 mutations for 1%.

The study also showed that most patients had a unique combination of genetic changes driving their leukemia. This genetic complexity helps explain why AML shows such variability in survival rates among patients.

Under their new schema, the scientists were able to unambiguously classify 80% of the 1540 patients with driver mutations in a single subgroup. Fifty-six of the patients (4%) met criteria for 2 or more categories, primarily in the TP53-aneuploidy and chromatin-spliceosome groups.

They were not able to classify 11% of patients with driver mutations. They explained that these patients might have had mutations in drivers that were either not sequenced or had mutations that were missed.

The scientists applied their classification schema to an independent cohort from the Cancer Genome Atlas (TCGA). The new schema was able to replicate the absence of overlap among subgroups, and relative frequencies of the mutations were equivalent to those in the AML cohort.

“For the first time we untangled the genetic complexity seen in most AML cancer genomes into distinct evolutionary paths that lead to AML,” joint first author Elli Papaemmanuil, PhD, of Memorial Sloan Kettering Cancer Center in New York, said.

“By understanding these paths, we can help develop more appropriate treatments for individual patients with AML. We are now extending such studies across other leukemias."

The investigators recommend prospective clinical trials to further validate the schema.

The work was supported by the Wellcome Trust, Bundesministerium fur Bildung und Forschung, Deutsche Krebshilfe and Deutsche Forschungsgemeinschaft, the European Hematology Association, Amgen and the Kay Kendall Leukaemia Fund.

Genome testing

Photo courtesy of NIGMS

Using patient samples from 3 prospective multicenter clinical trials of the German-Austrian AML Study Group, researchers have identified 5234 driver mutations involving 76 genes or regions in 1540 patients with acute myeloid leukemia (AML).

They say the sample size afforded a more comprehensive analysis than previously conducted, and as a result, they found patients were divided into at least 11 subgroups of AML.

They also identified 3 genomic categories beyond the existing World Health Organization (WHO) subgroups. These genomic categories are chromatin–spliceosome mutations, TP53–aneuploidy, and provisionally, IDH2^R172 mutations.

Their study, led by scientists at the Wellcome Trust Sanger Institute and international collaborators, could have an impact on clinical trial design and improve the way patients are diagnosed and treated in the future.

The scientists stated in their published paper that 736 patients (48%) in their study would not have fit into the molecular groups included in the 2008 WHO classification of adult AML. This prompted them to reevaluate genomic classification of AML from the beginning.

“We have shown that AML is an umbrella term for a group of at least 11 different types of leukemia,” said Peter Campbell, MBChB, PhD, co-leader of the study. “We can now start to decode these genetics to shape clinical trials and develop diagnostics.”

The scientists found NPM1-mutated AML to be the largest class in their cohort, accounting for 27% of the patients.

The second largest subgroup--the chromatin-spliceosome group—accounted for 18% of patients, the TP53-aneuploidy group accounted for 13%, and the IDH2^R172 mutations for 1%.

The study also showed that most patients had a unique combination of genetic changes driving their leukemia. This genetic complexity helps explain why AML shows such variability in survival rates among patients.

Under their new schema, the scientists were able to unambiguously classify 80% of the 1540 patients with driver mutations in a single subgroup. Fifty-six of the patients (4%) met criteria for 2 or more categories, primarily in the TP53-aneuploidy and chromatin-spliceosome groups.

They were not able to classify 11% of patients with driver mutations. They explained that these patients might have had mutations in drivers that were either not sequenced or had mutations that were missed.

The scientists applied their classification schema to an independent cohort from the Cancer Genome Atlas (TCGA). The new schema was able to replicate the absence of overlap among subgroups, and relative frequencies of the mutations were equivalent to those in the AML cohort.

“For the first time we untangled the genetic complexity seen in most AML cancer genomes into distinct evolutionary paths that lead to AML,” joint first author Elli Papaemmanuil, PhD, of Memorial Sloan Kettering Cancer Center in New York, said.

“By understanding these paths, we can help develop more appropriate treatments for individual patients with AML. We are now extending such studies across other leukemias."

The investigators recommend prospective clinical trials to further validate the schema.

The work was supported by the Wellcome Trust, Bundesministerium fur Bildung und Forschung, Deutsche Krebshilfe and Deutsche Forschungsgemeinschaft, the European Hematology Association, Amgen and the Kay Kendall Leukaemia Fund.

Genome testing

Photo courtesy of NIGMS

Using patient samples from 3 prospective multicenter clinical trials of the German-Austrian AML Study Group, researchers have identified 5234 driver mutations involving 76 genes or regions in 1540 patients with acute myeloid leukemia (AML).

They say the sample size afforded a more comprehensive analysis than previously conducted, and as a result, they found patients were divided into at least 11 subgroups of AML.

They also identified 3 genomic categories beyond the existing World Health Organization (WHO) subgroups. These genomic categories are chromatin–spliceosome mutations, TP53–aneuploidy, and provisionally, IDH2^R172 mutations.

Their study, led by scientists at the Wellcome Trust Sanger Institute and international collaborators, could have an impact on clinical trial design and improve the way patients are diagnosed and treated in the future.

The scientists stated in their published paper that 736 patients (48%) in their study would not have fit into the molecular groups included in the 2008 WHO classification of adult AML. This prompted them to reevaluate genomic classification of AML from the beginning.

“We have shown that AML is an umbrella term for a group of at least 11 different types of leukemia,” said Peter Campbell, MBChB, PhD, co-leader of the study. “We can now start to decode these genetics to shape clinical trials and develop diagnostics.”

The scientists found NPM1-mutated AML to be the largest class in their cohort, accounting for 27% of the patients.

The second largest subgroup--the chromatin-spliceosome group—accounted for 18% of patients, the TP53-aneuploidy group accounted for 13%, and the IDH2^R172 mutations for 1%.

The study also showed that most patients had a unique combination of genetic changes driving their leukemia. This genetic complexity helps explain why AML shows such variability in survival rates among patients.

Under their new schema, the scientists were able to unambiguously classify 80% of the 1540 patients with driver mutations in a single subgroup. Fifty-six of the patients (4%) met criteria for 2 or more categories, primarily in the TP53-aneuploidy and chromatin-spliceosome groups.

They were not able to classify 11% of patients with driver mutations. They explained that these patients might have had mutations in drivers that were either not sequenced or had mutations that were missed.

The scientists applied their classification schema to an independent cohort from the Cancer Genome Atlas (TCGA). The new schema was able to replicate the absence of overlap among subgroups, and relative frequencies of the mutations were equivalent to those in the AML cohort.

“For the first time we untangled the genetic complexity seen in most AML cancer genomes into distinct evolutionary paths that lead to AML,” joint first author Elli Papaemmanuil, PhD, of Memorial Sloan Kettering Cancer Center in New York, said.

“By understanding these paths, we can help develop more appropriate treatments for individual patients with AML. We are now extending such studies across other leukemias."

The investigators recommend prospective clinical trials to further validate the schema.

The work was supported by the Wellcome Trust, Bundesministerium fur Bildung und Forschung, Deutsche Krebshilfe and Deutsche Forschungsgemeinschaft, the European Hematology Association, Amgen and the Kay Kendall Leukaemia Fund.

Skin biopsy showing GVHD
Image courtesy of PLOS ONE

A team of researchers has found that risk-stratified, low-dose corticosteroid prophylaxis can significantly reduce the incidence of acute graft-versus-host disease (GVHD), accelerate platelet recovery, and reduce adverse events without increasing infections in patients who undergo haploidentical transplantation.

They believe this is the first test of a novel risk stratification–directed prophylaxis strategy. The strategy effectively prevented acute GVHD among patients who were at high risk for GVHD, without unnecessarily exposing patients who were at low risk to excessive toxicity from additional immunosuppressive agents.

To evaluate the prophylaxis strategy, the team enrolled 228 patients who underwent haploidentical transplant onto this controlled, open-label, randomized trial.

Corresponding author Xiao-Jun Huang, MD, of Peking University in Beijing, China, and colleagues reported the results in JCO.

The team stratified patients as high risk or low risk for developing GVHD based on biomarkers.

They categorized patients as high risk if they had CD4:CD8 ratios of 1.15 or greater in bone marrow grafts or more than 1.9 x 10⁶/kg CD56^bright NK cells in allogeneic grafts.

Patients who did not qualify for the high-risk group were considered to be low risk.

The team randomly assigned the high-risk patients to either receive or not receive the investigational intervention of methylprednisolone (MP).

All patients received cyclosporine, mycophenolate mofetil, and methotrexate for GVHD prevention.

Patients in any arm who developed acute GVHD higher than grade II received MP. If they did not respond, they received basiliximab.

Study population

Of the 228 patients enrolled, 83 were in the low-risk group, 72 in the high-risk experimental prophylaxis group, and 73 in the high-risk control group.

Patient characteristics were similar across all cohorts, including the conditioning regimens, except for their biomarker status.

Patients were a median age of about 30 years, (range 14 – 58), about half were male, and most had a diagnosis of acute myeloid leukemia or acute lymphoblastic leukemia.

GVHD incidence

The cumulative, 100-day incidence of acute GVHD grades II to IV was 21% in the high-risk prophylaxis arm.

This was similar to the incidence of 26% in the low-risk arm, P=0.43.

Both cohorts were significantly lower than the incidence of 48% in the high-risk control group, P<0.001.

Multivariate analysis showed that risk-stratified prophylaxis with low-dose corticosteroid significantly reduced the incidence of acute GVHD compared with no low-dose corticosteroid, with a hazard ratio of 0.66, P=0.007.

However, investigators found no differences between cohorts in the incidence of grades III to IV GVHD.

Corticosteroid-refractory acute GVHD developed in 14% of high-risk patients in the experimental arm, 18% in the control arm, and 23% in the low-risk group. Basiliximab, an anti-CD25 antibody, was used to treat it.

Hematopoietic and immune recovery

The median times to myeloid and platelet recovery were significantly shorter in the high-risk prophylaxis group (P<0.05 for both) and the low-risk group (P<0.05) than in the high-risk control group.

And immune reconstitution was comparable among all 3 cohorts.

Safety

Cumulative incidences among the low-risk, high-risk prophylaxis, and high-risk control groups, respectively, of cytomegalovirus reactivation (80%, 82%, 81%), Epstein-Barr virus reactivation (7%, 14%, 14%), post-transplantation lymphoproliferative disorder (0%, 1%, 4%), hemorrhagic cystitis (56%, 45%, 47%), bacteremia (13%, 10%, 11%), and invasive fungal infection (11%, 8%, 8%) were similar across the cohorts.

Osteonecrosis of the femoral head (P=0.034) and secondary hypertension (P=0.015) were significantly lower in the high-risk prophylaxis group than in the high-risk control group.

Transplant outcomes

Transplant outcomes, both relapse and non-relapse mortality at 100 days and 1 year, were similar among the 3 cohorts.

After a median follow-up of 505 days, the cumulative incidence of chronic GVHD was 44% in the high-risk prophylaxis group, 64% in the low-risk group, and 59% in the high-risk control group.

However, moderate to severe chronic GVHD was lower in the high-risk prophylaxis group, at 21%, compared to 50% in the low-risk group and 36% in the high-risk control group.

Thirty-two patients died of non-relapse causes, and the 3-year probabilities of leukemia-free survival and overall survival were similar among the 3 groups.

Skin biopsy showing GVHD
Image courtesy of PLOS ONE

A team of researchers has found that risk-stratified, low-dose corticosteroid prophylaxis can significantly reduce the incidence of acute graft-versus-host disease (GVHD), accelerate platelet recovery, and reduce adverse events without increasing infections in patients who undergo haploidentical transplantation.

They believe this is the first test of a novel risk stratification–directed prophylaxis strategy. The strategy effectively prevented acute GVHD among patients who were at high risk for GVHD, without unnecessarily exposing patients who were at low risk to excessive toxicity from additional immunosuppressive agents.

To evaluate the prophylaxis strategy, the team enrolled 228 patients who underwent haploidentical transplant onto this controlled, open-label, randomized trial.

Corresponding author Xiao-Jun Huang, MD, of Peking University in Beijing, China, and colleagues reported the results in JCO.

The team stratified patients as high risk or low risk for developing GVHD based on biomarkers.

They categorized patients as high risk if they had CD4:CD8 ratios of 1.15 or greater in bone marrow grafts or more than 1.9 x 10⁶/kg CD56^bright NK cells in allogeneic grafts.

Patients who did not qualify for the high-risk group were considered to be low risk.

The team randomly assigned the high-risk patients to either receive or not receive the investigational intervention of methylprednisolone (MP).

All patients received cyclosporine, mycophenolate mofetil, and methotrexate for GVHD prevention.

Patients in any arm who developed acute GVHD higher than grade II received MP. If they did not respond, they received basiliximab.

Study population

Of the 228 patients enrolled, 83 were in the low-risk group, 72 in the high-risk experimental prophylaxis group, and 73 in the high-risk control group.

Patient characteristics were similar across all cohorts, including the conditioning regimens, except for their biomarker status.

Patients were a median age of about 30 years, (range 14 – 58), about half were male, and most had a diagnosis of acute myeloid leukemia or acute lymphoblastic leukemia.

GVHD incidence

The cumulative, 100-day incidence of acute GVHD grades II to IV was 21% in the high-risk prophylaxis arm.

This was similar to the incidence of 26% in the low-risk arm, P=0.43.

Both cohorts were significantly lower than the incidence of 48% in the high-risk control group, P<0.001.

Multivariate analysis showed that risk-stratified prophylaxis with low-dose corticosteroid significantly reduced the incidence of acute GVHD compared with no low-dose corticosteroid, with a hazard ratio of 0.66, P=0.007.

However, investigators found no differences between cohorts in the incidence of grades III to IV GVHD.

Corticosteroid-refractory acute GVHD developed in 14% of high-risk patients in the experimental arm, 18% in the control arm, and 23% in the low-risk group. Basiliximab, an anti-CD25 antibody, was used to treat it.

Hematopoietic and immune recovery

The median times to myeloid and platelet recovery were significantly shorter in the high-risk prophylaxis group (P<0.05 for both) and the low-risk group (P<0.05) than in the high-risk control group.

And immune reconstitution was comparable among all 3 cohorts.

Safety

Cumulative incidences among the low-risk, high-risk prophylaxis, and high-risk control groups, respectively, of cytomegalovirus reactivation (80%, 82%, 81%), Epstein-Barr virus reactivation (7%, 14%, 14%), post-transplantation lymphoproliferative disorder (0%, 1%, 4%), hemorrhagic cystitis (56%, 45%, 47%), bacteremia (13%, 10%, 11%), and invasive fungal infection (11%, 8%, 8%) were similar across the cohorts.

Osteonecrosis of the femoral head (P=0.034) and secondary hypertension (P=0.015) were significantly lower in the high-risk prophylaxis group than in the high-risk control group.

Transplant outcomes

Transplant outcomes, both relapse and non-relapse mortality at 100 days and 1 year, were similar among the 3 cohorts.

After a median follow-up of 505 days, the cumulative incidence of chronic GVHD was 44% in the high-risk prophylaxis group, 64% in the low-risk group, and 59% in the high-risk control group.

However, moderate to severe chronic GVHD was lower in the high-risk prophylaxis group, at 21%, compared to 50% in the low-risk group and 36% in the high-risk control group.

Thirty-two patients died of non-relapse causes, and the 3-year probabilities of leukemia-free survival and overall survival were similar among the 3 groups.

Skin biopsy showing GVHD
Image courtesy of PLOS ONE

A team of researchers has found that risk-stratified, low-dose corticosteroid prophylaxis can significantly reduce the incidence of acute graft-versus-host disease (GVHD), accelerate platelet recovery, and reduce adverse events without increasing infections in patients who undergo haploidentical transplantation.

They believe this is the first test of a novel risk stratification–directed prophylaxis strategy. The strategy effectively prevented acute GVHD among patients who were at high risk for GVHD, without unnecessarily exposing patients who were at low risk to excessive toxicity from additional immunosuppressive agents.

To evaluate the prophylaxis strategy, the team enrolled 228 patients who underwent haploidentical transplant onto this controlled, open-label, randomized trial.

Corresponding author Xiao-Jun Huang, MD, of Peking University in Beijing, China, and colleagues reported the results in JCO.

The team stratified patients as high risk or low risk for developing GVHD based on biomarkers.

They categorized patients as high risk if they had CD4:CD8 ratios of 1.15 or greater in bone marrow grafts or more than 1.9 x 10⁶/kg CD56^bright NK cells in allogeneic grafts.

Patients who did not qualify for the high-risk group were considered to be low risk.

The team randomly assigned the high-risk patients to either receive or not receive the investigational intervention of methylprednisolone (MP).

All patients received cyclosporine, mycophenolate mofetil, and methotrexate for GVHD prevention.

Patients in any arm who developed acute GVHD higher than grade II received MP. If they did not respond, they received basiliximab.

Study population

Of the 228 patients enrolled, 83 were in the low-risk group, 72 in the high-risk experimental prophylaxis group, and 73 in the high-risk control group.

Patient characteristics were similar across all cohorts, including the conditioning regimens, except for their biomarker status.

Patients were a median age of about 30 years, (range 14 – 58), about half were male, and most had a diagnosis of acute myeloid leukemia or acute lymphoblastic leukemia.

GVHD incidence

The cumulative, 100-day incidence of acute GVHD grades II to IV was 21% in the high-risk prophylaxis arm.

This was similar to the incidence of 26% in the low-risk arm, P=0.43.

Both cohorts were significantly lower than the incidence of 48% in the high-risk control group, P<0.001.

Multivariate analysis showed that risk-stratified prophylaxis with low-dose corticosteroid significantly reduced the incidence of acute GVHD compared with no low-dose corticosteroid, with a hazard ratio of 0.66, P=0.007.

However, investigators found no differences between cohorts in the incidence of grades III to IV GVHD.

Corticosteroid-refractory acute GVHD developed in 14% of high-risk patients in the experimental arm, 18% in the control arm, and 23% in the low-risk group. Basiliximab, an anti-CD25 antibody, was used to treat it.

Hematopoietic and immune recovery

The median times to myeloid and platelet recovery were significantly shorter in the high-risk prophylaxis group (P<0.05 for both) and the low-risk group (P<0.05) than in the high-risk control group.

And immune reconstitution was comparable among all 3 cohorts.

Safety

Cumulative incidences among the low-risk, high-risk prophylaxis, and high-risk control groups, respectively, of cytomegalovirus reactivation (80%, 82%, 81%), Epstein-Barr virus reactivation (7%, 14%, 14%), post-transplantation lymphoproliferative disorder (0%, 1%, 4%), hemorrhagic cystitis (56%, 45%, 47%), bacteremia (13%, 10%, 11%), and invasive fungal infection (11%, 8%, 8%) were similar across the cohorts.

Osteonecrosis of the femoral head (P=0.034) and secondary hypertension (P=0.015) were significantly lower in the high-risk prophylaxis group than in the high-risk control group.

Transplant outcomes

Transplant outcomes, both relapse and non-relapse mortality at 100 days and 1 year, were similar among the 3 cohorts.

After a median follow-up of 505 days, the cumulative incidence of chronic GVHD was 44% in the high-risk prophylaxis group, 64% in the low-risk group, and 59% in the high-risk control group.

However, moderate to severe chronic GVHD was lower in the high-risk prophylaxis group, at 21%, compared to 50% in the low-risk group and 36% in the high-risk control group.

Thirty-two patients died of non-relapse causes, and the 3-year probabilities of leukemia-free survival and overall survival were similar among the 3 groups.

Presurgical neoadjuvant chemotherapy (NACT) altered the immune microenvironment in patients with stage IIIC/IV tubo-ovarian high-grade serous carcinoma (HGSC), perhaps enhancing the potential response to immunotherapy, investigators report.

“The results suggest that the effects of immunotherapy might be enhanced if given after chemotherapy, potentially improving disease control in patients with advanced HGSC and other cancer types,” wrote Dr. Steffen Bohm of Barts Cancer Institute in London and his associates (CCR. 2016. doi: 10.1158/1078-0432.CCR-15-2657).

Dr. Bohm and associates collected pre- and postchemotherapy biopsies and blood samples from 60 patients with stage IIIC or IV HGSC; 54 patients underwent platinum-based neoadjuvant chemotherapy and 6 received chemotherapy after debulking surgery. The investigators used immunohistochemistry and RNA sequencing to evaluate the changes before and after chemotherapy. The patients were grouped by their response to chemotherapy.

Results indicated that NACT induced T cell activation, with results most pronounced among those who had a good response to chemotherapy. Among a subset of 25 patients, omental metastases biopsies indicated CD8+ T cells and memory cells were present in the tumors after NACT. Proinflammatory cytokines decreased in all patients following NACT.

Immunohistochemical staining for PD-1 ligands showed that PD-L1 levels were significantly increased in post-NACT samples regardless of a patient’s response to chemotherapy.

“Our results suggest that NACT opens a window of opportunity for immunotherapies such as immune checkpoint blockade for patients with different levels of response to chemotherapy,” Dr. Bohm and associates said.

The study was funded by the Swiss Cancer League, the European Research Council, Cancer Research UK, and Barts and The London Charity. The authors had no relevant disclosures to report.

[email protected]

On Twitter @jessnicolecraig

Presurgical neoadjuvant chemotherapy (NACT) altered the immune microenvironment in patients with stage IIIC/IV tubo-ovarian high-grade serous carcinoma (HGSC), perhaps enhancing the potential response to immunotherapy, investigators report.

“The results suggest that the effects of immunotherapy might be enhanced if given after chemotherapy, potentially improving disease control in patients with advanced HGSC and other cancer types,” wrote Dr. Steffen Bohm of Barts Cancer Institute in London and his associates (CCR. 2016. doi: 10.1158/1078-0432.CCR-15-2657).

Dr. Bohm and associates collected pre- and postchemotherapy biopsies and blood samples from 60 patients with stage IIIC or IV HGSC; 54 patients underwent platinum-based neoadjuvant chemotherapy and 6 received chemotherapy after debulking surgery. The investigators used immunohistochemistry and RNA sequencing to evaluate the changes before and after chemotherapy. The patients were grouped by their response to chemotherapy.

Results indicated that NACT induced T cell activation, with results most pronounced among those who had a good response to chemotherapy. Among a subset of 25 patients, omental metastases biopsies indicated CD8+ T cells and memory cells were present in the tumors after NACT. Proinflammatory cytokines decreased in all patients following NACT.

Immunohistochemical staining for PD-1 ligands showed that PD-L1 levels were significantly increased in post-NACT samples regardless of a patient’s response to chemotherapy.

“Our results suggest that NACT opens a window of opportunity for immunotherapies such as immune checkpoint blockade for patients with different levels of response to chemotherapy,” Dr. Bohm and associates said.

The study was funded by the Swiss Cancer League, the European Research Council, Cancer Research UK, and Barts and The London Charity. The authors had no relevant disclosures to report.

[email protected]

On Twitter @jessnicolecraig

Presurgical neoadjuvant chemotherapy (NACT) altered the immune microenvironment in patients with stage IIIC/IV tubo-ovarian high-grade serous carcinoma (HGSC), perhaps enhancing the potential response to immunotherapy, investigators report.

“The results suggest that the effects of immunotherapy might be enhanced if given after chemotherapy, potentially improving disease control in patients with advanced HGSC and other cancer types,” wrote Dr. Steffen Bohm of Barts Cancer Institute in London and his associates (CCR. 2016. doi: 10.1158/1078-0432.CCR-15-2657).

Dr. Bohm and associates collected pre- and postchemotherapy biopsies and blood samples from 60 patients with stage IIIC or IV HGSC; 54 patients underwent platinum-based neoadjuvant chemotherapy and 6 received chemotherapy after debulking surgery. The investigators used immunohistochemistry and RNA sequencing to evaluate the changes before and after chemotherapy. The patients were grouped by their response to chemotherapy.

Results indicated that NACT induced T cell activation, with results most pronounced among those who had a good response to chemotherapy. Among a subset of 25 patients, omental metastases biopsies indicated CD8+ T cells and memory cells were present in the tumors after NACT. Proinflammatory cytokines decreased in all patients following NACT.

Immunohistochemical staining for PD-1 ligands showed that PD-L1 levels were significantly increased in post-NACT samples regardless of a patient’s response to chemotherapy.

“Our results suggest that NACT opens a window of opportunity for immunotherapies such as immune checkpoint blockade for patients with different levels of response to chemotherapy,” Dr. Bohm and associates said.

The study was funded by the Swiss Cancer League, the European Research Council, Cancer Research UK, and Barts and The London Charity. The authors had no relevant disclosures to report.

[email protected]

On Twitter @jessnicolecraig

LONDON – Cardiovascular disease (CVD) risk assessment for patients with rheumatic diseases can be simple and integrated into general practice or rheumatology clinics, experts said during an Outcomes Science Session at the European Congress of Rheumatology

Patients with rheumatoid arthritis have a 50% higher risk of heart disease than do their counterparts without the disease, but “just having RA on its own isn’t sufficient to render that individual at high risk,” Dr. Naveed Sattar, professor of metabolic medicine at the University of Glasgow’s Institute of Cardiovascular and Medical Sciences in Scotland, said in an interview.

It’s simple enough to use traditional CVD risk factors in an RA population by including a patient’s age, gender, smoking status, and family history of heart disease, in addition to measuring blood pressure and blood lipid levels. Most risk scores will compile those features into a 10-year risk of a fatal CVD event. To account for the contribution of RA, Dr. Sattar said, simply multiply that score by 1.5.

While “there’s a fixation in some parts of Europe for [measuring] fasting lipids,” it is not necessary, Dr. Sattar said. The two lipid parameters that go in risk scores tend to be cholesterol and HDL cholesterol, he said, which change only minimally in fasting versus nonfasting states.

“The evidence overwhelmingly shows that nonfasting lipids, which can be done easily on the same sample as other clinic tests, are just as predictive of CVD risk as fasting lipids,” he said. “That really matters because many of our patients with RA or other conditions come to the hospital when they’re not fasting, and we shouldn’t be sending them away to come back fasting to do risk scores for CVD. That just doesn’t make sense.”

Updated guidelines from the European Society of Cardiology and guidelines soon to be released from the European League Against Rheumatism suggest that risk scores can be calculated every 5 years for most patients, a change from previous recommendations to calculate risk annually. Risk scoring is not perfect, however, and there is some debate about whether additional blood tests or ultrasound scanning of the carotid artery could augment the ability to predict heart disease risk. “We’re not quite there yet,” Dr. Sattar said. “I think we should do the simple things first and do them well.”

CV risk raised in all inflammatory arthritic diseases

During the same session, Dr. Paola de Pablo of the University of Birmingham, England, focused on how immune-mediated diseases predispose to premature, accelerated atherosclerosis and subsequent increased cardiovascular morbidity and mortality.

Cardiovascular risk is not only elevated in those with RA, she observed, but also in those with systemic lupus erythematosus, ankylosing spondylitis, psoriatic arthritis, vasculitides, and inflammatory myopathies. The risk varies but as a rule is more than 50% higher than the rate seen in the general population.

The underlying mechanisms are not clear, but chronic inflammation is closely linked with atherosclerosis, which in turn ups the risk for myocardial infarction and cerebrovascular accident.

Despite treatment, the risk often remains, Dr. de Pablo said. She highlighted how treatment with methotrexate and anti–tumor necrosis factor (TNF)–alpha drugs in RA had been associated with a reduction in the risk for heart attack of 20% and 40%, respectively (Ann Rheum Dis. 2014;74:480–89) so targeting inflammation with these drugs may have positive effects, at least in RA.

Managing traditional cardiovascular risk factors remains important, Dr. de Pablo said. That was a sentiment echoed by Dr. Sattar and by rheumatologist Dr. Michael Nurmohamed of the VU Medical Center in Amsterdam. This includes controlling blood pressure with antihypertensive medications and blood lipids with statins, and advocating smoking cessation and perhaps other appropriate lifestyle changes such as increasing physical exercise and controlling weight.

Dr. Nurmohamed, who was involved in the 2015 update of the EULAR recommendations on cardiovascular risk management, noted that traditional risk factor management in patients with arthritis in current clinical practice is often poor and that strategies to address this were urgently needed.

Although treating to-target and preventing disease flares in the rheumatic diseases is important, it lowers but does not normalize cardiovascular risk. “This appears to be irrespective of the drug used,” Dr. Nurmohamed said. Rheumatologists need to be careful when tapering medication, particularly the biologics, as these are perhaps helping to temper cardiovascular inflammation, which could worsen when doses are reduced. “Antirheumatic treatment only is not good enough to decrease or normalize the cardiovascular risk of our patients”, he emphasized.

Norwegian project shows how to integrate CVD assessment into routine practice

In a separate presentation, Dr. Eirik Ikdahl, a PhD student at Diakonhjemmet Hospital in Oslo, discussed how some rheumatology clinics in Norway are successfully incorporating CVD risk screening.

Through the Norwegian Collaboration on Atherosclerotic disease in patients with Rheumatic joint diseases (NOCAR), which started in April 2014, annual cardiovascular disease risk evaluations of patients with inflammatory joint diseases are being implemented into the practices of 11 rheumatology outpatient clinics. While waiting for clinic appointments, patients are given electronic devices through which they can report CVD risk factors via an electronic patient journal program called GoTreatIt Rheuma. From there, the clinic can order nonfasting lipid measurements and nurses can record patients’ blood pressure. 

Then, using the ESC Systematic Coronary Risk Evaluation (SCORE) algorithm, the program automatically calculates a patient’s 10-year risk of a fatal CVD event. If the SCORE estimate is 5% or greater, the rheumatologist forwards a note to the patient’s primary care physician or cardiologist saying there is an indication for initiation of CVD-preventive measures such as medication or lifestyle changes. Rheumatologists and rheumatology nurses also deliver brief advice regarding smoking cessation and healthy diet.

“The main aim of the project is to raise awareness of the cardiovascular burden that these patients experience, and to ensure that patients with inflammatory joint diseases receive guideline-recommended cardiovascular preventive treatment,” Dr. Ikdahl said.

Of 6,150 patients defined as eligible for the NOCAR project in three of the centers, 41% (n = 2,519) received a CVD risk assessment during the first year and a half of the program, officers found in a recent review. Of those, 1,569 had RA, 418 had ankylosing spondylitis, 350 had psoriatic arthritis, and 122 had other spondyloarthritides. 

Through the program, “a large number of high-risk patients have received screening that they would not otherwise have been offered,” Dr. Ikdahl said.

The major obstacles to successful implementation were time scarcity, defining a date for annual CVD risk assessment among patients who visit the clinics multiple times per year, and making sure lipids were measured before seeing the rheumatologist, he said. “We acknowledge there is room for improvement. It is challenging to implement new work tasks in an already busy rheumatology outpatient clinic, and since the project does not offer financial incentives to the participating centers, we rely on a collective effort and voluntary work based on resources already available.”

Remember CVD, but don’t forget other comorbidities

Other research presented by Dr. Laure Gossec, professor of rheumatology at Pitie-Salpétriere Hospital and Pierre & Marie Curie University in Paris highlighted the importance of identifying all comorbidities and their risk factors in patients with rheumatic diseases, and not just cardiovascular disease.

Dr. Gossec presented the results of an initiative aiming to make the collection and management of comorbidities easier in routine rheumatologic practice. The aim was to develop a simple, more pragmatic form that could be used to help rheumatologists manage selected comorbidities, and know when to refer for other specialist assessment. The focus was on ischemic cardiovascular disease, malignancies, infections such as chronic bronchitis, gastrointestinal disease such as diverticulitis, osteoporosis, and depression.

A committee of 18 experts, both physicians and nurses, was convened to examine the results of a systematic literature review of recommendations on comorbidity management and come up with concise recommendations for rheumatologists. Each of their recommendations covered whether or not the comorbidity was present (yes/no/don’t know) and if screening had been undertaken, such as measurement of blood lipids, and when this had occurred if known. There was then guidance on how to interpret these findings, calculate risk, and what to do if findings were abnormal.

The project is ongoing, and so far the expert panel has developed a pragmatic document with forms to help collect, report, and manage each specific comorbidity and its known risk factors. But it is still perhaps too long to be feasibly used in everyday practice, Dr. Gossec conceded. So the aim is to create a short, 2-page form that could summarize the recommendations briefly, and also develop a questionnaire for the patient to fill out and understand how to self-manage some comorbidities.

“We feel that this is a way to disseminate and adapt to the national context for France the EULAR comorbidities initiative,” Dr. Gossec said. “It also defines exactly what rheumatologists should be doing and when they should refer, hopefully to the benefit of our patients.”

Dr. Sattar has participated in advisory boards for Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lily and UCB. He has also consulted for Merck and is a member of Roche’s speakers’ bureau. Dr. de Paolo and Dr. Nurmohamed reported no relevant financial disclosures. Dr. Ikdahl has received speaker’s honoraria from Pfizer. Dr. Gossec and coauthors have received honoraria from Abbvie France.

LONDON – Cardiovascular disease (CVD) risk assessment for patients with rheumatic diseases can be simple and integrated into general practice or rheumatology clinics, experts said during an Outcomes Science Session at the European Congress of Rheumatology

Patients with rheumatoid arthritis have a 50% higher risk of heart disease than do their counterparts without the disease, but “just having RA on its own isn’t sufficient to render that individual at high risk,” Dr. Naveed Sattar, professor of metabolic medicine at the University of Glasgow’s Institute of Cardiovascular and Medical Sciences in Scotland, said in an interview.

It’s simple enough to use traditional CVD risk factors in an RA population by including a patient’s age, gender, smoking status, and family history of heart disease, in addition to measuring blood pressure and blood lipid levels. Most risk scores will compile those features into a 10-year risk of a fatal CVD event. To account for the contribution of RA, Dr. Sattar said, simply multiply that score by 1.5.

While “there’s a fixation in some parts of Europe for [measuring] fasting lipids,” it is not necessary, Dr. Sattar said. The two lipid parameters that go in risk scores tend to be cholesterol and HDL cholesterol, he said, which change only minimally in fasting versus nonfasting states.

“The evidence overwhelmingly shows that nonfasting lipids, which can be done easily on the same sample as other clinic tests, are just as predictive of CVD risk as fasting lipids,” he said. “That really matters because many of our patients with RA or other conditions come to the hospital when they’re not fasting, and we shouldn’t be sending them away to come back fasting to do risk scores for CVD. That just doesn’t make sense.”

Updated guidelines from the European Society of Cardiology and guidelines soon to be released from the European League Against Rheumatism suggest that risk scores can be calculated every 5 years for most patients, a change from previous recommendations to calculate risk annually. Risk scoring is not perfect, however, and there is some debate about whether additional blood tests or ultrasound scanning of the carotid artery could augment the ability to predict heart disease risk. “We’re not quite there yet,” Dr. Sattar said. “I think we should do the simple things first and do them well.”

CV risk raised in all inflammatory arthritic diseases

During the same session, Dr. Paola de Pablo of the University of Birmingham, England, focused on how immune-mediated diseases predispose to premature, accelerated atherosclerosis and subsequent increased cardiovascular morbidity and mortality.

Cardiovascular risk is not only elevated in those with RA, she observed, but also in those with systemic lupus erythematosus, ankylosing spondylitis, psoriatic arthritis, vasculitides, and inflammatory myopathies. The risk varies but as a rule is more than 50% higher than the rate seen in the general population.

The underlying mechanisms are not clear, but chronic inflammation is closely linked with atherosclerosis, which in turn ups the risk for myocardial infarction and cerebrovascular accident.

Despite treatment, the risk often remains, Dr. de Pablo said. She highlighted how treatment with methotrexate and anti–tumor necrosis factor (TNF)–alpha drugs in RA had been associated with a reduction in the risk for heart attack of 20% and 40%, respectively (Ann Rheum Dis. 2014;74:480–89) so targeting inflammation with these drugs may have positive effects, at least in RA.

Managing traditional cardiovascular risk factors remains important, Dr. de Pablo said. That was a sentiment echoed by Dr. Sattar and by rheumatologist Dr. Michael Nurmohamed of the VU Medical Center in Amsterdam. This includes controlling blood pressure with antihypertensive medications and blood lipids with statins, and advocating smoking cessation and perhaps other appropriate lifestyle changes such as increasing physical exercise and controlling weight.

Dr. Nurmohamed, who was involved in the 2015 update of the EULAR recommendations on cardiovascular risk management, noted that traditional risk factor management in patients with arthritis in current clinical practice is often poor and that strategies to address this were urgently needed.

Although treating to-target and preventing disease flares in the rheumatic diseases is important, it lowers but does not normalize cardiovascular risk. “This appears to be irrespective of the drug used,” Dr. Nurmohamed said. Rheumatologists need to be careful when tapering medication, particularly the biologics, as these are perhaps helping to temper cardiovascular inflammation, which could worsen when doses are reduced. “Antirheumatic treatment only is not good enough to decrease or normalize the cardiovascular risk of our patients”, he emphasized.

Norwegian project shows how to integrate CVD assessment into routine practice

In a separate presentation, Dr. Eirik Ikdahl, a PhD student at Diakonhjemmet Hospital in Oslo, discussed how some rheumatology clinics in Norway are successfully incorporating CVD risk screening.

Through the Norwegian Collaboration on Atherosclerotic disease in patients with Rheumatic joint diseases (NOCAR), which started in April 2014, annual cardiovascular disease risk evaluations of patients with inflammatory joint diseases are being implemented into the practices of 11 rheumatology outpatient clinics. While waiting for clinic appointments, patients are given electronic devices through which they can report CVD risk factors via an electronic patient journal program called GoTreatIt Rheuma. From there, the clinic can order nonfasting lipid measurements and nurses can record patients’ blood pressure. 

Then, using the ESC Systematic Coronary Risk Evaluation (SCORE) algorithm, the program automatically calculates a patient’s 10-year risk of a fatal CVD event. If the SCORE estimate is 5% or greater, the rheumatologist forwards a note to the patient’s primary care physician or cardiologist saying there is an indication for initiation of CVD-preventive measures such as medication or lifestyle changes. Rheumatologists and rheumatology nurses also deliver brief advice regarding smoking cessation and healthy diet.

“The main aim of the project is to raise awareness of the cardiovascular burden that these patients experience, and to ensure that patients with inflammatory joint diseases receive guideline-recommended cardiovascular preventive treatment,” Dr. Ikdahl said.

Of 6,150 patients defined as eligible for the NOCAR project in three of the centers, 41% (n = 2,519) received a CVD risk assessment during the first year and a half of the program, officers found in a recent review. Of those, 1,569 had RA, 418 had ankylosing spondylitis, 350 had psoriatic arthritis, and 122 had other spondyloarthritides. 

Through the program, “a large number of high-risk patients have received screening that they would not otherwise have been offered,” Dr. Ikdahl said.

The major obstacles to successful implementation were time scarcity, defining a date for annual CVD risk assessment among patients who visit the clinics multiple times per year, and making sure lipids were measured before seeing the rheumatologist, he said. “We acknowledge there is room for improvement. It is challenging to implement new work tasks in an already busy rheumatology outpatient clinic, and since the project does not offer financial incentives to the participating centers, we rely on a collective effort and voluntary work based on resources already available.”

Remember CVD, but don’t forget other comorbidities

Other research presented by Dr. Laure Gossec, professor of rheumatology at Pitie-Salpétriere Hospital and Pierre & Marie Curie University in Paris highlighted the importance of identifying all comorbidities and their risk factors in patients with rheumatic diseases, and not just cardiovascular disease.

Dr. Gossec presented the results of an initiative aiming to make the collection and management of comorbidities easier in routine rheumatologic practice. The aim was to develop a simple, more pragmatic form that could be used to help rheumatologists manage selected comorbidities, and know when to refer for other specialist assessment. The focus was on ischemic cardiovascular disease, malignancies, infections such as chronic bronchitis, gastrointestinal disease such as diverticulitis, osteoporosis, and depression.

A committee of 18 experts, both physicians and nurses, was convened to examine the results of a systematic literature review of recommendations on comorbidity management and come up with concise recommendations for rheumatologists. Each of their recommendations covered whether or not the comorbidity was present (yes/no/don’t know) and if screening had been undertaken, such as measurement of blood lipids, and when this had occurred if known. There was then guidance on how to interpret these findings, calculate risk, and what to do if findings were abnormal.

The project is ongoing, and so far the expert panel has developed a pragmatic document with forms to help collect, report, and manage each specific comorbidity and its known risk factors. But it is still perhaps too long to be feasibly used in everyday practice, Dr. Gossec conceded. So the aim is to create a short, 2-page form that could summarize the recommendations briefly, and also develop a questionnaire for the patient to fill out and understand how to self-manage some comorbidities.

“We feel that this is a way to disseminate and adapt to the national context for France the EULAR comorbidities initiative,” Dr. Gossec said. “It also defines exactly what rheumatologists should be doing and when they should refer, hopefully to the benefit of our patients.”

Dr. Sattar has participated in advisory boards for Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lily and UCB. He has also consulted for Merck and is a member of Roche’s speakers’ bureau. Dr. de Paolo and Dr. Nurmohamed reported no relevant financial disclosures. Dr. Ikdahl has received speaker’s honoraria from Pfizer. Dr. Gossec and coauthors have received honoraria from Abbvie France.

LONDON – Cardiovascular disease (CVD) risk assessment for patients with rheumatic diseases can be simple and integrated into general practice or rheumatology clinics, experts said during an Outcomes Science Session at the European Congress of Rheumatology

Patients with rheumatoid arthritis have a 50% higher risk of heart disease than do their counterparts without the disease, but “just having RA on its own isn’t sufficient to render that individual at high risk,” Dr. Naveed Sattar, professor of metabolic medicine at the University of Glasgow’s Institute of Cardiovascular and Medical Sciences in Scotland, said in an interview.

It’s simple enough to use traditional CVD risk factors in an RA population by including a patient’s age, gender, smoking status, and family history of heart disease, in addition to measuring blood pressure and blood lipid levels. Most risk scores will compile those features into a 10-year risk of a fatal CVD event. To account for the contribution of RA, Dr. Sattar said, simply multiply that score by 1.5.

While “there’s a fixation in some parts of Europe for [measuring] fasting lipids,” it is not necessary, Dr. Sattar said. The two lipid parameters that go in risk scores tend to be cholesterol and HDL cholesterol, he said, which change only minimally in fasting versus nonfasting states.

“The evidence overwhelmingly shows that nonfasting lipids, which can be done easily on the same sample as other clinic tests, are just as predictive of CVD risk as fasting lipids,” he said. “That really matters because many of our patients with RA or other conditions come to the hospital when they’re not fasting, and we shouldn’t be sending them away to come back fasting to do risk scores for CVD. That just doesn’t make sense.”

Updated guidelines from the European Society of Cardiology and guidelines soon to be released from the European League Against Rheumatism suggest that risk scores can be calculated every 5 years for most patients, a change from previous recommendations to calculate risk annually. Risk scoring is not perfect, however, and there is some debate about whether additional blood tests or ultrasound scanning of the carotid artery could augment the ability to predict heart disease risk. “We’re not quite there yet,” Dr. Sattar said. “I think we should do the simple things first and do them well.”

CV risk raised in all inflammatory arthritic diseases

During the same session, Dr. Paola de Pablo of the University of Birmingham, England, focused on how immune-mediated diseases predispose to premature, accelerated atherosclerosis and subsequent increased cardiovascular morbidity and mortality.

Cardiovascular risk is not only elevated in those with RA, she observed, but also in those with systemic lupus erythematosus, ankylosing spondylitis, psoriatic arthritis, vasculitides, and inflammatory myopathies. The risk varies but as a rule is more than 50% higher than the rate seen in the general population.

The underlying mechanisms are not clear, but chronic inflammation is closely linked with atherosclerosis, which in turn ups the risk for myocardial infarction and cerebrovascular accident.

Despite treatment, the risk often remains, Dr. de Pablo said. She highlighted how treatment with methotrexate and anti–tumor necrosis factor (TNF)–alpha drugs in RA had been associated with a reduction in the risk for heart attack of 20% and 40%, respectively (Ann Rheum Dis. 2014;74:480–89) so targeting inflammation with these drugs may have positive effects, at least in RA.

Managing traditional cardiovascular risk factors remains important, Dr. de Pablo said. That was a sentiment echoed by Dr. Sattar and by rheumatologist Dr. Michael Nurmohamed of the VU Medical Center in Amsterdam. This includes controlling blood pressure with antihypertensive medications and blood lipids with statins, and advocating smoking cessation and perhaps other appropriate lifestyle changes such as increasing physical exercise and controlling weight.

Dr. Nurmohamed, who was involved in the 2015 update of the EULAR recommendations on cardiovascular risk management, noted that traditional risk factor management in patients with arthritis in current clinical practice is often poor and that strategies to address this were urgently needed.

Although treating to-target and preventing disease flares in the rheumatic diseases is important, it lowers but does not normalize cardiovascular risk. “This appears to be irrespective of the drug used,” Dr. Nurmohamed said. Rheumatologists need to be careful when tapering medication, particularly the biologics, as these are perhaps helping to temper cardiovascular inflammation, which could worsen when doses are reduced. “Antirheumatic treatment only is not good enough to decrease or normalize the cardiovascular risk of our patients”, he emphasized.

Norwegian project shows how to integrate CVD assessment into routine practice

In a separate presentation, Dr. Eirik Ikdahl, a PhD student at Diakonhjemmet Hospital in Oslo, discussed how some rheumatology clinics in Norway are successfully incorporating CVD risk screening.

Through the Norwegian Collaboration on Atherosclerotic disease in patients with Rheumatic joint diseases (NOCAR), which started in April 2014, annual cardiovascular disease risk evaluations of patients with inflammatory joint diseases are being implemented into the practices of 11 rheumatology outpatient clinics. While waiting for clinic appointments, patients are given electronic devices through which they can report CVD risk factors via an electronic patient journal program called GoTreatIt Rheuma. From there, the clinic can order nonfasting lipid measurements and nurses can record patients’ blood pressure. 

Then, using the ESC Systematic Coronary Risk Evaluation (SCORE) algorithm, the program automatically calculates a patient’s 10-year risk of a fatal CVD event. If the SCORE estimate is 5% or greater, the rheumatologist forwards a note to the patient’s primary care physician or cardiologist saying there is an indication for initiation of CVD-preventive measures such as medication or lifestyle changes. Rheumatologists and rheumatology nurses also deliver brief advice regarding smoking cessation and healthy diet.

“The main aim of the project is to raise awareness of the cardiovascular burden that these patients experience, and to ensure that patients with inflammatory joint diseases receive guideline-recommended cardiovascular preventive treatment,” Dr. Ikdahl said.

Of 6,150 patients defined as eligible for the NOCAR project in three of the centers, 41% (n = 2,519) received a CVD risk assessment during the first year and a half of the program, officers found in a recent review. Of those, 1,569 had RA, 418 had ankylosing spondylitis, 350 had psoriatic arthritis, and 122 had other spondyloarthritides. 

Through the program, “a large number of high-risk patients have received screening that they would not otherwise have been offered,” Dr. Ikdahl said.

The major obstacles to successful implementation were time scarcity, defining a date for annual CVD risk assessment among patients who visit the clinics multiple times per year, and making sure lipids were measured before seeing the rheumatologist, he said. “We acknowledge there is room for improvement. It is challenging to implement new work tasks in an already busy rheumatology outpatient clinic, and since the project does not offer financial incentives to the participating centers, we rely on a collective effort and voluntary work based on resources already available.”

Remember CVD, but don’t forget other comorbidities

Other research presented by Dr. Laure Gossec, professor of rheumatology at Pitie-Salpétriere Hospital and Pierre & Marie Curie University in Paris highlighted the importance of identifying all comorbidities and their risk factors in patients with rheumatic diseases, and not just cardiovascular disease.

Dr. Gossec presented the results of an initiative aiming to make the collection and management of comorbidities easier in routine rheumatologic practice. The aim was to develop a simple, more pragmatic form that could be used to help rheumatologists manage selected comorbidities, and know when to refer for other specialist assessment. The focus was on ischemic cardiovascular disease, malignancies, infections such as chronic bronchitis, gastrointestinal disease such as diverticulitis, osteoporosis, and depression.

A committee of 18 experts, both physicians and nurses, was convened to examine the results of a systematic literature review of recommendations on comorbidity management and come up with concise recommendations for rheumatologists. Each of their recommendations covered whether or not the comorbidity was present (yes/no/don’t know) and if screening had been undertaken, such as measurement of blood lipids, and when this had occurred if known. There was then guidance on how to interpret these findings, calculate risk, and what to do if findings were abnormal.

The project is ongoing, and so far the expert panel has developed a pragmatic document with forms to help collect, report, and manage each specific comorbidity and its known risk factors. But it is still perhaps too long to be feasibly used in everyday practice, Dr. Gossec conceded. So the aim is to create a short, 2-page form that could summarize the recommendations briefly, and also develop a questionnaire for the patient to fill out and understand how to self-manage some comorbidities.

“We feel that this is a way to disseminate and adapt to the national context for France the EULAR comorbidities initiative,” Dr. Gossec said. “It also defines exactly what rheumatologists should be doing and when they should refer, hopefully to the benefit of our patients.”

Dr. Sattar has participated in advisory boards for Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lily and UCB. He has also consulted for Merck and is a member of Roche’s speakers’ bureau. Dr. de Paolo and Dr. Nurmohamed reported no relevant financial disclosures. Dr. Ikdahl has received speaker’s honoraria from Pfizer. Dr. Gossec and coauthors have received honoraria from Abbvie France.

Among patients with high tumor burden follicular lymphoma (FL) that responded to rituximab chemotherapy but then underwent histologic transformation, median overall survival was not reached when patients received autologous stem cell transplantation (ASCT), but was only 1.7 years otherwise, based on results of an ancillary study of a clinical trial.

In contrast, ASCT did not affect overall survival when patients progressed to untransformed FL, said Dr. Clémentine Sarkozy of Centre Hospitalier Lyon-Sud in Pierre Bénite, France, and her associates. Fully 58% of histologic transformations occurred in the first year of follow-up, highlighting “the necessity for biopsy at the first recurrence of FL,” they wrote online June 13 in the Journal of Clinical Oncology.

Histologic transformation in FL signifies progression to aggressive lymphoma. Studies of histologic transformation and subsequent overall survival in the rituximab era have been retrospective, with variable patient populations and initial management regimens, according to the investigators. Therefore, they followed 1,018 patients from the multicenter, randomized, phase III PRIMA (Primary Rituximab and Maintenance) trial, which evaluated maintenance rituximab therapy among patients with symptomatic FL who had responded to induction chemotherapy plus rituximab (J Clin Oncol. 2016 Jun. doi: 10.1200/JCO.2015.65.7163).

A total of 463 patients (45.5%) experienced disease recurrence or progression, and 194 (42%) were biopsied over a median follow-up time of 6 years. A total of 40 (20.6%) biopsies showed histologic transformation, while 154 (79.4%) had untransformed FL. Median time to recurrence was 9.6 months for patients with histologic transformation and 22.8 months for patients with untransformed FL (P = .02). Median overall survival with histologic transformation was worse than with untransformed FL (3.8 years vs. 6.4 years; hazard ratio, 3.9; 95% confidence interval, 2.2-6.9; P = .001). Furthermore, among patients who progressed within 12 months, median overall survival with histologic transformation was 2 years, compared with 6.4 years for patients with untransformed FL (P = .007).

After salvage therapy, 17 (42%) patients with histologic transformation underwent consolidation with high-dose chemotherapy and ASCT. Median overall survival for these patients was not reached, versus 1.7 years when they did not undergo ASCT. In contrast, ASCT did not improve overall survival among patients with untransformed FL. Results were similar after excluding patients with early progression and patients who were older than 65 years, the investigators reported.

Risk factors for histologic transformation in the univariate analysis included performance status, anemia, high lactate dehydrogenase level, “B” symptoms, histologic grade 3a, and high Follicular Lymphoma International Prognostic Index scores at diagnosis. However, only Eastern Cooperative Oncology Group performance status of 2 to 4 (HR, 5.6; 95% CI, 1.7-17.7), and anemia (HR, 3.7; 95% CI, 1.4-9.7) remained significant in the multivariate analysis. Neither the choice of induction regimen nor the quality of response seemed to affect the likelihood of histologic transformation, and rituximab maintenance therapy did not seem to alter response to salvage treatment or survival after histologic transformation. By necessity, the study excluded patients who did not respond to initial immunochemotherapy, which could have limited the generalizability of the findings, the investigators noted.

The study was funded by Sandoz and Takeda Pharmaceuticals. Dr. Sarkozy disclosed research funding from Sandoz and Takeda Pharmaceuticals and honoraria from Gilead Sciences. Twelve coinvestigators also disclosed ties to Takeda and a number of other pharmaceutical companies. The other seven coinvestigators had no disclosures.

Among patients with high tumor burden follicular lymphoma (FL) that responded to rituximab chemotherapy but then underwent histologic transformation, median overall survival was not reached when patients received autologous stem cell transplantation (ASCT), but was only 1.7 years otherwise, based on results of an ancillary study of a clinical trial.

In contrast, ASCT did not affect overall survival when patients progressed to untransformed FL, said Dr. Clémentine Sarkozy of Centre Hospitalier Lyon-Sud in Pierre Bénite, France, and her associates. Fully 58% of histologic transformations occurred in the first year of follow-up, highlighting “the necessity for biopsy at the first recurrence of FL,” they wrote online June 13 in the Journal of Clinical Oncology.

Histologic transformation in FL signifies progression to aggressive lymphoma. Studies of histologic transformation and subsequent overall survival in the rituximab era have been retrospective, with variable patient populations and initial management regimens, according to the investigators. Therefore, they followed 1,018 patients from the multicenter, randomized, phase III PRIMA (Primary Rituximab and Maintenance) trial, which evaluated maintenance rituximab therapy among patients with symptomatic FL who had responded to induction chemotherapy plus rituximab (J Clin Oncol. 2016 Jun. doi: 10.1200/JCO.2015.65.7163).

A total of 463 patients (45.5%) experienced disease recurrence or progression, and 194 (42%) were biopsied over a median follow-up time of 6 years. A total of 40 (20.6%) biopsies showed histologic transformation, while 154 (79.4%) had untransformed FL. Median time to recurrence was 9.6 months for patients with histologic transformation and 22.8 months for patients with untransformed FL (P = .02). Median overall survival with histologic transformation was worse than with untransformed FL (3.8 years vs. 6.4 years; hazard ratio, 3.9; 95% confidence interval, 2.2-6.9; P = .001). Furthermore, among patients who progressed within 12 months, median overall survival with histologic transformation was 2 years, compared with 6.4 years for patients with untransformed FL (P = .007).

After salvage therapy, 17 (42%) patients with histologic transformation underwent consolidation with high-dose chemotherapy and ASCT. Median overall survival for these patients was not reached, versus 1.7 years when they did not undergo ASCT. In contrast, ASCT did not improve overall survival among patients with untransformed FL. Results were similar after excluding patients with early progression and patients who were older than 65 years, the investigators reported.

Risk factors for histologic transformation in the univariate analysis included performance status, anemia, high lactate dehydrogenase level, “B” symptoms, histologic grade 3a, and high Follicular Lymphoma International Prognostic Index scores at diagnosis. However, only Eastern Cooperative Oncology Group performance status of 2 to 4 (HR, 5.6; 95% CI, 1.7-17.7), and anemia (HR, 3.7; 95% CI, 1.4-9.7) remained significant in the multivariate analysis. Neither the choice of induction regimen nor the quality of response seemed to affect the likelihood of histologic transformation, and rituximab maintenance therapy did not seem to alter response to salvage treatment or survival after histologic transformation. By necessity, the study excluded patients who did not respond to initial immunochemotherapy, which could have limited the generalizability of the findings, the investigators noted.

The study was funded by Sandoz and Takeda Pharmaceuticals. Dr. Sarkozy disclosed research funding from Sandoz and Takeda Pharmaceuticals and honoraria from Gilead Sciences. Twelve coinvestigators also disclosed ties to Takeda and a number of other pharmaceutical companies. The other seven coinvestigators had no disclosures.

Among patients with high tumor burden follicular lymphoma (FL) that responded to rituximab chemotherapy but then underwent histologic transformation, median overall survival was not reached when patients received autologous stem cell transplantation (ASCT), but was only 1.7 years otherwise, based on results of an ancillary study of a clinical trial.

In contrast, ASCT did not affect overall survival when patients progressed to untransformed FL, said Dr. Clémentine Sarkozy of Centre Hospitalier Lyon-Sud in Pierre Bénite, France, and her associates. Fully 58% of histologic transformations occurred in the first year of follow-up, highlighting “the necessity for biopsy at the first recurrence of FL,” they wrote online June 13 in the Journal of Clinical Oncology.

Histologic transformation in FL signifies progression to aggressive lymphoma. Studies of histologic transformation and subsequent overall survival in the rituximab era have been retrospective, with variable patient populations and initial management regimens, according to the investigators. Therefore, they followed 1,018 patients from the multicenter, randomized, phase III PRIMA (Primary Rituximab and Maintenance) trial, which evaluated maintenance rituximab therapy among patients with symptomatic FL who had responded to induction chemotherapy plus rituximab (J Clin Oncol. 2016 Jun. doi: 10.1200/JCO.2015.65.7163).

A total of 463 patients (45.5%) experienced disease recurrence or progression, and 194 (42%) were biopsied over a median follow-up time of 6 years. A total of 40 (20.6%) biopsies showed histologic transformation, while 154 (79.4%) had untransformed FL. Median time to recurrence was 9.6 months for patients with histologic transformation and 22.8 months for patients with untransformed FL (P = .02). Median overall survival with histologic transformation was worse than with untransformed FL (3.8 years vs. 6.4 years; hazard ratio, 3.9; 95% confidence interval, 2.2-6.9; P = .001). Furthermore, among patients who progressed within 12 months, median overall survival with histologic transformation was 2 years, compared with 6.4 years for patients with untransformed FL (P = .007).

After salvage therapy, 17 (42%) patients with histologic transformation underwent consolidation with high-dose chemotherapy and ASCT. Median overall survival for these patients was not reached, versus 1.7 years when they did not undergo ASCT. In contrast, ASCT did not improve overall survival among patients with untransformed FL. Results were similar after excluding patients with early progression and patients who were older than 65 years, the investigators reported.

Risk factors for histologic transformation in the univariate analysis included performance status, anemia, high lactate dehydrogenase level, “B” symptoms, histologic grade 3a, and high Follicular Lymphoma International Prognostic Index scores at diagnosis. However, only Eastern Cooperative Oncology Group performance status of 2 to 4 (HR, 5.6; 95% CI, 1.7-17.7), and anemia (HR, 3.7; 95% CI, 1.4-9.7) remained significant in the multivariate analysis. Neither the choice of induction regimen nor the quality of response seemed to affect the likelihood of histologic transformation, and rituximab maintenance therapy did not seem to alter response to salvage treatment or survival after histologic transformation. By necessity, the study excluded patients who did not respond to initial immunochemotherapy, which could have limited the generalizability of the findings, the investigators noted.

The study was funded by Sandoz and Takeda Pharmaceuticals. Dr. Sarkozy disclosed research funding from Sandoz and Takeda Pharmaceuticals and honoraria from Gilead Sciences. Twelve coinvestigators also disclosed ties to Takeda and a number of other pharmaceutical companies. The other seven coinvestigators had no disclosures.

Dually active antiretroviral therapy (DAART) for HIV-infected patients may be the best treatment option to also protect these individuals against hepatitis B virus (HBV) infection, according to results of a study in the Journal of Infectious Diseases.

“Vaccination against HBV remains the mainstay of preventing HBV acquisition both in HIV-infected and uninfected individuals,” states the study, led by Roger Kouyos, Ph.D., of University Hospital Zürich. “However, owing to HIV’s effect on the immune system, mounting and maintaining a protective immune response against HBV is sometimes unattainable, with a success rate between 18% and 71%.”

©vchal/Thinkstock

Dr. Kouyos and his colleagues collected CD4, CD8, and HIV-1 viral load data for 1,716 patients in the Swiss HIV Cohort Study – an ongoing, prospective cohort study that began in 1988 – and updated the data continuously during follow-up visits every 3 months, on average. Subjects were enrolled if they had negative baseline HBV serology and at least one additional HBV test after the initial one, and were either a man who had sex with men, a heterosexual, or an intravenous drug user – the three major groups examined by the study (J Infect Dis. 2016 May 18. doi:10.1093/infdis/jiw195).

DAART treatment consisted of tenofovir, lamivudine, and emtricitabine. Antiretroviral treatment history was also collected, and at follow-up examinations every 6 months, subjects were asked about occasional sex partners and frequency of condom use during the preceding 6 months. All were tested for at least one HBV marker: surface antigen (HBsAg), anti–hepatitis B core antibodies (AntiHBc), or hepatitis B virus DNA.

Of the 1,716 subjects enrolled, 177 had HBV. Of these, 86 (49%) were men who had sex with men. Most subjects underwent at least two HBV tests, with the median time between tests being 29 months (range of 12-58 months). In the transmission group, the overall incidence rate of HBV was 16 (95% confidence interval, 14-19), while it was 25 (21-31) for men who had sex with men, 9 (6-11) for heterosexuals, and 28 (21-38) for intravenous drug users.

DAART, however, was shown to significantly reduce HBV-infection risk. Univariate analysis yielded a hazard ratio of 0.4 (95% CI, 0.2-0.6), and multivariate analysis showed even more significant effects for intravenous drug users (3.8, 2.4-6.1), men who had sex with men (2.7, 1.7-4.2), and those who had unprotected sex (1.9, 1.4-2.6).

“Our study confirms the importance of viral suppression (and the implicit adherence) in reaching the protective effect of DAART,” the authors concluded, noting that “Our study adds to the growing body of evidence that early antiretroviral therapy initiation, regardless of CD4 counts, has a strong beneficial public health impact, including preexposure prophylaxis of HBV coinfections.”

The study was supported by the Swiss HIV Cohort Study, the Swiss National Science Foundation, the European Community’s Seventh Framework Program, and the Union Bank of Switzerland. Dr. Kouyos reported travel grants from Gilead. Other coauthors reported research, educational, and travel grants from Roche, Abbott, Bristol-Myers Squibb, Gilead, Astra-Zeneca, GlaxoSmithKline, Pfizer, and Astellas.

[email protected]

Dually active antiretroviral therapy (DAART) for HIV-infected patients may be the best treatment option to also protect these individuals against hepatitis B virus (HBV) infection, according to results of a study in the Journal of Infectious Diseases.

“Vaccination against HBV remains the mainstay of preventing HBV acquisition both in HIV-infected and uninfected individuals,” states the study, led by Roger Kouyos, Ph.D., of University Hospital Zürich. “However, owing to HIV’s effect on the immune system, mounting and maintaining a protective immune response against HBV is sometimes unattainable, with a success rate between 18% and 71%.”

©vchal/Thinkstock

Dr. Kouyos and his colleagues collected CD4, CD8, and HIV-1 viral load data for 1,716 patients in the Swiss HIV Cohort Study – an ongoing, prospective cohort study that began in 1988 – and updated the data continuously during follow-up visits every 3 months, on average. Subjects were enrolled if they had negative baseline HBV serology and at least one additional HBV test after the initial one, and were either a man who had sex with men, a heterosexual, or an intravenous drug user – the three major groups examined by the study (J Infect Dis. 2016 May 18. doi:10.1093/infdis/jiw195).

DAART treatment consisted of tenofovir, lamivudine, and emtricitabine. Antiretroviral treatment history was also collected, and at follow-up examinations every 6 months, subjects were asked about occasional sex partners and frequency of condom use during the preceding 6 months. All were tested for at least one HBV marker: surface antigen (HBsAg), anti–hepatitis B core antibodies (AntiHBc), or hepatitis B virus DNA.

Of the 1,716 subjects enrolled, 177 had HBV. Of these, 86 (49%) were men who had sex with men. Most subjects underwent at least two HBV tests, with the median time between tests being 29 months (range of 12-58 months). In the transmission group, the overall incidence rate of HBV was 16 (95% confidence interval, 14-19), while it was 25 (21-31) for men who had sex with men, 9 (6-11) for heterosexuals, and 28 (21-38) for intravenous drug users.

DAART, however, was shown to significantly reduce HBV-infection risk. Univariate analysis yielded a hazard ratio of 0.4 (95% CI, 0.2-0.6), and multivariate analysis showed even more significant effects for intravenous drug users (3.8, 2.4-6.1), men who had sex with men (2.7, 1.7-4.2), and those who had unprotected sex (1.9, 1.4-2.6).

“Our study confirms the importance of viral suppression (and the implicit adherence) in reaching the protective effect of DAART,” the authors concluded, noting that “Our study adds to the growing body of evidence that early antiretroviral therapy initiation, regardless of CD4 counts, has a strong beneficial public health impact, including preexposure prophylaxis of HBV coinfections.”

The study was supported by the Swiss HIV Cohort Study, the Swiss National Science Foundation, the European Community’s Seventh Framework Program, and the Union Bank of Switzerland. Dr. Kouyos reported travel grants from Gilead. Other coauthors reported research, educational, and travel grants from Roche, Abbott, Bristol-Myers Squibb, Gilead, Astra-Zeneca, GlaxoSmithKline, Pfizer, and Astellas.

[email protected]

Dually active antiretroviral therapy (DAART) for HIV-infected patients may be the best treatment option to also protect these individuals against hepatitis B virus (HBV) infection, according to results of a study in the Journal of Infectious Diseases.

“Vaccination against HBV remains the mainstay of preventing HBV acquisition both in HIV-infected and uninfected individuals,” states the study, led by Roger Kouyos, Ph.D., of University Hospital Zürich. “However, owing to HIV’s effect on the immune system, mounting and maintaining a protective immune response against HBV is sometimes unattainable, with a success rate between 18% and 71%.”

©vchal/Thinkstock

Dr. Kouyos and his colleagues collected CD4, CD8, and HIV-1 viral load data for 1,716 patients in the Swiss HIV Cohort Study – an ongoing, prospective cohort study that began in 1988 – and updated the data continuously during follow-up visits every 3 months, on average. Subjects were enrolled if they had negative baseline HBV serology and at least one additional HBV test after the initial one, and were either a man who had sex with men, a heterosexual, or an intravenous drug user – the three major groups examined by the study (J Infect Dis. 2016 May 18. doi:10.1093/infdis/jiw195).

DAART treatment consisted of tenofovir, lamivudine, and emtricitabine. Antiretroviral treatment history was also collected, and at follow-up examinations every 6 months, subjects were asked about occasional sex partners and frequency of condom use during the preceding 6 months. All were tested for at least one HBV marker: surface antigen (HBsAg), anti–hepatitis B core antibodies (AntiHBc), or hepatitis B virus DNA.

Of the 1,716 subjects enrolled, 177 had HBV. Of these, 86 (49%) were men who had sex with men. Most subjects underwent at least two HBV tests, with the median time between tests being 29 months (range of 12-58 months). In the transmission group, the overall incidence rate of HBV was 16 (95% confidence interval, 14-19), while it was 25 (21-31) for men who had sex with men, 9 (6-11) for heterosexuals, and 28 (21-38) for intravenous drug users.

DAART, however, was shown to significantly reduce HBV-infection risk. Univariate analysis yielded a hazard ratio of 0.4 (95% CI, 0.2-0.6), and multivariate analysis showed even more significant effects for intravenous drug users (3.8, 2.4-6.1), men who had sex with men (2.7, 1.7-4.2), and those who had unprotected sex (1.9, 1.4-2.6).

“Our study confirms the importance of viral suppression (and the implicit adherence) in reaching the protective effect of DAART,” the authors concluded, noting that “Our study adds to the growing body of evidence that early antiretroviral therapy initiation, regardless of CD4 counts, has a strong beneficial public health impact, including preexposure prophylaxis of HBV coinfections.”

The study was supported by the Swiss HIV Cohort Study, the Swiss National Science Foundation, the European Community’s Seventh Framework Program, and the Union Bank of Switzerland. Dr. Kouyos reported travel grants from Gilead. Other coauthors reported research, educational, and travel grants from Roche, Abbott, Bristol-Myers Squibb, Gilead, Astra-Zeneca, GlaxoSmithKline, Pfizer, and Astellas.

[email protected]

CHICAGO – Hormonal maintenance therapy after primary treatment was associated with significantly prolonged progression-free survival when compared with surveillance in a retrospective study of women with stage II-IV low-grade serous carcinoma of the ovary or peritoneum.

The findings are “potentially practice-changing,” Dr. David Marc Gershenson of the University of Texas MD Anderson Cancer Center, Houston, said at the annual meeting of the American Society of Clinical Oncology.

©moodboard/Thinkstock

Of 204 women with newly diagnosed low-grade serous carcinoma (LGSC) who underwent primary cytoreductive surgery followed by platinum-based chemotherapy, 70 received hormonal maintenance therapy after completion of primary chemotherapy and 134 underwent surveillance. Median progression-free survival (PFS) was 64.9 vs. 27.3 months, respectively (33 months overall), Dr. Gershenson said.

“To date, 40% of the hormone maintenance therapy group has not relapsed, compared [with] only 12% in the surveillance group,” he said.

Median overall survival was not statistically different, but there was a trend toward an overall survival benefit in the hormonal maintenance therapy group (115.7 vs. 98.8 months). In a subset analysis in women who were clinically disease free at the completion of primary chemotherapy, the median PFS was 29.9 months in 121 women undergoing surveillance, vs. 81.1 months in 27 receiving hormone maintenance therapy. The mean overall survival was also statistically different in the subset analysis (106.8 vs. 191.3 months).

On multivariable analysis, four factors reached significance: hormone maintenance therapy vs. surveillance (hazard ratio, 0.23), peritoneum vs. ovary as primary site (HR, 0.45), no gross residual disease vs. gross residual disease (HR, 0.49),and persistent disease at completion of chemotherapy, vs. no evidence of disease (HR, 0.42).

Patients included in the study presented between 1981 and 2013. They had a median age of 47.6 years, about 3/4 had primary ovarian LGSC, and about 1/4 had primary peritoneal LGSC.

Patients in the hormonal therapy group were treated with letrozole (54%), tamoxifen (29%), anastrozole (3%), leuprolide acetate (7%), depot medroxyprogesterone acetate (1%), and leuprolide acetate + tamoxifen or letrozole (3% each). Median duration of hormonal maintenance therapy was 33.3 months (range of 1-223), and follow-up was at least 2 years in those who had not recurred.

LGSC is a rare subtype that accounts for about 10% of serous carcinomas of the ovary or peritoneum. These cancers may arise de novo or after a diagnosis of serous borderline tumor. LGSC, relative to high-grade serous carcinoma (HGSC), is characterized by younger age at diagnosis, chemoresistance, prolonged overall survival, and aberrations within the MAP kinase signaling pathway, Dr. Gershenson said.

The findings are of interest as primary postoperative platinum-based chemotherapy remains the standard for women with newly diagnosed metastatic ovarian or peritoneal LGSC despite multiple reports indicating that this subtype is relatively chemoresistant. For example, in the AGO database of 5,114 patients accrued to four separate phase III trials, the response rate to chemotherapy in women with suboptimally debulked LGSC was significantly lower than in women with suboptimally debulked HGSC (23% vs. 90%), he said.

However, no prospective clinical trials have been conducted in the front line setting in women with LGSC, he noted.

Recent reports of promising activity of hormonal therapy in the recurrent setting have led to an increase in interest in integrating the modality into the primary treatment setting. One study showed a high frequency of ER and PR expression in LGSC, and another showed that hormonal therapy for recurrent LGSC was associated with an objective response rate of 9%, stable disease rate of 66% and median progression-free survival of 7.4 months.

“Some patients derived several years of benefit,” he said. “In addition, low-grade serous carcinoma bears a striking resemblance to luminal breast cancer in that women who are 35 years of age or younger appear to have a significantly worse prognosis.”

Some have concluded, based on these findings, that platinum-based chemotherapy is of no value in the frontline treatment of LGSC and should be abandoned, Dr. Gershenson said.

The current findings, though limited by factors such as their retrospective nature, missing data, a long study period, and possible referral bias suggest that hormonal maintenance therapy deserves a closer look, Dr. Gershenson said.

“The findings of this hypotheses-generating study are potentially practice changing and warrant further investigation using a prospective trial design,” he concluded.

Dr. Gershenson reported stock ownership in AbbVie, Biogen Idec, Celgene, GlaxoSmithKline, Johnson & Johnson, Merck, and Pfizer; consulting or advisory roles with Clovis Oncology, and patents with Elsevier and UpToDate.

[email protected]

CHICAGO – Hormonal maintenance therapy after primary treatment was associated with significantly prolonged progression-free survival when compared with surveillance in a retrospective study of women with stage II-IV low-grade serous carcinoma of the ovary or peritoneum.

The findings are “potentially practice-changing,” Dr. David Marc Gershenson of the University of Texas MD Anderson Cancer Center, Houston, said at the annual meeting of the American Society of Clinical Oncology.

©moodboard/Thinkstock

Of 204 women with newly diagnosed low-grade serous carcinoma (LGSC) who underwent primary cytoreductive surgery followed by platinum-based chemotherapy, 70 received hormonal maintenance therapy after completion of primary chemotherapy and 134 underwent surveillance. Median progression-free survival (PFS) was 64.9 vs. 27.3 months, respectively (33 months overall), Dr. Gershenson said.

“To date, 40% of the hormone maintenance therapy group has not relapsed, compared [with] only 12% in the surveillance group,” he said.

Median overall survival was not statistically different, but there was a trend toward an overall survival benefit in the hormonal maintenance therapy group (115.7 vs. 98.8 months). In a subset analysis in women who were clinically disease free at the completion of primary chemotherapy, the median PFS was 29.9 months in 121 women undergoing surveillance, vs. 81.1 months in 27 receiving hormone maintenance therapy. The mean overall survival was also statistically different in the subset analysis (106.8 vs. 191.3 months).

On multivariable analysis, four factors reached significance: hormone maintenance therapy vs. surveillance (hazard ratio, 0.23), peritoneum vs. ovary as primary site (HR, 0.45), no gross residual disease vs. gross residual disease (HR, 0.49),and persistent disease at completion of chemotherapy, vs. no evidence of disease (HR, 0.42).

Patients included in the study presented between 1981 and 2013. They had a median age of 47.6 years, about 3/4 had primary ovarian LGSC, and about 1/4 had primary peritoneal LGSC.

Patients in the hormonal therapy group were treated with letrozole (54%), tamoxifen (29%), anastrozole (3%), leuprolide acetate (7%), depot medroxyprogesterone acetate (1%), and leuprolide acetate + tamoxifen or letrozole (3% each). Median duration of hormonal maintenance therapy was 33.3 months (range of 1-223), and follow-up was at least 2 years in those who had not recurred.

LGSC is a rare subtype that accounts for about 10% of serous carcinomas of the ovary or peritoneum. These cancers may arise de novo or after a diagnosis of serous borderline tumor. LGSC, relative to high-grade serous carcinoma (HGSC), is characterized by younger age at diagnosis, chemoresistance, prolonged overall survival, and aberrations within the MAP kinase signaling pathway, Dr. Gershenson said.

The findings are of interest as primary postoperative platinum-based chemotherapy remains the standard for women with newly diagnosed metastatic ovarian or peritoneal LGSC despite multiple reports indicating that this subtype is relatively chemoresistant. For example, in the AGO database of 5,114 patients accrued to four separate phase III trials, the response rate to chemotherapy in women with suboptimally debulked LGSC was significantly lower than in women with suboptimally debulked HGSC (23% vs. 90%), he said.

However, no prospective clinical trials have been conducted in the front line setting in women with LGSC, he noted.

Recent reports of promising activity of hormonal therapy in the recurrent setting have led to an increase in interest in integrating the modality into the primary treatment setting. One study showed a high frequency of ER and PR expression in LGSC, and another showed that hormonal therapy for recurrent LGSC was associated with an objective response rate of 9%, stable disease rate of 66% and median progression-free survival of 7.4 months.

“Some patients derived several years of benefit,” he said. “In addition, low-grade serous carcinoma bears a striking resemblance to luminal breast cancer in that women who are 35 years of age or younger appear to have a significantly worse prognosis.”

Some have concluded, based on these findings, that platinum-based chemotherapy is of no value in the frontline treatment of LGSC and should be abandoned, Dr. Gershenson said.

The current findings, though limited by factors such as their retrospective nature, missing data, a long study period, and possible referral bias suggest that hormonal maintenance therapy deserves a closer look, Dr. Gershenson said.

“The findings of this hypotheses-generating study are potentially practice changing and warrant further investigation using a prospective trial design,” he concluded.

Dr. Gershenson reported stock ownership in AbbVie, Biogen Idec, Celgene, GlaxoSmithKline, Johnson & Johnson, Merck, and Pfizer; consulting or advisory roles with Clovis Oncology, and patents with Elsevier and UpToDate.

[email protected]

CHICAGO – Hormonal maintenance therapy after primary treatment was associated with significantly prolonged progression-free survival when compared with surveillance in a retrospective study of women with stage II-IV low-grade serous carcinoma of the ovary or peritoneum.

The findings are “potentially practice-changing,” Dr. David Marc Gershenson of the University of Texas MD Anderson Cancer Center, Houston, said at the annual meeting of the American Society of Clinical Oncology.

©moodboard/Thinkstock

Of 204 women with newly diagnosed low-grade serous carcinoma (LGSC) who underwent primary cytoreductive surgery followed by platinum-based chemotherapy, 70 received hormonal maintenance therapy after completion of primary chemotherapy and 134 underwent surveillance. Median progression-free survival (PFS) was 64.9 vs. 27.3 months, respectively (33 months overall), Dr. Gershenson said.

“To date, 40% of the hormone maintenance therapy group has not relapsed, compared [with] only 12% in the surveillance group,” he said.

Median overall survival was not statistically different, but there was a trend toward an overall survival benefit in the hormonal maintenance therapy group (115.7 vs. 98.8 months). In a subset analysis in women who were clinically disease free at the completion of primary chemotherapy, the median PFS was 29.9 months in 121 women undergoing surveillance, vs. 81.1 months in 27 receiving hormone maintenance therapy. The mean overall survival was also statistically different in the subset analysis (106.8 vs. 191.3 months).

On multivariable analysis, four factors reached significance: hormone maintenance therapy vs. surveillance (hazard ratio, 0.23), peritoneum vs. ovary as primary site (HR, 0.45), no gross residual disease vs. gross residual disease (HR, 0.49),and persistent disease at completion of chemotherapy, vs. no evidence of disease (HR, 0.42).

Patients included in the study presented between 1981 and 2013. They had a median age of 47.6 years, about 3/4 had primary ovarian LGSC, and about 1/4 had primary peritoneal LGSC.

Patients in the hormonal therapy group were treated with letrozole (54%), tamoxifen (29%), anastrozole (3%), leuprolide acetate (7%), depot medroxyprogesterone acetate (1%), and leuprolide acetate + tamoxifen or letrozole (3% each). Median duration of hormonal maintenance therapy was 33.3 months (range of 1-223), and follow-up was at least 2 years in those who had not recurred.

LGSC is a rare subtype that accounts for about 10% of serous carcinomas of the ovary or peritoneum. These cancers may arise de novo or after a diagnosis of serous borderline tumor. LGSC, relative to high-grade serous carcinoma (HGSC), is characterized by younger age at diagnosis, chemoresistance, prolonged overall survival, and aberrations within the MAP kinase signaling pathway, Dr. Gershenson said.

The findings are of interest as primary postoperative platinum-based chemotherapy remains the standard for women with newly diagnosed metastatic ovarian or peritoneal LGSC despite multiple reports indicating that this subtype is relatively chemoresistant. For example, in the AGO database of 5,114 patients accrued to four separate phase III trials, the response rate to chemotherapy in women with suboptimally debulked LGSC was significantly lower than in women with suboptimally debulked HGSC (23% vs. 90%), he said.

However, no prospective clinical trials have been conducted in the front line setting in women with LGSC, he noted.

Recent reports of promising activity of hormonal therapy in the recurrent setting have led to an increase in interest in integrating the modality into the primary treatment setting. One study showed a high frequency of ER and PR expression in LGSC, and another showed that hormonal therapy for recurrent LGSC was associated with an objective response rate of 9%, stable disease rate of 66% and median progression-free survival of 7.4 months.

“Some patients derived several years of benefit,” he said. “In addition, low-grade serous carcinoma bears a striking resemblance to luminal breast cancer in that women who are 35 years of age or younger appear to have a significantly worse prognosis.”

Some have concluded, based on these findings, that platinum-based chemotherapy is of no value in the frontline treatment of LGSC and should be abandoned, Dr. Gershenson said.

The current findings, though limited by factors such as their retrospective nature, missing data, a long study period, and possible referral bias suggest that hormonal maintenance therapy deserves a closer look, Dr. Gershenson said.

“The findings of this hypotheses-generating study are potentially practice changing and warrant further investigation using a prospective trial design,” he concluded.

Dr. Gershenson reported stock ownership in AbbVie, Biogen Idec, Celgene, GlaxoSmithKline, Johnson & Johnson, Merck, and Pfizer; consulting or advisory roles with Clovis Oncology, and patents with Elsevier and UpToDate.

[email protected]