Background: Mortality rates in critically ill patients remain in excess of 20% in many institutions. In the last 2 decades, palliative care has become a core component of ICU care. Current literature recommends a palliative care consult in the ICU setting; however, implementing this recommendation in a meaningful way has been challenging. The purpose of this study is to evaluate whether consulting palliative care in ICU earlier improves patient outcomes.

The primary outcome of this study was a change in code status to Do Not Resuscitate/Do Not Intubate (DNR/DNI), which was significantly higher in the intervention group (50.5% vs. 23.4%; P less than .0001). The intervention group also had more hospice discharges, fewer ventilated days, a lower rate of tracheostomy, and fewer hospital readmissions. However, mortality and ICU/hospital length of stay were not significantly different between the two arms. Limitations of this study include using a single academic center and the fact that establishing a DNR/DNI may not measure quality of life or patient/family satisfaction. Further studies are needed to focus on clinical outcomes as well as patient and family satisfaction.

Bottom line: Early goal-directed palliative care consults with experienced clinicians board certified in palliative care influences goals of care, code status, and discharge plans for the critically ill and can improve medical resource utilization.

Citation: Ma J et al. Early palliative care consultation in the medical ICU: A cluster randomized crossover trial. Crit Care Med. 2019 Dec;47: 1707-15.

Dr. Ahmed is assistant professor in the division of hospital medicine, Loyola University Medical Center, Maywood, Ill.

Background: Mortality rates in critically ill patients remain in excess of 20% in many institutions. In the last 2 decades, palliative care has become a core component of ICU care. Current literature recommends a palliative care consult in the ICU setting; however, implementing this recommendation in a meaningful way has been challenging. The purpose of this study is to evaluate whether consulting palliative care in ICU earlier improves patient outcomes.

The primary outcome of this study was a change in code status to Do Not Resuscitate/Do Not Intubate (DNR/DNI), which was significantly higher in the intervention group (50.5% vs. 23.4%; P less than .0001). The intervention group also had more hospice discharges, fewer ventilated days, a lower rate of tracheostomy, and fewer hospital readmissions. However, mortality and ICU/hospital length of stay were not significantly different between the two arms. Limitations of this study include using a single academic center and the fact that establishing a DNR/DNI may not measure quality of life or patient/family satisfaction. Further studies are needed to focus on clinical outcomes as well as patient and family satisfaction.

Bottom line: Early goal-directed palliative care consults with experienced clinicians board certified in palliative care influences goals of care, code status, and discharge plans for the critically ill and can improve medical resource utilization.

Citation: Ma J et al. Early palliative care consultation in the medical ICU: A cluster randomized crossover trial. Crit Care Med. 2019 Dec;47: 1707-15.

Dr. Ahmed is assistant professor in the division of hospital medicine, Loyola University Medical Center, Maywood, Ill.

Background: Mortality rates in critically ill patients remain in excess of 20% in many institutions. In the last 2 decades, palliative care has become a core component of ICU care. Current literature recommends a palliative care consult in the ICU setting; however, implementing this recommendation in a meaningful way has been challenging. The purpose of this study is to evaluate whether consulting palliative care in ICU earlier improves patient outcomes.

The primary outcome of this study was a change in code status to Do Not Resuscitate/Do Not Intubate (DNR/DNI), which was significantly higher in the intervention group (50.5% vs. 23.4%; P less than .0001). The intervention group also had more hospice discharges, fewer ventilated days, a lower rate of tracheostomy, and fewer hospital readmissions. However, mortality and ICU/hospital length of stay were not significantly different between the two arms. Limitations of this study include using a single academic center and the fact that establishing a DNR/DNI may not measure quality of life or patient/family satisfaction. Further studies are needed to focus on clinical outcomes as well as patient and family satisfaction.

Bottom line: Early goal-directed palliative care consults with experienced clinicians board certified in palliative care influences goals of care, code status, and discharge plans for the critically ill and can improve medical resource utilization.

Citation: Ma J et al. Early palliative care consultation in the medical ICU: A cluster randomized crossover trial. Crit Care Med. 2019 Dec;47: 1707-15.

Dr. Ahmed is assistant professor in the division of hospital medicine, Loyola University Medical Center, Maywood, Ill.

As second- or third-line therapy in patients with locally advanced non–small cell lung cancer (NSCLC), tislelizumab was well tolerated and prolonged overall survival (OS), compared with docetaxel in the phase 3 RATIONALE 303 study.

The results were presented at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract CT039).

Tislelizumab is an anti–PD-1 antibody engineered to minimize Fc-gamma receptor binding on macrophages, a mechanism of T-cell clearance and potential anti–PD-1 resistance, according to investigator Caicun Zhou, MD, PhD, of Shanghai (China) Pulmonary Hospital.

Tislelizumab is approved for the treatment of relapsed/refractory classical Hodgkin lymphoma, the second-line treatment of locally advanced or metastatic urothelial carcinoma, and first-line treatment of advanced squamous NSCLC in China.

In patients with locally advanced or metastatic NSCLC whose disease has progressed after initial platinum-based chemotherapy, anti–PD-1/PD-L1 therapies have been shown to improve OS by 2-4 months versus docetaxel, Dr. Zhou said. A phase 1/2 study of second-line tislelizumab demonstrated antitumor activity in multiple advanced solid tumors, including NSCLC.

The phase 3 RATIONALE 303 study (NCT3358875) was designed to investigate the efficacy and safety of tislelizumab, compared with docetaxel in patients with locally advanced or metastatic NSCLC whose disease had progressed during or after platinum-containing doublet chemotherapy.
 

Study details

RATIONALE 303 enrolled 805 patients who had received up to two prior lines of systemic therapy and had no known EGFR mutations or ALK fusions.

The patients’ median age was 61 years, about 77% were male, about 80% were Asian, and about 70% were current or former smokers. Roughly 46% of patients had squamous histology, and about 43% had PD-L1 expression of 25% or greater.

Patients were stratified according to histology (squamous vs. nonsquamous), lines of prior therapy (second vs. third), and PD-L1 status (<25% vs. ≥25%).

Patients were randomized 2:1 to receive IV tislelizumab at 200 mg every 3 weeks (n = 535) or IV docetaxel at 75 mg/m² every 3 weeks (n = 270) until unacceptable toxicity or disease progression.

The dual primary endpoints were OS in the intention-to-treat (ITT) population and in patients with PD-L1 expression of 25% or higher.
 

Survival and safety

In the ITT population, the 1-year OS rate was 61.9% in the tislelizumab arm and 49.8% in the docetaxel arm. At 2 years, the OS rates were 39.4% and 25.0%, respectively.

The median OS was 17.2 months in the tislelizumab arm and 11.9 months in the docetaxel arm (hazard ratio, 0.64; 95% CI, 0.53-0.78; P < .0001).

In the PD-L1–high subgroup, the median OS was 19.1 months with tislelizumab and 11.9 months with docetaxel (HR, 0.52; 95% CI, 0.38-0.71; P < .0001). The 1-year OS rates in this group were 67.5% and 49.1%, respectively, and the 2-year OS rates were 44.7% and 24.5%, respectively.

The OS benefit with tislelizumab was observed across nearly all subgroups, Dr. Zhou noted.

In the ITT population, benefits were seen with tislelizumab over docetaxel for progression-free survival (4.1 months vs. 2.6 months, P < .0001), objective response rate (21.9% vs. 7.1%, P < .0001), and median duration of response (13.5 months vs. 6.2 months, P < .0001).

The rate of treatment-related adverse events (TRAEs) was 73.0% in the tislelizumab arm and 93.8% in the docetaxel arm. Rates of grade 3 or higher TRAEs were 14.4% and 66.3%, respectively. Rates of TRAEs leading to permanent discontinuation of treatment were 6.0% and 9.7%, respectively, and rates of TRAEs leading to death were 1.5% and 1.6%, respectively.

The most common treatment-emergent adverse events were anemia in the tislelizumab arm (28.5%) and alopecia in the docetaxel arm (47.3%). The most common grade 3 or higher treatment-emergent adverse event was neutropenia in the docetaxel arm (27.9% vs. 0.6% with tislelizumab).
 

‘Very important trial’

“RATIONALE 303 demonstrated that, as second- or third-line therapy in patients with advanced NSCLC, tislelizumab was tolerable and prolonged overall survival by 5-7 months. It also improved progression-free survival and objective response rate versus docetaxel, regardless of histology or PD-L1 expression,” Dr. Zhou concluded.

Session moderator Marina Chiara Garassino, MD, of the University of Chicago called RATIONALE 303 a “very important trial.”

Citing the range of immunotherapies available for NSCLC, Dr. Garassino said, “We have a very crowded space in the treatment of NSCLC. ... It is difficult to do a direct comparison [of immunotherapy trials] because we know that populations can be different and other factors can play a role. In the near future, we have to understand if they are all the same and interchangeable or if they are different.”

RATIONALE 303 was funded by BeiGene. Dr. Zhou disclosed relationships with Lily China, Sanofi, Roche, and several other companies, not including BeiGene. Dr. Garassino disclosed relationships with AstraZeneca, Novartis, Bristol-Myers Squibb, and several other companies, not including BeiGene.

As second- or third-line therapy in patients with locally advanced non–small cell lung cancer (NSCLC), tislelizumab was well tolerated and prolonged overall survival (OS), compared with docetaxel in the phase 3 RATIONALE 303 study.

The results were presented at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract CT039).

Tislelizumab is an anti–PD-1 antibody engineered to minimize Fc-gamma receptor binding on macrophages, a mechanism of T-cell clearance and potential anti–PD-1 resistance, according to investigator Caicun Zhou, MD, PhD, of Shanghai (China) Pulmonary Hospital.

Tislelizumab is approved for the treatment of relapsed/refractory classical Hodgkin lymphoma, the second-line treatment of locally advanced or metastatic urothelial carcinoma, and first-line treatment of advanced squamous NSCLC in China.

In patients with locally advanced or metastatic NSCLC whose disease has progressed after initial platinum-based chemotherapy, anti–PD-1/PD-L1 therapies have been shown to improve OS by 2-4 months versus docetaxel, Dr. Zhou said. A phase 1/2 study of second-line tislelizumab demonstrated antitumor activity in multiple advanced solid tumors, including NSCLC.

The phase 3 RATIONALE 303 study (NCT3358875) was designed to investigate the efficacy and safety of tislelizumab, compared with docetaxel in patients with locally advanced or metastatic NSCLC whose disease had progressed during or after platinum-containing doublet chemotherapy.
 

Study details

RATIONALE 303 enrolled 805 patients who had received up to two prior lines of systemic therapy and had no known EGFR mutations or ALK fusions.

The patients’ median age was 61 years, about 77% were male, about 80% were Asian, and about 70% were current or former smokers. Roughly 46% of patients had squamous histology, and about 43% had PD-L1 expression of 25% or greater.

Patients were stratified according to histology (squamous vs. nonsquamous), lines of prior therapy (second vs. third), and PD-L1 status (<25% vs. ≥25%).

Patients were randomized 2:1 to receive IV tislelizumab at 200 mg every 3 weeks (n = 535) or IV docetaxel at 75 mg/m² every 3 weeks (n = 270) until unacceptable toxicity or disease progression.

The dual primary endpoints were OS in the intention-to-treat (ITT) population and in patients with PD-L1 expression of 25% or higher.
 

Survival and safety

In the ITT population, the 1-year OS rate was 61.9% in the tislelizumab arm and 49.8% in the docetaxel arm. At 2 years, the OS rates were 39.4% and 25.0%, respectively.

The median OS was 17.2 months in the tislelizumab arm and 11.9 months in the docetaxel arm (hazard ratio, 0.64; 95% CI, 0.53-0.78; P < .0001).

In the PD-L1–high subgroup, the median OS was 19.1 months with tislelizumab and 11.9 months with docetaxel (HR, 0.52; 95% CI, 0.38-0.71; P < .0001). The 1-year OS rates in this group were 67.5% and 49.1%, respectively, and the 2-year OS rates were 44.7% and 24.5%, respectively.

The OS benefit with tislelizumab was observed across nearly all subgroups, Dr. Zhou noted.

In the ITT population, benefits were seen with tislelizumab over docetaxel for progression-free survival (4.1 months vs. 2.6 months, P < .0001), objective response rate (21.9% vs. 7.1%, P < .0001), and median duration of response (13.5 months vs. 6.2 months, P < .0001).

The rate of treatment-related adverse events (TRAEs) was 73.0% in the tislelizumab arm and 93.8% in the docetaxel arm. Rates of grade 3 or higher TRAEs were 14.4% and 66.3%, respectively. Rates of TRAEs leading to permanent discontinuation of treatment were 6.0% and 9.7%, respectively, and rates of TRAEs leading to death were 1.5% and 1.6%, respectively.

The most common treatment-emergent adverse events were anemia in the tislelizumab arm (28.5%) and alopecia in the docetaxel arm (47.3%). The most common grade 3 or higher treatment-emergent adverse event was neutropenia in the docetaxel arm (27.9% vs. 0.6% with tislelizumab).
 

‘Very important trial’

“RATIONALE 303 demonstrated that, as second- or third-line therapy in patients with advanced NSCLC, tislelizumab was tolerable and prolonged overall survival by 5-7 months. It also improved progression-free survival and objective response rate versus docetaxel, regardless of histology or PD-L1 expression,” Dr. Zhou concluded.

Session moderator Marina Chiara Garassino, MD, of the University of Chicago called RATIONALE 303 a “very important trial.”

Citing the range of immunotherapies available for NSCLC, Dr. Garassino said, “We have a very crowded space in the treatment of NSCLC. ... It is difficult to do a direct comparison [of immunotherapy trials] because we know that populations can be different and other factors can play a role. In the near future, we have to understand if they are all the same and interchangeable or if they are different.”

RATIONALE 303 was funded by BeiGene. Dr. Zhou disclosed relationships with Lily China, Sanofi, Roche, and several other companies, not including BeiGene. Dr. Garassino disclosed relationships with AstraZeneca, Novartis, Bristol-Myers Squibb, and several other companies, not including BeiGene.

As second- or third-line therapy in patients with locally advanced non–small cell lung cancer (NSCLC), tislelizumab was well tolerated and prolonged overall survival (OS), compared with docetaxel in the phase 3 RATIONALE 303 study.

The results were presented at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract CT039).

Tislelizumab is an anti–PD-1 antibody engineered to minimize Fc-gamma receptor binding on macrophages, a mechanism of T-cell clearance and potential anti–PD-1 resistance, according to investigator Caicun Zhou, MD, PhD, of Shanghai (China) Pulmonary Hospital.

Tislelizumab is approved for the treatment of relapsed/refractory classical Hodgkin lymphoma, the second-line treatment of locally advanced or metastatic urothelial carcinoma, and first-line treatment of advanced squamous NSCLC in China.

In patients with locally advanced or metastatic NSCLC whose disease has progressed after initial platinum-based chemotherapy, anti–PD-1/PD-L1 therapies have been shown to improve OS by 2-4 months versus docetaxel, Dr. Zhou said. A phase 1/2 study of second-line tislelizumab demonstrated antitumor activity in multiple advanced solid tumors, including NSCLC.

The phase 3 RATIONALE 303 study (NCT3358875) was designed to investigate the efficacy and safety of tislelizumab, compared with docetaxel in patients with locally advanced or metastatic NSCLC whose disease had progressed during or after platinum-containing doublet chemotherapy.
 

Study details

RATIONALE 303 enrolled 805 patients who had received up to two prior lines of systemic therapy and had no known EGFR mutations or ALK fusions.

The patients’ median age was 61 years, about 77% were male, about 80% were Asian, and about 70% were current or former smokers. Roughly 46% of patients had squamous histology, and about 43% had PD-L1 expression of 25% or greater.

Patients were stratified according to histology (squamous vs. nonsquamous), lines of prior therapy (second vs. third), and PD-L1 status (<25% vs. ≥25%).

Patients were randomized 2:1 to receive IV tislelizumab at 200 mg every 3 weeks (n = 535) or IV docetaxel at 75 mg/m² every 3 weeks (n = 270) until unacceptable toxicity or disease progression.

The dual primary endpoints were OS in the intention-to-treat (ITT) population and in patients with PD-L1 expression of 25% or higher.
 

Survival and safety

In the ITT population, the 1-year OS rate was 61.9% in the tislelizumab arm and 49.8% in the docetaxel arm. At 2 years, the OS rates were 39.4% and 25.0%, respectively.

The median OS was 17.2 months in the tislelizumab arm and 11.9 months in the docetaxel arm (hazard ratio, 0.64; 95% CI, 0.53-0.78; P < .0001).

In the PD-L1–high subgroup, the median OS was 19.1 months with tislelizumab and 11.9 months with docetaxel (HR, 0.52; 95% CI, 0.38-0.71; P < .0001). The 1-year OS rates in this group were 67.5% and 49.1%, respectively, and the 2-year OS rates were 44.7% and 24.5%, respectively.

The OS benefit with tislelizumab was observed across nearly all subgroups, Dr. Zhou noted.

In the ITT population, benefits were seen with tislelizumab over docetaxel for progression-free survival (4.1 months vs. 2.6 months, P < .0001), objective response rate (21.9% vs. 7.1%, P < .0001), and median duration of response (13.5 months vs. 6.2 months, P < .0001).

The rate of treatment-related adverse events (TRAEs) was 73.0% in the tislelizumab arm and 93.8% in the docetaxel arm. Rates of grade 3 or higher TRAEs were 14.4% and 66.3%, respectively. Rates of TRAEs leading to permanent discontinuation of treatment were 6.0% and 9.7%, respectively, and rates of TRAEs leading to death were 1.5% and 1.6%, respectively.

The most common treatment-emergent adverse events were anemia in the tislelizumab arm (28.5%) and alopecia in the docetaxel arm (47.3%). The most common grade 3 or higher treatment-emergent adverse event was neutropenia in the docetaxel arm (27.9% vs. 0.6% with tislelizumab).
 

‘Very important trial’

“RATIONALE 303 demonstrated that, as second- or third-line therapy in patients with advanced NSCLC, tislelizumab was tolerable and prolonged overall survival by 5-7 months. It also improved progression-free survival and objective response rate versus docetaxel, regardless of histology or PD-L1 expression,” Dr. Zhou concluded.

Session moderator Marina Chiara Garassino, MD, of the University of Chicago called RATIONALE 303 a “very important trial.”

Citing the range of immunotherapies available for NSCLC, Dr. Garassino said, “We have a very crowded space in the treatment of NSCLC. ... It is difficult to do a direct comparison [of immunotherapy trials] because we know that populations can be different and other factors can play a role. In the near future, we have to understand if they are all the same and interchangeable or if they are different.”

RATIONALE 303 was funded by BeiGene. Dr. Zhou disclosed relationships with Lily China, Sanofi, Roche, and several other companies, not including BeiGene. Dr. Garassino disclosed relationships with AstraZeneca, Novartis, Bristol-Myers Squibb, and several other companies, not including BeiGene.

A frontline treatment regimen including brentuximab vedotin (Bv) was well tolerated, was highly effective, and significantly reduced radiation exposure in pediatric patients with high-risk Hodgkin lymphoma, according to the results of an open-label, phase 2 trial.

Wikimedia Commons/Nephron/Creative Commons 3.0

Of 77 patients enrolled in the investigator-initiated, single-arm, multicenter trial, 27 (35%) achieved complete remission (CR) without radiation at the early response assessment (ERA) after two cycles of therapy, reported Monika L. Metzger, MD, of St. Jude Children’s Research Hospital, Memphis, Tenn. and colleagues. The report was published online in the Journal of Clinical Oncology.

The addition of Bv also resulted in superior event-free survival (97.4%) and overall survival (98.7%) at median follow-up of 3.4 years, compared with previously published pediatric trials, such as the HOD99 trial (EFS and OS of 80.8% and 96.5%, respectively), the authors noted.

Bv chemotherapy

Bv, a targeted anti-CD30 antibody-drug conjugate, received expanded Food and Drug Administration approval in March 2018 for frontline use in combination with chemotherapy in adults with stage III or IV classical Hodgkin lymphoma (HL). The current study is the first to include Bv as part of a chemotherapy regimen in the frontline setting for pediatric classical HL, the authors noted, adding that their primary aim was to reduce prescribed radiation thereby limiting late toxicities associated with radiation in this population.

Patients enrolled were children and adolescents aged 18 years and under with stage IIB, IIIB, or IV classical HL. Bv was used in place of vincristine in the standard OEPA/COPDac (vincristine, etoposide, prednisone, and doxorubicin/cyclophosphamide, vincristine, prednisone, and dacarbazine) frontline regimen for pediatric HL.

The Bv-based chemotherapy regimen was well tolerated and mostly limited to low-grade nausea, vomiting, and constipation, and the most common adverse events were hematologic events occurring mainly during the first two cycles of chemotherapy.

“Notably, we observed a very low incidence of neuropathy (4%) by both clinician and patient report, and no participants required Bv dose reduction or discontinuation,” they wrote, explaining that neuropathy is more common with vincristine.

Radiation exposure

Residual node radiotherapy (RNRT) was delivered at a prescribed dose of 25.5 Gy in 17 fractions of 1.5 Gy, 2-4 weeks after completion of chemotherapy only to nodal sites that did not achieve a CR at the early response assessment (ERA) after two cycles of therapy.

“Patients treated with RNRT had significantly lower integral radiation dose compared with patients treated on HOD99 with [involved-field radiation therapy] (78.1 J vs. 249.6 J),” the authors wrote. “Doses to specific organs were also compared ... [t]he mean heart dose was reduced to 5.29 Gy from 16.9 Gy, and the mean thyroid dose was reduced to 4.46 Gy from 25.9 Gy.”

Women also had significantly less breast radiation exposure (mean of 3.21 Gy vs. 6.85 Gy in HOD99).

One irradiated patient experienced disease progression at the end of therapy, but remained disease free more than 6 years following salvage therapy, and one unexpected death occurred, the authors said.

“We have already reduced the use of radiation for low-risk Hodgkin lymphoma patients. In this study we’ve shown that it is also possible to either omit or reduce the extent of radiation for high-risk patients, using highly focal methods such as proton beam radiation or intensity modulated radiation,” co–senior author Matthew Krasin, MD, of St. Jude’s department of radiation oncology, stated in a press release.
 

Next steps

Co–senior author Melissa Hudson, MD, the St. Jude cancer survivorship division director, added that “[b]eing able to offer Hodgkin lymphoma patients a targeted therapy in the frontline setting is an exciting development.

“The favorable safety and toxicity profile of Bv in combination with chemotherapy for high-risk pediatric patients supports its prospective evaluation in a randomized trial,” the authors concluded, noting that “[l]onger follow-up is required to establish if this approach reduces risk of late-occurring toxicities such as second malignant neoplasms in this cohort of minimally irradiated patients.”

The study was sponsored by Seattle Genetics. The research at St. Jude was funded in part by grants from the National Cancer Institute and ALSAC (American Lebanese Syrian Associated Charities), St. Jude’s fundraising and awareness organization. Dr. Metzger reported research funding from Seattle Genetics. Dr. Krasin reported a consulting or advisory role for Debiopharm Group. Dr. Hudson reported a consulting or advisory role for Oncology Research Information Exchange Network, Princess Máxima Center.

[email protected]

A frontline treatment regimen including brentuximab vedotin (Bv) was well tolerated, was highly effective, and significantly reduced radiation exposure in pediatric patients with high-risk Hodgkin lymphoma, according to the results of an open-label, phase 2 trial.

Wikimedia Commons/Nephron/Creative Commons 3.0

Of 77 patients enrolled in the investigator-initiated, single-arm, multicenter trial, 27 (35%) achieved complete remission (CR) without radiation at the early response assessment (ERA) after two cycles of therapy, reported Monika L. Metzger, MD, of St. Jude Children’s Research Hospital, Memphis, Tenn. and colleagues. The report was published online in the Journal of Clinical Oncology.

The addition of Bv also resulted in superior event-free survival (97.4%) and overall survival (98.7%) at median follow-up of 3.4 years, compared with previously published pediatric trials, such as the HOD99 trial (EFS and OS of 80.8% and 96.5%, respectively), the authors noted.

Bv chemotherapy

Bv, a targeted anti-CD30 antibody-drug conjugate, received expanded Food and Drug Administration approval in March 2018 for frontline use in combination with chemotherapy in adults with stage III or IV classical Hodgkin lymphoma (HL). The current study is the first to include Bv as part of a chemotherapy regimen in the frontline setting for pediatric classical HL, the authors noted, adding that their primary aim was to reduce prescribed radiation thereby limiting late toxicities associated with radiation in this population.

Patients enrolled were children and adolescents aged 18 years and under with stage IIB, IIIB, or IV classical HL. Bv was used in place of vincristine in the standard OEPA/COPDac (vincristine, etoposide, prednisone, and doxorubicin/cyclophosphamide, vincristine, prednisone, and dacarbazine) frontline regimen for pediatric HL.

The Bv-based chemotherapy regimen was well tolerated and mostly limited to low-grade nausea, vomiting, and constipation, and the most common adverse events were hematologic events occurring mainly during the first two cycles of chemotherapy.

“Notably, we observed a very low incidence of neuropathy (4%) by both clinician and patient report, and no participants required Bv dose reduction or discontinuation,” they wrote, explaining that neuropathy is more common with vincristine.

Radiation exposure

Residual node radiotherapy (RNRT) was delivered at a prescribed dose of 25.5 Gy in 17 fractions of 1.5 Gy, 2-4 weeks after completion of chemotherapy only to nodal sites that did not achieve a CR at the early response assessment (ERA) after two cycles of therapy.

“Patients treated with RNRT had significantly lower integral radiation dose compared with patients treated on HOD99 with [involved-field radiation therapy] (78.1 J vs. 249.6 J),” the authors wrote. “Doses to specific organs were also compared ... [t]he mean heart dose was reduced to 5.29 Gy from 16.9 Gy, and the mean thyroid dose was reduced to 4.46 Gy from 25.9 Gy.”

Women also had significantly less breast radiation exposure (mean of 3.21 Gy vs. 6.85 Gy in HOD99).

One irradiated patient experienced disease progression at the end of therapy, but remained disease free more than 6 years following salvage therapy, and one unexpected death occurred, the authors said.

“We have already reduced the use of radiation for low-risk Hodgkin lymphoma patients. In this study we’ve shown that it is also possible to either omit or reduce the extent of radiation for high-risk patients, using highly focal methods such as proton beam radiation or intensity modulated radiation,” co–senior author Matthew Krasin, MD, of St. Jude’s department of radiation oncology, stated in a press release.
 

Next steps

Co–senior author Melissa Hudson, MD, the St. Jude cancer survivorship division director, added that “[b]eing able to offer Hodgkin lymphoma patients a targeted therapy in the frontline setting is an exciting development.

“The favorable safety and toxicity profile of Bv in combination with chemotherapy for high-risk pediatric patients supports its prospective evaluation in a randomized trial,” the authors concluded, noting that “[l]onger follow-up is required to establish if this approach reduces risk of late-occurring toxicities such as second malignant neoplasms in this cohort of minimally irradiated patients.”

The study was sponsored by Seattle Genetics. The research at St. Jude was funded in part by grants from the National Cancer Institute and ALSAC (American Lebanese Syrian Associated Charities), St. Jude’s fundraising and awareness organization. Dr. Metzger reported research funding from Seattle Genetics. Dr. Krasin reported a consulting or advisory role for Debiopharm Group. Dr. Hudson reported a consulting or advisory role for Oncology Research Information Exchange Network, Princess Máxima Center.

[email protected]

A frontline treatment regimen including brentuximab vedotin (Bv) was well tolerated, was highly effective, and significantly reduced radiation exposure in pediatric patients with high-risk Hodgkin lymphoma, according to the results of an open-label, phase 2 trial.

Wikimedia Commons/Nephron/Creative Commons 3.0

Of 77 patients enrolled in the investigator-initiated, single-arm, multicenter trial, 27 (35%) achieved complete remission (CR) without radiation at the early response assessment (ERA) after two cycles of therapy, reported Monika L. Metzger, MD, of St. Jude Children’s Research Hospital, Memphis, Tenn. and colleagues. The report was published online in the Journal of Clinical Oncology.

The addition of Bv also resulted in superior event-free survival (97.4%) and overall survival (98.7%) at median follow-up of 3.4 years, compared with previously published pediatric trials, such as the HOD99 trial (EFS and OS of 80.8% and 96.5%, respectively), the authors noted.

Bv chemotherapy

Bv, a targeted anti-CD30 antibody-drug conjugate, received expanded Food and Drug Administration approval in March 2018 for frontline use in combination with chemotherapy in adults with stage III or IV classical Hodgkin lymphoma (HL). The current study is the first to include Bv as part of a chemotherapy regimen in the frontline setting for pediatric classical HL, the authors noted, adding that their primary aim was to reduce prescribed radiation thereby limiting late toxicities associated with radiation in this population.

Patients enrolled were children and adolescents aged 18 years and under with stage IIB, IIIB, or IV classical HL. Bv was used in place of vincristine in the standard OEPA/COPDac (vincristine, etoposide, prednisone, and doxorubicin/cyclophosphamide, vincristine, prednisone, and dacarbazine) frontline regimen for pediatric HL.

The Bv-based chemotherapy regimen was well tolerated and mostly limited to low-grade nausea, vomiting, and constipation, and the most common adverse events were hematologic events occurring mainly during the first two cycles of chemotherapy.

“Notably, we observed a very low incidence of neuropathy (4%) by both clinician and patient report, and no participants required Bv dose reduction or discontinuation,” they wrote, explaining that neuropathy is more common with vincristine.

Radiation exposure

Residual node radiotherapy (RNRT) was delivered at a prescribed dose of 25.5 Gy in 17 fractions of 1.5 Gy, 2-4 weeks after completion of chemotherapy only to nodal sites that did not achieve a CR at the early response assessment (ERA) after two cycles of therapy.

“Patients treated with RNRT had significantly lower integral radiation dose compared with patients treated on HOD99 with [involved-field radiation therapy] (78.1 J vs. 249.6 J),” the authors wrote. “Doses to specific organs were also compared ... [t]he mean heart dose was reduced to 5.29 Gy from 16.9 Gy, and the mean thyroid dose was reduced to 4.46 Gy from 25.9 Gy.”

Women also had significantly less breast radiation exposure (mean of 3.21 Gy vs. 6.85 Gy in HOD99).

One irradiated patient experienced disease progression at the end of therapy, but remained disease free more than 6 years following salvage therapy, and one unexpected death occurred, the authors said.

“We have already reduced the use of radiation for low-risk Hodgkin lymphoma patients. In this study we’ve shown that it is also possible to either omit or reduce the extent of radiation for high-risk patients, using highly focal methods such as proton beam radiation or intensity modulated radiation,” co–senior author Matthew Krasin, MD, of St. Jude’s department of radiation oncology, stated in a press release.
 

Next steps

Co–senior author Melissa Hudson, MD, the St. Jude cancer survivorship division director, added that “[b]eing able to offer Hodgkin lymphoma patients a targeted therapy in the frontline setting is an exciting development.

“The favorable safety and toxicity profile of Bv in combination with chemotherapy for high-risk pediatric patients supports its prospective evaluation in a randomized trial,” the authors concluded, noting that “[l]onger follow-up is required to establish if this approach reduces risk of late-occurring toxicities such as second malignant neoplasms in this cohort of minimally irradiated patients.”

The study was sponsored by Seattle Genetics. The research at St. Jude was funded in part by grants from the National Cancer Institute and ALSAC (American Lebanese Syrian Associated Charities), St. Jude’s fundraising and awareness organization. Dr. Metzger reported research funding from Seattle Genetics. Dr. Krasin reported a consulting or advisory role for Debiopharm Group. Dr. Hudson reported a consulting or advisory role for Oncology Research Information Exchange Network, Princess Máxima Center.

[email protected]

Chronic lymphocytic leukemia (CLL) is a clinically heterogeneous disease associated with several known genetic abnormalities, including 17p deletion (del[17p]), 11q deletion (del[11q]), and TP53 gene mutations, which are adverse prognostic markers among patients treated with chemoimmunotherapy.

The Bruton tyrosine kinase (BTK) inhibitor ibrutinib is approved for patients with untreated, relapsed, or refractory disease, including those with del(17p). Clinicians will soon have the chance to pair it with ublituximab, a next-generation, glycoengineered, type I, anti-CD20 monoclonal antibody that binds to a unique epitope on CD20, differentiating it from rituximab, ofatumumab, and obinutuzumab. Results from the phase 3 GENUINE trial, which were recently published in The Lancet Haematology, showed that ublituximab plus ibrutinib was superior to ibrutinib alone for patients with relapsed or refractory high-risk CLL.

This news organization spoke with Jennifer R. Brown, MD, PhD, director of the CLL Center and institute physician at the Dana-Farber Cancer Institute and professor of medicine at Harvard Medical School, both in Boston, about the GENUINE trial and its potential impact on treatment choices going forward.
 

What type of patients were treated in the GENUINE trial?

Dr. Brown: This is a trial among relapsed/refractory CLL patients with 17p or 11q deletion or TP53 mutation. Patients aged 18 years or older with CLL who warranted treatment, as defined by International Workshop on CLL criteria, were eligible if they had previously received at least two cycles of at least one standard treatment regimen, had an Eastern Cooperative Oncology Group performance status of 2 or lower, and had high-risk cytogenetics, defined as the presence of at least one of del(17p), del(11q), or TP53 mutation confirmed by a central laboratory with fluorescence in situ hybridization and/or next-generation sequencing.

What were the main outcomes of the trial?

Originally, the GENUINE trial had coprimary endpoints of progression-free survival (PFS) and overall response rate. Because of slow accrual, it was amended to have one primary endpoint of independent review committee (IRC)–assessed ORR.

IRC-assessed ORR was improved from 65% to 83% with the addition of ublituximab. PFS also improved significantly in the ublituximab group, with an even greater improvement when the analysis was limited to those with del(17p) or TP53 aberrancy, but this outcome was limited by the reduced sample size of the study as well as the relatively short PFS of the ibrutinib arm.

After a median follow-up of 41.6 months, the median IRC-assessed PFS in all treated patients was not reached in the ublituximab plus ibrutinib group after 15 PFS events but was 35.9 months in the ibrutinib group after 25 PFS events (hazard ratio, 0.46; 95% confidence interval, 0.24-0.87; P = .016).

Undetectable minimal residual disease was also seen in 42% of the combination arm, compared with 6% of the ibrutinib arm.
 

What types of adverse events were found in the trial?

The researchers found mostly mild and known side effects of ibrutinib. More atrial fibrillation and neutropenia were seen in the antibody group, but this was not marked.

Most adverse events were of grade 1 or 2. The most common grade 3 and 4 adverse events were neutropenia (11 [19%] patients in the ublituximab plus ibrutinib group and 7 [12%] in the ibrutinib group), anemia (5 [8%] and 5 [9%], respectively), and diarrhea (6 [10%] and 3 [5%], respectively).
 

What about serious adverse events?

Hospitalization from infection was seen, as expected. There were two cardiac arrests and an unexplained death, across both arms, which was concerning, given the known association of ibrutinib with ventricular arrhythmia and sudden death. There were also several hemorrhages, including one fatal one, which was again consistent with the known side effects of ibrutinib.

Are there treatments comparable with ublituximab plus ibrutinib that clinicians should perhaps first consider using?

In terms of other anti-CD20 antibodies, we have two randomized trials that have failed to show a benefit from adding rituximab to ibrutinib.

Obinutuzumab, like ublituximab, is also a next-generation glycoengineered antibody, and it is reasonably likely that it might lead to similar results. However, the only data we have on ibrutinib with obinutuzumab are from a single arm in a more heterogeneous, lower-risk patient population, and it is unlikely that a randomized comparison will ever be done.
 

On the basis of these trial results, how would you use the combination of ublituximab and ibrutinib for your patients?

I would consider the addition of ublituximab to a BTK inhibitor in high-risk patients (once ublituximab is approved). I already usually use a next-generation BTK inhibitor rather than ibrutinib.

Are there any other implications of the GENUINE trial?

I think this trial underscores the importance of studying genetic subgroups of patients separately. In this case, that was done in high-risk patients, but this observation likely also applies to low-risk patients.

Most trials to date have enrolled unselected patient populations, often without stratification, and their results therefore tend to obscure the outcomes in both the very high risk (as studied here) and in the low risk (patients with immunoglobulin heavy chain variable region gene mutations).

Dr. Brown has served as a consultant for AbbVie, Acerta/AstraZeneca, Beigene, Bristol-Myers Squibb/Juno/Celgene, Catapult, Genentech/Roche, Janssen, MEI Pharma, Morphosys, and Novartis, and has received research funding from Gilead, Loxo/Lilly, TG Therapeutics, Verastem/SecuraBio.

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

Chronic lymphocytic leukemia (CLL) is a clinically heterogeneous disease associated with several known genetic abnormalities, including 17p deletion (del[17p]), 11q deletion (del[11q]), and TP53 gene mutations, which are adverse prognostic markers among patients treated with chemoimmunotherapy.

The Bruton tyrosine kinase (BTK) inhibitor ibrutinib is approved for patients with untreated, relapsed, or refractory disease, including those with del(17p). Clinicians will soon have the chance to pair it with ublituximab, a next-generation, glycoengineered, type I, anti-CD20 monoclonal antibody that binds to a unique epitope on CD20, differentiating it from rituximab, ofatumumab, and obinutuzumab. Results from the phase 3 GENUINE trial, which were recently published in The Lancet Haematology, showed that ublituximab plus ibrutinib was superior to ibrutinib alone for patients with relapsed or refractory high-risk CLL.

This news organization spoke with Jennifer R. Brown, MD, PhD, director of the CLL Center and institute physician at the Dana-Farber Cancer Institute and professor of medicine at Harvard Medical School, both in Boston, about the GENUINE trial and its potential impact on treatment choices going forward.
 

What type of patients were treated in the GENUINE trial?

Dr. Brown: This is a trial among relapsed/refractory CLL patients with 17p or 11q deletion or TP53 mutation. Patients aged 18 years or older with CLL who warranted treatment, as defined by International Workshop on CLL criteria, were eligible if they had previously received at least two cycles of at least one standard treatment regimen, had an Eastern Cooperative Oncology Group performance status of 2 or lower, and had high-risk cytogenetics, defined as the presence of at least one of del(17p), del(11q), or TP53 mutation confirmed by a central laboratory with fluorescence in situ hybridization and/or next-generation sequencing.

What were the main outcomes of the trial?

Originally, the GENUINE trial had coprimary endpoints of progression-free survival (PFS) and overall response rate. Because of slow accrual, it was amended to have one primary endpoint of independent review committee (IRC)–assessed ORR.

IRC-assessed ORR was improved from 65% to 83% with the addition of ublituximab. PFS also improved significantly in the ublituximab group, with an even greater improvement when the analysis was limited to those with del(17p) or TP53 aberrancy, but this outcome was limited by the reduced sample size of the study as well as the relatively short PFS of the ibrutinib arm.

After a median follow-up of 41.6 months, the median IRC-assessed PFS in all treated patients was not reached in the ublituximab plus ibrutinib group after 15 PFS events but was 35.9 months in the ibrutinib group after 25 PFS events (hazard ratio, 0.46; 95% confidence interval, 0.24-0.87; P = .016).

Undetectable minimal residual disease was also seen in 42% of the combination arm, compared with 6% of the ibrutinib arm.
 

What types of adverse events were found in the trial?

The researchers found mostly mild and known side effects of ibrutinib. More atrial fibrillation and neutropenia were seen in the antibody group, but this was not marked.

Most adverse events were of grade 1 or 2. The most common grade 3 and 4 adverse events were neutropenia (11 [19%] patients in the ublituximab plus ibrutinib group and 7 [12%] in the ibrutinib group), anemia (5 [8%] and 5 [9%], respectively), and diarrhea (6 [10%] and 3 [5%], respectively).
 

What about serious adverse events?

Hospitalization from infection was seen, as expected. There were two cardiac arrests and an unexplained death, across both arms, which was concerning, given the known association of ibrutinib with ventricular arrhythmia and sudden death. There were also several hemorrhages, including one fatal one, which was again consistent with the known side effects of ibrutinib.

Are there treatments comparable with ublituximab plus ibrutinib that clinicians should perhaps first consider using?

In terms of other anti-CD20 antibodies, we have two randomized trials that have failed to show a benefit from adding rituximab to ibrutinib.

Obinutuzumab, like ublituximab, is also a next-generation glycoengineered antibody, and it is reasonably likely that it might lead to similar results. However, the only data we have on ibrutinib with obinutuzumab are from a single arm in a more heterogeneous, lower-risk patient population, and it is unlikely that a randomized comparison will ever be done.
 

On the basis of these trial results, how would you use the combination of ublituximab and ibrutinib for your patients?

I would consider the addition of ublituximab to a BTK inhibitor in high-risk patients (once ublituximab is approved). I already usually use a next-generation BTK inhibitor rather than ibrutinib.

Are there any other implications of the GENUINE trial?

I think this trial underscores the importance of studying genetic subgroups of patients separately. In this case, that was done in high-risk patients, but this observation likely also applies to low-risk patients.

Most trials to date have enrolled unselected patient populations, often without stratification, and their results therefore tend to obscure the outcomes in both the very high risk (as studied here) and in the low risk (patients with immunoglobulin heavy chain variable region gene mutations).

Dr. Brown has served as a consultant for AbbVie, Acerta/AstraZeneca, Beigene, Bristol-Myers Squibb/Juno/Celgene, Catapult, Genentech/Roche, Janssen, MEI Pharma, Morphosys, and Novartis, and has received research funding from Gilead, Loxo/Lilly, TG Therapeutics, Verastem/SecuraBio.

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

Chronic lymphocytic leukemia (CLL) is a clinically heterogeneous disease associated with several known genetic abnormalities, including 17p deletion (del[17p]), 11q deletion (del[11q]), and TP53 gene mutations, which are adverse prognostic markers among patients treated with chemoimmunotherapy.

The Bruton tyrosine kinase (BTK) inhibitor ibrutinib is approved for patients with untreated, relapsed, or refractory disease, including those with del(17p). Clinicians will soon have the chance to pair it with ublituximab, a next-generation, glycoengineered, type I, anti-CD20 monoclonal antibody that binds to a unique epitope on CD20, differentiating it from rituximab, ofatumumab, and obinutuzumab. Results from the phase 3 GENUINE trial, which were recently published in The Lancet Haematology, showed that ublituximab plus ibrutinib was superior to ibrutinib alone for patients with relapsed or refractory high-risk CLL.

This news organization spoke with Jennifer R. Brown, MD, PhD, director of the CLL Center and institute physician at the Dana-Farber Cancer Institute and professor of medicine at Harvard Medical School, both in Boston, about the GENUINE trial and its potential impact on treatment choices going forward.
 

What type of patients were treated in the GENUINE trial?

Dr. Brown: This is a trial among relapsed/refractory CLL patients with 17p or 11q deletion or TP53 mutation. Patients aged 18 years or older with CLL who warranted treatment, as defined by International Workshop on CLL criteria, were eligible if they had previously received at least two cycles of at least one standard treatment regimen, had an Eastern Cooperative Oncology Group performance status of 2 or lower, and had high-risk cytogenetics, defined as the presence of at least one of del(17p), del(11q), or TP53 mutation confirmed by a central laboratory with fluorescence in situ hybridization and/or next-generation sequencing.

What were the main outcomes of the trial?

Originally, the GENUINE trial had coprimary endpoints of progression-free survival (PFS) and overall response rate. Because of slow accrual, it was amended to have one primary endpoint of independent review committee (IRC)–assessed ORR.

IRC-assessed ORR was improved from 65% to 83% with the addition of ublituximab. PFS also improved significantly in the ublituximab group, with an even greater improvement when the analysis was limited to those with del(17p) or TP53 aberrancy, but this outcome was limited by the reduced sample size of the study as well as the relatively short PFS of the ibrutinib arm.

After a median follow-up of 41.6 months, the median IRC-assessed PFS in all treated patients was not reached in the ublituximab plus ibrutinib group after 15 PFS events but was 35.9 months in the ibrutinib group after 25 PFS events (hazard ratio, 0.46; 95% confidence interval, 0.24-0.87; P = .016).

Undetectable minimal residual disease was also seen in 42% of the combination arm, compared with 6% of the ibrutinib arm.
 

What types of adverse events were found in the trial?

The researchers found mostly mild and known side effects of ibrutinib. More atrial fibrillation and neutropenia were seen in the antibody group, but this was not marked.

Most adverse events were of grade 1 or 2. The most common grade 3 and 4 adverse events were neutropenia (11 [19%] patients in the ublituximab plus ibrutinib group and 7 [12%] in the ibrutinib group), anemia (5 [8%] and 5 [9%], respectively), and diarrhea (6 [10%] and 3 [5%], respectively).
 

What about serious adverse events?

Hospitalization from infection was seen, as expected. There were two cardiac arrests and an unexplained death, across both arms, which was concerning, given the known association of ibrutinib with ventricular arrhythmia and sudden death. There were also several hemorrhages, including one fatal one, which was again consistent with the known side effects of ibrutinib.

Are there treatments comparable with ublituximab plus ibrutinib that clinicians should perhaps first consider using?

In terms of other anti-CD20 antibodies, we have two randomized trials that have failed to show a benefit from adding rituximab to ibrutinib.

Obinutuzumab, like ublituximab, is also a next-generation glycoengineered antibody, and it is reasonably likely that it might lead to similar results. However, the only data we have on ibrutinib with obinutuzumab are from a single arm in a more heterogeneous, lower-risk patient population, and it is unlikely that a randomized comparison will ever be done.
 

On the basis of these trial results, how would you use the combination of ublituximab and ibrutinib for your patients?

I would consider the addition of ublituximab to a BTK inhibitor in high-risk patients (once ublituximab is approved). I already usually use a next-generation BTK inhibitor rather than ibrutinib.

Are there any other implications of the GENUINE trial?

I think this trial underscores the importance of studying genetic subgroups of patients separately. In this case, that was done in high-risk patients, but this observation likely also applies to low-risk patients.

Most trials to date have enrolled unselected patient populations, often without stratification, and their results therefore tend to obscure the outcomes in both the very high risk (as studied here) and in the low risk (patients with immunoglobulin heavy chain variable region gene mutations).

Dr. Brown has served as a consultant for AbbVie, Acerta/AstraZeneca, Beigene, Bristol-Myers Squibb/Juno/Celgene, Catapult, Genentech/Roche, Janssen, MEI Pharma, Morphosys, and Novartis, and has received research funding from Gilead, Loxo/Lilly, TG Therapeutics, Verastem/SecuraBio.

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

There are three general classes of antifungal agents (number of agents): azole antifungals (9), echinocandins (3), and polyenes (5). The azole antifungals contain an azole ring and inhibit a wide range of fungi. Echinocandins target the fungal cell wall and the polyenes increase the fungal membrane permeability and lead to cell death.

Pregnancy

Azole antifungals inhibit the growth of fungi. Their trade names and molecular weights:

• Clotrimazole (Mycelex), an over-the-counter product, is available as a topical cream. Several studies have found no association between the drug and birth defects.
• Fluconazole (Diflucan) is a teratogen when doses of ≥400 mg/day are used during the first trimester. Smaller doses do not appear to cause embryo/fetal harm.
• Isavuconazonium (Cresemba) if used in pregnancy, exposure of the embryo/fetus would probably be low based on the >99% plasma protein binding, but the plasma half-life is 130 hours. Moreover, the drug is a potent animal teratogen and is best avoided in pregnancy.
• Itraconazole (Onmel, Sporanox, Tolsura), has a low risk, if any, of structural defects, according to what reported human experience suggests.
• Ketoconazole (Xolegel, Extina, Nizoral; 531) does not appear to adversely effect embryos and fetuses, but the human data are very limited. As with any drug, avoiding organogenesis is the best recommendation.
• Miconazole (Oravig) is usually used topically. Small amounts are absorbed from the vagina. The available evidence suggests that the drug does not increase the risk of congenital malformations.
• Posaconazole (Noxafil) does not have reported use in human pregnancy. The animal reproduction data suggest risk. Based on its molecular weight (about 701), the drug will most likely cross the placenta to the embryo/fetus. Thus, the best course is to avoid the drug during pregnancy, especially in the first trimester.
• Voriconazole (Vfend) has one human report of the drug use in pregnancy. The drug was started at about 19 weeks and continued until the woman gave birth at 35 weeks to a healthy male baby. At 6 months of age, the baby remained normal.

Echinocandin antifungals target the fungal cell wall by inhibiting its synthesis. Their trade names and molecular weights:

• Anidulafungin (Eraxis; 1,140) has no published human data. It is indicated for the treatment of candidemia and other forms of Candida infections. The animal data suggest low risk.
• Caspofungin (Cancidas; 1,213) has no published human data. It is indicated for presumed fungal infections in febrile, neutropenic patients. The animal data are suggestive of human risk, especially if exposure occurs in the first trimester. If possible, maternal treatment should be avoided in the first trimester.
• Micafungin (Mycamine; 1,292) has no published human data. It is indicated for the treatment of patients with esophageal candidiasis and for the prophylaxis of Candida infections in patients undergoing hematopoietic stem cell transplantation. The animal data in one species suggest high risk. If possible, maternal treatment should be avoided in the first trimester.

Polyene antifungals cause depolarization of the fungal cell membrane to increase the membrane permeability, which leads to cell death. Their trade names and molecular weights:

• Amphotericin b (Amphocin; Fungizone; 924) There are three other amphotericin agents: amphotericin b cholesteryl sulfate (Amphotec); amphotericin b lipid complex (Abelcet); amphotericin b liposomal (AmBisome). No reports linking amphotericin b with congenital defects have been found. The drug does cross the human placenta. Although there was a higher rate of spontaneous abortions in rabbits given amphotericin b, there was no fetal harm in rats and rabbits when given amphotericin b lipid complex.
• Nystatin (Bio-Statin; Mycostatin; Nilstat; 926). The drug does not appear to cause embryo-fetal harm. Based on published data, the drug can be used at any time in pregnancy.

Breastfeeding

Small amounts of all the above drugs are probably excreted into breast milk if they are used close to breastfeeding. Most can probably be used during breastfeeding, but there are no data for any of these agents. The safest decision is to not use these drugs when breastfeeding.

Mr. Briggs is clinical professor of pharmacy at the University of California, San Francisco, and adjunct professor of pharmacy at the University of Southern California, Los Angeles, as well as at Washington State University, Spokane. Mr. Briggs said he had no relevant financial disclosures. Email him at [email protected].

There are three general classes of antifungal agents (number of agents): azole antifungals (9), echinocandins (3), and polyenes (5). The azole antifungals contain an azole ring and inhibit a wide range of fungi. Echinocandins target the fungal cell wall and the polyenes increase the fungal membrane permeability and lead to cell death.

Pregnancy

Azole antifungals inhibit the growth of fungi. Their trade names and molecular weights:

• Clotrimazole (Mycelex), an over-the-counter product, is available as a topical cream. Several studies have found no association between the drug and birth defects.
• Fluconazole (Diflucan) is a teratogen when doses of ≥400 mg/day are used during the first trimester. Smaller doses do not appear to cause embryo/fetal harm.
• Isavuconazonium (Cresemba) if used in pregnancy, exposure of the embryo/fetus would probably be low based on the >99% plasma protein binding, but the plasma half-life is 130 hours. Moreover, the drug is a potent animal teratogen and is best avoided in pregnancy.
• Itraconazole (Onmel, Sporanox, Tolsura), has a low risk, if any, of structural defects, according to what reported human experience suggests.
• Ketoconazole (Xolegel, Extina, Nizoral; 531) does not appear to adversely effect embryos and fetuses, but the human data are very limited. As with any drug, avoiding organogenesis is the best recommendation.
• Miconazole (Oravig) is usually used topically. Small amounts are absorbed from the vagina. The available evidence suggests that the drug does not increase the risk of congenital malformations.
• Posaconazole (Noxafil) does not have reported use in human pregnancy. The animal reproduction data suggest risk. Based on its molecular weight (about 701), the drug will most likely cross the placenta to the embryo/fetus. Thus, the best course is to avoid the drug during pregnancy, especially in the first trimester.
• Voriconazole (Vfend) has one human report of the drug use in pregnancy. The drug was started at about 19 weeks and continued until the woman gave birth at 35 weeks to a healthy male baby. At 6 months of age, the baby remained normal.

Echinocandin antifungals target the fungal cell wall by inhibiting its synthesis. Their trade names and molecular weights:

• Anidulafungin (Eraxis; 1,140) has no published human data. It is indicated for the treatment of candidemia and other forms of Candida infections. The animal data suggest low risk.
• Caspofungin (Cancidas; 1,213) has no published human data. It is indicated for presumed fungal infections in febrile, neutropenic patients. The animal data are suggestive of human risk, especially if exposure occurs in the first trimester. If possible, maternal treatment should be avoided in the first trimester.
• Micafungin (Mycamine; 1,292) has no published human data. It is indicated for the treatment of patients with esophageal candidiasis and for the prophylaxis of Candida infections in patients undergoing hematopoietic stem cell transplantation. The animal data in one species suggest high risk. If possible, maternal treatment should be avoided in the first trimester.

Polyene antifungals cause depolarization of the fungal cell membrane to increase the membrane permeability, which leads to cell death. Their trade names and molecular weights:

• Amphotericin b (Amphocin; Fungizone; 924) There are three other amphotericin agents: amphotericin b cholesteryl sulfate (Amphotec); amphotericin b lipid complex (Abelcet); amphotericin b liposomal (AmBisome). No reports linking amphotericin b with congenital defects have been found. The drug does cross the human placenta. Although there was a higher rate of spontaneous abortions in rabbits given amphotericin b, there was no fetal harm in rats and rabbits when given amphotericin b lipid complex.
• Nystatin (Bio-Statin; Mycostatin; Nilstat; 926). The drug does not appear to cause embryo-fetal harm. Based on published data, the drug can be used at any time in pregnancy.

Breastfeeding

Small amounts of all the above drugs are probably excreted into breast milk if they are used close to breastfeeding. Most can probably be used during breastfeeding, but there are no data for any of these agents. The safest decision is to not use these drugs when breastfeeding.

Mr. Briggs is clinical professor of pharmacy at the University of California, San Francisco, and adjunct professor of pharmacy at the University of Southern California, Los Angeles, as well as at Washington State University, Spokane. Mr. Briggs said he had no relevant financial disclosures. Email him at [email protected].

There are three general classes of antifungal agents (number of agents): azole antifungals (9), echinocandins (3), and polyenes (5). The azole antifungals contain an azole ring and inhibit a wide range of fungi. Echinocandins target the fungal cell wall and the polyenes increase the fungal membrane permeability and lead to cell death.

Pregnancy

Azole antifungals inhibit the growth of fungi. Their trade names and molecular weights:

• Clotrimazole (Mycelex), an over-the-counter product, is available as a topical cream. Several studies have found no association between the drug and birth defects.
• Fluconazole (Diflucan) is a teratogen when doses of ≥400 mg/day are used during the first trimester. Smaller doses do not appear to cause embryo/fetal harm.
• Isavuconazonium (Cresemba) if used in pregnancy, exposure of the embryo/fetus would probably be low based on the >99% plasma protein binding, but the plasma half-life is 130 hours. Moreover, the drug is a potent animal teratogen and is best avoided in pregnancy.
• Itraconazole (Onmel, Sporanox, Tolsura), has a low risk, if any, of structural defects, according to what reported human experience suggests.
• Ketoconazole (Xolegel, Extina, Nizoral; 531) does not appear to adversely effect embryos and fetuses, but the human data are very limited. As with any drug, avoiding organogenesis is the best recommendation.
• Miconazole (Oravig) is usually used topically. Small amounts are absorbed from the vagina. The available evidence suggests that the drug does not increase the risk of congenital malformations.
• Posaconazole (Noxafil) does not have reported use in human pregnancy. The animal reproduction data suggest risk. Based on its molecular weight (about 701), the drug will most likely cross the placenta to the embryo/fetus. Thus, the best course is to avoid the drug during pregnancy, especially in the first trimester.
• Voriconazole (Vfend) has one human report of the drug use in pregnancy. The drug was started at about 19 weeks and continued until the woman gave birth at 35 weeks to a healthy male baby. At 6 months of age, the baby remained normal.

Echinocandin antifungals target the fungal cell wall by inhibiting its synthesis. Their trade names and molecular weights:

• Anidulafungin (Eraxis; 1,140) has no published human data. It is indicated for the treatment of candidemia and other forms of Candida infections. The animal data suggest low risk.
• Caspofungin (Cancidas; 1,213) has no published human data. It is indicated for presumed fungal infections in febrile, neutropenic patients. The animal data are suggestive of human risk, especially if exposure occurs in the first trimester. If possible, maternal treatment should be avoided in the first trimester.
• Micafungin (Mycamine; 1,292) has no published human data. It is indicated for the treatment of patients with esophageal candidiasis and for the prophylaxis of Candida infections in patients undergoing hematopoietic stem cell transplantation. The animal data in one species suggest high risk. If possible, maternal treatment should be avoided in the first trimester.

Polyene antifungals cause depolarization of the fungal cell membrane to increase the membrane permeability, which leads to cell death. Their trade names and molecular weights:

• Amphotericin b (Amphocin; Fungizone; 924) There are three other amphotericin agents: amphotericin b cholesteryl sulfate (Amphotec); amphotericin b lipid complex (Abelcet); amphotericin b liposomal (AmBisome). No reports linking amphotericin b with congenital defects have been found. The drug does cross the human placenta. Although there was a higher rate of spontaneous abortions in rabbits given amphotericin b, there was no fetal harm in rats and rabbits when given amphotericin b lipid complex.
• Nystatin (Bio-Statin; Mycostatin; Nilstat; 926). The drug does not appear to cause embryo-fetal harm. Based on published data, the drug can be used at any time in pregnancy.

Breastfeeding

Small amounts of all the above drugs are probably excreted into breast milk if they are used close to breastfeeding. Most can probably be used during breastfeeding, but there are no data for any of these agents. The safest decision is to not use these drugs when breastfeeding.

Mr. Briggs is clinical professor of pharmacy at the University of California, San Francisco, and adjunct professor of pharmacy at the University of Southern California, Los Angeles, as well as at Washington State University, Spokane. Mr. Briggs said he had no relevant financial disclosures. Email him at [email protected].

During the first 3 months of the COVID-19 pandemic last year, about one-third of people with rheumatoid arthritis in the United States made changes in their RA medications, and, before the American College of Rheumatology tweaked its guidelines midway through that period, they were about twice as likely to make medication changes on their own than before the pandemic, according to an analysis of data in FORWARD, the National Databank for Rheumatic Diseases.

The study, published in Arthritis Care & Research, also found that about 10% of RA patients on hydroxychloroquine lost access to the drug at a time it was drawing interest as a treatment for COVID-19. Another finding was that a high percentage of patients on non–tumor necrosis factor biologic disease-modifying antirheumatic drugs (bDMARDs) and Janus kinase (JAK) inhibitors canceled or postponed appointments.

“Our results show that persons with RA who had medication changes in the first 3 months of the COVID-19 pandemic in the U.S. were more likely to have worse disease activity and higher exposure to prior DMARDs, but no statistical difference was found in terms of comorbidities,” first author Kaleb Michaud, PhD, and coauthors wrote. Dr. Michaud is with the National Databank for Rheumatic Diseases, Wichita, Kan., and the University of Nebraska Medical Center, Omaha.

The study evaluated responses from 734 adults who participated in FORWARD, an observational, multidisease registry. They answered online surveys about COVID-19 in May 2020 and had provided data on their medication use before the pandemic. A total of 30% (n = 221) reported medication changes in that period.
 

Details on medication changes

Medication changers were more likely to use glucocorticoids (GCs) (32.6% vs. 18.1%) and less likely to use nonhydroxychloroquine conventional DMARDs (49.3% vs. 62%) pre-COVID. Changers also reported higher rates of economic hardship during the pandemic (22.6% vs. 14.6%).

In the midst of the study period, the ACR issued a clinical guideline for treatment of rheumatic and musculoskeletal diseases (RMDs), emphasizing the need to maintain DMARD therapy, control disease activity, and reduce prednisone/GC use. The guideline advised continuing hydroxychloroquine and interleukin-6 inhibitor biologics in people with suspected or confirmed COVID-19.

Dr. Michaud and coauthors acknowledged the ongoing lack of knowledge about real-world treatment patterns for RA during the pandemic. They set out with this study to fill those knowledge gaps.

They noted that patients on bDMARDs (17.6%) and JAK inhibitors (17.1%) were more than twice as likely to discontinue medications than were those on conventional DMARDs (8.2%).

Switching to telehealth was the most common pandemic-related behavior change among patients in all DMARD groups, with rates ranging from 31% to 47.1%, followed by canceling or postponing appointments, with rates ranging from 27.9% to 36.4% depending on the DMARD group.

The study also found that RA patients widely adopted the behavior changes that the Centers for Disease Control and Prevention recommended during the pandemic, although the rates of restricting social contacts were significantly lower than the 90% reported in an early Italian study.

Dr. Michaud and coauthors also provided some explanation of why people on GCs and DMARDs were more likely than others to change medication patterns. “This may reflect efforts to reduce the perceived risk of infections due to GCs as well as the likely less-controlled disease activity associated with GC use,” they wrote. While the ACR’s early pandemic guidance followed the 2015 guidelines – that patients should continue on GCs at the “lowest possible dose” and not stop them “abruptly” – most U.S. rheumatologists reported cutting back on GC use during the pandemic.

The researchers acknowledged that evidence linking GC use with hospitalization for COVID-19, which emerged after they had surveyed study participants, was consistent their findings, but that the overall risk of COVID-19 in RA patients still isn’t known.

Pfizer funded the analysis, and a coauthor is an employee of Pfizer.

During the first 3 months of the COVID-19 pandemic last year, about one-third of people with rheumatoid arthritis in the United States made changes in their RA medications, and, before the American College of Rheumatology tweaked its guidelines midway through that period, they were about twice as likely to make medication changes on their own than before the pandemic, according to an analysis of data in FORWARD, the National Databank for Rheumatic Diseases.

The study, published in Arthritis Care & Research, also found that about 10% of RA patients on hydroxychloroquine lost access to the drug at a time it was drawing interest as a treatment for COVID-19. Another finding was that a high percentage of patients on non–tumor necrosis factor biologic disease-modifying antirheumatic drugs (bDMARDs) and Janus kinase (JAK) inhibitors canceled or postponed appointments.

“Our results show that persons with RA who had medication changes in the first 3 months of the COVID-19 pandemic in the U.S. were more likely to have worse disease activity and higher exposure to prior DMARDs, but no statistical difference was found in terms of comorbidities,” first author Kaleb Michaud, PhD, and coauthors wrote. Dr. Michaud is with the National Databank for Rheumatic Diseases, Wichita, Kan., and the University of Nebraska Medical Center, Omaha.

The study evaluated responses from 734 adults who participated in FORWARD, an observational, multidisease registry. They answered online surveys about COVID-19 in May 2020 and had provided data on their medication use before the pandemic. A total of 30% (n = 221) reported medication changes in that period.
 

Details on medication changes

Medication changers were more likely to use glucocorticoids (GCs) (32.6% vs. 18.1%) and less likely to use nonhydroxychloroquine conventional DMARDs (49.3% vs. 62%) pre-COVID. Changers also reported higher rates of economic hardship during the pandemic (22.6% vs. 14.6%).

In the midst of the study period, the ACR issued a clinical guideline for treatment of rheumatic and musculoskeletal diseases (RMDs), emphasizing the need to maintain DMARD therapy, control disease activity, and reduce prednisone/GC use. The guideline advised continuing hydroxychloroquine and interleukin-6 inhibitor biologics in people with suspected or confirmed COVID-19.

Dr. Michaud and coauthors acknowledged the ongoing lack of knowledge about real-world treatment patterns for RA during the pandemic. They set out with this study to fill those knowledge gaps.

They noted that patients on bDMARDs (17.6%) and JAK inhibitors (17.1%) were more than twice as likely to discontinue medications than were those on conventional DMARDs (8.2%).

Switching to telehealth was the most common pandemic-related behavior change among patients in all DMARD groups, with rates ranging from 31% to 47.1%, followed by canceling or postponing appointments, with rates ranging from 27.9% to 36.4% depending on the DMARD group.

The study also found that RA patients widely adopted the behavior changes that the Centers for Disease Control and Prevention recommended during the pandemic, although the rates of restricting social contacts were significantly lower than the 90% reported in an early Italian study.

Dr. Michaud and coauthors also provided some explanation of why people on GCs and DMARDs were more likely than others to change medication patterns. “This may reflect efforts to reduce the perceived risk of infections due to GCs as well as the likely less-controlled disease activity associated with GC use,” they wrote. While the ACR’s early pandemic guidance followed the 2015 guidelines – that patients should continue on GCs at the “lowest possible dose” and not stop them “abruptly” – most U.S. rheumatologists reported cutting back on GC use during the pandemic.

The researchers acknowledged that evidence linking GC use with hospitalization for COVID-19, which emerged after they had surveyed study participants, was consistent their findings, but that the overall risk of COVID-19 in RA patients still isn’t known.

Pfizer funded the analysis, and a coauthor is an employee of Pfizer.

During the first 3 months of the COVID-19 pandemic last year, about one-third of people with rheumatoid arthritis in the United States made changes in their RA medications, and, before the American College of Rheumatology tweaked its guidelines midway through that period, they were about twice as likely to make medication changes on their own than before the pandemic, according to an analysis of data in FORWARD, the National Databank for Rheumatic Diseases.

The study, published in Arthritis Care & Research, also found that about 10% of RA patients on hydroxychloroquine lost access to the drug at a time it was drawing interest as a treatment for COVID-19. Another finding was that a high percentage of patients on non–tumor necrosis factor biologic disease-modifying antirheumatic drugs (bDMARDs) and Janus kinase (JAK) inhibitors canceled or postponed appointments.

“Our results show that persons with RA who had medication changes in the first 3 months of the COVID-19 pandemic in the U.S. were more likely to have worse disease activity and higher exposure to prior DMARDs, but no statistical difference was found in terms of comorbidities,” first author Kaleb Michaud, PhD, and coauthors wrote. Dr. Michaud is with the National Databank for Rheumatic Diseases, Wichita, Kan., and the University of Nebraska Medical Center, Omaha.

The study evaluated responses from 734 adults who participated in FORWARD, an observational, multidisease registry. They answered online surveys about COVID-19 in May 2020 and had provided data on their medication use before the pandemic. A total of 30% (n = 221) reported medication changes in that period.
 

Details on medication changes

Medication changers were more likely to use glucocorticoids (GCs) (32.6% vs. 18.1%) and less likely to use nonhydroxychloroquine conventional DMARDs (49.3% vs. 62%) pre-COVID. Changers also reported higher rates of economic hardship during the pandemic (22.6% vs. 14.6%).

In the midst of the study period, the ACR issued a clinical guideline for treatment of rheumatic and musculoskeletal diseases (RMDs), emphasizing the need to maintain DMARD therapy, control disease activity, and reduce prednisone/GC use. The guideline advised continuing hydroxychloroquine and interleukin-6 inhibitor biologics in people with suspected or confirmed COVID-19.

Dr. Michaud and coauthors acknowledged the ongoing lack of knowledge about real-world treatment patterns for RA during the pandemic. They set out with this study to fill those knowledge gaps.

They noted that patients on bDMARDs (17.6%) and JAK inhibitors (17.1%) were more than twice as likely to discontinue medications than were those on conventional DMARDs (8.2%).

Switching to telehealth was the most common pandemic-related behavior change among patients in all DMARD groups, with rates ranging from 31% to 47.1%, followed by canceling or postponing appointments, with rates ranging from 27.9% to 36.4% depending on the DMARD group.

The study also found that RA patients widely adopted the behavior changes that the Centers for Disease Control and Prevention recommended during the pandemic, although the rates of restricting social contacts were significantly lower than the 90% reported in an early Italian study.

Dr. Michaud and coauthors also provided some explanation of why people on GCs and DMARDs were more likely than others to change medication patterns. “This may reflect efforts to reduce the perceived risk of infections due to GCs as well as the likely less-controlled disease activity associated with GC use,” they wrote. While the ACR’s early pandemic guidance followed the 2015 guidelines – that patients should continue on GCs at the “lowest possible dose” and not stop them “abruptly” – most U.S. rheumatologists reported cutting back on GC use during the pandemic.

The researchers acknowledged that evidence linking GC use with hospitalization for COVID-19, which emerged after they had surveyed study participants, was consistent their findings, but that the overall risk of COVID-19 in RA patients still isn’t known.

Pfizer funded the analysis, and a coauthor is an employee of Pfizer.

Although most patients with chronic inflammatory diseases mounted immune responses after two doses of mRNA-based COVID-19 vaccines, glucocorticoids and B-cell–depleting therapies markedly reduced the response, according to a recently published preprint of a new study.

Mongkolchon Akesin/Getty Images

The study, published on MedRxiv and not yet peer reviewed, involved a prospective look at 133 patients with chronic inflammatory disease (CID) and 53 patients with healthy immune systems at Washington University, St. Louis, and the University of California, San Francisco. It is regarded as the largest and most detailed study yet in how vaccines perform in people with immune-mediated inflammatory disease. The patients were enrolled between December 2020 and March 2021, and the most common diseases were inflammatory bowel disease (32%), rheumatoid arthritis (29%), spondyloarthritis (15%), and systemic lupus erythematosus (11%).
 

A ‘modest’ reduction in antibody response

Senior author Alfred Kim, MD, PhD, of the department of medicine at Washington University, said the overall results so far are encouraging.

“Most patients with an autoimmune disease that are on immunosuppression can mount antibody responses,” he said. “We’re seeing the majority of our subjects respond.”

The immune-healthy controls and most of the patients with CID had a robust immune response against the spike protein, although the CID group had a mean reduction in antibody titers that was three times lower than the controls (P = .0092). The CID group similarly had a 2.7-fold reduction in preventing neutralization, or halting the virus’ ability to infect (P < .0001), researchers reported.

This reduction in response is “modest,” he said.

“Is the level of reduction going to be detrimental for protection? Time will tell,” he said, adding that researchers anticipate that it won’t have a critical effect on protection because responses tended to be within the range of the immunocompetent controls, who themselves had wildly varied antibody titers across a 20-fold range. “ ‘Optimal’ isn’t necessarily the same as ‘sufficient.’ ”
 

Type of medication has big impact on antibody titers

But there was a wide variety of effects on the immune response depending on the medication. Glucorticoids resulted in a response that was 10 times lower than the immune-healthy controls, as well as fewer circulating plasmablasts after vaccination. Researchers found that 98% of controls were seropositive for antibody, compared with 92% of those with CID who were not taking prednisone, and 65% of CID patients on prednisone (P = .0006 and .0115, respectively). Prevention of neutralization of the virus was similarly reduced in those groups, compared with the controls. Dr. Kim noted this was a small sample size, with about 15 patients. These effects were seen regardless of the dose.

“We would’ve anticipated this would have been dose dependent, so this was a little bit surprising,” Dr. Kim said.

B-cell–depleting therapies, such as rituximab (Rituxan) and ocrelizumab (Ocrevus), reduced antibody titers by 36 times, compared with controls (P < .0001), with a similar reduction in preventing infection (P = .0066), the researchers found. The reduction in antibody titers was the most pronounced among those who had received B-cell–depleting therapies within the previous 6 months. Dr. Kim noted this was a small sample size, with about 10 patients.

CID study subjects taking an antimetabolite, including methotrexate, had an average of a two- to threefold reduction in antibody titers and in neutralization (P = .0006). This reduction was greatest with methotrexate, researchers found (P = .0027).

JAK inhibitors also significantly reduced antibody titers (P = .0066), but the reduction in neutralization of the virus was not significant. In addition, researchers found a reduction in antibody titers, the prevention of viral infection, and circulating plasmablasts among those on tumor necrosis factor (TNF) inhibitors, compared with controls, but these were insignificant statistically except for virus neutralization.

Dr. Kim said he hopes the glucocorticoid data spur physicians to try harder to wean patients off the drugs, when possible, in keeping with recommendations already in place.

“The general culture in rheumatology has been very lax about the need to reduce glucocorticoids,” he said. “This reinvigorates that call.” Questions about possible drug holidays from glucocorticoids remain, regarding how long a holiday would be needed, he said. He noted that many patients on glucocorticoids nonetheless mounted responses.

Those on B-cell–depleting therapies present a “much more difficult” question, he said. Some patients possibly could wait a bit longer than their normal, every-6-month schedule, but it’s an individual decision, he said. Since a booster of influenza vaccine has been found to enhance the response even within the 6-month window among ocrelizumab patients, a booster of COVID-19 vaccine might also help, although this remains to be studied.

The study group has already increased its sample size and is looking at adverse reactions and long-term immune responses, Dr. Kim said.

Encouraging, rather than discouraging, results

Leonard Calabrese, DO, professor of medicine at the Cleveland Clinic in Ohio, said the findings shouldn’t discourage clinicians from encouraging vaccination.

“There’s still a preponderance of people who will develop a robust antibody vaccine response,” he said.

He cautioned that the findings look only at antibodies to the spike protein and at plasmablasts. The reduction in these titers is “of concern,” he said, but “we don’t really know with certainty what are the effects of these drugs, and these data are on the overall biologic protective effect of the vaccine. There’s much more to a vaccine response than anti–spike protein and plasmablasts,” including cell-mediated immune response.

For an individual patient, the findings “mean a lot,” he said.

“I think that people who are on significant prednisone and B-cell–depleting agents, I think you have to share with them that there’s a reasonable chance that you’re not going to be making a response similar to healthy people,” he said. “Thus, even with your vaccine, we’re not going to cut you loose to do things that are violating social distancing and group settings. … Should you be hugging your grandchildren if you’re a rituximab vaccine recipient? I think I would wait until we have a little bit more data.”

Kevin Winthrop, MD, MPH, professor of ophthalmology at Oregon Health & Science University, Portland, where he studies vaccinations in the immunocompromised, said that glucocorticoids tend to have little effect on vaccinations generally at low doses.

When effects are seen they can be difficult to interpret, he said.

“It’s hard to extricate that from the effect of the underlying disease,” he said. The drug can be a proxy for worse disease control.

Although it’s a small study, it’s reassuring that overall the responses were similar to healthy controls.

For B-cell–depleting therapies, his usual guidance is to not give vaccine until a patient is at least 3 months out from their last dose, and not to restart until at least 2 weeks after vaccination.

“It’s not surprising that some of these DMARDs [disease-modifying antirheumatic drugs] do negatively affect vaccine response, particularly B-cell–depletion therapy. We need to do some studies to find a way to overcome that, or optimize delivery of the vaccine.”

Dr. Kim reported participating in consulting, advisory board, or speaker’s bureau for Alexion, Aurinia, Annexon Biosciences, Exagen Diagnostics, and GlaxoSmithKline, and receiving funding under a sponsored research agreement unrelated to the data in the paper from GlaxoSmithKline. Dr. Winthrop reported receiving consulting fees from Pfizer, AbbVie, UCB, Eli Lilly, Galapagos, GlaxoSmithKline, Roche, Gilead, Bristol-Myers Squibb, Regeneron, Sanofi, AstraZeneca, Novartis, and research grants from Bristol-Myers Squibb and Pfizer. Dr. Calabrese reported no relevant disclosures.

Although most patients with chronic inflammatory diseases mounted immune responses after two doses of mRNA-based COVID-19 vaccines, glucocorticoids and B-cell–depleting therapies markedly reduced the response, according to a recently published preprint of a new study.

Mongkolchon Akesin/Getty Images

The study, published on MedRxiv and not yet peer reviewed, involved a prospective look at 133 patients with chronic inflammatory disease (CID) and 53 patients with healthy immune systems at Washington University, St. Louis, and the University of California, San Francisco. It is regarded as the largest and most detailed study yet in how vaccines perform in people with immune-mediated inflammatory disease. The patients were enrolled between December 2020 and March 2021, and the most common diseases were inflammatory bowel disease (32%), rheumatoid arthritis (29%), spondyloarthritis (15%), and systemic lupus erythematosus (11%).
 

A ‘modest’ reduction in antibody response

Senior author Alfred Kim, MD, PhD, of the department of medicine at Washington University, said the overall results so far are encouraging.

“Most patients with an autoimmune disease that are on immunosuppression can mount antibody responses,” he said. “We’re seeing the majority of our subjects respond.”

The immune-healthy controls and most of the patients with CID had a robust immune response against the spike protein, although the CID group had a mean reduction in antibody titers that was three times lower than the controls (P = .0092). The CID group similarly had a 2.7-fold reduction in preventing neutralization, or halting the virus’ ability to infect (P < .0001), researchers reported.

This reduction in response is “modest,” he said.

“Is the level of reduction going to be detrimental for protection? Time will tell,” he said, adding that researchers anticipate that it won’t have a critical effect on protection because responses tended to be within the range of the immunocompetent controls, who themselves had wildly varied antibody titers across a 20-fold range. “ ‘Optimal’ isn’t necessarily the same as ‘sufficient.’ ”
 

Type of medication has big impact on antibody titers

But there was a wide variety of effects on the immune response depending on the medication. Glucorticoids resulted in a response that was 10 times lower than the immune-healthy controls, as well as fewer circulating plasmablasts after vaccination. Researchers found that 98% of controls were seropositive for antibody, compared with 92% of those with CID who were not taking prednisone, and 65% of CID patients on prednisone (P = .0006 and .0115, respectively). Prevention of neutralization of the virus was similarly reduced in those groups, compared with the controls. Dr. Kim noted this was a small sample size, with about 15 patients. These effects were seen regardless of the dose.

“We would’ve anticipated this would have been dose dependent, so this was a little bit surprising,” Dr. Kim said.

B-cell–depleting therapies, such as rituximab (Rituxan) and ocrelizumab (Ocrevus), reduced antibody titers by 36 times, compared with controls (P < .0001), with a similar reduction in preventing infection (P = .0066), the researchers found. The reduction in antibody titers was the most pronounced among those who had received B-cell–depleting therapies within the previous 6 months. Dr. Kim noted this was a small sample size, with about 10 patients.

CID study subjects taking an antimetabolite, including methotrexate, had an average of a two- to threefold reduction in antibody titers and in neutralization (P = .0006). This reduction was greatest with methotrexate, researchers found (P = .0027).

JAK inhibitors also significantly reduced antibody titers (P = .0066), but the reduction in neutralization of the virus was not significant. In addition, researchers found a reduction in antibody titers, the prevention of viral infection, and circulating plasmablasts among those on tumor necrosis factor (TNF) inhibitors, compared with controls, but these were insignificant statistically except for virus neutralization.

Dr. Kim said he hopes the glucocorticoid data spur physicians to try harder to wean patients off the drugs, when possible, in keeping with recommendations already in place.

“The general culture in rheumatology has been very lax about the need to reduce glucocorticoids,” he said. “This reinvigorates that call.” Questions about possible drug holidays from glucocorticoids remain, regarding how long a holiday would be needed, he said. He noted that many patients on glucocorticoids nonetheless mounted responses.

Those on B-cell–depleting therapies present a “much more difficult” question, he said. Some patients possibly could wait a bit longer than their normal, every-6-month schedule, but it’s an individual decision, he said. Since a booster of influenza vaccine has been found to enhance the response even within the 6-month window among ocrelizumab patients, a booster of COVID-19 vaccine might also help, although this remains to be studied.

The study group has already increased its sample size and is looking at adverse reactions and long-term immune responses, Dr. Kim said.

Encouraging, rather than discouraging, results

Leonard Calabrese, DO, professor of medicine at the Cleveland Clinic in Ohio, said the findings shouldn’t discourage clinicians from encouraging vaccination.

“There’s still a preponderance of people who will develop a robust antibody vaccine response,” he said.

He cautioned that the findings look only at antibodies to the spike protein and at plasmablasts. The reduction in these titers is “of concern,” he said, but “we don’t really know with certainty what are the effects of these drugs, and these data are on the overall biologic protective effect of the vaccine. There’s much more to a vaccine response than anti–spike protein and plasmablasts,” including cell-mediated immune response.

For an individual patient, the findings “mean a lot,” he said.

“I think that people who are on significant prednisone and B-cell–depleting agents, I think you have to share with them that there’s a reasonable chance that you’re not going to be making a response similar to healthy people,” he said. “Thus, even with your vaccine, we’re not going to cut you loose to do things that are violating social distancing and group settings. … Should you be hugging your grandchildren if you’re a rituximab vaccine recipient? I think I would wait until we have a little bit more data.”

Kevin Winthrop, MD, MPH, professor of ophthalmology at Oregon Health & Science University, Portland, where he studies vaccinations in the immunocompromised, said that glucocorticoids tend to have little effect on vaccinations generally at low doses.

When effects are seen they can be difficult to interpret, he said.

“It’s hard to extricate that from the effect of the underlying disease,” he said. The drug can be a proxy for worse disease control.

Although it’s a small study, it’s reassuring that overall the responses were similar to healthy controls.

For B-cell–depleting therapies, his usual guidance is to not give vaccine until a patient is at least 3 months out from their last dose, and not to restart until at least 2 weeks after vaccination.

“It’s not surprising that some of these DMARDs [disease-modifying antirheumatic drugs] do negatively affect vaccine response, particularly B-cell–depletion therapy. We need to do some studies to find a way to overcome that, or optimize delivery of the vaccine.”

Dr. Kim reported participating in consulting, advisory board, or speaker’s bureau for Alexion, Aurinia, Annexon Biosciences, Exagen Diagnostics, and GlaxoSmithKline, and receiving funding under a sponsored research agreement unrelated to the data in the paper from GlaxoSmithKline. Dr. Winthrop reported receiving consulting fees from Pfizer, AbbVie, UCB, Eli Lilly, Galapagos, GlaxoSmithKline, Roche, Gilead, Bristol-Myers Squibb, Regeneron, Sanofi, AstraZeneca, Novartis, and research grants from Bristol-Myers Squibb and Pfizer. Dr. Calabrese reported no relevant disclosures.

Although most patients with chronic inflammatory diseases mounted immune responses after two doses of mRNA-based COVID-19 vaccines, glucocorticoids and B-cell–depleting therapies markedly reduced the response, according to a recently published preprint of a new study.

Mongkolchon Akesin/Getty Images

The study, published on MedRxiv and not yet peer reviewed, involved a prospective look at 133 patients with chronic inflammatory disease (CID) and 53 patients with healthy immune systems at Washington University, St. Louis, and the University of California, San Francisco. It is regarded as the largest and most detailed study yet in how vaccines perform in people with immune-mediated inflammatory disease. The patients were enrolled between December 2020 and March 2021, and the most common diseases were inflammatory bowel disease (32%), rheumatoid arthritis (29%), spondyloarthritis (15%), and systemic lupus erythematosus (11%).
 

A ‘modest’ reduction in antibody response

Senior author Alfred Kim, MD, PhD, of the department of medicine at Washington University, said the overall results so far are encouraging.

“Most patients with an autoimmune disease that are on immunosuppression can mount antibody responses,” he said. “We’re seeing the majority of our subjects respond.”

The immune-healthy controls and most of the patients with CID had a robust immune response against the spike protein, although the CID group had a mean reduction in antibody titers that was three times lower than the controls (P = .0092). The CID group similarly had a 2.7-fold reduction in preventing neutralization, or halting the virus’ ability to infect (P < .0001), researchers reported.

This reduction in response is “modest,” he said.

“Is the level of reduction going to be detrimental for protection? Time will tell,” he said, adding that researchers anticipate that it won’t have a critical effect on protection because responses tended to be within the range of the immunocompetent controls, who themselves had wildly varied antibody titers across a 20-fold range. “ ‘Optimal’ isn’t necessarily the same as ‘sufficient.’ ”
 

Type of medication has big impact on antibody titers

But there was a wide variety of effects on the immune response depending on the medication. Glucorticoids resulted in a response that was 10 times lower than the immune-healthy controls, as well as fewer circulating plasmablasts after vaccination. Researchers found that 98% of controls were seropositive for antibody, compared with 92% of those with CID who were not taking prednisone, and 65% of CID patients on prednisone (P = .0006 and .0115, respectively). Prevention of neutralization of the virus was similarly reduced in those groups, compared with the controls. Dr. Kim noted this was a small sample size, with about 15 patients. These effects were seen regardless of the dose.

“We would’ve anticipated this would have been dose dependent, so this was a little bit surprising,” Dr. Kim said.

B-cell–depleting therapies, such as rituximab (Rituxan) and ocrelizumab (Ocrevus), reduced antibody titers by 36 times, compared with controls (P < .0001), with a similar reduction in preventing infection (P = .0066), the researchers found. The reduction in antibody titers was the most pronounced among those who had received B-cell–depleting therapies within the previous 6 months. Dr. Kim noted this was a small sample size, with about 10 patients.

CID study subjects taking an antimetabolite, including methotrexate, had an average of a two- to threefold reduction in antibody titers and in neutralization (P = .0006). This reduction was greatest with methotrexate, researchers found (P = .0027).

JAK inhibitors also significantly reduced antibody titers (P = .0066), but the reduction in neutralization of the virus was not significant. In addition, researchers found a reduction in antibody titers, the prevention of viral infection, and circulating plasmablasts among those on tumor necrosis factor (TNF) inhibitors, compared with controls, but these were insignificant statistically except for virus neutralization.

Dr. Kim said he hopes the glucocorticoid data spur physicians to try harder to wean patients off the drugs, when possible, in keeping with recommendations already in place.

“The general culture in rheumatology has been very lax about the need to reduce glucocorticoids,” he said. “This reinvigorates that call.” Questions about possible drug holidays from glucocorticoids remain, regarding how long a holiday would be needed, he said. He noted that many patients on glucocorticoids nonetheless mounted responses.

Those on B-cell–depleting therapies present a “much more difficult” question, he said. Some patients possibly could wait a bit longer than their normal, every-6-month schedule, but it’s an individual decision, he said. Since a booster of influenza vaccine has been found to enhance the response even within the 6-month window among ocrelizumab patients, a booster of COVID-19 vaccine might also help, although this remains to be studied.

The study group has already increased its sample size and is looking at adverse reactions and long-term immune responses, Dr. Kim said.

Encouraging, rather than discouraging, results

Leonard Calabrese, DO, professor of medicine at the Cleveland Clinic in Ohio, said the findings shouldn’t discourage clinicians from encouraging vaccination.

“There’s still a preponderance of people who will develop a robust antibody vaccine response,” he said.

He cautioned that the findings look only at antibodies to the spike protein and at plasmablasts. The reduction in these titers is “of concern,” he said, but “we don’t really know with certainty what are the effects of these drugs, and these data are on the overall biologic protective effect of the vaccine. There’s much more to a vaccine response than anti–spike protein and plasmablasts,” including cell-mediated immune response.

For an individual patient, the findings “mean a lot,” he said.

“I think that people who are on significant prednisone and B-cell–depleting agents, I think you have to share with them that there’s a reasonable chance that you’re not going to be making a response similar to healthy people,” he said. “Thus, even with your vaccine, we’re not going to cut you loose to do things that are violating social distancing and group settings. … Should you be hugging your grandchildren if you’re a rituximab vaccine recipient? I think I would wait until we have a little bit more data.”

Kevin Winthrop, MD, MPH, professor of ophthalmology at Oregon Health & Science University, Portland, where he studies vaccinations in the immunocompromised, said that glucocorticoids tend to have little effect on vaccinations generally at low doses.

When effects are seen they can be difficult to interpret, he said.

“It’s hard to extricate that from the effect of the underlying disease,” he said. The drug can be a proxy for worse disease control.

Although it’s a small study, it’s reassuring that overall the responses were similar to healthy controls.

For B-cell–depleting therapies, his usual guidance is to not give vaccine until a patient is at least 3 months out from their last dose, and not to restart until at least 2 weeks after vaccination.

“It’s not surprising that some of these DMARDs [disease-modifying antirheumatic drugs] do negatively affect vaccine response, particularly B-cell–depletion therapy. We need to do some studies to find a way to overcome that, or optimize delivery of the vaccine.”

Dr. Kim reported participating in consulting, advisory board, or speaker’s bureau for Alexion, Aurinia, Annexon Biosciences, Exagen Diagnostics, and GlaxoSmithKline, and receiving funding under a sponsored research agreement unrelated to the data in the paper from GlaxoSmithKline. Dr. Winthrop reported receiving consulting fees from Pfizer, AbbVie, UCB, Eli Lilly, Galapagos, GlaxoSmithKline, Roche, Gilead, Bristol-Myers Squibb, Regeneron, Sanofi, AstraZeneca, Novartis, and research grants from Bristol-Myers Squibb and Pfizer. Dr. Calabrese reported no relevant disclosures.

The Food and Drug Administration has approved a new estrogen for the first time in more than 50 years.

The novel combined oral contraceptive, marketed as Nextstellis, contains 3 mg drospirenone (DRSP) and 14.2 mg of estetrol (E4) in tablet form. Estetrol is an estrogen that is naturally produced during pregnancy, but will now be produced from a plant source; it has not previously been used in oral contraceptives.

Approval of the unique estetrol/drospirenone combination was based on data from a pair of phase 3 clinical trials including 3,725 women. Overall, Nextstellis was safe and effective while meeting its primary endpoint of pregnancy prevention, according to a company press release. Participants also reported favorable results on secondary endpoints including cycle control, bleeding profile, safety, and tolerability.

Although many women take short-acting contraceptives containing estrogen and progestin, concerns persist about side effects, said Mitchell Creinin, MD, of the University of California, in the press release. In addition to providing effective contraception, the drug showed minimal impact on specific markers of concern, including triglycerides, cholesterol, and glucose, as well as weight and endocrine markers, Dr. Creinin said.

Nextstellis was developed by the Belgian biotech company Mithra Pharmaceuticals, and the drug is licensed for distribution in Australia and the United States by Mayne Pharma, with an expected launch at the end of June 2021.

The Food and Drug Administration has approved a new estrogen for the first time in more than 50 years.

The novel combined oral contraceptive, marketed as Nextstellis, contains 3 mg drospirenone (DRSP) and 14.2 mg of estetrol (E4) in tablet form. Estetrol is an estrogen that is naturally produced during pregnancy, but will now be produced from a plant source; it has not previously been used in oral contraceptives.

Approval of the unique estetrol/drospirenone combination was based on data from a pair of phase 3 clinical trials including 3,725 women. Overall, Nextstellis was safe and effective while meeting its primary endpoint of pregnancy prevention, according to a company press release. Participants also reported favorable results on secondary endpoints including cycle control, bleeding profile, safety, and tolerability.

Although many women take short-acting contraceptives containing estrogen and progestin, concerns persist about side effects, said Mitchell Creinin, MD, of the University of California, in the press release. In addition to providing effective contraception, the drug showed minimal impact on specific markers of concern, including triglycerides, cholesterol, and glucose, as well as weight and endocrine markers, Dr. Creinin said.

Nextstellis was developed by the Belgian biotech company Mithra Pharmaceuticals, and the drug is licensed for distribution in Australia and the United States by Mayne Pharma, with an expected launch at the end of June 2021.

The Food and Drug Administration has approved a new estrogen for the first time in more than 50 years.

The novel combined oral contraceptive, marketed as Nextstellis, contains 3 mg drospirenone (DRSP) and 14.2 mg of estetrol (E4) in tablet form. Estetrol is an estrogen that is naturally produced during pregnancy, but will now be produced from a plant source; it has not previously been used in oral contraceptives.

Approval of the unique estetrol/drospirenone combination was based on data from a pair of phase 3 clinical trials including 3,725 women. Overall, Nextstellis was safe and effective while meeting its primary endpoint of pregnancy prevention, according to a company press release. Participants also reported favorable results on secondary endpoints including cycle control, bleeding profile, safety, and tolerability.

Although many women take short-acting contraceptives containing estrogen and progestin, concerns persist about side effects, said Mitchell Creinin, MD, of the University of California, in the press release. In addition to providing effective contraception, the drug showed minimal impact on specific markers of concern, including triglycerides, cholesterol, and glucose, as well as weight and endocrine markers, Dr. Creinin said.

Nextstellis was developed by the Belgian biotech company Mithra Pharmaceuticals, and the drug is licensed for distribution in Australia and the United States by Mayne Pharma, with an expected launch at the end of June 2021.

Bovine meat and milk factors (BMMF), the recently discovered pathogenic agents found in milk products and beef, could play a role in the development of colorectal cancer, say German scientists.

The team was headed by Harald zur Hausen, MD, PhD, division of episomal-persistent DNA in cancer and chronic diseases, German Cancer Research Center, Heidelberg, who received the Nobel Prize in Physiology or Medicine in 2008 for his discovery of the role of human papillomaviruses in the development of cervical cancer.

The team has been researching the link between BMMF and colorectal cancer for some years, and the latest study was published in the Proceedings of the National Academy of Sciences.

“The results support our hypothesis that the consumption of milk and beef is causally linked to the development of colon cancer,” Dr. Hausen said in a related press statement.
 

Pathogenic agents, found in vicinity of tumors

BMMF are infectious agents that occur as circular single strands of DNA and have a notable similarity to the sequences of some bacterial plasmids.

A few years ago, Dr. Hausen and colleagues found these pathogenic agents in colon cancer patients, in the immediate vicinity of tumors.

They therefore put forward the hypothesis that BMMF could trigger chronic local inflammation, which in turn could cause genetic mutations via oxidative stress and lead to the development of cancer over the long term.

The German researchers were also able to show in in vitro models that BMMF multiply in human cells where the H1MSB.1 Rep protein, which is required for their replication, is synthesized.

In their latest study, the scientists analyzed tissue samples from colorectal cancer patients and from individuals without the disease.

The team found that BMMF could trigger chronic inflammation in the intestinal tissue of cancer patients, as demonstrated via the presence of proinflammatory macrophages.

The researchers also used anti-Rep antibodies to show that the Rep protein was present around and inside the macrophages. In cancer patients, 7.3% of all the intestinal cells in the tumor environment were positive for Rep versus just 1.7% of those in the control group.

In addition, the researchers reported increased levels of reactive oxygen species close to Rep-positive cells.

“These oxygen radicals promote the development of genetic changes,” Dr. Hausen said.

The inflammation was particularly localized to the immediate vicinity of the intestinal crypts, where the intestinal stem cells, which are responsible for the constant regeneration of the intestinal mucosa, are found.

“We therefore think of the BMMF as indirect carcinogens, some of which will probably have an impact on dividing cells in the intestinal mucosa for decades,” Dr. Hausen explained.

He assumes that infection with BMMF typically occurs early in life. This “opens up the possibility of early intervention,” he suggested.

The early detection of BMMF could allow the identification of individuals particularly at risk, and for these patients to be offered timely colon cancer screening.

The researchers stressed, however, that further study will be required to confirm the results.

They nevertheless believed that BMMF could help explain the link between the consumption of red meat and dairy products and other cancers and diseases, in particular breast, prostate, and lung cancers.

Finally, the pathogenic agents could partially explain the preventive effect of anti-inflammatory dugs such as aspirin and ibuprofen on the incidence of colon cancer and other cancers via the reduction of chronic inflammation.

This work was supported by an unrestricted grant from ORYX Alpha. One coauthor was supported by the EOS Foundation, the SFBTR-179 and 209, and a European Research Council consolidator grant. The other coauthors disclosed no relevant financial relationships.

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

Bovine meat and milk factors (BMMF), the recently discovered pathogenic agents found in milk products and beef, could play a role in the development of colorectal cancer, say German scientists.

The team was headed by Harald zur Hausen, MD, PhD, division of episomal-persistent DNA in cancer and chronic diseases, German Cancer Research Center, Heidelberg, who received the Nobel Prize in Physiology or Medicine in 2008 for his discovery of the role of human papillomaviruses in the development of cervical cancer.

The team has been researching the link between BMMF and colorectal cancer for some years, and the latest study was published in the Proceedings of the National Academy of Sciences.

“The results support our hypothesis that the consumption of milk and beef is causally linked to the development of colon cancer,” Dr. Hausen said in a related press statement.
 

Pathogenic agents, found in vicinity of tumors

BMMF are infectious agents that occur as circular single strands of DNA and have a notable similarity to the sequences of some bacterial plasmids.

A few years ago, Dr. Hausen and colleagues found these pathogenic agents in colon cancer patients, in the immediate vicinity of tumors.

They therefore put forward the hypothesis that BMMF could trigger chronic local inflammation, which in turn could cause genetic mutations via oxidative stress and lead to the development of cancer over the long term.

The German researchers were also able to show in in vitro models that BMMF multiply in human cells where the H1MSB.1 Rep protein, which is required for their replication, is synthesized.

In their latest study, the scientists analyzed tissue samples from colorectal cancer patients and from individuals without the disease.

The team found that BMMF could trigger chronic inflammation in the intestinal tissue of cancer patients, as demonstrated via the presence of proinflammatory macrophages.

The researchers also used anti-Rep antibodies to show that the Rep protein was present around and inside the macrophages. In cancer patients, 7.3% of all the intestinal cells in the tumor environment were positive for Rep versus just 1.7% of those in the control group.

In addition, the researchers reported increased levels of reactive oxygen species close to Rep-positive cells.

“These oxygen radicals promote the development of genetic changes,” Dr. Hausen said.

The inflammation was particularly localized to the immediate vicinity of the intestinal crypts, where the intestinal stem cells, which are responsible for the constant regeneration of the intestinal mucosa, are found.

“We therefore think of the BMMF as indirect carcinogens, some of which will probably have an impact on dividing cells in the intestinal mucosa for decades,” Dr. Hausen explained.

He assumes that infection with BMMF typically occurs early in life. This “opens up the possibility of early intervention,” he suggested.

The early detection of BMMF could allow the identification of individuals particularly at risk, and for these patients to be offered timely colon cancer screening.

The researchers stressed, however, that further study will be required to confirm the results.

They nevertheless believed that BMMF could help explain the link between the consumption of red meat and dairy products and other cancers and diseases, in particular breast, prostate, and lung cancers.

Finally, the pathogenic agents could partially explain the preventive effect of anti-inflammatory dugs such as aspirin and ibuprofen on the incidence of colon cancer and other cancers via the reduction of chronic inflammation.

This work was supported by an unrestricted grant from ORYX Alpha. One coauthor was supported by the EOS Foundation, the SFBTR-179 and 209, and a European Research Council consolidator grant. The other coauthors disclosed no relevant financial relationships.

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

Bovine meat and milk factors (BMMF), the recently discovered pathogenic agents found in milk products and beef, could play a role in the development of colorectal cancer, say German scientists.

The team was headed by Harald zur Hausen, MD, PhD, division of episomal-persistent DNA in cancer and chronic diseases, German Cancer Research Center, Heidelberg, who received the Nobel Prize in Physiology or Medicine in 2008 for his discovery of the role of human papillomaviruses in the development of cervical cancer.

The team has been researching the link between BMMF and colorectal cancer for some years, and the latest study was published in the Proceedings of the National Academy of Sciences.

“The results support our hypothesis that the consumption of milk and beef is causally linked to the development of colon cancer,” Dr. Hausen said in a related press statement.
 

Pathogenic agents, found in vicinity of tumors

BMMF are infectious agents that occur as circular single strands of DNA and have a notable similarity to the sequences of some bacterial plasmids.

A few years ago, Dr. Hausen and colleagues found these pathogenic agents in colon cancer patients, in the immediate vicinity of tumors.

They therefore put forward the hypothesis that BMMF could trigger chronic local inflammation, which in turn could cause genetic mutations via oxidative stress and lead to the development of cancer over the long term.

The German researchers were also able to show in in vitro models that BMMF multiply in human cells where the H1MSB.1 Rep protein, which is required for their replication, is synthesized.

In their latest study, the scientists analyzed tissue samples from colorectal cancer patients and from individuals without the disease.

The team found that BMMF could trigger chronic inflammation in the intestinal tissue of cancer patients, as demonstrated via the presence of proinflammatory macrophages.

The researchers also used anti-Rep antibodies to show that the Rep protein was present around and inside the macrophages. In cancer patients, 7.3% of all the intestinal cells in the tumor environment were positive for Rep versus just 1.7% of those in the control group.

In addition, the researchers reported increased levels of reactive oxygen species close to Rep-positive cells.

“These oxygen radicals promote the development of genetic changes,” Dr. Hausen said.

The inflammation was particularly localized to the immediate vicinity of the intestinal crypts, where the intestinal stem cells, which are responsible for the constant regeneration of the intestinal mucosa, are found.

“We therefore think of the BMMF as indirect carcinogens, some of which will probably have an impact on dividing cells in the intestinal mucosa for decades,” Dr. Hausen explained.

He assumes that infection with BMMF typically occurs early in life. This “opens up the possibility of early intervention,” he suggested.

The early detection of BMMF could allow the identification of individuals particularly at risk, and for these patients to be offered timely colon cancer screening.

The researchers stressed, however, that further study will be required to confirm the results.

They nevertheless believed that BMMF could help explain the link between the consumption of red meat and dairy products and other cancers and diseases, in particular breast, prostate, and lung cancers.

Finally, the pathogenic agents could partially explain the preventive effect of anti-inflammatory dugs such as aspirin and ibuprofen on the incidence of colon cancer and other cancers via the reduction of chronic inflammation.

This work was supported by an unrestricted grant from ORYX Alpha. One coauthor was supported by the EOS Foundation, the SFBTR-179 and 209, and a European Research Council consolidator grant. The other coauthors disclosed no relevant financial relationships.

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

Rare is the parent who has never so much as thought about spanking an unruly child. But a new study provides another reason to avoid corporal punishment: Spanking may cause changes in the same areas of a child’s brain that are affected by more severe physical and sexual abuse.

Previous research has consistently found links between spanking and behavioral problems, aggression, depression, and anxiety, says Jorge Cuartas, a doctoral candidate at the Harvard Graduate School of Education and first author of the study. “We wanted to look at one potential mechanism, brain development, that might explain how corporal punishment can impact children’s behavior and cognitive development.”

The study, published in Child Development, used functional MRIs to map brain changes in 147 tweens who’d never experienced physical or sexual abuse. Researchers tracked which parts of the children’s brains activated in response to neutral or fearful facial expressions. When shown pictures of someone looking fearful, kids who reported having been spanked had a larger response in certain parts of the brain than kids who hadn’t been. Those areas drive the response to environmental cues, recognizing threats and reacting to them. If a child’s brain overreacts, behavioral challenges can result.

“We saw those changes in the same areas as more severe forms of abuse or domestic violence. It suggests the difference is of degree rather than type,” Mr. Cuartas says. As far as a child’s brain is concerned, “It’s all violence.”

It’s a significant finding because many parents don’t think of spanking as being violent, says Vincent J. Palusci, MD, a pediatrician and editor-in-chief of the journal Child Maltreatment. “We want to raise kids who are happy and healthy, and many parents who use spanking are doing it with that goal.”
 

Spanking in the U.S.

Around the world, 62 states and countries have outlawed corporal punishment. While the U.S. has no such protections, both the American Academy of Pediatrics and the American Psychological Association have condemned the practice. Acceptance of spanking seems to be shrinking: The percentage of parents in this country who say they spank their children is trending downward. In 1993, 50% of parents surveyed said they did, but by 2017 that number had fallen to 35%. Still far too many, Mr. Cuartas and Dr. Palusci say, but a promising trend.

“While we wouldn’t as parents want to hurt our kids,” Dr. Palusci says, “we need to understand that spanking can be just as bad as things we’d never do.”
 

Discipline vs. punishment

For some parents, it may require a shift in thinking, differentiating between discipline and punishment. “Discipline changes behavior – it teaches positive behavior, empathy, essential social skills. But that’s different from punishment,” Mr. Cuartas says. “That makes somebody feel pain or shame. We have to start thinking about spanking as punishment.”

That can be difficult, especially for adults who’ve been spanked themselves. They may believe that since they turned out fine, spanking must be fine, too. But the study doesn’t suggest that every child who’s spanked will have these difficulties – it just shows they happen, Mr. Cuartas says. “Compare this to smoking. We all know someone who smokes who’s healthy, but that doesn’t mean smoking is good,” he says. “Individual cases aren’t enough to understand whether certain experiences are good or bad.”

Dr. Palusci draws parallels to the advice pregnant women receive about taking medications: If it hasn’t been tested in pregnancy specifically, no amount can be considered safe. “We don’t have the studies to say how much spanking is dangerous, so we have to think that any amount has this potential.”

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

Rare is the parent who has never so much as thought about spanking an unruly child. But a new study provides another reason to avoid corporal punishment: Spanking may cause changes in the same areas of a child’s brain that are affected by more severe physical and sexual abuse.

Previous research has consistently found links between spanking and behavioral problems, aggression, depression, and anxiety, says Jorge Cuartas, a doctoral candidate at the Harvard Graduate School of Education and first author of the study. “We wanted to look at one potential mechanism, brain development, that might explain how corporal punishment can impact children’s behavior and cognitive development.”

The study, published in Child Development, used functional MRIs to map brain changes in 147 tweens who’d never experienced physical or sexual abuse. Researchers tracked which parts of the children’s brains activated in response to neutral or fearful facial expressions. When shown pictures of someone looking fearful, kids who reported having been spanked had a larger response in certain parts of the brain than kids who hadn’t been. Those areas drive the response to environmental cues, recognizing threats and reacting to them. If a child’s brain overreacts, behavioral challenges can result.

“We saw those changes in the same areas as more severe forms of abuse or domestic violence. It suggests the difference is of degree rather than type,” Mr. Cuartas says. As far as a child’s brain is concerned, “It’s all violence.”

It’s a significant finding because many parents don’t think of spanking as being violent, says Vincent J. Palusci, MD, a pediatrician and editor-in-chief of the journal Child Maltreatment. “We want to raise kids who are happy and healthy, and many parents who use spanking are doing it with that goal.”
 

Spanking in the U.S.

Around the world, 62 states and countries have outlawed corporal punishment. While the U.S. has no such protections, both the American Academy of Pediatrics and the American Psychological Association have condemned the practice. Acceptance of spanking seems to be shrinking: The percentage of parents in this country who say they spank their children is trending downward. In 1993, 50% of parents surveyed said they did, but by 2017 that number had fallen to 35%. Still far too many, Mr. Cuartas and Dr. Palusci say, but a promising trend.

“While we wouldn’t as parents want to hurt our kids,” Dr. Palusci says, “we need to understand that spanking can be just as bad as things we’d never do.”
 

Discipline vs. punishment

For some parents, it may require a shift in thinking, differentiating between discipline and punishment. “Discipline changes behavior – it teaches positive behavior, empathy, essential social skills. But that’s different from punishment,” Mr. Cuartas says. “That makes somebody feel pain or shame. We have to start thinking about spanking as punishment.”

That can be difficult, especially for adults who’ve been spanked themselves. They may believe that since they turned out fine, spanking must be fine, too. But the study doesn’t suggest that every child who’s spanked will have these difficulties – it just shows they happen, Mr. Cuartas says. “Compare this to smoking. We all know someone who smokes who’s healthy, but that doesn’t mean smoking is good,” he says. “Individual cases aren’t enough to understand whether certain experiences are good or bad.”

Dr. Palusci draws parallels to the advice pregnant women receive about taking medications: If it hasn’t been tested in pregnancy specifically, no amount can be considered safe. “We don’t have the studies to say how much spanking is dangerous, so we have to think that any amount has this potential.”

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

Rare is the parent who has never so much as thought about spanking an unruly child. But a new study provides another reason to avoid corporal punishment: Spanking may cause changes in the same areas of a child’s brain that are affected by more severe physical and sexual abuse.

Previous research has consistently found links between spanking and behavioral problems, aggression, depression, and anxiety, says Jorge Cuartas, a doctoral candidate at the Harvard Graduate School of Education and first author of the study. “We wanted to look at one potential mechanism, brain development, that might explain how corporal punishment can impact children’s behavior and cognitive development.”

The study, published in Child Development, used functional MRIs to map brain changes in 147 tweens who’d never experienced physical or sexual abuse. Researchers tracked which parts of the children’s brains activated in response to neutral or fearful facial expressions. When shown pictures of someone looking fearful, kids who reported having been spanked had a larger response in certain parts of the brain than kids who hadn’t been. Those areas drive the response to environmental cues, recognizing threats and reacting to them. If a child’s brain overreacts, behavioral challenges can result.

“We saw those changes in the same areas as more severe forms of abuse or domestic violence. It suggests the difference is of degree rather than type,” Mr. Cuartas says. As far as a child’s brain is concerned, “It’s all violence.”

It’s a significant finding because many parents don’t think of spanking as being violent, says Vincent J. Palusci, MD, a pediatrician and editor-in-chief of the journal Child Maltreatment. “We want to raise kids who are happy and healthy, and many parents who use spanking are doing it with that goal.”
 

Spanking in the U.S.

Around the world, 62 states and countries have outlawed corporal punishment. While the U.S. has no such protections, both the American Academy of Pediatrics and the American Psychological Association have condemned the practice. Acceptance of spanking seems to be shrinking: The percentage of parents in this country who say they spank their children is trending downward. In 1993, 50% of parents surveyed said they did, but by 2017 that number had fallen to 35%. Still far too many, Mr. Cuartas and Dr. Palusci say, but a promising trend.

“While we wouldn’t as parents want to hurt our kids,” Dr. Palusci says, “we need to understand that spanking can be just as bad as things we’d never do.”
 

Discipline vs. punishment

For some parents, it may require a shift in thinking, differentiating between discipline and punishment. “Discipline changes behavior – it teaches positive behavior, empathy, essential social skills. But that’s different from punishment,” Mr. Cuartas says. “That makes somebody feel pain or shame. We have to start thinking about spanking as punishment.”

That can be difficult, especially for adults who’ve been spanked themselves. They may believe that since they turned out fine, spanking must be fine, too. But the study doesn’t suggest that every child who’s spanked will have these difficulties – it just shows they happen, Mr. Cuartas says. “Compare this to smoking. We all know someone who smokes who’s healthy, but that doesn’t mean smoking is good,” he says. “Individual cases aren’t enough to understand whether certain experiences are good or bad.”

Dr. Palusci draws parallels to the advice pregnant women receive about taking medications: If it hasn’t been tested in pregnancy specifically, no amount can be considered safe. “We don’t have the studies to say how much spanking is dangerous, so we have to think that any amount has this potential.”

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