Hematology News

A “hospital at home” (HaH) program at Atrium Health, a large integrated delivery system in the Southeast, expanded its hospital capacity during the early phase of the COVID-19 pandemic by providing hospital-level acute care to COVID-19 patients at home, according to a new study in Annals of Internal Medicine.

“Virtual hospital programs have the potential to provide health systems with additional inpatient capacity during the COVID-19 pandemic and beyond,” wrote Kranthi Sitammagari, MD, from the Atrium Health Hospitalist Group, Monroe, N.C., and colleagues.

Whereas most previous HaH programs have relied on visiting nurses and physicians, the new study uses telemedicine to connect with patients. Advocate Health Care researchers published the only other study using the telemedicine-powered model in 2015.

The new Atrium Health study evaluated 1,477 patients who received care in the HaH program between March 23 and May 7 of this year after having been diagnosed with COVID-19. The program provided home monitoring and hospital-level care in a home-based virtual observation unit (VOU) and a virtual acute care unit (VACU).

Patients were tested for the virus in Atrium emergency departments, primary care clinics, urgent care centers, and external testing sites. Those who tested positive were invited to be cared for either in the VOU, if they had mild to moderate symptoms, or in the VACU, if they were sick enough to be admitted to the hospital.
 

Patients hop onboard

Nearly all COVID-positive patients tested in these sites agreed to be admitted to the hospital at home, coauthor Stephanie Murphy, DO, medical director of the Atrium Health HaH program, said in an interview.

Patients with moderate symptoms were glad to be monitored at home, she said. When they got to the point where the nurse supervising their care felt they needed escalation to acute care, they were asked whether they wanted to continue to be cared for at home. Most opted to stay home rather than be admitted to the hospital, where their loved ones couldn’t visit them.

Low-acuity patients in the VOU received daily telemonitoring by a nurse to identify disease progression and escalate care as needed. For those who required more care and were admitted to the VACU, a team of paramedics and registered nurses (RNs; mobile clinicians) visited the patient’s home within 24 hours, setting up a hospital bed, other necessary medical equipment, videoconferencing gear, and a remote-monitoring kit that included a blood pressure cuff, a pulse oximeter, and a thermometer.

Dedicated hospitalists and nurses managed patients with 24/7 coverage and monitoring, bringing in other specialties as needed for virtual consults. Mobile clinician and virtual provider visits continued daily until a patient’s condition improved to the point where they could be deescalated back to the VOU. After that, patients received mobile app-driven symptom monitoring and telephone follow-up with a nurse until they got better.
 

Few patients go to hospital

Overall, patients had a median length of stay of 11 days in the VOU or the VACU or both. The vast majority, 1,293 patients (88%), received care in the VOU only. In that cohort, just 40 patients (3%) required hospitalization in an Atrium facility. Sixteen of those patients spent time in an ICU, seven required ventilator support, and two died in the hospital.

A total of 184 patients (12%) were admitted to the VACU. Twenty-one (11%) required intravenous fluids, 16 (9%) received antibiotics, 40 (22%) required inhaler or nebulizer treatments, 41 (22%) used supplemental oxygen, and 24 (13%) were admitted to a conventional hospital. Of the latter patients, 10 were admitted to an ICU, one required a ventilator, and none died in the hospital.

Dr. Sitammagari, a hospitalist and comedical director for quality at Atrium Health, told this news organization that, overall, the outcomes for patients in the system’s HaH were comparable to those seen in the literature among other COVID-19 cohorts.
 

Augmenting hospital capacity

The authors note that treating the 160 VACU patients within the HaH saved hospital beds for other patients. The HaH maintained a consistent census of between 20 and 30 patients for the first 6 weeks as COVID-19 cases spread.

Since last spring, Dr. Murphy said, the Atrium HaH’s daily census has grown to between 30 and 45 patients. “We could absorb 50 patients if our hospitals required it.”

How much capacity does that add to Atrium Health? While there are 50 hospitals in the health system, the HaH was set up mainly to care for COVID-19 patients who would otherwise have been admitted to the 10 acute-care hospitals in the Charlotte, N.C., area. In the 4 weeks ending Nov. 16, these facilities carried an average daily census of around 160 COVID-19 patients, Dr. Murphy noted. “During that time, the Atrium Health HaH has carried, on average, about 20%-25% of that census.”

If the pandemic were to overwhelm area hospitals, she added, “the structure would support flexing up our staffing and supplies to expand to crisis capacity,” which could be up to 200 patients a day.

For the nurses who make most of the phone calls to patients, patients average about 12 to 15 per RN, Dr. Murphy said, and there’s one mobile clinician for every six to nine patients. That’s pretty consistent with the staffing on med-surg floors in hospitals, she said.

The physicians in the program include hospitalists dedicated to telemedicine and some doctors who can’t work in the regular hospital because they’re immunocompromised. The physicians round virtually, covering 12-17 HaH patients per day, according to Dr. Murphy.
 

Prior planning paid off

Unlike some other health care systems that have launched HaH programs with the aid of outside vendors, Atrium Health developed its own HaH and brought it online just 2 weeks after deciding to launch the program. Atrium was able to do this, Dr. Sitammagari explained, because before the pandemic its hospitalist program was already developing an HaH model to improve the care of high-risk patients after hospital discharge to prevent readmission.

While Atrium’s electronic health record system wasn’t designed for hospital at home, its health information technology department and clinicians collaborated in rewriting some of the workflows and order sets in the EHR. For example, they set up a nursing questionnaire to administer after VACU admission, and they created another form for automatic admission to the HaH after a patient tested positive for COVID-19. Atrium staff also modified a patient-doctor communications app to help clinicians monitor HaH patients, Dr. Murphy noted.

Other hospital systems have gotten up to speed on HaH pretty quickly by using platforms supplied by outside vendors. Adventist Health in Los Angeles, for example, started admitting patients to its hospital at home just a month after approaching a vendor called Medically Home.
 

COVID vs. non-COVID patients

Atrium’s decision to focus its HaH effort on COVID-19 patients is unusual among the small but growing number of health systems that have adopted the HaH model to increase their capacity. (Atrium is now transferring some hospitalized patients with other conditions to its HaH, but is still focusing mainly on COVID-19 in its HaH program.)

Bruce Leff, MD, a professor of health policy and management at Johns Hopkins Bloomberg School of Public Health, Baltimore, a leading expert on the HaH model, agrees that it can increase hospital capacity significantly.

Dr. Leff praised the Atrium Health study. “It proves that within an integrated delivery system you can quickly deploy and implement a virtual hospital in the specific-use case of COVID, and help patients and help the system at scale,” he said. “They took a bunch of people into the virtual observation unit and thereby kept people from overwhelming their [emergency department] and treated those people safely at home.”

Dr. Leff had no problem with Atrium’s focus on patients with COVID-19 rather than other conditions. “My guess is that they have the ability to take what they developed and apply it to other conditions. Once you have the ability to do acute care at home, you can do a lot at home.”

The biggest barrier to the spread of hospital at home remains the lack of insurer coverage. Dr. Murphy said that health plans are covering virtual physician consultations with patients in the HaH, as well as some other bits and pieces, but not the entire episode of acute care.

Dr. Leff believes that this will start changing soon. COVID-19 has altered the attitudes of physicians and hospitals toward telehealth, he noted, “and it has moved policy makers and payers to start thinking about the new models – home-based care in general and hospital at home in particular. For the first time in 25 years, payers are starting to get interested.”

Most of the authors are employees of Atrium Health. In addition, one coauthor reports being the cofounder of a digital health company, iEnroll, and receiving grants from The Heineman Foundation. Dr. Leff is an advisor to Medically Home, which provides support to hospital at home programs.

A version of this article originally appeared on Medscape.com.

A “hospital at home” (HaH) program at Atrium Health, a large integrated delivery system in the Southeast, expanded its hospital capacity during the early phase of the COVID-19 pandemic by providing hospital-level acute care to COVID-19 patients at home, according to a new study in Annals of Internal Medicine.

“Virtual hospital programs have the potential to provide health systems with additional inpatient capacity during the COVID-19 pandemic and beyond,” wrote Kranthi Sitammagari, MD, from the Atrium Health Hospitalist Group, Monroe, N.C., and colleagues.

Whereas most previous HaH programs have relied on visiting nurses and physicians, the new study uses telemedicine to connect with patients. Advocate Health Care researchers published the only other study using the telemedicine-powered model in 2015.

The new Atrium Health study evaluated 1,477 patients who received care in the HaH program between March 23 and May 7 of this year after having been diagnosed with COVID-19. The program provided home monitoring and hospital-level care in a home-based virtual observation unit (VOU) and a virtual acute care unit (VACU).

Patients were tested for the virus in Atrium emergency departments, primary care clinics, urgent care centers, and external testing sites. Those who tested positive were invited to be cared for either in the VOU, if they had mild to moderate symptoms, or in the VACU, if they were sick enough to be admitted to the hospital.
 

Patients hop onboard

Nearly all COVID-positive patients tested in these sites agreed to be admitted to the hospital at home, coauthor Stephanie Murphy, DO, medical director of the Atrium Health HaH program, said in an interview.

Patients with moderate symptoms were glad to be monitored at home, she said. When they got to the point where the nurse supervising their care felt they needed escalation to acute care, they were asked whether they wanted to continue to be cared for at home. Most opted to stay home rather than be admitted to the hospital, where their loved ones couldn’t visit them.

Low-acuity patients in the VOU received daily telemonitoring by a nurse to identify disease progression and escalate care as needed. For those who required more care and were admitted to the VACU, a team of paramedics and registered nurses (RNs; mobile clinicians) visited the patient’s home within 24 hours, setting up a hospital bed, other necessary medical equipment, videoconferencing gear, and a remote-monitoring kit that included a blood pressure cuff, a pulse oximeter, and a thermometer.

Dedicated hospitalists and nurses managed patients with 24/7 coverage and monitoring, bringing in other specialties as needed for virtual consults. Mobile clinician and virtual provider visits continued daily until a patient’s condition improved to the point where they could be deescalated back to the VOU. After that, patients received mobile app-driven symptom monitoring and telephone follow-up with a nurse until they got better.
 

Few patients go to hospital

Overall, patients had a median length of stay of 11 days in the VOU or the VACU or both. The vast majority, 1,293 patients (88%), received care in the VOU only. In that cohort, just 40 patients (3%) required hospitalization in an Atrium facility. Sixteen of those patients spent time in an ICU, seven required ventilator support, and two died in the hospital.

A total of 184 patients (12%) were admitted to the VACU. Twenty-one (11%) required intravenous fluids, 16 (9%) received antibiotics, 40 (22%) required inhaler or nebulizer treatments, 41 (22%) used supplemental oxygen, and 24 (13%) were admitted to a conventional hospital. Of the latter patients, 10 were admitted to an ICU, one required a ventilator, and none died in the hospital.

Dr. Sitammagari, a hospitalist and comedical director for quality at Atrium Health, told this news organization that, overall, the outcomes for patients in the system’s HaH were comparable to those seen in the literature among other COVID-19 cohorts.
 

Augmenting hospital capacity

The authors note that treating the 160 VACU patients within the HaH saved hospital beds for other patients. The HaH maintained a consistent census of between 20 and 30 patients for the first 6 weeks as COVID-19 cases spread.

Since last spring, Dr. Murphy said, the Atrium HaH’s daily census has grown to between 30 and 45 patients. “We could absorb 50 patients if our hospitals required it.”

How much capacity does that add to Atrium Health? While there are 50 hospitals in the health system, the HaH was set up mainly to care for COVID-19 patients who would otherwise have been admitted to the 10 acute-care hospitals in the Charlotte, N.C., area. In the 4 weeks ending Nov. 16, these facilities carried an average daily census of around 160 COVID-19 patients, Dr. Murphy noted. “During that time, the Atrium Health HaH has carried, on average, about 20%-25% of that census.”

If the pandemic were to overwhelm area hospitals, she added, “the structure would support flexing up our staffing and supplies to expand to crisis capacity,” which could be up to 200 patients a day.

For the nurses who make most of the phone calls to patients, patients average about 12 to 15 per RN, Dr. Murphy said, and there’s one mobile clinician for every six to nine patients. That’s pretty consistent with the staffing on med-surg floors in hospitals, she said.

The physicians in the program include hospitalists dedicated to telemedicine and some doctors who can’t work in the regular hospital because they’re immunocompromised. The physicians round virtually, covering 12-17 HaH patients per day, according to Dr. Murphy.
 

Prior planning paid off

Unlike some other health care systems that have launched HaH programs with the aid of outside vendors, Atrium Health developed its own HaH and brought it online just 2 weeks after deciding to launch the program. Atrium was able to do this, Dr. Sitammagari explained, because before the pandemic its hospitalist program was already developing an HaH model to improve the care of high-risk patients after hospital discharge to prevent readmission.

While Atrium’s electronic health record system wasn’t designed for hospital at home, its health information technology department and clinicians collaborated in rewriting some of the workflows and order sets in the EHR. For example, they set up a nursing questionnaire to administer after VACU admission, and they created another form for automatic admission to the HaH after a patient tested positive for COVID-19. Atrium staff also modified a patient-doctor communications app to help clinicians monitor HaH patients, Dr. Murphy noted.

Other hospital systems have gotten up to speed on HaH pretty quickly by using platforms supplied by outside vendors. Adventist Health in Los Angeles, for example, started admitting patients to its hospital at home just a month after approaching a vendor called Medically Home.
 

COVID vs. non-COVID patients

Atrium’s decision to focus its HaH effort on COVID-19 patients is unusual among the small but growing number of health systems that have adopted the HaH model to increase their capacity. (Atrium is now transferring some hospitalized patients with other conditions to its HaH, but is still focusing mainly on COVID-19 in its HaH program.)

Bruce Leff, MD, a professor of health policy and management at Johns Hopkins Bloomberg School of Public Health, Baltimore, a leading expert on the HaH model, agrees that it can increase hospital capacity significantly.

Dr. Leff praised the Atrium Health study. “It proves that within an integrated delivery system you can quickly deploy and implement a virtual hospital in the specific-use case of COVID, and help patients and help the system at scale,” he said. “They took a bunch of people into the virtual observation unit and thereby kept people from overwhelming their [emergency department] and treated those people safely at home.”

Dr. Leff had no problem with Atrium’s focus on patients with COVID-19 rather than other conditions. “My guess is that they have the ability to take what they developed and apply it to other conditions. Once you have the ability to do acute care at home, you can do a lot at home.”

The biggest barrier to the spread of hospital at home remains the lack of insurer coverage. Dr. Murphy said that health plans are covering virtual physician consultations with patients in the HaH, as well as some other bits and pieces, but not the entire episode of acute care.

Dr. Leff believes that this will start changing soon. COVID-19 has altered the attitudes of physicians and hospitals toward telehealth, he noted, “and it has moved policy makers and payers to start thinking about the new models – home-based care in general and hospital at home in particular. For the first time in 25 years, payers are starting to get interested.”

Most of the authors are employees of Atrium Health. In addition, one coauthor reports being the cofounder of a digital health company, iEnroll, and receiving grants from The Heineman Foundation. Dr. Leff is an advisor to Medically Home, which provides support to hospital at home programs.

A version of this article originally appeared on Medscape.com.

A “hospital at home” (HaH) program at Atrium Health, a large integrated delivery system in the Southeast, expanded its hospital capacity during the early phase of the COVID-19 pandemic by providing hospital-level acute care to COVID-19 patients at home, according to a new study in Annals of Internal Medicine.

“Virtual hospital programs have the potential to provide health systems with additional inpatient capacity during the COVID-19 pandemic and beyond,” wrote Kranthi Sitammagari, MD, from the Atrium Health Hospitalist Group, Monroe, N.C., and colleagues.

Whereas most previous HaH programs have relied on visiting nurses and physicians, the new study uses telemedicine to connect with patients. Advocate Health Care researchers published the only other study using the telemedicine-powered model in 2015.

The new Atrium Health study evaluated 1,477 patients who received care in the HaH program between March 23 and May 7 of this year after having been diagnosed with COVID-19. The program provided home monitoring and hospital-level care in a home-based virtual observation unit (VOU) and a virtual acute care unit (VACU).

Patients were tested for the virus in Atrium emergency departments, primary care clinics, urgent care centers, and external testing sites. Those who tested positive were invited to be cared for either in the VOU, if they had mild to moderate symptoms, or in the VACU, if they were sick enough to be admitted to the hospital.
 

Patients hop onboard

Nearly all COVID-positive patients tested in these sites agreed to be admitted to the hospital at home, coauthor Stephanie Murphy, DO, medical director of the Atrium Health HaH program, said in an interview.

Patients with moderate symptoms were glad to be monitored at home, she said. When they got to the point where the nurse supervising their care felt they needed escalation to acute care, they were asked whether they wanted to continue to be cared for at home. Most opted to stay home rather than be admitted to the hospital, where their loved ones couldn’t visit them.

Low-acuity patients in the VOU received daily telemonitoring by a nurse to identify disease progression and escalate care as needed. For those who required more care and were admitted to the VACU, a team of paramedics and registered nurses (RNs; mobile clinicians) visited the patient’s home within 24 hours, setting up a hospital bed, other necessary medical equipment, videoconferencing gear, and a remote-monitoring kit that included a blood pressure cuff, a pulse oximeter, and a thermometer.

Dedicated hospitalists and nurses managed patients with 24/7 coverage and monitoring, bringing in other specialties as needed for virtual consults. Mobile clinician and virtual provider visits continued daily until a patient’s condition improved to the point where they could be deescalated back to the VOU. After that, patients received mobile app-driven symptom monitoring and telephone follow-up with a nurse until they got better.
 

Few patients go to hospital

Overall, patients had a median length of stay of 11 days in the VOU or the VACU or both. The vast majority, 1,293 patients (88%), received care in the VOU only. In that cohort, just 40 patients (3%) required hospitalization in an Atrium facility. Sixteen of those patients spent time in an ICU, seven required ventilator support, and two died in the hospital.

A total of 184 patients (12%) were admitted to the VACU. Twenty-one (11%) required intravenous fluids, 16 (9%) received antibiotics, 40 (22%) required inhaler or nebulizer treatments, 41 (22%) used supplemental oxygen, and 24 (13%) were admitted to a conventional hospital. Of the latter patients, 10 were admitted to an ICU, one required a ventilator, and none died in the hospital.

Dr. Sitammagari, a hospitalist and comedical director for quality at Atrium Health, told this news organization that, overall, the outcomes for patients in the system’s HaH were comparable to those seen in the literature among other COVID-19 cohorts.
 

Augmenting hospital capacity

The authors note that treating the 160 VACU patients within the HaH saved hospital beds for other patients. The HaH maintained a consistent census of between 20 and 30 patients for the first 6 weeks as COVID-19 cases spread.

Since last spring, Dr. Murphy said, the Atrium HaH’s daily census has grown to between 30 and 45 patients. “We could absorb 50 patients if our hospitals required it.”

How much capacity does that add to Atrium Health? While there are 50 hospitals in the health system, the HaH was set up mainly to care for COVID-19 patients who would otherwise have been admitted to the 10 acute-care hospitals in the Charlotte, N.C., area. In the 4 weeks ending Nov. 16, these facilities carried an average daily census of around 160 COVID-19 patients, Dr. Murphy noted. “During that time, the Atrium Health HaH has carried, on average, about 20%-25% of that census.”

If the pandemic were to overwhelm area hospitals, she added, “the structure would support flexing up our staffing and supplies to expand to crisis capacity,” which could be up to 200 patients a day.

For the nurses who make most of the phone calls to patients, patients average about 12 to 15 per RN, Dr. Murphy said, and there’s one mobile clinician for every six to nine patients. That’s pretty consistent with the staffing on med-surg floors in hospitals, she said.

The physicians in the program include hospitalists dedicated to telemedicine and some doctors who can’t work in the regular hospital because they’re immunocompromised. The physicians round virtually, covering 12-17 HaH patients per day, according to Dr. Murphy.
 

Prior planning paid off

Unlike some other health care systems that have launched HaH programs with the aid of outside vendors, Atrium Health developed its own HaH and brought it online just 2 weeks after deciding to launch the program. Atrium was able to do this, Dr. Sitammagari explained, because before the pandemic its hospitalist program was already developing an HaH model to improve the care of high-risk patients after hospital discharge to prevent readmission.

While Atrium’s electronic health record system wasn’t designed for hospital at home, its health information technology department and clinicians collaborated in rewriting some of the workflows and order sets in the EHR. For example, they set up a nursing questionnaire to administer after VACU admission, and they created another form for automatic admission to the HaH after a patient tested positive for COVID-19. Atrium staff also modified a patient-doctor communications app to help clinicians monitor HaH patients, Dr. Murphy noted.

Other hospital systems have gotten up to speed on HaH pretty quickly by using platforms supplied by outside vendors. Adventist Health in Los Angeles, for example, started admitting patients to its hospital at home just a month after approaching a vendor called Medically Home.
 

COVID vs. non-COVID patients

Atrium’s decision to focus its HaH effort on COVID-19 patients is unusual among the small but growing number of health systems that have adopted the HaH model to increase their capacity. (Atrium is now transferring some hospitalized patients with other conditions to its HaH, but is still focusing mainly on COVID-19 in its HaH program.)

Bruce Leff, MD, a professor of health policy and management at Johns Hopkins Bloomberg School of Public Health, Baltimore, a leading expert on the HaH model, agrees that it can increase hospital capacity significantly.

Dr. Leff praised the Atrium Health study. “It proves that within an integrated delivery system you can quickly deploy and implement a virtual hospital in the specific-use case of COVID, and help patients and help the system at scale,” he said. “They took a bunch of people into the virtual observation unit and thereby kept people from overwhelming their [emergency department] and treated those people safely at home.”

Dr. Leff had no problem with Atrium’s focus on patients with COVID-19 rather than other conditions. “My guess is that they have the ability to take what they developed and apply it to other conditions. Once you have the ability to do acute care at home, you can do a lot at home.”

The biggest barrier to the spread of hospital at home remains the lack of insurer coverage. Dr. Murphy said that health plans are covering virtual physician consultations with patients in the HaH, as well as some other bits and pieces, but not the entire episode of acute care.

Dr. Leff believes that this will start changing soon. COVID-19 has altered the attitudes of physicians and hospitals toward telehealth, he noted, “and it has moved policy makers and payers to start thinking about the new models – home-based care in general and hospital at home in particular. For the first time in 25 years, payers are starting to get interested.”

Most of the authors are employees of Atrium Health. In addition, one coauthor reports being the cofounder of a digital health company, iEnroll, and receiving grants from The Heineman Foundation. Dr. Leff is an advisor to Medically Home, which provides support to hospital at home programs.

A version of this article originally appeared on Medscape.com.

The days of using chemotherapy to treat Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ ALL) may be numbered.

In a phase 2 trial, upfront chemotherapy-free induction/consolidation with the tyrosine kinase inhibitor dasatinib (Sprycel) and the bispecific T-cell engager antibody blinatumomab (Blincyto) yielded high rates of molecular response, “impressive” survival at 18 months, and few toxic effects of grade 3 or higher, say researchers.

With this approach, “60% of adult Ph+ ALL patients, of all ages, can obtain a molecular response, and this percent can increase further with more cycles of blinatumomab,” lead researcher Robin Foà, MD, from Sapienza University of Rome, said in an interview.

“The rates of disease-free survival and overall survival at 18 months are highly favorable, and the protocol is associated with limited toxicity,” Dr. Foà added.

“I see this chemo-free approach becoming a realistic approach for a substantial proportion of adult Ph+ ALL patients, particularly for the older patients, keeping in mind that the incidence of Ph+ ALL increases with age,” Dr. Foà said.

The results of the study were published Oct. 22 in the New England Journal of Medicine.
 

‘Innovative’ and ‘highly successful’

This “innovative” chemotherapy-free approach proved “highly successful” with “surprisingly” few toxic effects, Dieter Hoelzer, MD, PhD, University of Frankfurt (Germany), wrote in a linked editorial.

The Italian GIMEMA LAL2116 D-ALBA trial enrolled 63 adults (median age, 54 years; range, 24-82 years) with newly diagnosed Ph+ ALL. All patients received a glucocorticoid for 31 days beginning 7 days before starting treatment with dasatinib.

Dasatinib (140 mg once daily) induction therapy lasted 85 days. All patients who completed the induction phase received blinatumomab (28 mcg/d) consolidation therapy. Dexamethasone (20 mg) was administered before each blinatumomab cycle. To prevent central nervous system adverse events, levetiracetam (500 mg twice daily) was administered.

All but two patients completed dasatinib induction. One was a 73-year-old woman who withdrew from the trial because of toxic effects after 10 days of dasatinib treatment. She later died of pneumonia. The other was an 82-year-old woman who had a complete hematologic response but left the trial because of pneumonia and pneumonitis.

At the end of the induction phase, 98% of the patients (62 of 63) had a complete hematologic response, including the patient with a complete hematologic response who withdrew; 29% (17 of 59 patients) had a molecular response.

Of the 61 patients who completed the induction phase, 58 received one cycle of blinatumomab, 56 received two cycles, 45 received three cycles, 37 received four cycles, and 29 received five cycles. At the end of the second blinatumomab cycle, 60% of the patients (33 of 55 patients) had a molecular response.

The percentage of patients with a molecular response increased further after receiving additional cycles of blinatumomab – to 70% (28 of 40 patients) after the third cycle, 81% (29 of 36 patients) after the fourth cycle, and 72% (21 of 29 patients) after the fifth cycle.

At a median follow-up of 18 months, overall survival was 95%, and disease-free survival was 88%.

There were no significant differences in DFS between patients with p190-kd fusion protein (85%) and those with p210-kd fusion protein (95%). However, DFS was lower in patients with IKZF1 deletion plus additional genetic aberrations (CDKN2A or CDKN2B, PAX5, or both).

ABL1 mutations were present in six patients who had increased minimal residual disease during induction therapy. All these mutations were cleared by blinatumomab.

There were six relapses, of which three were hematologic. One occurred in a patient with a major protocol violation (a delay of more than 2 months in receiving blinatumomab), one occurred after 12 months in the patient who discontinued the trial after receiving dasatinib for 12 days, and one occurred in a patient after the second cycle of blinatumomab.

A total of 21 adverse events of grade 3 or higher were noted. They included cytomegalovirus reactivation or infection in six patients; neutropenia in four patients; persistent fever in two patients; and pleural effusion, pulmonary hypertension, and a neurologic disorder in one patient each.

Of the 24 patients who received a stem-cell allograft, two died, but only one death was related to transplant (4%).

The very low nonrelapse mortality among patients who underwent transplant during remission is “remarkable,” Dr. Hoelzer wrote. It suggests that toxicity from induction chemotherapy puts the patient at risk for toxic effects and death from subsequent stem-cell transplant – “a consequence that is avoided with targeted therapy.”
 

Unanswered questions

“Will the excellent outcomes be preserved with longer follow-up? The answer is probably yes, given that the majority of relapses in ALL occur within the first 1.5 to 2.0 years after the initiation of treatment,” Dr. Hoelzer wrote.

He said other outstanding questions include whether long-term outcomes will differ between patients who undergo transplant and those who do not; whether ABL1 mutations emerge; whether minimal residual disease recurs with longer follow-up; and whether this treatment approach can be used for patients with other subtypes of ALL, such as Ph-negative, B-lineage ALL, or even T-cell ALL.

“If these promising trial results hold, chemotherapy-free induction without the immediate and long-term toxic effects of intensive chemotherapy regimens could also be used in adolescents and, finally, in children. These questions will need to be addressed with longer follow-up and large, prospective trials,” Dr. Hoelzer concluded.

The study was supported by grants from the Italian Association for Cancer Research and Sapienza University of Rome.

A version of this article originally appeared on Medscape.com

The days of using chemotherapy to treat Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ ALL) may be numbered.

In a phase 2 trial, upfront chemotherapy-free induction/consolidation with the tyrosine kinase inhibitor dasatinib (Sprycel) and the bispecific T-cell engager antibody blinatumomab (Blincyto) yielded high rates of molecular response, “impressive” survival at 18 months, and few toxic effects of grade 3 or higher, say researchers.

With this approach, “60% of adult Ph+ ALL patients, of all ages, can obtain a molecular response, and this percent can increase further with more cycles of blinatumomab,” lead researcher Robin Foà, MD, from Sapienza University of Rome, said in an interview.

“The rates of disease-free survival and overall survival at 18 months are highly favorable, and the protocol is associated with limited toxicity,” Dr. Foà added.

“I see this chemo-free approach becoming a realistic approach for a substantial proportion of adult Ph+ ALL patients, particularly for the older patients, keeping in mind that the incidence of Ph+ ALL increases with age,” Dr. Foà said.

The results of the study were published Oct. 22 in the New England Journal of Medicine.
 

‘Innovative’ and ‘highly successful’

This “innovative” chemotherapy-free approach proved “highly successful” with “surprisingly” few toxic effects, Dieter Hoelzer, MD, PhD, University of Frankfurt (Germany), wrote in a linked editorial.

The Italian GIMEMA LAL2116 D-ALBA trial enrolled 63 adults (median age, 54 years; range, 24-82 years) with newly diagnosed Ph+ ALL. All patients received a glucocorticoid for 31 days beginning 7 days before starting treatment with dasatinib.

Dasatinib (140 mg once daily) induction therapy lasted 85 days. All patients who completed the induction phase received blinatumomab (28 mcg/d) consolidation therapy. Dexamethasone (20 mg) was administered before each blinatumomab cycle. To prevent central nervous system adverse events, levetiracetam (500 mg twice daily) was administered.

All but two patients completed dasatinib induction. One was a 73-year-old woman who withdrew from the trial because of toxic effects after 10 days of dasatinib treatment. She later died of pneumonia. The other was an 82-year-old woman who had a complete hematologic response but left the trial because of pneumonia and pneumonitis.

At the end of the induction phase, 98% of the patients (62 of 63) had a complete hematologic response, including the patient with a complete hematologic response who withdrew; 29% (17 of 59 patients) had a molecular response.

Of the 61 patients who completed the induction phase, 58 received one cycle of blinatumomab, 56 received two cycles, 45 received three cycles, 37 received four cycles, and 29 received five cycles. At the end of the second blinatumomab cycle, 60% of the patients (33 of 55 patients) had a molecular response.

The percentage of patients with a molecular response increased further after receiving additional cycles of blinatumomab – to 70% (28 of 40 patients) after the third cycle, 81% (29 of 36 patients) after the fourth cycle, and 72% (21 of 29 patients) after the fifth cycle.

At a median follow-up of 18 months, overall survival was 95%, and disease-free survival was 88%.

There were no significant differences in DFS between patients with p190-kd fusion protein (85%) and those with p210-kd fusion protein (95%). However, DFS was lower in patients with IKZF1 deletion plus additional genetic aberrations (CDKN2A or CDKN2B, PAX5, or both).

ABL1 mutations were present in six patients who had increased minimal residual disease during induction therapy. All these mutations were cleared by blinatumomab.

There were six relapses, of which three were hematologic. One occurred in a patient with a major protocol violation (a delay of more than 2 months in receiving blinatumomab), one occurred after 12 months in the patient who discontinued the trial after receiving dasatinib for 12 days, and one occurred in a patient after the second cycle of blinatumomab.

A total of 21 adverse events of grade 3 or higher were noted. They included cytomegalovirus reactivation or infection in six patients; neutropenia in four patients; persistent fever in two patients; and pleural effusion, pulmonary hypertension, and a neurologic disorder in one patient each.

Of the 24 patients who received a stem-cell allograft, two died, but only one death was related to transplant (4%).

The very low nonrelapse mortality among patients who underwent transplant during remission is “remarkable,” Dr. Hoelzer wrote. It suggests that toxicity from induction chemotherapy puts the patient at risk for toxic effects and death from subsequent stem-cell transplant – “a consequence that is avoided with targeted therapy.”
 

Unanswered questions

“Will the excellent outcomes be preserved with longer follow-up? The answer is probably yes, given that the majority of relapses in ALL occur within the first 1.5 to 2.0 years after the initiation of treatment,” Dr. Hoelzer wrote.

He said other outstanding questions include whether long-term outcomes will differ between patients who undergo transplant and those who do not; whether ABL1 mutations emerge; whether minimal residual disease recurs with longer follow-up; and whether this treatment approach can be used for patients with other subtypes of ALL, such as Ph-negative, B-lineage ALL, or even T-cell ALL.

“If these promising trial results hold, chemotherapy-free induction without the immediate and long-term toxic effects of intensive chemotherapy regimens could also be used in adolescents and, finally, in children. These questions will need to be addressed with longer follow-up and large, prospective trials,” Dr. Hoelzer concluded.

The study was supported by grants from the Italian Association for Cancer Research and Sapienza University of Rome.

A version of this article originally appeared on Medscape.com

The days of using chemotherapy to treat Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ ALL) may be numbered.

In a phase 2 trial, upfront chemotherapy-free induction/consolidation with the tyrosine kinase inhibitor dasatinib (Sprycel) and the bispecific T-cell engager antibody blinatumomab (Blincyto) yielded high rates of molecular response, “impressive” survival at 18 months, and few toxic effects of grade 3 or higher, say researchers.

With this approach, “60% of adult Ph+ ALL patients, of all ages, can obtain a molecular response, and this percent can increase further with more cycles of blinatumomab,” lead researcher Robin Foà, MD, from Sapienza University of Rome, said in an interview.

“The rates of disease-free survival and overall survival at 18 months are highly favorable, and the protocol is associated with limited toxicity,” Dr. Foà added.

“I see this chemo-free approach becoming a realistic approach for a substantial proportion of adult Ph+ ALL patients, particularly for the older patients, keeping in mind that the incidence of Ph+ ALL increases with age,” Dr. Foà said.

The results of the study were published Oct. 22 in the New England Journal of Medicine.
 

‘Innovative’ and ‘highly successful’

This “innovative” chemotherapy-free approach proved “highly successful” with “surprisingly” few toxic effects, Dieter Hoelzer, MD, PhD, University of Frankfurt (Germany), wrote in a linked editorial.

The Italian GIMEMA LAL2116 D-ALBA trial enrolled 63 adults (median age, 54 years; range, 24-82 years) with newly diagnosed Ph+ ALL. All patients received a glucocorticoid for 31 days beginning 7 days before starting treatment with dasatinib.

Dasatinib (140 mg once daily) induction therapy lasted 85 days. All patients who completed the induction phase received blinatumomab (28 mcg/d) consolidation therapy. Dexamethasone (20 mg) was administered before each blinatumomab cycle. To prevent central nervous system adverse events, levetiracetam (500 mg twice daily) was administered.

All but two patients completed dasatinib induction. One was a 73-year-old woman who withdrew from the trial because of toxic effects after 10 days of dasatinib treatment. She later died of pneumonia. The other was an 82-year-old woman who had a complete hematologic response but left the trial because of pneumonia and pneumonitis.

At the end of the induction phase, 98% of the patients (62 of 63) had a complete hematologic response, including the patient with a complete hematologic response who withdrew; 29% (17 of 59 patients) had a molecular response.

Of the 61 patients who completed the induction phase, 58 received one cycle of blinatumomab, 56 received two cycles, 45 received three cycles, 37 received four cycles, and 29 received five cycles. At the end of the second blinatumomab cycle, 60% of the patients (33 of 55 patients) had a molecular response.

The percentage of patients with a molecular response increased further after receiving additional cycles of blinatumomab – to 70% (28 of 40 patients) after the third cycle, 81% (29 of 36 patients) after the fourth cycle, and 72% (21 of 29 patients) after the fifth cycle.

At a median follow-up of 18 months, overall survival was 95%, and disease-free survival was 88%.

There were no significant differences in DFS between patients with p190-kd fusion protein (85%) and those with p210-kd fusion protein (95%). However, DFS was lower in patients with IKZF1 deletion plus additional genetic aberrations (CDKN2A or CDKN2B, PAX5, or both).

ABL1 mutations were present in six patients who had increased minimal residual disease during induction therapy. All these mutations were cleared by blinatumomab.

There were six relapses, of which three were hematologic. One occurred in a patient with a major protocol violation (a delay of more than 2 months in receiving blinatumomab), one occurred after 12 months in the patient who discontinued the trial after receiving dasatinib for 12 days, and one occurred in a patient after the second cycle of blinatumomab.

A total of 21 adverse events of grade 3 or higher were noted. They included cytomegalovirus reactivation or infection in six patients; neutropenia in four patients; persistent fever in two patients; and pleural effusion, pulmonary hypertension, and a neurologic disorder in one patient each.

Of the 24 patients who received a stem-cell allograft, two died, but only one death was related to transplant (4%).

The very low nonrelapse mortality among patients who underwent transplant during remission is “remarkable,” Dr. Hoelzer wrote. It suggests that toxicity from induction chemotherapy puts the patient at risk for toxic effects and death from subsequent stem-cell transplant – “a consequence that is avoided with targeted therapy.”
 

Unanswered questions

“Will the excellent outcomes be preserved with longer follow-up? The answer is probably yes, given that the majority of relapses in ALL occur within the first 1.5 to 2.0 years after the initiation of treatment,” Dr. Hoelzer wrote.

He said other outstanding questions include whether long-term outcomes will differ between patients who undergo transplant and those who do not; whether ABL1 mutations emerge; whether minimal residual disease recurs with longer follow-up; and whether this treatment approach can be used for patients with other subtypes of ALL, such as Ph-negative, B-lineage ALL, or even T-cell ALL.

“If these promising trial results hold, chemotherapy-free induction without the immediate and long-term toxic effects of intensive chemotherapy regimens could also be used in adolescents and, finally, in children. These questions will need to be addressed with longer follow-up and large, prospective trials,” Dr. Hoelzer concluded.

The study was supported by grants from the Italian Association for Cancer Research and Sapienza University of Rome.

A version of this article originally appeared on Medscape.com

An international autopsy study of 21 patients who died from COVID-19 has shown the presence of multifocal lymphocytic myocarditis in three patients (14%). In an additional six patients, focally increased interstitial T-lymphocytes within the myocardium were noted, with only focal or no myocyte injury.

However, increased interstitial macrophage infiltration, possibly related to cytokine infiltration, was seen in 86% of patients.

“One way to think about this is that, if these patients were having biopsies and not autopsies, there would be myocardial injury in the patients with myocarditis, even after they recovered. But with interstitial macrophages, there may or may not be any injury,” said cardiovascular pathologist James R. Stone, MD, PhD, Massachusetts General Hospital, Boston.

Dr. Stone and colleagues from Mass General, two hospitals in Italy, the University of Amsterdam, and the Mayo Clinic in Rochester, Minn., conducted the autopsies in March and April. The results were published in the October 14 issue of the European Heart Journal.

Their technique was rigorous: a median of 20 full-thickness blocks of myocardium were examined histologically (range, 5-29 blocks).

The presence of myocarditis, defined by the presence of multiple foci of inflammation with associated myocyte injury, was determined, and the inflammatory cell composition analyzed by immunohistochemistry.

“I think one of the take-homes from this study is that you have to do a thorough sampling of the heart in order to exclude myocardial injury. You cannot exclude myocarditis with just a biopsy or two,” said Dr. Stone in an interview.

“We looked at multiple different sections of tissue preserved in paraffin for every case and found only 14% had myocarditis. The vast majority of autopsies done on patients dying from COVID-19 have short-changed the autopsy and not been done in a way to exclude myocarditis,” he added.

For all patients, COVID-19 was the underlying cause of death, but the mechanisms of death were acute respiratory distress syndrome in 15, viral pneumonia in 4, cardiogenic shock in 1, and cardiac arrest in 1. Seven patients had a history of cardiovascular disease, including atrial fibrillation in four, coronary artery disease in three, left ventricular hypertrophy in one, and previous valve replacement in one. A total of 16 had hypertension, 7 had diabetes mellitus, and 1 had chronic obstructive pulmonary disease. In four cases, mild pericarditis was present. Acute myocyte injury in the right ventricle, most probably from strain or overload, was also present in four cases.

A nonsignificant trend was seen toward higher serum troponin levels in the patients with myocarditis compared with those without myocarditis. There were no reports of disrupted coronary artery plaques, coronary artery aneurysms, or large pulmonary emboli.

Macrophage infiltration rather than myocarditis, myocardial injury?

The study sheds more light on previous cardiac magnetic resonance (CMR) imaging findings that have suggested that many patients who recover from COVID-19 show signs suggestive of myocarditis. These earlier studies include a recent one in competitive athletes and the earlier Puntmann and colleagues study of relatively young COVID-19 patients, which showed ongoing myocardial involvement in a majority of patients.

“It would not surprise me if some or all of the cardiac MR changes seen in some of these recent imaging studies are due to the macrophages,” said Dr. Stone.

“What we saw was not a routine pathology by any means. It was a huge amount of macrophages, higher that what we saw in SARS and more similar to a study published in 2007 that looked at patients with bacterial sepsis,” said Dr. Stone.

In an older study of SARS patients, 35% had the virus detected in myocardial tissue by polymerase chain reaction. In that subset, the degree of myocardial macrophage infiltrate was comparable to that seen in 86% of the COVID-19 cases described in this series.

Another possibility is that the macrophage infiltration reflects underlying disease rather than COVID-19. All but one of the patients had known underlying medical conditions associated with cardiac remodeling, said Nikolaos G. Frangogiannis, MD, a cardiologist who studies the mechanisms of cardiac injury, repair, and remodeling.

Frangogiannis, from Albert Einstein College of Medicine, New York, wrote an editorial that accompanied the autopsy study.

“The problem with this finding of increased macrophage infiltration is that it’s very hard to interpret because as we age, and especially in a less healthy population, the numbers and the density of macrophages in the heart increase, so it’s impossible to interpret as an effect of the infection itself unless you have an appropriate control population that matches the same characteristics, which is almost impossible to ask for,” he said.

“I’ve observed since the beginning of the pandemic that there seemed to be some people who wanted every single case to be myocarditis and others who had a bias toward not wanting COVID-19 to be a cause of myocarditis. I think what we’re seeing is it’s not either/or for anything with this virus, it’s a bit of everything,” said Dr. Stone.

Dr. Stone and Dr. Frangogiannis reported no conflict of interest.
 

A version of this article originally appeared on Medscape.com.

An international autopsy study of 21 patients who died from COVID-19 has shown the presence of multifocal lymphocytic myocarditis in three patients (14%). In an additional six patients, focally increased interstitial T-lymphocytes within the myocardium were noted, with only focal or no myocyte injury.

However, increased interstitial macrophage infiltration, possibly related to cytokine infiltration, was seen in 86% of patients.

“One way to think about this is that, if these patients were having biopsies and not autopsies, there would be myocardial injury in the patients with myocarditis, even after they recovered. But with interstitial macrophages, there may or may not be any injury,” said cardiovascular pathologist James R. Stone, MD, PhD, Massachusetts General Hospital, Boston.

Dr. Stone and colleagues from Mass General, two hospitals in Italy, the University of Amsterdam, and the Mayo Clinic in Rochester, Minn., conducted the autopsies in March and April. The results were published in the October 14 issue of the European Heart Journal.

Their technique was rigorous: a median of 20 full-thickness blocks of myocardium were examined histologically (range, 5-29 blocks).

The presence of myocarditis, defined by the presence of multiple foci of inflammation with associated myocyte injury, was determined, and the inflammatory cell composition analyzed by immunohistochemistry.

“I think one of the take-homes from this study is that you have to do a thorough sampling of the heart in order to exclude myocardial injury. You cannot exclude myocarditis with just a biopsy or two,” said Dr. Stone in an interview.

“We looked at multiple different sections of tissue preserved in paraffin for every case and found only 14% had myocarditis. The vast majority of autopsies done on patients dying from COVID-19 have short-changed the autopsy and not been done in a way to exclude myocarditis,” he added.

For all patients, COVID-19 was the underlying cause of death, but the mechanisms of death were acute respiratory distress syndrome in 15, viral pneumonia in 4, cardiogenic shock in 1, and cardiac arrest in 1. Seven patients had a history of cardiovascular disease, including atrial fibrillation in four, coronary artery disease in three, left ventricular hypertrophy in one, and previous valve replacement in one. A total of 16 had hypertension, 7 had diabetes mellitus, and 1 had chronic obstructive pulmonary disease. In four cases, mild pericarditis was present. Acute myocyte injury in the right ventricle, most probably from strain or overload, was also present in four cases.

A nonsignificant trend was seen toward higher serum troponin levels in the patients with myocarditis compared with those without myocarditis. There were no reports of disrupted coronary artery plaques, coronary artery aneurysms, or large pulmonary emboli.

Macrophage infiltration rather than myocarditis, myocardial injury?

The study sheds more light on previous cardiac magnetic resonance (CMR) imaging findings that have suggested that many patients who recover from COVID-19 show signs suggestive of myocarditis. These earlier studies include a recent one in competitive athletes and the earlier Puntmann and colleagues study of relatively young COVID-19 patients, which showed ongoing myocardial involvement in a majority of patients.

“It would not surprise me if some or all of the cardiac MR changes seen in some of these recent imaging studies are due to the macrophages,” said Dr. Stone.

“What we saw was not a routine pathology by any means. It was a huge amount of macrophages, higher that what we saw in SARS and more similar to a study published in 2007 that looked at patients with bacterial sepsis,” said Dr. Stone.

In an older study of SARS patients, 35% had the virus detected in myocardial tissue by polymerase chain reaction. In that subset, the degree of myocardial macrophage infiltrate was comparable to that seen in 86% of the COVID-19 cases described in this series.

Another possibility is that the macrophage infiltration reflects underlying disease rather than COVID-19. All but one of the patients had known underlying medical conditions associated with cardiac remodeling, said Nikolaos G. Frangogiannis, MD, a cardiologist who studies the mechanisms of cardiac injury, repair, and remodeling.

Frangogiannis, from Albert Einstein College of Medicine, New York, wrote an editorial that accompanied the autopsy study.

“The problem with this finding of increased macrophage infiltration is that it’s very hard to interpret because as we age, and especially in a less healthy population, the numbers and the density of macrophages in the heart increase, so it’s impossible to interpret as an effect of the infection itself unless you have an appropriate control population that matches the same characteristics, which is almost impossible to ask for,” he said.

“I’ve observed since the beginning of the pandemic that there seemed to be some people who wanted every single case to be myocarditis and others who had a bias toward not wanting COVID-19 to be a cause of myocarditis. I think what we’re seeing is it’s not either/or for anything with this virus, it’s a bit of everything,” said Dr. Stone.

Dr. Stone and Dr. Frangogiannis reported no conflict of interest.
 

A version of this article originally appeared on Medscape.com.

An international autopsy study of 21 patients who died from COVID-19 has shown the presence of multifocal lymphocytic myocarditis in three patients (14%). In an additional six patients, focally increased interstitial T-lymphocytes within the myocardium were noted, with only focal or no myocyte injury.

However, increased interstitial macrophage infiltration, possibly related to cytokine infiltration, was seen in 86% of patients.

“One way to think about this is that, if these patients were having biopsies and not autopsies, there would be myocardial injury in the patients with myocarditis, even after they recovered. But with interstitial macrophages, there may or may not be any injury,” said cardiovascular pathologist James R. Stone, MD, PhD, Massachusetts General Hospital, Boston.

Dr. Stone and colleagues from Mass General, two hospitals in Italy, the University of Amsterdam, and the Mayo Clinic in Rochester, Minn., conducted the autopsies in March and April. The results were published in the October 14 issue of the European Heart Journal.

Their technique was rigorous: a median of 20 full-thickness blocks of myocardium were examined histologically (range, 5-29 blocks).

The presence of myocarditis, defined by the presence of multiple foci of inflammation with associated myocyte injury, was determined, and the inflammatory cell composition analyzed by immunohistochemistry.

“I think one of the take-homes from this study is that you have to do a thorough sampling of the heart in order to exclude myocardial injury. You cannot exclude myocarditis with just a biopsy or two,” said Dr. Stone in an interview.

“We looked at multiple different sections of tissue preserved in paraffin for every case and found only 14% had myocarditis. The vast majority of autopsies done on patients dying from COVID-19 have short-changed the autopsy and not been done in a way to exclude myocarditis,” he added.

For all patients, COVID-19 was the underlying cause of death, but the mechanisms of death were acute respiratory distress syndrome in 15, viral pneumonia in 4, cardiogenic shock in 1, and cardiac arrest in 1. Seven patients had a history of cardiovascular disease, including atrial fibrillation in four, coronary artery disease in three, left ventricular hypertrophy in one, and previous valve replacement in one. A total of 16 had hypertension, 7 had diabetes mellitus, and 1 had chronic obstructive pulmonary disease. In four cases, mild pericarditis was present. Acute myocyte injury in the right ventricle, most probably from strain or overload, was also present in four cases.

A nonsignificant trend was seen toward higher serum troponin levels in the patients with myocarditis compared with those without myocarditis. There were no reports of disrupted coronary artery plaques, coronary artery aneurysms, or large pulmonary emboli.

Macrophage infiltration rather than myocarditis, myocardial injury?

The study sheds more light on previous cardiac magnetic resonance (CMR) imaging findings that have suggested that many patients who recover from COVID-19 show signs suggestive of myocarditis. These earlier studies include a recent one in competitive athletes and the earlier Puntmann and colleagues study of relatively young COVID-19 patients, which showed ongoing myocardial involvement in a majority of patients.

“It would not surprise me if some or all of the cardiac MR changes seen in some of these recent imaging studies are due to the macrophages,” said Dr. Stone.

“What we saw was not a routine pathology by any means. It was a huge amount of macrophages, higher that what we saw in SARS and more similar to a study published in 2007 that looked at patients with bacterial sepsis,” said Dr. Stone.

In an older study of SARS patients, 35% had the virus detected in myocardial tissue by polymerase chain reaction. In that subset, the degree of myocardial macrophage infiltrate was comparable to that seen in 86% of the COVID-19 cases described in this series.

Another possibility is that the macrophage infiltration reflects underlying disease rather than COVID-19. All but one of the patients had known underlying medical conditions associated with cardiac remodeling, said Nikolaos G. Frangogiannis, MD, a cardiologist who studies the mechanisms of cardiac injury, repair, and remodeling.

Frangogiannis, from Albert Einstein College of Medicine, New York, wrote an editorial that accompanied the autopsy study.

“The problem with this finding of increased macrophage infiltration is that it’s very hard to interpret because as we age, and especially in a less healthy population, the numbers and the density of macrophages in the heart increase, so it’s impossible to interpret as an effect of the infection itself unless you have an appropriate control population that matches the same characteristics, which is almost impossible to ask for,” he said.

“I’ve observed since the beginning of the pandemic that there seemed to be some people who wanted every single case to be myocarditis and others who had a bias toward not wanting COVID-19 to be a cause of myocarditis. I think what we’re seeing is it’s not either/or for anything with this virus, it’s a bit of everything,” said Dr. Stone.

Dr. Stone and Dr. Frangogiannis reported no conflict of interest.
 

A version of this article originally appeared on Medscape.com.

Much has changed in the 10 years since Medscape’s first survey on what physicians would do when faced with painful choices in patient care.

A new report, Ethics 2020: Life, Death, and Painful Dilemmas, shows that physicians’ value judgments have shifted in many respects, sometimes as a result of increased regulations and fears of litigation.
 

 End-of-life decisions

Several of the questions in the survey revolved around end-of-life decisions, and in some cases, the differences seen in just a decade were striking. One example concerned life support decisions in the context of a family’s choices.

Age also seemed to play a role in the 2020 answers to that question: Physicians younger than 45 were more likely (28%) to answer “yes” (that they would withdraw life support in that instance) than were those 45 and older (16%).

A critical care physician said, “If the family appears to have an underlying motivation that may not be in the patient’s best interest, I might be inclined to pursue a legal decision prior to withdrawing support.”

A cardiologist had a more pointed response to the question: “To me, that would be murder.”

Another example of how perspectives have changed over the past 10 years concerns whether physician-aided dying should be legal for terminally ill patients. The practice is now mandated by law in eight states and the District of Columbia, and it is mandated by court ruling in two additional states.

In 2010, 41% said “no.” That number dropped to 28% in 2020.

On legalization, a psychiatrist said, “Yes, when there is truly no hope and the quality of remaining life is too poor. We show more compassion to our sick animals than we do to our human population.”

Conversely, a neurologist answered, “No, I see younger physicians already becoming comfortable with the idea of deciding ASAP whether there is a reasonable chance of survival and then pressing for the right code status. This change would make things worse.”
 

Assisted death and incurable suffering

Far fewer physicians supported physician-assisted death for those who had years to live but faced incurable suffering: Thirty-seven percent said “yes,” 34% said “no,” and 29% said “it depends.”

However, support was significantly higher than it was just 2 years ago, in 2018, when only 27% supported the concept, the report authors noted.

“The shift reflects movements by many states to legalize assisted dying for the terminally ill,” Arthur Caplan, PhD, director of the division of medical ethics, New York University, said in the report. “Legalization has not been abused, so some doctors are more willing to press further beyond terminal illness as a trigger to suffering.”

Conversely, many more physicians (44% vs. 24% a decade ago) said they would provide life-sustaining therapy if the family requested it, even if the physician thought it was futile.

“Concerns over a malpractice lawsuit and potential negative patient/family online reviews are factors that play into this change,” the survey authors wrote.

Shared decision making also increased in the past decade.
 

Would you undertreat pain?

Primary care physicians fear the consequences of what they consider adequate pain management more than specialists do (24% vs. 17%), the survey authors noted.

Ten years ago, Medscape asked physicians whether they would undertreat a patient’s pain because of fear of repercussions or the patient’s becoming addicted: Eighty-four percent said “no,” and 6% said “yes.” The rest said “it depends.”

In 2020, the question was asked slightly differently: “Would you undertreat a patient’s pain for fear of addiction or Drug Enforcement Administration or medical board scrutiny?” This year, three times as many said “yes” (18%); 63% said “no.”

“Respondents this year talked about investigations and reprimands by medical boards, and how much they wanted to avoid that,” the survey authors wrote.
 

Should physicians be required to treat COVID-19 patients?

Some questions were new this year, including one on whether physicians should be required to treat COVID-19 patients. Fewer than half (47%) answered “yes,” 24% said “no,” and 29% answered “it depends.”

Doctors’ answers to this question differed slightly by gender: Fifty percent of men and 43% of women said “yes.” In their responses, many physicians said consideration should be given to risk factors, such as age, underlying conditions, risk of family members, and availability of personal protective equipment (PPE).

Another pandemic-related question asked whether physicians felt they should correct physicians who post misinformation about the pandemic on social media. Half (50%) said “yes,” 19% said “no,” and 31% said “it depends.”
 

Speaking out against the workplace

This year, many physicians have felt betrayed when they didn’t have adequate PPE during the pandemic.

Asked, “Is it right to speak out against your hospital or workplace when they don’t give you what you need?” 53% of physicians said “yes,” 8% said “no,” and 40% said “it depends.”

A cardiologist made the value judgment this way: “Speaking out just because you had an argument with your boss is inappropriate. Bringing to the public repeated failures to correct situations that have been brought through the proper channels is necessary to incite change.”
 

Random drug testing for physicians?

Another question in the survey asked whether physicians should be subjected to random drug testing for alcohol and drug abuse. About one-third (34%) said yes, 43% said no, and 23% said “it depends.” A study found that between 10% and 15% of physicians have abused a substance at some point in their careers.

The subject continues to hit a nerve in medicine.

A family physician wrote, “This should not be done unless a particular physician had a problem with drug or alcohol abuse and shows signs of impairment.”

An internist took a different view, saying, “Military service men and women, police, firefighters, airline pilots, and other professions that have responsibilities affecting people’s lives are subject to testing; why not physicians?”
 

A version of this article originally appeared on Medscape.com.

Much has changed in the 10 years since Medscape’s first survey on what physicians would do when faced with painful choices in patient care.

A new report, Ethics 2020: Life, Death, and Painful Dilemmas, shows that physicians’ value judgments have shifted in many respects, sometimes as a result of increased regulations and fears of litigation.
 

 End-of-life decisions

Several of the questions in the survey revolved around end-of-life decisions, and in some cases, the differences seen in just a decade were striking. One example concerned life support decisions in the context of a family’s choices.

Age also seemed to play a role in the 2020 answers to that question: Physicians younger than 45 were more likely (28%) to answer “yes” (that they would withdraw life support in that instance) than were those 45 and older (16%).

A critical care physician said, “If the family appears to have an underlying motivation that may not be in the patient’s best interest, I might be inclined to pursue a legal decision prior to withdrawing support.”

A cardiologist had a more pointed response to the question: “To me, that would be murder.”

Another example of how perspectives have changed over the past 10 years concerns whether physician-aided dying should be legal for terminally ill patients. The practice is now mandated by law in eight states and the District of Columbia, and it is mandated by court ruling in two additional states.

In 2010, 41% said “no.” That number dropped to 28% in 2020.

On legalization, a psychiatrist said, “Yes, when there is truly no hope and the quality of remaining life is too poor. We show more compassion to our sick animals than we do to our human population.”

Conversely, a neurologist answered, “No, I see younger physicians already becoming comfortable with the idea of deciding ASAP whether there is a reasonable chance of survival and then pressing for the right code status. This change would make things worse.”
 

Assisted death and incurable suffering

Far fewer physicians supported physician-assisted death for those who had years to live but faced incurable suffering: Thirty-seven percent said “yes,” 34% said “no,” and 29% said “it depends.”

However, support was significantly higher than it was just 2 years ago, in 2018, when only 27% supported the concept, the report authors noted.

“The shift reflects movements by many states to legalize assisted dying for the terminally ill,” Arthur Caplan, PhD, director of the division of medical ethics, New York University, said in the report. “Legalization has not been abused, so some doctors are more willing to press further beyond terminal illness as a trigger to suffering.”

Conversely, many more physicians (44% vs. 24% a decade ago) said they would provide life-sustaining therapy if the family requested it, even if the physician thought it was futile.

“Concerns over a malpractice lawsuit and potential negative patient/family online reviews are factors that play into this change,” the survey authors wrote.

Shared decision making also increased in the past decade.
 

Would you undertreat pain?

Primary care physicians fear the consequences of what they consider adequate pain management more than specialists do (24% vs. 17%), the survey authors noted.

Ten years ago, Medscape asked physicians whether they would undertreat a patient’s pain because of fear of repercussions or the patient’s becoming addicted: Eighty-four percent said “no,” and 6% said “yes.” The rest said “it depends.”

In 2020, the question was asked slightly differently: “Would you undertreat a patient’s pain for fear of addiction or Drug Enforcement Administration or medical board scrutiny?” This year, three times as many said “yes” (18%); 63% said “no.”

“Respondents this year talked about investigations and reprimands by medical boards, and how much they wanted to avoid that,” the survey authors wrote.
 

Should physicians be required to treat COVID-19 patients?

Some questions were new this year, including one on whether physicians should be required to treat COVID-19 patients. Fewer than half (47%) answered “yes,” 24% said “no,” and 29% answered “it depends.”

Doctors’ answers to this question differed slightly by gender: Fifty percent of men and 43% of women said “yes.” In their responses, many physicians said consideration should be given to risk factors, such as age, underlying conditions, risk of family members, and availability of personal protective equipment (PPE).

Another pandemic-related question asked whether physicians felt they should correct physicians who post misinformation about the pandemic on social media. Half (50%) said “yes,” 19% said “no,” and 31% said “it depends.”
 

Speaking out against the workplace

This year, many physicians have felt betrayed when they didn’t have adequate PPE during the pandemic.

Asked, “Is it right to speak out against your hospital or workplace when they don’t give you what you need?” 53% of physicians said “yes,” 8% said “no,” and 40% said “it depends.”

A cardiologist made the value judgment this way: “Speaking out just because you had an argument with your boss is inappropriate. Bringing to the public repeated failures to correct situations that have been brought through the proper channels is necessary to incite change.”
 

Random drug testing for physicians?

Another question in the survey asked whether physicians should be subjected to random drug testing for alcohol and drug abuse. About one-third (34%) said yes, 43% said no, and 23% said “it depends.” A study found that between 10% and 15% of physicians have abused a substance at some point in their careers.

The subject continues to hit a nerve in medicine.

A family physician wrote, “This should not be done unless a particular physician had a problem with drug or alcohol abuse and shows signs of impairment.”

An internist took a different view, saying, “Military service men and women, police, firefighters, airline pilots, and other professions that have responsibilities affecting people’s lives are subject to testing; why not physicians?”
 

A version of this article originally appeared on Medscape.com.

Much has changed in the 10 years since Medscape’s first survey on what physicians would do when faced with painful choices in patient care.

A new report, Ethics 2020: Life, Death, and Painful Dilemmas, shows that physicians’ value judgments have shifted in many respects, sometimes as a result of increased regulations and fears of litigation.
 

 End-of-life decisions

Several of the questions in the survey revolved around end-of-life decisions, and in some cases, the differences seen in just a decade were striking. One example concerned life support decisions in the context of a family’s choices.

Age also seemed to play a role in the 2020 answers to that question: Physicians younger than 45 were more likely (28%) to answer “yes” (that they would withdraw life support in that instance) than were those 45 and older (16%).

A critical care physician said, “If the family appears to have an underlying motivation that may not be in the patient’s best interest, I might be inclined to pursue a legal decision prior to withdrawing support.”

A cardiologist had a more pointed response to the question: “To me, that would be murder.”

Another example of how perspectives have changed over the past 10 years concerns whether physician-aided dying should be legal for terminally ill patients. The practice is now mandated by law in eight states and the District of Columbia, and it is mandated by court ruling in two additional states.

In 2010, 41% said “no.” That number dropped to 28% in 2020.

On legalization, a psychiatrist said, “Yes, when there is truly no hope and the quality of remaining life is too poor. We show more compassion to our sick animals than we do to our human population.”

Conversely, a neurologist answered, “No, I see younger physicians already becoming comfortable with the idea of deciding ASAP whether there is a reasonable chance of survival and then pressing for the right code status. This change would make things worse.”
 

Assisted death and incurable suffering

Far fewer physicians supported physician-assisted death for those who had years to live but faced incurable suffering: Thirty-seven percent said “yes,” 34% said “no,” and 29% said “it depends.”

However, support was significantly higher than it was just 2 years ago, in 2018, when only 27% supported the concept, the report authors noted.

“The shift reflects movements by many states to legalize assisted dying for the terminally ill,” Arthur Caplan, PhD, director of the division of medical ethics, New York University, said in the report. “Legalization has not been abused, so some doctors are more willing to press further beyond terminal illness as a trigger to suffering.”

Conversely, many more physicians (44% vs. 24% a decade ago) said they would provide life-sustaining therapy if the family requested it, even if the physician thought it was futile.

“Concerns over a malpractice lawsuit and potential negative patient/family online reviews are factors that play into this change,” the survey authors wrote.

Shared decision making also increased in the past decade.
 

Would you undertreat pain?

Primary care physicians fear the consequences of what they consider adequate pain management more than specialists do (24% vs. 17%), the survey authors noted.

Ten years ago, Medscape asked physicians whether they would undertreat a patient’s pain because of fear of repercussions or the patient’s becoming addicted: Eighty-four percent said “no,” and 6% said “yes.” The rest said “it depends.”

In 2020, the question was asked slightly differently: “Would you undertreat a patient’s pain for fear of addiction or Drug Enforcement Administration or medical board scrutiny?” This year, three times as many said “yes” (18%); 63% said “no.”

“Respondents this year talked about investigations and reprimands by medical boards, and how much they wanted to avoid that,” the survey authors wrote.
 

Should physicians be required to treat COVID-19 patients?

Some questions were new this year, including one on whether physicians should be required to treat COVID-19 patients. Fewer than half (47%) answered “yes,” 24% said “no,” and 29% answered “it depends.”

Doctors’ answers to this question differed slightly by gender: Fifty percent of men and 43% of women said “yes.” In their responses, many physicians said consideration should be given to risk factors, such as age, underlying conditions, risk of family members, and availability of personal protective equipment (PPE).

Another pandemic-related question asked whether physicians felt they should correct physicians who post misinformation about the pandemic on social media. Half (50%) said “yes,” 19% said “no,” and 31% said “it depends.”
 

Speaking out against the workplace

This year, many physicians have felt betrayed when they didn’t have adequate PPE during the pandemic.

Asked, “Is it right to speak out against your hospital or workplace when they don’t give you what you need?” 53% of physicians said “yes,” 8% said “no,” and 40% said “it depends.”

A cardiologist made the value judgment this way: “Speaking out just because you had an argument with your boss is inappropriate. Bringing to the public repeated failures to correct situations that have been brought through the proper channels is necessary to incite change.”
 

Random drug testing for physicians?

Another question in the survey asked whether physicians should be subjected to random drug testing for alcohol and drug abuse. About one-third (34%) said yes, 43% said no, and 23% said “it depends.” A study found that between 10% and 15% of physicians have abused a substance at some point in their careers.

The subject continues to hit a nerve in medicine.

A family physician wrote, “This should not be done unless a particular physician had a problem with drug or alcohol abuse and shows signs of impairment.”

An internist took a different view, saying, “Military service men and women, police, firefighters, airline pilots, and other professions that have responsibilities affecting people’s lives are subject to testing; why not physicians?”
 

A version of this article originally appeared on Medscape.com.

More patients are surviving critical illnesses requiring ICU care but many emerge with physical debility that may or may not eventually resolve.

Over the past decade, functional status deterioration after critical illness has become more common and of greater magnitude, despite concurrent efforts to reduce post–intensive care syndrome, based on a retrospective analysis of more than 100,000 patients.

Almost one-third of patients who survived nonsurgical ICU admission had evidence of functional status decline, reported lead author Nicholas E. Ingraham, MD, of the University of Minnesota, Minneapolis, and colleagues.

“Increasing capacity and decreasing mortality have created an evolving and diverse population of ICU survivors,” the investigators wrote in Critical Care Medicine. “Today’s survivors of critical illness are increasingly burdened by extensive physical and psychological comorbidities, often resulting in reduced quality of life.”

To determine trends in post–intensive care syndrome from 2008 to 2016, Dr. Ingraham and colleagues analyzed data from the Cerner Acute Physiology and Chronic Health Evaluation outcomes database, a national prospective cohort. Out of 202,786 adult patients admitted to the ICU, 129,917 were eligible for the study. Patients were excluded because of surgical admission, death, lack of functional status documentation, or inadequate hospital size or duration of participation. The final dataset had a median age of 63 years, with a slight predominance of male patients (54.0%). Most patients (80.9%) were White.

The primary outcome was defined as presence or absence of functional status deterioration, based on functional status at admission versus time of discharge. The secondary outcome was magnitude of deterioration over time.

The analysis, which controlled for age and severity of illness, revealed concerning trends for both outcomes.

Across the entire cohort 38,116 patients (29.3%) had functional status deterioration, with a 15% increase in prevalence over the course of the decade that spanned all disease categories (prevalence rate ratio, 1.15; 95% confidence interval, 1.13-1.17; P < .001). The magnitude of functional status decline also increased by 4% (odds ratio, 1.04; P < .001), with all but nonsurgical trauma patients showing greater deterioration over time.

“However, despite the decreasing magnitude of functional status deterioration in nonsurgical trauma, many admission diagnoses in this category remain in the top quartile of higher risk for functional status deterioration,” the investigators noted.

Functional status decline was most common among patients with head and polytrauma (OR, 3.39), followed closely by chest and spine trauma (OR, 3.38), and spine trauma (OR, 3.19). The top quartile of categories for prevalence of deterioration included nonsurgical trauma, neurologic, pulmonary, and gastrointestinal diseases.

Functional status decline was least common among patients diagnosed with diabetic ketoacidosis (OR, 0.27) or asthma (OR, 0.35).

“We believe our study provides important information that can be used in beginning to identify patients at high risk of functional status decline,” the investigators concluded. “Improving the identification of these patients and targeting appropriate interventions to mitigate this decline will be important directions for future studies in this area.”

According to David L. Bowton, MD, FCCP, professor emeritus, section on critical care, Wake Forest Baptist Health, Winston-Salem, N.C., the findings show just how common functional decline is after critical illness, and may actually underestimate prevalence.

“Because the authors employed a course evaluation tool employing only three categories of ability/disability and abstracted the level of disability from the medical record, they likely underestimated the frequency of clinically important, though not detected, disability at the time of hospital discharge,” Dr. Bowton said. “The study did not address cognitive impairment which can be detected in half of patients at 3 months following critical illness, and which significantly affects patients’ quality of life (Am J Respir Crit Care Med. 2020;202[2]:193-201).”

Dr. Bowton suggested that evidence-based methods of preventing post–intensive care syndrome are limited.

“Current efforts to improve post-ICU functional and cognitive outcomes suffer from the lack of proven effective interventions (Crit Care Med. 2019;47[11]:1607-18),” he said. “Observational data indicates that compliance with the ABCDEF bundle decreases the duration and incidence of delirium, ICU length of stay, duration of mechanical ventilation, and mortality (Crit Care Med. 2019;47[1]:3-14). However, the implications of these improvements on postdischarge functional outcomes are unknown as area the relative importance of individual elements of the bundle. Early mobility and patient and family diaries appear to improve functional status at discharge and postdischarge anxiety and depression, though the evidence supporting this is thin.”

Appropriate intervention may be especially challenging during the COVID-19 pandemic, he added.

“The impact of COVID on ICU staffing adequacy and stress is significant and the impact on quality bundle compliance and the availability of support services is currently not clear, but likely to be detrimental, especially to support services such as physical therapy that are already commonly understaffed,” Dr. Bowton said.

The study was supported by grants from the University of Minnesota’s Critical Care Research and Programmatic Development Program; the National Heart, Lung, and Blood Institute; and the University of Minnesota Clinical and Translational Science via the National Center for Advancing Translational Sciences. The investigators reported financial relationships with no other relevant organizations. Dr. Bowton reported no conflicts of interest.

SOURCE: Ingraham NE et al. Crit Care Med. 2020 Nov. doi: 10.1097/CCM.0000000000004524.

More patients are surviving critical illnesses requiring ICU care but many emerge with physical debility that may or may not eventually resolve.

Over the past decade, functional status deterioration after critical illness has become more common and of greater magnitude, despite concurrent efforts to reduce post–intensive care syndrome, based on a retrospective analysis of more than 100,000 patients.

Almost one-third of patients who survived nonsurgical ICU admission had evidence of functional status decline, reported lead author Nicholas E. Ingraham, MD, of the University of Minnesota, Minneapolis, and colleagues.

“Increasing capacity and decreasing mortality have created an evolving and diverse population of ICU survivors,” the investigators wrote in Critical Care Medicine. “Today’s survivors of critical illness are increasingly burdened by extensive physical and psychological comorbidities, often resulting in reduced quality of life.”

To determine trends in post–intensive care syndrome from 2008 to 2016, Dr. Ingraham and colleagues analyzed data from the Cerner Acute Physiology and Chronic Health Evaluation outcomes database, a national prospective cohort. Out of 202,786 adult patients admitted to the ICU, 129,917 were eligible for the study. Patients were excluded because of surgical admission, death, lack of functional status documentation, or inadequate hospital size or duration of participation. The final dataset had a median age of 63 years, with a slight predominance of male patients (54.0%). Most patients (80.9%) were White.

The primary outcome was defined as presence or absence of functional status deterioration, based on functional status at admission versus time of discharge. The secondary outcome was magnitude of deterioration over time.

The analysis, which controlled for age and severity of illness, revealed concerning trends for both outcomes.

Across the entire cohort 38,116 patients (29.3%) had functional status deterioration, with a 15% increase in prevalence over the course of the decade that spanned all disease categories (prevalence rate ratio, 1.15; 95% confidence interval, 1.13-1.17; P < .001). The magnitude of functional status decline also increased by 4% (odds ratio, 1.04; P < .001), with all but nonsurgical trauma patients showing greater deterioration over time.

“However, despite the decreasing magnitude of functional status deterioration in nonsurgical trauma, many admission diagnoses in this category remain in the top quartile of higher risk for functional status deterioration,” the investigators noted.

Functional status decline was most common among patients with head and polytrauma (OR, 3.39), followed closely by chest and spine trauma (OR, 3.38), and spine trauma (OR, 3.19). The top quartile of categories for prevalence of deterioration included nonsurgical trauma, neurologic, pulmonary, and gastrointestinal diseases.

Functional status decline was least common among patients diagnosed with diabetic ketoacidosis (OR, 0.27) or asthma (OR, 0.35).

“We believe our study provides important information that can be used in beginning to identify patients at high risk of functional status decline,” the investigators concluded. “Improving the identification of these patients and targeting appropriate interventions to mitigate this decline will be important directions for future studies in this area.”

According to David L. Bowton, MD, FCCP, professor emeritus, section on critical care, Wake Forest Baptist Health, Winston-Salem, N.C., the findings show just how common functional decline is after critical illness, and may actually underestimate prevalence.

“Because the authors employed a course evaluation tool employing only three categories of ability/disability and abstracted the level of disability from the medical record, they likely underestimated the frequency of clinically important, though not detected, disability at the time of hospital discharge,” Dr. Bowton said. “The study did not address cognitive impairment which can be detected in half of patients at 3 months following critical illness, and which significantly affects patients’ quality of life (Am J Respir Crit Care Med. 2020;202[2]:193-201).”

Dr. Bowton suggested that evidence-based methods of preventing post–intensive care syndrome are limited.

“Current efforts to improve post-ICU functional and cognitive outcomes suffer from the lack of proven effective interventions (Crit Care Med. 2019;47[11]:1607-18),” he said. “Observational data indicates that compliance with the ABCDEF bundle decreases the duration and incidence of delirium, ICU length of stay, duration of mechanical ventilation, and mortality (Crit Care Med. 2019;47[1]:3-14). However, the implications of these improvements on postdischarge functional outcomes are unknown as area the relative importance of individual elements of the bundle. Early mobility and patient and family diaries appear to improve functional status at discharge and postdischarge anxiety and depression, though the evidence supporting this is thin.”

Appropriate intervention may be especially challenging during the COVID-19 pandemic, he added.

“The impact of COVID on ICU staffing adequacy and stress is significant and the impact on quality bundle compliance and the availability of support services is currently not clear, but likely to be detrimental, especially to support services such as physical therapy that are already commonly understaffed,” Dr. Bowton said.

The study was supported by grants from the University of Minnesota’s Critical Care Research and Programmatic Development Program; the National Heart, Lung, and Blood Institute; and the University of Minnesota Clinical and Translational Science via the National Center for Advancing Translational Sciences. The investigators reported financial relationships with no other relevant organizations. Dr. Bowton reported no conflicts of interest.

SOURCE: Ingraham NE et al. Crit Care Med. 2020 Nov. doi: 10.1097/CCM.0000000000004524.

More patients are surviving critical illnesses requiring ICU care but many emerge with physical debility that may or may not eventually resolve.

Over the past decade, functional status deterioration after critical illness has become more common and of greater magnitude, despite concurrent efforts to reduce post–intensive care syndrome, based on a retrospective analysis of more than 100,000 patients.

Almost one-third of patients who survived nonsurgical ICU admission had evidence of functional status decline, reported lead author Nicholas E. Ingraham, MD, of the University of Minnesota, Minneapolis, and colleagues.

“Increasing capacity and decreasing mortality have created an evolving and diverse population of ICU survivors,” the investigators wrote in Critical Care Medicine. “Today’s survivors of critical illness are increasingly burdened by extensive physical and psychological comorbidities, often resulting in reduced quality of life.”

To determine trends in post–intensive care syndrome from 2008 to 2016, Dr. Ingraham and colleagues analyzed data from the Cerner Acute Physiology and Chronic Health Evaluation outcomes database, a national prospective cohort. Out of 202,786 adult patients admitted to the ICU, 129,917 were eligible for the study. Patients were excluded because of surgical admission, death, lack of functional status documentation, or inadequate hospital size or duration of participation. The final dataset had a median age of 63 years, with a slight predominance of male patients (54.0%). Most patients (80.9%) were White.

The primary outcome was defined as presence or absence of functional status deterioration, based on functional status at admission versus time of discharge. The secondary outcome was magnitude of deterioration over time.

The analysis, which controlled for age and severity of illness, revealed concerning trends for both outcomes.

Across the entire cohort 38,116 patients (29.3%) had functional status deterioration, with a 15% increase in prevalence over the course of the decade that spanned all disease categories (prevalence rate ratio, 1.15; 95% confidence interval, 1.13-1.17; P < .001). The magnitude of functional status decline also increased by 4% (odds ratio, 1.04; P < .001), with all but nonsurgical trauma patients showing greater deterioration over time.

“However, despite the decreasing magnitude of functional status deterioration in nonsurgical trauma, many admission diagnoses in this category remain in the top quartile of higher risk for functional status deterioration,” the investigators noted.

Functional status decline was most common among patients with head and polytrauma (OR, 3.39), followed closely by chest and spine trauma (OR, 3.38), and spine trauma (OR, 3.19). The top quartile of categories for prevalence of deterioration included nonsurgical trauma, neurologic, pulmonary, and gastrointestinal diseases.

Functional status decline was least common among patients diagnosed with diabetic ketoacidosis (OR, 0.27) or asthma (OR, 0.35).

“We believe our study provides important information that can be used in beginning to identify patients at high risk of functional status decline,” the investigators concluded. “Improving the identification of these patients and targeting appropriate interventions to mitigate this decline will be important directions for future studies in this area.”

According to David L. Bowton, MD, FCCP, professor emeritus, section on critical care, Wake Forest Baptist Health, Winston-Salem, N.C., the findings show just how common functional decline is after critical illness, and may actually underestimate prevalence.

“Because the authors employed a course evaluation tool employing only three categories of ability/disability and abstracted the level of disability from the medical record, they likely underestimated the frequency of clinically important, though not detected, disability at the time of hospital discharge,” Dr. Bowton said. “The study did not address cognitive impairment which can be detected in half of patients at 3 months following critical illness, and which significantly affects patients’ quality of life (Am J Respir Crit Care Med. 2020;202[2]:193-201).”

Dr. Bowton suggested that evidence-based methods of preventing post–intensive care syndrome are limited.

“Current efforts to improve post-ICU functional and cognitive outcomes suffer from the lack of proven effective interventions (Crit Care Med. 2019;47[11]:1607-18),” he said. “Observational data indicates that compliance with the ABCDEF bundle decreases the duration and incidence of delirium, ICU length of stay, duration of mechanical ventilation, and mortality (Crit Care Med. 2019;47[1]:3-14). However, the implications of these improvements on postdischarge functional outcomes are unknown as area the relative importance of individual elements of the bundle. Early mobility and patient and family diaries appear to improve functional status at discharge and postdischarge anxiety and depression, though the evidence supporting this is thin.”

Appropriate intervention may be especially challenging during the COVID-19 pandemic, he added.

“The impact of COVID on ICU staffing adequacy and stress is significant and the impact on quality bundle compliance and the availability of support services is currently not clear, but likely to be detrimental, especially to support services such as physical therapy that are already commonly understaffed,” Dr. Bowton said.

The study was supported by grants from the University of Minnesota’s Critical Care Research and Programmatic Development Program; the National Heart, Lung, and Blood Institute; and the University of Minnesota Clinical and Translational Science via the National Center for Advancing Translational Sciences. The investigators reported financial relationships with no other relevant organizations. Dr. Bowton reported no conflicts of interest.

SOURCE: Ingraham NE et al. Crit Care Med. 2020 Nov. doi: 10.1097/CCM.0000000000004524.

COVID-19 patients who survive their hospitalization don’t leave the disease behind upon discharge, as a significant percentage died within 60 days of discharge, with an ICU admission heightening the risk, according to an observational study of 38 Michigan hospitals. What’s more, many of them were burdened with health and emotional challenges ranging from hospital readmission to job loss and financial problems.

“These data confirm that the toll of COVID-19 extends well beyond hospitalization, a finding consistent with long-term sequelae from sepsis and other severe respiratory viral illnesses,” wrote lead author Vineet Chopra, MBBS, of the University of Michigan, Ann Arbor, and colleagues (Ann Intern Med. 2020 Nov 11: doi: 10.7326/M20-5661)

The researchers found that 29.2% of all patients hospitalized for COVID-19 from March 16 to July 1 died. The observational cohort study included 1,648 COVID-19 patients hospitalized at 38 Michigan hospitals participating in a statewide collaborative.

The bulk of those deaths occurred during hospitalization: 24.2% of patients (n = 398). Of the 1,250 patients discharged, 78% (n = 975) went home and 12.6% (n = 158) went to a skilled nursing facility, with the remainder unaccounted for. Within 60 days of discharge, 6.7% (n = 84) of hospitalized survivors had died and 15.2% (n = 189) were readmitted. The researchers gathered 60-day postdischarge data via a telephone survey, contacting 41.8% (n = 488) of discharged patients.

Outcomes were even worse for discharged patients who spent time in the ICU. The death rate among this group was 10.4% (17 of 165) after discharge. That resulted in an overall study death rate of 63.5% (n = 257) for the 405 patients who were in the ICU.

While the study data were in the first wave of the novel coronavirus, the findings have relevance today, said Mary Jo Farmer, MD, PhD, FCCP, directory of pulmonary hypertension services at Baystate Health in Springfield, Mass.

“This is the best information we have to date,” she said. “We have to continue to have an open mind and expect that this information may change as the virus possibly mutates as it spreads, and we should continue doing these types of outcomes studies at 90 days, 120 days, etc.”

The median age of study patients was 62, with a range of 50-72. The three leading comorbidities among discharged patients were hypertension (n = 800, 64%), diabetes (34.9%, n = 436), and cardiovascular disease (24.1%, n = 301).

Poor postdischarge outcomes weren’t limited to mortality and readmission. Almost 19% (n = 92) reported new or worsening cardiopulmonary symptoms such as cough and dyspnea, 13.3% had a persistent loss of taste or smell, and 12% (n = 58) reported more difficulty with daily living tasks.

The after-effects were not only physical. Nearly half of discharged patients (48.7%, n = 238) reported emotional effects and almost 6% (n = 28) sought mental health care. Among the 40% (n = 195) employed before they were hospitalized, 36% (n = 78) couldn’t return to work because of health issues or layoffs. Sixty percent (n = 117) of the pre-employed discharged patients did return to work, but 25% (n = 30) did so with reduced hours or modified job duties because of health problems.

Financial problems were also a burden. More than a third, 36.7% (n = 179), reported some financial impact from their hospitalization. About 10% (n = 47) said they used most or all of their savings, and 7% (n = 35) said they resorted to rationing necessities such as food or medications.

The researchers noted that one in five patients had no primary care follow-up at 2 months post discharge. “Collectively, these findings suggest that better models to support COVID-19 survivors are necessary,” said Dr. Chopra and colleagues.

The postdischarge course for patients involves two humps, said Sachin Gupta, MD, FCCP a pulmonary and critical care specialist at Alameda Health System in Oakland, Calif.: Getting over the hospitalization itself and the recovery phase. “As you look at the median age of the survivors, elderly patients who survive a hospital stay are still going to have a period of recovery, and like any viral illness that leads to someone being hospitalized, when you have an elderly patient with comorbidities, not all of them can make it over that final hump.”

SOURCE: Chopra V et al. Ann Intern Med. 2020 Nov 11. doi: 10.7326/M20-5661.

COVID-19 patients who survive their hospitalization don’t leave the disease behind upon discharge, as a significant percentage died within 60 days of discharge, with an ICU admission heightening the risk, according to an observational study of 38 Michigan hospitals. What’s more, many of them were burdened with health and emotional challenges ranging from hospital readmission to job loss and financial problems.

“These data confirm that the toll of COVID-19 extends well beyond hospitalization, a finding consistent with long-term sequelae from sepsis and other severe respiratory viral illnesses,” wrote lead author Vineet Chopra, MBBS, of the University of Michigan, Ann Arbor, and colleagues (Ann Intern Med. 2020 Nov 11: doi: 10.7326/M20-5661)

The researchers found that 29.2% of all patients hospitalized for COVID-19 from March 16 to July 1 died. The observational cohort study included 1,648 COVID-19 patients hospitalized at 38 Michigan hospitals participating in a statewide collaborative.

The bulk of those deaths occurred during hospitalization: 24.2% of patients (n = 398). Of the 1,250 patients discharged, 78% (n = 975) went home and 12.6% (n = 158) went to a skilled nursing facility, with the remainder unaccounted for. Within 60 days of discharge, 6.7% (n = 84) of hospitalized survivors had died and 15.2% (n = 189) were readmitted. The researchers gathered 60-day postdischarge data via a telephone survey, contacting 41.8% (n = 488) of discharged patients.

Outcomes were even worse for discharged patients who spent time in the ICU. The death rate among this group was 10.4% (17 of 165) after discharge. That resulted in an overall study death rate of 63.5% (n = 257) for the 405 patients who were in the ICU.

While the study data were in the first wave of the novel coronavirus, the findings have relevance today, said Mary Jo Farmer, MD, PhD, FCCP, directory of pulmonary hypertension services at Baystate Health in Springfield, Mass.

“This is the best information we have to date,” she said. “We have to continue to have an open mind and expect that this information may change as the virus possibly mutates as it spreads, and we should continue doing these types of outcomes studies at 90 days, 120 days, etc.”

The median age of study patients was 62, with a range of 50-72. The three leading comorbidities among discharged patients were hypertension (n = 800, 64%), diabetes (34.9%, n = 436), and cardiovascular disease (24.1%, n = 301).

Poor postdischarge outcomes weren’t limited to mortality and readmission. Almost 19% (n = 92) reported new or worsening cardiopulmonary symptoms such as cough and dyspnea, 13.3% had a persistent loss of taste or smell, and 12% (n = 58) reported more difficulty with daily living tasks.

The after-effects were not only physical. Nearly half of discharged patients (48.7%, n = 238) reported emotional effects and almost 6% (n = 28) sought mental health care. Among the 40% (n = 195) employed before they were hospitalized, 36% (n = 78) couldn’t return to work because of health issues or layoffs. Sixty percent (n = 117) of the pre-employed discharged patients did return to work, but 25% (n = 30) did so with reduced hours or modified job duties because of health problems.

Financial problems were also a burden. More than a third, 36.7% (n = 179), reported some financial impact from their hospitalization. About 10% (n = 47) said they used most or all of their savings, and 7% (n = 35) said they resorted to rationing necessities such as food or medications.

The researchers noted that one in five patients had no primary care follow-up at 2 months post discharge. “Collectively, these findings suggest that better models to support COVID-19 survivors are necessary,” said Dr. Chopra and colleagues.

The postdischarge course for patients involves two humps, said Sachin Gupta, MD, FCCP a pulmonary and critical care specialist at Alameda Health System in Oakland, Calif.: Getting over the hospitalization itself and the recovery phase. “As you look at the median age of the survivors, elderly patients who survive a hospital stay are still going to have a period of recovery, and like any viral illness that leads to someone being hospitalized, when you have an elderly patient with comorbidities, not all of them can make it over that final hump.”

SOURCE: Chopra V et al. Ann Intern Med. 2020 Nov 11. doi: 10.7326/M20-5661.

COVID-19 patients who survive their hospitalization don’t leave the disease behind upon discharge, as a significant percentage died within 60 days of discharge, with an ICU admission heightening the risk, according to an observational study of 38 Michigan hospitals. What’s more, many of them were burdened with health and emotional challenges ranging from hospital readmission to job loss and financial problems.

“These data confirm that the toll of COVID-19 extends well beyond hospitalization, a finding consistent with long-term sequelae from sepsis and other severe respiratory viral illnesses,” wrote lead author Vineet Chopra, MBBS, of the University of Michigan, Ann Arbor, and colleagues (Ann Intern Med. 2020 Nov 11: doi: 10.7326/M20-5661)

The researchers found that 29.2% of all patients hospitalized for COVID-19 from March 16 to July 1 died. The observational cohort study included 1,648 COVID-19 patients hospitalized at 38 Michigan hospitals participating in a statewide collaborative.

The bulk of those deaths occurred during hospitalization: 24.2% of patients (n = 398). Of the 1,250 patients discharged, 78% (n = 975) went home and 12.6% (n = 158) went to a skilled nursing facility, with the remainder unaccounted for. Within 60 days of discharge, 6.7% (n = 84) of hospitalized survivors had died and 15.2% (n = 189) were readmitted. The researchers gathered 60-day postdischarge data via a telephone survey, contacting 41.8% (n = 488) of discharged patients.

Outcomes were even worse for discharged patients who spent time in the ICU. The death rate among this group was 10.4% (17 of 165) after discharge. That resulted in an overall study death rate of 63.5% (n = 257) for the 405 patients who were in the ICU.

While the study data were in the first wave of the novel coronavirus, the findings have relevance today, said Mary Jo Farmer, MD, PhD, FCCP, directory of pulmonary hypertension services at Baystate Health in Springfield, Mass.

“This is the best information we have to date,” she said. “We have to continue to have an open mind and expect that this information may change as the virus possibly mutates as it spreads, and we should continue doing these types of outcomes studies at 90 days, 120 days, etc.”

The median age of study patients was 62, with a range of 50-72. The three leading comorbidities among discharged patients were hypertension (n = 800, 64%), diabetes (34.9%, n = 436), and cardiovascular disease (24.1%, n = 301).

Poor postdischarge outcomes weren’t limited to mortality and readmission. Almost 19% (n = 92) reported new or worsening cardiopulmonary symptoms such as cough and dyspnea, 13.3% had a persistent loss of taste or smell, and 12% (n = 58) reported more difficulty with daily living tasks.

The after-effects were not only physical. Nearly half of discharged patients (48.7%, n = 238) reported emotional effects and almost 6% (n = 28) sought mental health care. Among the 40% (n = 195) employed before they were hospitalized, 36% (n = 78) couldn’t return to work because of health issues or layoffs. Sixty percent (n = 117) of the pre-employed discharged patients did return to work, but 25% (n = 30) did so with reduced hours or modified job duties because of health problems.

Financial problems were also a burden. More than a third, 36.7% (n = 179), reported some financial impact from their hospitalization. About 10% (n = 47) said they used most or all of their savings, and 7% (n = 35) said they resorted to rationing necessities such as food or medications.

The researchers noted that one in five patients had no primary care follow-up at 2 months post discharge. “Collectively, these findings suggest that better models to support COVID-19 survivors are necessary,” said Dr. Chopra and colleagues.

The postdischarge course for patients involves two humps, said Sachin Gupta, MD, FCCP a pulmonary and critical care specialist at Alameda Health System in Oakland, Calif.: Getting over the hospitalization itself and the recovery phase. “As you look at the median age of the survivors, elderly patients who survive a hospital stay are still going to have a period of recovery, and like any viral illness that leads to someone being hospitalized, when you have an elderly patient with comorbidities, not all of them can make it over that final hump.”

SOURCE: Chopra V et al. Ann Intern Med. 2020 Nov 11. doi: 10.7326/M20-5661.

Factor XI has emerged as a promising target for new anticoagulants, and several strategies for inhibiting the enzyme to reduce stroke, thromboembolism, and bleeding risk are under investigation, according to Jeffrey I. Weitz, MD.

These strategies could pick up where direct-acting oral anticoagulants leave off, he suggested during a presentation at the biennial summit of the Thrombosis & Hemostasis Societies of North America.

“We all know that the direct oral anticoagulants – the DOACs – are an advance over vitamin K antagonists,” said Dr. Weitz, professor of medicine and biochemistry at McMaster University, Hamilton, Ontario.

Not only are DOACs at least as effective as vitamin K antagonists such as warfarin for stroke prevention in atrial fibrillation or for treatment of venous thromboembolism (VTE), but they also reduce intracranial bleeding and major bleeding risk in those settings, respectively, and they are more convenient to administer because they can be delivered using fixed doses without the need for coagulation monitoring, he added.

Still, new targets are needed, he said, explaining that, although DOACs moved closer to the goal of attenuating thrombosis without increasing the risk of bleeding, annual rates of major bleeding remain at 2%-3% in the atrial fibrillation population, and rates of major and clinically relevant nonmajor bleeding are about 10%.

“The fear of bleeding leads to underuse of anticoagulants for eligible patients with atrial fibrillation and inappropriate use of low-dose [non–vitamin K antagonist oral anticoagulant] regimens, which can leave patients unprotected from thrombotic complications,” he said.
 

Factor XI

That’s where Factor XI (FXI) may come in, Dr. Weitz said.

Current anticoagulants target enzymes, including FXa or thrombin, in the common pathway of coagulation, but the intrinsic pathway at the level of FXI and FXII has attracted attention in recent years.

The intrinsic pathway is activated when blood comes into contact with medical devices like stents, mechanical heart valves, or central venous catheters, but evidence also suggests that it plays a role in clot stabilization and growth, he explained, noting additional evidence of attenuation of thrombosis in mice deficient in FXI or FXII and in animals with FXI or FXII inhibitors.

“There is no bleeding with congenital FXII deficiency, and patients with FXI deficiency rarely have spontaneous bleeding, although they can bleed with surgery or trauma,” he noted. “Therefore, the promise of contact pathway inhibition is that we can attenuate thrombosis with little or no disruption of hemostasis.”

The initiators of the intrinsic pathway are naturally occurring polyphosphates that can activate FXI and FXII, promote platelet activation, and lead to thrombosis. A number of agents are being investigated to target these enzymes – particularly FXI, for which the strongest epidemiological and other evidence of its link with thrombosis exists. He noted that FXI deficiency appears protective against deep-vein thrombosis (DVT) and ischemic stroke, whereas high levels are linked with an increased risk of venous and arterial thrombosis.

Investigative strategies include the use of antisense oligonucleotides to reduce hepatic synthesis of FXI, aptamers to bind FXI and block its activity, antibodies to bind FXI and block its activation or activity, and small molecules to bind reversibly to the active site of FXI and block its activity “much like the DOACs block the activity of FXa or thrombin.”

“We have to remember that the DOACs have taken over from vitamin K antagonists, like warfarin, for many indications, and as they go generic their uptake will increase even further,” Dr. Weitz said. “When we compare the FXI inhibitors with existing anticoagulants, we don’t necessarily want to go up against the DOACs – we’re looking for indications where [DOACs] have yet to be tested or may be unsafe.”

Potential indications include the following:

Prevention of major adverse cardiovascular events in patients with end-stage renal disease with or without atrial fibrillation.

Provision of a safer platform for antiplatelet therapy in patients with acute coronary syndrome.

Secondary stroke prevention.

Prevention or treatment of cancer-associated VTE.

Prevention of thrombosis associated with central venous catheters, left ventricular assist devices, or mechanical heart valves.

Agents in development

Of the FXI inhibitors in development, ISIS-FXI_Rx, an antisense oligonucleotide against FXI, is furthest along. In a study published in Blood, ISIS-FXI_Rx produced a dose-dependent and sustained reduction in FXI levels in healthy volunteers, and in a later randomized study published in The New England Journal of Medicine, it significantly reduced the incidence of DVT in patients undergoing voluntary total knee arthroplasty (30.4% with enoxaparin vs. 4.2% with ISIS-FXI_Rx at a dose of 300 mg). Bleeding rates were 8.3% and 2.6%, respectively.

The findings showed the potential for reducing thrombosis without increasing bleeding by targeting FXI, Dr. Weitz said, adding that ISIS-FXIR_x was also evaluated in a small study of patients with end-stage renal disease undergoing hemodialysis and was shown to produce a dose-dependent reduction in FXI levels and to reduce the incidence of category 3 and 4 clotting in the air trap and dialyzer, compared with placebo, when given in addition to heparin.

This suggests that FXI knockdown can attenuate device-associated clotting to a greater extent than heparin alone, Dr. Weitz said.

The FXIa-directed inhibitory antibody osocimab has also been evaluated in both healthy volunteers and in patients undergoing total knee arthroplasty. In a 2019 study of healthy volunteers, a single IV injection showed a dose-dependent pharmacokinetic profile and produced FXI inhibition for about 1 month, and in the FOXTROT trial published in January in JAMA by Dr. Weitz and colleagues, osocimab was shown to reduce the incidence of symptomatic VTE, asymptomatic DVT, and VTE-related death up to day 10-13 after total knee arthroplasty.

Osocimab at doses ranging from 0.3-1.8 mg/kg given postoperatively or preoperatively were noninferior to enoxaparin (rates of 15.7%-23.7% vs. 26.3%), and osocimab at a preoperative dose of 1.8 mg/kg was superior to both enoxaparin and apixaban (11.5% vs. 26.3% and 14.5%, respectively), he said.

Bleeding rates ranged from 0%-5% with osocimab, compared with 6% with enoxaparin and 2% with apixaban
 

Ongoing studies

Currently ongoing studies of FXI-directed anticoagulation strategies include a study comparing ISIS-FXI_Rx with placebo in 200 patients with end-stage renal disease, a study comparing osocimab with placebo in 600 patients with end-stage renal disease, and a study comparing abelacimab – an antibody that binds to FXI and prevents its activation by either FXIIa or thrombin, with enoxaparin in 700 patients undergoing total knee arthroplasty, Dr. Weitz said.

Additionally, there is “considerable activity” with small molecule inhibitors of FXIa, including a phase 2, placebo-controlled, dose-ranging study looking at the novel JNG-7003/BMS-986177 agent for secondary stroke/transient ischemic attack prevention in 2,500 patients and a phase 2 study comparing it with enoxaparin for postoperative thromboprophylaxis in 1,200 patients undergoing total knee arthroplasty.

Parallel phase 2 studies are also underway to compare the novel BAY-2433334 small molecule inhibitor with placebo for stroke/transient ischemic attack prevention, with apixaban for atrial fibrillation, and for prevention of major adverse cardiovascular events in patients with acute MI.

These ongoing trials will help determine the risk-benefit profile of FXI inhibitors he said.

Session comoderator Anne Rose, PharmD, pharmacy coordinator at the University of Wisconsin, Madison, noted that these types of agents have been discussed “for quite some time” and asked whether they will be available for use in clinical practice in the near future.

Dr. Weitz predicted it will be at least a few years. The studies are just now moving to phase 2b and will still need to be evaluated in phase 3 trials and for appropriate new indications, he said.

Dr. Weitz reported research support from Canadian Institutes of Health research, Heart and Stroke Foundation, and Canadian Fund for Innovation, and he is a consultant and/or scientific advisory board member for Anthos, Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, Ionis Pharmaceuticals, Janssen, Merck, Novartis, Pfizer, Portola, Servier , and Thetherex.

[email protected]

Factor XI has emerged as a promising target for new anticoagulants, and several strategies for inhibiting the enzyme to reduce stroke, thromboembolism, and bleeding risk are under investigation, according to Jeffrey I. Weitz, MD.

These strategies could pick up where direct-acting oral anticoagulants leave off, he suggested during a presentation at the biennial summit of the Thrombosis & Hemostasis Societies of North America.

“We all know that the direct oral anticoagulants – the DOACs – are an advance over vitamin K antagonists,” said Dr. Weitz, professor of medicine and biochemistry at McMaster University, Hamilton, Ontario.

Not only are DOACs at least as effective as vitamin K antagonists such as warfarin for stroke prevention in atrial fibrillation or for treatment of venous thromboembolism (VTE), but they also reduce intracranial bleeding and major bleeding risk in those settings, respectively, and they are more convenient to administer because they can be delivered using fixed doses without the need for coagulation monitoring, he added.

Still, new targets are needed, he said, explaining that, although DOACs moved closer to the goal of attenuating thrombosis without increasing the risk of bleeding, annual rates of major bleeding remain at 2%-3% in the atrial fibrillation population, and rates of major and clinically relevant nonmajor bleeding are about 10%.

“The fear of bleeding leads to underuse of anticoagulants for eligible patients with atrial fibrillation and inappropriate use of low-dose [non–vitamin K antagonist oral anticoagulant] regimens, which can leave patients unprotected from thrombotic complications,” he said.
 

Factor XI

That’s where Factor XI (FXI) may come in, Dr. Weitz said.

Current anticoagulants target enzymes, including FXa or thrombin, in the common pathway of coagulation, but the intrinsic pathway at the level of FXI and FXII has attracted attention in recent years.

The intrinsic pathway is activated when blood comes into contact with medical devices like stents, mechanical heart valves, or central venous catheters, but evidence also suggests that it plays a role in clot stabilization and growth, he explained, noting additional evidence of attenuation of thrombosis in mice deficient in FXI or FXII and in animals with FXI or FXII inhibitors.

“There is no bleeding with congenital FXII deficiency, and patients with FXI deficiency rarely have spontaneous bleeding, although they can bleed with surgery or trauma,” he noted. “Therefore, the promise of contact pathway inhibition is that we can attenuate thrombosis with little or no disruption of hemostasis.”

The initiators of the intrinsic pathway are naturally occurring polyphosphates that can activate FXI and FXII, promote platelet activation, and lead to thrombosis. A number of agents are being investigated to target these enzymes – particularly FXI, for which the strongest epidemiological and other evidence of its link with thrombosis exists. He noted that FXI deficiency appears protective against deep-vein thrombosis (DVT) and ischemic stroke, whereas high levels are linked with an increased risk of venous and arterial thrombosis.

Investigative strategies include the use of antisense oligonucleotides to reduce hepatic synthesis of FXI, aptamers to bind FXI and block its activity, antibodies to bind FXI and block its activation or activity, and small molecules to bind reversibly to the active site of FXI and block its activity “much like the DOACs block the activity of FXa or thrombin.”

“We have to remember that the DOACs have taken over from vitamin K antagonists, like warfarin, for many indications, and as they go generic their uptake will increase even further,” Dr. Weitz said. “When we compare the FXI inhibitors with existing anticoagulants, we don’t necessarily want to go up against the DOACs – we’re looking for indications where [DOACs] have yet to be tested or may be unsafe.”

Potential indications include the following:

Prevention of major adverse cardiovascular events in patients with end-stage renal disease with or without atrial fibrillation.

Provision of a safer platform for antiplatelet therapy in patients with acute coronary syndrome.

Secondary stroke prevention.

Prevention or treatment of cancer-associated VTE.

Prevention of thrombosis associated with central venous catheters, left ventricular assist devices, or mechanical heart valves.

Agents in development

Of the FXI inhibitors in development, ISIS-FXI_Rx, an antisense oligonucleotide against FXI, is furthest along. In a study published in Blood, ISIS-FXI_Rx produced a dose-dependent and sustained reduction in FXI levels in healthy volunteers, and in a later randomized study published in The New England Journal of Medicine, it significantly reduced the incidence of DVT in patients undergoing voluntary total knee arthroplasty (30.4% with enoxaparin vs. 4.2% with ISIS-FXI_Rx at a dose of 300 mg). Bleeding rates were 8.3% and 2.6%, respectively.

The findings showed the potential for reducing thrombosis without increasing bleeding by targeting FXI, Dr. Weitz said, adding that ISIS-FXIR_x was also evaluated in a small study of patients with end-stage renal disease undergoing hemodialysis and was shown to produce a dose-dependent reduction in FXI levels and to reduce the incidence of category 3 and 4 clotting in the air trap and dialyzer, compared with placebo, when given in addition to heparin.

This suggests that FXI knockdown can attenuate device-associated clotting to a greater extent than heparin alone, Dr. Weitz said.

The FXIa-directed inhibitory antibody osocimab has also been evaluated in both healthy volunteers and in patients undergoing total knee arthroplasty. In a 2019 study of healthy volunteers, a single IV injection showed a dose-dependent pharmacokinetic profile and produced FXI inhibition for about 1 month, and in the FOXTROT trial published in January in JAMA by Dr. Weitz and colleagues, osocimab was shown to reduce the incidence of symptomatic VTE, asymptomatic DVT, and VTE-related death up to day 10-13 after total knee arthroplasty.

Osocimab at doses ranging from 0.3-1.8 mg/kg given postoperatively or preoperatively were noninferior to enoxaparin (rates of 15.7%-23.7% vs. 26.3%), and osocimab at a preoperative dose of 1.8 mg/kg was superior to both enoxaparin and apixaban (11.5% vs. 26.3% and 14.5%, respectively), he said.

Bleeding rates ranged from 0%-5% with osocimab, compared with 6% with enoxaparin and 2% with apixaban
 

Ongoing studies

Currently ongoing studies of FXI-directed anticoagulation strategies include a study comparing ISIS-FXI_Rx with placebo in 200 patients with end-stage renal disease, a study comparing osocimab with placebo in 600 patients with end-stage renal disease, and a study comparing abelacimab – an antibody that binds to FXI and prevents its activation by either FXIIa or thrombin, with enoxaparin in 700 patients undergoing total knee arthroplasty, Dr. Weitz said.

Additionally, there is “considerable activity” with small molecule inhibitors of FXIa, including a phase 2, placebo-controlled, dose-ranging study looking at the novel JNG-7003/BMS-986177 agent for secondary stroke/transient ischemic attack prevention in 2,500 patients and a phase 2 study comparing it with enoxaparin for postoperative thromboprophylaxis in 1,200 patients undergoing total knee arthroplasty.

Parallel phase 2 studies are also underway to compare the novel BAY-2433334 small molecule inhibitor with placebo for stroke/transient ischemic attack prevention, with apixaban for atrial fibrillation, and for prevention of major adverse cardiovascular events in patients with acute MI.

These ongoing trials will help determine the risk-benefit profile of FXI inhibitors he said.

Session comoderator Anne Rose, PharmD, pharmacy coordinator at the University of Wisconsin, Madison, noted that these types of agents have been discussed “for quite some time” and asked whether they will be available for use in clinical practice in the near future.

Dr. Weitz predicted it will be at least a few years. The studies are just now moving to phase 2b and will still need to be evaluated in phase 3 trials and for appropriate new indications, he said.

Dr. Weitz reported research support from Canadian Institutes of Health research, Heart and Stroke Foundation, and Canadian Fund for Innovation, and he is a consultant and/or scientific advisory board member for Anthos, Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, Ionis Pharmaceuticals, Janssen, Merck, Novartis, Pfizer, Portola, Servier , and Thetherex.

[email protected]

Factor XI has emerged as a promising target for new anticoagulants, and several strategies for inhibiting the enzyme to reduce stroke, thromboembolism, and bleeding risk are under investigation, according to Jeffrey I. Weitz, MD.

These strategies could pick up where direct-acting oral anticoagulants leave off, he suggested during a presentation at the biennial summit of the Thrombosis & Hemostasis Societies of North America.

“We all know that the direct oral anticoagulants – the DOACs – are an advance over vitamin K antagonists,” said Dr. Weitz, professor of medicine and biochemistry at McMaster University, Hamilton, Ontario.

Not only are DOACs at least as effective as vitamin K antagonists such as warfarin for stroke prevention in atrial fibrillation or for treatment of venous thromboembolism (VTE), but they also reduce intracranial bleeding and major bleeding risk in those settings, respectively, and they are more convenient to administer because they can be delivered using fixed doses without the need for coagulation monitoring, he added.

Still, new targets are needed, he said, explaining that, although DOACs moved closer to the goal of attenuating thrombosis without increasing the risk of bleeding, annual rates of major bleeding remain at 2%-3% in the atrial fibrillation population, and rates of major and clinically relevant nonmajor bleeding are about 10%.

“The fear of bleeding leads to underuse of anticoagulants for eligible patients with atrial fibrillation and inappropriate use of low-dose [non–vitamin K antagonist oral anticoagulant] regimens, which can leave patients unprotected from thrombotic complications,” he said.
 

Factor XI

That’s where Factor XI (FXI) may come in, Dr. Weitz said.

Current anticoagulants target enzymes, including FXa or thrombin, in the common pathway of coagulation, but the intrinsic pathway at the level of FXI and FXII has attracted attention in recent years.

The intrinsic pathway is activated when blood comes into contact with medical devices like stents, mechanical heart valves, or central venous catheters, but evidence also suggests that it plays a role in clot stabilization and growth, he explained, noting additional evidence of attenuation of thrombosis in mice deficient in FXI or FXII and in animals with FXI or FXII inhibitors.

“There is no bleeding with congenital FXII deficiency, and patients with FXI deficiency rarely have spontaneous bleeding, although they can bleed with surgery or trauma,” he noted. “Therefore, the promise of contact pathway inhibition is that we can attenuate thrombosis with little or no disruption of hemostasis.”

The initiators of the intrinsic pathway are naturally occurring polyphosphates that can activate FXI and FXII, promote platelet activation, and lead to thrombosis. A number of agents are being investigated to target these enzymes – particularly FXI, for which the strongest epidemiological and other evidence of its link with thrombosis exists. He noted that FXI deficiency appears protective against deep-vein thrombosis (DVT) and ischemic stroke, whereas high levels are linked with an increased risk of venous and arterial thrombosis.

Investigative strategies include the use of antisense oligonucleotides to reduce hepatic synthesis of FXI, aptamers to bind FXI and block its activity, antibodies to bind FXI and block its activation or activity, and small molecules to bind reversibly to the active site of FXI and block its activity “much like the DOACs block the activity of FXa or thrombin.”

“We have to remember that the DOACs have taken over from vitamin K antagonists, like warfarin, for many indications, and as they go generic their uptake will increase even further,” Dr. Weitz said. “When we compare the FXI inhibitors with existing anticoagulants, we don’t necessarily want to go up against the DOACs – we’re looking for indications where [DOACs] have yet to be tested or may be unsafe.”

Potential indications include the following:

Prevention of major adverse cardiovascular events in patients with end-stage renal disease with or without atrial fibrillation.

Provision of a safer platform for antiplatelet therapy in patients with acute coronary syndrome.

Secondary stroke prevention.

Prevention or treatment of cancer-associated VTE.

Prevention of thrombosis associated with central venous catheters, left ventricular assist devices, or mechanical heart valves.

Agents in development

Of the FXI inhibitors in development, ISIS-FXI_Rx, an antisense oligonucleotide against FXI, is furthest along. In a study published in Blood, ISIS-FXI_Rx produced a dose-dependent and sustained reduction in FXI levels in healthy volunteers, and in a later randomized study published in The New England Journal of Medicine, it significantly reduced the incidence of DVT in patients undergoing voluntary total knee arthroplasty (30.4% with enoxaparin vs. 4.2% with ISIS-FXI_Rx at a dose of 300 mg). Bleeding rates were 8.3% and 2.6%, respectively.

The findings showed the potential for reducing thrombosis without increasing bleeding by targeting FXI, Dr. Weitz said, adding that ISIS-FXIR_x was also evaluated in a small study of patients with end-stage renal disease undergoing hemodialysis and was shown to produce a dose-dependent reduction in FXI levels and to reduce the incidence of category 3 and 4 clotting in the air trap and dialyzer, compared with placebo, when given in addition to heparin.

This suggests that FXI knockdown can attenuate device-associated clotting to a greater extent than heparin alone, Dr. Weitz said.

The FXIa-directed inhibitory antibody osocimab has also been evaluated in both healthy volunteers and in patients undergoing total knee arthroplasty. In a 2019 study of healthy volunteers, a single IV injection showed a dose-dependent pharmacokinetic profile and produced FXI inhibition for about 1 month, and in the FOXTROT trial published in January in JAMA by Dr. Weitz and colleagues, osocimab was shown to reduce the incidence of symptomatic VTE, asymptomatic DVT, and VTE-related death up to day 10-13 after total knee arthroplasty.

Osocimab at doses ranging from 0.3-1.8 mg/kg given postoperatively or preoperatively were noninferior to enoxaparin (rates of 15.7%-23.7% vs. 26.3%), and osocimab at a preoperative dose of 1.8 mg/kg was superior to both enoxaparin and apixaban (11.5% vs. 26.3% and 14.5%, respectively), he said.

Bleeding rates ranged from 0%-5% with osocimab, compared with 6% with enoxaparin and 2% with apixaban
 

Ongoing studies

Currently ongoing studies of FXI-directed anticoagulation strategies include a study comparing ISIS-FXI_Rx with placebo in 200 patients with end-stage renal disease, a study comparing osocimab with placebo in 600 patients with end-stage renal disease, and a study comparing abelacimab – an antibody that binds to FXI and prevents its activation by either FXIIa or thrombin, with enoxaparin in 700 patients undergoing total knee arthroplasty, Dr. Weitz said.

Additionally, there is “considerable activity” with small molecule inhibitors of FXIa, including a phase 2, placebo-controlled, dose-ranging study looking at the novel JNG-7003/BMS-986177 agent for secondary stroke/transient ischemic attack prevention in 2,500 patients and a phase 2 study comparing it with enoxaparin for postoperative thromboprophylaxis in 1,200 patients undergoing total knee arthroplasty.

Parallel phase 2 studies are also underway to compare the novel BAY-2433334 small molecule inhibitor with placebo for stroke/transient ischemic attack prevention, with apixaban for atrial fibrillation, and for prevention of major adverse cardiovascular events in patients with acute MI.

These ongoing trials will help determine the risk-benefit profile of FXI inhibitors he said.

Session comoderator Anne Rose, PharmD, pharmacy coordinator at the University of Wisconsin, Madison, noted that these types of agents have been discussed “for quite some time” and asked whether they will be available for use in clinical practice in the near future.

Dr. Weitz predicted it will be at least a few years. The studies are just now moving to phase 2b and will still need to be evaluated in phase 3 trials and for appropriate new indications, he said.

Dr. Weitz reported research support from Canadian Institutes of Health research, Heart and Stroke Foundation, and Canadian Fund for Innovation, and he is a consultant and/or scientific advisory board member for Anthos, Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, Ionis Pharmaceuticals, Janssen, Merck, Novartis, Pfizer, Portola, Servier , and Thetherex.

[email protected]

Immunotherapy is a rising star among emerging therapies for acute lymphoblastic leukemia (ALL), according to Patrick A. Brown, MD.

“Most of the emerging therapies in ALL are immunotherapies that have really made an impact in the relapsed and refractory setting,” he said during a presentation at the National Comprehensive Cancer Network Hematologic Malignancies Annual Congress. “Another very exciting development is that these immunotherapies are now demonstrating efficacy and increased tolerability over chemotherapy in the minimal residual disease (MRD)-positive setting up front.”

Dr. Brown, director of the pediatric leukemia program at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, focused on blinatumomab, inotuzumab, and chimeric antigen receptor (CAR) T-cell therapy for ALL, and explained the rationale for their use.
 

Why immunotherapy?

“It turns out that in normal B cell development there are a number of proteins that are expressed on the surface of B cells and these same proteins are expressed on the surface of many B-cell malignancies,” he said, noting that ALL is “probably the least differentiated of the B-lineage malignancies,” but the vast majority of ALL cases will express CD19 and CD22, and – in adults more often than pediatric patients – CD20.

These antigens make good targets for ALL therapy because they aren’t expressed on bone marrow stem cells or other tissues in the body.

“They really are specific for B cells,” he said, explaining that inotuzumab, a CD22 antibody drug conjugate (ADC), and blinatumomab, a bi-specific T cell-engaging antibody (BiTE) that targets CD19, are antibody-based immunotherapies, whereas CAR T-cell therapies are a separate category that can be single- or multi-antigen targeted.
 

Inotuzumab, blinatumomab, and CAR T cells

Inotuzumab targets the CD22 immunotoxin antigen via a T-cell independent process and is delivered as a once-weekly 1-hour infusion. It is approved for adult relapsed/refractory B-ALL. Blinatumomab binds CD19 on the surface of the tumor cells and CD3 on the surface of any T cell in the vicinity of the tumor cell.

“The recognition that blinatumomab allows between the tumor cell and the T cell is independent of the specificity of the T-cell receptor. It also does not require [major histocompatibility complex] class 1 or peptide antigens on the surface of the T cell,” he said, adding that it does, however, rely on a functional endogenous cytotoxic T-cell response, unlike inotuzumab. “It’s also very difficult technically to give because it’s given as a 28-day continuous IV infusion with bag changes required every 4-7 days.”

Blinatumomab is approved for adult and pediatric Philadelphia chromosome-negative relapsed/refractory B-cell precursor ALL and MRD-positive B-cell precursor ALL.

CAR T-cell therapy, an autologous immunotherapy, is “really kind of the pinnacle of technological advances in immunotherapy in that it combine three different modalities into one: cellular therapy, gene therapy, and immunotherapy,” he said, noting that the process of genetically engineering T cells to express a CAR is complex and costly and access is limited, but expanding with about 90 centers in the U.S. now providing CAR T-cell therapy.

Response rates with each of these therapies represent a paradigm shift in the relapsed/refractory ALL setting, Dr. Brown said.

Studies have shown complete remission (CR) and minimum residual disease (MRD)-negative CR rates of 81% and 78%, respectively, with inotuzumab, and 43% and 33%, respectively, with blinatumomab.

“This depth of remission was really not seen with prior salvage therapies,” he noted, but added that neither has shown significant durable improvement in overall survival (OS) rates.

CAR T-cell therapy, however, has the highest response rates, with tisagenlecleucel – which targets CD19 and was the first CAR T-cell therapy approved for refractory or second or greater relapse in patients up to age 26 years – showing 81% CR and MRD-negative CR rates and providing a durable survival advantage without subsequent therapy in 40-50% of patients.

“So CAR T cells can represent definitive therapy in a subset of patients,” Dr. Brown said. “One thing we’re struggling with is to be able to predict which patients those are, and there are some emerging biomarkers that may help us with that, but as of now it’s very difficult to predict which patients, when you’re treating them, are going to be in [that group].”

Toxicities and limitations

Cytokine release syndrome and neurotoxicity are the primary toxicities associated with both blinatumomab and tisagenlecleucel. Hepatotoxicity is a major concern with inotuzumab.

“This is particularly important because that hepatotoxicity appears to be primarily a problem in patients who receive inotuzumab either after or prior to hematopoietic stem cell transplant, and since this therapy does not represent definitive therapy and often is really a bridge to transplant, this ... can be a significant limitation to this product,” Dr. Brown said.

A limitation of CAR T cells is failure to manufacture the product, which occurs most often in very young and heavily pretreated patients in whom it can be difficult to obtain enough functional T cells to create the product. Failure to engraft or lack of persistence of the CAR T cells can also occur.

Endogenous or CAR T-cell exhaustion is another potential limitation with blinatumomab and CAR T-cell therapy, and antigen escape can occur with both therapies, as well.

Strategies are being investigated to overcome treatment challenges, Dr. Brown noted.

Examples include efforts to develop universal “off-the-shelf” allogeneic CAR T-cell products to address failure to manufacture, working on more co-stimulatory domains that may be more effective to promote engraftment and persistence, adding immune checkpoint inhibitors to therapy to combat endogenous or CAR T-cell exhaustion, and developing multi-antigen targeted approaches to overcome antigen escape, he said.
 

NCCN Treatment Guidelines

Based on the currently available data, the NCCN has included these immunotherapies in guidelines for both adolescent and young adult (AYA)/adult ALL and for pediatric ALL.

Each of the treatments is listed as an option to consider in both Philadelphia chromosome-positive and -negative AYA and adult patients under age 65 years. Additionally, blinatumomab is listed as an option for up-front treatment of MRD-positive Philadelphia chromosome-negative AYA patients and older patients.

Pediatric guidelines include blinatumomab and tisagenlecleucel as options for patients with MRD-positive disease after induction and for first relapse, and they include all three therapies as options in patients with multiple relapses or refractory disease, said Dr. Brown who chairs the NCCN Clinical Practice Guidelines panel for adult and pediatric ALL.
 

Treatment decision making

Asked by session moderator Ranjana H. Advani, MD, how to decide between the available immunotherapies, Dr. Brown said there is no one-size-fits-all answer.

“Is it availability, insurance coverage, the patient fits better with one therapy,” asked Dr. Advani, the Saul Rosenberg Professor of Lymphoma and the Physician Leader of the Lymphoma Clinical Care Program of Stanford Cancer Institute, Palo Alto, Calif.

“All of the above,” Dr. Brown said. “In 2020 with all these options available, we are a little bit spoiled for choice ... but every patient is an individual case and the risk -benefit ratios of all these therapies differ.”

An exception is that CAR T-cell therapy is a clear stand-out for the patient who isn’t transplant eligible, he noted, adding that CAR T cells “probably give that patient the best chance of survival.”

In a patient who could potentially go to transplant, selection is a bit more challenging, but given the risks associated with inotuzumab, blinatumomab is generally the preferred non-CAR T option, he said.

“It’s a complicated question, and the answer ... is [that it is] an individualized patient-by-patient decision,” he added.

Dr. Brown reported consulting, advisory board, or expert witness activity for Novartis Pharmaceuticals Corporation and Takeda Pharmaceuticals North America Inc.

[email protected]

Immunotherapy is a rising star among emerging therapies for acute lymphoblastic leukemia (ALL), according to Patrick A. Brown, MD.

“Most of the emerging therapies in ALL are immunotherapies that have really made an impact in the relapsed and refractory setting,” he said during a presentation at the National Comprehensive Cancer Network Hematologic Malignancies Annual Congress. “Another very exciting development is that these immunotherapies are now demonstrating efficacy and increased tolerability over chemotherapy in the minimal residual disease (MRD)-positive setting up front.”

Dr. Brown, director of the pediatric leukemia program at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, focused on blinatumomab, inotuzumab, and chimeric antigen receptor (CAR) T-cell therapy for ALL, and explained the rationale for their use.
 

Why immunotherapy?

“It turns out that in normal B cell development there are a number of proteins that are expressed on the surface of B cells and these same proteins are expressed on the surface of many B-cell malignancies,” he said, noting that ALL is “probably the least differentiated of the B-lineage malignancies,” but the vast majority of ALL cases will express CD19 and CD22, and – in adults more often than pediatric patients – CD20.

These antigens make good targets for ALL therapy because they aren’t expressed on bone marrow stem cells or other tissues in the body.

“They really are specific for B cells,” he said, explaining that inotuzumab, a CD22 antibody drug conjugate (ADC), and blinatumomab, a bi-specific T cell-engaging antibody (BiTE) that targets CD19, are antibody-based immunotherapies, whereas CAR T-cell therapies are a separate category that can be single- or multi-antigen targeted.
 

Inotuzumab, blinatumomab, and CAR T cells

Inotuzumab targets the CD22 immunotoxin antigen via a T-cell independent process and is delivered as a once-weekly 1-hour infusion. It is approved for adult relapsed/refractory B-ALL. Blinatumomab binds CD19 on the surface of the tumor cells and CD3 on the surface of any T cell in the vicinity of the tumor cell.

“The recognition that blinatumomab allows between the tumor cell and the T cell is independent of the specificity of the T-cell receptor. It also does not require [major histocompatibility complex] class 1 or peptide antigens on the surface of the T cell,” he said, adding that it does, however, rely on a functional endogenous cytotoxic T-cell response, unlike inotuzumab. “It’s also very difficult technically to give because it’s given as a 28-day continuous IV infusion with bag changes required every 4-7 days.”

Blinatumomab is approved for adult and pediatric Philadelphia chromosome-negative relapsed/refractory B-cell precursor ALL and MRD-positive B-cell precursor ALL.

CAR T-cell therapy, an autologous immunotherapy, is “really kind of the pinnacle of technological advances in immunotherapy in that it combine three different modalities into one: cellular therapy, gene therapy, and immunotherapy,” he said, noting that the process of genetically engineering T cells to express a CAR is complex and costly and access is limited, but expanding with about 90 centers in the U.S. now providing CAR T-cell therapy.

Response rates with each of these therapies represent a paradigm shift in the relapsed/refractory ALL setting, Dr. Brown said.

Studies have shown complete remission (CR) and minimum residual disease (MRD)-negative CR rates of 81% and 78%, respectively, with inotuzumab, and 43% and 33%, respectively, with blinatumomab.

“This depth of remission was really not seen with prior salvage therapies,” he noted, but added that neither has shown significant durable improvement in overall survival (OS) rates.

CAR T-cell therapy, however, has the highest response rates, with tisagenlecleucel – which targets CD19 and was the first CAR T-cell therapy approved for refractory or second or greater relapse in patients up to age 26 years – showing 81% CR and MRD-negative CR rates and providing a durable survival advantage without subsequent therapy in 40-50% of patients.

“So CAR T cells can represent definitive therapy in a subset of patients,” Dr. Brown said. “One thing we’re struggling with is to be able to predict which patients those are, and there are some emerging biomarkers that may help us with that, but as of now it’s very difficult to predict which patients, when you’re treating them, are going to be in [that group].”

Toxicities and limitations

Cytokine release syndrome and neurotoxicity are the primary toxicities associated with both blinatumomab and tisagenlecleucel. Hepatotoxicity is a major concern with inotuzumab.

“This is particularly important because that hepatotoxicity appears to be primarily a problem in patients who receive inotuzumab either after or prior to hematopoietic stem cell transplant, and since this therapy does not represent definitive therapy and often is really a bridge to transplant, this ... can be a significant limitation to this product,” Dr. Brown said.

A limitation of CAR T cells is failure to manufacture the product, which occurs most often in very young and heavily pretreated patients in whom it can be difficult to obtain enough functional T cells to create the product. Failure to engraft or lack of persistence of the CAR T cells can also occur.

Endogenous or CAR T-cell exhaustion is another potential limitation with blinatumomab and CAR T-cell therapy, and antigen escape can occur with both therapies, as well.

Strategies are being investigated to overcome treatment challenges, Dr. Brown noted.

Examples include efforts to develop universal “off-the-shelf” allogeneic CAR T-cell products to address failure to manufacture, working on more co-stimulatory domains that may be more effective to promote engraftment and persistence, adding immune checkpoint inhibitors to therapy to combat endogenous or CAR T-cell exhaustion, and developing multi-antigen targeted approaches to overcome antigen escape, he said.
 

NCCN Treatment Guidelines

Based on the currently available data, the NCCN has included these immunotherapies in guidelines for both adolescent and young adult (AYA)/adult ALL and for pediatric ALL.

Each of the treatments is listed as an option to consider in both Philadelphia chromosome-positive and -negative AYA and adult patients under age 65 years. Additionally, blinatumomab is listed as an option for up-front treatment of MRD-positive Philadelphia chromosome-negative AYA patients and older patients.

Pediatric guidelines include blinatumomab and tisagenlecleucel as options for patients with MRD-positive disease after induction and for first relapse, and they include all three therapies as options in patients with multiple relapses or refractory disease, said Dr. Brown who chairs the NCCN Clinical Practice Guidelines panel for adult and pediatric ALL.
 

Treatment decision making

Asked by session moderator Ranjana H. Advani, MD, how to decide between the available immunotherapies, Dr. Brown said there is no one-size-fits-all answer.

“Is it availability, insurance coverage, the patient fits better with one therapy,” asked Dr. Advani, the Saul Rosenberg Professor of Lymphoma and the Physician Leader of the Lymphoma Clinical Care Program of Stanford Cancer Institute, Palo Alto, Calif.

“All of the above,” Dr. Brown said. “In 2020 with all these options available, we are a little bit spoiled for choice ... but every patient is an individual case and the risk -benefit ratios of all these therapies differ.”

An exception is that CAR T-cell therapy is a clear stand-out for the patient who isn’t transplant eligible, he noted, adding that CAR T cells “probably give that patient the best chance of survival.”

In a patient who could potentially go to transplant, selection is a bit more challenging, but given the risks associated with inotuzumab, blinatumomab is generally the preferred non-CAR T option, he said.

“It’s a complicated question, and the answer ... is [that it is] an individualized patient-by-patient decision,” he added.

Dr. Brown reported consulting, advisory board, or expert witness activity for Novartis Pharmaceuticals Corporation and Takeda Pharmaceuticals North America Inc.

[email protected]

Immunotherapy is a rising star among emerging therapies for acute lymphoblastic leukemia (ALL), according to Patrick A. Brown, MD.

“Most of the emerging therapies in ALL are immunotherapies that have really made an impact in the relapsed and refractory setting,” he said during a presentation at the National Comprehensive Cancer Network Hematologic Malignancies Annual Congress. “Another very exciting development is that these immunotherapies are now demonstrating efficacy and increased tolerability over chemotherapy in the minimal residual disease (MRD)-positive setting up front.”

Dr. Brown, director of the pediatric leukemia program at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, focused on blinatumomab, inotuzumab, and chimeric antigen receptor (CAR) T-cell therapy for ALL, and explained the rationale for their use.
 

Why immunotherapy?

“It turns out that in normal B cell development there are a number of proteins that are expressed on the surface of B cells and these same proteins are expressed on the surface of many B-cell malignancies,” he said, noting that ALL is “probably the least differentiated of the B-lineage malignancies,” but the vast majority of ALL cases will express CD19 and CD22, and – in adults more often than pediatric patients – CD20.

These antigens make good targets for ALL therapy because they aren’t expressed on bone marrow stem cells or other tissues in the body.

“They really are specific for B cells,” he said, explaining that inotuzumab, a CD22 antibody drug conjugate (ADC), and blinatumomab, a bi-specific T cell-engaging antibody (BiTE) that targets CD19, are antibody-based immunotherapies, whereas CAR T-cell therapies are a separate category that can be single- or multi-antigen targeted.
 

Inotuzumab, blinatumomab, and CAR T cells

Inotuzumab targets the CD22 immunotoxin antigen via a T-cell independent process and is delivered as a once-weekly 1-hour infusion. It is approved for adult relapsed/refractory B-ALL. Blinatumomab binds CD19 on the surface of the tumor cells and CD3 on the surface of any T cell in the vicinity of the tumor cell.

“The recognition that blinatumomab allows between the tumor cell and the T cell is independent of the specificity of the T-cell receptor. It also does not require [major histocompatibility complex] class 1 or peptide antigens on the surface of the T cell,” he said, adding that it does, however, rely on a functional endogenous cytotoxic T-cell response, unlike inotuzumab. “It’s also very difficult technically to give because it’s given as a 28-day continuous IV infusion with bag changes required every 4-7 days.”

Blinatumomab is approved for adult and pediatric Philadelphia chromosome-negative relapsed/refractory B-cell precursor ALL and MRD-positive B-cell precursor ALL.

CAR T-cell therapy, an autologous immunotherapy, is “really kind of the pinnacle of technological advances in immunotherapy in that it combine three different modalities into one: cellular therapy, gene therapy, and immunotherapy,” he said, noting that the process of genetically engineering T cells to express a CAR is complex and costly and access is limited, but expanding with about 90 centers in the U.S. now providing CAR T-cell therapy.

Response rates with each of these therapies represent a paradigm shift in the relapsed/refractory ALL setting, Dr. Brown said.

Studies have shown complete remission (CR) and minimum residual disease (MRD)-negative CR rates of 81% and 78%, respectively, with inotuzumab, and 43% and 33%, respectively, with blinatumomab.

“This depth of remission was really not seen with prior salvage therapies,” he noted, but added that neither has shown significant durable improvement in overall survival (OS) rates.

CAR T-cell therapy, however, has the highest response rates, with tisagenlecleucel – which targets CD19 and was the first CAR T-cell therapy approved for refractory or second or greater relapse in patients up to age 26 years – showing 81% CR and MRD-negative CR rates and providing a durable survival advantage without subsequent therapy in 40-50% of patients.

“So CAR T cells can represent definitive therapy in a subset of patients,” Dr. Brown said. “One thing we’re struggling with is to be able to predict which patients those are, and there are some emerging biomarkers that may help us with that, but as of now it’s very difficult to predict which patients, when you’re treating them, are going to be in [that group].”

Toxicities and limitations

Cytokine release syndrome and neurotoxicity are the primary toxicities associated with both blinatumomab and tisagenlecleucel. Hepatotoxicity is a major concern with inotuzumab.

“This is particularly important because that hepatotoxicity appears to be primarily a problem in patients who receive inotuzumab either after or prior to hematopoietic stem cell transplant, and since this therapy does not represent definitive therapy and often is really a bridge to transplant, this ... can be a significant limitation to this product,” Dr. Brown said.

A limitation of CAR T cells is failure to manufacture the product, which occurs most often in very young and heavily pretreated patients in whom it can be difficult to obtain enough functional T cells to create the product. Failure to engraft or lack of persistence of the CAR T cells can also occur.

Endogenous or CAR T-cell exhaustion is another potential limitation with blinatumomab and CAR T-cell therapy, and antigen escape can occur with both therapies, as well.

Strategies are being investigated to overcome treatment challenges, Dr. Brown noted.

Examples include efforts to develop universal “off-the-shelf” allogeneic CAR T-cell products to address failure to manufacture, working on more co-stimulatory domains that may be more effective to promote engraftment and persistence, adding immune checkpoint inhibitors to therapy to combat endogenous or CAR T-cell exhaustion, and developing multi-antigen targeted approaches to overcome antigen escape, he said.
 

NCCN Treatment Guidelines

Based on the currently available data, the NCCN has included these immunotherapies in guidelines for both adolescent and young adult (AYA)/adult ALL and for pediatric ALL.

Each of the treatments is listed as an option to consider in both Philadelphia chromosome-positive and -negative AYA and adult patients under age 65 years. Additionally, blinatumomab is listed as an option for up-front treatment of MRD-positive Philadelphia chromosome-negative AYA patients and older patients.

Pediatric guidelines include blinatumomab and tisagenlecleucel as options for patients with MRD-positive disease after induction and for first relapse, and they include all three therapies as options in patients with multiple relapses or refractory disease, said Dr. Brown who chairs the NCCN Clinical Practice Guidelines panel for adult and pediatric ALL.
 

Treatment decision making

Asked by session moderator Ranjana H. Advani, MD, how to decide between the available immunotherapies, Dr. Brown said there is no one-size-fits-all answer.

“Is it availability, insurance coverage, the patient fits better with one therapy,” asked Dr. Advani, the Saul Rosenberg Professor of Lymphoma and the Physician Leader of the Lymphoma Clinical Care Program of Stanford Cancer Institute, Palo Alto, Calif.

“All of the above,” Dr. Brown said. “In 2020 with all these options available, we are a little bit spoiled for choice ... but every patient is an individual case and the risk -benefit ratios of all these therapies differ.”

An exception is that CAR T-cell therapy is a clear stand-out for the patient who isn’t transplant eligible, he noted, adding that CAR T cells “probably give that patient the best chance of survival.”

In a patient who could potentially go to transplant, selection is a bit more challenging, but given the risks associated with inotuzumab, blinatumomab is generally the preferred non-CAR T option, he said.

“It’s a complicated question, and the answer ... is [that it is] an individualized patient-by-patient decision,” he added.

Dr. Brown reported consulting, advisory board, or expert witness activity for Novartis Pharmaceuticals Corporation and Takeda Pharmaceuticals North America Inc.

[email protected]

Cancer patients who receive an immune checkpoint inhibitor have more than a doubled rate of venous thromboembolism during the subsequent 2 years, compared with their rate during the 2 years before treatment, according to a retrospective analysis of more than 2,800 patients treated at a single U.S. center.

The study focused on cancer patients treated with an immune checkpoint inhibitor (ICI) at Massachusetts General Hospital in Boston. It showed that during the 2 years prior to treatment with any type of ICI, the incidence of venous thromboembolic events (VTE) was 4.85/100 patient-years that then jumped to 11.75/100 patient-years during the 2 years following treatment. This translated into an incidence rate ratio of 2.43 during posttreatment follow-up, compared with pretreatment, Jingyi Gong, MD, said at the virtual American Heart Association scientific sessions.

The increased VTE rate resulted from rises in both the rate of deep vein thrombosis, which had an IRR of 3.23 during the posttreatment period, and for pulmonary embolism, which showed an IRR of 2.24, said Dr. Gong, a physician at Brigham and Women’s Hospital in Boston. She hypothesized that this effect may result from a procoagulant effect of the immune activation and inflammation triggered by ICIs.


Hypothesis-generating results

Cardiologists cautioned that these findings should only be considered hypothesis generating, but raise an important alert for clinicians to have heightened awareness of the potential for VTE following ICI treatment.

“A clear message is to be aware that there is this signal, and be vigilant for patients who might present with VTE following ICI treatment,” commented Richard J. Kovacs, MD, a cardiologist and professor at Indiana University, Indianapolis. The data that Dr. Gong reported are “moderately convincing,” he added in an interview.

“Awareness that patients who receive ICI may be at increased VTE risk is very important,” agreed Umberto Campia, MD, a cardiologist, vascular specialist, and member of the cardio-oncology group at Brigham and Women’s Hospital, who was not involved in the new study.

The potential impact of ICI treatment on VTE risk is slowly emerging, added Dr. Campia. Until recently, the literature primarily was case reports, but recently another retrospective, single-center study came out that reported a 13% incidence of VTE in cancer patients following ICI treatment. On the other hand, a recently published meta-analysis of more than 20,000 patients from 68 ICI studies failed to find a suggestion of increased VTE incidence following ICI interventions.

Attempting to assess the impact of treatment on VTE risk in cancer patients is challenging because cancer itself boosts the risk. Recommendations on the use of VTE prophylaxis in cancer patients most recently came out in 2014 from the American Society of Clinical Oncology, which said that VTE prophylaxis for ambulatory cancer patients “may be considered for highly select high-risk patients.” The impact of cancer therapy on VTE risk and the need for prophylaxis is usually assessed by applying the Khorana score, Dr. Campia said in an interview.
 

VTE spikes acutely after ICI treatment

Dr. Gong analyzed VTE incidence rates by time during the total 4-year period studied, and found that the rate gradually and steadily rose with time throughout the 2 years preceding treatment, spiked immediately following ICI treatment, and then gradually and steadily fell back to roughly the rate seen just before treatment, reaching that level about a year after treatment. She ran a sensitivity analysis that excluded patients who died during the first year following their ICI treatment, and in this calculation an acute spike in VTE following ICI treatment still occurred but with reduced magnitude.

She also reported the results of several subgroup analyses. The IRRs remained consistent among women and men, among patients who were aged over or under 65 years, and regardless of cancer type or treatment with corticosteroids. But the subgroup analyses identified two parameters that seemed to clearly split VTE rates.

Among patients on treatment with an anticoagulant agent at the time of their ICI treatment, roughly 10% of the patients, the IRR was 0.56, compared with a ratio of 3.86 among the other patients, suggesting possible protection. A second factor that seemed linked with VTE incidence was the number of ICI treatment cycles a patient received. Those who received more than five cycles had a risk ratio of 3.95, while those who received five or fewer cycles had a RR of 1.66.

Her analysis included 2,842 cancer patients who received treatment with an ICI at Massachusetts General Hospital. Patients averaged 64 years of age, slightly more than half were men, and 13% had a prior history of VTE. Patients received an average of 5 ICI treatment cycles, but a quarter of the patients received more than 10 cycles.

During the 2-year follow-up, 244 patients (9%) developed VTE. The patients who developed VTE were significantly younger than those who did not, with an average age of 63 years, compared with 65. And the patients who eventually developed VTE had a significantly higher prevalence of prior VTE at 18%, compared with 12% among the patients who stayed VTE free.

The cancer types patients had were non–small cell lung, 29%; melanoma, 28%; head and neck, 12%; renal genitourinary, 6%; and other, 25%. ICIs have been available for routine U.S. practice since 2011. The class includes agents such as pembrolizumab (Keytruda) and durvalumab (Imfinzi).

Researchers would need to perform a prospective, randomized study to determine whether anticoagulant prophylaxis is clearly beneficial for patients receiving ICI treatment, Dr. Gong said. But both Dr. Kovacs and Dr. Campia said that more data on this topic are first needed.

“We need to confirm that treatment with ICI is associated with VTEs. Retrospective data are not definitive,” said Dr. Campia. “We would need to prospectively assess the impact of ICI,” which will not be easy, as it’s quickly become a cornerstone for treating many cancers. “We need to become more familiar with the adverse effects of these drugs. We are still learning about their toxicities.”

The study had no commercial funding. Dr. Gong, Dr. Kovacs, and Dr. Campia had no disclosures.

[email protected]

Cancer patients who receive an immune checkpoint inhibitor have more than a doubled rate of venous thromboembolism during the subsequent 2 years, compared with their rate during the 2 years before treatment, according to a retrospective analysis of more than 2,800 patients treated at a single U.S. center.

The study focused on cancer patients treated with an immune checkpoint inhibitor (ICI) at Massachusetts General Hospital in Boston. It showed that during the 2 years prior to treatment with any type of ICI, the incidence of venous thromboembolic events (VTE) was 4.85/100 patient-years that then jumped to 11.75/100 patient-years during the 2 years following treatment. This translated into an incidence rate ratio of 2.43 during posttreatment follow-up, compared with pretreatment, Jingyi Gong, MD, said at the virtual American Heart Association scientific sessions.

The increased VTE rate resulted from rises in both the rate of deep vein thrombosis, which had an IRR of 3.23 during the posttreatment period, and for pulmonary embolism, which showed an IRR of 2.24, said Dr. Gong, a physician at Brigham and Women’s Hospital in Boston. She hypothesized that this effect may result from a procoagulant effect of the immune activation and inflammation triggered by ICIs.


Hypothesis-generating results

Cardiologists cautioned that these findings should only be considered hypothesis generating, but raise an important alert for clinicians to have heightened awareness of the potential for VTE following ICI treatment.

“A clear message is to be aware that there is this signal, and be vigilant for patients who might present with VTE following ICI treatment,” commented Richard J. Kovacs, MD, a cardiologist and professor at Indiana University, Indianapolis. The data that Dr. Gong reported are “moderately convincing,” he added in an interview.

“Awareness that patients who receive ICI may be at increased VTE risk is very important,” agreed Umberto Campia, MD, a cardiologist, vascular specialist, and member of the cardio-oncology group at Brigham and Women’s Hospital, who was not involved in the new study.

The potential impact of ICI treatment on VTE risk is slowly emerging, added Dr. Campia. Until recently, the literature primarily was case reports, but recently another retrospective, single-center study came out that reported a 13% incidence of VTE in cancer patients following ICI treatment. On the other hand, a recently published meta-analysis of more than 20,000 patients from 68 ICI studies failed to find a suggestion of increased VTE incidence following ICI interventions.

Attempting to assess the impact of treatment on VTE risk in cancer patients is challenging because cancer itself boosts the risk. Recommendations on the use of VTE prophylaxis in cancer patients most recently came out in 2014 from the American Society of Clinical Oncology, which said that VTE prophylaxis for ambulatory cancer patients “may be considered for highly select high-risk patients.” The impact of cancer therapy on VTE risk and the need for prophylaxis is usually assessed by applying the Khorana score, Dr. Campia said in an interview.
 

VTE spikes acutely after ICI treatment

Dr. Gong analyzed VTE incidence rates by time during the total 4-year period studied, and found that the rate gradually and steadily rose with time throughout the 2 years preceding treatment, spiked immediately following ICI treatment, and then gradually and steadily fell back to roughly the rate seen just before treatment, reaching that level about a year after treatment. She ran a sensitivity analysis that excluded patients who died during the first year following their ICI treatment, and in this calculation an acute spike in VTE following ICI treatment still occurred but with reduced magnitude.

She also reported the results of several subgroup analyses. The IRRs remained consistent among women and men, among patients who were aged over or under 65 years, and regardless of cancer type or treatment with corticosteroids. But the subgroup analyses identified two parameters that seemed to clearly split VTE rates.

Among patients on treatment with an anticoagulant agent at the time of their ICI treatment, roughly 10% of the patients, the IRR was 0.56, compared with a ratio of 3.86 among the other patients, suggesting possible protection. A second factor that seemed linked with VTE incidence was the number of ICI treatment cycles a patient received. Those who received more than five cycles had a risk ratio of 3.95, while those who received five or fewer cycles had a RR of 1.66.

Her analysis included 2,842 cancer patients who received treatment with an ICI at Massachusetts General Hospital. Patients averaged 64 years of age, slightly more than half were men, and 13% had a prior history of VTE. Patients received an average of 5 ICI treatment cycles, but a quarter of the patients received more than 10 cycles.

During the 2-year follow-up, 244 patients (9%) developed VTE. The patients who developed VTE were significantly younger than those who did not, with an average age of 63 years, compared with 65. And the patients who eventually developed VTE had a significantly higher prevalence of prior VTE at 18%, compared with 12% among the patients who stayed VTE free.

The cancer types patients had were non–small cell lung, 29%; melanoma, 28%; head and neck, 12%; renal genitourinary, 6%; and other, 25%. ICIs have been available for routine U.S. practice since 2011. The class includes agents such as pembrolizumab (Keytruda) and durvalumab (Imfinzi).

Researchers would need to perform a prospective, randomized study to determine whether anticoagulant prophylaxis is clearly beneficial for patients receiving ICI treatment, Dr. Gong said. But both Dr. Kovacs and Dr. Campia said that more data on this topic are first needed.

“We need to confirm that treatment with ICI is associated with VTEs. Retrospective data are not definitive,” said Dr. Campia. “We would need to prospectively assess the impact of ICI,” which will not be easy, as it’s quickly become a cornerstone for treating many cancers. “We need to become more familiar with the adverse effects of these drugs. We are still learning about their toxicities.”

The study had no commercial funding. Dr. Gong, Dr. Kovacs, and Dr. Campia had no disclosures.

[email protected]

Cancer patients who receive an immune checkpoint inhibitor have more than a doubled rate of venous thromboembolism during the subsequent 2 years, compared with their rate during the 2 years before treatment, according to a retrospective analysis of more than 2,800 patients treated at a single U.S. center.

The study focused on cancer patients treated with an immune checkpoint inhibitor (ICI) at Massachusetts General Hospital in Boston. It showed that during the 2 years prior to treatment with any type of ICI, the incidence of venous thromboembolic events (VTE) was 4.85/100 patient-years that then jumped to 11.75/100 patient-years during the 2 years following treatment. This translated into an incidence rate ratio of 2.43 during posttreatment follow-up, compared with pretreatment, Jingyi Gong, MD, said at the virtual American Heart Association scientific sessions.

The increased VTE rate resulted from rises in both the rate of deep vein thrombosis, which had an IRR of 3.23 during the posttreatment period, and for pulmonary embolism, which showed an IRR of 2.24, said Dr. Gong, a physician at Brigham and Women’s Hospital in Boston. She hypothesized that this effect may result from a procoagulant effect of the immune activation and inflammation triggered by ICIs.


Hypothesis-generating results

Cardiologists cautioned that these findings should only be considered hypothesis generating, but raise an important alert for clinicians to have heightened awareness of the potential for VTE following ICI treatment.

“A clear message is to be aware that there is this signal, and be vigilant for patients who might present with VTE following ICI treatment,” commented Richard J. Kovacs, MD, a cardiologist and professor at Indiana University, Indianapolis. The data that Dr. Gong reported are “moderately convincing,” he added in an interview.

“Awareness that patients who receive ICI may be at increased VTE risk is very important,” agreed Umberto Campia, MD, a cardiologist, vascular specialist, and member of the cardio-oncology group at Brigham and Women’s Hospital, who was not involved in the new study.

The potential impact of ICI treatment on VTE risk is slowly emerging, added Dr. Campia. Until recently, the literature primarily was case reports, but recently another retrospective, single-center study came out that reported a 13% incidence of VTE in cancer patients following ICI treatment. On the other hand, a recently published meta-analysis of more than 20,000 patients from 68 ICI studies failed to find a suggestion of increased VTE incidence following ICI interventions.

Attempting to assess the impact of treatment on VTE risk in cancer patients is challenging because cancer itself boosts the risk. Recommendations on the use of VTE prophylaxis in cancer patients most recently came out in 2014 from the American Society of Clinical Oncology, which said that VTE prophylaxis for ambulatory cancer patients “may be considered for highly select high-risk patients.” The impact of cancer therapy on VTE risk and the need for prophylaxis is usually assessed by applying the Khorana score, Dr. Campia said in an interview.
 

VTE spikes acutely after ICI treatment

Dr. Gong analyzed VTE incidence rates by time during the total 4-year period studied, and found that the rate gradually and steadily rose with time throughout the 2 years preceding treatment, spiked immediately following ICI treatment, and then gradually and steadily fell back to roughly the rate seen just before treatment, reaching that level about a year after treatment. She ran a sensitivity analysis that excluded patients who died during the first year following their ICI treatment, and in this calculation an acute spike in VTE following ICI treatment still occurred but with reduced magnitude.

She also reported the results of several subgroup analyses. The IRRs remained consistent among women and men, among patients who were aged over or under 65 years, and regardless of cancer type or treatment with corticosteroids. But the subgroup analyses identified two parameters that seemed to clearly split VTE rates.

Among patients on treatment with an anticoagulant agent at the time of their ICI treatment, roughly 10% of the patients, the IRR was 0.56, compared with a ratio of 3.86 among the other patients, suggesting possible protection. A second factor that seemed linked with VTE incidence was the number of ICI treatment cycles a patient received. Those who received more than five cycles had a risk ratio of 3.95, while those who received five or fewer cycles had a RR of 1.66.

Her analysis included 2,842 cancer patients who received treatment with an ICI at Massachusetts General Hospital. Patients averaged 64 years of age, slightly more than half were men, and 13% had a prior history of VTE. Patients received an average of 5 ICI treatment cycles, but a quarter of the patients received more than 10 cycles.

During the 2-year follow-up, 244 patients (9%) developed VTE. The patients who developed VTE were significantly younger than those who did not, with an average age of 63 years, compared with 65. And the patients who eventually developed VTE had a significantly higher prevalence of prior VTE at 18%, compared with 12% among the patients who stayed VTE free.

The cancer types patients had were non–small cell lung, 29%; melanoma, 28%; head and neck, 12%; renal genitourinary, 6%; and other, 25%. ICIs have been available for routine U.S. practice since 2011. The class includes agents such as pembrolizumab (Keytruda) and durvalumab (Imfinzi).

Researchers would need to perform a prospective, randomized study to determine whether anticoagulant prophylaxis is clearly beneficial for patients receiving ICI treatment, Dr. Gong said. But both Dr. Kovacs and Dr. Campia said that more data on this topic are first needed.

“We need to confirm that treatment with ICI is associated with VTEs. Retrospective data are not definitive,” said Dr. Campia. “We would need to prospectively assess the impact of ICI,” which will not be easy, as it’s quickly become a cornerstone for treating many cancers. “We need to become more familiar with the adverse effects of these drugs. We are still learning about their toxicities.”

The study had no commercial funding. Dr. Gong, Dr. Kovacs, and Dr. Campia had no disclosures.

[email protected]

"The writing is on the wall” that virtual care is not meeting the needs of people with HIV who struggled with viral suppression even before the COVID-19 pandemic, said Jason Farley, PhD, ANP-BC, AACRN, associate professor of nursing at Johns Hopkins University, Baltimore. So it’s time for HIV care teams, especially clinics in the Ryan White HIV/AIDS Program, to get creative in bringing wraparound services to patients.

That may mean reallocating the workforce so that one person serves as a community health worker. Or it could mean increasing texts and video calls; helping patients find online support groups to address problems with alcohol or drug use; and conducting an overall assessment of patients’ needs as the pandemic continues.

“The virtual patient-centered medical home may be the new normal after COVID-19, and we have to be thinking about how we use this model with patients for whom it works, but supplement this model in patients that it does not,” Farley said at the virtual Association of Nurses in AIDS Care (ANAC) 2020 Annual Meeting. That work “is essential to our being able to facilitate the best patient outcomes possible.”
 

Early data, tiered interventions

Farley referred to an article published in September in the Journal AIDS that confirmed unpublished data mentioned at the International AIDS Conference 2020. The article reported that viral suppression rates among people with HIV who attended San Francisco’s Ward 86 HIV clinic dropped by 31% from pre-COVID levels.

Of the 1766 people who attended the clinic, about 1 in 5 had detectable HIV viral loads at any point in 2019. But that rate was 31% higher after shelter-in-place orders were issued. And although patients participated in telemedicine visits at more or less the same rate before and after the pandemic (31% vs. 30% no-shows), viral suppression rates dropped. The impact was especially acute for homeless individuals.

“This destabilization occurred despite our population attending telemedicine visits at a higher rate than expected, given the 60% drop in ambulatory care visit volume nationwide,” the authors stated in their article. “Telehealth visits, while offering greater patient convenience, may lead to less access to clinic-based social support services essential to achieving viral suppression among vulnerable groups.”

That’s the challenge HIV clinics now face, Farley said at the ANAC meeting.

He suggested a differentiated care approach in which there are four tiers of care, starting with the standard level of outreach, which may include email, electronic health record blasts, and robo-calls to remind people of their appointments and to refill their medications. Those with sustained viral suppression may only need 90-day automatic refills of their medications. Those who are vulnerable to nonadherence may need to be contacted weekly or more often by the clinic. Such contact could be made by a social worker, a community health worker, or through some form of virtual support.

Patients at tier 4, who have labile viral suppression, need far more than that. These are the 15% of patients with HIV who struggled with viral suppression before the pandemic. They are the patients that Farley’s team focuses on at Baltimore’s John G. Bartlett Specialty Clinic for Infectious Disease.

“We’ve completely deconstructed the patient-centered medical home,” he said of the early move to virtual care. He suggested that clinicians assess their services and ask themselves some questions:

• Has someone on the team reached out to every patient and checked in to see what their biggest needs are, medical or not, during the pandemic? Have they assessed the patient’s ability to receive video calls or text messages?
• How have group-support programs that address stigma or the social determinants of health fared in the transition to virtual medicine?
• Are patients who are in recovery being supported in order that they may engage with recovery programs online?
• How well have counseling services done in engaging people in virtual care? Currently, given the overall increase in mental health challenges during the pandemic, one would expect that the use of mental health counseling is increasing. “If they’re stagnant or going down, someone needs to be reflecting on that issue internally in the clinic,” he said.
• Are patients being contacted regarding the effects that isolation is having on their lives? “The things that would normally allow us to self-mitigate and self-manage these conditions, like going to the gym, meeting with friends, religious services – all of those are being cut,” he said.
• Is there an early alert from an in-person pharmacy to trigger outreach via a community health worker for patients who haven’t picked up their medications in a week or more?

Farley pointed to a 2015 model for an enhanced e-health approach to chronic care management that called for e-support from the community and that was enhanced through virtual communities.

These are some of the approaches Farley has taken at his clinic. He leads a team that focuses specifically on patients who struggled with engagement before the pandemic. Through a grant from the US Department of Health & Human Services’ Health Resources and Services Administration – even before the pandemic – that team has been funding community health workers who have multiple contacts with patients online and virtually and are able to offer what he calls “unapologetically enabling” support for patients so that they are able to focus on their health.

He gave the following example. Before the pandemic, a community health worker on the team had been working with a patient who showed up at every scheduled visit and swore that she was taking her medications, although clearly she was not. A community health worker, who was made available through the grant, was able to recognize that the patient’s biggest challenge in her life was providing childcare for her special-needs child. The community health worker worked with the patient for months to find stable childcare for the child, paid 2 months of rent for the patient so that she would not become homeless, and helped her find transitional housing. When the pandemic hit, the community health worker was already texting and conducting video calls with the patient regularly.

For the past 9 months, that patient has had an undetectable viral load, Farley said.

“Nine months during a pandemic,” Farley reiterated, “and the community health worker keeps working with her, keeps meeting with her.”
 

Stigma on stigma

The need for this level of support from the clinic may be even more important for people with HIV who acquire COVID-19, said Orlando Harris, PhD, assistant professor of community health systems at the University of California, San Francisco, (UCSF) School of Nursing. HIV-related stigma is a well-known deterrent to care for people living with the virus. During the presentation, Harris asked Farley about the impact of COVID-19 stigma on people with both HIV and COVID-19.

Farley said that patients at his clinic have told him that they have “ostracized” friends who have tested positive for COVID-19. Harris remembered a person with HIV who participated in one of his trials telling the researchers that despite all his precautions – wearing a mask, staying socially distant – he still acquired COVID-19. There was nothing he could have done, Harris said, other than just not go to the grocery store.

The fear of contracting another disease that is associated with stigma, as well as the need to disclose it, can inflame memories of the trauma of being diagnosed with HIV, Harris said. And with patient-centered medical homes struggling to reconstitute their wraparound services via telehealth, he said he wonders whether clinicians should be doing more.

“I worry about people who have survived being diagnosed with HIV in the ‘80s and the ‘90s before antiretroviral therapy showed up on the scene,” he told Medscape Medical News. “I worry that the folks that survived one pandemic [may] be feeling fearful or living in that fear that this new pandemic might take them out. That’s why I’m stressing the need for us to really consider, as clinicians and also as researchers the support systems, the coping mechanisms, the counseling, or what have you to support those living with HIV and vulnerable to COVID-19.”

During telehealth visits, that can be achieved simply by asking people how they are really doing and what their coping mechanisms are.

For their part, the clinicians at San Francisco’s Ward 86 are not trying to provide that support through telehealth on the same level as they were at the beginning of the pandemic, said Matthew Spinelli, MD, assistant professor of medicine, and Monica Gandhi, MD, associate chief of the Division of HIV, Infectious Diseases and Global Medicine, who are both at UCSF and are coauthors of the study.

They still offer telemedicine appointments to patients who request them, said Spinelli. He said about one-third of his patients still prefer to receive their care virtually. The rest have gone back to face-to-face support.

“The analysis led us to promptly open up care as much as possible to our patients, with the idea that telehealth is not cutting it for vulnerable patients with HIV,” Gandhi told Medscape Medical News via email. “We don’t think it’s right for a population who relies on social support from the clinic.”
 

This article first appeared on Medscape.com.

"The writing is on the wall” that virtual care is not meeting the needs of people with HIV who struggled with viral suppression even before the COVID-19 pandemic, said Jason Farley, PhD, ANP-BC, AACRN, associate professor of nursing at Johns Hopkins University, Baltimore. So it’s time for HIV care teams, especially clinics in the Ryan White HIV/AIDS Program, to get creative in bringing wraparound services to patients.

That may mean reallocating the workforce so that one person serves as a community health worker. Or it could mean increasing texts and video calls; helping patients find online support groups to address problems with alcohol or drug use; and conducting an overall assessment of patients’ needs as the pandemic continues.

“The virtual patient-centered medical home may be the new normal after COVID-19, and we have to be thinking about how we use this model with patients for whom it works, but supplement this model in patients that it does not,” Farley said at the virtual Association of Nurses in AIDS Care (ANAC) 2020 Annual Meeting. That work “is essential to our being able to facilitate the best patient outcomes possible.”
 

Early data, tiered interventions

Farley referred to an article published in September in the Journal AIDS that confirmed unpublished data mentioned at the International AIDS Conference 2020. The article reported that viral suppression rates among people with HIV who attended San Francisco’s Ward 86 HIV clinic dropped by 31% from pre-COVID levels.

Of the 1766 people who attended the clinic, about 1 in 5 had detectable HIV viral loads at any point in 2019. But that rate was 31% higher after shelter-in-place orders were issued. And although patients participated in telemedicine visits at more or less the same rate before and after the pandemic (31% vs. 30% no-shows), viral suppression rates dropped. The impact was especially acute for homeless individuals.

“This destabilization occurred despite our population attending telemedicine visits at a higher rate than expected, given the 60% drop in ambulatory care visit volume nationwide,” the authors stated in their article. “Telehealth visits, while offering greater patient convenience, may lead to less access to clinic-based social support services essential to achieving viral suppression among vulnerable groups.”

That’s the challenge HIV clinics now face, Farley said at the ANAC meeting.

He suggested a differentiated care approach in which there are four tiers of care, starting with the standard level of outreach, which may include email, electronic health record blasts, and robo-calls to remind people of their appointments and to refill their medications. Those with sustained viral suppression may only need 90-day automatic refills of their medications. Those who are vulnerable to nonadherence may need to be contacted weekly or more often by the clinic. Such contact could be made by a social worker, a community health worker, or through some form of virtual support.

Patients at tier 4, who have labile viral suppression, need far more than that. These are the 15% of patients with HIV who struggled with viral suppression before the pandemic. They are the patients that Farley’s team focuses on at Baltimore’s John G. Bartlett Specialty Clinic for Infectious Disease.

“We’ve completely deconstructed the patient-centered medical home,” he said of the early move to virtual care. He suggested that clinicians assess their services and ask themselves some questions:

• Has someone on the team reached out to every patient and checked in to see what their biggest needs are, medical or not, during the pandemic? Have they assessed the patient’s ability to receive video calls or text messages?
• How have group-support programs that address stigma or the social determinants of health fared in the transition to virtual medicine?
• Are patients who are in recovery being supported in order that they may engage with recovery programs online?
• How well have counseling services done in engaging people in virtual care? Currently, given the overall increase in mental health challenges during the pandemic, one would expect that the use of mental health counseling is increasing. “If they’re stagnant or going down, someone needs to be reflecting on that issue internally in the clinic,” he said.
• Are patients being contacted regarding the effects that isolation is having on their lives? “The things that would normally allow us to self-mitigate and self-manage these conditions, like going to the gym, meeting with friends, religious services – all of those are being cut,” he said.
• Is there an early alert from an in-person pharmacy to trigger outreach via a community health worker for patients who haven’t picked up their medications in a week or more?

Farley pointed to a 2015 model for an enhanced e-health approach to chronic care management that called for e-support from the community and that was enhanced through virtual communities.

These are some of the approaches Farley has taken at his clinic. He leads a team that focuses specifically on patients who struggled with engagement before the pandemic. Through a grant from the US Department of Health & Human Services’ Health Resources and Services Administration – even before the pandemic – that team has been funding community health workers who have multiple contacts with patients online and virtually and are able to offer what he calls “unapologetically enabling” support for patients so that they are able to focus on their health.

He gave the following example. Before the pandemic, a community health worker on the team had been working with a patient who showed up at every scheduled visit and swore that she was taking her medications, although clearly she was not. A community health worker, who was made available through the grant, was able to recognize that the patient’s biggest challenge in her life was providing childcare for her special-needs child. The community health worker worked with the patient for months to find stable childcare for the child, paid 2 months of rent for the patient so that she would not become homeless, and helped her find transitional housing. When the pandemic hit, the community health worker was already texting and conducting video calls with the patient regularly.

For the past 9 months, that patient has had an undetectable viral load, Farley said.

“Nine months during a pandemic,” Farley reiterated, “and the community health worker keeps working with her, keeps meeting with her.”
 

Stigma on stigma

The need for this level of support from the clinic may be even more important for people with HIV who acquire COVID-19, said Orlando Harris, PhD, assistant professor of community health systems at the University of California, San Francisco, (UCSF) School of Nursing. HIV-related stigma is a well-known deterrent to care for people living with the virus. During the presentation, Harris asked Farley about the impact of COVID-19 stigma on people with both HIV and COVID-19.

Farley said that patients at his clinic have told him that they have “ostracized” friends who have tested positive for COVID-19. Harris remembered a person with HIV who participated in one of his trials telling the researchers that despite all his precautions – wearing a mask, staying socially distant – he still acquired COVID-19. There was nothing he could have done, Harris said, other than just not go to the grocery store.

The fear of contracting another disease that is associated with stigma, as well as the need to disclose it, can inflame memories of the trauma of being diagnosed with HIV, Harris said. And with patient-centered medical homes struggling to reconstitute their wraparound services via telehealth, he said he wonders whether clinicians should be doing more.

“I worry about people who have survived being diagnosed with HIV in the ‘80s and the ‘90s before antiretroviral therapy showed up on the scene,” he told Medscape Medical News. “I worry that the folks that survived one pandemic [may] be feeling fearful or living in that fear that this new pandemic might take them out. That’s why I’m stressing the need for us to really consider, as clinicians and also as researchers the support systems, the coping mechanisms, the counseling, or what have you to support those living with HIV and vulnerable to COVID-19.”

During telehealth visits, that can be achieved simply by asking people how they are really doing and what their coping mechanisms are.

For their part, the clinicians at San Francisco’s Ward 86 are not trying to provide that support through telehealth on the same level as they were at the beginning of the pandemic, said Matthew Spinelli, MD, assistant professor of medicine, and Monica Gandhi, MD, associate chief of the Division of HIV, Infectious Diseases and Global Medicine, who are both at UCSF and are coauthors of the study.

They still offer telemedicine appointments to patients who request them, said Spinelli. He said about one-third of his patients still prefer to receive their care virtually. The rest have gone back to face-to-face support.

“The analysis led us to promptly open up care as much as possible to our patients, with the idea that telehealth is not cutting it for vulnerable patients with HIV,” Gandhi told Medscape Medical News via email. “We don’t think it’s right for a population who relies on social support from the clinic.”
 

This article first appeared on Medscape.com.

"The writing is on the wall” that virtual care is not meeting the needs of people with HIV who struggled with viral suppression even before the COVID-19 pandemic, said Jason Farley, PhD, ANP-BC, AACRN, associate professor of nursing at Johns Hopkins University, Baltimore. So it’s time for HIV care teams, especially clinics in the Ryan White HIV/AIDS Program, to get creative in bringing wraparound services to patients.

That may mean reallocating the workforce so that one person serves as a community health worker. Or it could mean increasing texts and video calls; helping patients find online support groups to address problems with alcohol or drug use; and conducting an overall assessment of patients’ needs as the pandemic continues.

“The virtual patient-centered medical home may be the new normal after COVID-19, and we have to be thinking about how we use this model with patients for whom it works, but supplement this model in patients that it does not,” Farley said at the virtual Association of Nurses in AIDS Care (ANAC) 2020 Annual Meeting. That work “is essential to our being able to facilitate the best patient outcomes possible.”
 

Early data, tiered interventions

Farley referred to an article published in September in the Journal AIDS that confirmed unpublished data mentioned at the International AIDS Conference 2020. The article reported that viral suppression rates among people with HIV who attended San Francisco’s Ward 86 HIV clinic dropped by 31% from pre-COVID levels.

Of the 1766 people who attended the clinic, about 1 in 5 had detectable HIV viral loads at any point in 2019. But that rate was 31% higher after shelter-in-place orders were issued. And although patients participated in telemedicine visits at more or less the same rate before and after the pandemic (31% vs. 30% no-shows), viral suppression rates dropped. The impact was especially acute for homeless individuals.

“This destabilization occurred despite our population attending telemedicine visits at a higher rate than expected, given the 60% drop in ambulatory care visit volume nationwide,” the authors stated in their article. “Telehealth visits, while offering greater patient convenience, may lead to less access to clinic-based social support services essential to achieving viral suppression among vulnerable groups.”

That’s the challenge HIV clinics now face, Farley said at the ANAC meeting.

He suggested a differentiated care approach in which there are four tiers of care, starting with the standard level of outreach, which may include email, electronic health record blasts, and robo-calls to remind people of their appointments and to refill their medications. Those with sustained viral suppression may only need 90-day automatic refills of their medications. Those who are vulnerable to nonadherence may need to be contacted weekly or more often by the clinic. Such contact could be made by a social worker, a community health worker, or through some form of virtual support.

Patients at tier 4, who have labile viral suppression, need far more than that. These are the 15% of patients with HIV who struggled with viral suppression before the pandemic. They are the patients that Farley’s team focuses on at Baltimore’s John G. Bartlett Specialty Clinic for Infectious Disease.

“We’ve completely deconstructed the patient-centered medical home,” he said of the early move to virtual care. He suggested that clinicians assess their services and ask themselves some questions:

• Has someone on the team reached out to every patient and checked in to see what their biggest needs are, medical or not, during the pandemic? Have they assessed the patient’s ability to receive video calls or text messages?
• How have group-support programs that address stigma or the social determinants of health fared in the transition to virtual medicine?
• Are patients who are in recovery being supported in order that they may engage with recovery programs online?
• How well have counseling services done in engaging people in virtual care? Currently, given the overall increase in mental health challenges during the pandemic, one would expect that the use of mental health counseling is increasing. “If they’re stagnant or going down, someone needs to be reflecting on that issue internally in the clinic,” he said.
• Are patients being contacted regarding the effects that isolation is having on their lives? “The things that would normally allow us to self-mitigate and self-manage these conditions, like going to the gym, meeting with friends, religious services – all of those are being cut,” he said.
• Is there an early alert from an in-person pharmacy to trigger outreach via a community health worker for patients who haven’t picked up their medications in a week or more?

Farley pointed to a 2015 model for an enhanced e-health approach to chronic care management that called for e-support from the community and that was enhanced through virtual communities.

These are some of the approaches Farley has taken at his clinic. He leads a team that focuses specifically on patients who struggled with engagement before the pandemic. Through a grant from the US Department of Health & Human Services’ Health Resources and Services Administration – even before the pandemic – that team has been funding community health workers who have multiple contacts with patients online and virtually and are able to offer what he calls “unapologetically enabling” support for patients so that they are able to focus on their health.

He gave the following example. Before the pandemic, a community health worker on the team had been working with a patient who showed up at every scheduled visit and swore that she was taking her medications, although clearly she was not. A community health worker, who was made available through the grant, was able to recognize that the patient’s biggest challenge in her life was providing childcare for her special-needs child. The community health worker worked with the patient for months to find stable childcare for the child, paid 2 months of rent for the patient so that she would not become homeless, and helped her find transitional housing. When the pandemic hit, the community health worker was already texting and conducting video calls with the patient regularly.

For the past 9 months, that patient has had an undetectable viral load, Farley said.

“Nine months during a pandemic,” Farley reiterated, “and the community health worker keeps working with her, keeps meeting with her.”
 

Stigma on stigma

The need for this level of support from the clinic may be even more important for people with HIV who acquire COVID-19, said Orlando Harris, PhD, assistant professor of community health systems at the University of California, San Francisco, (UCSF) School of Nursing. HIV-related stigma is a well-known deterrent to care for people living with the virus. During the presentation, Harris asked Farley about the impact of COVID-19 stigma on people with both HIV and COVID-19.

Farley said that patients at his clinic have told him that they have “ostracized” friends who have tested positive for COVID-19. Harris remembered a person with HIV who participated in one of his trials telling the researchers that despite all his precautions – wearing a mask, staying socially distant – he still acquired COVID-19. There was nothing he could have done, Harris said, other than just not go to the grocery store.

The fear of contracting another disease that is associated with stigma, as well as the need to disclose it, can inflame memories of the trauma of being diagnosed with HIV, Harris said. And with patient-centered medical homes struggling to reconstitute their wraparound services via telehealth, he said he wonders whether clinicians should be doing more.

“I worry about people who have survived being diagnosed with HIV in the ‘80s and the ‘90s before antiretroviral therapy showed up on the scene,” he told Medscape Medical News. “I worry that the folks that survived one pandemic [may] be feeling fearful or living in that fear that this new pandemic might take them out. That’s why I’m stressing the need for us to really consider, as clinicians and also as researchers the support systems, the coping mechanisms, the counseling, or what have you to support those living with HIV and vulnerable to COVID-19.”

During telehealth visits, that can be achieved simply by asking people how they are really doing and what their coping mechanisms are.

For their part, the clinicians at San Francisco’s Ward 86 are not trying to provide that support through telehealth on the same level as they were at the beginning of the pandemic, said Matthew Spinelli, MD, assistant professor of medicine, and Monica Gandhi, MD, associate chief of the Division of HIV, Infectious Diseases and Global Medicine, who are both at UCSF and are coauthors of the study.

They still offer telemedicine appointments to patients who request them, said Spinelli. He said about one-third of his patients still prefer to receive their care virtually. The rest have gone back to face-to-face support.

“The analysis led us to promptly open up care as much as possible to our patients, with the idea that telehealth is not cutting it for vulnerable patients with HIV,” Gandhi told Medscape Medical News via email. “We don’t think it’s right for a population who relies on social support from the clinic.”
 

This article first appeared on Medscape.com.