Neil Osterweil

Promoting to the front line two drugs normally used in rearguard action to treat advanced renal cell carcinoma (RCC) – nivolumab (Opdivo) and cabozantinib (Cabometyx) – doubled overall response rates and progression-free survival (PFS) and significantly improved overall survival (OS), compared with first-line sunitinib (Sutent), investigators in the Checkmate 9ER trial reported.

Median PFS among patients with advanced RCC, which was the trial’s primary endpoint, was 16.6 months with nivolumab plus cabozantinib, compared with 8.3 months with sunitinib, translating into a hazard ratio of 0.51 for the combination (P < .0001). The median follow-up was 18.1 months.

Median OS had not been reached in either arm at the time of data cutoff, but the survival curves at the time of the analysis clearly favored nivolumab-cabozatinib, with an HR for death of .060 (P = .0010), said Tony K. Choueri, MD, from the Dana-Farber Cancer Institute in Boston.

“With expanding options in our patients with advanced RCC, the overall efficacy, safety, and quality-of-life benefit, as well as individual patient characteristics, are very important considerations when you select appropriate therapy,” he said in a press briefing prior to his presentation of the data in a presidential symposium at the European Society of Medical Oncology Virtual Congress 2020.

Although the nivolumab-cabozantinib combination therapy looks good, it’s late to the game, commented Dominik Berthold, MD, from the Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland, the invited discussant for the briefing.

“The question is, what’s the only drawback of this trial? It’s probably the fact that it’s not first in class in this situation,” he said.

Dr. Berthold noted that nivolumab-cabozantinib, if approved for the frontline setting, will join the combination of the tyrosine kinase inhibitor (TKI) axitinib (Inlyta) plus pembrolizumab (Keytruda), which, as previously reported, was associated with a nearly 50% reduction in the risk for death in the KEYNOTE-426 trial. This combination was approved by the Food and Drug Administration for the frontline setting in April 2019.

As shown in the CheckMate-214 study, the combination of the programmed cell death protein–1 (PD-1) inhibitor nivolumab with the CTLA-4 inhibitor ipilimumab (Yervoy) was associated with significantly higher objective response rates and OS rates compared with sunitinib. This combination was approved by the FDA in April 2018 as first-line therapy for patients with advanced intermediate- or poor-risk RCC.
 

CheckMate 9ER details

A total of 651 patients with previously untreated advanced or metastatic RCC that had a clear cell component in all International Metastatic RCC Database Consortium risk groups were enrolled and randomly assigned to receive either intravenous nivolumab at 240 mg every 2 weeks plus oral cabozantinib at 40 mg daily or oral sunitinib at 50 mg daily in cycles of 4 weeks on therapy/2 weeks off therapy. Patients were treated until disease progression or unacceptable toxicities occurred.

The primary PFS endpoint and the secondary OS endpoint both favored the combination, as did the objective response rate, which was 55.7% with nivolumab-cabozantinib versus 27.1% with sunitinib (P < .0001).

Complete responses were seen in 8% of patients who received the combination versus 4.6% with the patients who received sunitinib. Partial responses were seen in 47.7% and 22.6%, respectively.

Patients generally tolerated the combination. The incidence of the most common high-grade treatment-emergent adverse events and other adverse events of any grade was similar to that seen with sunitinib, Dr. Choueri said.

The rates of treatment-related events that led to discontinuation was 3.1% among patients who received the combination, 5.6% among patients who received the nivolumab component only, and 6.6% among patients who received cabozantinib only. It was 8.8% among patients who received sunitinib. More than 50% of patients in the combination arm needed a dose reduction of nivolumab-cabozantinib because of adverse events, however.

“Overall, it seems that the combination has a somewhat manageable safety profile in patients with advanced RCC,” Dr. Choueri said.

Patient-reported quality of life, as measured by the National Comprehensive Cancer Network/Functional Assessment of Cancer Therapy–Kidney Symptom Index 19 total score, was an exploratory endpoint. It was maintained over time with the combination but deteriorated over time with sunitinib, with statistically significant differences between the study arms at most time points to 91 weeks, he reported.
 

Making choices

Dr. Berthold acknowledged the benefit that having an additional therapy offers clinicians and patients.

“What we still need to learn here is, ‘Are there any patient populations who may benefit more on this combination compared with other combinations?’ ” he said. “Cabozantinib is quite a unique TKI which may target better bone metastases, for example, so I think there are things we need to learn from further data and longer follow-up.”

Camillo Porta, MD, from the University of Bari (Italy), the invited discussant for the presidential symposium, urged caution in comparing the three regimens, owing to differences in the drug used, study endpoints, baseline patient characteristics, and the distribution of patients among different prognostic groups.

When it comes to deciding between frontline regimens, “the only possible, though highly empiric, driver of our therapeutical choice should be the biological aggressiveness of the tumor,” he said.

For patients with highly aggressive disease, the use of an immune checkpoint inhibitor plus a vascular endothelial growth factor receptor (VEGFR)–directed TKI may help control disease long enough to give the checkpoint inhibitor time to work.

“Otherwise, one could head for the long-term benefit of the immune combo as well as for complete responses, trying to spare [patients] the additional toxicities deriving from the continuous use of the VEGFR TKI,” he added.

Dr. Porta noted that when considering the trade-off between efficacy and safety in the first-line setting, many patients are willing to accept more toxicities in exchange for clinical benefit.

The study was sponsored by Bristol-Myers Squibb. Dr. Choueri disclosed consultancy fees, advisory board activity, manuscript preparation, travel/lodging, honoraria, and grants for clinical trials from BMS and others. Dr. Berthold disclosed an advisory role for Ipsen, BMS, Merck, and Pfizer. Dr. Porta disclosed advisory/consulting activities and speakers bureau participation for BMS and others.

This article first appeared on Medscape.com.

Promoting to the front line two drugs normally used in rearguard action to treat advanced renal cell carcinoma (RCC) – nivolumab (Opdivo) and cabozantinib (Cabometyx) – doubled overall response rates and progression-free survival (PFS) and significantly improved overall survival (OS), compared with first-line sunitinib (Sutent), investigators in the Checkmate 9ER trial reported.

Median PFS among patients with advanced RCC, which was the trial’s primary endpoint, was 16.6 months with nivolumab plus cabozantinib, compared with 8.3 months with sunitinib, translating into a hazard ratio of 0.51 for the combination (P < .0001). The median follow-up was 18.1 months.

Median OS had not been reached in either arm at the time of data cutoff, but the survival curves at the time of the analysis clearly favored nivolumab-cabozatinib, with an HR for death of .060 (P = .0010), said Tony K. Choueri, MD, from the Dana-Farber Cancer Institute in Boston.

“With expanding options in our patients with advanced RCC, the overall efficacy, safety, and quality-of-life benefit, as well as individual patient characteristics, are very important considerations when you select appropriate therapy,” he said in a press briefing prior to his presentation of the data in a presidential symposium at the European Society of Medical Oncology Virtual Congress 2020.

Although the nivolumab-cabozantinib combination therapy looks good, it’s late to the game, commented Dominik Berthold, MD, from the Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland, the invited discussant for the briefing.

“The question is, what’s the only drawback of this trial? It’s probably the fact that it’s not first in class in this situation,” he said.

Dr. Berthold noted that nivolumab-cabozantinib, if approved for the frontline setting, will join the combination of the tyrosine kinase inhibitor (TKI) axitinib (Inlyta) plus pembrolizumab (Keytruda), which, as previously reported, was associated with a nearly 50% reduction in the risk for death in the KEYNOTE-426 trial. This combination was approved by the Food and Drug Administration for the frontline setting in April 2019.

As shown in the CheckMate-214 study, the combination of the programmed cell death protein–1 (PD-1) inhibitor nivolumab with the CTLA-4 inhibitor ipilimumab (Yervoy) was associated with significantly higher objective response rates and OS rates compared with sunitinib. This combination was approved by the FDA in April 2018 as first-line therapy for patients with advanced intermediate- or poor-risk RCC.
 

CheckMate 9ER details

A total of 651 patients with previously untreated advanced or metastatic RCC that had a clear cell component in all International Metastatic RCC Database Consortium risk groups were enrolled and randomly assigned to receive either intravenous nivolumab at 240 mg every 2 weeks plus oral cabozantinib at 40 mg daily or oral sunitinib at 50 mg daily in cycles of 4 weeks on therapy/2 weeks off therapy. Patients were treated until disease progression or unacceptable toxicities occurred.

The primary PFS endpoint and the secondary OS endpoint both favored the combination, as did the objective response rate, which was 55.7% with nivolumab-cabozantinib versus 27.1% with sunitinib (P < .0001).

Complete responses were seen in 8% of patients who received the combination versus 4.6% with the patients who received sunitinib. Partial responses were seen in 47.7% and 22.6%, respectively.

Patients generally tolerated the combination. The incidence of the most common high-grade treatment-emergent adverse events and other adverse events of any grade was similar to that seen with sunitinib, Dr. Choueri said.

The rates of treatment-related events that led to discontinuation was 3.1% among patients who received the combination, 5.6% among patients who received the nivolumab component only, and 6.6% among patients who received cabozantinib only. It was 8.8% among patients who received sunitinib. More than 50% of patients in the combination arm needed a dose reduction of nivolumab-cabozantinib because of adverse events, however.

“Overall, it seems that the combination has a somewhat manageable safety profile in patients with advanced RCC,” Dr. Choueri said.

Patient-reported quality of life, as measured by the National Comprehensive Cancer Network/Functional Assessment of Cancer Therapy–Kidney Symptom Index 19 total score, was an exploratory endpoint. It was maintained over time with the combination but deteriorated over time with sunitinib, with statistically significant differences between the study arms at most time points to 91 weeks, he reported.
 

Making choices

Dr. Berthold acknowledged the benefit that having an additional therapy offers clinicians and patients.

“What we still need to learn here is, ‘Are there any patient populations who may benefit more on this combination compared with other combinations?’ ” he said. “Cabozantinib is quite a unique TKI which may target better bone metastases, for example, so I think there are things we need to learn from further data and longer follow-up.”

Camillo Porta, MD, from the University of Bari (Italy), the invited discussant for the presidential symposium, urged caution in comparing the three regimens, owing to differences in the drug used, study endpoints, baseline patient characteristics, and the distribution of patients among different prognostic groups.

When it comes to deciding between frontline regimens, “the only possible, though highly empiric, driver of our therapeutical choice should be the biological aggressiveness of the tumor,” he said.

For patients with highly aggressive disease, the use of an immune checkpoint inhibitor plus a vascular endothelial growth factor receptor (VEGFR)–directed TKI may help control disease long enough to give the checkpoint inhibitor time to work.

“Otherwise, one could head for the long-term benefit of the immune combo as well as for complete responses, trying to spare [patients] the additional toxicities deriving from the continuous use of the VEGFR TKI,” he added.

Dr. Porta noted that when considering the trade-off between efficacy and safety in the first-line setting, many patients are willing to accept more toxicities in exchange for clinical benefit.

The study was sponsored by Bristol-Myers Squibb. Dr. Choueri disclosed consultancy fees, advisory board activity, manuscript preparation, travel/lodging, honoraria, and grants for clinical trials from BMS and others. Dr. Berthold disclosed an advisory role for Ipsen, BMS, Merck, and Pfizer. Dr. Porta disclosed advisory/consulting activities and speakers bureau participation for BMS and others.

This article first appeared on Medscape.com.

Promoting to the front line two drugs normally used in rearguard action to treat advanced renal cell carcinoma (RCC) – nivolumab (Opdivo) and cabozantinib (Cabometyx) – doubled overall response rates and progression-free survival (PFS) and significantly improved overall survival (OS), compared with first-line sunitinib (Sutent), investigators in the Checkmate 9ER trial reported.

Median PFS among patients with advanced RCC, which was the trial’s primary endpoint, was 16.6 months with nivolumab plus cabozantinib, compared with 8.3 months with sunitinib, translating into a hazard ratio of 0.51 for the combination (P < .0001). The median follow-up was 18.1 months.

Median OS had not been reached in either arm at the time of data cutoff, but the survival curves at the time of the analysis clearly favored nivolumab-cabozatinib, with an HR for death of .060 (P = .0010), said Tony K. Choueri, MD, from the Dana-Farber Cancer Institute in Boston.

“With expanding options in our patients with advanced RCC, the overall efficacy, safety, and quality-of-life benefit, as well as individual patient characteristics, are very important considerations when you select appropriate therapy,” he said in a press briefing prior to his presentation of the data in a presidential symposium at the European Society of Medical Oncology Virtual Congress 2020.

Although the nivolumab-cabozantinib combination therapy looks good, it’s late to the game, commented Dominik Berthold, MD, from the Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland, the invited discussant for the briefing.

“The question is, what’s the only drawback of this trial? It’s probably the fact that it’s not first in class in this situation,” he said.

Dr. Berthold noted that nivolumab-cabozantinib, if approved for the frontline setting, will join the combination of the tyrosine kinase inhibitor (TKI) axitinib (Inlyta) plus pembrolizumab (Keytruda), which, as previously reported, was associated with a nearly 50% reduction in the risk for death in the KEYNOTE-426 trial. This combination was approved by the Food and Drug Administration for the frontline setting in April 2019.

As shown in the CheckMate-214 study, the combination of the programmed cell death protein–1 (PD-1) inhibitor nivolumab with the CTLA-4 inhibitor ipilimumab (Yervoy) was associated with significantly higher objective response rates and OS rates compared with sunitinib. This combination was approved by the FDA in April 2018 as first-line therapy for patients with advanced intermediate- or poor-risk RCC.
 

CheckMate 9ER details

A total of 651 patients with previously untreated advanced or metastatic RCC that had a clear cell component in all International Metastatic RCC Database Consortium risk groups were enrolled and randomly assigned to receive either intravenous nivolumab at 240 mg every 2 weeks plus oral cabozantinib at 40 mg daily or oral sunitinib at 50 mg daily in cycles of 4 weeks on therapy/2 weeks off therapy. Patients were treated until disease progression or unacceptable toxicities occurred.

The primary PFS endpoint and the secondary OS endpoint both favored the combination, as did the objective response rate, which was 55.7% with nivolumab-cabozantinib versus 27.1% with sunitinib (P < .0001).

Complete responses were seen in 8% of patients who received the combination versus 4.6% with the patients who received sunitinib. Partial responses were seen in 47.7% and 22.6%, respectively.

Patients generally tolerated the combination. The incidence of the most common high-grade treatment-emergent adverse events and other adverse events of any grade was similar to that seen with sunitinib, Dr. Choueri said.

The rates of treatment-related events that led to discontinuation was 3.1% among patients who received the combination, 5.6% among patients who received the nivolumab component only, and 6.6% among patients who received cabozantinib only. It was 8.8% among patients who received sunitinib. More than 50% of patients in the combination arm needed a dose reduction of nivolumab-cabozantinib because of adverse events, however.

“Overall, it seems that the combination has a somewhat manageable safety profile in patients with advanced RCC,” Dr. Choueri said.

Patient-reported quality of life, as measured by the National Comprehensive Cancer Network/Functional Assessment of Cancer Therapy–Kidney Symptom Index 19 total score, was an exploratory endpoint. It was maintained over time with the combination but deteriorated over time with sunitinib, with statistically significant differences between the study arms at most time points to 91 weeks, he reported.
 

Making choices

Dr. Berthold acknowledged the benefit that having an additional therapy offers clinicians and patients.

“What we still need to learn here is, ‘Are there any patient populations who may benefit more on this combination compared with other combinations?’ ” he said. “Cabozantinib is quite a unique TKI which may target better bone metastases, for example, so I think there are things we need to learn from further data and longer follow-up.”

Camillo Porta, MD, from the University of Bari (Italy), the invited discussant for the presidential symposium, urged caution in comparing the three regimens, owing to differences in the drug used, study endpoints, baseline patient characteristics, and the distribution of patients among different prognostic groups.

When it comes to deciding between frontline regimens, “the only possible, though highly empiric, driver of our therapeutical choice should be the biological aggressiveness of the tumor,” he said.

For patients with highly aggressive disease, the use of an immune checkpoint inhibitor plus a vascular endothelial growth factor receptor (VEGFR)–directed TKI may help control disease long enough to give the checkpoint inhibitor time to work.

“Otherwise, one could head for the long-term benefit of the immune combo as well as for complete responses, trying to spare [patients] the additional toxicities deriving from the continuous use of the VEGFR TKI,” he added.

Dr. Porta noted that when considering the trade-off between efficacy and safety in the first-line setting, many patients are willing to accept more toxicities in exchange for clinical benefit.

The study was sponsored by Bristol-Myers Squibb. Dr. Choueri disclosed consultancy fees, advisory board activity, manuscript preparation, travel/lodging, honoraria, and grants for clinical trials from BMS and others. Dr. Berthold disclosed an advisory role for Ipsen, BMS, Merck, and Pfizer. Dr. Porta disclosed advisory/consulting activities and speakers bureau participation for BMS and others.

This article first appeared on Medscape.com.

Maintenance is a important component of therapy for acute lymphoblastic leukemia, but it’s still a relatively new concept in the treat of patients with acute myeloid leukemia (AML).

The topic of AML maintenance “has become quite hot actually, recently, after languishing for years behind ALL, a disease where maintenance is absolutely critical to overall survival; we haven’t had that much to talk about it in AML until recently,” said Gail J. Roboz, MD, from Weill Cornell Medicine and The New York Presbyterian Hospital, both in New York.

Dr. Roboz discussed her approach to AML maintenance during the virtual American Society of Hematology Meeting on Hematologic Malignancies.

The current AML treatment paradigm starts with remission induction via intensive or less-intensive therapies, followed by consolidation with chemotherapy or with autologous or allogeneic stem cell transplantation (SCT), with maintenance considered as a possibility for some patients.

“Strictly speaking, maintenance is the idea of keeping someone in remission, but we’ve gotten used to it that maintenance is postremission therapy that is different from what you had in your induction,” she noted. “That said, the exact nature of maintenance, while it most traditionally refers to an ongoing lower-intensity therapy, is a little bit complicated these days of what exactly constitutes maintenance.”

Current AML treatments generally fail to completely eliminate leukemic cells, so nearly all patients have remissions with minimal residual disease (MRD).

“You have a heterogeneous mix of leukemia stem cells, progenitors, blast cells, and you are in remission but there are still leftovers, and those leftovers result in disease relapse, and the goal of postremission therapy to basically target and hopefully eradicate the leftovers,” Dr. Roboz said.

Focusing on the postremission period is vital because most patients with AML will die within 1 year after disease relapse.
 

Many options, none great

National Comprehensive Cancer Network AML guidelines recommend a variety of approaches to postremission therapy for patients younger than 60 years with AML, including, depending on risk, either histone deacetylase inhibitors, gemtuzumab ozogamicin (Mylotarg), chemotherapy, and/or SCT, but none of these options, strictly speaking, is called maintenance, she noted.

For patients 60 years and older, “there’s also a likelihood of proceeding with hypomethylating [HMA]-based therapy in such a way that, if they’re responding to initial treatment, they get ongoing therapy with whatever HMA or hypomethylating-based regimen they’re responding to. So is that called maintenance? Is that called ongoing therapy? Continuing therapy? It’s a subject of some controversy,” she added.

For patients younger than 60, hematopoietic SCT has been the ultimate form of maintenance, and increasingly allogeneic SCT is being employed in the United States for patients older than 60 years, including those 70 years and older.

“That has been a good thing, because we’ve been able to offer more patients potentially curative therapy, but the problem is that allo transplant is not a free lunch either, and there are significant risks of nonrelapse mortality, especially for patients going into the transplant with other comorbidities,” Dr. Roboz said.

The majority of older patients may not be cured with transplant because of the use of reduced-intensity conditioning regimens with the result of extended disease-free survival but eventual relapse from residual disease.

“The question is, if you’re an older patient and you can’t get an ablative transplant and you do have residual disease, what’s the likelihood of actually being cured at 2 years, and do you really want to go through the headaches of having a transplant?” she said.
 

Nontransplant options

In the RATIFY trial, patients 60 years and younger with newly diagnosed AML with activating FLT3-mutations were randomized to induction chemotherapy with daunorubicin and cytarabine, consolidation with an histone deacetylase inhibitor, and then maintenance for up to 12 cycles with either midostaurin or placebo.

Although the trial met its primary endpoint of an improvement in overall survival with midostaurin (4-year overall survival, 51.4% vs. 44.3% with placebo), there is still uncertainty as to whether the observed survival benefit was caused by midostaurin or by something else, Dr. Roboz said.

“That said, it certainly has become common to use FLT3 inhibitors as postremission strategy for patients, with consolidation, with allo transplant, after allo transplant – wherever you can get the inhibitor in there,” she said.

The isocitrate dehydrogenase inhibitors ivosidenib (for IDH1) and enasidenib (IDH2) have also been tried in a postremission maintenance-like setting, but have thus far not been demonstrated in clinical trials to be effective in this setting, she added.

Gemtuzumab ozogamicin, an anti-CD33 antibody conjugated to calicheamicin, was approved in 2000 for adults 60 years and older with CD33+ AML in first remission, and in 2017 for adults with newly diagnosed CD33+ AML, as well as adults and children 2 years and older with relapsed or refractory CD33+ AML, but there are no data to show whether this antibody-drug conjugate could have benefit in a maintenance setting.

As previously reported, the combination of the BCL-2 inhibitor venetoclax (Venclexta) with azacitidine was associated with a significant improvement in overall survival, compared with azacitidine alone, in the VIALE-A trial.

“The question now is, in these studies most of the time patients are given a combination of aza and venetoclax that actually continues until they progress; is that called maintenance if you’re getting ongoing cycles? Not sure what to call it, but this is quite myelosuppressive, and there are many, many postremission modifications in dose and schedule that could take up a whole separate lecture,” Dr. Roboz commented.

She added, however, that the combination is effective across nearly all subgroups, and may be more generally applicable for maintenance-style therapy in older patients with AML.
 

Survival benefit

Dr. Roboz was a coinvestigator for the QUAZAR AML-001 trial (NCT01757535), results of which were reported at the 2019 ASH annual meeting. It was the first trial to show that a maintenance therapy with CC-486, an oral formulation of azacitidine, can improve overall survival in patients with AML in remission.

Among 472 patients with poor-risk AML in first complete remission who were not eligible for transplantation, median relapse-free survival was 10.2 months with CC-486 vs. 4.8 months with placebo plus best supportive care, and median overall survival with CC-486 was 24.7 months vs. 14.8 months, an absolute difference of 9.9 months.

This oral formulation of azacitidine was approved by U.S. Food and Drug Administration on Sept. 1, 2020 for use in adult patients with AML in complete remission or complete remission with incomplete blood count recovery following intensive induction chemotherapy and are not able to complete intensive curative therapy. It is sold under the trade name Onureg.

“This is likely to become now the standard of care for AML patients, for the group that was shown to benefit in the clinical trial,” Dr. Roboz said.

The drug was effective at prolonging relapse-free survival regardless of sex, age, remission status (complete remission or complete remission with incomplete blood count recovery) at randomization, cytogenetic risk category, or MRD status.

“We were very gratified to see that there was no reduction in health-related quality of life, which meant that the agent was tolerable, it could be continued for multiple cycles, and there are actually patients, including one of mine, who are many years out with ongoing therapy,” she said.

No funding source for the presentation was reported. Dr. Roboz disclosed consultancy/advisory board activity for multiple pharmaceutical companies; data safety and monitoring committee activity for MEI Pharma, Helsinn, and Takeda; and research funding from Cellectis.

Maintenance is a important component of therapy for acute lymphoblastic leukemia, but it’s still a relatively new concept in the treat of patients with acute myeloid leukemia (AML).

The topic of AML maintenance “has become quite hot actually, recently, after languishing for years behind ALL, a disease where maintenance is absolutely critical to overall survival; we haven’t had that much to talk about it in AML until recently,” said Gail J. Roboz, MD, from Weill Cornell Medicine and The New York Presbyterian Hospital, both in New York.

Dr. Roboz discussed her approach to AML maintenance during the virtual American Society of Hematology Meeting on Hematologic Malignancies.

The current AML treatment paradigm starts with remission induction via intensive or less-intensive therapies, followed by consolidation with chemotherapy or with autologous or allogeneic stem cell transplantation (SCT), with maintenance considered as a possibility for some patients.

“Strictly speaking, maintenance is the idea of keeping someone in remission, but we’ve gotten used to it that maintenance is postremission therapy that is different from what you had in your induction,” she noted. “That said, the exact nature of maintenance, while it most traditionally refers to an ongoing lower-intensity therapy, is a little bit complicated these days of what exactly constitutes maintenance.”

Current AML treatments generally fail to completely eliminate leukemic cells, so nearly all patients have remissions with minimal residual disease (MRD).

“You have a heterogeneous mix of leukemia stem cells, progenitors, blast cells, and you are in remission but there are still leftovers, and those leftovers result in disease relapse, and the goal of postremission therapy to basically target and hopefully eradicate the leftovers,” Dr. Roboz said.

Focusing on the postremission period is vital because most patients with AML will die within 1 year after disease relapse.
 

Many options, none great

National Comprehensive Cancer Network AML guidelines recommend a variety of approaches to postremission therapy for patients younger than 60 years with AML, including, depending on risk, either histone deacetylase inhibitors, gemtuzumab ozogamicin (Mylotarg), chemotherapy, and/or SCT, but none of these options, strictly speaking, is called maintenance, she noted.

For patients 60 years and older, “there’s also a likelihood of proceeding with hypomethylating [HMA]-based therapy in such a way that, if they’re responding to initial treatment, they get ongoing therapy with whatever HMA or hypomethylating-based regimen they’re responding to. So is that called maintenance? Is that called ongoing therapy? Continuing therapy? It’s a subject of some controversy,” she added.

For patients younger than 60, hematopoietic SCT has been the ultimate form of maintenance, and increasingly allogeneic SCT is being employed in the United States for patients older than 60 years, including those 70 years and older.

“That has been a good thing, because we’ve been able to offer more patients potentially curative therapy, but the problem is that allo transplant is not a free lunch either, and there are significant risks of nonrelapse mortality, especially for patients going into the transplant with other comorbidities,” Dr. Roboz said.

The majority of older patients may not be cured with transplant because of the use of reduced-intensity conditioning regimens with the result of extended disease-free survival but eventual relapse from residual disease.

“The question is, if you’re an older patient and you can’t get an ablative transplant and you do have residual disease, what’s the likelihood of actually being cured at 2 years, and do you really want to go through the headaches of having a transplant?” she said.
 

Nontransplant options

In the RATIFY trial, patients 60 years and younger with newly diagnosed AML with activating FLT3-mutations were randomized to induction chemotherapy with daunorubicin and cytarabine, consolidation with an histone deacetylase inhibitor, and then maintenance for up to 12 cycles with either midostaurin or placebo.

Although the trial met its primary endpoint of an improvement in overall survival with midostaurin (4-year overall survival, 51.4% vs. 44.3% with placebo), there is still uncertainty as to whether the observed survival benefit was caused by midostaurin or by something else, Dr. Roboz said.

“That said, it certainly has become common to use FLT3 inhibitors as postremission strategy for patients, with consolidation, with allo transplant, after allo transplant – wherever you can get the inhibitor in there,” she said.

The isocitrate dehydrogenase inhibitors ivosidenib (for IDH1) and enasidenib (IDH2) have also been tried in a postremission maintenance-like setting, but have thus far not been demonstrated in clinical trials to be effective in this setting, she added.

Gemtuzumab ozogamicin, an anti-CD33 antibody conjugated to calicheamicin, was approved in 2000 for adults 60 years and older with CD33+ AML in first remission, and in 2017 for adults with newly diagnosed CD33+ AML, as well as adults and children 2 years and older with relapsed or refractory CD33+ AML, but there are no data to show whether this antibody-drug conjugate could have benefit in a maintenance setting.

As previously reported, the combination of the BCL-2 inhibitor venetoclax (Venclexta) with azacitidine was associated with a significant improvement in overall survival, compared with azacitidine alone, in the VIALE-A trial.

“The question now is, in these studies most of the time patients are given a combination of aza and venetoclax that actually continues until they progress; is that called maintenance if you’re getting ongoing cycles? Not sure what to call it, but this is quite myelosuppressive, and there are many, many postremission modifications in dose and schedule that could take up a whole separate lecture,” Dr. Roboz commented.

She added, however, that the combination is effective across nearly all subgroups, and may be more generally applicable for maintenance-style therapy in older patients with AML.
 

Survival benefit

Dr. Roboz was a coinvestigator for the QUAZAR AML-001 trial (NCT01757535), results of which were reported at the 2019 ASH annual meeting. It was the first trial to show that a maintenance therapy with CC-486, an oral formulation of azacitidine, can improve overall survival in patients with AML in remission.

Among 472 patients with poor-risk AML in first complete remission who were not eligible for transplantation, median relapse-free survival was 10.2 months with CC-486 vs. 4.8 months with placebo plus best supportive care, and median overall survival with CC-486 was 24.7 months vs. 14.8 months, an absolute difference of 9.9 months.

This oral formulation of azacitidine was approved by U.S. Food and Drug Administration on Sept. 1, 2020 for use in adult patients with AML in complete remission or complete remission with incomplete blood count recovery following intensive induction chemotherapy and are not able to complete intensive curative therapy. It is sold under the trade name Onureg.

“This is likely to become now the standard of care for AML patients, for the group that was shown to benefit in the clinical trial,” Dr. Roboz said.

The drug was effective at prolonging relapse-free survival regardless of sex, age, remission status (complete remission or complete remission with incomplete blood count recovery) at randomization, cytogenetic risk category, or MRD status.

“We were very gratified to see that there was no reduction in health-related quality of life, which meant that the agent was tolerable, it could be continued for multiple cycles, and there are actually patients, including one of mine, who are many years out with ongoing therapy,” she said.

No funding source for the presentation was reported. Dr. Roboz disclosed consultancy/advisory board activity for multiple pharmaceutical companies; data safety and monitoring committee activity for MEI Pharma, Helsinn, and Takeda; and research funding from Cellectis.

Maintenance is a important component of therapy for acute lymphoblastic leukemia, but it’s still a relatively new concept in the treat of patients with acute myeloid leukemia (AML).

The topic of AML maintenance “has become quite hot actually, recently, after languishing for years behind ALL, a disease where maintenance is absolutely critical to overall survival; we haven’t had that much to talk about it in AML until recently,” said Gail J. Roboz, MD, from Weill Cornell Medicine and The New York Presbyterian Hospital, both in New York.

Dr. Roboz discussed her approach to AML maintenance during the virtual American Society of Hematology Meeting on Hematologic Malignancies.

The current AML treatment paradigm starts with remission induction via intensive or less-intensive therapies, followed by consolidation with chemotherapy or with autologous or allogeneic stem cell transplantation (SCT), with maintenance considered as a possibility for some patients.

“Strictly speaking, maintenance is the idea of keeping someone in remission, but we’ve gotten used to it that maintenance is postremission therapy that is different from what you had in your induction,” she noted. “That said, the exact nature of maintenance, while it most traditionally refers to an ongoing lower-intensity therapy, is a little bit complicated these days of what exactly constitutes maintenance.”

Current AML treatments generally fail to completely eliminate leukemic cells, so nearly all patients have remissions with minimal residual disease (MRD).

“You have a heterogeneous mix of leukemia stem cells, progenitors, blast cells, and you are in remission but there are still leftovers, and those leftovers result in disease relapse, and the goal of postremission therapy to basically target and hopefully eradicate the leftovers,” Dr. Roboz said.

Focusing on the postremission period is vital because most patients with AML will die within 1 year after disease relapse.
 

Many options, none great

National Comprehensive Cancer Network AML guidelines recommend a variety of approaches to postremission therapy for patients younger than 60 years with AML, including, depending on risk, either histone deacetylase inhibitors, gemtuzumab ozogamicin (Mylotarg), chemotherapy, and/or SCT, but none of these options, strictly speaking, is called maintenance, she noted.

For patients 60 years and older, “there’s also a likelihood of proceeding with hypomethylating [HMA]-based therapy in such a way that, if they’re responding to initial treatment, they get ongoing therapy with whatever HMA or hypomethylating-based regimen they’re responding to. So is that called maintenance? Is that called ongoing therapy? Continuing therapy? It’s a subject of some controversy,” she added.

For patients younger than 60, hematopoietic SCT has been the ultimate form of maintenance, and increasingly allogeneic SCT is being employed in the United States for patients older than 60 years, including those 70 years and older.

“That has been a good thing, because we’ve been able to offer more patients potentially curative therapy, but the problem is that allo transplant is not a free lunch either, and there are significant risks of nonrelapse mortality, especially for patients going into the transplant with other comorbidities,” Dr. Roboz said.

The majority of older patients may not be cured with transplant because of the use of reduced-intensity conditioning regimens with the result of extended disease-free survival but eventual relapse from residual disease.

“The question is, if you’re an older patient and you can’t get an ablative transplant and you do have residual disease, what’s the likelihood of actually being cured at 2 years, and do you really want to go through the headaches of having a transplant?” she said.
 

Nontransplant options

In the RATIFY trial, patients 60 years and younger with newly diagnosed AML with activating FLT3-mutations were randomized to induction chemotherapy with daunorubicin and cytarabine, consolidation with an histone deacetylase inhibitor, and then maintenance for up to 12 cycles with either midostaurin or placebo.

Although the trial met its primary endpoint of an improvement in overall survival with midostaurin (4-year overall survival, 51.4% vs. 44.3% with placebo), there is still uncertainty as to whether the observed survival benefit was caused by midostaurin or by something else, Dr. Roboz said.

“That said, it certainly has become common to use FLT3 inhibitors as postremission strategy for patients, with consolidation, with allo transplant, after allo transplant – wherever you can get the inhibitor in there,” she said.

The isocitrate dehydrogenase inhibitors ivosidenib (for IDH1) and enasidenib (IDH2) have also been tried in a postremission maintenance-like setting, but have thus far not been demonstrated in clinical trials to be effective in this setting, she added.

Gemtuzumab ozogamicin, an anti-CD33 antibody conjugated to calicheamicin, was approved in 2000 for adults 60 years and older with CD33+ AML in first remission, and in 2017 for adults with newly diagnosed CD33+ AML, as well as adults and children 2 years and older with relapsed or refractory CD33+ AML, but there are no data to show whether this antibody-drug conjugate could have benefit in a maintenance setting.

As previously reported, the combination of the BCL-2 inhibitor venetoclax (Venclexta) with azacitidine was associated with a significant improvement in overall survival, compared with azacitidine alone, in the VIALE-A trial.

“The question now is, in these studies most of the time patients are given a combination of aza and venetoclax that actually continues until they progress; is that called maintenance if you’re getting ongoing cycles? Not sure what to call it, but this is quite myelosuppressive, and there are many, many postremission modifications in dose and schedule that could take up a whole separate lecture,” Dr. Roboz commented.

She added, however, that the combination is effective across nearly all subgroups, and may be more generally applicable for maintenance-style therapy in older patients with AML.
 

Survival benefit

Dr. Roboz was a coinvestigator for the QUAZAR AML-001 trial (NCT01757535), results of which were reported at the 2019 ASH annual meeting. It was the first trial to show that a maintenance therapy with CC-486, an oral formulation of azacitidine, can improve overall survival in patients with AML in remission.

Among 472 patients with poor-risk AML in first complete remission who were not eligible for transplantation, median relapse-free survival was 10.2 months with CC-486 vs. 4.8 months with placebo plus best supportive care, and median overall survival with CC-486 was 24.7 months vs. 14.8 months, an absolute difference of 9.9 months.

This oral formulation of azacitidine was approved by U.S. Food and Drug Administration on Sept. 1, 2020 for use in adult patients with AML in complete remission or complete remission with incomplete blood count recovery following intensive induction chemotherapy and are not able to complete intensive curative therapy. It is sold under the trade name Onureg.

“This is likely to become now the standard of care for AML patients, for the group that was shown to benefit in the clinical trial,” Dr. Roboz said.

The drug was effective at prolonging relapse-free survival regardless of sex, age, remission status (complete remission or complete remission with incomplete blood count recovery) at randomization, cytogenetic risk category, or MRD status.

“We were very gratified to see that there was no reduction in health-related quality of life, which meant that the agent was tolerable, it could be continued for multiple cycles, and there are actually patients, including one of mine, who are many years out with ongoing therapy,” she said.

No funding source for the presentation was reported. Dr. Roboz disclosed consultancy/advisory board activity for multiple pharmaceutical companies; data safety and monitoring committee activity for MEI Pharma, Helsinn, and Takeda; and research funding from Cellectis.

Several recently approved and late-phase investigational agents may improve care for patients with higher risk myelodysplastic syndrome (MDS) by augmenting hypomethylating agents (HMAs), which are the current standard of care.

“HMA failure remains a challenge, and new approaches, such as ex vivo drug screening, are needed to improve outcomes,” said Brian A. Jonas, MD, PhD, from the University of California, Davis, in an online presentation during the virtual American Society of Hematology (ASH) Meeting on Hematologic Malignancies.

The goal of treatment for patients with higher-risk MDS – defined as a Revised International Prognostic Scoring System (R-IPSS) intermediate, high-risk, or very high–risk category – is to alter as much as possible the natural history of the disease.

Treatment options include monotherapy with HMAs, HMAs in combination with other agents, high-intensity chemotherapy, allogeneic hematopoietic stem cell transplant (allo-HSCT), or a clinical trial, Dr. Jonas said.
 

Improving bioavailability

Although HMAs, either azacitidine or decitabine, remain the standard of care for patients with higher-risk MDS, the oral bioavailability of these agents is limited by the rapid clearance of cytidine deaminase in the gut and liver.

But as Savona and colleagues reported in The Lancet Haematology, the combination of oral decitabine with cedazuridine, a novel cytidine deaminase inhibitor, significantly improved the bioavailability of the HMA, with an efficacy comparable to that of intravenous decitabine. The findings were confirmed by results from the phase 2 ASCERTAIN trial.

The combination (Inqovi) was approved by the US Food and Drug Administration in July 2020 for the treatment of MDS and chronic myelomonocytic leukemia in IPSS intermediate-1 or higher risk categories. The approved dose is 35 mg decitabine and 100 mg cedazuridine in a single oral tablet once daily on days 1 through 5 of each 28-day cycle.
 

New drugs, potential new targets

Another promising approach to improving HMA therapy is the combination of azacitidine and the BCL-2 inhibitor venetoclax (Venclexta).

Results of a phase 1b study of the combination as first-line therapy for patients with higher-risk MDS showed a combined complete response and marrow complete response rate of 77.2%, with estimated 6-month and 12-month survival rates of 100% and 93.8%, respectively, for patients who had a complete response and 85.9% at both 6 and 12 months for patients with a marrow complete response.

“The question is does this challenge the standard of care for higher-risk MDS? I would argue that many are using the regimen since the abstract came out, and I myself consider this regimen for use in select patients with high–blast count MDS who are maybe going to transplant or need to have their disease controlled rapidly,” Dr. Jonas said.

A randomized trial of the combination (NCT04401748) is currently recruiting.
 

Novel checkpoint inhibitor

Another promising combination pairs azacitidine with magrolimab, an experimental immune checkpoint inhibitor that targets CD47, the “don’t eat me” signal that inhibits macrophages from carrying out their crucial phagocytosis role.

As previously reported, magrolimab in combination with rituximab showed good efficacy in patients with relapsed or refractory indolent or aggressive non-Hodgkin lymphomas, and more recently showed promise in combination with azacitidine in a phase 1b study for the treatment of MDS and acute myeloid leukemia (AML).

Among patients with MDS in the trial, the overall response rate was 91% (30 of 33 patients). In all, 14 patients had complete responses, one had a partial response, eight had marrow complete responses, and seven had hematologic improvement.

The tolerability profile was similar to that seen with azacitidine monotherapy, with no significant worsening of cytopenias or infections or autoimmune adverse events. There were no deaths in the first 60 days on therapy, and no treatment discontinuation for drug-related adverse events.

Azacitidine was paired with a different novel agent, APR-246 in a clinical trial testing the combination in patients with TP53 mutant MDS and AML. APR-246 is a novel, first-in-class small molecule that binds covalently to p53, and selectively induces apoptosis in metastatic TP53 cells via thermodynamically stabilizing the p53 protein and shifting equilibrium toward the wild-type conformation.

Among 33 evaluable patients with higher-risk MDS, the combination was associated with an overall response in 29 (81%) including 20 patients (61%) with a complete response. After a median follow-up of 10.8 months, the median duration of response was 7.3 months, and 17 patients went on to allo-HSCT.

The combination of magrolimab and azacitidine has also shown preliminary activity in TP53-mutated MDS, Dr. Jonas noted.
 

HMA-refractory disease

Patients who experience disease progression to AML or to higher-risk MDS; have stable disease but no complete, partial, or marrow responses; or have hematologic improvement after four to six cycles of HMA may have primary resistance to this class of agents. Patients can also have disease that develops resistance to HMAs after an initial response.

“Unfortunately, the prognosis is very dismal for these patients,” with a median overall survival of 5.6 months and 2-year overall survival of just 15%, Dr. Jonas said.

As reported at the 2019 ASH annual meeting, in patients with relapsed/refractory MDS, venetoclax plus azacitidine was associated with a median progression-free survival of 9.1 months versus 3.3 months for venetoclax alone, and a median overall survival for the combination that was not reached, with a 12-month overall survival estimate of 65%. The median overall survival with venetoclax monotherapy was 5.5 months.

Adverse events included cytopenias, gastrointestinal events, and infections in both arms (ASH 2019 Abstract 565).

There are also data to suggest benefits of the isocitrate dehydrogenase inhibitors ivosidenib in patients with HMA-refractory MDS with IDH1 mutations and enasidenib in patients with HMA-refractory MDS with IDH2 mutations, Dr. Jonas said.

Finally, he described a pilot and feasibility study of ex vivo screening of myeloid neoplasms for drug sensitivity conducted at Stanford (Calif.) University. In 21 patients with HMA-refractory MDS, the ex vivo screening system provided results in a clinically actionable time frame comparable to that of a 596-gene panel. The positive predictive value of the screen was 92%, the negative predictive value was 82%, and the accuracy was 85%.

“This looks like a potentially promising approach to offer personalized therapy in patients with MDS,” he said.

No funding source for the presentation was reported. Dr. Jonas disclosed consulting activities for AbbVie, Celgen, GlycoMimetics, Jazz, Takeda, Tolero, and Treadwell; institutional research funding from multiple companies; and discussion of off-label use of various drugs not specifically approved for MDS.

Several recently approved and late-phase investigational agents may improve care for patients with higher risk myelodysplastic syndrome (MDS) by augmenting hypomethylating agents (HMAs), which are the current standard of care.

“HMA failure remains a challenge, and new approaches, such as ex vivo drug screening, are needed to improve outcomes,” said Brian A. Jonas, MD, PhD, from the University of California, Davis, in an online presentation during the virtual American Society of Hematology (ASH) Meeting on Hematologic Malignancies.

The goal of treatment for patients with higher-risk MDS – defined as a Revised International Prognostic Scoring System (R-IPSS) intermediate, high-risk, or very high–risk category – is to alter as much as possible the natural history of the disease.

Treatment options include monotherapy with HMAs, HMAs in combination with other agents, high-intensity chemotherapy, allogeneic hematopoietic stem cell transplant (allo-HSCT), or a clinical trial, Dr. Jonas said.
 

Improving bioavailability

Although HMAs, either azacitidine or decitabine, remain the standard of care for patients with higher-risk MDS, the oral bioavailability of these agents is limited by the rapid clearance of cytidine deaminase in the gut and liver.

But as Savona and colleagues reported in The Lancet Haematology, the combination of oral decitabine with cedazuridine, a novel cytidine deaminase inhibitor, significantly improved the bioavailability of the HMA, with an efficacy comparable to that of intravenous decitabine. The findings were confirmed by results from the phase 2 ASCERTAIN trial.

The combination (Inqovi) was approved by the US Food and Drug Administration in July 2020 for the treatment of MDS and chronic myelomonocytic leukemia in IPSS intermediate-1 or higher risk categories. The approved dose is 35 mg decitabine and 100 mg cedazuridine in a single oral tablet once daily on days 1 through 5 of each 28-day cycle.
 

New drugs, potential new targets

Another promising approach to improving HMA therapy is the combination of azacitidine and the BCL-2 inhibitor venetoclax (Venclexta).

Results of a phase 1b study of the combination as first-line therapy for patients with higher-risk MDS showed a combined complete response and marrow complete response rate of 77.2%, with estimated 6-month and 12-month survival rates of 100% and 93.8%, respectively, for patients who had a complete response and 85.9% at both 6 and 12 months for patients with a marrow complete response.

“The question is does this challenge the standard of care for higher-risk MDS? I would argue that many are using the regimen since the abstract came out, and I myself consider this regimen for use in select patients with high–blast count MDS who are maybe going to transplant or need to have their disease controlled rapidly,” Dr. Jonas said.

A randomized trial of the combination (NCT04401748) is currently recruiting.
 

Novel checkpoint inhibitor

Another promising combination pairs azacitidine with magrolimab, an experimental immune checkpoint inhibitor that targets CD47, the “don’t eat me” signal that inhibits macrophages from carrying out their crucial phagocytosis role.

As previously reported, magrolimab in combination with rituximab showed good efficacy in patients with relapsed or refractory indolent or aggressive non-Hodgkin lymphomas, and more recently showed promise in combination with azacitidine in a phase 1b study for the treatment of MDS and acute myeloid leukemia (AML).

Among patients with MDS in the trial, the overall response rate was 91% (30 of 33 patients). In all, 14 patients had complete responses, one had a partial response, eight had marrow complete responses, and seven had hematologic improvement.

The tolerability profile was similar to that seen with azacitidine monotherapy, with no significant worsening of cytopenias or infections or autoimmune adverse events. There were no deaths in the first 60 days on therapy, and no treatment discontinuation for drug-related adverse events.

Azacitidine was paired with a different novel agent, APR-246 in a clinical trial testing the combination in patients with TP53 mutant MDS and AML. APR-246 is a novel, first-in-class small molecule that binds covalently to p53, and selectively induces apoptosis in metastatic TP53 cells via thermodynamically stabilizing the p53 protein and shifting equilibrium toward the wild-type conformation.

Among 33 evaluable patients with higher-risk MDS, the combination was associated with an overall response in 29 (81%) including 20 patients (61%) with a complete response. After a median follow-up of 10.8 months, the median duration of response was 7.3 months, and 17 patients went on to allo-HSCT.

The combination of magrolimab and azacitidine has also shown preliminary activity in TP53-mutated MDS, Dr. Jonas noted.
 

HMA-refractory disease

Patients who experience disease progression to AML or to higher-risk MDS; have stable disease but no complete, partial, or marrow responses; or have hematologic improvement after four to six cycles of HMA may have primary resistance to this class of agents. Patients can also have disease that develops resistance to HMAs after an initial response.

“Unfortunately, the prognosis is very dismal for these patients,” with a median overall survival of 5.6 months and 2-year overall survival of just 15%, Dr. Jonas said.

As reported at the 2019 ASH annual meeting, in patients with relapsed/refractory MDS, venetoclax plus azacitidine was associated with a median progression-free survival of 9.1 months versus 3.3 months for venetoclax alone, and a median overall survival for the combination that was not reached, with a 12-month overall survival estimate of 65%. The median overall survival with venetoclax monotherapy was 5.5 months.

Adverse events included cytopenias, gastrointestinal events, and infections in both arms (ASH 2019 Abstract 565).

There are also data to suggest benefits of the isocitrate dehydrogenase inhibitors ivosidenib in patients with HMA-refractory MDS with IDH1 mutations and enasidenib in patients with HMA-refractory MDS with IDH2 mutations, Dr. Jonas said.

Finally, he described a pilot and feasibility study of ex vivo screening of myeloid neoplasms for drug sensitivity conducted at Stanford (Calif.) University. In 21 patients with HMA-refractory MDS, the ex vivo screening system provided results in a clinically actionable time frame comparable to that of a 596-gene panel. The positive predictive value of the screen was 92%, the negative predictive value was 82%, and the accuracy was 85%.

“This looks like a potentially promising approach to offer personalized therapy in patients with MDS,” he said.

No funding source for the presentation was reported. Dr. Jonas disclosed consulting activities for AbbVie, Celgen, GlycoMimetics, Jazz, Takeda, Tolero, and Treadwell; institutional research funding from multiple companies; and discussion of off-label use of various drugs not specifically approved for MDS.

Several recently approved and late-phase investigational agents may improve care for patients with higher risk myelodysplastic syndrome (MDS) by augmenting hypomethylating agents (HMAs), which are the current standard of care.

“HMA failure remains a challenge, and new approaches, such as ex vivo drug screening, are needed to improve outcomes,” said Brian A. Jonas, MD, PhD, from the University of California, Davis, in an online presentation during the virtual American Society of Hematology (ASH) Meeting on Hematologic Malignancies.

The goal of treatment for patients with higher-risk MDS – defined as a Revised International Prognostic Scoring System (R-IPSS) intermediate, high-risk, or very high–risk category – is to alter as much as possible the natural history of the disease.

Treatment options include monotherapy with HMAs, HMAs in combination with other agents, high-intensity chemotherapy, allogeneic hematopoietic stem cell transplant (allo-HSCT), or a clinical trial, Dr. Jonas said.
 

Improving bioavailability

Although HMAs, either azacitidine or decitabine, remain the standard of care for patients with higher-risk MDS, the oral bioavailability of these agents is limited by the rapid clearance of cytidine deaminase in the gut and liver.

But as Savona and colleagues reported in The Lancet Haematology, the combination of oral decitabine with cedazuridine, a novel cytidine deaminase inhibitor, significantly improved the bioavailability of the HMA, with an efficacy comparable to that of intravenous decitabine. The findings were confirmed by results from the phase 2 ASCERTAIN trial.

The combination (Inqovi) was approved by the US Food and Drug Administration in July 2020 for the treatment of MDS and chronic myelomonocytic leukemia in IPSS intermediate-1 or higher risk categories. The approved dose is 35 mg decitabine and 100 mg cedazuridine in a single oral tablet once daily on days 1 through 5 of each 28-day cycle.
 

New drugs, potential new targets

Another promising approach to improving HMA therapy is the combination of azacitidine and the BCL-2 inhibitor venetoclax (Venclexta).

Results of a phase 1b study of the combination as first-line therapy for patients with higher-risk MDS showed a combined complete response and marrow complete response rate of 77.2%, with estimated 6-month and 12-month survival rates of 100% and 93.8%, respectively, for patients who had a complete response and 85.9% at both 6 and 12 months for patients with a marrow complete response.

“The question is does this challenge the standard of care for higher-risk MDS? I would argue that many are using the regimen since the abstract came out, and I myself consider this regimen for use in select patients with high–blast count MDS who are maybe going to transplant or need to have their disease controlled rapidly,” Dr. Jonas said.

A randomized trial of the combination (NCT04401748) is currently recruiting.
 

Novel checkpoint inhibitor

Another promising combination pairs azacitidine with magrolimab, an experimental immune checkpoint inhibitor that targets CD47, the “don’t eat me” signal that inhibits macrophages from carrying out their crucial phagocytosis role.

As previously reported, magrolimab in combination with rituximab showed good efficacy in patients with relapsed or refractory indolent or aggressive non-Hodgkin lymphomas, and more recently showed promise in combination with azacitidine in a phase 1b study for the treatment of MDS and acute myeloid leukemia (AML).

Among patients with MDS in the trial, the overall response rate was 91% (30 of 33 patients). In all, 14 patients had complete responses, one had a partial response, eight had marrow complete responses, and seven had hematologic improvement.

The tolerability profile was similar to that seen with azacitidine monotherapy, with no significant worsening of cytopenias or infections or autoimmune adverse events. There were no deaths in the first 60 days on therapy, and no treatment discontinuation for drug-related adverse events.

Azacitidine was paired with a different novel agent, APR-246 in a clinical trial testing the combination in patients with TP53 mutant MDS and AML. APR-246 is a novel, first-in-class small molecule that binds covalently to p53, and selectively induces apoptosis in metastatic TP53 cells via thermodynamically stabilizing the p53 protein and shifting equilibrium toward the wild-type conformation.

Among 33 evaluable patients with higher-risk MDS, the combination was associated with an overall response in 29 (81%) including 20 patients (61%) with a complete response. After a median follow-up of 10.8 months, the median duration of response was 7.3 months, and 17 patients went on to allo-HSCT.

The combination of magrolimab and azacitidine has also shown preliminary activity in TP53-mutated MDS, Dr. Jonas noted.
 

HMA-refractory disease

Patients who experience disease progression to AML or to higher-risk MDS; have stable disease but no complete, partial, or marrow responses; or have hematologic improvement after four to six cycles of HMA may have primary resistance to this class of agents. Patients can also have disease that develops resistance to HMAs after an initial response.

“Unfortunately, the prognosis is very dismal for these patients,” with a median overall survival of 5.6 months and 2-year overall survival of just 15%, Dr. Jonas said.

As reported at the 2019 ASH annual meeting, in patients with relapsed/refractory MDS, venetoclax plus azacitidine was associated with a median progression-free survival of 9.1 months versus 3.3 months for venetoclax alone, and a median overall survival for the combination that was not reached, with a 12-month overall survival estimate of 65%. The median overall survival with venetoclax monotherapy was 5.5 months.

Adverse events included cytopenias, gastrointestinal events, and infections in both arms (ASH 2019 Abstract 565).

There are also data to suggest benefits of the isocitrate dehydrogenase inhibitors ivosidenib in patients with HMA-refractory MDS with IDH1 mutations and enasidenib in patients with HMA-refractory MDS with IDH2 mutations, Dr. Jonas said.

Finally, he described a pilot and feasibility study of ex vivo screening of myeloid neoplasms for drug sensitivity conducted at Stanford (Calif.) University. In 21 patients with HMA-refractory MDS, the ex vivo screening system provided results in a clinically actionable time frame comparable to that of a 596-gene panel. The positive predictive value of the screen was 92%, the negative predictive value was 82%, and the accuracy was 85%.

“This looks like a potentially promising approach to offer personalized therapy in patients with MDS,” he said.

No funding source for the presentation was reported. Dr. Jonas disclosed consulting activities for AbbVie, Celgen, GlycoMimetics, Jazz, Takeda, Tolero, and Treadwell; institutional research funding from multiple companies; and discussion of off-label use of various drugs not specifically approved for MDS.

Adding tyrosine kinase inhibitors to the treatment of patients with Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ALL) has significantly improved outcomes in recent years, but it’s still unclear which patients will also benefit from bone marrow transplants, and whether chemotherapy will gradually fade into the therapeutic background, a leukemia researcher contended.

“I think it’s likely in future that we’re going to use less chemotherapy, and more combinations of TKI and antibody-based therapy,” said Anjali S. Advani, MD, of the Cleveland Clinic Taussig Cancer Institute.

Dr. Advani discussed her approach to treating both fit and frail patients with Ph+ALL during the virtual American Society of Hematology (ASH) Meeting on Hematologic Malignancies.

Increasing understanding of the importance of eliminating minimal residual disease (MRD) colors decisions about the best TKI to use in the first line.

“In terms of which TKI to use in the upfront setting, no randomized study has been done, but since MRD is associated with improved response, we often use this data to make a decision,” she said. “This, however, is complicated, because TKIs are combined with chemotherapy, there are many new TKIs, and finally, although we can start with one TKI, we can change to another TKI if we see that a patient is not responding appropriately.”

With the use of second-generation TKIs in combination with chemotherapy, rates of complete molecular remission (CMR) and major molecular remission (MMR) improved significantly over those seen with the first-in-class agent imatinib.

Notably, she said, the combination of ponatinib (Iclusig) with steroids as frontline therapy for elderly or frail patients with Ph+ALL was associated with a 60.5% CMR at week 24 in a phase 2 Italian trial (Blood 2017;130[Suppl. 1]:99).

Combining ponatinib with the hyper-CVAD regimen (cyclophosphamide, vincristine, doxorubicin, dexamethasone) improved the 3-month CMR rate to 74% and, the MMR rate to 15% (Lancet Haematol Dec. 2018 Dec 1;5[12]:e618-e627).

A 2016 propensity-score analysis comparing hyper-CVAD plus ponatinib with the hyper-CVAD plus dasatinib showed significantly better event-free survival (P = .035) and overall survival (P = .025) with the ponatinib-containing combination (Cancer 2016;122[23]:3650-6).

As with all potent regimens, however, the combination of hyper-CVAD and ponatinib is associated with relatively high percentages of grade 3 or greater nonhematologic toxicities, including transaminase and bilirubin elevation, pancreatitis, hypertension, venous thromboembolic events and arterial cardiovascular events.
 

Transplants in the TKI era

Prior to the advent of TKIs, there was strong evidence of the benefit of allogeneic stem cell transplant in patients with Ph+ALL in first remission (BMT 2003;31:623-32).

“The question is, now that we use TKIs, should we be transplanting patients still?” Dr. Advani said.

In the U.S. intergroup S0805 study looking at the combination of dasatinib and chemotherapy, there were distinct relapse-free and overall survival benefits for patients who underwent transplant. This trial did not evaluate MRD, however, ”so what we don’t know is for those patients achieving a complete molecular remission, would those patients do okay without transplant?” she said.

The current standard of care at Cleveland Clinic is to transplant eligible patients in first remission, ”but I think that’s likely to change as we get more data from these trials.”

In the COG AALL0031 trial of imatinib and chemotherapy in children with Ph+ALL, there was no significant benefit to stem cell transplant (Leukemia 2014 Jan 20;28:1467-71), Dr. Advani noted.

Other prognostic features associated with poor risk, such as 1KZF1 mutations with CDKN2A and/or PAX5 deletions, have been suggested as indicators for transplant, but “what’s less clear is what the impact of these abnormalities is now with the second- and third-generation TKIs, and also whether these various abnormalities correlate with molecular responses or achievement of complete molecular remission,” she said.


 

Frail/unfit patients

Therapeutic options for frail or unfit patients include the combination of dasatinib and prednisone, which was associated in one study with a 93% complete hematologic remission rate by day 22, and at 20 months with a 69.2% overall survival rate, and 51.1% disease-free survival rate.(Blood. 2011;118[25]:6521-8).

In this study MRD correlated with disease-free survival, but 23 of 53 patients experienced relapse, and 12 patients with relapsed disease had the T3151 mutation. Ponatinib would be a second-line option for this latter group of patients, Dr. Advani said.

A study reported at the 2017 ASH annual meeting looked at the combination of ponatinib with steroids in patients either 60 and older or younger unfit patients with Ph+ALL.

The primary endpoint of complete hematological response at 24 weeks in at least 75% of patients was reached early, with 40 of 42 patients (95.2%) having a complete hematologic response after 1 course of therapy (6 weeks). The CMR rate at 24 weeks was 61%, and 1-year overall survival was 87.5%.

There were 13 serious adverse events related to ponatinib, however, including one death, and one patient who experienced a relapse was found to have the T315L ponatinib-resistance mutation. (Blood 2017 Dec. 7;130[Suppl. 1]:99).

“I think a few things with ponatinib and steroids that we still don’t know are the long-term follow-up results of this as a single agent in combination with steroids, and second, in this elderly population, if you look, patients are dropping out due to adverse events and toxicities,” she said.
 

TKIs plus antibodies

The S1318 trial conducted by the SWOG cancer research network contains both a Ph+ALL and a Ph-negative ALL cohort. In this trial, patients with Ph+ALL receive dasatinib and steroids as induction, then go on to receive blinatumomab (Blincyto) with dasatinib for three cycles, followed by maintenance therapy with dasitinib and prednisone.

A trial currently in the planning stages, EA9181, will compare in a randomized fashion induction regimens with either dasatinib or ponatinib at the investigator’s discretion with steroids and either blinatumomab or chemotherapy.

No funding source was reported for the presentation. Dr. Advani disclosed steering committee activities, honoraria/consulting, and research funding from multiple companies.

Adding tyrosine kinase inhibitors to the treatment of patients with Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ALL) has significantly improved outcomes in recent years, but it’s still unclear which patients will also benefit from bone marrow transplants, and whether chemotherapy will gradually fade into the therapeutic background, a leukemia researcher contended.

“I think it’s likely in future that we’re going to use less chemotherapy, and more combinations of TKI and antibody-based therapy,” said Anjali S. Advani, MD, of the Cleveland Clinic Taussig Cancer Institute.

Dr. Advani discussed her approach to treating both fit and frail patients with Ph+ALL during the virtual American Society of Hematology (ASH) Meeting on Hematologic Malignancies.

Increasing understanding of the importance of eliminating minimal residual disease (MRD) colors decisions about the best TKI to use in the first line.

“In terms of which TKI to use in the upfront setting, no randomized study has been done, but since MRD is associated with improved response, we often use this data to make a decision,” she said. “This, however, is complicated, because TKIs are combined with chemotherapy, there are many new TKIs, and finally, although we can start with one TKI, we can change to another TKI if we see that a patient is not responding appropriately.”

With the use of second-generation TKIs in combination with chemotherapy, rates of complete molecular remission (CMR) and major molecular remission (MMR) improved significantly over those seen with the first-in-class agent imatinib.

Notably, she said, the combination of ponatinib (Iclusig) with steroids as frontline therapy for elderly or frail patients with Ph+ALL was associated with a 60.5% CMR at week 24 in a phase 2 Italian trial (Blood 2017;130[Suppl. 1]:99).

Combining ponatinib with the hyper-CVAD regimen (cyclophosphamide, vincristine, doxorubicin, dexamethasone) improved the 3-month CMR rate to 74% and, the MMR rate to 15% (Lancet Haematol Dec. 2018 Dec 1;5[12]:e618-e627).

A 2016 propensity-score analysis comparing hyper-CVAD plus ponatinib with the hyper-CVAD plus dasatinib showed significantly better event-free survival (P = .035) and overall survival (P = .025) with the ponatinib-containing combination (Cancer 2016;122[23]:3650-6).

As with all potent regimens, however, the combination of hyper-CVAD and ponatinib is associated with relatively high percentages of grade 3 or greater nonhematologic toxicities, including transaminase and bilirubin elevation, pancreatitis, hypertension, venous thromboembolic events and arterial cardiovascular events.
 

Transplants in the TKI era

Prior to the advent of TKIs, there was strong evidence of the benefit of allogeneic stem cell transplant in patients with Ph+ALL in first remission (BMT 2003;31:623-32).

“The question is, now that we use TKIs, should we be transplanting patients still?” Dr. Advani said.

In the U.S. intergroup S0805 study looking at the combination of dasatinib and chemotherapy, there were distinct relapse-free and overall survival benefits for patients who underwent transplant. This trial did not evaluate MRD, however, ”so what we don’t know is for those patients achieving a complete molecular remission, would those patients do okay without transplant?” she said.

The current standard of care at Cleveland Clinic is to transplant eligible patients in first remission, ”but I think that’s likely to change as we get more data from these trials.”

In the COG AALL0031 trial of imatinib and chemotherapy in children with Ph+ALL, there was no significant benefit to stem cell transplant (Leukemia 2014 Jan 20;28:1467-71), Dr. Advani noted.

Other prognostic features associated with poor risk, such as 1KZF1 mutations with CDKN2A and/or PAX5 deletions, have been suggested as indicators for transplant, but “what’s less clear is what the impact of these abnormalities is now with the second- and third-generation TKIs, and also whether these various abnormalities correlate with molecular responses or achievement of complete molecular remission,” she said.


 

Frail/unfit patients

Therapeutic options for frail or unfit patients include the combination of dasatinib and prednisone, which was associated in one study with a 93% complete hematologic remission rate by day 22, and at 20 months with a 69.2% overall survival rate, and 51.1% disease-free survival rate.(Blood. 2011;118[25]:6521-8).

In this study MRD correlated with disease-free survival, but 23 of 53 patients experienced relapse, and 12 patients with relapsed disease had the T3151 mutation. Ponatinib would be a second-line option for this latter group of patients, Dr. Advani said.

A study reported at the 2017 ASH annual meeting looked at the combination of ponatinib with steroids in patients either 60 and older or younger unfit patients with Ph+ALL.

The primary endpoint of complete hematological response at 24 weeks in at least 75% of patients was reached early, with 40 of 42 patients (95.2%) having a complete hematologic response after 1 course of therapy (6 weeks). The CMR rate at 24 weeks was 61%, and 1-year overall survival was 87.5%.

There were 13 serious adverse events related to ponatinib, however, including one death, and one patient who experienced a relapse was found to have the T315L ponatinib-resistance mutation. (Blood 2017 Dec. 7;130[Suppl. 1]:99).

“I think a few things with ponatinib and steroids that we still don’t know are the long-term follow-up results of this as a single agent in combination with steroids, and second, in this elderly population, if you look, patients are dropping out due to adverse events and toxicities,” she said.
 

TKIs plus antibodies

The S1318 trial conducted by the SWOG cancer research network contains both a Ph+ALL and a Ph-negative ALL cohort. In this trial, patients with Ph+ALL receive dasatinib and steroids as induction, then go on to receive blinatumomab (Blincyto) with dasatinib for three cycles, followed by maintenance therapy with dasitinib and prednisone.

A trial currently in the planning stages, EA9181, will compare in a randomized fashion induction regimens with either dasatinib or ponatinib at the investigator’s discretion with steroids and either blinatumomab or chemotherapy.

No funding source was reported for the presentation. Dr. Advani disclosed steering committee activities, honoraria/consulting, and research funding from multiple companies.

Adding tyrosine kinase inhibitors to the treatment of patients with Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ALL) has significantly improved outcomes in recent years, but it’s still unclear which patients will also benefit from bone marrow transplants, and whether chemotherapy will gradually fade into the therapeutic background, a leukemia researcher contended.

“I think it’s likely in future that we’re going to use less chemotherapy, and more combinations of TKI and antibody-based therapy,” said Anjali S. Advani, MD, of the Cleveland Clinic Taussig Cancer Institute.

Dr. Advani discussed her approach to treating both fit and frail patients with Ph+ALL during the virtual American Society of Hematology (ASH) Meeting on Hematologic Malignancies.

Increasing understanding of the importance of eliminating minimal residual disease (MRD) colors decisions about the best TKI to use in the first line.

“In terms of which TKI to use in the upfront setting, no randomized study has been done, but since MRD is associated with improved response, we often use this data to make a decision,” she said. “This, however, is complicated, because TKIs are combined with chemotherapy, there are many new TKIs, and finally, although we can start with one TKI, we can change to another TKI if we see that a patient is not responding appropriately.”

With the use of second-generation TKIs in combination with chemotherapy, rates of complete molecular remission (CMR) and major molecular remission (MMR) improved significantly over those seen with the first-in-class agent imatinib.

Notably, she said, the combination of ponatinib (Iclusig) with steroids as frontline therapy for elderly or frail patients with Ph+ALL was associated with a 60.5% CMR at week 24 in a phase 2 Italian trial (Blood 2017;130[Suppl. 1]:99).

Combining ponatinib with the hyper-CVAD regimen (cyclophosphamide, vincristine, doxorubicin, dexamethasone) improved the 3-month CMR rate to 74% and, the MMR rate to 15% (Lancet Haematol Dec. 2018 Dec 1;5[12]:e618-e627).

A 2016 propensity-score analysis comparing hyper-CVAD plus ponatinib with the hyper-CVAD plus dasatinib showed significantly better event-free survival (P = .035) and overall survival (P = .025) with the ponatinib-containing combination (Cancer 2016;122[23]:3650-6).

As with all potent regimens, however, the combination of hyper-CVAD and ponatinib is associated with relatively high percentages of grade 3 or greater nonhematologic toxicities, including transaminase and bilirubin elevation, pancreatitis, hypertension, venous thromboembolic events and arterial cardiovascular events.
 

Transplants in the TKI era

Prior to the advent of TKIs, there was strong evidence of the benefit of allogeneic stem cell transplant in patients with Ph+ALL in first remission (BMT 2003;31:623-32).

“The question is, now that we use TKIs, should we be transplanting patients still?” Dr. Advani said.

In the U.S. intergroup S0805 study looking at the combination of dasatinib and chemotherapy, there were distinct relapse-free and overall survival benefits for patients who underwent transplant. This trial did not evaluate MRD, however, ”so what we don’t know is for those patients achieving a complete molecular remission, would those patients do okay without transplant?” she said.

The current standard of care at Cleveland Clinic is to transplant eligible patients in first remission, ”but I think that’s likely to change as we get more data from these trials.”

In the COG AALL0031 trial of imatinib and chemotherapy in children with Ph+ALL, there was no significant benefit to stem cell transplant (Leukemia 2014 Jan 20;28:1467-71), Dr. Advani noted.

Other prognostic features associated with poor risk, such as 1KZF1 mutations with CDKN2A and/or PAX5 deletions, have been suggested as indicators for transplant, but “what’s less clear is what the impact of these abnormalities is now with the second- and third-generation TKIs, and also whether these various abnormalities correlate with molecular responses or achievement of complete molecular remission,” she said.


 

Frail/unfit patients

Therapeutic options for frail or unfit patients include the combination of dasatinib and prednisone, which was associated in one study with a 93% complete hematologic remission rate by day 22, and at 20 months with a 69.2% overall survival rate, and 51.1% disease-free survival rate.(Blood. 2011;118[25]:6521-8).

In this study MRD correlated with disease-free survival, but 23 of 53 patients experienced relapse, and 12 patients with relapsed disease had the T3151 mutation. Ponatinib would be a second-line option for this latter group of patients, Dr. Advani said.

A study reported at the 2017 ASH annual meeting looked at the combination of ponatinib with steroids in patients either 60 and older or younger unfit patients with Ph+ALL.

The primary endpoint of complete hematological response at 24 weeks in at least 75% of patients was reached early, with 40 of 42 patients (95.2%) having a complete hematologic response after 1 course of therapy (6 weeks). The CMR rate at 24 weeks was 61%, and 1-year overall survival was 87.5%.

There were 13 serious adverse events related to ponatinib, however, including one death, and one patient who experienced a relapse was found to have the T315L ponatinib-resistance mutation. (Blood 2017 Dec. 7;130[Suppl. 1]:99).

“I think a few things with ponatinib and steroids that we still don’t know are the long-term follow-up results of this as a single agent in combination with steroids, and second, in this elderly population, if you look, patients are dropping out due to adverse events and toxicities,” she said.
 

TKIs plus antibodies

The S1318 trial conducted by the SWOG cancer research network contains both a Ph+ALL and a Ph-negative ALL cohort. In this trial, patients with Ph+ALL receive dasatinib and steroids as induction, then go on to receive blinatumomab (Blincyto) with dasatinib for three cycles, followed by maintenance therapy with dasitinib and prednisone.

A trial currently in the planning stages, EA9181, will compare in a randomized fashion induction regimens with either dasatinib or ponatinib at the investigator’s discretion with steroids and either blinatumomab or chemotherapy.

No funding source was reported for the presentation. Dr. Advani disclosed steering committee activities, honoraria/consulting, and research funding from multiple companies.

Clinicians who treat patients with lower-risk myelodysplastic syndrome should focus on “what bugs patients most,” with therapeutic goals reflecting and respecting the patients’ goals, a specialist in MDS recommended.

“There’s an uncomfortable truth in treating lower-risk MDS: No treatment that we have has ever been demonstrated in a prospective trial to prolong survival in lower-risk MDS, so in the end, what we’re doing is trying to improve transfusion needs and to improve quality of life,” said Michael A. Sekeres, MD, MS, from the Cleveland Clinic.

Dr. Sekeres described optimal therapy for patients with lower-risk MDS in an online presentation during the virtual American Society of Hematology Meeting on Hematologic Malignancies.

He acknowledged that the definition of MDS as “a heterogeneous clonal hematopoietic disorder derived from an abnormal multipotent progenitor cell, characterized by a hyperproliferative bone marrow, dysplasia of the cellular elements, and ineffective hematopoiesis” can be confusing even for hematologists well versed in the disorder.

An easier-to-grasp explanation, he said, is that “MDS is considered a cancer, and like other cancers it has a clonal origin, involves the abnormal growth of cells that exceeds the growth of other cells around them and don’t know when to stop growing, and it takes over normal tissue, so that the normal tissues – in this case the hematopoietic precursors in the bone marrow – don’t function normally, resulting in cytopenias.”
 

‘Mild displeasure syndrome’

Approximately 95% of patients with MDS have a discrete genetic abnormality, but only one driver mutation, in the gene SF3B1, is considered to be a lower-risk abnormality, with a more favorable prognosis.

Treatment options for patients with lower-risk MDS, defined as an International Prognostic Scoring System score of 1 or less, or a Revised IPSS score of 3.5 or less, will depend on the patients’ transfusion needs and quality of life.

Patients with no transfusion requirements and a generally good quality of life may be followed by observation alone, with blood counts every 1 to 6 months depending on clinical presentation.

“We have some folks coming in who really don’t have very bad blood counts and have a good quality of life,” Dr. Sekeres said. “Those folks we would consider to have a very good risk type of MDS, which one of my patients referred to once as ‘mild displeasure syndrome.’ It was a displeasure to him to have to fight the traffic to come into Cleveland to see me every month, or 2 months, or 6 months, but beyond that we didn’t have to treat his MDS.”
 

Isolated cytopenias

Patients with isolated anemia, with hemoglobin less than 10 g/dL and/or transfusion dependence, and who are symptomatic should be started on an erythopoiesis-stimulating agent (ESA), either recombinant humanized erythropoietin or darbepoetin, or the erythroid-maturing agent luspatercept (Reblozyl).

The probability of a response to ESAs in this populations ranges from about 15% to 35%, with patients who have low baseline serum erythropoietin and no or few transfusions most likely to respond.

“On the other hand, patients who come into our clinic who are already dependent on red blood cell transfusions and have a sky-high [erythropoietin] level in the hundreds or even thousands have a very low likelihood of responding to exogenously administered ESAs,” he said.

Patients with no response to ESAs or luspatercept or a loss of response suggestive of disease progression should undergo repeat bone marrow biopsy. Patients who develop deletion 5q should be started on lenalidomide (Revlimid). In these patients, next-generation sequencing may also reveal targetable abnormalities.

For patients with isolated thrombocytopenia, thrombopoietin agonists such as romiplostim or eltrombopag may help to reduce platelet transfusion requirements and clinically significant bleeding events, but these agents come with a very important caveat: in addition to promoting platelet production, thrombopoietin receptor agonists can promote the growth of blasts, which could in turn promote the transformation of MDS to acute myeloid leukemia.

“This is an off-label use of romiplostim for the treatment of MDS with thrombocytopenia, and this drug should never, never, never be given to a patient who has excess blasts at baseline MDS; the same is true of its cousin eltrombopag.” Dr. Sekeres said.
 

Multlineage dysplasia

Patients with multilineage dysplasia can have good responses to hypomethylating agents, either azacitidine 75 mg/m2 IV or subcutaneously for 3 days every 4 weeks, or decitabine 20 mg/m² IV for 3 days every 4 weeks.

“Another approach to treating patients with multilineage dysplasia is to consider the use of antithymocyte globulin; in other words, treat these patients as if they have aplastic anemia, because there are some types of MDS in which immune-mediated destruction of bone marrow plays a role,” Dr. Sekeres said.

“This is particularly appealing in patients who have a hyperplastic marrow, or those who have other autoimmune conditions that are going on that may indicate a broader autoimmune process that’s involved in the bone marrow,” he added.

Patients treated with antithymocyte globulin require hospitalization with discharge on steroids for 1 month to prevent serum sickness in response to the treatment, and maintenance on low-dose cyclosporine.

“In MDS, unfortunately, our understanding of the biology of the disease far exceeds what we can do about it, but we’re starting to catch up,” Dr. Sekeres said.

No funding source for the presentation was disclosed. Dr. Sekeres disclosed serving on advisory boards for Celegene/Bristol-Myers Squibb, Takeda/Millenium, and Pfizer.

Clinicians who treat patients with lower-risk myelodysplastic syndrome should focus on “what bugs patients most,” with therapeutic goals reflecting and respecting the patients’ goals, a specialist in MDS recommended.

“There’s an uncomfortable truth in treating lower-risk MDS: No treatment that we have has ever been demonstrated in a prospective trial to prolong survival in lower-risk MDS, so in the end, what we’re doing is trying to improve transfusion needs and to improve quality of life,” said Michael A. Sekeres, MD, MS, from the Cleveland Clinic.

Dr. Sekeres described optimal therapy for patients with lower-risk MDS in an online presentation during the virtual American Society of Hematology Meeting on Hematologic Malignancies.

He acknowledged that the definition of MDS as “a heterogeneous clonal hematopoietic disorder derived from an abnormal multipotent progenitor cell, characterized by a hyperproliferative bone marrow, dysplasia of the cellular elements, and ineffective hematopoiesis” can be confusing even for hematologists well versed in the disorder.

An easier-to-grasp explanation, he said, is that “MDS is considered a cancer, and like other cancers it has a clonal origin, involves the abnormal growth of cells that exceeds the growth of other cells around them and don’t know when to stop growing, and it takes over normal tissue, so that the normal tissues – in this case the hematopoietic precursors in the bone marrow – don’t function normally, resulting in cytopenias.”
 

‘Mild displeasure syndrome’

Approximately 95% of patients with MDS have a discrete genetic abnormality, but only one driver mutation, in the gene SF3B1, is considered to be a lower-risk abnormality, with a more favorable prognosis.

Treatment options for patients with lower-risk MDS, defined as an International Prognostic Scoring System score of 1 or less, or a Revised IPSS score of 3.5 or less, will depend on the patients’ transfusion needs and quality of life.

Patients with no transfusion requirements and a generally good quality of life may be followed by observation alone, with blood counts every 1 to 6 months depending on clinical presentation.

“We have some folks coming in who really don’t have very bad blood counts and have a good quality of life,” Dr. Sekeres said. “Those folks we would consider to have a very good risk type of MDS, which one of my patients referred to once as ‘mild displeasure syndrome.’ It was a displeasure to him to have to fight the traffic to come into Cleveland to see me every month, or 2 months, or 6 months, but beyond that we didn’t have to treat his MDS.”
 

Isolated cytopenias

Patients with isolated anemia, with hemoglobin less than 10 g/dL and/or transfusion dependence, and who are symptomatic should be started on an erythopoiesis-stimulating agent (ESA), either recombinant humanized erythropoietin or darbepoetin, or the erythroid-maturing agent luspatercept (Reblozyl).

The probability of a response to ESAs in this populations ranges from about 15% to 35%, with patients who have low baseline serum erythropoietin and no or few transfusions most likely to respond.

“On the other hand, patients who come into our clinic who are already dependent on red blood cell transfusions and have a sky-high [erythropoietin] level in the hundreds or even thousands have a very low likelihood of responding to exogenously administered ESAs,” he said.

Patients with no response to ESAs or luspatercept or a loss of response suggestive of disease progression should undergo repeat bone marrow biopsy. Patients who develop deletion 5q should be started on lenalidomide (Revlimid). In these patients, next-generation sequencing may also reveal targetable abnormalities.

For patients with isolated thrombocytopenia, thrombopoietin agonists such as romiplostim or eltrombopag may help to reduce platelet transfusion requirements and clinically significant bleeding events, but these agents come with a very important caveat: in addition to promoting platelet production, thrombopoietin receptor agonists can promote the growth of blasts, which could in turn promote the transformation of MDS to acute myeloid leukemia.

“This is an off-label use of romiplostim for the treatment of MDS with thrombocytopenia, and this drug should never, never, never be given to a patient who has excess blasts at baseline MDS; the same is true of its cousin eltrombopag.” Dr. Sekeres said.
 

Multlineage dysplasia

Patients with multilineage dysplasia can have good responses to hypomethylating agents, either azacitidine 75 mg/m2 IV or subcutaneously for 3 days every 4 weeks, or decitabine 20 mg/m² IV for 3 days every 4 weeks.

“Another approach to treating patients with multilineage dysplasia is to consider the use of antithymocyte globulin; in other words, treat these patients as if they have aplastic anemia, because there are some types of MDS in which immune-mediated destruction of bone marrow plays a role,” Dr. Sekeres said.

“This is particularly appealing in patients who have a hyperplastic marrow, or those who have other autoimmune conditions that are going on that may indicate a broader autoimmune process that’s involved in the bone marrow,” he added.

Patients treated with antithymocyte globulin require hospitalization with discharge on steroids for 1 month to prevent serum sickness in response to the treatment, and maintenance on low-dose cyclosporine.

“In MDS, unfortunately, our understanding of the biology of the disease far exceeds what we can do about it, but we’re starting to catch up,” Dr. Sekeres said.

No funding source for the presentation was disclosed. Dr. Sekeres disclosed serving on advisory boards for Celegene/Bristol-Myers Squibb, Takeda/Millenium, and Pfizer.

Clinicians who treat patients with lower-risk myelodysplastic syndrome should focus on “what bugs patients most,” with therapeutic goals reflecting and respecting the patients’ goals, a specialist in MDS recommended.

“There’s an uncomfortable truth in treating lower-risk MDS: No treatment that we have has ever been demonstrated in a prospective trial to prolong survival in lower-risk MDS, so in the end, what we’re doing is trying to improve transfusion needs and to improve quality of life,” said Michael A. Sekeres, MD, MS, from the Cleveland Clinic.

Dr. Sekeres described optimal therapy for patients with lower-risk MDS in an online presentation during the virtual American Society of Hematology Meeting on Hematologic Malignancies.

He acknowledged that the definition of MDS as “a heterogeneous clonal hematopoietic disorder derived from an abnormal multipotent progenitor cell, characterized by a hyperproliferative bone marrow, dysplasia of the cellular elements, and ineffective hematopoiesis” can be confusing even for hematologists well versed in the disorder.

An easier-to-grasp explanation, he said, is that “MDS is considered a cancer, and like other cancers it has a clonal origin, involves the abnormal growth of cells that exceeds the growth of other cells around them and don’t know when to stop growing, and it takes over normal tissue, so that the normal tissues – in this case the hematopoietic precursors in the bone marrow – don’t function normally, resulting in cytopenias.”
 

‘Mild displeasure syndrome’

Approximately 95% of patients with MDS have a discrete genetic abnormality, but only one driver mutation, in the gene SF3B1, is considered to be a lower-risk abnormality, with a more favorable prognosis.

Treatment options for patients with lower-risk MDS, defined as an International Prognostic Scoring System score of 1 or less, or a Revised IPSS score of 3.5 or less, will depend on the patients’ transfusion needs and quality of life.

Patients with no transfusion requirements and a generally good quality of life may be followed by observation alone, with blood counts every 1 to 6 months depending on clinical presentation.

“We have some folks coming in who really don’t have very bad blood counts and have a good quality of life,” Dr. Sekeres said. “Those folks we would consider to have a very good risk type of MDS, which one of my patients referred to once as ‘mild displeasure syndrome.’ It was a displeasure to him to have to fight the traffic to come into Cleveland to see me every month, or 2 months, or 6 months, but beyond that we didn’t have to treat his MDS.”
 

Isolated cytopenias

Patients with isolated anemia, with hemoglobin less than 10 g/dL and/or transfusion dependence, and who are symptomatic should be started on an erythopoiesis-stimulating agent (ESA), either recombinant humanized erythropoietin or darbepoetin, or the erythroid-maturing agent luspatercept (Reblozyl).

The probability of a response to ESAs in this populations ranges from about 15% to 35%, with patients who have low baseline serum erythropoietin and no or few transfusions most likely to respond.

“On the other hand, patients who come into our clinic who are already dependent on red blood cell transfusions and have a sky-high [erythropoietin] level in the hundreds or even thousands have a very low likelihood of responding to exogenously administered ESAs,” he said.

Patients with no response to ESAs or luspatercept or a loss of response suggestive of disease progression should undergo repeat bone marrow biopsy. Patients who develop deletion 5q should be started on lenalidomide (Revlimid). In these patients, next-generation sequencing may also reveal targetable abnormalities.

For patients with isolated thrombocytopenia, thrombopoietin agonists such as romiplostim or eltrombopag may help to reduce platelet transfusion requirements and clinically significant bleeding events, but these agents come with a very important caveat: in addition to promoting platelet production, thrombopoietin receptor agonists can promote the growth of blasts, which could in turn promote the transformation of MDS to acute myeloid leukemia.

“This is an off-label use of romiplostim for the treatment of MDS with thrombocytopenia, and this drug should never, never, never be given to a patient who has excess blasts at baseline MDS; the same is true of its cousin eltrombopag.” Dr. Sekeres said.
 

Multlineage dysplasia

Patients with multilineage dysplasia can have good responses to hypomethylating agents, either azacitidine 75 mg/m2 IV or subcutaneously for 3 days every 4 weeks, or decitabine 20 mg/m² IV for 3 days every 4 weeks.

“Another approach to treating patients with multilineage dysplasia is to consider the use of antithymocyte globulin; in other words, treat these patients as if they have aplastic anemia, because there are some types of MDS in which immune-mediated destruction of bone marrow plays a role,” Dr. Sekeres said.

“This is particularly appealing in patients who have a hyperplastic marrow, or those who have other autoimmune conditions that are going on that may indicate a broader autoimmune process that’s involved in the bone marrow,” he added.

Patients treated with antithymocyte globulin require hospitalization with discharge on steroids for 1 month to prevent serum sickness in response to the treatment, and maintenance on low-dose cyclosporine.

“In MDS, unfortunately, our understanding of the biology of the disease far exceeds what we can do about it, but we’re starting to catch up,” Dr. Sekeres said.

No funding source for the presentation was disclosed. Dr. Sekeres disclosed serving on advisory boards for Celegene/Bristol-Myers Squibb, Takeda/Millenium, and Pfizer.

Malignant melanomas in children and adolescents are thankfully rare, but they can be challenging to diagnose, and fatal disease can manifest itself in any of several different ways, results of a retrospective multicenter study showed.

“The most striking thing that we learned from this study is that pediatric melanoma can present in so many different ways, and it’s distinct from the adult population in that we see more presentations associated with congenital nevi, or spitz melanoma, which is a special class of pigmented lesions that looks a little different under the microscope,” Elena B. Hawryluk, MD, PhD, of the department of dermatology at Massachusetts General Hospital (MGH) and Harvard University, Boston, said in an interview. Dr. Hawryluk is lead author of the study, which was published online ahead of print in the Journal of the American Academy of Dermatology.

Dr. Hawryluk and colleagues at MGH and 11 other centers conducted a retrospective review of all cases of fatal pediatric melanoma among patients younger than 20 years diagnosed from late 1994 through early 2017.

They identified a total of 38 fatal cases over more than 2 decades. The cases were distinguished primarily by their heterogeneous clinical presentation and by the diversity of the patients, their precursor lesions, and the tumor histopathology, she said in an interview.

“We were surprised to find that patients with each of these presentations could end up with a fatal course, it wasn’t just all the adolescents, or all the patients with giant congenital nevi; it really presented quite diversely.”
 

Rare malignancy

Melanoma is far less common in the pediatric population than in adults, with an annual incidence of 18 per 1 million among adolescents aged 15-18 years, and 1 per 1 million in children under 10 years, the authors noted.

“Melanoma in children and adolescents often has distinct clinical presentations such as association with a congenital melanocytic nevus (CMN), spitzoid melanoma, or amelanotic melanoma, which are more rarely observed in adult melanoma patients. Unique pediatric-specific clinical detection criteria have been proposed to highlight these differences, such as a tendency to present amelanotically,” they wrote.

Factors associated with worse prognosis, such as higher Breslow thickness and mitotic index, are more frequently present at the time of diagnosis in children compared with adults, particularly those diagnosed before age 11 years.

“It is unclear if this difference is secondary to diagnostic delays due to low clinical suspicion, atypical clinical presentations, or more rapid tumor growth rate, as many childhood melanomas are of nodular or spitzoid subtypes,” Dr. Hawryluk and her coauthors wrote.
 

Study details

The investigators sought to characterize the clinical and histopathologic features of fatal pediatric melanomas.

They found that 21 of the 38 patients (57%) were of White heritage, 7 (19%) were of Hispanic or Latino background, 1 (3%) was of Asian lineage, and 1 each were of Black African American or Black Hispanic background. The remaining children were classified as “other” or did not have their ethnic backgrounds recorded.

The “striking prevalence” of Hispanic patients observed in the study is consistent with surveillance reports of an increasing incidence of melanoma among children of Hispanic background, they noted.

The mean age at diagnosis was 12.7 years, and the mean age at death was 15.6 years.

Of the 16 cases with known identifiable disease subtypes, 8 (50%) were nodular, 5 (31%) were superficial spreading, and 3 (19%) were spitzoid melanomas. Of the 38 fatal melanomas, 10 were thought to have originated from congenital melanocytic nevi.
 

Outlook improving

Recent therapeutic breakthroughs such as targeted agents and immunotherapy with checkpoint inhibitors augur well for children diagnosed with melanoma, Dr. Hawryluk said.

“Fortunately, it’s not superaggressive in children at high frequency, so we generally use adult algorithms to inform treatment decisions,” she said. “It’s just important to note that melanomas that arise in congenital nevi tend to have different driver mutations than those that arise in older patients who may have lots of sun exposure.”

“Nowadays, we’re lucky to have a lot of extra tests and workups so that, if a patient does have metastatic or advance disease, they can have a better genetic profile that would guide our choice of medications,” she added.

The study was supported by a Pediatric Dermatology Research Alliance Study Support grant and Society for Pediatric Dermatology, Pediatric Dermatology Research Alliance Pilot award. Dr. Hawryluk is supported by the Dermatology Foundation and the Harvard Medical School Eleanor and Miles Shore Fellowship award. The authors reported no conflicts of interest.

SOURCE: Hawryluk EB et al. J Am Acad Dermatol. 2020 Jul 1. doi: 10.1016/j.jaad.2020.06.1010.

Malignant melanomas in children and adolescents are thankfully rare, but they can be challenging to diagnose, and fatal disease can manifest itself in any of several different ways, results of a retrospective multicenter study showed.

“The most striking thing that we learned from this study is that pediatric melanoma can present in so many different ways, and it’s distinct from the adult population in that we see more presentations associated with congenital nevi, or spitz melanoma, which is a special class of pigmented lesions that looks a little different under the microscope,” Elena B. Hawryluk, MD, PhD, of the department of dermatology at Massachusetts General Hospital (MGH) and Harvard University, Boston, said in an interview. Dr. Hawryluk is lead author of the study, which was published online ahead of print in the Journal of the American Academy of Dermatology.

Dr. Hawryluk and colleagues at MGH and 11 other centers conducted a retrospective review of all cases of fatal pediatric melanoma among patients younger than 20 years diagnosed from late 1994 through early 2017.

They identified a total of 38 fatal cases over more than 2 decades. The cases were distinguished primarily by their heterogeneous clinical presentation and by the diversity of the patients, their precursor lesions, and the tumor histopathology, she said in an interview.

“We were surprised to find that patients with each of these presentations could end up with a fatal course, it wasn’t just all the adolescents, or all the patients with giant congenital nevi; it really presented quite diversely.”
 

Rare malignancy

Melanoma is far less common in the pediatric population than in adults, with an annual incidence of 18 per 1 million among adolescents aged 15-18 years, and 1 per 1 million in children under 10 years, the authors noted.

“Melanoma in children and adolescents often has distinct clinical presentations such as association with a congenital melanocytic nevus (CMN), spitzoid melanoma, or amelanotic melanoma, which are more rarely observed in adult melanoma patients. Unique pediatric-specific clinical detection criteria have been proposed to highlight these differences, such as a tendency to present amelanotically,” they wrote.

Factors associated with worse prognosis, such as higher Breslow thickness and mitotic index, are more frequently present at the time of diagnosis in children compared with adults, particularly those diagnosed before age 11 years.

“It is unclear if this difference is secondary to diagnostic delays due to low clinical suspicion, atypical clinical presentations, or more rapid tumor growth rate, as many childhood melanomas are of nodular or spitzoid subtypes,” Dr. Hawryluk and her coauthors wrote.
 

Study details

The investigators sought to characterize the clinical and histopathologic features of fatal pediatric melanomas.

They found that 21 of the 38 patients (57%) were of White heritage, 7 (19%) were of Hispanic or Latino background, 1 (3%) was of Asian lineage, and 1 each were of Black African American or Black Hispanic background. The remaining children were classified as “other” or did not have their ethnic backgrounds recorded.

The “striking prevalence” of Hispanic patients observed in the study is consistent with surveillance reports of an increasing incidence of melanoma among children of Hispanic background, they noted.

The mean age at diagnosis was 12.7 years, and the mean age at death was 15.6 years.

Of the 16 cases with known identifiable disease subtypes, 8 (50%) were nodular, 5 (31%) were superficial spreading, and 3 (19%) were spitzoid melanomas. Of the 38 fatal melanomas, 10 were thought to have originated from congenital melanocytic nevi.
 

Outlook improving

Recent therapeutic breakthroughs such as targeted agents and immunotherapy with checkpoint inhibitors augur well for children diagnosed with melanoma, Dr. Hawryluk said.

“Fortunately, it’s not superaggressive in children at high frequency, so we generally use adult algorithms to inform treatment decisions,” she said. “It’s just important to note that melanomas that arise in congenital nevi tend to have different driver mutations than those that arise in older patients who may have lots of sun exposure.”

“Nowadays, we’re lucky to have a lot of extra tests and workups so that, if a patient does have metastatic or advance disease, they can have a better genetic profile that would guide our choice of medications,” she added.

The study was supported by a Pediatric Dermatology Research Alliance Study Support grant and Society for Pediatric Dermatology, Pediatric Dermatology Research Alliance Pilot award. Dr. Hawryluk is supported by the Dermatology Foundation and the Harvard Medical School Eleanor and Miles Shore Fellowship award. The authors reported no conflicts of interest.

SOURCE: Hawryluk EB et al. J Am Acad Dermatol. 2020 Jul 1. doi: 10.1016/j.jaad.2020.06.1010.

Malignant melanomas in children and adolescents are thankfully rare, but they can be challenging to diagnose, and fatal disease can manifest itself in any of several different ways, results of a retrospective multicenter study showed.

“The most striking thing that we learned from this study is that pediatric melanoma can present in so many different ways, and it’s distinct from the adult population in that we see more presentations associated with congenital nevi, or spitz melanoma, which is a special class of pigmented lesions that looks a little different under the microscope,” Elena B. Hawryluk, MD, PhD, of the department of dermatology at Massachusetts General Hospital (MGH) and Harvard University, Boston, said in an interview. Dr. Hawryluk is lead author of the study, which was published online ahead of print in the Journal of the American Academy of Dermatology.

Dr. Hawryluk and colleagues at MGH and 11 other centers conducted a retrospective review of all cases of fatal pediatric melanoma among patients younger than 20 years diagnosed from late 1994 through early 2017.

They identified a total of 38 fatal cases over more than 2 decades. The cases were distinguished primarily by their heterogeneous clinical presentation and by the diversity of the patients, their precursor lesions, and the tumor histopathology, she said in an interview.

“We were surprised to find that patients with each of these presentations could end up with a fatal course, it wasn’t just all the adolescents, or all the patients with giant congenital nevi; it really presented quite diversely.”
 

Rare malignancy

Melanoma is far less common in the pediatric population than in adults, with an annual incidence of 18 per 1 million among adolescents aged 15-18 years, and 1 per 1 million in children under 10 years, the authors noted.

“Melanoma in children and adolescents often has distinct clinical presentations such as association with a congenital melanocytic nevus (CMN), spitzoid melanoma, or amelanotic melanoma, which are more rarely observed in adult melanoma patients. Unique pediatric-specific clinical detection criteria have been proposed to highlight these differences, such as a tendency to present amelanotically,” they wrote.

Factors associated with worse prognosis, such as higher Breslow thickness and mitotic index, are more frequently present at the time of diagnosis in children compared with adults, particularly those diagnosed before age 11 years.

“It is unclear if this difference is secondary to diagnostic delays due to low clinical suspicion, atypical clinical presentations, or more rapid tumor growth rate, as many childhood melanomas are of nodular or spitzoid subtypes,” Dr. Hawryluk and her coauthors wrote.
 

Study details

The investigators sought to characterize the clinical and histopathologic features of fatal pediatric melanomas.

They found that 21 of the 38 patients (57%) were of White heritage, 7 (19%) were of Hispanic or Latino background, 1 (3%) was of Asian lineage, and 1 each were of Black African American or Black Hispanic background. The remaining children were classified as “other” or did not have their ethnic backgrounds recorded.

The “striking prevalence” of Hispanic patients observed in the study is consistent with surveillance reports of an increasing incidence of melanoma among children of Hispanic background, they noted.

The mean age at diagnosis was 12.7 years, and the mean age at death was 15.6 years.

Of the 16 cases with known identifiable disease subtypes, 8 (50%) were nodular, 5 (31%) were superficial spreading, and 3 (19%) were spitzoid melanomas. Of the 38 fatal melanomas, 10 were thought to have originated from congenital melanocytic nevi.
 

Outlook improving

Recent therapeutic breakthroughs such as targeted agents and immunotherapy with checkpoint inhibitors augur well for children diagnosed with melanoma, Dr. Hawryluk said.

“Fortunately, it’s not superaggressive in children at high frequency, so we generally use adult algorithms to inform treatment decisions,” she said. “It’s just important to note that melanomas that arise in congenital nevi tend to have different driver mutations than those that arise in older patients who may have lots of sun exposure.”

“Nowadays, we’re lucky to have a lot of extra tests and workups so that, if a patient does have metastatic or advance disease, they can have a better genetic profile that would guide our choice of medications,” she added.

The study was supported by a Pediatric Dermatology Research Alliance Study Support grant and Society for Pediatric Dermatology, Pediatric Dermatology Research Alliance Pilot award. Dr. Hawryluk is supported by the Dermatology Foundation and the Harvard Medical School Eleanor and Miles Shore Fellowship award. The authors reported no conflicts of interest.

SOURCE: Hawryluk EB et al. J Am Acad Dermatol. 2020 Jul 1. doi: 10.1016/j.jaad.2020.06.1010.

Researchers are beginning to make some headway in identifying the role of secondary infections in the course and outcomes of COVID-19.

CDC/ Dr. William Kaplan

Patients who are on ventilatory support for severe COVID-19 infections appear to be at high risk for invasive pulmonary aspergillosis, which in a small prospective study was associated with a more than threefold risk for 30-day mortality. The findings were published online in Clinical Infectious Diseases.

Among 108 patients with COVID-19 on mechanical ventilation in one of three intensive care units, 30 (27.7%) were diagnosed with coronavirus-associated pulmonary aspergillosis (CAPA) based on consensus definitions similar to those used to diagnose influenza-associated pulmonary aspergillosis (IAPA).

Of the patients with CAPA, 44% died within 30 days of ICU admission, compared with 19% of patients who did not meet the criteria for aspergillosis (P = .002). This difference translated into an odds ratio (OR) for death with CAPA of 3.55 (P = .014), reported Michele Bartoletti, MD, PhD, of the infectious diseases unit at Sant’Orsola Malpighi Hospital in Bologna, Italy, and colleagues.

When the investigators applied a proposed definition of putative invasive pulmonary aspergillosis, or “PIPA” to the same patients, the 30-day mortality rate jumped to 74% vs. 26% for patients without PIPA (P < .001), with an OR of 11.60 (P < .001). “We found a high incidence of CAPA among critically ill COVID-19 patients and that its occurrence seems to change the natural history of disease,” they wrote.

“[T]he study from Bartoletti et al. alerts the clinical audience to be aware of CAPA and take appropriate (and where needed repetitive) actions that fits their clinical setting,” Roger J. Brüggemann, PharmD, of the department of pharmacy, Radboud University Medical Center, Nijmegen, the Netherlands, and colleagues wrote in an editorial accompanying the study.
 

Diagnosis challenging

At the best of times, the diagnosis of pulmonary aspergillosis is difficult, subject to both false-positive and false-negative results, said a critical care specialist who was not involved in the study.

“Critically ill patients are susceptible to having aspergillus, so in reading the article, my only concerns are that I don’t know how accurate the testing is, and I don’t know if their population is truly different from a general population of patients in the ICU,” Daniel R. Ouellette, MD, FCCP, associate director of medical critical care at Henry Ford Hospital in Detroit, said in an interview.

As seen in ICU patients with severe influenza or other viral infections, patients with severe COVID-19 disease are susceptible to secondary infections, he said, making it difficult to know whether the worse outcomes seen in patients with COVID-19 and presumed aspergillosis are a reflection of their being more critically ill or whether the secondary infections themselves account for the difference in mortality.
 

Three ICUs

Dr. Bartoletti and colleagues conducted a study on all adult patients with microbiologically confirmed COVID-19 receiving mechanical ventilation in three ICUs in Bologna.

All patients included in the study were screened for invasive pulmonary aspergillosis with bronchoalveolar lavage and galactomannan detection and cultures. The lavage was performed on ICU admission, one day from the first day of mechanical ventilation, and if patients had evidence of clinical disease progression.

Samples that tested positive for galactomannan, a component of the aspergillus cell wall, were stored and later analyzed with a commercial quantitative real-time polymerase chain reaction assay for aspergillus; these results were not reported to clinicians on the patient floors.

The investigators defined invasive pulmonary aspergillosis according to a recently proposed definition for CAPA. This definition applies to COVID-19–positive patients admitted to an ICU with pulmonary infiltrates and at least one of the following:

• A serum galactomannan > 0.5.
• Bronchoalveolar lavage galactomannan > 1.0.
• Positive aspergillus bronchoalveolar lavage culture or cavitating infiltrate not attributed to another cause in the area of the pulmonary infiltrate.

They compared the CAPA diagnostic criteria with those of PIPA criteria as described by Stijn J. Blot, PhD, and colleagues in study published in the American Journal of Respiratory and Critical Care Medicine (2012 Jul 1;186(1):56-64).

A total of 108 patients were screened for aspergillosis, with a median age of 64. The majority of patients (78%) were male. The median age-adjusted Charlson Comorbidity Index was 2.5 (range 1-4). The median Sequential Organ Failure Assessment (SOFA) score at ICU admission was 4 (range 3-5).

As noted, probable aspergillosis by CAPA criteria was diagnosed in 30 patients (27.7%), with the diagnosis made after a median of 4 days after intubation and a median of 14 days from onset of COVID-19 symptoms.

The incidence rate of probable CAPA was 38.83 per 10,000 ICU patient days.

A comparison of clinical characteristics of patients with and without probable CAPA showed that only chronic steroid therapy at ≥ 16 mg/day prednisone for at least 15 days was significantly associated with risk for CAPA (P = .02).

At a median follow-up of 31 days, 54 patients (50%) had been discharged, 44 (41%) had died, and the remaining patients were still on follow-up.

As noted before, the mortality rate with 30 days of ICU admission was 44% for patients with probable CAPA vs. 19% for patients without. Among patients deemed to have PIPA, 74% died within 30 days of admission, compared with 26% without PIPA.

In a logistic regression model, the association of CAPA with increased risk for 30-day mortality remained even after adjustment for the need for renal replacement therapy (OR 3.02, P = .015) and SOFA score at ICU admission (OR 1.38, P = .004).

In a logistic regression using the PIPA rather than CAPA definition, the OR for 30-day mortality was 11.60 (P = .001).
 

Prognostic marker

The investigators noted that bronchoalveolar lavage galactomannan index appeared to be predictive of death. Each 1-point increase in the index was associated with 1.41-fold increase in the risk for 30-day mortality (P = .0070), a relationship that held up after adjustment for age, need for renal replacement therapy, and SOFA score.

Sixteen patients who met the CAPA definition received antifungal therapy, primarily voriconazole. The use of voriconazole was associated with a nonsignificant trend toward lower mortality.

They noted that the heavy use of immunomodulating agents in the patients in their study may have contributed to the high prevalence of CAPA.

Dr. Ouellette agreed that many of the therapies used to treat COVID-19 in the ICU are experimental, and that agents used to suppress the cytokine storm that is believed to contribute to disease severity may increase risk for secondary infections such as invasive aspergillosis.

“Many of our treatments may be associated with adverse consequences,” he said. “There is a trend toward treating patients with COVID-19 pneumonia with corticosteroids, and certainly that could have an immunosuppressant effect and predispose patients to secondary infections.”

He noted that the World Health Organization recommendations current in March 2020, when the pandemic began in earnest in the United States, advised against the use of corticosteroids, likely because of a lack of evidence of efficacy and concerns about risk for secondary infections.

“Regardless of the strategic choice made, all efforts should be put into improving our ability to reliably identify patients that may benefit from therapeutic interventions, which include host and risk factors, clinical factors and CAPA disease markers,” Dr. Brüggemann and colleagues wrote in their editorial.

The study was performed without external funding. The authors and Dr. Ouellette reported no conflicts of interest. Dr. Brüggemann and coauthors report grants and/or personal fees from various companies outside the submitted work.

SOURCE: Bartoletti M et al. Clin Infect Dis. 2020 Jul 28. doi: 10.1093/cid/ciaa1065.

Researchers are beginning to make some headway in identifying the role of secondary infections in the course and outcomes of COVID-19.

CDC/ Dr. William Kaplan

Patients who are on ventilatory support for severe COVID-19 infections appear to be at high risk for invasive pulmonary aspergillosis, which in a small prospective study was associated with a more than threefold risk for 30-day mortality. The findings were published online in Clinical Infectious Diseases.

Among 108 patients with COVID-19 on mechanical ventilation in one of three intensive care units, 30 (27.7%) were diagnosed with coronavirus-associated pulmonary aspergillosis (CAPA) based on consensus definitions similar to those used to diagnose influenza-associated pulmonary aspergillosis (IAPA).

Of the patients with CAPA, 44% died within 30 days of ICU admission, compared with 19% of patients who did not meet the criteria for aspergillosis (P = .002). This difference translated into an odds ratio (OR) for death with CAPA of 3.55 (P = .014), reported Michele Bartoletti, MD, PhD, of the infectious diseases unit at Sant’Orsola Malpighi Hospital in Bologna, Italy, and colleagues.

When the investigators applied a proposed definition of putative invasive pulmonary aspergillosis, or “PIPA” to the same patients, the 30-day mortality rate jumped to 74% vs. 26% for patients without PIPA (P < .001), with an OR of 11.60 (P < .001). “We found a high incidence of CAPA among critically ill COVID-19 patients and that its occurrence seems to change the natural history of disease,” they wrote.

“[T]he study from Bartoletti et al. alerts the clinical audience to be aware of CAPA and take appropriate (and where needed repetitive) actions that fits their clinical setting,” Roger J. Brüggemann, PharmD, of the department of pharmacy, Radboud University Medical Center, Nijmegen, the Netherlands, and colleagues wrote in an editorial accompanying the study.
 

Diagnosis challenging

At the best of times, the diagnosis of pulmonary aspergillosis is difficult, subject to both false-positive and false-negative results, said a critical care specialist who was not involved in the study.

“Critically ill patients are susceptible to having aspergillus, so in reading the article, my only concerns are that I don’t know how accurate the testing is, and I don’t know if their population is truly different from a general population of patients in the ICU,” Daniel R. Ouellette, MD, FCCP, associate director of medical critical care at Henry Ford Hospital in Detroit, said in an interview.

As seen in ICU patients with severe influenza or other viral infections, patients with severe COVID-19 disease are susceptible to secondary infections, he said, making it difficult to know whether the worse outcomes seen in patients with COVID-19 and presumed aspergillosis are a reflection of their being more critically ill or whether the secondary infections themselves account for the difference in mortality.
 

Three ICUs

Dr. Bartoletti and colleagues conducted a study on all adult patients with microbiologically confirmed COVID-19 receiving mechanical ventilation in three ICUs in Bologna.

All patients included in the study were screened for invasive pulmonary aspergillosis with bronchoalveolar lavage and galactomannan detection and cultures. The lavage was performed on ICU admission, one day from the first day of mechanical ventilation, and if patients had evidence of clinical disease progression.

Samples that tested positive for galactomannan, a component of the aspergillus cell wall, were stored and later analyzed with a commercial quantitative real-time polymerase chain reaction assay for aspergillus; these results were not reported to clinicians on the patient floors.

The investigators defined invasive pulmonary aspergillosis according to a recently proposed definition for CAPA. This definition applies to COVID-19–positive patients admitted to an ICU with pulmonary infiltrates and at least one of the following:

• A serum galactomannan > 0.5.
• Bronchoalveolar lavage galactomannan > 1.0.
• Positive aspergillus bronchoalveolar lavage culture or cavitating infiltrate not attributed to another cause in the area of the pulmonary infiltrate.

They compared the CAPA diagnostic criteria with those of PIPA criteria as described by Stijn J. Blot, PhD, and colleagues in study published in the American Journal of Respiratory and Critical Care Medicine (2012 Jul 1;186(1):56-64).

A total of 108 patients were screened for aspergillosis, with a median age of 64. The majority of patients (78%) were male. The median age-adjusted Charlson Comorbidity Index was 2.5 (range 1-4). The median Sequential Organ Failure Assessment (SOFA) score at ICU admission was 4 (range 3-5).

As noted, probable aspergillosis by CAPA criteria was diagnosed in 30 patients (27.7%), with the diagnosis made after a median of 4 days after intubation and a median of 14 days from onset of COVID-19 symptoms.

The incidence rate of probable CAPA was 38.83 per 10,000 ICU patient days.

A comparison of clinical characteristics of patients with and without probable CAPA showed that only chronic steroid therapy at ≥ 16 mg/day prednisone for at least 15 days was significantly associated with risk for CAPA (P = .02).

At a median follow-up of 31 days, 54 patients (50%) had been discharged, 44 (41%) had died, and the remaining patients were still on follow-up.

As noted before, the mortality rate with 30 days of ICU admission was 44% for patients with probable CAPA vs. 19% for patients without. Among patients deemed to have PIPA, 74% died within 30 days of admission, compared with 26% without PIPA.

In a logistic regression model, the association of CAPA with increased risk for 30-day mortality remained even after adjustment for the need for renal replacement therapy (OR 3.02, P = .015) and SOFA score at ICU admission (OR 1.38, P = .004).

In a logistic regression using the PIPA rather than CAPA definition, the OR for 30-day mortality was 11.60 (P = .001).
 

Prognostic marker

The investigators noted that bronchoalveolar lavage galactomannan index appeared to be predictive of death. Each 1-point increase in the index was associated with 1.41-fold increase in the risk for 30-day mortality (P = .0070), a relationship that held up after adjustment for age, need for renal replacement therapy, and SOFA score.

Sixteen patients who met the CAPA definition received antifungal therapy, primarily voriconazole. The use of voriconazole was associated with a nonsignificant trend toward lower mortality.

They noted that the heavy use of immunomodulating agents in the patients in their study may have contributed to the high prevalence of CAPA.

Dr. Ouellette agreed that many of the therapies used to treat COVID-19 in the ICU are experimental, and that agents used to suppress the cytokine storm that is believed to contribute to disease severity may increase risk for secondary infections such as invasive aspergillosis.

“Many of our treatments may be associated with adverse consequences,” he said. “There is a trend toward treating patients with COVID-19 pneumonia with corticosteroids, and certainly that could have an immunosuppressant effect and predispose patients to secondary infections.”

He noted that the World Health Organization recommendations current in March 2020, when the pandemic began in earnest in the United States, advised against the use of corticosteroids, likely because of a lack of evidence of efficacy and concerns about risk for secondary infections.

“Regardless of the strategic choice made, all efforts should be put into improving our ability to reliably identify patients that may benefit from therapeutic interventions, which include host and risk factors, clinical factors and CAPA disease markers,” Dr. Brüggemann and colleagues wrote in their editorial.

The study was performed without external funding. The authors and Dr. Ouellette reported no conflicts of interest. Dr. Brüggemann and coauthors report grants and/or personal fees from various companies outside the submitted work.

SOURCE: Bartoletti M et al. Clin Infect Dis. 2020 Jul 28. doi: 10.1093/cid/ciaa1065.

Researchers are beginning to make some headway in identifying the role of secondary infections in the course and outcomes of COVID-19.

CDC/ Dr. William Kaplan

Patients who are on ventilatory support for severe COVID-19 infections appear to be at high risk for invasive pulmonary aspergillosis, which in a small prospective study was associated with a more than threefold risk for 30-day mortality. The findings were published online in Clinical Infectious Diseases.

Among 108 patients with COVID-19 on mechanical ventilation in one of three intensive care units, 30 (27.7%) were diagnosed with coronavirus-associated pulmonary aspergillosis (CAPA) based on consensus definitions similar to those used to diagnose influenza-associated pulmonary aspergillosis (IAPA).

Of the patients with CAPA, 44% died within 30 days of ICU admission, compared with 19% of patients who did not meet the criteria for aspergillosis (P = .002). This difference translated into an odds ratio (OR) for death with CAPA of 3.55 (P = .014), reported Michele Bartoletti, MD, PhD, of the infectious diseases unit at Sant’Orsola Malpighi Hospital in Bologna, Italy, and colleagues.

When the investigators applied a proposed definition of putative invasive pulmonary aspergillosis, or “PIPA” to the same patients, the 30-day mortality rate jumped to 74% vs. 26% for patients without PIPA (P < .001), with an OR of 11.60 (P < .001). “We found a high incidence of CAPA among critically ill COVID-19 patients and that its occurrence seems to change the natural history of disease,” they wrote.

“[T]he study from Bartoletti et al. alerts the clinical audience to be aware of CAPA and take appropriate (and where needed repetitive) actions that fits their clinical setting,” Roger J. Brüggemann, PharmD, of the department of pharmacy, Radboud University Medical Center, Nijmegen, the Netherlands, and colleagues wrote in an editorial accompanying the study.
 

Diagnosis challenging

At the best of times, the diagnosis of pulmonary aspergillosis is difficult, subject to both false-positive and false-negative results, said a critical care specialist who was not involved in the study.

“Critically ill patients are susceptible to having aspergillus, so in reading the article, my only concerns are that I don’t know how accurate the testing is, and I don’t know if their population is truly different from a general population of patients in the ICU,” Daniel R. Ouellette, MD, FCCP, associate director of medical critical care at Henry Ford Hospital in Detroit, said in an interview.

As seen in ICU patients with severe influenza or other viral infections, patients with severe COVID-19 disease are susceptible to secondary infections, he said, making it difficult to know whether the worse outcomes seen in patients with COVID-19 and presumed aspergillosis are a reflection of their being more critically ill or whether the secondary infections themselves account for the difference in mortality.
 

Three ICUs

Dr. Bartoletti and colleagues conducted a study on all adult patients with microbiologically confirmed COVID-19 receiving mechanical ventilation in three ICUs in Bologna.

All patients included in the study were screened for invasive pulmonary aspergillosis with bronchoalveolar lavage and galactomannan detection and cultures. The lavage was performed on ICU admission, one day from the first day of mechanical ventilation, and if patients had evidence of clinical disease progression.

Samples that tested positive for galactomannan, a component of the aspergillus cell wall, were stored and later analyzed with a commercial quantitative real-time polymerase chain reaction assay for aspergillus; these results were not reported to clinicians on the patient floors.

The investigators defined invasive pulmonary aspergillosis according to a recently proposed definition for CAPA. This definition applies to COVID-19–positive patients admitted to an ICU with pulmonary infiltrates and at least one of the following:

• A serum galactomannan > 0.5.
• Bronchoalveolar lavage galactomannan > 1.0.
• Positive aspergillus bronchoalveolar lavage culture or cavitating infiltrate not attributed to another cause in the area of the pulmonary infiltrate.

They compared the CAPA diagnostic criteria with those of PIPA criteria as described by Stijn J. Blot, PhD, and colleagues in study published in the American Journal of Respiratory and Critical Care Medicine (2012 Jul 1;186(1):56-64).

A total of 108 patients were screened for aspergillosis, with a median age of 64. The majority of patients (78%) were male. The median age-adjusted Charlson Comorbidity Index was 2.5 (range 1-4). The median Sequential Organ Failure Assessment (SOFA) score at ICU admission was 4 (range 3-5).

As noted, probable aspergillosis by CAPA criteria was diagnosed in 30 patients (27.7%), with the diagnosis made after a median of 4 days after intubation and a median of 14 days from onset of COVID-19 symptoms.

The incidence rate of probable CAPA was 38.83 per 10,000 ICU patient days.

A comparison of clinical characteristics of patients with and without probable CAPA showed that only chronic steroid therapy at ≥ 16 mg/day prednisone for at least 15 days was significantly associated with risk for CAPA (P = .02).

At a median follow-up of 31 days, 54 patients (50%) had been discharged, 44 (41%) had died, and the remaining patients were still on follow-up.

As noted before, the mortality rate with 30 days of ICU admission was 44% for patients with probable CAPA vs. 19% for patients without. Among patients deemed to have PIPA, 74% died within 30 days of admission, compared with 26% without PIPA.

In a logistic regression model, the association of CAPA with increased risk for 30-day mortality remained even after adjustment for the need for renal replacement therapy (OR 3.02, P = .015) and SOFA score at ICU admission (OR 1.38, P = .004).

In a logistic regression using the PIPA rather than CAPA definition, the OR for 30-day mortality was 11.60 (P = .001).
 

Prognostic marker

The investigators noted that bronchoalveolar lavage galactomannan index appeared to be predictive of death. Each 1-point increase in the index was associated with 1.41-fold increase in the risk for 30-day mortality (P = .0070), a relationship that held up after adjustment for age, need for renal replacement therapy, and SOFA score.

Sixteen patients who met the CAPA definition received antifungal therapy, primarily voriconazole. The use of voriconazole was associated with a nonsignificant trend toward lower mortality.

They noted that the heavy use of immunomodulating agents in the patients in their study may have contributed to the high prevalence of CAPA.

Dr. Ouellette agreed that many of the therapies used to treat COVID-19 in the ICU are experimental, and that agents used to suppress the cytokine storm that is believed to contribute to disease severity may increase risk for secondary infections such as invasive aspergillosis.

“Many of our treatments may be associated with adverse consequences,” he said. “There is a trend toward treating patients with COVID-19 pneumonia with corticosteroids, and certainly that could have an immunosuppressant effect and predispose patients to secondary infections.”

He noted that the World Health Organization recommendations current in March 2020, when the pandemic began in earnest in the United States, advised against the use of corticosteroids, likely because of a lack of evidence of efficacy and concerns about risk for secondary infections.

“Regardless of the strategic choice made, all efforts should be put into improving our ability to reliably identify patients that may benefit from therapeutic interventions, which include host and risk factors, clinical factors and CAPA disease markers,” Dr. Brüggemann and colleagues wrote in their editorial.

The study was performed without external funding. The authors and Dr. Ouellette reported no conflicts of interest. Dr. Brüggemann and coauthors report grants and/or personal fees from various companies outside the submitted work.

SOURCE: Bartoletti M et al. Clin Infect Dis. 2020 Jul 28. doi: 10.1093/cid/ciaa1065.

An experimental cell-collection device that can be administered without anesthesia in a primary care practice was shown to be better at detecting Barrett esophagus than the standard of care in a community-based clinical trial.

Use of this patient-swallowed device, called Cytosponge-TFF3, could allow clinicians to diagnose esophageal conditions such as dysplasia or cancer at an earlier and potentially curable stage, said the investigators. However, it would also increase the likelihood of unnecessary endoscopies, owing to false-positive results.

“In this multicenter, pragmatic, randomized controlled trial we found that an invitation to have a Cytosponge-TFF3 test led to increased diagnosis of Barrett’s esophagus when compared with usual care by general practitioners,” write Rebecca C. Fitzgerald, MD, from the Hutchison/MRC Research Center in Cambridge, England, and colleagues.

The study was published online on Aug. 1 in The Lancet.

“This is a very important study, a landmark study,” said Stephen J. Meltzer, MD, professor of medicine and oncology at Johns Hopkins University, Baltimore, who was approached for comment.

“What it shows is that if you opt to have this procedure, you’re much more likely to have your Barrett’s diagnosed than if you don’t opt to have it,” he said.

He congratulated Dr. Fitzgerald and colleagues for successful completion of a large, primary practice–based clinical utility study.

“Those studies are very difficult to do. This is looking at the actual impact of an intervention, which is the sponge,” he said in an interview.

Soaking up cells

Dr. Meltzer was senior author of a case-control study published in 2019 in Clinical Cancer Research that described use of a similar device. As previously reported, that device, called EsophaCap, uses a “methylation on bead” technique to collect DNA on a swallowed sponge. The DNA is then extracted from the sponge and analyzed with a methylation biomarker panel.

Like the EsophaCap device, the Cytosponge-TFF3 device consists of a compressed, gelatin-coated collection sponge attached to a thread. The patient swallows the device. After the gelatin dissolves and the sponge expands, it is gently withdrawn through the esophagus, picking up cells as it passes through.

The collected cells are then analyzed with an in vitro test for biomarker trefoil factor 3 (TFF3), a sign of intestinal metaplasia that is a histopathologic hallmark of Barrett esophagus, the authors explained.

Cytosponge-TFF3 study

The study by Dr. Fitzgerald and colleagues was conducted in patients taking medications for gastroesophageal reflux. The patients were undergoing treatment at 109 general practice clinics in England.

Eligible patients included adults aged 50 years and older who had been taking acid-suppressing medication for gastroesophageal reflux for more than 6 months and had not undergone endoscopy within the previous 5 years.

The study was randomized at both the clinic level (cluster randomization) and the individual patient level. Patients were assigned to either standard management of gastroesophageal reflux, with endoscopies performed only if recommended by the practitioner, or to the intervention group, where individuals received usual care and were offered the Cytosponge-TFF3 procedure. Those patients whose samples yielded TFF3-positive cells subsequently underwent endoscopy.

Among 6,834 patients assigned to the intervention group, 2,679 (39%) expressed willingness to undergo the Cytosponge-TFF3 procedure. Of this group, 1,750 patients met all of the eligibility criteria on telephone screening and underwent the procedure.

The large majority of patients (95%) who agreed to undergo the procedure were able to swallow the capsule and the attached thread.

Patients in the intervention group who declined the Cytosponge-TFF3 and all patients assigned to the usual-care arm underwent endoscopy only at the recommendation of their primary practitioner.

During a mean follow-up of 12 months, 140 of the 6,834 patients in the intervention group (2%) were diagnosed with Barrett esophagus, compared with 13 of 6,388 patients in the usual-care group (0.2%). The absolute difference per 1000 person-years, the trial’s primary endpoint, was 18.3. The rate ratio adjusted for cluster randomization was 10.6 (P < .001).

A total of four patients in the intervention group were diagnosed with dysplastic Barrett esophagus, and five were diagnosed with stage I esophagogastric cancer. No patients in the usual-care group were diagnosed with either condition.

Of the 1,654 patients in the intervention group who opted for the Cytosponge device and swallowed it successfully, 221 underwent endoscopy after testing positive for TFF3. Of these patients, 131 (59%) were diagnosed with either Barrett esophagus or cancer.

The most common adverse event with the Cytosponge procedure was sore throat, reported by 4% of those who opted for it. In one patient, the thread became detach from the Cytopsonge, necessitating endoscopy to remove the device.

Promising, but refinements needed

In an editorial accompanying the study, Yuri Hanada, MD, and Kenneth K. Wang, MD, from the department of gastroenterology at the Mayo Clinic in Rochester, Minn., said that the Cytosponge-TFF3 procedure “is a promising nonendoscopic screening tool and will represent a component in the screening for Barrett’s esophagus and esophagogastric cancer.”

They noted, however, that it is unlikely to be the sole screening tool for Barrett esophagus and that its use in primary practice may be problematic during the COVID-19 pandemic, because of the release of aerosolized particles as the sponge is withdrawn from the esophagus.

“It might also be necessary to enrich disease prevalence in the screened population by limiting this population to males and people with other risk factors, in order to make this test more cost-effective than previously shown,” they wrote.

Acceptance rate low?

Dr. Meltzer noted that, despite being less invasive than endoscopy, only 39% of the group who could try it agreed to do so.

“It was kind of surprising, because in my experience, when I offer it to my patients, the acceptance is much higher, but that’s not in a controlled clinical trial situation, so I don’t really know what the true percentage is,” he said.

He pointed out that the patients he sees in his clinic are more likely to be symptomatic and highly motivated to accept a test, in contrast to the general patient population in the study.

He also noted that the endoscopy-confirmed prevalence rate of Barrett esophagus or cancer in 221 patients in the intervention group was 59%, suggesting that 41% underwent an unnecessary endoscopy after the Cytosponge screening.

Dr. Fitzgerald and colleagues acknowledged the potential for overdiagnosis with screening. They noted a debate as to whether 1 cm or short segments of Barrett esophagus are a cause for clinical concern.

They also note that the TFF3 test (used in the CytoSponge device) is sensitive and detects some short segments of Barrett esophagus and that, “since this was a pragmatic trial that relied on a coded diagnosis of Barrett’s esophagus, we also identified patients in the usual care group who had short segments of Barrett’s esophagus (1 cm or less in length) and were diagnosed as having the condition, reflecting the variable practice in U.K. hospitals.

“We expect that these patients can be reassured and probably do not require surveillance,” they continued. “This expectation is consistent with the clinical guidelines, which suggest that patients with over 1 cm of salmon-colored epithelium containing intestinal metaplasia should be monitored.”

The study was funded by Cancer Research UK, the U.K. National Institute for Health Research, the U.K. National Health Service, Medtronic, and the Medical Research Council. Dr. Fitzgerald is named on patents related to the Cytosponge-TFF3 test. Dr. Meltzer has cofounded a company, Capsulomics, to commercialize the methylation biomarker panel used in EsophaCap studies. Dr. Wang has received research funding from eNose for research on a device used in a screening study of Barrett esophagus.

Help your patients better understand the risks, testing and treatment options for Barrett’s esophagus by sharing education from the AGA GI Patient Center at http://ow.ly/p9hU30r4oya.

This article first appeared on Medscape.com.

An experimental cell-collection device that can be administered without anesthesia in a primary care practice was shown to be better at detecting Barrett esophagus than the standard of care in a community-based clinical trial.

Use of this patient-swallowed device, called Cytosponge-TFF3, could allow clinicians to diagnose esophageal conditions such as dysplasia or cancer at an earlier and potentially curable stage, said the investigators. However, it would also increase the likelihood of unnecessary endoscopies, owing to false-positive results.

“In this multicenter, pragmatic, randomized controlled trial we found that an invitation to have a Cytosponge-TFF3 test led to increased diagnosis of Barrett’s esophagus when compared with usual care by general practitioners,” write Rebecca C. Fitzgerald, MD, from the Hutchison/MRC Research Center in Cambridge, England, and colleagues.

The study was published online on Aug. 1 in The Lancet.

“This is a very important study, a landmark study,” said Stephen J. Meltzer, MD, professor of medicine and oncology at Johns Hopkins University, Baltimore, who was approached for comment.

“What it shows is that if you opt to have this procedure, you’re much more likely to have your Barrett’s diagnosed than if you don’t opt to have it,” he said.

He congratulated Dr. Fitzgerald and colleagues for successful completion of a large, primary practice–based clinical utility study.

“Those studies are very difficult to do. This is looking at the actual impact of an intervention, which is the sponge,” he said in an interview.

Soaking up cells

Dr. Meltzer was senior author of a case-control study published in 2019 in Clinical Cancer Research that described use of a similar device. As previously reported, that device, called EsophaCap, uses a “methylation on bead” technique to collect DNA on a swallowed sponge. The DNA is then extracted from the sponge and analyzed with a methylation biomarker panel.

Like the EsophaCap device, the Cytosponge-TFF3 device consists of a compressed, gelatin-coated collection sponge attached to a thread. The patient swallows the device. After the gelatin dissolves and the sponge expands, it is gently withdrawn through the esophagus, picking up cells as it passes through.

The collected cells are then analyzed with an in vitro test for biomarker trefoil factor 3 (TFF3), a sign of intestinal metaplasia that is a histopathologic hallmark of Barrett esophagus, the authors explained.

Cytosponge-TFF3 study

The study by Dr. Fitzgerald and colleagues was conducted in patients taking medications for gastroesophageal reflux. The patients were undergoing treatment at 109 general practice clinics in England.

Eligible patients included adults aged 50 years and older who had been taking acid-suppressing medication for gastroesophageal reflux for more than 6 months and had not undergone endoscopy within the previous 5 years.

The study was randomized at both the clinic level (cluster randomization) and the individual patient level. Patients were assigned to either standard management of gastroesophageal reflux, with endoscopies performed only if recommended by the practitioner, or to the intervention group, where individuals received usual care and were offered the Cytosponge-TFF3 procedure. Those patients whose samples yielded TFF3-positive cells subsequently underwent endoscopy.

Among 6,834 patients assigned to the intervention group, 2,679 (39%) expressed willingness to undergo the Cytosponge-TFF3 procedure. Of this group, 1,750 patients met all of the eligibility criteria on telephone screening and underwent the procedure.

The large majority of patients (95%) who agreed to undergo the procedure were able to swallow the capsule and the attached thread.

Patients in the intervention group who declined the Cytosponge-TFF3 and all patients assigned to the usual-care arm underwent endoscopy only at the recommendation of their primary practitioner.

During a mean follow-up of 12 months, 140 of the 6,834 patients in the intervention group (2%) were diagnosed with Barrett esophagus, compared with 13 of 6,388 patients in the usual-care group (0.2%). The absolute difference per 1000 person-years, the trial’s primary endpoint, was 18.3. The rate ratio adjusted for cluster randomization was 10.6 (P < .001).

A total of four patients in the intervention group were diagnosed with dysplastic Barrett esophagus, and five were diagnosed with stage I esophagogastric cancer. No patients in the usual-care group were diagnosed with either condition.

Of the 1,654 patients in the intervention group who opted for the Cytosponge device and swallowed it successfully, 221 underwent endoscopy after testing positive for TFF3. Of these patients, 131 (59%) were diagnosed with either Barrett esophagus or cancer.

The most common adverse event with the Cytosponge procedure was sore throat, reported by 4% of those who opted for it. In one patient, the thread became detach from the Cytopsonge, necessitating endoscopy to remove the device.

Promising, but refinements needed

In an editorial accompanying the study, Yuri Hanada, MD, and Kenneth K. Wang, MD, from the department of gastroenterology at the Mayo Clinic in Rochester, Minn., said that the Cytosponge-TFF3 procedure “is a promising nonendoscopic screening tool and will represent a component in the screening for Barrett’s esophagus and esophagogastric cancer.”

They noted, however, that it is unlikely to be the sole screening tool for Barrett esophagus and that its use in primary practice may be problematic during the COVID-19 pandemic, because of the release of aerosolized particles as the sponge is withdrawn from the esophagus.

“It might also be necessary to enrich disease prevalence in the screened population by limiting this population to males and people with other risk factors, in order to make this test more cost-effective than previously shown,” they wrote.

Acceptance rate low?

Dr. Meltzer noted that, despite being less invasive than endoscopy, only 39% of the group who could try it agreed to do so.

“It was kind of surprising, because in my experience, when I offer it to my patients, the acceptance is much higher, but that’s not in a controlled clinical trial situation, so I don’t really know what the true percentage is,” he said.

He pointed out that the patients he sees in his clinic are more likely to be symptomatic and highly motivated to accept a test, in contrast to the general patient population in the study.

He also noted that the endoscopy-confirmed prevalence rate of Barrett esophagus or cancer in 221 patients in the intervention group was 59%, suggesting that 41% underwent an unnecessary endoscopy after the Cytosponge screening.

Dr. Fitzgerald and colleagues acknowledged the potential for overdiagnosis with screening. They noted a debate as to whether 1 cm or short segments of Barrett esophagus are a cause for clinical concern.

They also note that the TFF3 test (used in the CytoSponge device) is sensitive and detects some short segments of Barrett esophagus and that, “since this was a pragmatic trial that relied on a coded diagnosis of Barrett’s esophagus, we also identified patients in the usual care group who had short segments of Barrett’s esophagus (1 cm or less in length) and were diagnosed as having the condition, reflecting the variable practice in U.K. hospitals.

“We expect that these patients can be reassured and probably do not require surveillance,” they continued. “This expectation is consistent with the clinical guidelines, which suggest that patients with over 1 cm of salmon-colored epithelium containing intestinal metaplasia should be monitored.”

The study was funded by Cancer Research UK, the U.K. National Institute for Health Research, the U.K. National Health Service, Medtronic, and the Medical Research Council. Dr. Fitzgerald is named on patents related to the Cytosponge-TFF3 test. Dr. Meltzer has cofounded a company, Capsulomics, to commercialize the methylation biomarker panel used in EsophaCap studies. Dr. Wang has received research funding from eNose for research on a device used in a screening study of Barrett esophagus.

Help your patients better understand the risks, testing and treatment options for Barrett’s esophagus by sharing education from the AGA GI Patient Center at http://ow.ly/p9hU30r4oya.

This article first appeared on Medscape.com.

An experimental cell-collection device that can be administered without anesthesia in a primary care practice was shown to be better at detecting Barrett esophagus than the standard of care in a community-based clinical trial.

Use of this patient-swallowed device, called Cytosponge-TFF3, could allow clinicians to diagnose esophageal conditions such as dysplasia or cancer at an earlier and potentially curable stage, said the investigators. However, it would also increase the likelihood of unnecessary endoscopies, owing to false-positive results.

“In this multicenter, pragmatic, randomized controlled trial we found that an invitation to have a Cytosponge-TFF3 test led to increased diagnosis of Barrett’s esophagus when compared with usual care by general practitioners,” write Rebecca C. Fitzgerald, MD, from the Hutchison/MRC Research Center in Cambridge, England, and colleagues.

The study was published online on Aug. 1 in The Lancet.

“This is a very important study, a landmark study,” said Stephen J. Meltzer, MD, professor of medicine and oncology at Johns Hopkins University, Baltimore, who was approached for comment.

“What it shows is that if you opt to have this procedure, you’re much more likely to have your Barrett’s diagnosed than if you don’t opt to have it,” he said.

He congratulated Dr. Fitzgerald and colleagues for successful completion of a large, primary practice–based clinical utility study.

“Those studies are very difficult to do. This is looking at the actual impact of an intervention, which is the sponge,” he said in an interview.

Soaking up cells

Dr. Meltzer was senior author of a case-control study published in 2019 in Clinical Cancer Research that described use of a similar device. As previously reported, that device, called EsophaCap, uses a “methylation on bead” technique to collect DNA on a swallowed sponge. The DNA is then extracted from the sponge and analyzed with a methylation biomarker panel.

Like the EsophaCap device, the Cytosponge-TFF3 device consists of a compressed, gelatin-coated collection sponge attached to a thread. The patient swallows the device. After the gelatin dissolves and the sponge expands, it is gently withdrawn through the esophagus, picking up cells as it passes through.

The collected cells are then analyzed with an in vitro test for biomarker trefoil factor 3 (TFF3), a sign of intestinal metaplasia that is a histopathologic hallmark of Barrett esophagus, the authors explained.

Cytosponge-TFF3 study

The study by Dr. Fitzgerald and colleagues was conducted in patients taking medications for gastroesophageal reflux. The patients were undergoing treatment at 109 general practice clinics in England.

Eligible patients included adults aged 50 years and older who had been taking acid-suppressing medication for gastroesophageal reflux for more than 6 months and had not undergone endoscopy within the previous 5 years.

The study was randomized at both the clinic level (cluster randomization) and the individual patient level. Patients were assigned to either standard management of gastroesophageal reflux, with endoscopies performed only if recommended by the practitioner, or to the intervention group, where individuals received usual care and were offered the Cytosponge-TFF3 procedure. Those patients whose samples yielded TFF3-positive cells subsequently underwent endoscopy.

Among 6,834 patients assigned to the intervention group, 2,679 (39%) expressed willingness to undergo the Cytosponge-TFF3 procedure. Of this group, 1,750 patients met all of the eligibility criteria on telephone screening and underwent the procedure.

The large majority of patients (95%) who agreed to undergo the procedure were able to swallow the capsule and the attached thread.

Patients in the intervention group who declined the Cytosponge-TFF3 and all patients assigned to the usual-care arm underwent endoscopy only at the recommendation of their primary practitioner.

During a mean follow-up of 12 months, 140 of the 6,834 patients in the intervention group (2%) were diagnosed with Barrett esophagus, compared with 13 of 6,388 patients in the usual-care group (0.2%). The absolute difference per 1000 person-years, the trial’s primary endpoint, was 18.3. The rate ratio adjusted for cluster randomization was 10.6 (P < .001).

A total of four patients in the intervention group were diagnosed with dysplastic Barrett esophagus, and five were diagnosed with stage I esophagogastric cancer. No patients in the usual-care group were diagnosed with either condition.

Of the 1,654 patients in the intervention group who opted for the Cytosponge device and swallowed it successfully, 221 underwent endoscopy after testing positive for TFF3. Of these patients, 131 (59%) were diagnosed with either Barrett esophagus or cancer.

The most common adverse event with the Cytosponge procedure was sore throat, reported by 4% of those who opted for it. In one patient, the thread became detach from the Cytopsonge, necessitating endoscopy to remove the device.

Promising, but refinements needed

In an editorial accompanying the study, Yuri Hanada, MD, and Kenneth K. Wang, MD, from the department of gastroenterology at the Mayo Clinic in Rochester, Minn., said that the Cytosponge-TFF3 procedure “is a promising nonendoscopic screening tool and will represent a component in the screening for Barrett’s esophagus and esophagogastric cancer.”

They noted, however, that it is unlikely to be the sole screening tool for Barrett esophagus and that its use in primary practice may be problematic during the COVID-19 pandemic, because of the release of aerosolized particles as the sponge is withdrawn from the esophagus.

“It might also be necessary to enrich disease prevalence in the screened population by limiting this population to males and people with other risk factors, in order to make this test more cost-effective than previously shown,” they wrote.

Acceptance rate low?

Dr. Meltzer noted that, despite being less invasive than endoscopy, only 39% of the group who could try it agreed to do so.

“It was kind of surprising, because in my experience, when I offer it to my patients, the acceptance is much higher, but that’s not in a controlled clinical trial situation, so I don’t really know what the true percentage is,” he said.

He pointed out that the patients he sees in his clinic are more likely to be symptomatic and highly motivated to accept a test, in contrast to the general patient population in the study.

He also noted that the endoscopy-confirmed prevalence rate of Barrett esophagus or cancer in 221 patients in the intervention group was 59%, suggesting that 41% underwent an unnecessary endoscopy after the Cytosponge screening.

Dr. Fitzgerald and colleagues acknowledged the potential for overdiagnosis with screening. They noted a debate as to whether 1 cm or short segments of Barrett esophagus are a cause for clinical concern.

They also note that the TFF3 test (used in the CytoSponge device) is sensitive and detects some short segments of Barrett esophagus and that, “since this was a pragmatic trial that relied on a coded diagnosis of Barrett’s esophagus, we also identified patients in the usual care group who had short segments of Barrett’s esophagus (1 cm or less in length) and were diagnosed as having the condition, reflecting the variable practice in U.K. hospitals.

“We expect that these patients can be reassured and probably do not require surveillance,” they continued. “This expectation is consistent with the clinical guidelines, which suggest that patients with over 1 cm of salmon-colored epithelium containing intestinal metaplasia should be monitored.”

The study was funded by Cancer Research UK, the U.K. National Institute for Health Research, the U.K. National Health Service, Medtronic, and the Medical Research Council. Dr. Fitzgerald is named on patents related to the Cytosponge-TFF3 test. Dr. Meltzer has cofounded a company, Capsulomics, to commercialize the methylation biomarker panel used in EsophaCap studies. Dr. Wang has received research funding from eNose for research on a device used in a screening study of Barrett esophagus.

Help your patients better understand the risks, testing and treatment options for Barrett’s esophagus by sharing education from the AGA GI Patient Center at http://ow.ly/p9hU30r4oya.

This article first appeared on Medscape.com.

An experimental cell-collection device that can be administered without anesthesia in a primary care practice was shown to be better at detecting Barrett esophagus than the standard of care in a community-based clinical trial.

Use of this patient-swallowed device, called Cytosponge-TFF3, could allow clinicians to diagnose esophageal conditions such as dysplasia or cancer at an earlier and potentially curable stage, said the investigators. However, it would also increase the likelihood of unnecessary endoscopies, owing to false-positive results.

“In this multicenter, pragmatic, randomized controlled trial we found that an invitation to have a Cytosponge-TFF3 test led to increased diagnosis of Barrett’s esophagus when compared with usual care by general practitioners,” write Rebecca C. Fitzgerald, MD, from the Hutchison/MRC Research Center in Cambridge, England, and colleagues.

The study was published online on Aug. 1 in The Lancet.

“This is a very important study, a landmark study,” said Stephen J. Meltzer, MD, professor of medicine and oncology at Johns Hopkins University, Baltimore, who was approached for comment.

“What it shows is that if you opt to have this procedure, you’re much more likely to have your Barrett’s diagnosed than if you don’t opt to have it,” he said.

He congratulated Dr. Fitzgerald and colleagues for successful completion of a large, primary practice–based clinical utility study.

“Those studies are very difficult to do. This is looking at the actual impact of an intervention, which is the sponge,” he said in an interview.

Soaking up cells

Dr. Meltzer was senior author of a case-control study published in 2019 in Clinical Cancer Research that described use of a similar device. As previously reported, that device, called EsophaCap, uses a “methylation on bead” technique to collect DNA on a swallowed sponge. The DNA is then extracted from the sponge and analyzed with a methylation biomarker panel.

Like the EsophaCap device, the Cytosponge-TFF3 device consists of a compressed, gelatin-coated collection sponge attached to a thread. The patient swallows the device. After the gelatin dissolves and the sponge expands, it is gently withdrawn through the esophagus, picking up cells as it passes through.

The collected cells are then analyzed with an in vitro test for biomarker trefoil factor 3 (TFF3), a sign of intestinal metaplasia that is a histopathologic hallmark of Barrett esophagus, the authors explained.

Cytosponge-TFF3 study

The study by Dr. Fitzgerald and colleagues was conducted in patients taking medications for gastroesophageal reflux. The patients were undergoing treatment at 109 general practice clinics in England.

Eligible patients included adults aged 50 years and older who had been taking acid-suppressing medication for gastroesophageal reflux for more than 6 months and had not undergone endoscopy within the previous 5 years.

The study was randomized at both the clinic level (cluster randomization) and the individual patient level. Patients were assigned to either standard management of gastroesophageal reflux, with endoscopies performed only if recommended by the practitioner, or to the intervention group, where individuals received usual care and were offered the Cytosponge-TFF3 procedure. Those patients whose samples yielded TFF3-positive cells subsequently underwent endoscopy.

Among 6,834 patients assigned to the intervention group, 2,679 (39%) expressed willingness to undergo the Cytosponge-TFF3 procedure. Of this group, 1,750 patients met all of the eligibility criteria on telephone screening and underwent the procedure.

The large majority of patients (95%) who agreed to undergo the procedure were able to swallow the capsule and the attached thread.

Patients in the intervention group who declined the Cytosponge-TFF3 and all patients assigned to the usual-care arm underwent endoscopy only at the recommendation of their primary practitioner.

During a mean follow-up of 12 months, 140 of the 6,834 patients in the intervention group (2%) were diagnosed with Barrett esophagus, compared with 13 of 6,388 patients in the usual-care group (0.2%). The absolute difference per 1000 person-years, the trial’s primary endpoint, was 18.3. The rate ratio adjusted for cluster randomization was 10.6 (P < .001).

A total of four patients in the intervention group were diagnosed with dysplastic Barrett esophagus, and five were diagnosed with stage I esophagogastric cancer. No patients in the usual-care group were diagnosed with either condition.

Of the 1,654 patients in the intervention group who opted for the Cytosponge device and swallowed it successfully, 221 underwent endoscopy after testing positive for TFF3. Of these patients, 131 (59%) were diagnosed with either Barrett esophagus or cancer.

The most common adverse event with the Cytosponge procedure was sore throat, reported by 4% of those who opted for it. In one patient, the thread became detach from the Cytopsonge, necessitating endoscopy to remove the device.

Promising, but refinements needed

In an editorial accompanying the study, Yuri Hanada, MD, and Kenneth K. Wang, MD, from the department of gastroenterology at the Mayo Clinic in Rochester, Minn., said that the Cytosponge-TFF3 procedure “is a promising nonendoscopic screening tool and will represent a component in the screening for Barrett’s esophagus and esophagogastric cancer.”

They noted, however, that it is unlikely to be the sole screening tool for Barrett esophagus and that its use in primary practice may be problematic during the COVID-19 pandemic, because of the release of aerosolized particles as the sponge is withdrawn from the esophagus.

“It might also be necessary to enrich disease prevalence in the screened population by limiting this population to males and people with other risk factors, in order to make this test more cost-effective than previously shown,” they wrote.

Acceptance rate low?

Dr. Meltzer noted that, despite being less invasive than endoscopy, only 39% of the group who could try it agreed to do so.

“It was kind of surprising, because in my experience, when I offer it to my patients, the acceptance is much higher, but that’s not in a controlled clinical trial situation, so I don’t really know what the true percentage is,” he said.

He pointed out that the patients he sees in his clinic are more likely to be symptomatic and highly motivated to accept a test, in contrast to the general patient population in the study.

He also noted that the endoscopy-confirmed prevalence rate of Barrett esophagus or cancer in 221 patients in the intervention group was 59%, suggesting that 41% underwent an unnecessary endoscopy after the Cytosponge screening.

Dr. Fitzgerald and colleagues acknowledged the potential for overdiagnosis with screening. They noted a debate as to whether 1 cm or short segments of Barrett esophagus are a cause for clinical concern.

They also note that the TFF3 test (used in the CytoSponge device) is sensitive and detects some short segments of Barrett esophagus and that, “since this was a pragmatic trial that relied on a coded diagnosis of Barrett’s esophagus, we also identified patients in the usual care group who had short segments of Barrett’s esophagus (1 cm or less in length) and were diagnosed as having the condition, reflecting the variable practice in U.K. hospitals.

“We expect that these patients can be reassured and probably do not require surveillance,” they continued. “This expectation is consistent with the clinical guidelines, which suggest that patients with over 1 cm of salmon-colored epithelium containing intestinal metaplasia should be monitored.”

The study was funded by Cancer Research UK, the U.K. National Institute for Health Research, the U.K. National Health Service, Medtronic, and the Medical Research Council. Dr. Fitzgerald is named on patents related to the Cytosponge-TFF3 test. Dr. Meltzer has cofounded a company, Capsulomics, to commercialize the methylation biomarker panel used in EsophaCap studies. Dr. Wang has received research funding from eNose for research on a device used in a screening study of Barrett esophagus.

This article first appeared on Medscape.com.

An experimental cell-collection device that can be administered without anesthesia in a primary care practice was shown to be better at detecting Barrett esophagus than the standard of care in a community-based clinical trial.

Use of this patient-swallowed device, called Cytosponge-TFF3, could allow clinicians to diagnose esophageal conditions such as dysplasia or cancer at an earlier and potentially curable stage, said the investigators. However, it would also increase the likelihood of unnecessary endoscopies, owing to false-positive results.

“In this multicenter, pragmatic, randomized controlled trial we found that an invitation to have a Cytosponge-TFF3 test led to increased diagnosis of Barrett’s esophagus when compared with usual care by general practitioners,” write Rebecca C. Fitzgerald, MD, from the Hutchison/MRC Research Center in Cambridge, England, and colleagues.

The study was published online on Aug. 1 in The Lancet.

“This is a very important study, a landmark study,” said Stephen J. Meltzer, MD, professor of medicine and oncology at Johns Hopkins University, Baltimore, who was approached for comment.

“What it shows is that if you opt to have this procedure, you’re much more likely to have your Barrett’s diagnosed than if you don’t opt to have it,” he said.

He congratulated Dr. Fitzgerald and colleagues for successful completion of a large, primary practice–based clinical utility study.

“Those studies are very difficult to do. This is looking at the actual impact of an intervention, which is the sponge,” he said in an interview.

Soaking up cells

Dr. Meltzer was senior author of a case-control study published in 2019 in Clinical Cancer Research that described use of a similar device. As previously reported, that device, called EsophaCap, uses a “methylation on bead” technique to collect DNA on a swallowed sponge. The DNA is then extracted from the sponge and analyzed with a methylation biomarker panel.

Like the EsophaCap device, the Cytosponge-TFF3 device consists of a compressed, gelatin-coated collection sponge attached to a thread. The patient swallows the device. After the gelatin dissolves and the sponge expands, it is gently withdrawn through the esophagus, picking up cells as it passes through.

The collected cells are then analyzed with an in vitro test for biomarker trefoil factor 3 (TFF3), a sign of intestinal metaplasia that is a histopathologic hallmark of Barrett esophagus, the authors explained.

Cytosponge-TFF3 study

The study by Dr. Fitzgerald and colleagues was conducted in patients taking medications for gastroesophageal reflux. The patients were undergoing treatment at 109 general practice clinics in England.

Eligible patients included adults aged 50 years and older who had been taking acid-suppressing medication for gastroesophageal reflux for more than 6 months and had not undergone endoscopy within the previous 5 years.

The study was randomized at both the clinic level (cluster randomization) and the individual patient level. Patients were assigned to either standard management of gastroesophageal reflux, with endoscopies performed only if recommended by the practitioner, or to the intervention group, where individuals received usual care and were offered the Cytosponge-TFF3 procedure. Those patients whose samples yielded TFF3-positive cells subsequently underwent endoscopy.

Among 6,834 patients assigned to the intervention group, 2,679 (39%) expressed willingness to undergo the Cytosponge-TFF3 procedure. Of this group, 1,750 patients met all of the eligibility criteria on telephone screening and underwent the procedure.

The large majority of patients (95%) who agreed to undergo the procedure were able to swallow the capsule and the attached thread.

Patients in the intervention group who declined the Cytosponge-TFF3 and all patients assigned to the usual-care arm underwent endoscopy only at the recommendation of their primary practitioner.

During a mean follow-up of 12 months, 140 of the 6,834 patients in the intervention group (2%) were diagnosed with Barrett esophagus, compared with 13 of 6,388 patients in the usual-care group (0.2%). The absolute difference per 1000 person-years, the trial’s primary endpoint, was 18.3. The rate ratio adjusted for cluster randomization was 10.6 (P < .001).

A total of four patients in the intervention group were diagnosed with dysplastic Barrett esophagus, and five were diagnosed with stage I esophagogastric cancer. No patients in the usual-care group were diagnosed with either condition.

Of the 1,654 patients in the intervention group who opted for the Cytosponge device and swallowed it successfully, 221 underwent endoscopy after testing positive for TFF3. Of these patients, 131 (59%) were diagnosed with either Barrett esophagus or cancer.

The most common adverse event with the Cytosponge procedure was sore throat, reported by 4% of those who opted for it. In one patient, the thread became detach from the Cytopsonge, necessitating endoscopy to remove the device.

Promising, but refinements needed

In an editorial accompanying the study, Yuri Hanada, MD, and Kenneth K. Wang, MD, from the department of gastroenterology at the Mayo Clinic in Rochester, Minn., said that the Cytosponge-TFF3 procedure “is a promising nonendoscopic screening tool and will represent a component in the screening for Barrett’s esophagus and esophagogastric cancer.”

They noted, however, that it is unlikely to be the sole screening tool for Barrett esophagus and that its use in primary practice may be problematic during the COVID-19 pandemic, because of the release of aerosolized particles as the sponge is withdrawn from the esophagus.

“It might also be necessary to enrich disease prevalence in the screened population by limiting this population to males and people with other risk factors, in order to make this test more cost-effective than previously shown,” they wrote.

Acceptance rate low?

Dr. Meltzer noted that, despite being less invasive than endoscopy, only 39% of the group who could try it agreed to do so.

“It was kind of surprising, because in my experience, when I offer it to my patients, the acceptance is much higher, but that’s not in a controlled clinical trial situation, so I don’t really know what the true percentage is,” he said.

He pointed out that the patients he sees in his clinic are more likely to be symptomatic and highly motivated to accept a test, in contrast to the general patient population in the study.

He also noted that the endoscopy-confirmed prevalence rate of Barrett esophagus or cancer in 221 patients in the intervention group was 59%, suggesting that 41% underwent an unnecessary endoscopy after the Cytosponge screening.

Dr. Fitzgerald and colleagues acknowledged the potential for overdiagnosis with screening. They noted a debate as to whether 1 cm or short segments of Barrett esophagus are a cause for clinical concern.

They also note that the TFF3 test (used in the CytoSponge device) is sensitive and detects some short segments of Barrett esophagus and that, “since this was a pragmatic trial that relied on a coded diagnosis of Barrett’s esophagus, we also identified patients in the usual care group who had short segments of Barrett’s esophagus (1 cm or less in length) and were diagnosed as having the condition, reflecting the variable practice in U.K. hospitals.

“We expect that these patients can be reassured and probably do not require surveillance,” they continued. “This expectation is consistent with the clinical guidelines, which suggest that patients with over 1 cm of salmon-colored epithelium containing intestinal metaplasia should be monitored.”

The study was funded by Cancer Research UK, the U.K. National Institute for Health Research, the U.K. National Health Service, Medtronic, and the Medical Research Council. Dr. Fitzgerald is named on patents related to the Cytosponge-TFF3 test. Dr. Meltzer has cofounded a company, Capsulomics, to commercialize the methylation biomarker panel used in EsophaCap studies. Dr. Wang has received research funding from eNose for research on a device used in a screening study of Barrett esophagus.

This article first appeared on Medscape.com.

An experimental cell-collection device that can be administered without anesthesia in a primary care practice was shown to be better at detecting Barrett esophagus than the standard of care in a community-based clinical trial.

Use of this patient-swallowed device, called Cytosponge-TFF3, could allow clinicians to diagnose esophageal conditions such as dysplasia or cancer at an earlier and potentially curable stage, said the investigators. However, it would also increase the likelihood of unnecessary endoscopies, owing to false-positive results.

“In this multicenter, pragmatic, randomized controlled trial we found that an invitation to have a Cytosponge-TFF3 test led to increased diagnosis of Barrett’s esophagus when compared with usual care by general practitioners,” write Rebecca C. Fitzgerald, MD, from the Hutchison/MRC Research Center in Cambridge, England, and colleagues.

The study was published online on Aug. 1 in The Lancet.

“This is a very important study, a landmark study,” said Stephen J. Meltzer, MD, professor of medicine and oncology at Johns Hopkins University, Baltimore, who was approached for comment.

“What it shows is that if you opt to have this procedure, you’re much more likely to have your Barrett’s diagnosed than if you don’t opt to have it,” he said.

He congratulated Dr. Fitzgerald and colleagues for successful completion of a large, primary practice–based clinical utility study.

“Those studies are very difficult to do. This is looking at the actual impact of an intervention, which is the sponge,” he said in an interview.

Soaking up cells

Dr. Meltzer was senior author of a case-control study published in 2019 in Clinical Cancer Research that described use of a similar device. As previously reported, that device, called EsophaCap, uses a “methylation on bead” technique to collect DNA on a swallowed sponge. The DNA is then extracted from the sponge and analyzed with a methylation biomarker panel.

Like the EsophaCap device, the Cytosponge-TFF3 device consists of a compressed, gelatin-coated collection sponge attached to a thread. The patient swallows the device. After the gelatin dissolves and the sponge expands, it is gently withdrawn through the esophagus, picking up cells as it passes through.

The collected cells are then analyzed with an in vitro test for biomarker trefoil factor 3 (TFF3), a sign of intestinal metaplasia that is a histopathologic hallmark of Barrett esophagus, the authors explained.

Cytosponge-TFF3 study

The study by Dr. Fitzgerald and colleagues was conducted in patients taking medications for gastroesophageal reflux. The patients were undergoing treatment at 109 general practice clinics in England.

Eligible patients included adults aged 50 years and older who had been taking acid-suppressing medication for gastroesophageal reflux for more than 6 months and had not undergone endoscopy within the previous 5 years.

The study was randomized at both the clinic level (cluster randomization) and the individual patient level. Patients were assigned to either standard management of gastroesophageal reflux, with endoscopies performed only if recommended by the practitioner, or to the intervention group, where individuals received usual care and were offered the Cytosponge-TFF3 procedure. Those patients whose samples yielded TFF3-positive cells subsequently underwent endoscopy.

Among 6,834 patients assigned to the intervention group, 2,679 (39%) expressed willingness to undergo the Cytosponge-TFF3 procedure. Of this group, 1,750 patients met all of the eligibility criteria on telephone screening and underwent the procedure.

The large majority of patients (95%) who agreed to undergo the procedure were able to swallow the capsule and the attached thread.

Patients in the intervention group who declined the Cytosponge-TFF3 and all patients assigned to the usual-care arm underwent endoscopy only at the recommendation of their primary practitioner.

During a mean follow-up of 12 months, 140 of the 6,834 patients in the intervention group (2%) were diagnosed with Barrett esophagus, compared with 13 of 6,388 patients in the usual-care group (0.2%). The absolute difference per 1000 person-years, the trial’s primary endpoint, was 18.3. The rate ratio adjusted for cluster randomization was 10.6 (P < .001).

A total of four patients in the intervention group were diagnosed with dysplastic Barrett esophagus, and five were diagnosed with stage I esophagogastric cancer. No patients in the usual-care group were diagnosed with either condition.

Of the 1,654 patients in the intervention group who opted for the Cytosponge device and swallowed it successfully, 221 underwent endoscopy after testing positive for TFF3. Of these patients, 131 (59%) were diagnosed with either Barrett esophagus or cancer.

The most common adverse event with the Cytosponge procedure was sore throat, reported by 4% of those who opted for it. In one patient, the thread became detach from the Cytopsonge, necessitating endoscopy to remove the device.

Promising, but refinements needed

In an editorial accompanying the study, Yuri Hanada, MD, and Kenneth K. Wang, MD, from the department of gastroenterology at the Mayo Clinic in Rochester, Minn., said that the Cytosponge-TFF3 procedure “is a promising nonendoscopic screening tool and will represent a component in the screening for Barrett’s esophagus and esophagogastric cancer.”

They noted, however, that it is unlikely to be the sole screening tool for Barrett esophagus and that its use in primary practice may be problematic during the COVID-19 pandemic, because of the release of aerosolized particles as the sponge is withdrawn from the esophagus.

“It might also be necessary to enrich disease prevalence in the screened population by limiting this population to males and people with other risk factors, in order to make this test more cost-effective than previously shown,” they wrote.

Acceptance rate low?

Dr. Meltzer noted that, despite being less invasive than endoscopy, only 39% of the group who could try it agreed to do so.

“It was kind of surprising, because in my experience, when I offer it to my patients, the acceptance is much higher, but that’s not in a controlled clinical trial situation, so I don’t really know what the true percentage is,” he said.

He pointed out that the patients he sees in his clinic are more likely to be symptomatic and highly motivated to accept a test, in contrast to the general patient population in the study.

He also noted that the endoscopy-confirmed prevalence rate of Barrett esophagus or cancer in 221 patients in the intervention group was 59%, suggesting that 41% underwent an unnecessary endoscopy after the Cytosponge screening.

Dr. Fitzgerald and colleagues acknowledged the potential for overdiagnosis with screening. They noted a debate as to whether 1 cm or short segments of Barrett esophagus are a cause for clinical concern.

They also note that the TFF3 test (used in the CytoSponge device) is sensitive and detects some short segments of Barrett esophagus and that, “since this was a pragmatic trial that relied on a coded diagnosis of Barrett’s esophagus, we also identified patients in the usual care group who had short segments of Barrett’s esophagus (1 cm or less in length) and were diagnosed as having the condition, reflecting the variable practice in U.K. hospitals.

“We expect that these patients can be reassured and probably do not require surveillance,” they continued. “This expectation is consistent with the clinical guidelines, which suggest that patients with over 1 cm of salmon-colored epithelium containing intestinal metaplasia should be monitored.”

The study was funded by Cancer Research UK, the U.K. National Institute for Health Research, the U.K. National Health Service, Medtronic, and the Medical Research Council. Dr. Fitzgerald is named on patents related to the Cytosponge-TFF3 test. Dr. Meltzer has cofounded a company, Capsulomics, to commercialize the methylation biomarker panel used in EsophaCap studies. Dr. Wang has received research funding from eNose for research on a device used in a screening study of Barrett esophagus.

This article first appeared on Medscape.com.

As if the management of patients with severe COVID-19 infections is not complicated enough, an estimated 50%-60% of patients admitted to an ICU with the disease will have some form of cardiovascular involvement, which further increases their already high risk for morbidity and mortality.

Multimodality cardiovascular imaging, chosen wisely, can both help to direct management of cardiovascular complications associated with COVID-19 and lessen risk of exposure of health care workers to SARS-CoV-2, said members of an expert panel from the American College of Cardiology Cardiovascular Imaging Leadership Council.

“When we face a patient with known or suspected COVID-19, it’s not like any other disease because we face potential exposure risk to personnel doing imaging studies and also to other patients,” corresponding author Marcelo F. Di Carli, MD, of Brigham and Women’s Hospital Boston said in an interview.

“Any imaging study that is being considered should be performed only if we think it will help us make a change in the way that we’re going to treat that particular patient. This is true for imaging in any disease – why would you do an imaging study that will make no difference in treatment? – but the stakes are even higher in COVID-19,” he said.

The panel’s recommendations for cardiovascular imaging in patients with COVID-19 are outlined in a guidance document published online in the Journal of the American College of Cardiology.
 

Testing and biomarkers

The guidance begins by highlighting the importance of diagnostic testing for COVID-19 infection and the use of universal precautions for health care personnel performing imaging studies, as well as disinfection of imaging equipment and rooms after each use.

Circulating biomarkers that measure end-organ stress or injury, inflammation, hypoperfusion, and activation of thrombosis/hemostasis pathways may be prognostically useful, but “almost none of the widely measured biomarkers represent a specific trigger for imaging outside of that supported by clinical judgment,” the guidance states.

In contrast, low to moderate, nonrising concentrations of markers for myocardial stress, such as B-type natriuretic peptide (BNP) and N-terminal pro-BNP (NT-proBNP), or of myocardial injury, such as cardiac troponins (cTn), may be helpful for excluding the need for imaging.

“Importantly, clinicians should be aware that most patients with abnormal BNP/NT-proBNP or cTn do not have acute heart failure or myocardial infarction; and rise in concentration of either class of biomarker presumably reflects complex processes including direct myocardial stress/injury related to systemic illness,” the panel members wrote.
 

Oldies but goodies

“One thing that we found out in our review of the literature and in our experiences in our own work settings is that cardiac ultrasound plays a huge role in this disease – like in any disease – but this one in particular,” Dr. Di Carli said. “One of the most feared complications in COVID-19 leads to inflammation of the heart muscle, which then leads to heart dysfunction. And of course cardiac ultrasound, because of its portability, can be performed at bedside to help clinicians ascertain an abnormality in the heart.”

Cardiac CT is also extremely helpful for determining whether patients with ECG findings suggestive of infarction have suffered an actual thrombotic event.

“These patients may best be served by a noninvasive study as compared to an invasive coronary angiogram,” he said.
 

Clinical scenarios

Cardiologists may be called in to consult on the evaluation of possible cardiogenic components of pulmonary abnormalities in patients who present with dyspnea and chest x-rays showing airspace or interstitial infiltrates suggestive of pneumonia, the authors noted.

“Clinicians will rely on history, physical exam, ECG [electrocardiogram] and biomarkers, and recent cardiac imaging tests if available. Underlying cardiac history including [coronary artery disease], cardiomyopathy, heart failure, and arrhythmia should be sought, and frequent contributors to decompensation should be eliminated,” they wrote.

For patients with suspected cardiac injury, either point-of-care ultrasound or limited echocardiography can be used for the initial evaluation, with additional, more advanced technologies called into play for specific clinical scenarios outlined in the guidance.

For example, the guidance recommends that patients with chest pain and abnormal ECG readings with clinical concern for ST-elevation acute coronary syndrome or high clinical risk for in-hospital mortality from conditions such as cardiogenic shock, dynamic ST-segment changes, or left ventricular ejection fraction less than 40% thought to be caused by non–ST-elevation myocardial infarction be referred for emergent coronary angiography and reperfusion.

In contrast, in patients with chest pain and abnormal ECG but equivocal symptoms, atypical or equivocal ECG abnormalities, or late presentations, point-of-care ultrasound or limited echocardiogram could be used to look for regional wall motion abnormalities and left ventricular ejection fraction, whereas in patients with chest pain and ST-elevation without clear evidence of ST-elevation myocardial infarction, coronary CT angiography can help to rule out ACS and point to alternate diagnoses, the authors said.

The guidance also offers recommendations for imaging in patients with hemodynamic instability (shock or hypotension), patients with new left ventricular dysfunction in the absence of shock or hypotension, and patients with subacute and chronic-phase disease.

Development of the guidance document was supported by the ACC. Dr. Di Carli disclosed institutional grant support from Gilead Sciences and Spectrum Dynamics, and consulting income from Janssen and Bayer.

SOURCE: Rudski L et al. J Am Coll Cardiol. 2020 Jul 22. doi: 10.1016/j.jacc.2020.06.080.

As if the management of patients with severe COVID-19 infections is not complicated enough, an estimated 50%-60% of patients admitted to an ICU with the disease will have some form of cardiovascular involvement, which further increases their already high risk for morbidity and mortality.

Multimodality cardiovascular imaging, chosen wisely, can both help to direct management of cardiovascular complications associated with COVID-19 and lessen risk of exposure of health care workers to SARS-CoV-2, said members of an expert panel from the American College of Cardiology Cardiovascular Imaging Leadership Council.

“When we face a patient with known or suspected COVID-19, it’s not like any other disease because we face potential exposure risk to personnel doing imaging studies and also to other patients,” corresponding author Marcelo F. Di Carli, MD, of Brigham and Women’s Hospital Boston said in an interview.

“Any imaging study that is being considered should be performed only if we think it will help us make a change in the way that we’re going to treat that particular patient. This is true for imaging in any disease – why would you do an imaging study that will make no difference in treatment? – but the stakes are even higher in COVID-19,” he said.

The panel’s recommendations for cardiovascular imaging in patients with COVID-19 are outlined in a guidance document published online in the Journal of the American College of Cardiology.
 

Testing and biomarkers

The guidance begins by highlighting the importance of diagnostic testing for COVID-19 infection and the use of universal precautions for health care personnel performing imaging studies, as well as disinfection of imaging equipment and rooms after each use.

Circulating biomarkers that measure end-organ stress or injury, inflammation, hypoperfusion, and activation of thrombosis/hemostasis pathways may be prognostically useful, but “almost none of the widely measured biomarkers represent a specific trigger for imaging outside of that supported by clinical judgment,” the guidance states.

In contrast, low to moderate, nonrising concentrations of markers for myocardial stress, such as B-type natriuretic peptide (BNP) and N-terminal pro-BNP (NT-proBNP), or of myocardial injury, such as cardiac troponins (cTn), may be helpful for excluding the need for imaging.

“Importantly, clinicians should be aware that most patients with abnormal BNP/NT-proBNP or cTn do not have acute heart failure or myocardial infarction; and rise in concentration of either class of biomarker presumably reflects complex processes including direct myocardial stress/injury related to systemic illness,” the panel members wrote.
 

Oldies but goodies

“One thing that we found out in our review of the literature and in our experiences in our own work settings is that cardiac ultrasound plays a huge role in this disease – like in any disease – but this one in particular,” Dr. Di Carli said. “One of the most feared complications in COVID-19 leads to inflammation of the heart muscle, which then leads to heart dysfunction. And of course cardiac ultrasound, because of its portability, can be performed at bedside to help clinicians ascertain an abnormality in the heart.”

Cardiac CT is also extremely helpful for determining whether patients with ECG findings suggestive of infarction have suffered an actual thrombotic event.

“These patients may best be served by a noninvasive study as compared to an invasive coronary angiogram,” he said.
 

Clinical scenarios

Cardiologists may be called in to consult on the evaluation of possible cardiogenic components of pulmonary abnormalities in patients who present with dyspnea and chest x-rays showing airspace or interstitial infiltrates suggestive of pneumonia, the authors noted.

“Clinicians will rely on history, physical exam, ECG [electrocardiogram] and biomarkers, and recent cardiac imaging tests if available. Underlying cardiac history including [coronary artery disease], cardiomyopathy, heart failure, and arrhythmia should be sought, and frequent contributors to decompensation should be eliminated,” they wrote.

For patients with suspected cardiac injury, either point-of-care ultrasound or limited echocardiography can be used for the initial evaluation, with additional, more advanced technologies called into play for specific clinical scenarios outlined in the guidance.

For example, the guidance recommends that patients with chest pain and abnormal ECG readings with clinical concern for ST-elevation acute coronary syndrome or high clinical risk for in-hospital mortality from conditions such as cardiogenic shock, dynamic ST-segment changes, or left ventricular ejection fraction less than 40% thought to be caused by non–ST-elevation myocardial infarction be referred for emergent coronary angiography and reperfusion.

In contrast, in patients with chest pain and abnormal ECG but equivocal symptoms, atypical or equivocal ECG abnormalities, or late presentations, point-of-care ultrasound or limited echocardiogram could be used to look for regional wall motion abnormalities and left ventricular ejection fraction, whereas in patients with chest pain and ST-elevation without clear evidence of ST-elevation myocardial infarction, coronary CT angiography can help to rule out ACS and point to alternate diagnoses, the authors said.

The guidance also offers recommendations for imaging in patients with hemodynamic instability (shock or hypotension), patients with new left ventricular dysfunction in the absence of shock or hypotension, and patients with subacute and chronic-phase disease.

Development of the guidance document was supported by the ACC. Dr. Di Carli disclosed institutional grant support from Gilead Sciences and Spectrum Dynamics, and consulting income from Janssen and Bayer.

SOURCE: Rudski L et al. J Am Coll Cardiol. 2020 Jul 22. doi: 10.1016/j.jacc.2020.06.080.

As if the management of patients with severe COVID-19 infections is not complicated enough, an estimated 50%-60% of patients admitted to an ICU with the disease will have some form of cardiovascular involvement, which further increases their already high risk for morbidity and mortality.

Multimodality cardiovascular imaging, chosen wisely, can both help to direct management of cardiovascular complications associated with COVID-19 and lessen risk of exposure of health care workers to SARS-CoV-2, said members of an expert panel from the American College of Cardiology Cardiovascular Imaging Leadership Council.

“When we face a patient with known or suspected COVID-19, it’s not like any other disease because we face potential exposure risk to personnel doing imaging studies and also to other patients,” corresponding author Marcelo F. Di Carli, MD, of Brigham and Women’s Hospital Boston said in an interview.

“Any imaging study that is being considered should be performed only if we think it will help us make a change in the way that we’re going to treat that particular patient. This is true for imaging in any disease – why would you do an imaging study that will make no difference in treatment? – but the stakes are even higher in COVID-19,” he said.

The panel’s recommendations for cardiovascular imaging in patients with COVID-19 are outlined in a guidance document published online in the Journal of the American College of Cardiology.
 

Testing and biomarkers

The guidance begins by highlighting the importance of diagnostic testing for COVID-19 infection and the use of universal precautions for health care personnel performing imaging studies, as well as disinfection of imaging equipment and rooms after each use.

Circulating biomarkers that measure end-organ stress or injury, inflammation, hypoperfusion, and activation of thrombosis/hemostasis pathways may be prognostically useful, but “almost none of the widely measured biomarkers represent a specific trigger for imaging outside of that supported by clinical judgment,” the guidance states.

In contrast, low to moderate, nonrising concentrations of markers for myocardial stress, such as B-type natriuretic peptide (BNP) and N-terminal pro-BNP (NT-proBNP), or of myocardial injury, such as cardiac troponins (cTn), may be helpful for excluding the need for imaging.

“Importantly, clinicians should be aware that most patients with abnormal BNP/NT-proBNP or cTn do not have acute heart failure or myocardial infarction; and rise in concentration of either class of biomarker presumably reflects complex processes including direct myocardial stress/injury related to systemic illness,” the panel members wrote.
 

Oldies but goodies

“One thing that we found out in our review of the literature and in our experiences in our own work settings is that cardiac ultrasound plays a huge role in this disease – like in any disease – but this one in particular,” Dr. Di Carli said. “One of the most feared complications in COVID-19 leads to inflammation of the heart muscle, which then leads to heart dysfunction. And of course cardiac ultrasound, because of its portability, can be performed at bedside to help clinicians ascertain an abnormality in the heart.”

Cardiac CT is also extremely helpful for determining whether patients with ECG findings suggestive of infarction have suffered an actual thrombotic event.

“These patients may best be served by a noninvasive study as compared to an invasive coronary angiogram,” he said.
 

Clinical scenarios

Cardiologists may be called in to consult on the evaluation of possible cardiogenic components of pulmonary abnormalities in patients who present with dyspnea and chest x-rays showing airspace or interstitial infiltrates suggestive of pneumonia, the authors noted.

“Clinicians will rely on history, physical exam, ECG [electrocardiogram] and biomarkers, and recent cardiac imaging tests if available. Underlying cardiac history including [coronary artery disease], cardiomyopathy, heart failure, and arrhythmia should be sought, and frequent contributors to decompensation should be eliminated,” they wrote.

For patients with suspected cardiac injury, either point-of-care ultrasound or limited echocardiography can be used for the initial evaluation, with additional, more advanced technologies called into play for specific clinical scenarios outlined in the guidance.

For example, the guidance recommends that patients with chest pain and abnormal ECG readings with clinical concern for ST-elevation acute coronary syndrome or high clinical risk for in-hospital mortality from conditions such as cardiogenic shock, dynamic ST-segment changes, or left ventricular ejection fraction less than 40% thought to be caused by non–ST-elevation myocardial infarction be referred for emergent coronary angiography and reperfusion.

In contrast, in patients with chest pain and abnormal ECG but equivocal symptoms, atypical or equivocal ECG abnormalities, or late presentations, point-of-care ultrasound or limited echocardiogram could be used to look for regional wall motion abnormalities and left ventricular ejection fraction, whereas in patients with chest pain and ST-elevation without clear evidence of ST-elevation myocardial infarction, coronary CT angiography can help to rule out ACS and point to alternate diagnoses, the authors said.

The guidance also offers recommendations for imaging in patients with hemodynamic instability (shock or hypotension), patients with new left ventricular dysfunction in the absence of shock or hypotension, and patients with subacute and chronic-phase disease.

Development of the guidance document was supported by the ACC. Dr. Di Carli disclosed institutional grant support from Gilead Sciences and Spectrum Dynamics, and consulting income from Janssen and Bayer.

SOURCE: Rudski L et al. J Am Coll Cardiol. 2020 Jul 22. doi: 10.1016/j.jacc.2020.06.080.