Sharon Worcester

Long-term outcomes now being reported confirm earlier reports from the same trial showing efficacy for the use of targeted intraoperative radiotherapy (TARGIT) in patients with early breast cancer.

This novel approach, which delivers a one-off blast of radiation directed at the tumor bed and is given during lumpectomy, has similar efficacy and lowers non–breast cancer mortality when compared with whole-breast external beam radiotherapy (EBRT), which is delivered in fractions over 3-6 weeks after surgery.

Giving the boost of radiation during surgery has numerous benefits, say the authors: it is more convenient for patients and saves on healthcare costs.

However, the controversy over local recurrence rates, sparked by the earlier results, still remains. The difference in the 5-year local recurrence rate between TARGIT and EBRT was within the 2.5% margin for non-inferiority: the rate was 2.11% in 1140 TARGIT recipients, compared with 0.95% in 1158 EBRT recipients, for a difference of 1.16% (13 recurrences).

The new longer-term results from the TARGIT-A trial were published August 20 in the BMJ, and confirm earlier results from this trial published in 2014. Meanwhile, other approaches to intraoperative radiotherapy (IORT) have also been reported.  

Nevertheless, whole-breast radiotherapy remains the standard of care today, note the authors.

“The biggest battle the TARGIT investigator family has faced is our challenge to the conventional dogma that radiotherapy has to be given in multiple daily doses, and moreover that whole-breast radiotherapy is always essential,” said lead author Jayant Vaidya, MD, professor of surgery and oncology at University College London, UK. He was one of the team of investigators that together developed the TARGIT approach in the 1990s, as he recalls in a related BMJ blog post.

It is unclear whether the TARGIT-A long-term outcomes will change practice, Rachel Jimenez, MD, associate program director of the Harvard Radiation Oncology Residency Program and assistant professor of radiation oncology at Massachusetts General Hospital, Boston, told Medscape Medical News.

She noted there was controversy and debate over the earlier reports from TARGIT-A, and those findings “did little to change practice patterns over the past 6 years,” she said.

“With the publication of longer-term follow-up, my expectation would be that perceptions of IORT will remain unchanged in the radiation oncology community, and that those previously supportive of the TARGIT-A approach will continue to embrace it while those initially skeptical will be unlikely to change practice despite the longer-term results,” she said.

“However, despite the controversy surrounding TARGIT-A, it is heartening as a clinician who cares for breast cancer patients to see a trend within the early breast cancer clinical trials space toward the evaluation of increasingly targeted and abbreviated courses of radiation,” Jimenez commented.
 

Details of new long-term results

TARGIT-A is an open-label, 32-center multinational study conducted in 2298 women aged 45 years or older with early-stage invasive ductal carcinoma who were eligible for breast-conserving surgery. Between March 24, 2000, and June 25, 2012, participants were randomized 1:1 to risk-adapted TARGIT immediately after lumpectomy or to whole-breast EBRT delivered for the standard 3-6 week daily fractionated course.

At a median follow-up of 8.6 years — with some patients followed for nearly 19 years — no significant difference was seen between the treatment groups in local recurrence-free survival (167 vs 147 events; hazard ratio, 1.13); invasive local recurrence-free survival (154 vs 146 events; HR, 1.04); mastectomy-free survival (170 vs 175 events; HR, 0.96); distant disease-free survival (133 vs 148 events; HR, 0.88); overall survival (110 vs 131 events; HR, 0.82); or breast cancer mortality (6 vs 57 events; HR, 1.12).

“Mortality from other causes was significantly lower (45 vs 74 events; HR, 0.59),” the authors note.
 

Controversy of Earlier Results

Vaidya and colleagues comment that these new results confirm earlier findings from this trial. They were initially presented in 2012 by Vaidya at the San Antonio Breast Cancer Symposium and subsequently published in The Lancet, as previously reported by Medscape Medical News. Those earlier results showed a trend toward lower overall mortality with TARGIT (absolute difference, -1.3%; P = .01) and significantly fewer deaths from causes other than breast cancer (absolute difference, -2.1%; P = .009).

However, TARGIT was associated with slightly more same-breast recurrences at that time (3.3% vs 1.3%; P = 0.42), even though this was still within the 2.5% margin for non-inferiority.

The new longer-term results show a similar pattern.

It was this risk of same-breast recurrences that sparked the heated debate over the findings, as some breast cancer experts argued that this needs to be weighed against various potential benefits of IORT for patients: greater convenience, potentially improved mortality, and lower costs.

The extent of that “vigorous debate” was highlighted in 2015 in the International Journal of Radiation Oncology, Biology, Physics, (the Red Journal), in which editor-in-chief Anthony Zietman, MD, shared numerous letters to the editor, written in response to two editorials, that contained “passionately and articulately expressed” views from “senior investigators and breast cancer physicians from around the globe.”

At the same time, in 2015, another approach to IORT was reported at the American Society for Radiation Oncology (ASTRO) annual meeting and simultaneously published online in The Lancet. This was accelerated partial-breast irradiation (APBI) delivered directly to the tumor bed using multicatheter brachytherapy at the time of lumpectomy in women with early breast cancer. The results showed outcomes that were comparable with whole-breast irradiation, but with fewer side effects.

Those findings prompted a 2016 update to the ASTRO consensus statement on APBI to note that APBI after lumpectomy may be suitable for more women with early-stage breast cancer, including younger patients and those with ductal carcinoma in situ.

In comments to Medscape Medical News, Jimenez noted that several recent studies have shown efficacy for various IORT approaches. There have been two phase 3 non-inferiority studies, namely the NSABP B-39 and the RAPID trial, that evaluate the use of APBI in lieu of whole-breast radiation. There have also been two trials as well as the evaluation of a 5-day ultrahypofractionated whole-breast radiation course per the UK Fast and Fast-Forward trials, compared with several weeks of whole-breast radiation.  

“Collectively, these studies lend support for fewer and/or more targeted radiotherapy treatments for our patients and have the potential to reduce patient burden and limit healthcare costs,” Jimenez told Medscape Medical News.

Indeed, the TARGIT-A researchers write that their long-term findings “have shown that risk-adapted single-dose TARGIT-IORT given during lumpectomy can effectively replace the mandatory use of several weeks of daily postoperative whole-breast radiotherapy in patients with breast cancer undergoing breast conservation.”

Given the numerous benefits to patients that this approach provides, the choice should ultimately rest with the patient, the authors conclude.

An extended follow-up of the trial (TARGIT-Ex) is ongoing, as is the TARGIT-B(oost) trial looking at TARGIT-IORT as a tumor bed boost with EBRT boost in younger women and those with higher-risk disease.

The TARGIT-A trial was sponsored by University College London Hospitals (UCLH) Comprehensive Biomedical Research Centre and funded by UCLH Charities, the National Institute for Health Research Health Technology Assessment program, Ninewells Cancer Campaign, the National Health and Medical Research Council, and the German Federal Ministry of Education and Research. The authors reported numerous disclosures, as detailed in the publication.
 

This article first appeared on Medscape.com.

Long-term outcomes now being reported confirm earlier reports from the same trial showing efficacy for the use of targeted intraoperative radiotherapy (TARGIT) in patients with early breast cancer.

This novel approach, which delivers a one-off blast of radiation directed at the tumor bed and is given during lumpectomy, has similar efficacy and lowers non–breast cancer mortality when compared with whole-breast external beam radiotherapy (EBRT), which is delivered in fractions over 3-6 weeks after surgery.

Giving the boost of radiation during surgery has numerous benefits, say the authors: it is more convenient for patients and saves on healthcare costs.

However, the controversy over local recurrence rates, sparked by the earlier results, still remains. The difference in the 5-year local recurrence rate between TARGIT and EBRT was within the 2.5% margin for non-inferiority: the rate was 2.11% in 1140 TARGIT recipients, compared with 0.95% in 1158 EBRT recipients, for a difference of 1.16% (13 recurrences).

The new longer-term results from the TARGIT-A trial were published August 20 in the BMJ, and confirm earlier results from this trial published in 2014. Meanwhile, other approaches to intraoperative radiotherapy (IORT) have also been reported.  

Nevertheless, whole-breast radiotherapy remains the standard of care today, note the authors.

“The biggest battle the TARGIT investigator family has faced is our challenge to the conventional dogma that radiotherapy has to be given in multiple daily doses, and moreover that whole-breast radiotherapy is always essential,” said lead author Jayant Vaidya, MD, professor of surgery and oncology at University College London, UK. He was one of the team of investigators that together developed the TARGIT approach in the 1990s, as he recalls in a related BMJ blog post.

It is unclear whether the TARGIT-A long-term outcomes will change practice, Rachel Jimenez, MD, associate program director of the Harvard Radiation Oncology Residency Program and assistant professor of radiation oncology at Massachusetts General Hospital, Boston, told Medscape Medical News.

She noted there was controversy and debate over the earlier reports from TARGIT-A, and those findings “did little to change practice patterns over the past 6 years,” she said.

“With the publication of longer-term follow-up, my expectation would be that perceptions of IORT will remain unchanged in the radiation oncology community, and that those previously supportive of the TARGIT-A approach will continue to embrace it while those initially skeptical will be unlikely to change practice despite the longer-term results,” she said.

“However, despite the controversy surrounding TARGIT-A, it is heartening as a clinician who cares for breast cancer patients to see a trend within the early breast cancer clinical trials space toward the evaluation of increasingly targeted and abbreviated courses of radiation,” Jimenez commented.
 

Details of new long-term results

TARGIT-A is an open-label, 32-center multinational study conducted in 2298 women aged 45 years or older with early-stage invasive ductal carcinoma who were eligible for breast-conserving surgery. Between March 24, 2000, and June 25, 2012, participants were randomized 1:1 to risk-adapted TARGIT immediately after lumpectomy or to whole-breast EBRT delivered for the standard 3-6 week daily fractionated course.

At a median follow-up of 8.6 years — with some patients followed for nearly 19 years — no significant difference was seen between the treatment groups in local recurrence-free survival (167 vs 147 events; hazard ratio, 1.13); invasive local recurrence-free survival (154 vs 146 events; HR, 1.04); mastectomy-free survival (170 vs 175 events; HR, 0.96); distant disease-free survival (133 vs 148 events; HR, 0.88); overall survival (110 vs 131 events; HR, 0.82); or breast cancer mortality (6 vs 57 events; HR, 1.12).

“Mortality from other causes was significantly lower (45 vs 74 events; HR, 0.59),” the authors note.
 

Controversy of Earlier Results

Vaidya and colleagues comment that these new results confirm earlier findings from this trial. They were initially presented in 2012 by Vaidya at the San Antonio Breast Cancer Symposium and subsequently published in The Lancet, as previously reported by Medscape Medical News. Those earlier results showed a trend toward lower overall mortality with TARGIT (absolute difference, -1.3%; P = .01) and significantly fewer deaths from causes other than breast cancer (absolute difference, -2.1%; P = .009).

However, TARGIT was associated with slightly more same-breast recurrences at that time (3.3% vs 1.3%; P = 0.42), even though this was still within the 2.5% margin for non-inferiority.

The new longer-term results show a similar pattern.

It was this risk of same-breast recurrences that sparked the heated debate over the findings, as some breast cancer experts argued that this needs to be weighed against various potential benefits of IORT for patients: greater convenience, potentially improved mortality, and lower costs.

The extent of that “vigorous debate” was highlighted in 2015 in the International Journal of Radiation Oncology, Biology, Physics, (the Red Journal), in which editor-in-chief Anthony Zietman, MD, shared numerous letters to the editor, written in response to two editorials, that contained “passionately and articulately expressed” views from “senior investigators and breast cancer physicians from around the globe.”

At the same time, in 2015, another approach to IORT was reported at the American Society for Radiation Oncology (ASTRO) annual meeting and simultaneously published online in The Lancet. This was accelerated partial-breast irradiation (APBI) delivered directly to the tumor bed using multicatheter brachytherapy at the time of lumpectomy in women with early breast cancer. The results showed outcomes that were comparable with whole-breast irradiation, but with fewer side effects.

Those findings prompted a 2016 update to the ASTRO consensus statement on APBI to note that APBI after lumpectomy may be suitable for more women with early-stage breast cancer, including younger patients and those with ductal carcinoma in situ.

In comments to Medscape Medical News, Jimenez noted that several recent studies have shown efficacy for various IORT approaches. There have been two phase 3 non-inferiority studies, namely the NSABP B-39 and the RAPID trial, that evaluate the use of APBI in lieu of whole-breast radiation. There have also been two trials as well as the evaluation of a 5-day ultrahypofractionated whole-breast radiation course per the UK Fast and Fast-Forward trials, compared with several weeks of whole-breast radiation.  

“Collectively, these studies lend support for fewer and/or more targeted radiotherapy treatments for our patients and have the potential to reduce patient burden and limit healthcare costs,” Jimenez told Medscape Medical News.

Indeed, the TARGIT-A researchers write that their long-term findings “have shown that risk-adapted single-dose TARGIT-IORT given during lumpectomy can effectively replace the mandatory use of several weeks of daily postoperative whole-breast radiotherapy in patients with breast cancer undergoing breast conservation.”

Given the numerous benefits to patients that this approach provides, the choice should ultimately rest with the patient, the authors conclude.

An extended follow-up of the trial (TARGIT-Ex) is ongoing, as is the TARGIT-B(oost) trial looking at TARGIT-IORT as a tumor bed boost with EBRT boost in younger women and those with higher-risk disease.

The TARGIT-A trial was sponsored by University College London Hospitals (UCLH) Comprehensive Biomedical Research Centre and funded by UCLH Charities, the National Institute for Health Research Health Technology Assessment program, Ninewells Cancer Campaign, the National Health and Medical Research Council, and the German Federal Ministry of Education and Research. The authors reported numerous disclosures, as detailed in the publication.
 

This article first appeared on Medscape.com.

Long-term outcomes now being reported confirm earlier reports from the same trial showing efficacy for the use of targeted intraoperative radiotherapy (TARGIT) in patients with early breast cancer.

This novel approach, which delivers a one-off blast of radiation directed at the tumor bed and is given during lumpectomy, has similar efficacy and lowers non–breast cancer mortality when compared with whole-breast external beam radiotherapy (EBRT), which is delivered in fractions over 3-6 weeks after surgery.

Giving the boost of radiation during surgery has numerous benefits, say the authors: it is more convenient for patients and saves on healthcare costs.

However, the controversy over local recurrence rates, sparked by the earlier results, still remains. The difference in the 5-year local recurrence rate between TARGIT and EBRT was within the 2.5% margin for non-inferiority: the rate was 2.11% in 1140 TARGIT recipients, compared with 0.95% in 1158 EBRT recipients, for a difference of 1.16% (13 recurrences).

The new longer-term results from the TARGIT-A trial were published August 20 in the BMJ, and confirm earlier results from this trial published in 2014. Meanwhile, other approaches to intraoperative radiotherapy (IORT) have also been reported.  

Nevertheless, whole-breast radiotherapy remains the standard of care today, note the authors.

“The biggest battle the TARGIT investigator family has faced is our challenge to the conventional dogma that radiotherapy has to be given in multiple daily doses, and moreover that whole-breast radiotherapy is always essential,” said lead author Jayant Vaidya, MD, professor of surgery and oncology at University College London, UK. He was one of the team of investigators that together developed the TARGIT approach in the 1990s, as he recalls in a related BMJ blog post.

It is unclear whether the TARGIT-A long-term outcomes will change practice, Rachel Jimenez, MD, associate program director of the Harvard Radiation Oncology Residency Program and assistant professor of radiation oncology at Massachusetts General Hospital, Boston, told Medscape Medical News.

She noted there was controversy and debate over the earlier reports from TARGIT-A, and those findings “did little to change practice patterns over the past 6 years,” she said.

“With the publication of longer-term follow-up, my expectation would be that perceptions of IORT will remain unchanged in the radiation oncology community, and that those previously supportive of the TARGIT-A approach will continue to embrace it while those initially skeptical will be unlikely to change practice despite the longer-term results,” she said.

“However, despite the controversy surrounding TARGIT-A, it is heartening as a clinician who cares for breast cancer patients to see a trend within the early breast cancer clinical trials space toward the evaluation of increasingly targeted and abbreviated courses of radiation,” Jimenez commented.
 

Details of new long-term results

TARGIT-A is an open-label, 32-center multinational study conducted in 2298 women aged 45 years or older with early-stage invasive ductal carcinoma who were eligible for breast-conserving surgery. Between March 24, 2000, and June 25, 2012, participants were randomized 1:1 to risk-adapted TARGIT immediately after lumpectomy or to whole-breast EBRT delivered for the standard 3-6 week daily fractionated course.

At a median follow-up of 8.6 years — with some patients followed for nearly 19 years — no significant difference was seen between the treatment groups in local recurrence-free survival (167 vs 147 events; hazard ratio, 1.13); invasive local recurrence-free survival (154 vs 146 events; HR, 1.04); mastectomy-free survival (170 vs 175 events; HR, 0.96); distant disease-free survival (133 vs 148 events; HR, 0.88); overall survival (110 vs 131 events; HR, 0.82); or breast cancer mortality (6 vs 57 events; HR, 1.12).

“Mortality from other causes was significantly lower (45 vs 74 events; HR, 0.59),” the authors note.
 

Controversy of Earlier Results

Vaidya and colleagues comment that these new results confirm earlier findings from this trial. They were initially presented in 2012 by Vaidya at the San Antonio Breast Cancer Symposium and subsequently published in The Lancet, as previously reported by Medscape Medical News. Those earlier results showed a trend toward lower overall mortality with TARGIT (absolute difference, -1.3%; P = .01) and significantly fewer deaths from causes other than breast cancer (absolute difference, -2.1%; P = .009).

However, TARGIT was associated with slightly more same-breast recurrences at that time (3.3% vs 1.3%; P = 0.42), even though this was still within the 2.5% margin for non-inferiority.

The new longer-term results show a similar pattern.

It was this risk of same-breast recurrences that sparked the heated debate over the findings, as some breast cancer experts argued that this needs to be weighed against various potential benefits of IORT for patients: greater convenience, potentially improved mortality, and lower costs.

The extent of that “vigorous debate” was highlighted in 2015 in the International Journal of Radiation Oncology, Biology, Physics, (the Red Journal), in which editor-in-chief Anthony Zietman, MD, shared numerous letters to the editor, written in response to two editorials, that contained “passionately and articulately expressed” views from “senior investigators and breast cancer physicians from around the globe.”

At the same time, in 2015, another approach to IORT was reported at the American Society for Radiation Oncology (ASTRO) annual meeting and simultaneously published online in The Lancet. This was accelerated partial-breast irradiation (APBI) delivered directly to the tumor bed using multicatheter brachytherapy at the time of lumpectomy in women with early breast cancer. The results showed outcomes that were comparable with whole-breast irradiation, but with fewer side effects.

Those findings prompted a 2016 update to the ASTRO consensus statement on APBI to note that APBI after lumpectomy may be suitable for more women with early-stage breast cancer, including younger patients and those with ductal carcinoma in situ.

In comments to Medscape Medical News, Jimenez noted that several recent studies have shown efficacy for various IORT approaches. There have been two phase 3 non-inferiority studies, namely the NSABP B-39 and the RAPID trial, that evaluate the use of APBI in lieu of whole-breast radiation. There have also been two trials as well as the evaluation of a 5-day ultrahypofractionated whole-breast radiation course per the UK Fast and Fast-Forward trials, compared with several weeks of whole-breast radiation.  

“Collectively, these studies lend support for fewer and/or more targeted radiotherapy treatments for our patients and have the potential to reduce patient burden and limit healthcare costs,” Jimenez told Medscape Medical News.

Indeed, the TARGIT-A researchers write that their long-term findings “have shown that risk-adapted single-dose TARGIT-IORT given during lumpectomy can effectively replace the mandatory use of several weeks of daily postoperative whole-breast radiotherapy in patients with breast cancer undergoing breast conservation.”

Given the numerous benefits to patients that this approach provides, the choice should ultimately rest with the patient, the authors conclude.

An extended follow-up of the trial (TARGIT-Ex) is ongoing, as is the TARGIT-B(oost) trial looking at TARGIT-IORT as a tumor bed boost with EBRT boost in younger women and those with higher-risk disease.

The TARGIT-A trial was sponsored by University College London Hospitals (UCLH) Comprehensive Biomedical Research Centre and funded by UCLH Charities, the National Institute for Health Research Health Technology Assessment program, Ninewells Cancer Campaign, the National Health and Medical Research Council, and the German Federal Ministry of Education and Research. The authors reported numerous disclosures, as detailed in the publication.
 

This article first appeared on Medscape.com.

Early testing for actionable genomic alterations is now recommended for metastatic pancreatic cancer patients who progress on therapy or experience intolerable toxicity and who are potential candidates for additional treatment after first-line therapy, according to an American Society of Clinical Oncology guideline update.

Both germline and somatic testing, including for microsatellite instability/mismatch repair deficiency, BRCA mutations with known significance, and NTRK gene fusions, are recommended in this population, reported Davendra P.S. Sohal, MD, MPH, of the University of Cincinnati, and colleagues on ASCO’s expert panel. The update was published online Aug. 5 in the Journal of Clinical Oncology.

The ASCO guideline on clinical decision making for patients with metastatic pancreatic cancer was first published in 2016 to address initial assessment and first- and second-line treatment options, supportive care, and follow-up and was updated in 2018. The current update is based on new evidence of benefit with targeted therapy options after first-line therapy or as maintenance therapy.

The phase 3 POLO trial, for example, showed significantly improved progression-free survival with the poly (ADP-ribose) polymerase (PARP) inhibitor olaparib for maintenance therapy after first-line treatment in patients with a germline BRCA1 or BRCA2 mutation and metastatic pancreatic cancer that had not progressed during first-line platinum-based chemotherapy. An integrated analysis of three studies showed that entrectinib, a potent inhibitor of tropomyosin receptor kinase (TRK) A, B, and C, safely induced durable and clinically meaningful responses in patients with NTRK fusion-positive solid tumors, and a phase 1-2 study showed that the highly selective TRK inhibitor larotrectinib had marked and durable antitumor activity in both children and adults with TRK fusion-positive solid tumors.

With respect to the new recommendation endorsing early testing for actionable genomic alterations (Recommendation 1.5), the authors noted that the results of testing can lead to treatment with PARP inhibitors, programmed death-1 (PD-1) checkpoint inhibitor therapy, TRK fusion inhibitors, and clinical trials of targeted therapies.

“Genomic testing is recommended as part of an initial assessment to ensure that the results of testing are available at the time of treatment decision where applicable after first-line therapy,” the new recommendation states.

A “qualifying statement” further notes that the decision to test should “involve a discussion between the patient and physician regarding the frequency of actionable findings, treatment implications of testing results, and genetic counseling related to germline testing.”

Recommendation 1.5 is rated by the panel as “strong” and is based on informal consensus.

The panel also added two recommendations on treatment options after first-line therapy:

• Recommendation 3.1 calls for treatment with larotrectinib or entrectinib in patient with tumors harboring NTRK fusions.
• Recommendation 3.3 states that patients with a germline BRCA1 or BCA2 mutation who have received first-line platinum-based chemotherapy without disease progression for at least 16 weeks can receive chemotherapy or PARP inhibition with olaparib.

The relevant evidence for these two recommendations is of low quality, but shows that the benefits outweigh the harms; the strength of both recommendations is “moderate.”

A qualifying statement for the latter notes that “the decision to continue treatment with chemotherapy or proceed to maintenance therapy with olaparib should be based on a discussion between the patient and the oncologist, including consideration of whether a maximum response and plateau in response to chemotherapy have been achieved, the level of cumulative toxicities associated with chemotherapy treatment, patient preference, convenience, toxicity, goals of care, cost, and clinical evidence, including a lack of overall survival benefit demonstrated in the POLO randomized controlled trial.”

This focused update includes minor modifications to three existing recommendations:

• In addition to capecitabine or erlotinib, nab-paclitaxel is now included in Recommendation 2.3 as another possible add-on to gemcitabine alone for patients with either an Eastern Cooperative Oncology Group (ECOG) performance score of 2 or a comorbidity profile that precludes more aggressive regimens. The recommendation was also updated to encourage proactive dose and schedule adjustments to minimize toxicities.
• Recommendation 3.5 now includes patients treated previously with a gemcitabine-based regimen in the criteria for the preferred second-line treatment combination of fluorouracil plus nanoliposomal irinotecan or fluorouracil plus irinotecan “where the former is unavailable.”
• Recommendation 3.7 now includes nab-paclitaxel as an add-on option to gemcitabine, and nanoliposomal irinotecan as an add-on option to fluorouracil for second-line therapy – with proactive dose and schedule adjustments to minimize toxicities – in patients with ECOG performance score of 2 or a comorbidity profile that precludes more aggressive regimens.

These three minor modifications reflect new evidence in the first-line treatment setting, including from the FRAGRANCE trial, and are based on expert panel consensus. All other recommendations in the 2018 update are endorsed for the current update, which is available at the ASCO website.

Dr. Sohal reported honoraria from Foundation Medicine, and consulting or advisory roles with Perthera, Ability Pharma, and PierianDx. He reported research funding to his institution from Novartis, Celgene, OncoMed, Bayer, Genentech, Bristol Myers Squibb, Agios, Incyte, Loxo, and Rafael Pharmaceuticals.

[email protected]

SOURCE: Sohal D et al. J Clin Oncol. 2020 Aug 5. doi: 10.1200/JCO.20.01364.

Early testing for actionable genomic alterations is now recommended for metastatic pancreatic cancer patients who progress on therapy or experience intolerable toxicity and who are potential candidates for additional treatment after first-line therapy, according to an American Society of Clinical Oncology guideline update.

Both germline and somatic testing, including for microsatellite instability/mismatch repair deficiency, BRCA mutations with known significance, and NTRK gene fusions, are recommended in this population, reported Davendra P.S. Sohal, MD, MPH, of the University of Cincinnati, and colleagues on ASCO’s expert panel. The update was published online Aug. 5 in the Journal of Clinical Oncology.

The ASCO guideline on clinical decision making for patients with metastatic pancreatic cancer was first published in 2016 to address initial assessment and first- and second-line treatment options, supportive care, and follow-up and was updated in 2018. The current update is based on new evidence of benefit with targeted therapy options after first-line therapy or as maintenance therapy.

The phase 3 POLO trial, for example, showed significantly improved progression-free survival with the poly (ADP-ribose) polymerase (PARP) inhibitor olaparib for maintenance therapy after first-line treatment in patients with a germline BRCA1 or BRCA2 mutation and metastatic pancreatic cancer that had not progressed during first-line platinum-based chemotherapy. An integrated analysis of three studies showed that entrectinib, a potent inhibitor of tropomyosin receptor kinase (TRK) A, B, and C, safely induced durable and clinically meaningful responses in patients with NTRK fusion-positive solid tumors, and a phase 1-2 study showed that the highly selective TRK inhibitor larotrectinib had marked and durable antitumor activity in both children and adults with TRK fusion-positive solid tumors.

With respect to the new recommendation endorsing early testing for actionable genomic alterations (Recommendation 1.5), the authors noted that the results of testing can lead to treatment with PARP inhibitors, programmed death-1 (PD-1) checkpoint inhibitor therapy, TRK fusion inhibitors, and clinical trials of targeted therapies.

“Genomic testing is recommended as part of an initial assessment to ensure that the results of testing are available at the time of treatment decision where applicable after first-line therapy,” the new recommendation states.

A “qualifying statement” further notes that the decision to test should “involve a discussion between the patient and physician regarding the frequency of actionable findings, treatment implications of testing results, and genetic counseling related to germline testing.”

Recommendation 1.5 is rated by the panel as “strong” and is based on informal consensus.

The panel also added two recommendations on treatment options after first-line therapy:

• Recommendation 3.1 calls for treatment with larotrectinib or entrectinib in patient with tumors harboring NTRK fusions.
• Recommendation 3.3 states that patients with a germline BRCA1 or BCA2 mutation who have received first-line platinum-based chemotherapy without disease progression for at least 16 weeks can receive chemotherapy or PARP inhibition with olaparib.

The relevant evidence for these two recommendations is of low quality, but shows that the benefits outweigh the harms; the strength of both recommendations is “moderate.”

A qualifying statement for the latter notes that “the decision to continue treatment with chemotherapy or proceed to maintenance therapy with olaparib should be based on a discussion between the patient and the oncologist, including consideration of whether a maximum response and plateau in response to chemotherapy have been achieved, the level of cumulative toxicities associated with chemotherapy treatment, patient preference, convenience, toxicity, goals of care, cost, and clinical evidence, including a lack of overall survival benefit demonstrated in the POLO randomized controlled trial.”

This focused update includes minor modifications to three existing recommendations:

• In addition to capecitabine or erlotinib, nab-paclitaxel is now included in Recommendation 2.3 as another possible add-on to gemcitabine alone for patients with either an Eastern Cooperative Oncology Group (ECOG) performance score of 2 or a comorbidity profile that precludes more aggressive regimens. The recommendation was also updated to encourage proactive dose and schedule adjustments to minimize toxicities.
• Recommendation 3.5 now includes patients treated previously with a gemcitabine-based regimen in the criteria for the preferred second-line treatment combination of fluorouracil plus nanoliposomal irinotecan or fluorouracil plus irinotecan “where the former is unavailable.”
• Recommendation 3.7 now includes nab-paclitaxel as an add-on option to gemcitabine, and nanoliposomal irinotecan as an add-on option to fluorouracil for second-line therapy – with proactive dose and schedule adjustments to minimize toxicities – in patients with ECOG performance score of 2 or a comorbidity profile that precludes more aggressive regimens.

These three minor modifications reflect new evidence in the first-line treatment setting, including from the FRAGRANCE trial, and are based on expert panel consensus. All other recommendations in the 2018 update are endorsed for the current update, which is available at the ASCO website.

Dr. Sohal reported honoraria from Foundation Medicine, and consulting or advisory roles with Perthera, Ability Pharma, and PierianDx. He reported research funding to his institution from Novartis, Celgene, OncoMed, Bayer, Genentech, Bristol Myers Squibb, Agios, Incyte, Loxo, and Rafael Pharmaceuticals.

[email protected]

SOURCE: Sohal D et al. J Clin Oncol. 2020 Aug 5. doi: 10.1200/JCO.20.01364.

Early testing for actionable genomic alterations is now recommended for metastatic pancreatic cancer patients who progress on therapy or experience intolerable toxicity and who are potential candidates for additional treatment after first-line therapy, according to an American Society of Clinical Oncology guideline update.

Both germline and somatic testing, including for microsatellite instability/mismatch repair deficiency, BRCA mutations with known significance, and NTRK gene fusions, are recommended in this population, reported Davendra P.S. Sohal, MD, MPH, of the University of Cincinnati, and colleagues on ASCO’s expert panel. The update was published online Aug. 5 in the Journal of Clinical Oncology.

The ASCO guideline on clinical decision making for patients with metastatic pancreatic cancer was first published in 2016 to address initial assessment and first- and second-line treatment options, supportive care, and follow-up and was updated in 2018. The current update is based on new evidence of benefit with targeted therapy options after first-line therapy or as maintenance therapy.

The phase 3 POLO trial, for example, showed significantly improved progression-free survival with the poly (ADP-ribose) polymerase (PARP) inhibitor olaparib for maintenance therapy after first-line treatment in patients with a germline BRCA1 or BRCA2 mutation and metastatic pancreatic cancer that had not progressed during first-line platinum-based chemotherapy. An integrated analysis of three studies showed that entrectinib, a potent inhibitor of tropomyosin receptor kinase (TRK) A, B, and C, safely induced durable and clinically meaningful responses in patients with NTRK fusion-positive solid tumors, and a phase 1-2 study showed that the highly selective TRK inhibitor larotrectinib had marked and durable antitumor activity in both children and adults with TRK fusion-positive solid tumors.

With respect to the new recommendation endorsing early testing for actionable genomic alterations (Recommendation 1.5), the authors noted that the results of testing can lead to treatment with PARP inhibitors, programmed death-1 (PD-1) checkpoint inhibitor therapy, TRK fusion inhibitors, and clinical trials of targeted therapies.

“Genomic testing is recommended as part of an initial assessment to ensure that the results of testing are available at the time of treatment decision where applicable after first-line therapy,” the new recommendation states.

A “qualifying statement” further notes that the decision to test should “involve a discussion between the patient and physician regarding the frequency of actionable findings, treatment implications of testing results, and genetic counseling related to germline testing.”

Recommendation 1.5 is rated by the panel as “strong” and is based on informal consensus.

The panel also added two recommendations on treatment options after first-line therapy:

• Recommendation 3.1 calls for treatment with larotrectinib or entrectinib in patient with tumors harboring NTRK fusions.
• Recommendation 3.3 states that patients with a germline BRCA1 or BCA2 mutation who have received first-line platinum-based chemotherapy without disease progression for at least 16 weeks can receive chemotherapy or PARP inhibition with olaparib.

The relevant evidence for these two recommendations is of low quality, but shows that the benefits outweigh the harms; the strength of both recommendations is “moderate.”

A qualifying statement for the latter notes that “the decision to continue treatment with chemotherapy or proceed to maintenance therapy with olaparib should be based on a discussion between the patient and the oncologist, including consideration of whether a maximum response and plateau in response to chemotherapy have been achieved, the level of cumulative toxicities associated with chemotherapy treatment, patient preference, convenience, toxicity, goals of care, cost, and clinical evidence, including a lack of overall survival benefit demonstrated in the POLO randomized controlled trial.”

This focused update includes minor modifications to three existing recommendations:

• In addition to capecitabine or erlotinib, nab-paclitaxel is now included in Recommendation 2.3 as another possible add-on to gemcitabine alone for patients with either an Eastern Cooperative Oncology Group (ECOG) performance score of 2 or a comorbidity profile that precludes more aggressive regimens. The recommendation was also updated to encourage proactive dose and schedule adjustments to minimize toxicities.
• Recommendation 3.5 now includes patients treated previously with a gemcitabine-based regimen in the criteria for the preferred second-line treatment combination of fluorouracil plus nanoliposomal irinotecan or fluorouracil plus irinotecan “where the former is unavailable.”
• Recommendation 3.7 now includes nab-paclitaxel as an add-on option to gemcitabine, and nanoliposomal irinotecan as an add-on option to fluorouracil for second-line therapy – with proactive dose and schedule adjustments to minimize toxicities – in patients with ECOG performance score of 2 or a comorbidity profile that precludes more aggressive regimens.

These three minor modifications reflect new evidence in the first-line treatment setting, including from the FRAGRANCE trial, and are based on expert panel consensus. All other recommendations in the 2018 update are endorsed for the current update, which is available at the ASCO website.

Dr. Sohal reported honoraria from Foundation Medicine, and consulting or advisory roles with Perthera, Ability Pharma, and PierianDx. He reported research funding to his institution from Novartis, Celgene, OncoMed, Bayer, Genentech, Bristol Myers Squibb, Agios, Incyte, Loxo, and Rafael Pharmaceuticals.

[email protected]

SOURCE: Sohal D et al. J Clin Oncol. 2020 Aug 5. doi: 10.1200/JCO.20.01364.

Perioperative administration of the beta blocker propranolol and the COX2 inhibitor etodolac significantly improved biomarkers of malignancy and metastasis and was associated with a reduction in recurrence rates after colorectal tumor resection in a randomized, placebo-controlled study.

The study included 34 patients (median age, 58 years) who underwent colorectal tumor resection in Israel. It was published online June 13 in Cancer.

On intent-to-treat analysis, 3-year recurrence rates were 12.5% in the placebo group (n = 16) and 33.3% in the treatment group (n = 18). This difference was not statistically significant (P = .239). However, in protocol-compliant patients, the respective rates were 0% and 29.4% (P = .054), but the study was not powered to assess drug effects on recurrence and survival, the researchers note.

With regard to tumor molecular markers, results showed that the combination reduced epithelial-to-mesenchymal transition and tumor-infiltrating CD14-positive monocytes and CD19-positive B cells. There was an increase in tumor-infiltrating CD56-positive natural killer cells, Rita Haldar, MA, of Tel Aviv University, Israel, and her colleagues note.

Transcriptional activity analysis showed a favorable effect on 12 of 19 potential colorectal cancer–related transcription factors, with alterations that have previously been linked with improved outcomes.

In the trial, the patients in the treatment group received oral etodolac 400 mg twice daily for 20 perioperative days beginning 5 days before surgery and oral propranolol at twice-daily doses of 20 mg for the 5 days before surgery, 80 mg on the day of surgery, 40 mg on postoperative days 1 to 7, and 20 mg for the last 7 days.

The treatments were well tolerated. Minor complications occurred at similar rates in the treatment and placebo groups, note the researchers. No severe surgical complications occurred in the treatment group; one occurred in the placebo group.

The findings indicate that the treatment protocol is “empirically safe, easy to administer, and inexpensive and has overall favorable molecular impacts on tumor tissues,” the researchers conclude.

Data from the study provide a strong rationale for future trials powered to assess the impact of this combination on disease-free and overall survival in patients with colorectal cancer.

“Haldar et al should be applauded for their steadfast pursuit of repurposed drugs for the treatment of cancer,” Michael Low, MD, and his colleagues at Morningside Center for Innovative and Affordable Medicine at Emory University, Atlanta, Georgia, write in an accompanying editorial.

The concept of using perioperative interventions “to alter the deleterious effects of surgery” is not new, and evidence of potential benefit is abundant, the editorialists note.

The focus of the current study on beta-adrenergic blockade and COX2 inhibition is supported both by the agents’ known suppressive effects on relevant pathways and by preclinical data, the editorialists write.

The study is limited by several factors, including small sample size, patient-reported compliance, and a failure to account for use of chemotherapy. The editorialists emphasize that use of these agents in the perioperative period “is of paramount importance and may have long-lasting antitumoral effects.” They hope “that larger trials focusing on these and other agents will soon prove that to be true.”

The study was supported by an Israel Science Foundation grant. The authors and Lowe have disclosed no relevant financial relationships.
 

This article first appeared on Medscape.com.

Perioperative administration of the beta blocker propranolol and the COX2 inhibitor etodolac significantly improved biomarkers of malignancy and metastasis and was associated with a reduction in recurrence rates after colorectal tumor resection in a randomized, placebo-controlled study.

The study included 34 patients (median age, 58 years) who underwent colorectal tumor resection in Israel. It was published online June 13 in Cancer.

On intent-to-treat analysis, 3-year recurrence rates were 12.5% in the placebo group (n = 16) and 33.3% in the treatment group (n = 18). This difference was not statistically significant (P = .239). However, in protocol-compliant patients, the respective rates were 0% and 29.4% (P = .054), but the study was not powered to assess drug effects on recurrence and survival, the researchers note.

With regard to tumor molecular markers, results showed that the combination reduced epithelial-to-mesenchymal transition and tumor-infiltrating CD14-positive monocytes and CD19-positive B cells. There was an increase in tumor-infiltrating CD56-positive natural killer cells, Rita Haldar, MA, of Tel Aviv University, Israel, and her colleagues note.

Transcriptional activity analysis showed a favorable effect on 12 of 19 potential colorectal cancer–related transcription factors, with alterations that have previously been linked with improved outcomes.

In the trial, the patients in the treatment group received oral etodolac 400 mg twice daily for 20 perioperative days beginning 5 days before surgery and oral propranolol at twice-daily doses of 20 mg for the 5 days before surgery, 80 mg on the day of surgery, 40 mg on postoperative days 1 to 7, and 20 mg for the last 7 days.

The treatments were well tolerated. Minor complications occurred at similar rates in the treatment and placebo groups, note the researchers. No severe surgical complications occurred in the treatment group; one occurred in the placebo group.

The findings indicate that the treatment protocol is “empirically safe, easy to administer, and inexpensive and has overall favorable molecular impacts on tumor tissues,” the researchers conclude.

Data from the study provide a strong rationale for future trials powered to assess the impact of this combination on disease-free and overall survival in patients with colorectal cancer.

“Haldar et al should be applauded for their steadfast pursuit of repurposed drugs for the treatment of cancer,” Michael Low, MD, and his colleagues at Morningside Center for Innovative and Affordable Medicine at Emory University, Atlanta, Georgia, write in an accompanying editorial.

The concept of using perioperative interventions “to alter the deleterious effects of surgery” is not new, and evidence of potential benefit is abundant, the editorialists note.

The focus of the current study on beta-adrenergic blockade and COX2 inhibition is supported both by the agents’ known suppressive effects on relevant pathways and by preclinical data, the editorialists write.

The study is limited by several factors, including small sample size, patient-reported compliance, and a failure to account for use of chemotherapy. The editorialists emphasize that use of these agents in the perioperative period “is of paramount importance and may have long-lasting antitumoral effects.” They hope “that larger trials focusing on these and other agents will soon prove that to be true.”

The study was supported by an Israel Science Foundation grant. The authors and Lowe have disclosed no relevant financial relationships.
 

This article first appeared on Medscape.com.

Perioperative administration of the beta blocker propranolol and the COX2 inhibitor etodolac significantly improved biomarkers of malignancy and metastasis and was associated with a reduction in recurrence rates after colorectal tumor resection in a randomized, placebo-controlled study.

The study included 34 patients (median age, 58 years) who underwent colorectal tumor resection in Israel. It was published online June 13 in Cancer.

On intent-to-treat analysis, 3-year recurrence rates were 12.5% in the placebo group (n = 16) and 33.3% in the treatment group (n = 18). This difference was not statistically significant (P = .239). However, in protocol-compliant patients, the respective rates were 0% and 29.4% (P = .054), but the study was not powered to assess drug effects on recurrence and survival, the researchers note.

With regard to tumor molecular markers, results showed that the combination reduced epithelial-to-mesenchymal transition and tumor-infiltrating CD14-positive monocytes and CD19-positive B cells. There was an increase in tumor-infiltrating CD56-positive natural killer cells, Rita Haldar, MA, of Tel Aviv University, Israel, and her colleagues note.

Transcriptional activity analysis showed a favorable effect on 12 of 19 potential colorectal cancer–related transcription factors, with alterations that have previously been linked with improved outcomes.

In the trial, the patients in the treatment group received oral etodolac 400 mg twice daily for 20 perioperative days beginning 5 days before surgery and oral propranolol at twice-daily doses of 20 mg for the 5 days before surgery, 80 mg on the day of surgery, 40 mg on postoperative days 1 to 7, and 20 mg for the last 7 days.

The treatments were well tolerated. Minor complications occurred at similar rates in the treatment and placebo groups, note the researchers. No severe surgical complications occurred in the treatment group; one occurred in the placebo group.

The findings indicate that the treatment protocol is “empirically safe, easy to administer, and inexpensive and has overall favorable molecular impacts on tumor tissues,” the researchers conclude.

Data from the study provide a strong rationale for future trials powered to assess the impact of this combination on disease-free and overall survival in patients with colorectal cancer.

“Haldar et al should be applauded for their steadfast pursuit of repurposed drugs for the treatment of cancer,” Michael Low, MD, and his colleagues at Morningside Center for Innovative and Affordable Medicine at Emory University, Atlanta, Georgia, write in an accompanying editorial.

The concept of using perioperative interventions “to alter the deleterious effects of surgery” is not new, and evidence of potential benefit is abundant, the editorialists note.

The focus of the current study on beta-adrenergic blockade and COX2 inhibition is supported both by the agents’ known suppressive effects on relevant pathways and by preclinical data, the editorialists write.

The study is limited by several factors, including small sample size, patient-reported compliance, and a failure to account for use of chemotherapy. The editorialists emphasize that use of these agents in the perioperative period “is of paramount importance and may have long-lasting antitumoral effects.” They hope “that larger trials focusing on these and other agents will soon prove that to be true.”

The study was supported by an Israel Science Foundation grant. The authors and Lowe have disclosed no relevant financial relationships.
 

This article first appeared on Medscape.com.

Immune checkpoint inhibition was not associated with an increased mortality risk from COVID-19 in patients with cancer in an international observational study.

The study included 113 cancer patients who had laboratory-confirmed COVID-19 within 12 months of receiving immune checkpoint inhibitor therapy. The patients did not receive chemotherapy within 3 months of testing positive for COVID-19.

In all, 33 patients were admitted to the hospital, including 6 who were admitted to the ICU, and 9 patients died.

“Nine out of 113 patients is a mortality rate of 8%, which is in the middle of the earlier reported rates for cancer patients in general [7.6%-12%],” said Aljosja Rogiers, MD, PhD, of the Melanoma Institute Australia in Sydney.

COVID-19 was the primary cause of death in seven of the patients, including three of those who were admitted to the ICU, Dr. Rogiers noted.

He reported these results during the AACR virtual meeting: COVID-19 and Cancer.
 

Study details

Patients in this study were treated at 19 hospitals in North America, Europe, and Australia, and the data cutoff was May 15, 2020. Most patients (64%) were treated in Europe, which was the epicenter for the COVID-19 pandemic at the time of data collection, Dr. Rogiers noted. A third of patients were in North America, and 3% were in Australia.

The patients’ median age was 63 years (range, 27-86 years). Most patients were men (65%), and most had Eastern Cooperative Oncology Group performance scores of 0-1 (90%).

The most common malignancies were melanoma (57%), non–small cell lung cancer (17%), and renal cell carcinoma (9%). Treatment was for early cancer in 26% of patients and for advanced cancer in 74%. Comorbidities included cardiovascular disease in 27% of patients, diabetes in 15%, pulmonary disease in 12%, and renal disease in 5%.

Immunosuppressive therapy equivalent to a prednisone dose of 10 mg or greater daily was given in 13% of patients, and other immunosuppressive therapies, such as infliximab, were given in 3%.

Among the 60% of patients with COVID-19 symptoms, 68% had fever, 59% had cough, 34% had dyspnea, and 15% had myalgia. Most of the 40% of asymptomatic patients were tested because they had COVID-19–positive contact, Dr. Rogiers noted.

Immune checkpoint inhibitor treatment included monotherapy with a programmed death–1/PD–ligand 1 inhibitor in 82% of patients, combination anti-PD-1 and anti-CTLA4 therapy in 13%, and other therapy – usually a checkpoint inhibitor combined with a different type of targeted agent – in 5%.

At the time of COVID-19 diagnosis, 30% of patients had achieved a partial response, complete response, or had no evidence of disease, 18% had stable disease, and 15% had progression. Response data were not available in 37% of cases, usually because treatment was only recently started prior to COVID-19 diagnosis, Dr. Rogiers said.

Treatments administered for COVID-19 included antibiotic therapy in 25% of patients, oxygen therapy in 20%, glucocorticoids in 10%, antiviral drugs in 6%, and intravenous immunoglobulin or anti–interleukin-6 in 2% each.

Among patients admitted to the ICU, 3% required mechanical ventilation, 2% had vasopressin, and 1% received renal replacement therapy.

At the data cutoff, 20 of 33 hospitalized patients (61%) had been discharged, and 4 (12%) were still in the hospital.
 

Mortality results

Nine patients died. The rate of death was 8% overall and 27% among hospitalized patients.

“The mortality rate of COVID-19 in the general population without comorbidities is about 1.4%,” Dr. Rogiers said. “For cancer patients, this is reported to be in the range of 7.6%-12%. To what extent patients on immune checkpoint inhibition are at a higher risk of mortality is currently unknown.”

Theoretically, immune checkpoint inhibition could either mitigate or exacerbate COVID-19 infection. It has been hypothesized that immune checkpoint inhibitors could increase the risk of severe acute lung injury or other complications of COVID-19, Dr. Rogiers said, explaining the rationale for the study.

The study shows that the patients who died had a median age of 72 years (range, 49-81 years), which is slightly higher than the median overall age of 63 years. Six patients were from North America, and three were from Italy.

“Two melanoma patients and two non–small cell lung cancer patients died,” Dr. Rogiers said. He noted that two other deaths were in patients with renal cell carcinoma, and three deaths were in other cancer types. All patients had advanced or metastatic disease.

Given that 57% of patients in the study had melanoma and 17% had NSCLC, this finding may indicate that COVID-19 has a slightly higher mortality rate in NSCLC patients than in melanoma patients, but the numbers are small, Dr. Rogiers said.

Notably, six of the patients who died were not admitted to the ICU. In four cases, this was because of underlying malignancy; in the other two cases, it was because of a constrained health care system, Dr. Rogiers said.

Overall, the findings show that the mortality rate of patients with COVID-19 and cancer treated with immune checkpoint inhibitors is similar to the mortality rate reported in the general cancer population, Dr. Rogiers said.

“Treatment with immune checkpoint inhibition does not seem to pose an additional mortality risk for cancer patients with COVID-19,” he concluded.

Dr. Rogiers reported having no conflicts of interest. There was no funding disclosed for the study.

[email protected]

SOURCE: Rogiers A et al. AACR: COVID-19 and Cancer, Abstract S02-01.

Immune checkpoint inhibition was not associated with an increased mortality risk from COVID-19 in patients with cancer in an international observational study.

The study included 113 cancer patients who had laboratory-confirmed COVID-19 within 12 months of receiving immune checkpoint inhibitor therapy. The patients did not receive chemotherapy within 3 months of testing positive for COVID-19.

In all, 33 patients were admitted to the hospital, including 6 who were admitted to the ICU, and 9 patients died.

“Nine out of 113 patients is a mortality rate of 8%, which is in the middle of the earlier reported rates for cancer patients in general [7.6%-12%],” said Aljosja Rogiers, MD, PhD, of the Melanoma Institute Australia in Sydney.

COVID-19 was the primary cause of death in seven of the patients, including three of those who were admitted to the ICU, Dr. Rogiers noted.

He reported these results during the AACR virtual meeting: COVID-19 and Cancer.
 

Study details

Patients in this study were treated at 19 hospitals in North America, Europe, and Australia, and the data cutoff was May 15, 2020. Most patients (64%) were treated in Europe, which was the epicenter for the COVID-19 pandemic at the time of data collection, Dr. Rogiers noted. A third of patients were in North America, and 3% were in Australia.

The patients’ median age was 63 years (range, 27-86 years). Most patients were men (65%), and most had Eastern Cooperative Oncology Group performance scores of 0-1 (90%).

The most common malignancies were melanoma (57%), non–small cell lung cancer (17%), and renal cell carcinoma (9%). Treatment was for early cancer in 26% of patients and for advanced cancer in 74%. Comorbidities included cardiovascular disease in 27% of patients, diabetes in 15%, pulmonary disease in 12%, and renal disease in 5%.

Immunosuppressive therapy equivalent to a prednisone dose of 10 mg or greater daily was given in 13% of patients, and other immunosuppressive therapies, such as infliximab, were given in 3%.

Among the 60% of patients with COVID-19 symptoms, 68% had fever, 59% had cough, 34% had dyspnea, and 15% had myalgia. Most of the 40% of asymptomatic patients were tested because they had COVID-19–positive contact, Dr. Rogiers noted.

Immune checkpoint inhibitor treatment included monotherapy with a programmed death–1/PD–ligand 1 inhibitor in 82% of patients, combination anti-PD-1 and anti-CTLA4 therapy in 13%, and other therapy – usually a checkpoint inhibitor combined with a different type of targeted agent – in 5%.

At the time of COVID-19 diagnosis, 30% of patients had achieved a partial response, complete response, or had no evidence of disease, 18% had stable disease, and 15% had progression. Response data were not available in 37% of cases, usually because treatment was only recently started prior to COVID-19 diagnosis, Dr. Rogiers said.

Treatments administered for COVID-19 included antibiotic therapy in 25% of patients, oxygen therapy in 20%, glucocorticoids in 10%, antiviral drugs in 6%, and intravenous immunoglobulin or anti–interleukin-6 in 2% each.

Among patients admitted to the ICU, 3% required mechanical ventilation, 2% had vasopressin, and 1% received renal replacement therapy.

At the data cutoff, 20 of 33 hospitalized patients (61%) had been discharged, and 4 (12%) were still in the hospital.
 

Mortality results

Nine patients died. The rate of death was 8% overall and 27% among hospitalized patients.

“The mortality rate of COVID-19 in the general population without comorbidities is about 1.4%,” Dr. Rogiers said. “For cancer patients, this is reported to be in the range of 7.6%-12%. To what extent patients on immune checkpoint inhibition are at a higher risk of mortality is currently unknown.”

Theoretically, immune checkpoint inhibition could either mitigate or exacerbate COVID-19 infection. It has been hypothesized that immune checkpoint inhibitors could increase the risk of severe acute lung injury or other complications of COVID-19, Dr. Rogiers said, explaining the rationale for the study.

The study shows that the patients who died had a median age of 72 years (range, 49-81 years), which is slightly higher than the median overall age of 63 years. Six patients were from North America, and three were from Italy.

“Two melanoma patients and two non–small cell lung cancer patients died,” Dr. Rogiers said. He noted that two other deaths were in patients with renal cell carcinoma, and three deaths were in other cancer types. All patients had advanced or metastatic disease.

Given that 57% of patients in the study had melanoma and 17% had NSCLC, this finding may indicate that COVID-19 has a slightly higher mortality rate in NSCLC patients than in melanoma patients, but the numbers are small, Dr. Rogiers said.

Notably, six of the patients who died were not admitted to the ICU. In four cases, this was because of underlying malignancy; in the other two cases, it was because of a constrained health care system, Dr. Rogiers said.

Overall, the findings show that the mortality rate of patients with COVID-19 and cancer treated with immune checkpoint inhibitors is similar to the mortality rate reported in the general cancer population, Dr. Rogiers said.

“Treatment with immune checkpoint inhibition does not seem to pose an additional mortality risk for cancer patients with COVID-19,” he concluded.

Dr. Rogiers reported having no conflicts of interest. There was no funding disclosed for the study.

[email protected]

SOURCE: Rogiers A et al. AACR: COVID-19 and Cancer, Abstract S02-01.

Immune checkpoint inhibition was not associated with an increased mortality risk from COVID-19 in patients with cancer in an international observational study.

The study included 113 cancer patients who had laboratory-confirmed COVID-19 within 12 months of receiving immune checkpoint inhibitor therapy. The patients did not receive chemotherapy within 3 months of testing positive for COVID-19.

In all, 33 patients were admitted to the hospital, including 6 who were admitted to the ICU, and 9 patients died.

“Nine out of 113 patients is a mortality rate of 8%, which is in the middle of the earlier reported rates for cancer patients in general [7.6%-12%],” said Aljosja Rogiers, MD, PhD, of the Melanoma Institute Australia in Sydney.

COVID-19 was the primary cause of death in seven of the patients, including three of those who were admitted to the ICU, Dr. Rogiers noted.

He reported these results during the AACR virtual meeting: COVID-19 and Cancer.
 

Study details

Patients in this study were treated at 19 hospitals in North America, Europe, and Australia, and the data cutoff was May 15, 2020. Most patients (64%) were treated in Europe, which was the epicenter for the COVID-19 pandemic at the time of data collection, Dr. Rogiers noted. A third of patients were in North America, and 3% were in Australia.

The patients’ median age was 63 years (range, 27-86 years). Most patients were men (65%), and most had Eastern Cooperative Oncology Group performance scores of 0-1 (90%).

The most common malignancies were melanoma (57%), non–small cell lung cancer (17%), and renal cell carcinoma (9%). Treatment was for early cancer in 26% of patients and for advanced cancer in 74%. Comorbidities included cardiovascular disease in 27% of patients, diabetes in 15%, pulmonary disease in 12%, and renal disease in 5%.

Immunosuppressive therapy equivalent to a prednisone dose of 10 mg or greater daily was given in 13% of patients, and other immunosuppressive therapies, such as infliximab, were given in 3%.

Among the 60% of patients with COVID-19 symptoms, 68% had fever, 59% had cough, 34% had dyspnea, and 15% had myalgia. Most of the 40% of asymptomatic patients were tested because they had COVID-19–positive contact, Dr. Rogiers noted.

Immune checkpoint inhibitor treatment included monotherapy with a programmed death–1/PD–ligand 1 inhibitor in 82% of patients, combination anti-PD-1 and anti-CTLA4 therapy in 13%, and other therapy – usually a checkpoint inhibitor combined with a different type of targeted agent – in 5%.

At the time of COVID-19 diagnosis, 30% of patients had achieved a partial response, complete response, or had no evidence of disease, 18% had stable disease, and 15% had progression. Response data were not available in 37% of cases, usually because treatment was only recently started prior to COVID-19 diagnosis, Dr. Rogiers said.

Treatments administered for COVID-19 included antibiotic therapy in 25% of patients, oxygen therapy in 20%, glucocorticoids in 10%, antiviral drugs in 6%, and intravenous immunoglobulin or anti–interleukin-6 in 2% each.

Among patients admitted to the ICU, 3% required mechanical ventilation, 2% had vasopressin, and 1% received renal replacement therapy.

At the data cutoff, 20 of 33 hospitalized patients (61%) had been discharged, and 4 (12%) were still in the hospital.
 

Mortality results

Nine patients died. The rate of death was 8% overall and 27% among hospitalized patients.

“The mortality rate of COVID-19 in the general population without comorbidities is about 1.4%,” Dr. Rogiers said. “For cancer patients, this is reported to be in the range of 7.6%-12%. To what extent patients on immune checkpoint inhibition are at a higher risk of mortality is currently unknown.”

Theoretically, immune checkpoint inhibition could either mitigate or exacerbate COVID-19 infection. It has been hypothesized that immune checkpoint inhibitors could increase the risk of severe acute lung injury or other complications of COVID-19, Dr. Rogiers said, explaining the rationale for the study.

The study shows that the patients who died had a median age of 72 years (range, 49-81 years), which is slightly higher than the median overall age of 63 years. Six patients were from North America, and three were from Italy.

“Two melanoma patients and two non–small cell lung cancer patients died,” Dr. Rogiers said. He noted that two other deaths were in patients with renal cell carcinoma, and three deaths were in other cancer types. All patients had advanced or metastatic disease.

Given that 57% of patients in the study had melanoma and 17% had NSCLC, this finding may indicate that COVID-19 has a slightly higher mortality rate in NSCLC patients than in melanoma patients, but the numbers are small, Dr. Rogiers said.

Notably, six of the patients who died were not admitted to the ICU. In four cases, this was because of underlying malignancy; in the other two cases, it was because of a constrained health care system, Dr. Rogiers said.

Overall, the findings show that the mortality rate of patients with COVID-19 and cancer treated with immune checkpoint inhibitors is similar to the mortality rate reported in the general cancer population, Dr. Rogiers said.

“Treatment with immune checkpoint inhibition does not seem to pose an additional mortality risk for cancer patients with COVID-19,” he concluded.

Dr. Rogiers reported having no conflicts of interest. There was no funding disclosed for the study.

[email protected]

SOURCE: Rogiers A et al. AACR: COVID-19 and Cancer, Abstract S02-01.

All patients with cancer who are candidates for systemic anticancer therapy should be screened for hepatitis B virus (HBV) infection prior to or at the start of therapy, according to an updated provisional clinical opinion (PCO) from the American Society of Clinical Oncology.

“This is a new approach [that] will actively take system changes ... but it will ultimately be safer for patients – and that is crucial,” commented Jessica P. Hwang, MD, MPH, cochair of the American Society of Clinical Oncology HBV Screening Expert Panel and the first author of the PCO.

Uptake of this universal screening approach would streamline testing protocols and identify more patients at risk for HBV reactivation who should receive prophylactic antiviral therapy, Dr. Hwang said in an interview.

The PCO calls for antiviral prophylaxis during and for at least 12 months after therapy for those with chronic HBV infection who are receiving any systemic anticancer treatment and for those with have had HBV in the past and are receiving any therapies that pose a risk for HBV reactivation.

“Hepatitis B reactivation can cause really terrible outcomes, like organ failure and even death,” Dr. Hwang, who is also a professor at the University of Texas MD Anderson Cancer Center, Houston, commented in an interview.

“This whole [issue of] reactivation and adverse outcomes with anticancer therapies is completely preventable with good planning, good communication, comanagement with specialists, and antiviral therapy and monitoring,” she added.

The updated opinion was published online July 27 in the Journal of Clinical Oncology.

It was developed in response to new data that call into question the previously recommended risk-adaptive approach to HBV screening of cancer patients, say the authors.

ASCO PCOs are developed “to provide timely clinical guidance” on the basis of emerging practice-changing information. This is the second update to follow the initial HBV screening PCO, published in 2010. In the absence of clear consensus because of limited data, the original PCO called for a risk-based approach to screening. A 2015 update extended the recommendation for screening to patients starting anti-CD20 therapy or who are to undergo stem cell transplant and to those with risk factors for HBV exposure.

The current update provides “a clinically pragmatic approach to HBV screening and management” that is based on the latest findings, say the authors. These include findings from a multicenter prospective cohort study of more than 3000 patients. In that study, 21% of patients with chronic HBV had no known risk factors for the infection. In another large prospective observational cohort study, led by Dr. Hwang, which included more than 2100 patients with cancer, 90% had one or more significant risk factors for HBV infection, making selective screening “inefficient and impractical,” she said.

“The results of these two studies suggest that a universal screening approach, its potential harms (e.g., patient and clinician anxiety about management, financial burden associated with antiviral therapy) notwithstanding, is the most efficient, clinically pragmatic approach to HBV screening in persons anticipating systemic anticancer treatment,” the authors comment.

The screening recommended in the PCO requires three tests: hepatitis B surface antigen (HBsAg), core antibody total immunoglobulin or IgG, and antibody to HBsAg tests.

Anticancer therapy should not be delayed pending the results, they write.

Planning for monitoring and long-term prophylaxis for chronic HBV infection should involve a clinician experienced in HBV management, the authors write. Management of those with past infection should be individualized. Alternatively, patients with past infection can be carefully monitored rather than given prophylactic treatment, as long as frequent and consistent follow-up is possible to allow for rapid initiation of antiviral therapy in the event of reactivation, they say.

Hormonal therapy without systemic anticancer therapy is not likely to lead to HBV reactivation in patients with chronic or past infection; antiviral therapy and management of these patients should follow relevant national HBV guidelines, they note.

Challenges in implementing universal HBV screening

The expert panel acknowledges the challenges associated with implementation of universal HBV screening as recommended in their report and notes that electronic health record–based approaches that use alerts to prompt screening have demonstrated success. In one study of high-risk primary care patients, an EHR alert system significantly increased testing rates (odds ratio, 2.64 in comparison with a control group without alerts), and another study that used a simple “sticky-note” alert system to promote referral of HBsAg patients to hepatologists increased referrals from 28% to 73%.

In a cancer population, a “comprehensive set of multimodal interventions,” including pharmacy staff checks for screening prior to anti-CD20 therapy administration and electronic medication order reviews to assess for appropriate testing and treatment before anti-CD20 therapy, increased testing rates to greater than 90% and antiviral prophylaxis rates to more than 80%.

A study of 965 patients in Taiwan showed that a computer-assisted reminder system that prompted for testing prior to ordering anticancer therapy increased screening from 8% to 86% but was less effective for improving the rates of antiviral prophylaxis for those who tested positive for HBV, particularly among physicians treating patients with nonhematologic malignancies.

“Future studies will be needed to make universal HBV screening and linkage to care efficient and systematic, likely based in EHR systems,” the panel says. The authors note that “[o]ngoing studies of HBV tests such as ultrasensitive HBsAg, HBV RNA, and hepatitis B core antigen are being studied and may be useful in predicting risk of HBV reactivation.”

The panel also identified a research gap related to HBV reactivation risks “for the growing list of agents that deplete or modulate B cells.” It notes a need for additional research on the cost-effectiveness of HBV screening. The results of prior cost analyses have been inconsistent and vary with respect to the population studied. For example, universal screening and antiviral prophylaxis approaches have been shown to be cost-effective for patients with hematologic malignancies and high HBV reactivation risk but are less so for patients with solid tumors and lower reactivation risk, they explain.

Dr. Hwang said that not one of the more than 2100 patients in her HBV screening cohort study encountered problems with receiving insurance payment for their HBV screening.

“That’s a really strong statement that insurance payers are accepting of this kind of preventative service,” she said.

Expert panel cochair Andrew Artz, MD, commented that there is now greater acceptance of the need for HBV screening across medical specialties.

“There’s growing consensus among hepatologists, infectious disease specialists, oncologists, and HBV specialists that we need to do a better job of finding patients with hepatitis B [who are] about to receive immunocompromising treatment,” Dr. Artz said in an interview.

Dr. Artz is director of the Program for Aging and Blood Cancers and deputy director of the Center for Cancer and Aging at City of Hope Comprehensive Cancer Center, Duarte, California.

He suggested that the growing acceptance is due in part to the increasing number of anticancer therapies available and the resulting increase in the likelihood of patients receiving therapies that could cause reactivation.

More therapies – and more lines of therapy – could mean greater risk, he explained. He said that testing is easy and that universal screening is the simplest approach to determining who needs it. “There’s no question we will have to change practice,” Dr. Artz said in an interview. “But this is easier than the previous approach that essentially wasn’t being followed because it was too difficult to follow and patients were being missed.”

Most clinicians will appreciate having an approach that’s easier to follow, Dr. Artz predicted.

If there’s a challenge it will be in developing partnerships with HBV specialists, particularly in rural areas. In areas where there is a paucity of subspecialists, oncologists will have to “take some ownership of the issue,” as they often do in such settings, he said.

However, with support from pharmacists, administrators, and others in embracing this guidance, implementation can take place at a systems level rather than an individual clinician level, he added.

The recommendations in this updated PCO were all rated as “strong,” with the exception of the recommendation on hormonal therapy in the absence of systemic anticancer therapy, which was rated as “moderate.” All were based on “informal consensus,” with the exception of the key recommendation for universal HBV screening – use of three specific tests – which was “evidence based.”

The expert panel agreed that the benefits outweigh the harms for each recommendation in the update.

Dr. Hwang received research funding to her institution from Gilead Sciences and Merck Sharp & Dohme. She also has a relationship with the Asian Health Foundation. Dr. Artz received research funding from Miltenyi Biotec. All expert panel members’ disclosures are available in the PCO update.

This article first appeared on Medscape.com.

All patients with cancer who are candidates for systemic anticancer therapy should be screened for hepatitis B virus (HBV) infection prior to or at the start of therapy, according to an updated provisional clinical opinion (PCO) from the American Society of Clinical Oncology.

“This is a new approach [that] will actively take system changes ... but it will ultimately be safer for patients – and that is crucial,” commented Jessica P. Hwang, MD, MPH, cochair of the American Society of Clinical Oncology HBV Screening Expert Panel and the first author of the PCO.

Uptake of this universal screening approach would streamline testing protocols and identify more patients at risk for HBV reactivation who should receive prophylactic antiviral therapy, Dr. Hwang said in an interview.

The PCO calls for antiviral prophylaxis during and for at least 12 months after therapy for those with chronic HBV infection who are receiving any systemic anticancer treatment and for those with have had HBV in the past and are receiving any therapies that pose a risk for HBV reactivation.

“Hepatitis B reactivation can cause really terrible outcomes, like organ failure and even death,” Dr. Hwang, who is also a professor at the University of Texas MD Anderson Cancer Center, Houston, commented in an interview.

“This whole [issue of] reactivation and adverse outcomes with anticancer therapies is completely preventable with good planning, good communication, comanagement with specialists, and antiviral therapy and monitoring,” she added.

The updated opinion was published online July 27 in the Journal of Clinical Oncology.

It was developed in response to new data that call into question the previously recommended risk-adaptive approach to HBV screening of cancer patients, say the authors.

ASCO PCOs are developed “to provide timely clinical guidance” on the basis of emerging practice-changing information. This is the second update to follow the initial HBV screening PCO, published in 2010. In the absence of clear consensus because of limited data, the original PCO called for a risk-based approach to screening. A 2015 update extended the recommendation for screening to patients starting anti-CD20 therapy or who are to undergo stem cell transplant and to those with risk factors for HBV exposure.

The current update provides “a clinically pragmatic approach to HBV screening and management” that is based on the latest findings, say the authors. These include findings from a multicenter prospective cohort study of more than 3000 patients. In that study, 21% of patients with chronic HBV had no known risk factors for the infection. In another large prospective observational cohort study, led by Dr. Hwang, which included more than 2100 patients with cancer, 90% had one or more significant risk factors for HBV infection, making selective screening “inefficient and impractical,” she said.

“The results of these two studies suggest that a universal screening approach, its potential harms (e.g., patient and clinician anxiety about management, financial burden associated with antiviral therapy) notwithstanding, is the most efficient, clinically pragmatic approach to HBV screening in persons anticipating systemic anticancer treatment,” the authors comment.

The screening recommended in the PCO requires three tests: hepatitis B surface antigen (HBsAg), core antibody total immunoglobulin or IgG, and antibody to HBsAg tests.

Anticancer therapy should not be delayed pending the results, they write.

Planning for monitoring and long-term prophylaxis for chronic HBV infection should involve a clinician experienced in HBV management, the authors write. Management of those with past infection should be individualized. Alternatively, patients with past infection can be carefully monitored rather than given prophylactic treatment, as long as frequent and consistent follow-up is possible to allow for rapid initiation of antiviral therapy in the event of reactivation, they say.

Hormonal therapy without systemic anticancer therapy is not likely to lead to HBV reactivation in patients with chronic or past infection; antiviral therapy and management of these patients should follow relevant national HBV guidelines, they note.

Challenges in implementing universal HBV screening

The expert panel acknowledges the challenges associated with implementation of universal HBV screening as recommended in their report and notes that electronic health record–based approaches that use alerts to prompt screening have demonstrated success. In one study of high-risk primary care patients, an EHR alert system significantly increased testing rates (odds ratio, 2.64 in comparison with a control group without alerts), and another study that used a simple “sticky-note” alert system to promote referral of HBsAg patients to hepatologists increased referrals from 28% to 73%.

In a cancer population, a “comprehensive set of multimodal interventions,” including pharmacy staff checks for screening prior to anti-CD20 therapy administration and electronic medication order reviews to assess for appropriate testing and treatment before anti-CD20 therapy, increased testing rates to greater than 90% and antiviral prophylaxis rates to more than 80%.

A study of 965 patients in Taiwan showed that a computer-assisted reminder system that prompted for testing prior to ordering anticancer therapy increased screening from 8% to 86% but was less effective for improving the rates of antiviral prophylaxis for those who tested positive for HBV, particularly among physicians treating patients with nonhematologic malignancies.

“Future studies will be needed to make universal HBV screening and linkage to care efficient and systematic, likely based in EHR systems,” the panel says. The authors note that “[o]ngoing studies of HBV tests such as ultrasensitive HBsAg, HBV RNA, and hepatitis B core antigen are being studied and may be useful in predicting risk of HBV reactivation.”

The panel also identified a research gap related to HBV reactivation risks “for the growing list of agents that deplete or modulate B cells.” It notes a need for additional research on the cost-effectiveness of HBV screening. The results of prior cost analyses have been inconsistent and vary with respect to the population studied. For example, universal screening and antiviral prophylaxis approaches have been shown to be cost-effective for patients with hematologic malignancies and high HBV reactivation risk but are less so for patients with solid tumors and lower reactivation risk, they explain.

Dr. Hwang said that not one of the more than 2100 patients in her HBV screening cohort study encountered problems with receiving insurance payment for their HBV screening.

“That’s a really strong statement that insurance payers are accepting of this kind of preventative service,” she said.

Expert panel cochair Andrew Artz, MD, commented that there is now greater acceptance of the need for HBV screening across medical specialties.

“There’s growing consensus among hepatologists, infectious disease specialists, oncologists, and HBV specialists that we need to do a better job of finding patients with hepatitis B [who are] about to receive immunocompromising treatment,” Dr. Artz said in an interview.

Dr. Artz is director of the Program for Aging and Blood Cancers and deputy director of the Center for Cancer and Aging at City of Hope Comprehensive Cancer Center, Duarte, California.

He suggested that the growing acceptance is due in part to the increasing number of anticancer therapies available and the resulting increase in the likelihood of patients receiving therapies that could cause reactivation.

More therapies – and more lines of therapy – could mean greater risk, he explained. He said that testing is easy and that universal screening is the simplest approach to determining who needs it. “There’s no question we will have to change practice,” Dr. Artz said in an interview. “But this is easier than the previous approach that essentially wasn’t being followed because it was too difficult to follow and patients were being missed.”

Most clinicians will appreciate having an approach that’s easier to follow, Dr. Artz predicted.

If there’s a challenge it will be in developing partnerships with HBV specialists, particularly in rural areas. In areas where there is a paucity of subspecialists, oncologists will have to “take some ownership of the issue,” as they often do in such settings, he said.

However, with support from pharmacists, administrators, and others in embracing this guidance, implementation can take place at a systems level rather than an individual clinician level, he added.

The recommendations in this updated PCO were all rated as “strong,” with the exception of the recommendation on hormonal therapy in the absence of systemic anticancer therapy, which was rated as “moderate.” All were based on “informal consensus,” with the exception of the key recommendation for universal HBV screening – use of three specific tests – which was “evidence based.”

The expert panel agreed that the benefits outweigh the harms for each recommendation in the update.

Dr. Hwang received research funding to her institution from Gilead Sciences and Merck Sharp & Dohme. She also has a relationship with the Asian Health Foundation. Dr. Artz received research funding from Miltenyi Biotec. All expert panel members’ disclosures are available in the PCO update.

This article first appeared on Medscape.com.

All patients with cancer who are candidates for systemic anticancer therapy should be screened for hepatitis B virus (HBV) infection prior to or at the start of therapy, according to an updated provisional clinical opinion (PCO) from the American Society of Clinical Oncology.

“This is a new approach [that] will actively take system changes ... but it will ultimately be safer for patients – and that is crucial,” commented Jessica P. Hwang, MD, MPH, cochair of the American Society of Clinical Oncology HBV Screening Expert Panel and the first author of the PCO.

Uptake of this universal screening approach would streamline testing protocols and identify more patients at risk for HBV reactivation who should receive prophylactic antiviral therapy, Dr. Hwang said in an interview.

The PCO calls for antiviral prophylaxis during and for at least 12 months after therapy for those with chronic HBV infection who are receiving any systemic anticancer treatment and for those with have had HBV in the past and are receiving any therapies that pose a risk for HBV reactivation.

“Hepatitis B reactivation can cause really terrible outcomes, like organ failure and even death,” Dr. Hwang, who is also a professor at the University of Texas MD Anderson Cancer Center, Houston, commented in an interview.

“This whole [issue of] reactivation and adverse outcomes with anticancer therapies is completely preventable with good planning, good communication, comanagement with specialists, and antiviral therapy and monitoring,” she added.

The updated opinion was published online July 27 in the Journal of Clinical Oncology.

It was developed in response to new data that call into question the previously recommended risk-adaptive approach to HBV screening of cancer patients, say the authors.

ASCO PCOs are developed “to provide timely clinical guidance” on the basis of emerging practice-changing information. This is the second update to follow the initial HBV screening PCO, published in 2010. In the absence of clear consensus because of limited data, the original PCO called for a risk-based approach to screening. A 2015 update extended the recommendation for screening to patients starting anti-CD20 therapy or who are to undergo stem cell transplant and to those with risk factors for HBV exposure.

The current update provides “a clinically pragmatic approach to HBV screening and management” that is based on the latest findings, say the authors. These include findings from a multicenter prospective cohort study of more than 3000 patients. In that study, 21% of patients with chronic HBV had no known risk factors for the infection. In another large prospective observational cohort study, led by Dr. Hwang, which included more than 2100 patients with cancer, 90% had one or more significant risk factors for HBV infection, making selective screening “inefficient and impractical,” she said.

“The results of these two studies suggest that a universal screening approach, its potential harms (e.g., patient and clinician anxiety about management, financial burden associated with antiviral therapy) notwithstanding, is the most efficient, clinically pragmatic approach to HBV screening in persons anticipating systemic anticancer treatment,” the authors comment.

The screening recommended in the PCO requires three tests: hepatitis B surface antigen (HBsAg), core antibody total immunoglobulin or IgG, and antibody to HBsAg tests.

Anticancer therapy should not be delayed pending the results, they write.

Planning for monitoring and long-term prophylaxis for chronic HBV infection should involve a clinician experienced in HBV management, the authors write. Management of those with past infection should be individualized. Alternatively, patients with past infection can be carefully monitored rather than given prophylactic treatment, as long as frequent and consistent follow-up is possible to allow for rapid initiation of antiviral therapy in the event of reactivation, they say.

Hormonal therapy without systemic anticancer therapy is not likely to lead to HBV reactivation in patients with chronic or past infection; antiviral therapy and management of these patients should follow relevant national HBV guidelines, they note.

Challenges in implementing universal HBV screening

The expert panel acknowledges the challenges associated with implementation of universal HBV screening as recommended in their report and notes that electronic health record–based approaches that use alerts to prompt screening have demonstrated success. In one study of high-risk primary care patients, an EHR alert system significantly increased testing rates (odds ratio, 2.64 in comparison with a control group without alerts), and another study that used a simple “sticky-note” alert system to promote referral of HBsAg patients to hepatologists increased referrals from 28% to 73%.

In a cancer population, a “comprehensive set of multimodal interventions,” including pharmacy staff checks for screening prior to anti-CD20 therapy administration and electronic medication order reviews to assess for appropriate testing and treatment before anti-CD20 therapy, increased testing rates to greater than 90% and antiviral prophylaxis rates to more than 80%.

A study of 965 patients in Taiwan showed that a computer-assisted reminder system that prompted for testing prior to ordering anticancer therapy increased screening from 8% to 86% but was less effective for improving the rates of antiviral prophylaxis for those who tested positive for HBV, particularly among physicians treating patients with nonhematologic malignancies.

“Future studies will be needed to make universal HBV screening and linkage to care efficient and systematic, likely based in EHR systems,” the panel says. The authors note that “[o]ngoing studies of HBV tests such as ultrasensitive HBsAg, HBV RNA, and hepatitis B core antigen are being studied and may be useful in predicting risk of HBV reactivation.”

The panel also identified a research gap related to HBV reactivation risks “for the growing list of agents that deplete or modulate B cells.” It notes a need for additional research on the cost-effectiveness of HBV screening. The results of prior cost analyses have been inconsistent and vary with respect to the population studied. For example, universal screening and antiviral prophylaxis approaches have been shown to be cost-effective for patients with hematologic malignancies and high HBV reactivation risk but are less so for patients with solid tumors and lower reactivation risk, they explain.

Dr. Hwang said that not one of the more than 2100 patients in her HBV screening cohort study encountered problems with receiving insurance payment for their HBV screening.

“That’s a really strong statement that insurance payers are accepting of this kind of preventative service,” she said.

Expert panel cochair Andrew Artz, MD, commented that there is now greater acceptance of the need for HBV screening across medical specialties.

“There’s growing consensus among hepatologists, infectious disease specialists, oncologists, and HBV specialists that we need to do a better job of finding patients with hepatitis B [who are] about to receive immunocompromising treatment,” Dr. Artz said in an interview.

Dr. Artz is director of the Program for Aging and Blood Cancers and deputy director of the Center for Cancer and Aging at City of Hope Comprehensive Cancer Center, Duarte, California.

He suggested that the growing acceptance is due in part to the increasing number of anticancer therapies available and the resulting increase in the likelihood of patients receiving therapies that could cause reactivation.

More therapies – and more lines of therapy – could mean greater risk, he explained. He said that testing is easy and that universal screening is the simplest approach to determining who needs it. “There’s no question we will have to change practice,” Dr. Artz said in an interview. “But this is easier than the previous approach that essentially wasn’t being followed because it was too difficult to follow and patients were being missed.”

Most clinicians will appreciate having an approach that’s easier to follow, Dr. Artz predicted.

If there’s a challenge it will be in developing partnerships with HBV specialists, particularly in rural areas. In areas where there is a paucity of subspecialists, oncologists will have to “take some ownership of the issue,” as they often do in such settings, he said.

However, with support from pharmacists, administrators, and others in embracing this guidance, implementation can take place at a systems level rather than an individual clinician level, he added.

The recommendations in this updated PCO were all rated as “strong,” with the exception of the recommendation on hormonal therapy in the absence of systemic anticancer therapy, which was rated as “moderate.” All were based on “informal consensus,” with the exception of the key recommendation for universal HBV screening – use of three specific tests – which was “evidence based.”

The expert panel agreed that the benefits outweigh the harms for each recommendation in the update.

Dr. Hwang received research funding to her institution from Gilead Sciences and Merck Sharp & Dohme. She also has a relationship with the Asian Health Foundation. Dr. Artz received research funding from Miltenyi Biotec. All expert panel members’ disclosures are available in the PCO update.

This article first appeared on Medscape.com.

Perioperative bleeding risk was not associated with platelet count in a fairly large cohort of patients with liver cirrhosis, according to a review of cases, including some involving severe thrombocytopenia.

The findings raise questions about current recommendations that call for transfusing platelet concentrates to reduce bleeding risk during surgery in cirrhosis patients with extremely low platelet counts, Gian Marco Podda, MD, PhD, said at the International Society on Thrombosis and Haemostasis virtual congress.

The overall rate of perioperative bleeding was 8.9% in 996 patients who underwent excision of hepatocellular carcinoma by resection (42%) or radiofrequency ablation (58%) without platelet transfusion between 1998 and 2018. The rates were slightly higher among 65 patients with platelet count of fewer than 50 × 10⁹/L indicating severe thrombocytopenia, and in 292 patients with counts of 50-100 × 10⁹/L, indicating moderate thrombocytopenia (10.8% and 10.2%, respectively), compared with those with a platelet count of higher than 100 × 10⁹/L (8.1%), but the differences were not statistically significant, said Dr. Podda of the University of Milan (Italy).

The corresponding rates among those who underwent radiofrequency ablation were 8.6%, 5.9%, and 5%, and among those who underwent resection, they were 18.8%, 17.7%, and 15.9%.

On multivariate analysis, factors associated with an increased incidence of major bleeding were low hemoglobin level (odds ratio, 0.57), age over 65 years (OR, 1.19), aspartate aminotransferase level greater than twice the upper limit of normal (OR, 2.12), hepatitis B or C cirrhosis versus cryptogenic cirrhosis (OR, 0.08), and resection versus radiofrequency ablation (OR, 3.74), he noted. Logistic regression analysis showed no significant association between platelet count and major bleeding events.

Mortality, a secondary outcome measure, was significantly higher among those with moderate or severe thrombocytopenia (rate of 5.5% for each), compared with those with mild or no thrombocytopenia (2.4%), Dr. Podda said.

Factors associated with mortality on multivariate analysis were severe liver dysfunction as demonstrated by Model for End-Stage Liver Disease score of 10 or greater versus less than 10 (OR, 3.13) and Child-Pugh B and C score versus Child-Pugh A score (OR, 16.72), advanced tumor status as measured by Barcelona-Clínic Liver Cancer staging greater than A4 versus A1 (OR, 5.78), major bleeding (OR, 4.59), and resection versus radiofrequency ablation (OR, 3.31).

“Low platelet count was associated with an increased risk of mortality at 3 months. However, this association disappeared at the multivariate analysis, which took into account markers of severity of liver cirrhosis,” he said.

Dr. Podda and his colleagues conducted the study in light of a recommendation from a consensus conference of the Italian Association for the Study of Liver Disease and the Italian Society of Internal Medicine that called for increasing platelet count by platelet transfusions in patients with cirrhosis who undergo an invasive procedure and who have a platelet count lower than 50 × 10⁹/L.

“This recommendation mostly stemmed from consideration of biological plausibility prospects rather than being based on hard experimental evidence,” he explained, noting that such severe thrombocytopenia affects about 10% of patients with liver cirrhosis.

Based on the findings of this study, the practice is not supported, he concluded.

Dr. Podda reported honoraria from Sanofi, Boehringer Ingelheim.

[email protected]

SOURCE: Ronca V et al. ISTH 2020, Abstract OC 13.4.

Perioperative bleeding risk was not associated with platelet count in a fairly large cohort of patients with liver cirrhosis, according to a review of cases, including some involving severe thrombocytopenia.

The findings raise questions about current recommendations that call for transfusing platelet concentrates to reduce bleeding risk during surgery in cirrhosis patients with extremely low platelet counts, Gian Marco Podda, MD, PhD, said at the International Society on Thrombosis and Haemostasis virtual congress.

The overall rate of perioperative bleeding was 8.9% in 996 patients who underwent excision of hepatocellular carcinoma by resection (42%) or radiofrequency ablation (58%) without platelet transfusion between 1998 and 2018. The rates were slightly higher among 65 patients with platelet count of fewer than 50 × 10⁹/L indicating severe thrombocytopenia, and in 292 patients with counts of 50-100 × 10⁹/L, indicating moderate thrombocytopenia (10.8% and 10.2%, respectively), compared with those with a platelet count of higher than 100 × 10⁹/L (8.1%), but the differences were not statistically significant, said Dr. Podda of the University of Milan (Italy).

The corresponding rates among those who underwent radiofrequency ablation were 8.6%, 5.9%, and 5%, and among those who underwent resection, they were 18.8%, 17.7%, and 15.9%.

On multivariate analysis, factors associated with an increased incidence of major bleeding were low hemoglobin level (odds ratio, 0.57), age over 65 years (OR, 1.19), aspartate aminotransferase level greater than twice the upper limit of normal (OR, 2.12), hepatitis B or C cirrhosis versus cryptogenic cirrhosis (OR, 0.08), and resection versus radiofrequency ablation (OR, 3.74), he noted. Logistic regression analysis showed no significant association between platelet count and major bleeding events.

Mortality, a secondary outcome measure, was significantly higher among those with moderate or severe thrombocytopenia (rate of 5.5% for each), compared with those with mild or no thrombocytopenia (2.4%), Dr. Podda said.

Factors associated with mortality on multivariate analysis were severe liver dysfunction as demonstrated by Model for End-Stage Liver Disease score of 10 or greater versus less than 10 (OR, 3.13) and Child-Pugh B and C score versus Child-Pugh A score (OR, 16.72), advanced tumor status as measured by Barcelona-Clínic Liver Cancer staging greater than A4 versus A1 (OR, 5.78), major bleeding (OR, 4.59), and resection versus radiofrequency ablation (OR, 3.31).

“Low platelet count was associated with an increased risk of mortality at 3 months. However, this association disappeared at the multivariate analysis, which took into account markers of severity of liver cirrhosis,” he said.

Dr. Podda and his colleagues conducted the study in light of a recommendation from a consensus conference of the Italian Association for the Study of Liver Disease and the Italian Society of Internal Medicine that called for increasing platelet count by platelet transfusions in patients with cirrhosis who undergo an invasive procedure and who have a platelet count lower than 50 × 10⁹/L.

“This recommendation mostly stemmed from consideration of biological plausibility prospects rather than being based on hard experimental evidence,” he explained, noting that such severe thrombocytopenia affects about 10% of patients with liver cirrhosis.

Based on the findings of this study, the practice is not supported, he concluded.

Dr. Podda reported honoraria from Sanofi, Boehringer Ingelheim.

[email protected]

SOURCE: Ronca V et al. ISTH 2020, Abstract OC 13.4.

Perioperative bleeding risk was not associated with platelet count in a fairly large cohort of patients with liver cirrhosis, according to a review of cases, including some involving severe thrombocytopenia.

The findings raise questions about current recommendations that call for transfusing platelet concentrates to reduce bleeding risk during surgery in cirrhosis patients with extremely low platelet counts, Gian Marco Podda, MD, PhD, said at the International Society on Thrombosis and Haemostasis virtual congress.

The overall rate of perioperative bleeding was 8.9% in 996 patients who underwent excision of hepatocellular carcinoma by resection (42%) or radiofrequency ablation (58%) without platelet transfusion between 1998 and 2018. The rates were slightly higher among 65 patients with platelet count of fewer than 50 × 10⁹/L indicating severe thrombocytopenia, and in 292 patients with counts of 50-100 × 10⁹/L, indicating moderate thrombocytopenia (10.8% and 10.2%, respectively), compared with those with a platelet count of higher than 100 × 10⁹/L (8.1%), but the differences were not statistically significant, said Dr. Podda of the University of Milan (Italy).

The corresponding rates among those who underwent radiofrequency ablation were 8.6%, 5.9%, and 5%, and among those who underwent resection, they were 18.8%, 17.7%, and 15.9%.

On multivariate analysis, factors associated with an increased incidence of major bleeding were low hemoglobin level (odds ratio, 0.57), age over 65 years (OR, 1.19), aspartate aminotransferase level greater than twice the upper limit of normal (OR, 2.12), hepatitis B or C cirrhosis versus cryptogenic cirrhosis (OR, 0.08), and resection versus radiofrequency ablation (OR, 3.74), he noted. Logistic regression analysis showed no significant association between platelet count and major bleeding events.

Mortality, a secondary outcome measure, was significantly higher among those with moderate or severe thrombocytopenia (rate of 5.5% for each), compared with those with mild or no thrombocytopenia (2.4%), Dr. Podda said.

Factors associated with mortality on multivariate analysis were severe liver dysfunction as demonstrated by Model for End-Stage Liver Disease score of 10 or greater versus less than 10 (OR, 3.13) and Child-Pugh B and C score versus Child-Pugh A score (OR, 16.72), advanced tumor status as measured by Barcelona-Clínic Liver Cancer staging greater than A4 versus A1 (OR, 5.78), major bleeding (OR, 4.59), and resection versus radiofrequency ablation (OR, 3.31).

“Low platelet count was associated with an increased risk of mortality at 3 months. However, this association disappeared at the multivariate analysis, which took into account markers of severity of liver cirrhosis,” he said.

Dr. Podda and his colleagues conducted the study in light of a recommendation from a consensus conference of the Italian Association for the Study of Liver Disease and the Italian Society of Internal Medicine that called for increasing platelet count by platelet transfusions in patients with cirrhosis who undergo an invasive procedure and who have a platelet count lower than 50 × 10⁹/L.

“This recommendation mostly stemmed from consideration of biological plausibility prospects rather than being based on hard experimental evidence,” he explained, noting that such severe thrombocytopenia affects about 10% of patients with liver cirrhosis.

Based on the findings of this study, the practice is not supported, he concluded.

Dr. Podda reported honoraria from Sanofi, Boehringer Ingelheim.

[email protected]

SOURCE: Ronca V et al. ISTH 2020, Abstract OC 13.4.

Hospitalized cancer patients have a high risk of nosocomial COVID-19 that is associated with increased mortality, so these patients should be treated in COVID-free zones, according to researchers.

In an observational study of patients with COVID-19 and cancer, 19% of patients had COVID-19 acquired during a non-COVID-related hospital stay, and 81% had community-acquired COVID-19.

At a median follow-up of 23 days, the overall mortality rate was 28%. However, the all-cause mortality rate in patients with nosocomial COVID-19 was more than double that of patients with community-acquired COVID-19, at 47% and 23%, respectively.

Arielle Elkrief, MD, of the University of Montreal, reported these results during the AACR virtual meeting: COVID-19 and Cancer.

“This is the first report that describes a high rate of hospital-acquired COVID-19 in patients with cancer, at a rate of 19%,” Dr. Elkrief said. “This was associated with high mortality in both univariate and multivariate analyses.”

The study included 250 adults and 3 children with COVID-19 and cancer who were identified between March 3 and May 23, 2020. They ranged in age from 4 to 95 years, but the median age was 73 years.

All patients had either laboratory-confirmed (95%) or presumed COVID-19 (5%) and invasive cancer. The most common cancer types were similar to those seen in the general population. Lung and breast cancer were the most common, followed by lymphoma, prostate cancer, and colorectal cancer. Most patients were on active anticancer therapy, most often chemotherapy.

Most patients (n = 236) were residents of Quebec, but 17 patients were residents of British Columbia.

“It is important to note that Quebec was one of the most heavily affected areas in North America at the time of the study,” Dr. Elkrief said.
 

Outcomes by group

There were 206 patients (81%) who had community-acquired COVID-19 and 47 (19%) who had nosocomial COVID-19. The two groups were similar with respect to sex, performance status, and cancer stage. A small trend toward more patients on active therapy was seen in the nosocomial group, but the difference did not reach statistical significance.

The median overall survival was 27 days in the nosocomial group and 71 days in the community-acquired group (hazard ratio, 2.2; P = .002).

A multivariate analysis showed that nosocomial infection was “strongly and independently associated with death,” Dr. Elkrief said. “Other risk factors for poor prognosis included age, poor [performance] status, and advanced stage of cancer.”

There were no significant differences between the hospital-acquired and community-acquired groups for other outcomes, including oxygen requirements (43% and 47%, respectively), ICU admission (13% and 11%), need for mechanical ventilation (6% and 5%), or length of stay (median, 9.5 days and 8.5 days).

The low rate of ICU admission, considering the mortality rate of 28%, “could reflect that patients with cancer are less likely to be admitted to the ICU,” Dr. Elkrief noted.
 

Applying the findings to practice

The findings reinforce the importance of adherence to stringent infection control guidelines to protect vulnerable patients, such as those with cancer, Dr. Elkrief said.

In ambulatory settings, this means decreasing in-person visits through increased use of teleconsultations, and for those who need to be seen in person, screening for symptoms or use of polymerase chain reaction testing should be used when resources are available, she said.

“Similar principles apply to chemotherapy treatment units,” Dr. Elkrief said. She added that staff must avoid cross-contamination between COVID and COVID-free zones, and that “dedicated personnel and equipment should be maintained and separate between these two zones.

“Adequate protective personal equipment and strict hand hygiene protocols are also of utmost importance,” Dr. Elkrief said. “The threat of COVID-19 is not behind us, and so we continue to enforce these strategies to protect our patients.”

Session moderator Gypsyamber D’Souza, PhD, an infectious disease epidemiologist at Johns Hopkins University in Baltimore, raised the question of whether the high nosocomial infection and death rate in this study was related to patients having more severe disease because of underlying comorbidities.

Dr. Elkrief explained that the overall mortality rate was indeed higher than the 13% reported in other studies, and it may reflect an overrepresentation of hospitalized or more severely ill patients in the cohort.

However, the investigators made every effort to include all patients with both cancer and COVID-19 by using systematic screening of inpatient and outpatients lists and registries.

Further, the multivariate analysis included both inpatients and outpatients and adjusted for known negative prognostic factors for COVID-19 outcomes. These included increasing age, poor performance status, and different comorbidities.

The finding that nosocomial infection was an independent predictor of death “pushed us to look at nosocomial infection as a new independent risk factor,” Dr. Elkrief said.

Dr. Elkrief reported grant support from AstraZeneca. Dr. D’Souza did not report any disclosures.

[email protected]

SOURCE: Elkrief A et al. AACR: COVID and Cancer, Abstract S12-01.

Hospitalized cancer patients have a high risk of nosocomial COVID-19 that is associated with increased mortality, so these patients should be treated in COVID-free zones, according to researchers.

In an observational study of patients with COVID-19 and cancer, 19% of patients had COVID-19 acquired during a non-COVID-related hospital stay, and 81% had community-acquired COVID-19.

At a median follow-up of 23 days, the overall mortality rate was 28%. However, the all-cause mortality rate in patients with nosocomial COVID-19 was more than double that of patients with community-acquired COVID-19, at 47% and 23%, respectively.

Arielle Elkrief, MD, of the University of Montreal, reported these results during the AACR virtual meeting: COVID-19 and Cancer.

“This is the first report that describes a high rate of hospital-acquired COVID-19 in patients with cancer, at a rate of 19%,” Dr. Elkrief said. “This was associated with high mortality in both univariate and multivariate analyses.”

The study included 250 adults and 3 children with COVID-19 and cancer who were identified between March 3 and May 23, 2020. They ranged in age from 4 to 95 years, but the median age was 73 years.

All patients had either laboratory-confirmed (95%) or presumed COVID-19 (5%) and invasive cancer. The most common cancer types were similar to those seen in the general population. Lung and breast cancer were the most common, followed by lymphoma, prostate cancer, and colorectal cancer. Most patients were on active anticancer therapy, most often chemotherapy.

Most patients (n = 236) were residents of Quebec, but 17 patients were residents of British Columbia.

“It is important to note that Quebec was one of the most heavily affected areas in North America at the time of the study,” Dr. Elkrief said.
 

Outcomes by group

There were 206 patients (81%) who had community-acquired COVID-19 and 47 (19%) who had nosocomial COVID-19. The two groups were similar with respect to sex, performance status, and cancer stage. A small trend toward more patients on active therapy was seen in the nosocomial group, but the difference did not reach statistical significance.

The median overall survival was 27 days in the nosocomial group and 71 days in the community-acquired group (hazard ratio, 2.2; P = .002).

A multivariate analysis showed that nosocomial infection was “strongly and independently associated with death,” Dr. Elkrief said. “Other risk factors for poor prognosis included age, poor [performance] status, and advanced stage of cancer.”

There were no significant differences between the hospital-acquired and community-acquired groups for other outcomes, including oxygen requirements (43% and 47%, respectively), ICU admission (13% and 11%), need for mechanical ventilation (6% and 5%), or length of stay (median, 9.5 days and 8.5 days).

The low rate of ICU admission, considering the mortality rate of 28%, “could reflect that patients with cancer are less likely to be admitted to the ICU,” Dr. Elkrief noted.
 

Applying the findings to practice

The findings reinforce the importance of adherence to stringent infection control guidelines to protect vulnerable patients, such as those with cancer, Dr. Elkrief said.

In ambulatory settings, this means decreasing in-person visits through increased use of teleconsultations, and for those who need to be seen in person, screening for symptoms or use of polymerase chain reaction testing should be used when resources are available, she said.

“Similar principles apply to chemotherapy treatment units,” Dr. Elkrief said. She added that staff must avoid cross-contamination between COVID and COVID-free zones, and that “dedicated personnel and equipment should be maintained and separate between these two zones.

“Adequate protective personal equipment and strict hand hygiene protocols are also of utmost importance,” Dr. Elkrief said. “The threat of COVID-19 is not behind us, and so we continue to enforce these strategies to protect our patients.”

Session moderator Gypsyamber D’Souza, PhD, an infectious disease epidemiologist at Johns Hopkins University in Baltimore, raised the question of whether the high nosocomial infection and death rate in this study was related to patients having more severe disease because of underlying comorbidities.

Dr. Elkrief explained that the overall mortality rate was indeed higher than the 13% reported in other studies, and it may reflect an overrepresentation of hospitalized or more severely ill patients in the cohort.

However, the investigators made every effort to include all patients with both cancer and COVID-19 by using systematic screening of inpatient and outpatients lists and registries.

Further, the multivariate analysis included both inpatients and outpatients and adjusted for known negative prognostic factors for COVID-19 outcomes. These included increasing age, poor performance status, and different comorbidities.

The finding that nosocomial infection was an independent predictor of death “pushed us to look at nosocomial infection as a new independent risk factor,” Dr. Elkrief said.

Dr. Elkrief reported grant support from AstraZeneca. Dr. D’Souza did not report any disclosures.

[email protected]

SOURCE: Elkrief A et al. AACR: COVID and Cancer, Abstract S12-01.

Hospitalized cancer patients have a high risk of nosocomial COVID-19 that is associated with increased mortality, so these patients should be treated in COVID-free zones, according to researchers.

In an observational study of patients with COVID-19 and cancer, 19% of patients had COVID-19 acquired during a non-COVID-related hospital stay, and 81% had community-acquired COVID-19.

At a median follow-up of 23 days, the overall mortality rate was 28%. However, the all-cause mortality rate in patients with nosocomial COVID-19 was more than double that of patients with community-acquired COVID-19, at 47% and 23%, respectively.

Arielle Elkrief, MD, of the University of Montreal, reported these results during the AACR virtual meeting: COVID-19 and Cancer.

“This is the first report that describes a high rate of hospital-acquired COVID-19 in patients with cancer, at a rate of 19%,” Dr. Elkrief said. “This was associated with high mortality in both univariate and multivariate analyses.”

The study included 250 adults and 3 children with COVID-19 and cancer who were identified between March 3 and May 23, 2020. They ranged in age from 4 to 95 years, but the median age was 73 years.

All patients had either laboratory-confirmed (95%) or presumed COVID-19 (5%) and invasive cancer. The most common cancer types were similar to those seen in the general population. Lung and breast cancer were the most common, followed by lymphoma, prostate cancer, and colorectal cancer. Most patients were on active anticancer therapy, most often chemotherapy.

Most patients (n = 236) were residents of Quebec, but 17 patients were residents of British Columbia.

“It is important to note that Quebec was one of the most heavily affected areas in North America at the time of the study,” Dr. Elkrief said.
 

Outcomes by group

There were 206 patients (81%) who had community-acquired COVID-19 and 47 (19%) who had nosocomial COVID-19. The two groups were similar with respect to sex, performance status, and cancer stage. A small trend toward more patients on active therapy was seen in the nosocomial group, but the difference did not reach statistical significance.

The median overall survival was 27 days in the nosocomial group and 71 days in the community-acquired group (hazard ratio, 2.2; P = .002).

A multivariate analysis showed that nosocomial infection was “strongly and independently associated with death,” Dr. Elkrief said. “Other risk factors for poor prognosis included age, poor [performance] status, and advanced stage of cancer.”

There were no significant differences between the hospital-acquired and community-acquired groups for other outcomes, including oxygen requirements (43% and 47%, respectively), ICU admission (13% and 11%), need for mechanical ventilation (6% and 5%), or length of stay (median, 9.5 days and 8.5 days).

The low rate of ICU admission, considering the mortality rate of 28%, “could reflect that patients with cancer are less likely to be admitted to the ICU,” Dr. Elkrief noted.
 

Applying the findings to practice

The findings reinforce the importance of adherence to stringent infection control guidelines to protect vulnerable patients, such as those with cancer, Dr. Elkrief said.

In ambulatory settings, this means decreasing in-person visits through increased use of teleconsultations, and for those who need to be seen in person, screening for symptoms or use of polymerase chain reaction testing should be used when resources are available, she said.

“Similar principles apply to chemotherapy treatment units,” Dr. Elkrief said. She added that staff must avoid cross-contamination between COVID and COVID-free zones, and that “dedicated personnel and equipment should be maintained and separate between these two zones.

“Adequate protective personal equipment and strict hand hygiene protocols are also of utmost importance,” Dr. Elkrief said. “The threat of COVID-19 is not behind us, and so we continue to enforce these strategies to protect our patients.”

Session moderator Gypsyamber D’Souza, PhD, an infectious disease epidemiologist at Johns Hopkins University in Baltimore, raised the question of whether the high nosocomial infection and death rate in this study was related to patients having more severe disease because of underlying comorbidities.

Dr. Elkrief explained that the overall mortality rate was indeed higher than the 13% reported in other studies, and it may reflect an overrepresentation of hospitalized or more severely ill patients in the cohort.

However, the investigators made every effort to include all patients with both cancer and COVID-19 by using systematic screening of inpatient and outpatients lists and registries.

Further, the multivariate analysis included both inpatients and outpatients and adjusted for known negative prognostic factors for COVID-19 outcomes. These included increasing age, poor performance status, and different comorbidities.

The finding that nosocomial infection was an independent predictor of death “pushed us to look at nosocomial infection as a new independent risk factor,” Dr. Elkrief said.

Dr. Elkrief reported grant support from AstraZeneca. Dr. D’Souza did not report any disclosures.

[email protected]

SOURCE: Elkrief A et al. AACR: COVID and Cancer, Abstract S12-01.

Systemic bevacizumab is safe and highly effective for the management of chronic bleeding and anemia in patients with hereditary hemorrhagic telangiectasia (HHT), according to findings from an international observational study.

In 238 patients from 12 international centers who were treated with bevacizumab for a median of 12 months, mean hemoglobin levels increased by 3.2 g/dL (mean pre- and posttreatment levels, 8.6 vs. 11.8 g/dL), and epistaxis severity scores (ESS) decreased by a mean of 3.4 points (pre- and posttreatment scores, 6.8 vs. 3.4 points), Hanny Al-Samkari, MD, reported at the International Society on Thrombosis and Haemostasis virtual congress.

As established in prior studies, the minimal clinically important difference in the ESS, a well-validated 10-point bleeding score in HHT, is 0.71 points; the mean reduction seen in this study was 4.75 times that, noted Dr. Al-Samkari, a clinical investigator and hematologist at Massachusetts General Hospital, Boston.

Further, the median number of red blood cell units transfused during the first year of treatment decreased by 82%, compared with the 6 months prior to treatment (9.0 vs. 0 units), and median iron infusions decreased by 70% during the same period (8.0 vs. 2.0 infusions), he said, adding that these improvements occurred within the first 6 months of treatment and were maintained through 12 months.

Study subjects were adults with a mean age of 63 years who were treated with systemic bevacizumab, a vascular endothelial growth factor receptor (VEGF) monoclonal antibody, between 2011 and 2019 for the primary indication of moderate to severe chronic HHT-related bleeding and anemia. Treatment involved four to eight induction infusions – typically at a dose of 5 mg/kg and given 4 weeks apart – followed by bevacizumab maintenance, either as continuous or scheduled maintenance at 4-, 8-, or 12-week intervals regardless of symptoms, or on an as-needed basis, with 2-6 infusions for signs or symptoms of rebleeding.

Patients received a median of 11 infusions, and 181 received maintenance treatment, including continuous or scheduled maintenance in 136 patients and as-needed maintenance in 45 patients, Dr. Al-Samkari said.

The treatment was generally well tolerated; the most common adverse events during 344 patient-years of treatment were hypertension, fatigue, and proteinuria. No fatal treatment-related adverse events occurred, and no increase in adverse events occurred with longer treatment, he noted

Venous thromboembolism occurred in five patients, including two patients who had “provoked events immediately following joint replacement surgery,” he said.

Thirteen patients (5%) discontinued treatment – 11 for inadequate effect and 2 for side effects, he noted.

Subgroup analyses showed that outcomes were similar regardless of underlying pathogenic mutation, but among those receiving bevacizumab maintenance, the continuous approach, compared with as-needed maintenance, was associated with greater improvement in hemoglobin (10.8 vs. 12.3 g/dL) and ESS (mean, 4.96 vs. 2.88) during months 7-12 of treatment, “which is the time most reflective of the effect of maintenance,” he said.

HHT, also known as Osler-Weber-Rendu disease, is a “rare, genetic, progressive, multisystem bleeding disorder resulting from disorder of angiogenesis,” Dr. Al-Samkari explained, adding that the condition is characterized by severe, recurrent epistaxis and chronic gastrointestinal bleeding.

“Bleeding frequently leads to iron deficiency anemia, which may be severe and dependent on regular iron infusions and/or blood transfusions,” he said.

Though rare, it is the second most common bleeding disorder worldwide, with a prevalence about twice that of hemophilia A and six times that of hemophilia B.

“Despite this, it has no FDA-approved therapies,” he said. “The current mainstay of care is surgical or procedural local hemostatic intervention – which is usually temporizing – and hematological support in the form of blood and iron.”

However, given that the underlying genetic defects that cause HHT result in elevations in VEGF, targeting VEGF with existing antiangiogenic agents is a promising approach.

In fact, several centers have been using bevacizumab for several years as an off-label treatment for bleeding in this setting, and while scattered case reports and small case series suggest efficacy, no “large or definitive studies” have been conducted, and safety hasn’t been carefully evaluated, he said.

To that end, the International Hereditary Hemorrhagic Telangiectasia Intravenous Bevacizumab Investigative Team (InHIBIT) was formed. The current report, “the largest study of antiangiogenic therapy to date in HHT,” represents the results of the InHIBIT-Bleed study, the first completed by the team. The next study will address bevacizumab for the treatment of high-output cardiac failure in HHT (the InHIBIT-HF study), Dr. Al-Samkari said.

Though limited by its retrospective nature and lack of a unified treatment protocol, the InHIBIT-Bleed study provides important information and is strengthened by the large cohort size, especially given that HHT is a rare disease, and by other factors, such as the substantial number of patient-years of treatment.

“Bevacizumab was effective in the management of severe HHT-related epistaxis and GI bleeds,” he said, noting the “significant and striking improvements” on a variety of measures.

Questioned about the durability of treatment effects after treatment discontinuation, Dr. Al-Samkari said outcomes are variable, “highly patient dependent,” and “something that we really need to investigate thoroughly.”

As for the potential for anti-VEGF therapy for bleeding in certain non-HHT settings, session moderator Michael Makris, MD, professor of haemostasis and thrombosis at the University of Sheffield, England, said the possibilities are intriguing.

“I work with lots of patients with von Willebrand disease and angiodysplasia,” he said, adding that angiodysplasia-related bleeding in type 2A von Willebrand disease is a major issue.

Dr. Al-Samkari agreed that the possibility is worth exploring.

“We have looked at this in a small number of patients, and the jury is still out,” he said. “But there is a publication in Gastroenterology – Albitar et al. – that evaluated bevacizumab in patients without HHT [who had] angiodysplasias from other causes – not specifically in type 2 von Willebrand syndrome ... and did find that it was effective at causing the angiodysplasias to regress, hemoglobin to improve.

“So the non-HHT use of this agent is certainly an important one [and] we do have retrospective evidence in a small group of patients who don’t have HHT, who do have angiodysplasias and bleeding, that it may be effective as well.”

Dr. Al-Samkari reported receiving research support and/or consulting fees from Agios, Amgen, and Dova.

[email protected]

SOURCE: Al-Samkari H et al. ISTH 2020, Abstract OC 09.2.

Systemic bevacizumab is safe and highly effective for the management of chronic bleeding and anemia in patients with hereditary hemorrhagic telangiectasia (HHT), according to findings from an international observational study.

In 238 patients from 12 international centers who were treated with bevacizumab for a median of 12 months, mean hemoglobin levels increased by 3.2 g/dL (mean pre- and posttreatment levels, 8.6 vs. 11.8 g/dL), and epistaxis severity scores (ESS) decreased by a mean of 3.4 points (pre- and posttreatment scores, 6.8 vs. 3.4 points), Hanny Al-Samkari, MD, reported at the International Society on Thrombosis and Haemostasis virtual congress.

As established in prior studies, the minimal clinically important difference in the ESS, a well-validated 10-point bleeding score in HHT, is 0.71 points; the mean reduction seen in this study was 4.75 times that, noted Dr. Al-Samkari, a clinical investigator and hematologist at Massachusetts General Hospital, Boston.

Further, the median number of red blood cell units transfused during the first year of treatment decreased by 82%, compared with the 6 months prior to treatment (9.0 vs. 0 units), and median iron infusions decreased by 70% during the same period (8.0 vs. 2.0 infusions), he said, adding that these improvements occurred within the first 6 months of treatment and were maintained through 12 months.

Study subjects were adults with a mean age of 63 years who were treated with systemic bevacizumab, a vascular endothelial growth factor receptor (VEGF) monoclonal antibody, between 2011 and 2019 for the primary indication of moderate to severe chronic HHT-related bleeding and anemia. Treatment involved four to eight induction infusions – typically at a dose of 5 mg/kg and given 4 weeks apart – followed by bevacizumab maintenance, either as continuous or scheduled maintenance at 4-, 8-, or 12-week intervals regardless of symptoms, or on an as-needed basis, with 2-6 infusions for signs or symptoms of rebleeding.

Patients received a median of 11 infusions, and 181 received maintenance treatment, including continuous or scheduled maintenance in 136 patients and as-needed maintenance in 45 patients, Dr. Al-Samkari said.

The treatment was generally well tolerated; the most common adverse events during 344 patient-years of treatment were hypertension, fatigue, and proteinuria. No fatal treatment-related adverse events occurred, and no increase in adverse events occurred with longer treatment, he noted

Venous thromboembolism occurred in five patients, including two patients who had “provoked events immediately following joint replacement surgery,” he said.

Thirteen patients (5%) discontinued treatment – 11 for inadequate effect and 2 for side effects, he noted.

Subgroup analyses showed that outcomes were similar regardless of underlying pathogenic mutation, but among those receiving bevacizumab maintenance, the continuous approach, compared with as-needed maintenance, was associated with greater improvement in hemoglobin (10.8 vs. 12.3 g/dL) and ESS (mean, 4.96 vs. 2.88) during months 7-12 of treatment, “which is the time most reflective of the effect of maintenance,” he said.

HHT, also known as Osler-Weber-Rendu disease, is a “rare, genetic, progressive, multisystem bleeding disorder resulting from disorder of angiogenesis,” Dr. Al-Samkari explained, adding that the condition is characterized by severe, recurrent epistaxis and chronic gastrointestinal bleeding.

“Bleeding frequently leads to iron deficiency anemia, which may be severe and dependent on regular iron infusions and/or blood transfusions,” he said.

Though rare, it is the second most common bleeding disorder worldwide, with a prevalence about twice that of hemophilia A and six times that of hemophilia B.

“Despite this, it has no FDA-approved therapies,” he said. “The current mainstay of care is surgical or procedural local hemostatic intervention – which is usually temporizing – and hematological support in the form of blood and iron.”

However, given that the underlying genetic defects that cause HHT result in elevations in VEGF, targeting VEGF with existing antiangiogenic agents is a promising approach.

In fact, several centers have been using bevacizumab for several years as an off-label treatment for bleeding in this setting, and while scattered case reports and small case series suggest efficacy, no “large or definitive studies” have been conducted, and safety hasn’t been carefully evaluated, he said.

To that end, the International Hereditary Hemorrhagic Telangiectasia Intravenous Bevacizumab Investigative Team (InHIBIT) was formed. The current report, “the largest study of antiangiogenic therapy to date in HHT,” represents the results of the InHIBIT-Bleed study, the first completed by the team. The next study will address bevacizumab for the treatment of high-output cardiac failure in HHT (the InHIBIT-HF study), Dr. Al-Samkari said.

Though limited by its retrospective nature and lack of a unified treatment protocol, the InHIBIT-Bleed study provides important information and is strengthened by the large cohort size, especially given that HHT is a rare disease, and by other factors, such as the substantial number of patient-years of treatment.

“Bevacizumab was effective in the management of severe HHT-related epistaxis and GI bleeds,” he said, noting the “significant and striking improvements” on a variety of measures.

Questioned about the durability of treatment effects after treatment discontinuation, Dr. Al-Samkari said outcomes are variable, “highly patient dependent,” and “something that we really need to investigate thoroughly.”

As for the potential for anti-VEGF therapy for bleeding in certain non-HHT settings, session moderator Michael Makris, MD, professor of haemostasis and thrombosis at the University of Sheffield, England, said the possibilities are intriguing.

“I work with lots of patients with von Willebrand disease and angiodysplasia,” he said, adding that angiodysplasia-related bleeding in type 2A von Willebrand disease is a major issue.

Dr. Al-Samkari agreed that the possibility is worth exploring.

“We have looked at this in a small number of patients, and the jury is still out,” he said. “But there is a publication in Gastroenterology – Albitar et al. – that evaluated bevacizumab in patients without HHT [who had] angiodysplasias from other causes – not specifically in type 2 von Willebrand syndrome ... and did find that it was effective at causing the angiodysplasias to regress, hemoglobin to improve.

“So the non-HHT use of this agent is certainly an important one [and] we do have retrospective evidence in a small group of patients who don’t have HHT, who do have angiodysplasias and bleeding, that it may be effective as well.”

Dr. Al-Samkari reported receiving research support and/or consulting fees from Agios, Amgen, and Dova.

[email protected]

SOURCE: Al-Samkari H et al. ISTH 2020, Abstract OC 09.2.

Systemic bevacizumab is safe and highly effective for the management of chronic bleeding and anemia in patients with hereditary hemorrhagic telangiectasia (HHT), according to findings from an international observational study.

In 238 patients from 12 international centers who were treated with bevacizumab for a median of 12 months, mean hemoglobin levels increased by 3.2 g/dL (mean pre- and posttreatment levels, 8.6 vs. 11.8 g/dL), and epistaxis severity scores (ESS) decreased by a mean of 3.4 points (pre- and posttreatment scores, 6.8 vs. 3.4 points), Hanny Al-Samkari, MD, reported at the International Society on Thrombosis and Haemostasis virtual congress.

As established in prior studies, the minimal clinically important difference in the ESS, a well-validated 10-point bleeding score in HHT, is 0.71 points; the mean reduction seen in this study was 4.75 times that, noted Dr. Al-Samkari, a clinical investigator and hematologist at Massachusetts General Hospital, Boston.

Further, the median number of red blood cell units transfused during the first year of treatment decreased by 82%, compared with the 6 months prior to treatment (9.0 vs. 0 units), and median iron infusions decreased by 70% during the same period (8.0 vs. 2.0 infusions), he said, adding that these improvements occurred within the first 6 months of treatment and were maintained through 12 months.

Study subjects were adults with a mean age of 63 years who were treated with systemic bevacizumab, a vascular endothelial growth factor receptor (VEGF) monoclonal antibody, between 2011 and 2019 for the primary indication of moderate to severe chronic HHT-related bleeding and anemia. Treatment involved four to eight induction infusions – typically at a dose of 5 mg/kg and given 4 weeks apart – followed by bevacizumab maintenance, either as continuous or scheduled maintenance at 4-, 8-, or 12-week intervals regardless of symptoms, or on an as-needed basis, with 2-6 infusions for signs or symptoms of rebleeding.

Patients received a median of 11 infusions, and 181 received maintenance treatment, including continuous or scheduled maintenance in 136 patients and as-needed maintenance in 45 patients, Dr. Al-Samkari said.

The treatment was generally well tolerated; the most common adverse events during 344 patient-years of treatment were hypertension, fatigue, and proteinuria. No fatal treatment-related adverse events occurred, and no increase in adverse events occurred with longer treatment, he noted

Venous thromboembolism occurred in five patients, including two patients who had “provoked events immediately following joint replacement surgery,” he said.

Thirteen patients (5%) discontinued treatment – 11 for inadequate effect and 2 for side effects, he noted.

Subgroup analyses showed that outcomes were similar regardless of underlying pathogenic mutation, but among those receiving bevacizumab maintenance, the continuous approach, compared with as-needed maintenance, was associated with greater improvement in hemoglobin (10.8 vs. 12.3 g/dL) and ESS (mean, 4.96 vs. 2.88) during months 7-12 of treatment, “which is the time most reflective of the effect of maintenance,” he said.

HHT, also known as Osler-Weber-Rendu disease, is a “rare, genetic, progressive, multisystem bleeding disorder resulting from disorder of angiogenesis,” Dr. Al-Samkari explained, adding that the condition is characterized by severe, recurrent epistaxis and chronic gastrointestinal bleeding.

“Bleeding frequently leads to iron deficiency anemia, which may be severe and dependent on regular iron infusions and/or blood transfusions,” he said.

Though rare, it is the second most common bleeding disorder worldwide, with a prevalence about twice that of hemophilia A and six times that of hemophilia B.

“Despite this, it has no FDA-approved therapies,” he said. “The current mainstay of care is surgical or procedural local hemostatic intervention – which is usually temporizing – and hematological support in the form of blood and iron.”

However, given that the underlying genetic defects that cause HHT result in elevations in VEGF, targeting VEGF with existing antiangiogenic agents is a promising approach.

In fact, several centers have been using bevacizumab for several years as an off-label treatment for bleeding in this setting, and while scattered case reports and small case series suggest efficacy, no “large or definitive studies” have been conducted, and safety hasn’t been carefully evaluated, he said.

To that end, the International Hereditary Hemorrhagic Telangiectasia Intravenous Bevacizumab Investigative Team (InHIBIT) was formed. The current report, “the largest study of antiangiogenic therapy to date in HHT,” represents the results of the InHIBIT-Bleed study, the first completed by the team. The next study will address bevacizumab for the treatment of high-output cardiac failure in HHT (the InHIBIT-HF study), Dr. Al-Samkari said.

Though limited by its retrospective nature and lack of a unified treatment protocol, the InHIBIT-Bleed study provides important information and is strengthened by the large cohort size, especially given that HHT is a rare disease, and by other factors, such as the substantial number of patient-years of treatment.

“Bevacizumab was effective in the management of severe HHT-related epistaxis and GI bleeds,” he said, noting the “significant and striking improvements” on a variety of measures.

Questioned about the durability of treatment effects after treatment discontinuation, Dr. Al-Samkari said outcomes are variable, “highly patient dependent,” and “something that we really need to investigate thoroughly.”

As for the potential for anti-VEGF therapy for bleeding in certain non-HHT settings, session moderator Michael Makris, MD, professor of haemostasis and thrombosis at the University of Sheffield, England, said the possibilities are intriguing.

“I work with lots of patients with von Willebrand disease and angiodysplasia,” he said, adding that angiodysplasia-related bleeding in type 2A von Willebrand disease is a major issue.

Dr. Al-Samkari agreed that the possibility is worth exploring.

“We have looked at this in a small number of patients, and the jury is still out,” he said. “But there is a publication in Gastroenterology – Albitar et al. – that evaluated bevacizumab in patients without HHT [who had] angiodysplasias from other causes – not specifically in type 2 von Willebrand syndrome ... and did find that it was effective at causing the angiodysplasias to regress, hemoglobin to improve.

“So the non-HHT use of this agent is certainly an important one [and] we do have retrospective evidence in a small group of patients who don’t have HHT, who do have angiodysplasias and bleeding, that it may be effective as well.”

Dr. Al-Samkari reported receiving research support and/or consulting fees from Agios, Amgen, and Dova.

[email protected]

SOURCE: Al-Samkari H et al. ISTH 2020, Abstract OC 09.2.

Non-Hispanic black patients with cancer and patients with hematologic malignancies have a significantly increased risk of death if they develop COVID-19, according to the latest data from the COVID-19 and Cancer Consortium (CCC19) registry.

Initial results from the CCC19 registry were reported as part of the American Society of Clinical Oncology (ASCO) virtual scientific program and published in The Lancet (Lancet. 2020 Jun 20;395[10241]:1907-18).

The latest data were presented at the AACR virtual meeting: COVID-19 and Cancer by Brian I. Rini, MD, of Vanderbilt University, Nashville, Tenn. They were simultaneously published in Cancer Discovery (Cancer Discov. 2020 Jul 22;CD-20-0941).

The CCC19 registry was launched in March by a few institutions as part of “a grassroots idea ... to collect granular data regarding cancer patients and their outcomes with COVID,” Dr. Rini said.

Within a few months of its inception, the registry had partnered with more than 100 institutions worldwide and accrued data from more than 2,000 patients.

The reports in The Lancet and at ASCO included outcomes for the first 928 patients and showed a 13% mortality rate as well as a fivefold increase in the risk of 30-day mortality among patients with COVID-19 and progressing cancer.

The data also showed an increased mortality risk among older patients, men, former smokers, those with poor performance status, those with multiple comorbidities, and those treated with hydroxychloroquine and azithromycin.

The latest data

The CCC19 registry has grown to include 114 sites worldwide, including major comprehensive cancer centers and community sites. As of June 26, there were 2,749 patients enrolled.

Since the last data were reported, the mortality rate increased from 13% to 16% (versus 5% globally). In addition, the increased mortality risk among non-Hispanic black patients and patients with hematologic malignancies reached statistical significance, Dr. Rini said. He noted that the increase in mortality rate was largely attributable to improved follow-up.

Mechanical ventilation was required in 12% of patients, ICU admission was required in 16%, oxygen was required in 45%, and hospitalization was required in 60%. The composite outcome of death, severe illness requiring hospitalization, ICU admission, or mechanical ventilation was reached in 29% of patients, Dr. Rini said.

Mortality rates across cancer types ranged from 3% to 26%, with thyroid and breast cancer patients having the lowest rates (3% and 8%, respectively), and with lymphoma and lung cancer patients having the highest (22% and 26%, respectively), Dr. Rini said.

He noted that the TERAVOLT registry, a COVID-19 registry for patients with thoracic cancers, also showed a very high mortality rate in this subgroup of patients.

Results from TERAVOLT were reported at the AACR virtual meeting I, presented at ASCO, and published in The Lancet (Lancet Oncol. 2020 Jul;21[7]:914-22). The most recent results showed a mortality rate of nearly 36% and reinforce the high mortality rate seen in lung cancer patients in CCC19, Dr. Rini said.
 

Increased mortality risk

After adjustment for several demographic and disease characteristics, the updated CCC19 data showed a significantly increased risk of mortality among:

• Older patients (adjusted odds ratio [aOR] per decade of age, 1.52).
• Men (aOR, 1.43).
• Current or former smokers vs. never smokers (aOR, 1.28).
• Patients with Eastern Cooperative Oncology Group performance scores of 1 vs. 0 (aOR of 1.80) or 2 vs. 0 (aOR, 4.22).
• Stable cancer vs. remission (aOR, 1.47).
• Progressive cancer vs. remission (aOR, 2.96).
• Non-Hispanic Black vs. White patients (aOR, 1.56).
• Hematologic malignancies vs. solid tumors (aOR, 1.80).

“Importantly, there were some factors that did not reach statistical significance,” Dr. Rini said. These include obesity (aOR, 1.23), recent surgery (aOR, 1.05), receipt of cytotoxic chemotherapy vs. no chemotherapy (aOR, 1.14), and receipt of noncytotoxic chemotherapy vs. no chemotherapy (aOR, 0.75).

“I think this provides some reassurance that cancer care can and should continue for these patients,” Dr. Rini said.

He noted, however, that in TERAVOLT, chemotherapy with or without other treatment was a risk factor for mortality in lung cancer patients when compared with no chemotherapy (OR, 1.71) and when compared with immunotherapy or targeted therapy (OR, 1.64).
 

NCCAPS and other registries

Dr. Rini discussed a number of registries looking at outcomes in COVID-19 patients with cancer, and he said the findings to date appear to confirm a higher mortality rate among cancer patients, particularly those with lung cancer.

Several factors are emerging that appear to be related to risk, including both cancer-related and non–cancer-related factors, he added.

The ongoing prospective National Cancer Institute COVID-19 in Cancer Patients Study (NCCAPS) “will provide much needed longitudinal data and, importantly, biospecimen collection in a large cohort of patients who have active cancer and are receiving treatment, said Dr. Rini, who is the study’s protocol chair. NCCAPS is a natural history study in that population, he said.

The planned accrual is about 2,000 patients who will be followed for up to 2 years for data collection, imaging scans, and research specimens.

The use of specimens is “a unique and special part of this study,” Dr. Rini said, explaining that the specimens will be used to look for development of antibodies over time, to describe the trajectory of cytokine abnormalities – especially in patients with more acute inpatient courses – to perform DNA-based genome-wide association studies, and to assess coagulation parameters.

NCCAPS is activated at 546 sties, 10 patients were enrolled as of June 21, and rapid accrual is expected over the next several months, he said.

Gypsyamber D’Souza, PhD, session moderator and an infectious disease epidemiologist at Johns Hopkins University in Baltimore, acknowledged the challenge that registry administrators face when trying to balance the need to get data out against the desire to ask the right questions and to have the right comparison groups, stratification, and analyses, especially amid a crisis like the COVID-19 pandemic.

Dr. Rini said it has indeed been a bit of a struggle with CCC19 to determine what information should be published and when, and what constitutes an important update.

“It’s been a learning experience, and frankly, I think we’re still learning,” he said. “This has been such a unique time in terms of a rush to get data out, balanced against making sure that there’s quality data and that you’re actually answering important questions.”

In fact, a number of ongoing registries “should start to produce great data [that will be presented] at upcoming big conferences,” Dr. Rini said. He added that those data “will help piece together different important aspects of this and different hypotheses, and hopefully complement the clinical data that’s starting to come out.”

The CCC19 registry is sponsored by Vanderbilt-Ingram Cancer Center. Dr. Rini disclosed relationships with Pfizer, Merck, Genentech/Roche, Aveo, AstraZeneca, Bristol Myers Squibb, Exelixis, Synthorx, Peloton, Compugen, Corvus, Surface Oncology, 3DMedicines, Aravive, Alkermes, Arrowhead, and PTC Therapeutics. Dr. D’Souza did not disclose any conflicts.

[email protected]

SOURCE: Rini BI. AACR: COVID-19 and Cancer. Abstract IA26.

Non-Hispanic black patients with cancer and patients with hematologic malignancies have a significantly increased risk of death if they develop COVID-19, according to the latest data from the COVID-19 and Cancer Consortium (CCC19) registry.

Initial results from the CCC19 registry were reported as part of the American Society of Clinical Oncology (ASCO) virtual scientific program and published in The Lancet (Lancet. 2020 Jun 20;395[10241]:1907-18).

The latest data were presented at the AACR virtual meeting: COVID-19 and Cancer by Brian I. Rini, MD, of Vanderbilt University, Nashville, Tenn. They were simultaneously published in Cancer Discovery (Cancer Discov. 2020 Jul 22;CD-20-0941).

The CCC19 registry was launched in March by a few institutions as part of “a grassroots idea ... to collect granular data regarding cancer patients and their outcomes with COVID,” Dr. Rini said.

Within a few months of its inception, the registry had partnered with more than 100 institutions worldwide and accrued data from more than 2,000 patients.

The reports in The Lancet and at ASCO included outcomes for the first 928 patients and showed a 13% mortality rate as well as a fivefold increase in the risk of 30-day mortality among patients with COVID-19 and progressing cancer.

The data also showed an increased mortality risk among older patients, men, former smokers, those with poor performance status, those with multiple comorbidities, and those treated with hydroxychloroquine and azithromycin.

The latest data

The CCC19 registry has grown to include 114 sites worldwide, including major comprehensive cancer centers and community sites. As of June 26, there were 2,749 patients enrolled.

Since the last data were reported, the mortality rate increased from 13% to 16% (versus 5% globally). In addition, the increased mortality risk among non-Hispanic black patients and patients with hematologic malignancies reached statistical significance, Dr. Rini said. He noted that the increase in mortality rate was largely attributable to improved follow-up.

Mechanical ventilation was required in 12% of patients, ICU admission was required in 16%, oxygen was required in 45%, and hospitalization was required in 60%. The composite outcome of death, severe illness requiring hospitalization, ICU admission, or mechanical ventilation was reached in 29% of patients, Dr. Rini said.

Mortality rates across cancer types ranged from 3% to 26%, with thyroid and breast cancer patients having the lowest rates (3% and 8%, respectively), and with lymphoma and lung cancer patients having the highest (22% and 26%, respectively), Dr. Rini said.

He noted that the TERAVOLT registry, a COVID-19 registry for patients with thoracic cancers, also showed a very high mortality rate in this subgroup of patients.

Results from TERAVOLT were reported at the AACR virtual meeting I, presented at ASCO, and published in The Lancet (Lancet Oncol. 2020 Jul;21[7]:914-22). The most recent results showed a mortality rate of nearly 36% and reinforce the high mortality rate seen in lung cancer patients in CCC19, Dr. Rini said.
 

Increased mortality risk

After adjustment for several demographic and disease characteristics, the updated CCC19 data showed a significantly increased risk of mortality among:

• Older patients (adjusted odds ratio [aOR] per decade of age, 1.52).
• Men (aOR, 1.43).
• Current or former smokers vs. never smokers (aOR, 1.28).
• Patients with Eastern Cooperative Oncology Group performance scores of 1 vs. 0 (aOR of 1.80) or 2 vs. 0 (aOR, 4.22).
• Stable cancer vs. remission (aOR, 1.47).
• Progressive cancer vs. remission (aOR, 2.96).
• Non-Hispanic Black vs. White patients (aOR, 1.56).
• Hematologic malignancies vs. solid tumors (aOR, 1.80).

“Importantly, there were some factors that did not reach statistical significance,” Dr. Rini said. These include obesity (aOR, 1.23), recent surgery (aOR, 1.05), receipt of cytotoxic chemotherapy vs. no chemotherapy (aOR, 1.14), and receipt of noncytotoxic chemotherapy vs. no chemotherapy (aOR, 0.75).

“I think this provides some reassurance that cancer care can and should continue for these patients,” Dr. Rini said.

He noted, however, that in TERAVOLT, chemotherapy with or without other treatment was a risk factor for mortality in lung cancer patients when compared with no chemotherapy (OR, 1.71) and when compared with immunotherapy or targeted therapy (OR, 1.64).
 

NCCAPS and other registries

Dr. Rini discussed a number of registries looking at outcomes in COVID-19 patients with cancer, and he said the findings to date appear to confirm a higher mortality rate among cancer patients, particularly those with lung cancer.

Several factors are emerging that appear to be related to risk, including both cancer-related and non–cancer-related factors, he added.

The ongoing prospective National Cancer Institute COVID-19 in Cancer Patients Study (NCCAPS) “will provide much needed longitudinal data and, importantly, biospecimen collection in a large cohort of patients who have active cancer and are receiving treatment, said Dr. Rini, who is the study’s protocol chair. NCCAPS is a natural history study in that population, he said.

The planned accrual is about 2,000 patients who will be followed for up to 2 years for data collection, imaging scans, and research specimens.

The use of specimens is “a unique and special part of this study,” Dr. Rini said, explaining that the specimens will be used to look for development of antibodies over time, to describe the trajectory of cytokine abnormalities – especially in patients with more acute inpatient courses – to perform DNA-based genome-wide association studies, and to assess coagulation parameters.

NCCAPS is activated at 546 sties, 10 patients were enrolled as of June 21, and rapid accrual is expected over the next several months, he said.

Gypsyamber D’Souza, PhD, session moderator and an infectious disease epidemiologist at Johns Hopkins University in Baltimore, acknowledged the challenge that registry administrators face when trying to balance the need to get data out against the desire to ask the right questions and to have the right comparison groups, stratification, and analyses, especially amid a crisis like the COVID-19 pandemic.

Dr. Rini said it has indeed been a bit of a struggle with CCC19 to determine what information should be published and when, and what constitutes an important update.

“It’s been a learning experience, and frankly, I think we’re still learning,” he said. “This has been such a unique time in terms of a rush to get data out, balanced against making sure that there’s quality data and that you’re actually answering important questions.”

In fact, a number of ongoing registries “should start to produce great data [that will be presented] at upcoming big conferences,” Dr. Rini said. He added that those data “will help piece together different important aspects of this and different hypotheses, and hopefully complement the clinical data that’s starting to come out.”

The CCC19 registry is sponsored by Vanderbilt-Ingram Cancer Center. Dr. Rini disclosed relationships with Pfizer, Merck, Genentech/Roche, Aveo, AstraZeneca, Bristol Myers Squibb, Exelixis, Synthorx, Peloton, Compugen, Corvus, Surface Oncology, 3DMedicines, Aravive, Alkermes, Arrowhead, and PTC Therapeutics. Dr. D’Souza did not disclose any conflicts.

[email protected]

SOURCE: Rini BI. AACR: COVID-19 and Cancer. Abstract IA26.

Non-Hispanic black patients with cancer and patients with hematologic malignancies have a significantly increased risk of death if they develop COVID-19, according to the latest data from the COVID-19 and Cancer Consortium (CCC19) registry.

Initial results from the CCC19 registry were reported as part of the American Society of Clinical Oncology (ASCO) virtual scientific program and published in The Lancet (Lancet. 2020 Jun 20;395[10241]:1907-18).

The latest data were presented at the AACR virtual meeting: COVID-19 and Cancer by Brian I. Rini, MD, of Vanderbilt University, Nashville, Tenn. They were simultaneously published in Cancer Discovery (Cancer Discov. 2020 Jul 22;CD-20-0941).

The CCC19 registry was launched in March by a few institutions as part of “a grassroots idea ... to collect granular data regarding cancer patients and their outcomes with COVID,” Dr. Rini said.

Within a few months of its inception, the registry had partnered with more than 100 institutions worldwide and accrued data from more than 2,000 patients.

The reports in The Lancet and at ASCO included outcomes for the first 928 patients and showed a 13% mortality rate as well as a fivefold increase in the risk of 30-day mortality among patients with COVID-19 and progressing cancer.

The data also showed an increased mortality risk among older patients, men, former smokers, those with poor performance status, those with multiple comorbidities, and those treated with hydroxychloroquine and azithromycin.

The latest data

The CCC19 registry has grown to include 114 sites worldwide, including major comprehensive cancer centers and community sites. As of June 26, there were 2,749 patients enrolled.

Since the last data were reported, the mortality rate increased from 13% to 16% (versus 5% globally). In addition, the increased mortality risk among non-Hispanic black patients and patients with hematologic malignancies reached statistical significance, Dr. Rini said. He noted that the increase in mortality rate was largely attributable to improved follow-up.

Mechanical ventilation was required in 12% of patients, ICU admission was required in 16%, oxygen was required in 45%, and hospitalization was required in 60%. The composite outcome of death, severe illness requiring hospitalization, ICU admission, or mechanical ventilation was reached in 29% of patients, Dr. Rini said.

Mortality rates across cancer types ranged from 3% to 26%, with thyroid and breast cancer patients having the lowest rates (3% and 8%, respectively), and with lymphoma and lung cancer patients having the highest (22% and 26%, respectively), Dr. Rini said.

He noted that the TERAVOLT registry, a COVID-19 registry for patients with thoracic cancers, also showed a very high mortality rate in this subgroup of patients.

Results from TERAVOLT were reported at the AACR virtual meeting I, presented at ASCO, and published in The Lancet (Lancet Oncol. 2020 Jul;21[7]:914-22). The most recent results showed a mortality rate of nearly 36% and reinforce the high mortality rate seen in lung cancer patients in CCC19, Dr. Rini said.
 

Increased mortality risk

After adjustment for several demographic and disease characteristics, the updated CCC19 data showed a significantly increased risk of mortality among:

• Older patients (adjusted odds ratio [aOR] per decade of age, 1.52).
• Men (aOR, 1.43).
• Current or former smokers vs. never smokers (aOR, 1.28).
• Patients with Eastern Cooperative Oncology Group performance scores of 1 vs. 0 (aOR of 1.80) or 2 vs. 0 (aOR, 4.22).
• Stable cancer vs. remission (aOR, 1.47).
• Progressive cancer vs. remission (aOR, 2.96).
• Non-Hispanic Black vs. White patients (aOR, 1.56).
• Hematologic malignancies vs. solid tumors (aOR, 1.80).

“Importantly, there were some factors that did not reach statistical significance,” Dr. Rini said. These include obesity (aOR, 1.23), recent surgery (aOR, 1.05), receipt of cytotoxic chemotherapy vs. no chemotherapy (aOR, 1.14), and receipt of noncytotoxic chemotherapy vs. no chemotherapy (aOR, 0.75).

“I think this provides some reassurance that cancer care can and should continue for these patients,” Dr. Rini said.

He noted, however, that in TERAVOLT, chemotherapy with or without other treatment was a risk factor for mortality in lung cancer patients when compared with no chemotherapy (OR, 1.71) and when compared with immunotherapy or targeted therapy (OR, 1.64).
 

NCCAPS and other registries

Dr. Rini discussed a number of registries looking at outcomes in COVID-19 patients with cancer, and he said the findings to date appear to confirm a higher mortality rate among cancer patients, particularly those with lung cancer.

Several factors are emerging that appear to be related to risk, including both cancer-related and non–cancer-related factors, he added.

The ongoing prospective National Cancer Institute COVID-19 in Cancer Patients Study (NCCAPS) “will provide much needed longitudinal data and, importantly, biospecimen collection in a large cohort of patients who have active cancer and are receiving treatment, said Dr. Rini, who is the study’s protocol chair. NCCAPS is a natural history study in that population, he said.

The planned accrual is about 2,000 patients who will be followed for up to 2 years for data collection, imaging scans, and research specimens.

The use of specimens is “a unique and special part of this study,” Dr. Rini said, explaining that the specimens will be used to look for development of antibodies over time, to describe the trajectory of cytokine abnormalities – especially in patients with more acute inpatient courses – to perform DNA-based genome-wide association studies, and to assess coagulation parameters.

NCCAPS is activated at 546 sties, 10 patients were enrolled as of June 21, and rapid accrual is expected over the next several months, he said.

Gypsyamber D’Souza, PhD, session moderator and an infectious disease epidemiologist at Johns Hopkins University in Baltimore, acknowledged the challenge that registry administrators face when trying to balance the need to get data out against the desire to ask the right questions and to have the right comparison groups, stratification, and analyses, especially amid a crisis like the COVID-19 pandemic.

Dr. Rini said it has indeed been a bit of a struggle with CCC19 to determine what information should be published and when, and what constitutes an important update.

“It’s been a learning experience, and frankly, I think we’re still learning,” he said. “This has been such a unique time in terms of a rush to get data out, balanced against making sure that there’s quality data and that you’re actually answering important questions.”

In fact, a number of ongoing registries “should start to produce great data [that will be presented] at upcoming big conferences,” Dr. Rini said. He added that those data “will help piece together different important aspects of this and different hypotheses, and hopefully complement the clinical data that’s starting to come out.”

The CCC19 registry is sponsored by Vanderbilt-Ingram Cancer Center. Dr. Rini disclosed relationships with Pfizer, Merck, Genentech/Roche, Aveo, AstraZeneca, Bristol Myers Squibb, Exelixis, Synthorx, Peloton, Compugen, Corvus, Surface Oncology, 3DMedicines, Aravive, Alkermes, Arrowhead, and PTC Therapeutics. Dr. D’Souza did not disclose any conflicts.

[email protected]

SOURCE: Rini BI. AACR: COVID-19 and Cancer. Abstract IA26.

SPK-8011, an investigational adeno-associated virus (AAV)–mediated gene therapy for hemophilia A, provides stable and durable factor VIII expression with no major safety concerns, according to findings at least 2 years after a single treatment in patients from a phase 1/2 trial.

The first 5 of 14 adult men with hemophilia A and who had factor VIII (FVIII) activity of 2% or less before treatment with SPK-8011 (at single doses of either 5 × 10^{11 or 1} × 10¹² vg/kg), showed no development of FVIII inhibitors or evidence of FVIII cellular immune response at 106-142 weeks’ follow-up after vector infusion, according to Lindsey A. George, MD, at the International Society of Thrombosis and Haemostasis 2020 virtual congress.

At follow-up, the two who had received a 5 × 10¹¹ vg/kg dose had FVIII activity of 6.9%-8.4%, and the three in the 1 × 10¹² vg/kg cohort had FVIII activity of 5.2%-19.8%, said Dr. George, of the Children’s Hospital of Philadelphia.

Overall, 12 of the 14 patients in the study had sustained FVIII expression, including 7 of 9 who received the highest SPK-8011 dose of 2 × 10¹² vg/kg. In the 12 with sustained expression, a “remarkable” 91% reduction in the annualized bleeding rate from the year prior to vs. the year after vector infusion was observed, she said.

“Similarly, looking at number of factor infusions before vector infusion relative to the number of factor infusions after vector infusion ... [there was] evidence of remarkable preliminary efficacy,” she added, noting a 96% reduction in factor consumption.

The findings are of note because, while clinical studies of Spark Therapeutic’s SPK-8011 product in hemophilia B and preclinical models in hemophilia A showed promising reductions in bleeds and stable, durable levels of FVIII expression after therapy, the first successful clinical trial of an AAV-mediated gene therapy in hemophilia A – the BioMarin AAV serotype 5 human FVIII-SQ (valoctocogene roxaparvovec) – showed an unexpected decline in FVIII expression at 1, 2, 3, and 4 years.

“This may be particularly relevant in the context of development of multi-serotype AAV neutralizing antibodies (NAb) following AAV vector administration,” Dr. George said, referencing a small study in which she and her colleagues showed long-term persistence of cross-reactive AAV NAb. The findings of that study, which is currently in press in Molecular Therapy, “suggest that repeat AAV vector infusion is unlikely to be possible with current methods.”

Initial results from the SPK-8011 study were presented at the 2018 American Society of Hematology annual meeting. No major safety issues have emerged since those data were presented at ASH; no deaths have occurred, and none of the patients developed FVIII inhibitors.

Treatment-related adverse events were limited to an infusion reaction in one patient, which resolved completely, and liver enzyme elevations in three patients, which also resolved. One serious adverse event – a grade 2 transaminitis that resulted in elective hospitalization for intravenous steroid administration, also resolved.

With respect to vector clearance, there was “no evidence of vector in either saliva, semen, serum, urine, or peripheral blood mononuclear cells by 6 weeks after vector infusion,” Dr. George said.

One-stage assay determination of FVIII activity showed that activity greater than 10% permits an absolute bleeding rate (ABR) of less than 1%, which is consistent with hemophilia natural history studies. Therefore “these data support that FVIII activity that is approximately greater than 10% “may be adequate to either eliminate or achieve an ABR of less than 1,” she said.

“With respect to assay discrepancy, our data at least preliminarily support that the one-stage assay determinant of hepatocyte-derived FVIII correlates with clinical phenotype,” she added.

The findings in the first five patients demonstrate preliminary stability of FVIII expression at follow up between 2 and 3.3 years, she said.

Further, of the nine patients who received the 2 × 10¹² vg/kg dose, seven had sustained FVIII expression at about 1.5 years, five of the seven had no bleeds, and two lost FVIII expression and returned to prophylaxis uneventfully, she noted.

“The future directions of this work are ultimately to explore the optimal vector dose and immunosuppression regimens to achieve predictable, safe, efficacious, and durable FVIII expression,” she said.

Asked during a question and answer period about potential reasons for the differences in durability seen with SBK-8011 versus valoctocogene roxaparvovec, Dr. George said they remain unclear but could be related to differences in vector doses and manufacturing platforms.

Emerging data may allow for better comparisons, she added.

Session moderator Sebastien Lacroix-Desmazes, MD, of Centre de Recherche des Cordeliers, Paris, further asked about plans to optimize the immunosuppression regimen.

Plans are indeed in the works to identify the optimal immunosuppression regimen and to optimize immunosuppression in this trial, Dr. George said, noting that Spark Therapeutics “has outlined a plan to further investigate this in phase 1/2 trial before progressing into phase 3 study.”

Spark Therapeutic sponsored the SPK-8011 study. Dr. George disclosed consulting and/or data safety monitoring board activity for Pfizer and AvroBio.

[email protected]

SOURCE: George L et al. 2020 ISTH Congress, Abstract OC 03.5.

SPK-8011, an investigational adeno-associated virus (AAV)–mediated gene therapy for hemophilia A, provides stable and durable factor VIII expression with no major safety concerns, according to findings at least 2 years after a single treatment in patients from a phase 1/2 trial.

The first 5 of 14 adult men with hemophilia A and who had factor VIII (FVIII) activity of 2% or less before treatment with SPK-8011 (at single doses of either 5 × 10^{11 or 1} × 10¹² vg/kg), showed no development of FVIII inhibitors or evidence of FVIII cellular immune response at 106-142 weeks’ follow-up after vector infusion, according to Lindsey A. George, MD, at the International Society of Thrombosis and Haemostasis 2020 virtual congress.

At follow-up, the two who had received a 5 × 10¹¹ vg/kg dose had FVIII activity of 6.9%-8.4%, and the three in the 1 × 10¹² vg/kg cohort had FVIII activity of 5.2%-19.8%, said Dr. George, of the Children’s Hospital of Philadelphia.

Overall, 12 of the 14 patients in the study had sustained FVIII expression, including 7 of 9 who received the highest SPK-8011 dose of 2 × 10¹² vg/kg. In the 12 with sustained expression, a “remarkable” 91% reduction in the annualized bleeding rate from the year prior to vs. the year after vector infusion was observed, she said.

“Similarly, looking at number of factor infusions before vector infusion relative to the number of factor infusions after vector infusion ... [there was] evidence of remarkable preliminary efficacy,” she added, noting a 96% reduction in factor consumption.

The findings are of note because, while clinical studies of Spark Therapeutic’s SPK-8011 product in hemophilia B and preclinical models in hemophilia A showed promising reductions in bleeds and stable, durable levels of FVIII expression after therapy, the first successful clinical trial of an AAV-mediated gene therapy in hemophilia A – the BioMarin AAV serotype 5 human FVIII-SQ (valoctocogene roxaparvovec) – showed an unexpected decline in FVIII expression at 1, 2, 3, and 4 years.

“This may be particularly relevant in the context of development of multi-serotype AAV neutralizing antibodies (NAb) following AAV vector administration,” Dr. George said, referencing a small study in which she and her colleagues showed long-term persistence of cross-reactive AAV NAb. The findings of that study, which is currently in press in Molecular Therapy, “suggest that repeat AAV vector infusion is unlikely to be possible with current methods.”

Initial results from the SPK-8011 study were presented at the 2018 American Society of Hematology annual meeting. No major safety issues have emerged since those data were presented at ASH; no deaths have occurred, and none of the patients developed FVIII inhibitors.

Treatment-related adverse events were limited to an infusion reaction in one patient, which resolved completely, and liver enzyme elevations in three patients, which also resolved. One serious adverse event – a grade 2 transaminitis that resulted in elective hospitalization for intravenous steroid administration, also resolved.

With respect to vector clearance, there was “no evidence of vector in either saliva, semen, serum, urine, or peripheral blood mononuclear cells by 6 weeks after vector infusion,” Dr. George said.

One-stage assay determination of FVIII activity showed that activity greater than 10% permits an absolute bleeding rate (ABR) of less than 1%, which is consistent with hemophilia natural history studies. Therefore “these data support that FVIII activity that is approximately greater than 10% “may be adequate to either eliminate or achieve an ABR of less than 1,” she said.

“With respect to assay discrepancy, our data at least preliminarily support that the one-stage assay determinant of hepatocyte-derived FVIII correlates with clinical phenotype,” she added.

The findings in the first five patients demonstrate preliminary stability of FVIII expression at follow up between 2 and 3.3 years, she said.

Further, of the nine patients who received the 2 × 10¹² vg/kg dose, seven had sustained FVIII expression at about 1.5 years, five of the seven had no bleeds, and two lost FVIII expression and returned to prophylaxis uneventfully, she noted.

“The future directions of this work are ultimately to explore the optimal vector dose and immunosuppression regimens to achieve predictable, safe, efficacious, and durable FVIII expression,” she said.

Asked during a question and answer period about potential reasons for the differences in durability seen with SBK-8011 versus valoctocogene roxaparvovec, Dr. George said they remain unclear but could be related to differences in vector doses and manufacturing platforms.

Emerging data may allow for better comparisons, she added.

Session moderator Sebastien Lacroix-Desmazes, MD, of Centre de Recherche des Cordeliers, Paris, further asked about plans to optimize the immunosuppression regimen.

Plans are indeed in the works to identify the optimal immunosuppression regimen and to optimize immunosuppression in this trial, Dr. George said, noting that Spark Therapeutics “has outlined a plan to further investigate this in phase 1/2 trial before progressing into phase 3 study.”

Spark Therapeutic sponsored the SPK-8011 study. Dr. George disclosed consulting and/or data safety monitoring board activity for Pfizer and AvroBio.

[email protected]

SOURCE: George L et al. 2020 ISTH Congress, Abstract OC 03.5.

SPK-8011, an investigational adeno-associated virus (AAV)–mediated gene therapy for hemophilia A, provides stable and durable factor VIII expression with no major safety concerns, according to findings at least 2 years after a single treatment in patients from a phase 1/2 trial.

The first 5 of 14 adult men with hemophilia A and who had factor VIII (FVIII) activity of 2% or less before treatment with SPK-8011 (at single doses of either 5 × 10^{11 or 1} × 10¹² vg/kg), showed no development of FVIII inhibitors or evidence of FVIII cellular immune response at 106-142 weeks’ follow-up after vector infusion, according to Lindsey A. George, MD, at the International Society of Thrombosis and Haemostasis 2020 virtual congress.

At follow-up, the two who had received a 5 × 10¹¹ vg/kg dose had FVIII activity of 6.9%-8.4%, and the three in the 1 × 10¹² vg/kg cohort had FVIII activity of 5.2%-19.8%, said Dr. George, of the Children’s Hospital of Philadelphia.

Overall, 12 of the 14 patients in the study had sustained FVIII expression, including 7 of 9 who received the highest SPK-8011 dose of 2 × 10¹² vg/kg. In the 12 with sustained expression, a “remarkable” 91% reduction in the annualized bleeding rate from the year prior to vs. the year after vector infusion was observed, she said.

“Similarly, looking at number of factor infusions before vector infusion relative to the number of factor infusions after vector infusion ... [there was] evidence of remarkable preliminary efficacy,” she added, noting a 96% reduction in factor consumption.

The findings are of note because, while clinical studies of Spark Therapeutic’s SPK-8011 product in hemophilia B and preclinical models in hemophilia A showed promising reductions in bleeds and stable, durable levels of FVIII expression after therapy, the first successful clinical trial of an AAV-mediated gene therapy in hemophilia A – the BioMarin AAV serotype 5 human FVIII-SQ (valoctocogene roxaparvovec) – showed an unexpected decline in FVIII expression at 1, 2, 3, and 4 years.

“This may be particularly relevant in the context of development of multi-serotype AAV neutralizing antibodies (NAb) following AAV vector administration,” Dr. George said, referencing a small study in which she and her colleagues showed long-term persistence of cross-reactive AAV NAb. The findings of that study, which is currently in press in Molecular Therapy, “suggest that repeat AAV vector infusion is unlikely to be possible with current methods.”

Initial results from the SPK-8011 study were presented at the 2018 American Society of Hematology annual meeting. No major safety issues have emerged since those data were presented at ASH; no deaths have occurred, and none of the patients developed FVIII inhibitors.

Treatment-related adverse events were limited to an infusion reaction in one patient, which resolved completely, and liver enzyme elevations in three patients, which also resolved. One serious adverse event – a grade 2 transaminitis that resulted in elective hospitalization for intravenous steroid administration, also resolved.

With respect to vector clearance, there was “no evidence of vector in either saliva, semen, serum, urine, or peripheral blood mononuclear cells by 6 weeks after vector infusion,” Dr. George said.

One-stage assay determination of FVIII activity showed that activity greater than 10% permits an absolute bleeding rate (ABR) of less than 1%, which is consistent with hemophilia natural history studies. Therefore “these data support that FVIII activity that is approximately greater than 10% “may be adequate to either eliminate or achieve an ABR of less than 1,” she said.

“With respect to assay discrepancy, our data at least preliminarily support that the one-stage assay determinant of hepatocyte-derived FVIII correlates with clinical phenotype,” she added.

The findings in the first five patients demonstrate preliminary stability of FVIII expression at follow up between 2 and 3.3 years, she said.

Further, of the nine patients who received the 2 × 10¹² vg/kg dose, seven had sustained FVIII expression at about 1.5 years, five of the seven had no bleeds, and two lost FVIII expression and returned to prophylaxis uneventfully, she noted.

“The future directions of this work are ultimately to explore the optimal vector dose and immunosuppression regimens to achieve predictable, safe, efficacious, and durable FVIII expression,” she said.

Asked during a question and answer period about potential reasons for the differences in durability seen with SBK-8011 versus valoctocogene roxaparvovec, Dr. George said they remain unclear but could be related to differences in vector doses and manufacturing platforms.

Emerging data may allow for better comparisons, she added.

Session moderator Sebastien Lacroix-Desmazes, MD, of Centre de Recherche des Cordeliers, Paris, further asked about plans to optimize the immunosuppression regimen.

Plans are indeed in the works to identify the optimal immunosuppression regimen and to optimize immunosuppression in this trial, Dr. George said, noting that Spark Therapeutics “has outlined a plan to further investigate this in phase 1/2 trial before progressing into phase 3 study.”

Spark Therapeutic sponsored the SPK-8011 study. Dr. George disclosed consulting and/or data safety monitoring board activity for Pfizer and AvroBio.

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SOURCE: George L et al. 2020 ISTH Congress, Abstract OC 03.5.