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Breast surgery may be a gateway to addictive medication use
After their surgery, 13.1% of opioid-naive patients become new persistent opioid users, and 6.6% of sedative-hypnotic–naive patients become new persistent users of sedative-hypnotics. Risk factors for persistent substance use included younger age, a breast cancer diagnosis, and chemotherapy.
“As the opioid epidemic in the United States continues, the rate of opioid dependence in the cancer population continues to increase as well,” study investigator Jacob Cogan, MD, of NewYork-Presbyterian/Columbia University Irving Medical Center in New York, said during a press conference.
“The perioperative period is one of high risk for cancer patients, with up to 10% becoming new persistent opioid users after cancer-related surgery. The rates surrounding mastectomy and reconstruction, however, are unknown. Another class of controlled substances worth our attention are the sedative-hypnotics. Despite the high rates of psychiatric disorders in the cancer population, there is little research into the rates of persistent sedative-hypnotic use in these patients.”
With this in mind, Dr. Cogan and colleagues analyzed MarketScan health care claims data for patients who underwent mastectomy and reconstruction (whether therapeutic or prophylactic) between 2008 and 2017.
The researchers then identified prescription claims for opioids and sedative-hypnotics during three periods:
- Preoperative period – 365 days to 31 days before surgery.
- Perioperative period – 31 days before to 90 days after surgery.
- Postoperative period – 90 days to 365 days after surgery.
‘Striking’ results
Analyses were based on 25,270 women who were not prior users of opioids and 27,651 women who were not prior users of sedative-hypnotics.
Women were considered new persistent substance users if they had no use in the preoperative period but filled at least one prescription in the perioperative period and at least two in the postoperative period.
Overall, 13.1% of opioid-naive patients became persistent opioid users, and 6.6% of sedative-hypnotic-naive patients became persistent sedative-hypnotic users after their mastectomy and reconstruction.
Proportions of substance use were even higher, 17.5% for opioids and 17.0% for sedative-hypnotics, after excluding women who did not receive or fill a perioperative prescription.
In multivariate analysis, patients were significantly more likely to become new persistent opioid users if they had Medicaid insurance (odds ratio, 2.31), had a breast cancer diagnosis vs a prophylactic indication (OR, 1.44), received chemotherapy (OR, 1.33), and were 50-64 years of age (OR, 1.29) or 49 years or younger (OR, 1.27), compared with 65 years or older.
Similarly, patients were significantly more likely to become new persistent sedative-hypnotic users if they received chemotherapy (OR, 2.24), had Medicaid insurance (OR, 1.85), had a breast cancer diagnosis (OR, 1.79), and were 50 to 64 years (OR, 1.65) or 49 years or younger (OR, 1.79).
Finally, patients’ likelihood of new persistent use increased with their number of risk factors. For persistent opioid use, the odds ratio rose from 2.27 in patients with two risk factors to 6.34 in those with five risk factors. For persistent sedative-hypnotic use, the odds ratio rose from 2.55 to 7.71, respectively.
The observed incidences of new persistent substance use in this patient population are “striking,” according to Dr. Cogan. Although the identified risk factors can help providers spot patients who should be monitored more closely, a proactive, systematic approach to postoperative follow-up for all patients is likely needed.
“When you are seeing patients in follow-up, this is something that you might want to explicitly ask about, for example, and not just assume that the postoperative opioids were taken and then disposed of,” Dr. Cogan recommended. “Ask them, ‘Are you still taking opioids, are you still taking your Ambien or whatever medication you were prescribed?’ That’s something to diligently follow up on and make sure the drug is disposed of, or if it somebody is still taking it, refer them for the appropriate services.”
In addition, patients should be encouraged to use over-the-counter medications as much as possible, he advised.
Prescribing: It’s complicated
“I wonder if perhaps we should not be giving opioids at all to certain patients. For example, a mastectomy and implant reconstruction, oftentimes, surprisingly, that’s not a terribly painful procedure. But a TRAM [transverse rectus abdominis] flap or abdominal flap, that really is,” commented press conference comoderator C. Kent Osborne, MD, of Baylor College of Medicine in Houston.
“I’ve been surprised that a lot of my patients get the prescription, but they don’t even use the pills, and I wonder if the prescription is given just so that we’re not bothered at nighttime by somebody calling with pain,” Dr. Osbourne added.
Prescribing opioids for postoperative pain is complicated, Dr. Cogan said, noting that the study did not assess the specific type of reconstruction patients had.
“You don’t want people in pain. Even if they need just one or two pills, it’s still reasonable for them to have it, and we certainly don’t want to imply from our study that people shouldn’t be getting these prescriptions if they need them,” Dr. Cogan elaborated. “But once patients have them, don’t just leave them there in their home because other studies have shown that that’s when people really get addicted to these medications, when they use them later on for other reasons, or they keep using them just because they have them around.”
The risk for persistent use of controlled substances “is something that all physicians need to be aware of for their patients. This is something that we are missing,” maintained press conference comoderator Virginia Kaklamani, MD, DSc, of UT Health San Antonio.
“It’s easy to just give a prescription instead of arguing with a patient about why you are not going to give them a prescription,” Dr. Kaklamani said. “And ultimately ... pain is subjective. If a patient tells you they are in pain, you are, quote-endquote, a bad physician if you tell them they should not be in pain.”
“We need to focus on other ways to deal with the pain, like physical therapy, sending patients to physical medicine and rehab physicians who are trained to help with symptoms from the surgery, with range of motion and all that; that can help with pain,” she recommended. “It’s much harder to do that, right, than to send a prescription in for a narcotic? But that easy answer is always the worst answer.”
This study was funded by the Breast Cancer Research Foundation and the National Institutes of Health. Dr. Cogan declared no conflicts of interest. Dr. Osborne disclosed relationships with Wolters Kluwer, Lilly, Tolmar, and GeneTex. Dr. Kaklamani disclosed relationships with Amgen, AstraZeneca, Athenex, Celgene, Celldex, Daiichi, Eisai, Genentech, Genomic Health, Immunomedics, Novartis, Pfizer, Puma, and Seattle Genetics.
SOURCE: Cogan JC et al. SABCS 2020, Abstract GS3-08.
After their surgery, 13.1% of opioid-naive patients become new persistent opioid users, and 6.6% of sedative-hypnotic–naive patients become new persistent users of sedative-hypnotics. Risk factors for persistent substance use included younger age, a breast cancer diagnosis, and chemotherapy.
“As the opioid epidemic in the United States continues, the rate of opioid dependence in the cancer population continues to increase as well,” study investigator Jacob Cogan, MD, of NewYork-Presbyterian/Columbia University Irving Medical Center in New York, said during a press conference.
“The perioperative period is one of high risk for cancer patients, with up to 10% becoming new persistent opioid users after cancer-related surgery. The rates surrounding mastectomy and reconstruction, however, are unknown. Another class of controlled substances worth our attention are the sedative-hypnotics. Despite the high rates of psychiatric disorders in the cancer population, there is little research into the rates of persistent sedative-hypnotic use in these patients.”
With this in mind, Dr. Cogan and colleagues analyzed MarketScan health care claims data for patients who underwent mastectomy and reconstruction (whether therapeutic or prophylactic) between 2008 and 2017.
The researchers then identified prescription claims for opioids and sedative-hypnotics during three periods:
- Preoperative period – 365 days to 31 days before surgery.
- Perioperative period – 31 days before to 90 days after surgery.
- Postoperative period – 90 days to 365 days after surgery.
‘Striking’ results
Analyses were based on 25,270 women who were not prior users of opioids and 27,651 women who were not prior users of sedative-hypnotics.
Women were considered new persistent substance users if they had no use in the preoperative period but filled at least one prescription in the perioperative period and at least two in the postoperative period.
Overall, 13.1% of opioid-naive patients became persistent opioid users, and 6.6% of sedative-hypnotic-naive patients became persistent sedative-hypnotic users after their mastectomy and reconstruction.
Proportions of substance use were even higher, 17.5% for opioids and 17.0% for sedative-hypnotics, after excluding women who did not receive or fill a perioperative prescription.
In multivariate analysis, patients were significantly more likely to become new persistent opioid users if they had Medicaid insurance (odds ratio, 2.31), had a breast cancer diagnosis vs a prophylactic indication (OR, 1.44), received chemotherapy (OR, 1.33), and were 50-64 years of age (OR, 1.29) or 49 years or younger (OR, 1.27), compared with 65 years or older.
Similarly, patients were significantly more likely to become new persistent sedative-hypnotic users if they received chemotherapy (OR, 2.24), had Medicaid insurance (OR, 1.85), had a breast cancer diagnosis (OR, 1.79), and were 50 to 64 years (OR, 1.65) or 49 years or younger (OR, 1.79).
Finally, patients’ likelihood of new persistent use increased with their number of risk factors. For persistent opioid use, the odds ratio rose from 2.27 in patients with two risk factors to 6.34 in those with five risk factors. For persistent sedative-hypnotic use, the odds ratio rose from 2.55 to 7.71, respectively.
The observed incidences of new persistent substance use in this patient population are “striking,” according to Dr. Cogan. Although the identified risk factors can help providers spot patients who should be monitored more closely, a proactive, systematic approach to postoperative follow-up for all patients is likely needed.
“When you are seeing patients in follow-up, this is something that you might want to explicitly ask about, for example, and not just assume that the postoperative opioids were taken and then disposed of,” Dr. Cogan recommended. “Ask them, ‘Are you still taking opioids, are you still taking your Ambien or whatever medication you were prescribed?’ That’s something to diligently follow up on and make sure the drug is disposed of, or if it somebody is still taking it, refer them for the appropriate services.”
In addition, patients should be encouraged to use over-the-counter medications as much as possible, he advised.
Prescribing: It’s complicated
“I wonder if perhaps we should not be giving opioids at all to certain patients. For example, a mastectomy and implant reconstruction, oftentimes, surprisingly, that’s not a terribly painful procedure. But a TRAM [transverse rectus abdominis] flap or abdominal flap, that really is,” commented press conference comoderator C. Kent Osborne, MD, of Baylor College of Medicine in Houston.
“I’ve been surprised that a lot of my patients get the prescription, but they don’t even use the pills, and I wonder if the prescription is given just so that we’re not bothered at nighttime by somebody calling with pain,” Dr. Osbourne added.
Prescribing opioids for postoperative pain is complicated, Dr. Cogan said, noting that the study did not assess the specific type of reconstruction patients had.
“You don’t want people in pain. Even if they need just one or two pills, it’s still reasonable for them to have it, and we certainly don’t want to imply from our study that people shouldn’t be getting these prescriptions if they need them,” Dr. Cogan elaborated. “But once patients have them, don’t just leave them there in their home because other studies have shown that that’s when people really get addicted to these medications, when they use them later on for other reasons, or they keep using them just because they have them around.”
The risk for persistent use of controlled substances “is something that all physicians need to be aware of for their patients. This is something that we are missing,” maintained press conference comoderator Virginia Kaklamani, MD, DSc, of UT Health San Antonio.
“It’s easy to just give a prescription instead of arguing with a patient about why you are not going to give them a prescription,” Dr. Kaklamani said. “And ultimately ... pain is subjective. If a patient tells you they are in pain, you are, quote-endquote, a bad physician if you tell them they should not be in pain.”
“We need to focus on other ways to deal with the pain, like physical therapy, sending patients to physical medicine and rehab physicians who are trained to help with symptoms from the surgery, with range of motion and all that; that can help with pain,” she recommended. “It’s much harder to do that, right, than to send a prescription in for a narcotic? But that easy answer is always the worst answer.”
This study was funded by the Breast Cancer Research Foundation and the National Institutes of Health. Dr. Cogan declared no conflicts of interest. Dr. Osborne disclosed relationships with Wolters Kluwer, Lilly, Tolmar, and GeneTex. Dr. Kaklamani disclosed relationships with Amgen, AstraZeneca, Athenex, Celgene, Celldex, Daiichi, Eisai, Genentech, Genomic Health, Immunomedics, Novartis, Pfizer, Puma, and Seattle Genetics.
SOURCE: Cogan JC et al. SABCS 2020, Abstract GS3-08.
After their surgery, 13.1% of opioid-naive patients become new persistent opioid users, and 6.6% of sedative-hypnotic–naive patients become new persistent users of sedative-hypnotics. Risk factors for persistent substance use included younger age, a breast cancer diagnosis, and chemotherapy.
“As the opioid epidemic in the United States continues, the rate of opioid dependence in the cancer population continues to increase as well,” study investigator Jacob Cogan, MD, of NewYork-Presbyterian/Columbia University Irving Medical Center in New York, said during a press conference.
“The perioperative period is one of high risk for cancer patients, with up to 10% becoming new persistent opioid users after cancer-related surgery. The rates surrounding mastectomy and reconstruction, however, are unknown. Another class of controlled substances worth our attention are the sedative-hypnotics. Despite the high rates of psychiatric disorders in the cancer population, there is little research into the rates of persistent sedative-hypnotic use in these patients.”
With this in mind, Dr. Cogan and colleagues analyzed MarketScan health care claims data for patients who underwent mastectomy and reconstruction (whether therapeutic or prophylactic) between 2008 and 2017.
The researchers then identified prescription claims for opioids and sedative-hypnotics during three periods:
- Preoperative period – 365 days to 31 days before surgery.
- Perioperative period – 31 days before to 90 days after surgery.
- Postoperative period – 90 days to 365 days after surgery.
‘Striking’ results
Analyses were based on 25,270 women who were not prior users of opioids and 27,651 women who were not prior users of sedative-hypnotics.
Women were considered new persistent substance users if they had no use in the preoperative period but filled at least one prescription in the perioperative period and at least two in the postoperative period.
Overall, 13.1% of opioid-naive patients became persistent opioid users, and 6.6% of sedative-hypnotic-naive patients became persistent sedative-hypnotic users after their mastectomy and reconstruction.
Proportions of substance use were even higher, 17.5% for opioids and 17.0% for sedative-hypnotics, after excluding women who did not receive or fill a perioperative prescription.
In multivariate analysis, patients were significantly more likely to become new persistent opioid users if they had Medicaid insurance (odds ratio, 2.31), had a breast cancer diagnosis vs a prophylactic indication (OR, 1.44), received chemotherapy (OR, 1.33), and were 50-64 years of age (OR, 1.29) or 49 years or younger (OR, 1.27), compared with 65 years or older.
Similarly, patients were significantly more likely to become new persistent sedative-hypnotic users if they received chemotherapy (OR, 2.24), had Medicaid insurance (OR, 1.85), had a breast cancer diagnosis (OR, 1.79), and were 50 to 64 years (OR, 1.65) or 49 years or younger (OR, 1.79).
Finally, patients’ likelihood of new persistent use increased with their number of risk factors. For persistent opioid use, the odds ratio rose from 2.27 in patients with two risk factors to 6.34 in those with five risk factors. For persistent sedative-hypnotic use, the odds ratio rose from 2.55 to 7.71, respectively.
The observed incidences of new persistent substance use in this patient population are “striking,” according to Dr. Cogan. Although the identified risk factors can help providers spot patients who should be monitored more closely, a proactive, systematic approach to postoperative follow-up for all patients is likely needed.
“When you are seeing patients in follow-up, this is something that you might want to explicitly ask about, for example, and not just assume that the postoperative opioids were taken and then disposed of,” Dr. Cogan recommended. “Ask them, ‘Are you still taking opioids, are you still taking your Ambien or whatever medication you were prescribed?’ That’s something to diligently follow up on and make sure the drug is disposed of, or if it somebody is still taking it, refer them for the appropriate services.”
In addition, patients should be encouraged to use over-the-counter medications as much as possible, he advised.
Prescribing: It’s complicated
“I wonder if perhaps we should not be giving opioids at all to certain patients. For example, a mastectomy and implant reconstruction, oftentimes, surprisingly, that’s not a terribly painful procedure. But a TRAM [transverse rectus abdominis] flap or abdominal flap, that really is,” commented press conference comoderator C. Kent Osborne, MD, of Baylor College of Medicine in Houston.
“I’ve been surprised that a lot of my patients get the prescription, but they don’t even use the pills, and I wonder if the prescription is given just so that we’re not bothered at nighttime by somebody calling with pain,” Dr. Osbourne added.
Prescribing opioids for postoperative pain is complicated, Dr. Cogan said, noting that the study did not assess the specific type of reconstruction patients had.
“You don’t want people in pain. Even if they need just one or two pills, it’s still reasonable for them to have it, and we certainly don’t want to imply from our study that people shouldn’t be getting these prescriptions if they need them,” Dr. Cogan elaborated. “But once patients have them, don’t just leave them there in their home because other studies have shown that that’s when people really get addicted to these medications, when they use them later on for other reasons, or they keep using them just because they have them around.”
The risk for persistent use of controlled substances “is something that all physicians need to be aware of for their patients. This is something that we are missing,” maintained press conference comoderator Virginia Kaklamani, MD, DSc, of UT Health San Antonio.
“It’s easy to just give a prescription instead of arguing with a patient about why you are not going to give them a prescription,” Dr. Kaklamani said. “And ultimately ... pain is subjective. If a patient tells you they are in pain, you are, quote-endquote, a bad physician if you tell them they should not be in pain.”
“We need to focus on other ways to deal with the pain, like physical therapy, sending patients to physical medicine and rehab physicians who are trained to help with symptoms from the surgery, with range of motion and all that; that can help with pain,” she recommended. “It’s much harder to do that, right, than to send a prescription in for a narcotic? But that easy answer is always the worst answer.”
This study was funded by the Breast Cancer Research Foundation and the National Institutes of Health. Dr. Cogan declared no conflicts of interest. Dr. Osborne disclosed relationships with Wolters Kluwer, Lilly, Tolmar, and GeneTex. Dr. Kaklamani disclosed relationships with Amgen, AstraZeneca, Athenex, Celgene, Celldex, Daiichi, Eisai, Genentech, Genomic Health, Immunomedics, Novartis, Pfizer, Puma, and Seattle Genetics.
SOURCE: Cogan JC et al. SABCS 2020, Abstract GS3-08.
FROM SABCS 2020
CTCs predict overall survival in metastatic breast cancer
The CTC results are available about 4 weeks after start of therapy. Conventional imaging is carried out after about 3 months.
But an expert is not convinced that this approach is currently ready for clinical use and suggests that, for now, it should remain a tool for use in research.
The new meta-analysis, which involved data on more than 4000 patients, showed that the presence or the absence of CTCs “strongly” predicts overall survival (OS).
Median OS was greatest (47 months) for patients who had no CTCs at baseline and at follow-up. In contrast, the median OS was shortest (17.8 months) for patients who had CTCs at both time points.
The risk for death was more than 200% greater for patients in the latter group than in the former group.
The results “suggest the potential for clinical utility” of CTC monitoring as an early response marker in metastatic breast cancer, said lead author Wolfgang Janni, MD, PhD, of the Ulm University Hospital, Ulm, Germany. He was speaking at an online press conference for the virtual San Antonio Breast Cancer Symposium (SABCS) 2020, where the new study will be presented this week.
The investigators say the findings from this meta-analysis add to literature in which “several studies suggest clinical utility” of measuring CTC levels as a means of assessing response status for patients with metastatic breast cancer.
Unfortunately, the new study does not show that assessing CTCs over time improves clinical outcomes, which is an ongoing problem in the literature, said Virginia Kaklamani, MD, University of Texas Health Sciences Center, San Antonio, Texas, who is also a meeting co-director.
“Previous randomized clinical trial data have shown that assessing CTCs does not benefit patients (vs not assessing),” Kaklamani told Medscape Medical News.
Kaklamani explained how CTC assessments have worked in practice. “You do these circulating tumor cell tests and you find, for example, that the number increases. The assumption is the treatment’s not working. So you switch treatments around,” she explained. That pattern can be repeated every 3 to 4 weeks, resulting in more toxicity, which, in turn, may nullify any treatment benefit.
However, she noted that, so far, key data have come from the era of chemotherapy and do not reflect targeted therapies, which may make a difference. In addition, the more recent ability to assess and identify circulating tumor DNA may allow clinicians to match drugs to mutations, which may have greater impact on cancer outcomes.
Currently, CTCs are best used by researchers, Kaklamani said during the press conference, because they have not been definitively proven to improve patient results.
Investigator Janni did not object to that description.
But in a press statement, he suggested that CTCs can be used currently by clinicians.
“These data indicate that CTC dynamics can predict the trajectory of the disease a little more than four weeks after initiating treatment,” Janni said in the press statement. “This provides an advantage over conventional imaging methods and can help physicians determine very early on whether a treatment should be continued.”
But, to Kaklamani’s point, an article published in November in JAMA Oncology showed that use of CTCs did not yield significant clinical benefit in comparison with use of other clinical factors in determining whether to choose endocrine therapy or chemotherapy. In that randomized trial, which was conducted in Europe and included women with HR-positive, HER2-negative breast cancer, progression-free survival was similar in both arms, as reported by Medscape Medical News. However, use of chemotherapy (and attendant toxicity) was greater among women in the CTC arm, which was considered an undesirable outcome by experts not involved with the trial.
Details of the study results
For their study, Janni and colleagues conducted a comprehensive pooled analysis of globally available data. They identified 4079 metastatic breast cancer patients who had undergone baseline and follow-up CTC measurements (at least one, at a median of 29 days later) in previous clinical trials.
The investigators analyzed changes in CTC levels between baseline and follow-up to determine whether they were associated with OS.
Of the 2961 patients who were CTC-positive at baseline, 1855 remained CTC-positive after treatment was initiated (positive/positive), and 1106 patients had converted to CTC-negative status (positive/negative).
Of the 1118 patients who were CTC-negative at baseline, 813 remained CTC-negative (negative/negative), and 305 had become CTC-positive (negative/positive).
As noted above, median OS was greatest for patients who were negative/negative (47 months), followed by patients who were positive/negative (32.2 months), negative/positive (29.6 months), and positive/positive (17.8 months).
Hazard ratios in which the reference group was negative/negative were 1.52 for the positive/negative group, 1.74 for the negative/positive group, and 3.15 for the positive/positive group (P < .0001 for all groups).
These CTC dynamics were found across all breast cancer subtypes, said Janni.
“These data indicate that CTC dynamics can predict the trajectory of the disease a little more than four weeks after initiating treatment,” said Janni in the press statement. “This provides an advantage over conventional imaging methods and can help physicians determine very early on whether a treatment should be continued. It is also very reassuring that CTC dynamics predicted outcomes for all breast cancer subtypes.”
The study was supported by Menarini Silicon Biosystems, the makers of CellSearch, the CTC test used for all of the patients and studies in the meta-analysis. Janni received a research grant from Menarini Silicon Biosystems. Other study authors have financial ties to healthcare industries. Kaklamani has received consulting fees from Amgen, Eisai, Puma, Celldex, AstraZeneca, and Athenex; fees for non-CME services received directly from commercial interest or their agents from Pfizer, Celgene, Genentech, Genomic Health, Puma, Eisai, and Novartis; and has contracted research with Eisai.
This article first appeared on Medscape.com.
The CTC results are available about 4 weeks after start of therapy. Conventional imaging is carried out after about 3 months.
But an expert is not convinced that this approach is currently ready for clinical use and suggests that, for now, it should remain a tool for use in research.
The new meta-analysis, which involved data on more than 4000 patients, showed that the presence or the absence of CTCs “strongly” predicts overall survival (OS).
Median OS was greatest (47 months) for patients who had no CTCs at baseline and at follow-up. In contrast, the median OS was shortest (17.8 months) for patients who had CTCs at both time points.
The risk for death was more than 200% greater for patients in the latter group than in the former group.
The results “suggest the potential for clinical utility” of CTC monitoring as an early response marker in metastatic breast cancer, said lead author Wolfgang Janni, MD, PhD, of the Ulm University Hospital, Ulm, Germany. He was speaking at an online press conference for the virtual San Antonio Breast Cancer Symposium (SABCS) 2020, where the new study will be presented this week.
The investigators say the findings from this meta-analysis add to literature in which “several studies suggest clinical utility” of measuring CTC levels as a means of assessing response status for patients with metastatic breast cancer.
Unfortunately, the new study does not show that assessing CTCs over time improves clinical outcomes, which is an ongoing problem in the literature, said Virginia Kaklamani, MD, University of Texas Health Sciences Center, San Antonio, Texas, who is also a meeting co-director.
“Previous randomized clinical trial data have shown that assessing CTCs does not benefit patients (vs not assessing),” Kaklamani told Medscape Medical News.
Kaklamani explained how CTC assessments have worked in practice. “You do these circulating tumor cell tests and you find, for example, that the number increases. The assumption is the treatment’s not working. So you switch treatments around,” she explained. That pattern can be repeated every 3 to 4 weeks, resulting in more toxicity, which, in turn, may nullify any treatment benefit.
However, she noted that, so far, key data have come from the era of chemotherapy and do not reflect targeted therapies, which may make a difference. In addition, the more recent ability to assess and identify circulating tumor DNA may allow clinicians to match drugs to mutations, which may have greater impact on cancer outcomes.
Currently, CTCs are best used by researchers, Kaklamani said during the press conference, because they have not been definitively proven to improve patient results.
Investigator Janni did not object to that description.
But in a press statement, he suggested that CTCs can be used currently by clinicians.
“These data indicate that CTC dynamics can predict the trajectory of the disease a little more than four weeks after initiating treatment,” Janni said in the press statement. “This provides an advantage over conventional imaging methods and can help physicians determine very early on whether a treatment should be continued.”
But, to Kaklamani’s point, an article published in November in JAMA Oncology showed that use of CTCs did not yield significant clinical benefit in comparison with use of other clinical factors in determining whether to choose endocrine therapy or chemotherapy. In that randomized trial, which was conducted in Europe and included women with HR-positive, HER2-negative breast cancer, progression-free survival was similar in both arms, as reported by Medscape Medical News. However, use of chemotherapy (and attendant toxicity) was greater among women in the CTC arm, which was considered an undesirable outcome by experts not involved with the trial.
Details of the study results
For their study, Janni and colleagues conducted a comprehensive pooled analysis of globally available data. They identified 4079 metastatic breast cancer patients who had undergone baseline and follow-up CTC measurements (at least one, at a median of 29 days later) in previous clinical trials.
The investigators analyzed changes in CTC levels between baseline and follow-up to determine whether they were associated with OS.
Of the 2961 patients who were CTC-positive at baseline, 1855 remained CTC-positive after treatment was initiated (positive/positive), and 1106 patients had converted to CTC-negative status (positive/negative).
Of the 1118 patients who were CTC-negative at baseline, 813 remained CTC-negative (negative/negative), and 305 had become CTC-positive (negative/positive).
As noted above, median OS was greatest for patients who were negative/negative (47 months), followed by patients who were positive/negative (32.2 months), negative/positive (29.6 months), and positive/positive (17.8 months).
Hazard ratios in which the reference group was negative/negative were 1.52 for the positive/negative group, 1.74 for the negative/positive group, and 3.15 for the positive/positive group (P < .0001 for all groups).
These CTC dynamics were found across all breast cancer subtypes, said Janni.
“These data indicate that CTC dynamics can predict the trajectory of the disease a little more than four weeks after initiating treatment,” said Janni in the press statement. “This provides an advantage over conventional imaging methods and can help physicians determine very early on whether a treatment should be continued. It is also very reassuring that CTC dynamics predicted outcomes for all breast cancer subtypes.”
The study was supported by Menarini Silicon Biosystems, the makers of CellSearch, the CTC test used for all of the patients and studies in the meta-analysis. Janni received a research grant from Menarini Silicon Biosystems. Other study authors have financial ties to healthcare industries. Kaklamani has received consulting fees from Amgen, Eisai, Puma, Celldex, AstraZeneca, and Athenex; fees for non-CME services received directly from commercial interest or their agents from Pfizer, Celgene, Genentech, Genomic Health, Puma, Eisai, and Novartis; and has contracted research with Eisai.
This article first appeared on Medscape.com.
The CTC results are available about 4 weeks after start of therapy. Conventional imaging is carried out after about 3 months.
But an expert is not convinced that this approach is currently ready for clinical use and suggests that, for now, it should remain a tool for use in research.
The new meta-analysis, which involved data on more than 4000 patients, showed that the presence or the absence of CTCs “strongly” predicts overall survival (OS).
Median OS was greatest (47 months) for patients who had no CTCs at baseline and at follow-up. In contrast, the median OS was shortest (17.8 months) for patients who had CTCs at both time points.
The risk for death was more than 200% greater for patients in the latter group than in the former group.
The results “suggest the potential for clinical utility” of CTC monitoring as an early response marker in metastatic breast cancer, said lead author Wolfgang Janni, MD, PhD, of the Ulm University Hospital, Ulm, Germany. He was speaking at an online press conference for the virtual San Antonio Breast Cancer Symposium (SABCS) 2020, where the new study will be presented this week.
The investigators say the findings from this meta-analysis add to literature in which “several studies suggest clinical utility” of measuring CTC levels as a means of assessing response status for patients with metastatic breast cancer.
Unfortunately, the new study does not show that assessing CTCs over time improves clinical outcomes, which is an ongoing problem in the literature, said Virginia Kaklamani, MD, University of Texas Health Sciences Center, San Antonio, Texas, who is also a meeting co-director.
“Previous randomized clinical trial data have shown that assessing CTCs does not benefit patients (vs not assessing),” Kaklamani told Medscape Medical News.
Kaklamani explained how CTC assessments have worked in practice. “You do these circulating tumor cell tests and you find, for example, that the number increases. The assumption is the treatment’s not working. So you switch treatments around,” she explained. That pattern can be repeated every 3 to 4 weeks, resulting in more toxicity, which, in turn, may nullify any treatment benefit.
However, she noted that, so far, key data have come from the era of chemotherapy and do not reflect targeted therapies, which may make a difference. In addition, the more recent ability to assess and identify circulating tumor DNA may allow clinicians to match drugs to mutations, which may have greater impact on cancer outcomes.
Currently, CTCs are best used by researchers, Kaklamani said during the press conference, because they have not been definitively proven to improve patient results.
Investigator Janni did not object to that description.
But in a press statement, he suggested that CTCs can be used currently by clinicians.
“These data indicate that CTC dynamics can predict the trajectory of the disease a little more than four weeks after initiating treatment,” Janni said in the press statement. “This provides an advantage over conventional imaging methods and can help physicians determine very early on whether a treatment should be continued.”
But, to Kaklamani’s point, an article published in November in JAMA Oncology showed that use of CTCs did not yield significant clinical benefit in comparison with use of other clinical factors in determining whether to choose endocrine therapy or chemotherapy. In that randomized trial, which was conducted in Europe and included women with HR-positive, HER2-negative breast cancer, progression-free survival was similar in both arms, as reported by Medscape Medical News. However, use of chemotherapy (and attendant toxicity) was greater among women in the CTC arm, which was considered an undesirable outcome by experts not involved with the trial.
Details of the study results
For their study, Janni and colleagues conducted a comprehensive pooled analysis of globally available data. They identified 4079 metastatic breast cancer patients who had undergone baseline and follow-up CTC measurements (at least one, at a median of 29 days later) in previous clinical trials.
The investigators analyzed changes in CTC levels between baseline and follow-up to determine whether they were associated with OS.
Of the 2961 patients who were CTC-positive at baseline, 1855 remained CTC-positive after treatment was initiated (positive/positive), and 1106 patients had converted to CTC-negative status (positive/negative).
Of the 1118 patients who were CTC-negative at baseline, 813 remained CTC-negative (negative/negative), and 305 had become CTC-positive (negative/positive).
As noted above, median OS was greatest for patients who were negative/negative (47 months), followed by patients who were positive/negative (32.2 months), negative/positive (29.6 months), and positive/positive (17.8 months).
Hazard ratios in which the reference group was negative/negative were 1.52 for the positive/negative group, 1.74 for the negative/positive group, and 3.15 for the positive/positive group (P < .0001 for all groups).
These CTC dynamics were found across all breast cancer subtypes, said Janni.
“These data indicate that CTC dynamics can predict the trajectory of the disease a little more than four weeks after initiating treatment,” said Janni in the press statement. “This provides an advantage over conventional imaging methods and can help physicians determine very early on whether a treatment should be continued. It is also very reassuring that CTC dynamics predicted outcomes for all breast cancer subtypes.”
The study was supported by Menarini Silicon Biosystems, the makers of CellSearch, the CTC test used for all of the patients and studies in the meta-analysis. Janni received a research grant from Menarini Silicon Biosystems. Other study authors have financial ties to healthcare industries. Kaklamani has received consulting fees from Amgen, Eisai, Puma, Celldex, AstraZeneca, and Athenex; fees for non-CME services received directly from commercial interest or their agents from Pfizer, Celgene, Genentech, Genomic Health, Puma, Eisai, and Novartis; and has contracted research with Eisai.
This article first appeared on Medscape.com.
FROM SABCS 2020
Five-minute SC injection of daratumumab in RRMM
Data from the Apollo study provide proof for the subcutaneous administration (SC) of daratumumab (Darzalex Faspro) in combination with pomalidomide (Pomalyst) and dexamethasone (Pd) for patients with relapsed or refractory multiple myeloma (RRMM).
The SC formulation of daratumumab (with hyaluronidase) was approved in the United States in May, and is administered by injection into the abdomen over 3-5 minutes. Previously the drug was available only as an intravenous infusion.
“The appeal of subcutaneous daratumumab is the 5 minutes it needs for administering, cutting down considerable on ‘chair/clinic’ time. Intravenous daratumumab is given over several hours,” said Joseph Mikhael, MD, MEd, chief medical officer of the International Myeloma Foundation. He also highlighted the low rates of infusion reactions seen with the subcutaneous daratumumab triplet.
“In the COVID era the subcutaneous route may be the way to go,” he said in an interview.
“This is an effective combination with a predictable safety profile that allows for the use of SC daratumumab along with oral pomalidomide and dexamethasone for patients who have received at least one prior line of therapy that included lenalidomide [Revlimid] and a proteasome inhibitor,” commented lead author Meletios A. Dimopoulos, MD, of the National and Kapodistrian University of Athens.
The triplet combination was associated with a 37% reduced risk for progression or death, compared with the two-drug combination of pomalidomide and dexamethasone.
He presented the results from the Apollo trial at the annual meeting of the American Society of Hematology.
Treatment landscape of RRMM
Dr. Mikhael, who is also professor in the applied cancer research and drug discovery division at the Translational Genomics Research Institute, Phoenix, provided his insights into Apollo as well as how this triplet fits into the treatment landscape of RRMM.
Daratumumab is approved for use in both RRMM and newly diagnosed MM, either alone or in combination with standard-of-care regimens. The drug already has eight specific indications for the intravenous formulation, and five indications for the SC formulation of daratumumab, Dr. Mikhael noted. The Apollo study “will likely provide the subcutaneous approval for the daratumumab triplet in MM.”
According to Dr. Mikhael, the triplet of daratumumab with pomalidomide and dexamethasone is the most commonly used combination at first relapse, and this phase 3 study provides confirmatory evidence for its initial approval. The initial approval for intravenous daratumumab and Pd was based on a phase 1b study, he noted.
“The Apollo study is the first randomized trial comparing the triplet of D-Pd to Pd,” Noopur Raje, MD, of the Massachusetts General Hospital, Boston, said in an interview. She explained that the majority of patients included in Apollo were refractory to lenalidomide, which is the patient population typically seen at the time of first relapse. “This regimen will be adopted at either first or second relapse in the majority of patients,” Dr. Raje said.
“In keeping with strategy in MM, we use the best triplet first and do not save the best for last,” Dr. Mikhael said. The triplet of the proteasome inhibitor bortezomib (Velcade), lenalidomide, and dexamethasone is used in first-line MM. “Most patients meet the criteria for using D-Pd at first relapse,” he added, noting that all patients in the study have received a proteasome inhibitor and lenalidomide as first-line therapy and had relapsed with or were refractory to these agents.
“The short administration time and significantly low rates of infusion-site reactions are two important considerations for using this triplet with the subcutaneous formulation of daratumumab [at first relapse],” he said.
In the treatment landscape of MM, the triplet of isatuximab (Sarclisa), pomalidomide, and dexamethasone has recently been approved for RRMM based on data from the ICARIA study. Isatuximab and daratumumab are both CD38-directed antibodies. Dr. Mikhael pointed out that the datasets from ICARIA and Apollo with respect to progression-free survival (PFS) and hazard ratios overlapped and were remarkably similar. However, daratumumab now has an advantage in being available as an SC formulation.
The landscape of MM treatment has been changing rapidly in recent years, and more changes may be afoot. Dr. Mikhael suggested that the quartet of daratumumab, bortezomib, lenalidomide, and dexamethasone is likely to move into the first-line setting for MM based on data from the GRIFFIN study (trial update in Abstract 3243), and then the choice of drugs to use in first relapse would also change.
Apollo study details
Apollo was an open-label, phase 3 study that randomly assigned patients with RRMM to receive SC daratumumab in combination with pomalidomide and low-dose dexamethasone (D-Pd; n = 151) or the two-drug combination of Pd (n = 153).
Approximately 80% of the patients were refractory to lenalidomide and half were refractory to a proteasome inhibitor.
Median duration of SC daratumumab administration was 5 minutes. Median duration of study treatment was longer for patients on D-Pd (11.5 months vs. 6.6 months for Pd).
For the primary endpoint, at a median follow up of 16.9 months, median PFS was 12.4 months for patients receiving D-Pd and 6.9 months for those receiving Pd. One-year PFS was 52% for patients receiving the triplet combination and 35% for those receiving Pd. Treatment effect was generally consistent across subgroups examined, Dr. Dimopoulos reported.
Depth of response was significantly higher for patients on D-Pd. Stringent complete remission or CR was seen in 25% of patients on D-Pd versus 4% on Pd. Overall response rate was 69% for patients on D-Pd and 45% for patients on Pd alone (P < .0001). Minimal residual disease negativity was more than four times higher with D-Pd (9% vs. 2% for Pd; P = .0102).
The safety profile of D-Pd was consistent with the known safety profile of SC daratumumab and Pd. Infusion-site reactions were grade 1-2 and occurred in 5% of patients; in addition, only grade 1 injection-site reactions were seen and occurred in 2% of patients. The most serious treatment-emergent adverse events in patients on D-Pd were pneumonia (15% vs. 8% for Pd) and lower respiratory tract infection (12% vs. 9% for Pd). Incidence of secondary primary malignancy was 2% for each group.
Apollo results were ‘no surprise’
“These results are of no surprise and further support the current practice of using a three-drug combination in the relapsed setting,” Henry Fung, MD, chair of the department of bone marrow transplant and cellular therapies at Fox Chase Cancer Center, Philadelphia, said in an interview.
Although Dr. Fung agreed that the triplet of a proteasome inhibitor, an immunomodulating drug such as lenalidomide, and the steroid dexamethasone is becoming the standard of care for newly diagnosed MM, D-Pd should be considered an excellent option for patients who have limited choices in the relapsed/refractory setting.
However, he said that the median PFS of 12.4 months for patients receiving D-Pd after a median of two prior regimens is not satisfactory.
“The impact on the natural history of the disease will be limited and the duration of responses decline with each treatment regimen, and the true impact on the disease will be an effective frontline strategy.” Dr. Fung said. “This will not be a practice-changing trial. We need to find out which three-drug regimen works best and what biomarkers can predict the response to individual regimen.”
Dr. Dimopoulos reported receiving honoraria from Beigene, Bristol-Myers Squibb, Amgen, Takeda, Celgene, and Janssen. Dr. Mikhael reported receiving honoraria from Amgen, GlaxoSmithKline, Janssen, Karyopharm, Sanofi, Takeda; consulting with Celgene; and receiving research funding from Celgene and Sanofi. Dr. Fung is on the speakers’ bureau of Apollo and receives honoraria from Jansen Oncology and Celgene/Bristol-Myers Squibb. Dr. Raje is a consultant for Bristol-Myers Squibb and Janssen.
A version of this article originally appeared on Medscape.com.
Data from the Apollo study provide proof for the subcutaneous administration (SC) of daratumumab (Darzalex Faspro) in combination with pomalidomide (Pomalyst) and dexamethasone (Pd) for patients with relapsed or refractory multiple myeloma (RRMM).
The SC formulation of daratumumab (with hyaluronidase) was approved in the United States in May, and is administered by injection into the abdomen over 3-5 minutes. Previously the drug was available only as an intravenous infusion.
“The appeal of subcutaneous daratumumab is the 5 minutes it needs for administering, cutting down considerable on ‘chair/clinic’ time. Intravenous daratumumab is given over several hours,” said Joseph Mikhael, MD, MEd, chief medical officer of the International Myeloma Foundation. He also highlighted the low rates of infusion reactions seen with the subcutaneous daratumumab triplet.
“In the COVID era the subcutaneous route may be the way to go,” he said in an interview.
“This is an effective combination with a predictable safety profile that allows for the use of SC daratumumab along with oral pomalidomide and dexamethasone for patients who have received at least one prior line of therapy that included lenalidomide [Revlimid] and a proteasome inhibitor,” commented lead author Meletios A. Dimopoulos, MD, of the National and Kapodistrian University of Athens.
The triplet combination was associated with a 37% reduced risk for progression or death, compared with the two-drug combination of pomalidomide and dexamethasone.
He presented the results from the Apollo trial at the annual meeting of the American Society of Hematology.
Treatment landscape of RRMM
Dr. Mikhael, who is also professor in the applied cancer research and drug discovery division at the Translational Genomics Research Institute, Phoenix, provided his insights into Apollo as well as how this triplet fits into the treatment landscape of RRMM.
Daratumumab is approved for use in both RRMM and newly diagnosed MM, either alone or in combination with standard-of-care regimens. The drug already has eight specific indications for the intravenous formulation, and five indications for the SC formulation of daratumumab, Dr. Mikhael noted. The Apollo study “will likely provide the subcutaneous approval for the daratumumab triplet in MM.”
According to Dr. Mikhael, the triplet of daratumumab with pomalidomide and dexamethasone is the most commonly used combination at first relapse, and this phase 3 study provides confirmatory evidence for its initial approval. The initial approval for intravenous daratumumab and Pd was based on a phase 1b study, he noted.
“The Apollo study is the first randomized trial comparing the triplet of D-Pd to Pd,” Noopur Raje, MD, of the Massachusetts General Hospital, Boston, said in an interview. She explained that the majority of patients included in Apollo were refractory to lenalidomide, which is the patient population typically seen at the time of first relapse. “This regimen will be adopted at either first or second relapse in the majority of patients,” Dr. Raje said.
“In keeping with strategy in MM, we use the best triplet first and do not save the best for last,” Dr. Mikhael said. The triplet of the proteasome inhibitor bortezomib (Velcade), lenalidomide, and dexamethasone is used in first-line MM. “Most patients meet the criteria for using D-Pd at first relapse,” he added, noting that all patients in the study have received a proteasome inhibitor and lenalidomide as first-line therapy and had relapsed with or were refractory to these agents.
“The short administration time and significantly low rates of infusion-site reactions are two important considerations for using this triplet with the subcutaneous formulation of daratumumab [at first relapse],” he said.
In the treatment landscape of MM, the triplet of isatuximab (Sarclisa), pomalidomide, and dexamethasone has recently been approved for RRMM based on data from the ICARIA study. Isatuximab and daratumumab are both CD38-directed antibodies. Dr. Mikhael pointed out that the datasets from ICARIA and Apollo with respect to progression-free survival (PFS) and hazard ratios overlapped and were remarkably similar. However, daratumumab now has an advantage in being available as an SC formulation.
The landscape of MM treatment has been changing rapidly in recent years, and more changes may be afoot. Dr. Mikhael suggested that the quartet of daratumumab, bortezomib, lenalidomide, and dexamethasone is likely to move into the first-line setting for MM based on data from the GRIFFIN study (trial update in Abstract 3243), and then the choice of drugs to use in first relapse would also change.
Apollo study details
Apollo was an open-label, phase 3 study that randomly assigned patients with RRMM to receive SC daratumumab in combination with pomalidomide and low-dose dexamethasone (D-Pd; n = 151) or the two-drug combination of Pd (n = 153).
Approximately 80% of the patients were refractory to lenalidomide and half were refractory to a proteasome inhibitor.
Median duration of SC daratumumab administration was 5 minutes. Median duration of study treatment was longer for patients on D-Pd (11.5 months vs. 6.6 months for Pd).
For the primary endpoint, at a median follow up of 16.9 months, median PFS was 12.4 months for patients receiving D-Pd and 6.9 months for those receiving Pd. One-year PFS was 52% for patients receiving the triplet combination and 35% for those receiving Pd. Treatment effect was generally consistent across subgroups examined, Dr. Dimopoulos reported.
Depth of response was significantly higher for patients on D-Pd. Stringent complete remission or CR was seen in 25% of patients on D-Pd versus 4% on Pd. Overall response rate was 69% for patients on D-Pd and 45% for patients on Pd alone (P < .0001). Minimal residual disease negativity was more than four times higher with D-Pd (9% vs. 2% for Pd; P = .0102).
The safety profile of D-Pd was consistent with the known safety profile of SC daratumumab and Pd. Infusion-site reactions were grade 1-2 and occurred in 5% of patients; in addition, only grade 1 injection-site reactions were seen and occurred in 2% of patients. The most serious treatment-emergent adverse events in patients on D-Pd were pneumonia (15% vs. 8% for Pd) and lower respiratory tract infection (12% vs. 9% for Pd). Incidence of secondary primary malignancy was 2% for each group.
Apollo results were ‘no surprise’
“These results are of no surprise and further support the current practice of using a three-drug combination in the relapsed setting,” Henry Fung, MD, chair of the department of bone marrow transplant and cellular therapies at Fox Chase Cancer Center, Philadelphia, said in an interview.
Although Dr. Fung agreed that the triplet of a proteasome inhibitor, an immunomodulating drug such as lenalidomide, and the steroid dexamethasone is becoming the standard of care for newly diagnosed MM, D-Pd should be considered an excellent option for patients who have limited choices in the relapsed/refractory setting.
However, he said that the median PFS of 12.4 months for patients receiving D-Pd after a median of two prior regimens is not satisfactory.
“The impact on the natural history of the disease will be limited and the duration of responses decline with each treatment regimen, and the true impact on the disease will be an effective frontline strategy.” Dr. Fung said. “This will not be a practice-changing trial. We need to find out which three-drug regimen works best and what biomarkers can predict the response to individual regimen.”
Dr. Dimopoulos reported receiving honoraria from Beigene, Bristol-Myers Squibb, Amgen, Takeda, Celgene, and Janssen. Dr. Mikhael reported receiving honoraria from Amgen, GlaxoSmithKline, Janssen, Karyopharm, Sanofi, Takeda; consulting with Celgene; and receiving research funding from Celgene and Sanofi. Dr. Fung is on the speakers’ bureau of Apollo and receives honoraria from Jansen Oncology and Celgene/Bristol-Myers Squibb. Dr. Raje is a consultant for Bristol-Myers Squibb and Janssen.
A version of this article originally appeared on Medscape.com.
Data from the Apollo study provide proof for the subcutaneous administration (SC) of daratumumab (Darzalex Faspro) in combination with pomalidomide (Pomalyst) and dexamethasone (Pd) for patients with relapsed or refractory multiple myeloma (RRMM).
The SC formulation of daratumumab (with hyaluronidase) was approved in the United States in May, and is administered by injection into the abdomen over 3-5 minutes. Previously the drug was available only as an intravenous infusion.
“The appeal of subcutaneous daratumumab is the 5 minutes it needs for administering, cutting down considerable on ‘chair/clinic’ time. Intravenous daratumumab is given over several hours,” said Joseph Mikhael, MD, MEd, chief medical officer of the International Myeloma Foundation. He also highlighted the low rates of infusion reactions seen with the subcutaneous daratumumab triplet.
“In the COVID era the subcutaneous route may be the way to go,” he said in an interview.
“This is an effective combination with a predictable safety profile that allows for the use of SC daratumumab along with oral pomalidomide and dexamethasone for patients who have received at least one prior line of therapy that included lenalidomide [Revlimid] and a proteasome inhibitor,” commented lead author Meletios A. Dimopoulos, MD, of the National and Kapodistrian University of Athens.
The triplet combination was associated with a 37% reduced risk for progression or death, compared with the two-drug combination of pomalidomide and dexamethasone.
He presented the results from the Apollo trial at the annual meeting of the American Society of Hematology.
Treatment landscape of RRMM
Dr. Mikhael, who is also professor in the applied cancer research and drug discovery division at the Translational Genomics Research Institute, Phoenix, provided his insights into Apollo as well as how this triplet fits into the treatment landscape of RRMM.
Daratumumab is approved for use in both RRMM and newly diagnosed MM, either alone or in combination with standard-of-care regimens. The drug already has eight specific indications for the intravenous formulation, and five indications for the SC formulation of daratumumab, Dr. Mikhael noted. The Apollo study “will likely provide the subcutaneous approval for the daratumumab triplet in MM.”
According to Dr. Mikhael, the triplet of daratumumab with pomalidomide and dexamethasone is the most commonly used combination at first relapse, and this phase 3 study provides confirmatory evidence for its initial approval. The initial approval for intravenous daratumumab and Pd was based on a phase 1b study, he noted.
“The Apollo study is the first randomized trial comparing the triplet of D-Pd to Pd,” Noopur Raje, MD, of the Massachusetts General Hospital, Boston, said in an interview. She explained that the majority of patients included in Apollo were refractory to lenalidomide, which is the patient population typically seen at the time of first relapse. “This regimen will be adopted at either first or second relapse in the majority of patients,” Dr. Raje said.
“In keeping with strategy in MM, we use the best triplet first and do not save the best for last,” Dr. Mikhael said. The triplet of the proteasome inhibitor bortezomib (Velcade), lenalidomide, and dexamethasone is used in first-line MM. “Most patients meet the criteria for using D-Pd at first relapse,” he added, noting that all patients in the study have received a proteasome inhibitor and lenalidomide as first-line therapy and had relapsed with or were refractory to these agents.
“The short administration time and significantly low rates of infusion-site reactions are two important considerations for using this triplet with the subcutaneous formulation of daratumumab [at first relapse],” he said.
In the treatment landscape of MM, the triplet of isatuximab (Sarclisa), pomalidomide, and dexamethasone has recently been approved for RRMM based on data from the ICARIA study. Isatuximab and daratumumab are both CD38-directed antibodies. Dr. Mikhael pointed out that the datasets from ICARIA and Apollo with respect to progression-free survival (PFS) and hazard ratios overlapped and were remarkably similar. However, daratumumab now has an advantage in being available as an SC formulation.
The landscape of MM treatment has been changing rapidly in recent years, and more changes may be afoot. Dr. Mikhael suggested that the quartet of daratumumab, bortezomib, lenalidomide, and dexamethasone is likely to move into the first-line setting for MM based on data from the GRIFFIN study (trial update in Abstract 3243), and then the choice of drugs to use in first relapse would also change.
Apollo study details
Apollo was an open-label, phase 3 study that randomly assigned patients with RRMM to receive SC daratumumab in combination with pomalidomide and low-dose dexamethasone (D-Pd; n = 151) or the two-drug combination of Pd (n = 153).
Approximately 80% of the patients were refractory to lenalidomide and half were refractory to a proteasome inhibitor.
Median duration of SC daratumumab administration was 5 minutes. Median duration of study treatment was longer for patients on D-Pd (11.5 months vs. 6.6 months for Pd).
For the primary endpoint, at a median follow up of 16.9 months, median PFS was 12.4 months for patients receiving D-Pd and 6.9 months for those receiving Pd. One-year PFS was 52% for patients receiving the triplet combination and 35% for those receiving Pd. Treatment effect was generally consistent across subgroups examined, Dr. Dimopoulos reported.
Depth of response was significantly higher for patients on D-Pd. Stringent complete remission or CR was seen in 25% of patients on D-Pd versus 4% on Pd. Overall response rate was 69% for patients on D-Pd and 45% for patients on Pd alone (P < .0001). Minimal residual disease negativity was more than four times higher with D-Pd (9% vs. 2% for Pd; P = .0102).
The safety profile of D-Pd was consistent with the known safety profile of SC daratumumab and Pd. Infusion-site reactions were grade 1-2 and occurred in 5% of patients; in addition, only grade 1 injection-site reactions were seen and occurred in 2% of patients. The most serious treatment-emergent adverse events in patients on D-Pd were pneumonia (15% vs. 8% for Pd) and lower respiratory tract infection (12% vs. 9% for Pd). Incidence of secondary primary malignancy was 2% for each group.
Apollo results were ‘no surprise’
“These results are of no surprise and further support the current practice of using a three-drug combination in the relapsed setting,” Henry Fung, MD, chair of the department of bone marrow transplant and cellular therapies at Fox Chase Cancer Center, Philadelphia, said in an interview.
Although Dr. Fung agreed that the triplet of a proteasome inhibitor, an immunomodulating drug such as lenalidomide, and the steroid dexamethasone is becoming the standard of care for newly diagnosed MM, D-Pd should be considered an excellent option for patients who have limited choices in the relapsed/refractory setting.
However, he said that the median PFS of 12.4 months for patients receiving D-Pd after a median of two prior regimens is not satisfactory.
“The impact on the natural history of the disease will be limited and the duration of responses decline with each treatment regimen, and the true impact on the disease will be an effective frontline strategy.” Dr. Fung said. “This will not be a practice-changing trial. We need to find out which three-drug regimen works best and what biomarkers can predict the response to individual regimen.”
Dr. Dimopoulos reported receiving honoraria from Beigene, Bristol-Myers Squibb, Amgen, Takeda, Celgene, and Janssen. Dr. Mikhael reported receiving honoraria from Amgen, GlaxoSmithKline, Janssen, Karyopharm, Sanofi, Takeda; consulting with Celgene; and receiving research funding from Celgene and Sanofi. Dr. Fung is on the speakers’ bureau of Apollo and receives honoraria from Jansen Oncology and Celgene/Bristol-Myers Squibb. Dr. Raje is a consultant for Bristol-Myers Squibb and Janssen.
A version of this article originally appeared on Medscape.com.
Emotions, worse attention linked to pain-related health care use in SCD
The cognitive and emotional status of children with sickle cell disease (SCD) appears to have a significant effect on how they cope with pain and use health care resources, investigators have found.
Results of a retrospective study of 112 children and adolescents with SCD, the majority of whom had sickle cell anemia, showed that ED visits and hospitalizations were significantly lower among children with SCD who performed better on an attention task, as well as those who were better able to cope emotionally with having SCD and pain, reported Zaria Williams, a second-year medical student at Howard University, Washington, and colleagues.
“Since I started learning more about sickle cell disease, I’ve been very concerned about the great disease burden that this condition can place on pediatric patients, particularly those who suffer from pain,” Ms. Williams said in an oral abstract presented at the annual meeting of the American Society of Hematology.
Although many children and adolescents with SCD can have their pain effectively managed at home with opioids and other medications, some require ED visits and potentially hospitalizations for pain management.
“There is great variability in health care utilization among patients with sickle cell disease, with some having to come to the ED and be admit to the hospital more than others. In searching for reasons why this might be the case, we thought about cognitive function and emotional differences between children with sickle cell disease as potentially affecting disease management,” she said.
Anxiety and catastrophizing
Children with SCD are known to be susceptible to affective comorbidities such as anxiety and catastrophizing, and to conditions that have the potential for deleterious effects on executive function, attention, and working memory. To determine whether cognitive and emotional factors affect the disease self-management in children and adolescents with SCD, Ms. Williams and coinvestigators looked at a cohort of 112 SCD patients aged 7-16 years treated at Children’s National Hospital in Washington, D.C.
The patients had participated in a previous pilot study of computerized working memory training. The authors reviewed charts for data on health care utilization, focusing on ED visits and hospitalization for pain 1 and 3 years after enrollment in the study.
They collected data on SCD genotype, disease-related variables, psychosocial information, and measures of cognition and emotion from the dataset. The information included socioeconomic status, parent education level, household income, and number of adults in the household.
Cognitive measures included the Weschler Intelligence Scale for Children full scale IQ, and the Cogstate computerized cognitive assessment system, which measures attention, executive function, and working memory.
Emotional measures were captured from the Pediatric Quality of Life Inventory Sickle Cell Disease module, including questions about worrying and emotions such as anger regarding SCD and pain.
The mean age of participants was 10.61 years. Of the 112 children/adolescents in the study, 65 (58%) were female, and 83 (74%) had sickle cell anemia (either HbSS or HbSβ0 thalassemia).
The participants had a median number of ED visits for pain of one within a year of enrollment, and a median of three within 3 years of enrollment,
The median number of hospital admissions for pain was zero and one, respectively.
Attention, emotions linked to higher use
Factors significantly associated with ED visits for pain within the first year were higher (worse) scores for attention (P = .001) and self-reported emotion (P = .049). ED visits within 3 years of enrollment were associated with attention (P = .003) and working memory (P = .039).
Similarly, hospitalizations for pain within the first year were significantly associated with worse attention scores (P = .009) and child-reported emotion (P = .013). Hospitalizations for pain within 3 years of enrollment were also significantly associated with attention deficits (P = .006) and with worse emotional function as reported by a parent (P = .020).
There was no significant effect of SCD genotype or socioeconomic status on either pain-related ED visits or hospitalizations, however.
The investigators theorized that poor attention may make it difficult to distract children from focusing on their pain, and could also hamper disease self-management strategies such as medication adherence and avoiding pain triggers.
Age-related differences?
In the question-and-answer session following her presentation, comoderator Susanna A Curtis, MD, from Yale New Haven (Conn.) Hospital, commented that “some previous work has shown that adolescents and young adults with sickle cell disease have higher utilization as compared to their younger counterparts,” and asked whether the investigators found differences between cognition and utilization among different age groups within the cohort.
“We didn’t find a significant association with age, but I’m also very interested in that as well, especially considering that maybe there is more or less parent involvement, considering how old the child is,” Ms. Williams said.
Dr. Curtis noted that many of the comorbidities of sickle cell disease such as stroke or degree of anemia can affect cognitive function, but can also have an effect on health care utilization as well, asked whether the investigators were able to look at the potential confounding effects of comorbidities.
Ms. Williams said that, although they have not looked at potential confounders as yet, they hope to do so in future research.
Asked by another audience member whether the authors had considered using the Pain Catastrophizing Scale for children and/or their parents, in addition to other markers, Ms. Williams replied that “I definitely have considered it. Under recommendations from my mentors, we just focused on the quality-of-life scale first, but catastrophizing is something I’m very interested in. Especially, I would love to have the parent factors as well, so along the journey I hope to include that.”
The study was sponsored in part by a grant from the Doris Duke Charitable Foundation. Ms Williams is the recipient of an ASH Minority Medical Student Award. Dr. Curtis and Ms. Williams both reported no relevant conflicts of interest to disclose.
SOURCE: Williams Z et al. ASH 2020, Abstract 366
The cognitive and emotional status of children with sickle cell disease (SCD) appears to have a significant effect on how they cope with pain and use health care resources, investigators have found.
Results of a retrospective study of 112 children and adolescents with SCD, the majority of whom had sickle cell anemia, showed that ED visits and hospitalizations were significantly lower among children with SCD who performed better on an attention task, as well as those who were better able to cope emotionally with having SCD and pain, reported Zaria Williams, a second-year medical student at Howard University, Washington, and colleagues.
“Since I started learning more about sickle cell disease, I’ve been very concerned about the great disease burden that this condition can place on pediatric patients, particularly those who suffer from pain,” Ms. Williams said in an oral abstract presented at the annual meeting of the American Society of Hematology.
Although many children and adolescents with SCD can have their pain effectively managed at home with opioids and other medications, some require ED visits and potentially hospitalizations for pain management.
“There is great variability in health care utilization among patients with sickle cell disease, with some having to come to the ED and be admit to the hospital more than others. In searching for reasons why this might be the case, we thought about cognitive function and emotional differences between children with sickle cell disease as potentially affecting disease management,” she said.
Anxiety and catastrophizing
Children with SCD are known to be susceptible to affective comorbidities such as anxiety and catastrophizing, and to conditions that have the potential for deleterious effects on executive function, attention, and working memory. To determine whether cognitive and emotional factors affect the disease self-management in children and adolescents with SCD, Ms. Williams and coinvestigators looked at a cohort of 112 SCD patients aged 7-16 years treated at Children’s National Hospital in Washington, D.C.
The patients had participated in a previous pilot study of computerized working memory training. The authors reviewed charts for data on health care utilization, focusing on ED visits and hospitalization for pain 1 and 3 years after enrollment in the study.
They collected data on SCD genotype, disease-related variables, psychosocial information, and measures of cognition and emotion from the dataset. The information included socioeconomic status, parent education level, household income, and number of adults in the household.
Cognitive measures included the Weschler Intelligence Scale for Children full scale IQ, and the Cogstate computerized cognitive assessment system, which measures attention, executive function, and working memory.
Emotional measures were captured from the Pediatric Quality of Life Inventory Sickle Cell Disease module, including questions about worrying and emotions such as anger regarding SCD and pain.
The mean age of participants was 10.61 years. Of the 112 children/adolescents in the study, 65 (58%) were female, and 83 (74%) had sickle cell anemia (either HbSS or HbSβ0 thalassemia).
The participants had a median number of ED visits for pain of one within a year of enrollment, and a median of three within 3 years of enrollment,
The median number of hospital admissions for pain was zero and one, respectively.
Attention, emotions linked to higher use
Factors significantly associated with ED visits for pain within the first year were higher (worse) scores for attention (P = .001) and self-reported emotion (P = .049). ED visits within 3 years of enrollment were associated with attention (P = .003) and working memory (P = .039).
Similarly, hospitalizations for pain within the first year were significantly associated with worse attention scores (P = .009) and child-reported emotion (P = .013). Hospitalizations for pain within 3 years of enrollment were also significantly associated with attention deficits (P = .006) and with worse emotional function as reported by a parent (P = .020).
There was no significant effect of SCD genotype or socioeconomic status on either pain-related ED visits or hospitalizations, however.
The investigators theorized that poor attention may make it difficult to distract children from focusing on their pain, and could also hamper disease self-management strategies such as medication adherence and avoiding pain triggers.
Age-related differences?
In the question-and-answer session following her presentation, comoderator Susanna A Curtis, MD, from Yale New Haven (Conn.) Hospital, commented that “some previous work has shown that adolescents and young adults with sickle cell disease have higher utilization as compared to their younger counterparts,” and asked whether the investigators found differences between cognition and utilization among different age groups within the cohort.
“We didn’t find a significant association with age, but I’m also very interested in that as well, especially considering that maybe there is more or less parent involvement, considering how old the child is,” Ms. Williams said.
Dr. Curtis noted that many of the comorbidities of sickle cell disease such as stroke or degree of anemia can affect cognitive function, but can also have an effect on health care utilization as well, asked whether the investigators were able to look at the potential confounding effects of comorbidities.
Ms. Williams said that, although they have not looked at potential confounders as yet, they hope to do so in future research.
Asked by another audience member whether the authors had considered using the Pain Catastrophizing Scale for children and/or their parents, in addition to other markers, Ms. Williams replied that “I definitely have considered it. Under recommendations from my mentors, we just focused on the quality-of-life scale first, but catastrophizing is something I’m very interested in. Especially, I would love to have the parent factors as well, so along the journey I hope to include that.”
The study was sponsored in part by a grant from the Doris Duke Charitable Foundation. Ms Williams is the recipient of an ASH Minority Medical Student Award. Dr. Curtis and Ms. Williams both reported no relevant conflicts of interest to disclose.
SOURCE: Williams Z et al. ASH 2020, Abstract 366
The cognitive and emotional status of children with sickle cell disease (SCD) appears to have a significant effect on how they cope with pain and use health care resources, investigators have found.
Results of a retrospective study of 112 children and adolescents with SCD, the majority of whom had sickle cell anemia, showed that ED visits and hospitalizations were significantly lower among children with SCD who performed better on an attention task, as well as those who were better able to cope emotionally with having SCD and pain, reported Zaria Williams, a second-year medical student at Howard University, Washington, and colleagues.
“Since I started learning more about sickle cell disease, I’ve been very concerned about the great disease burden that this condition can place on pediatric patients, particularly those who suffer from pain,” Ms. Williams said in an oral abstract presented at the annual meeting of the American Society of Hematology.
Although many children and adolescents with SCD can have their pain effectively managed at home with opioids and other medications, some require ED visits and potentially hospitalizations for pain management.
“There is great variability in health care utilization among patients with sickle cell disease, with some having to come to the ED and be admit to the hospital more than others. In searching for reasons why this might be the case, we thought about cognitive function and emotional differences between children with sickle cell disease as potentially affecting disease management,” she said.
Anxiety and catastrophizing
Children with SCD are known to be susceptible to affective comorbidities such as anxiety and catastrophizing, and to conditions that have the potential for deleterious effects on executive function, attention, and working memory. To determine whether cognitive and emotional factors affect the disease self-management in children and adolescents with SCD, Ms. Williams and coinvestigators looked at a cohort of 112 SCD patients aged 7-16 years treated at Children’s National Hospital in Washington, D.C.
The patients had participated in a previous pilot study of computerized working memory training. The authors reviewed charts for data on health care utilization, focusing on ED visits and hospitalization for pain 1 and 3 years after enrollment in the study.
They collected data on SCD genotype, disease-related variables, psychosocial information, and measures of cognition and emotion from the dataset. The information included socioeconomic status, parent education level, household income, and number of adults in the household.
Cognitive measures included the Weschler Intelligence Scale for Children full scale IQ, and the Cogstate computerized cognitive assessment system, which measures attention, executive function, and working memory.
Emotional measures were captured from the Pediatric Quality of Life Inventory Sickle Cell Disease module, including questions about worrying and emotions such as anger regarding SCD and pain.
The mean age of participants was 10.61 years. Of the 112 children/adolescents in the study, 65 (58%) were female, and 83 (74%) had sickle cell anemia (either HbSS or HbSβ0 thalassemia).
The participants had a median number of ED visits for pain of one within a year of enrollment, and a median of three within 3 years of enrollment,
The median number of hospital admissions for pain was zero and one, respectively.
Attention, emotions linked to higher use
Factors significantly associated with ED visits for pain within the first year were higher (worse) scores for attention (P = .001) and self-reported emotion (P = .049). ED visits within 3 years of enrollment were associated with attention (P = .003) and working memory (P = .039).
Similarly, hospitalizations for pain within the first year were significantly associated with worse attention scores (P = .009) and child-reported emotion (P = .013). Hospitalizations for pain within 3 years of enrollment were also significantly associated with attention deficits (P = .006) and with worse emotional function as reported by a parent (P = .020).
There was no significant effect of SCD genotype or socioeconomic status on either pain-related ED visits or hospitalizations, however.
The investigators theorized that poor attention may make it difficult to distract children from focusing on their pain, and could also hamper disease self-management strategies such as medication adherence and avoiding pain triggers.
Age-related differences?
In the question-and-answer session following her presentation, comoderator Susanna A Curtis, MD, from Yale New Haven (Conn.) Hospital, commented that “some previous work has shown that adolescents and young adults with sickle cell disease have higher utilization as compared to their younger counterparts,” and asked whether the investigators found differences between cognition and utilization among different age groups within the cohort.
“We didn’t find a significant association with age, but I’m also very interested in that as well, especially considering that maybe there is more or less parent involvement, considering how old the child is,” Ms. Williams said.
Dr. Curtis noted that many of the comorbidities of sickle cell disease such as stroke or degree of anemia can affect cognitive function, but can also have an effect on health care utilization as well, asked whether the investigators were able to look at the potential confounding effects of comorbidities.
Ms. Williams said that, although they have not looked at potential confounders as yet, they hope to do so in future research.
Asked by another audience member whether the authors had considered using the Pain Catastrophizing Scale for children and/or their parents, in addition to other markers, Ms. Williams replied that “I definitely have considered it. Under recommendations from my mentors, we just focused on the quality-of-life scale first, but catastrophizing is something I’m very interested in. Especially, I would love to have the parent factors as well, so along the journey I hope to include that.”
The study was sponsored in part by a grant from the Doris Duke Charitable Foundation. Ms Williams is the recipient of an ASH Minority Medical Student Award. Dr. Curtis and Ms. Williams both reported no relevant conflicts of interest to disclose.
SOURCE: Williams Z et al. ASH 2020, Abstract 366
FROM ASH 2020
Moving from subtypes to phenotypes is simplifying management of rosacea
When a new phenotype approach to the diagnosis of rosacea was proposed 2 years ago, this simpler and more accurate method was accompanied by several corollary advantages, including a more rational approach to treatment and better methods of measuring treatment efficacy, according to an expert speaking at the annual Coastal Dermatology Symposium, held virtually.
“By looking at rosacea in a more simple way – but a more accurate way – we are able to track what happens [to key features] over time,” explained Jerry Tan, MD, of the University of Western Ontario, London.
With the previous method of subtyping, many rosacea patients failed to fit neatly into any of the four categories, producing confusion and diverting attention from troublesome symptoms.
“Rosacea patients often present with a range of features that span multiple subtypes or progress between them,” Dr. Tan explained. The risk is not just a delay in diagnosis but a failure to focus on symptoms patients find most bothersome.
The previous diagnostic criteria for rosacea, published in 2002, identified primary and secondary symptoms within its four subtypes. The new diagnostic criteria, endorsed by the National Rosacea Society and published in 2018, rely on phenotypes defined by diagnostic, major, and minor symptoms. Rather than the four previous subtypes, which were erythematotelangiectatic, papulopustular, phymatous, and ocular, the phenotypes facilitate diagnosis in patients with mixed features.
By replacing “the old thought process of subtyping” with a newer focus on phenotypes, the updated criteria were “aimed toward accuracy, simplicity and practicality,” Dr. Tan said.
Moreover, without squeezing patients into subgroups where they do not neatly fit, the new criteria draw attention to the specific symptoms that bring patients to the clinician.
The phenotype approach to treatment strategies was reflected in a systematic review of treatments based on phenotypes that was published in 2019, not long after the new classification system became available. In this review, coauthored by Dr. Tan, the GRADE certainty-of-evidence approach was employed to identify effective therapies, matching specific symptoms with specific therapies such as low-dose isotretinoin for papules or omega-3 fatty acids for dry eyes.
Based on a patient-centric approach that emphasizes control of key symptoms, Dr. Tan also described a method of documenting the severity of major and minor symptoms at each visit. With this method, called a rosacea patient tracker, patients and physicians can determine whether therapies are effective against the signs and symptoms of disease that they find most burdensome, according to Dr. Tan, who was the first author of an article he cited as a reference to this phenotype-based methodology.
Overall, the phenotype approach to rosacea “rationalizes treatment,” he said.
Specifically, the heterogeneity of symptoms in rosacea is mirrored in the heterogeneity of underlying pathophysiology. According to Dr. Tan, the upregulation of cytokines for inflammation, of angiogenic pathways for vascular symptoms, and of matrix metalloproteinases for tissue remodeling are all implicated in rosacea but drive different types of symptoms. While appropriate skin care and efforts to identify and minimize symptom triggers is appropriate for all patients, phenotypes provide a guide to the most appropriate therapies.
He said he hopes that the focus on phenotypes will draw attention to differences in these pathophysiological mechanisms. According to Dr. Tan, evaluating rosacea from the perspective of phenotypes has represented an important paradigm shift that extends beyond diagnosis.
“The move to the phenotype approach is hopefully simpler, more accurate, and more relevant,” Dr. Tan said.
This same approach has been advocated by others, including Esther J. van Zurren, MD, professor of dermatology at Leiden University Medical Centre in the Netherlands, the lead author of the 2018 systematic review article discussed by Dr. Tan. In this review article on the phenotype approach, specific strategies were recommended for specific symptoms on the basis of grading by an international group of experts that included Dr. Tan, a coauthor.
“These strategies should be directed toward achieving improvements in general well-being by targeting those aspects most bothersome to the patient,” the article advises. Like Dr. Tan, she considers this phenotype-based approach to diagnosis and treatment to be a meaningful clinical advance over the guidelines published in 2002.
“Management strategies for people with rosacea should include phenotype-based treatments,” she agreed, adding that specific choices should be made on the basis of these phenotypes “instead of the previous subtype classification.”
The meeting was jointly presented by the University of Louisville and Global Academy for Medical Education. This publication and Global Academy for Medical Education are owned by the same parent company.
When a new phenotype approach to the diagnosis of rosacea was proposed 2 years ago, this simpler and more accurate method was accompanied by several corollary advantages, including a more rational approach to treatment and better methods of measuring treatment efficacy, according to an expert speaking at the annual Coastal Dermatology Symposium, held virtually.
“By looking at rosacea in a more simple way – but a more accurate way – we are able to track what happens [to key features] over time,” explained Jerry Tan, MD, of the University of Western Ontario, London.
With the previous method of subtyping, many rosacea patients failed to fit neatly into any of the four categories, producing confusion and diverting attention from troublesome symptoms.
“Rosacea patients often present with a range of features that span multiple subtypes or progress between them,” Dr. Tan explained. The risk is not just a delay in diagnosis but a failure to focus on symptoms patients find most bothersome.
The previous diagnostic criteria for rosacea, published in 2002, identified primary and secondary symptoms within its four subtypes. The new diagnostic criteria, endorsed by the National Rosacea Society and published in 2018, rely on phenotypes defined by diagnostic, major, and minor symptoms. Rather than the four previous subtypes, which were erythematotelangiectatic, papulopustular, phymatous, and ocular, the phenotypes facilitate diagnosis in patients with mixed features.
By replacing “the old thought process of subtyping” with a newer focus on phenotypes, the updated criteria were “aimed toward accuracy, simplicity and practicality,” Dr. Tan said.
Moreover, without squeezing patients into subgroups where they do not neatly fit, the new criteria draw attention to the specific symptoms that bring patients to the clinician.
The phenotype approach to treatment strategies was reflected in a systematic review of treatments based on phenotypes that was published in 2019, not long after the new classification system became available. In this review, coauthored by Dr. Tan, the GRADE certainty-of-evidence approach was employed to identify effective therapies, matching specific symptoms with specific therapies such as low-dose isotretinoin for papules or omega-3 fatty acids for dry eyes.
Based on a patient-centric approach that emphasizes control of key symptoms, Dr. Tan also described a method of documenting the severity of major and minor symptoms at each visit. With this method, called a rosacea patient tracker, patients and physicians can determine whether therapies are effective against the signs and symptoms of disease that they find most burdensome, according to Dr. Tan, who was the first author of an article he cited as a reference to this phenotype-based methodology.
Overall, the phenotype approach to rosacea “rationalizes treatment,” he said.
Specifically, the heterogeneity of symptoms in rosacea is mirrored in the heterogeneity of underlying pathophysiology. According to Dr. Tan, the upregulation of cytokines for inflammation, of angiogenic pathways for vascular symptoms, and of matrix metalloproteinases for tissue remodeling are all implicated in rosacea but drive different types of symptoms. While appropriate skin care and efforts to identify and minimize symptom triggers is appropriate for all patients, phenotypes provide a guide to the most appropriate therapies.
He said he hopes that the focus on phenotypes will draw attention to differences in these pathophysiological mechanisms. According to Dr. Tan, evaluating rosacea from the perspective of phenotypes has represented an important paradigm shift that extends beyond diagnosis.
“The move to the phenotype approach is hopefully simpler, more accurate, and more relevant,” Dr. Tan said.
This same approach has been advocated by others, including Esther J. van Zurren, MD, professor of dermatology at Leiden University Medical Centre in the Netherlands, the lead author of the 2018 systematic review article discussed by Dr. Tan. In this review article on the phenotype approach, specific strategies were recommended for specific symptoms on the basis of grading by an international group of experts that included Dr. Tan, a coauthor.
“These strategies should be directed toward achieving improvements in general well-being by targeting those aspects most bothersome to the patient,” the article advises. Like Dr. Tan, she considers this phenotype-based approach to diagnosis and treatment to be a meaningful clinical advance over the guidelines published in 2002.
“Management strategies for people with rosacea should include phenotype-based treatments,” she agreed, adding that specific choices should be made on the basis of these phenotypes “instead of the previous subtype classification.”
The meeting was jointly presented by the University of Louisville and Global Academy for Medical Education. This publication and Global Academy for Medical Education are owned by the same parent company.
When a new phenotype approach to the diagnosis of rosacea was proposed 2 years ago, this simpler and more accurate method was accompanied by several corollary advantages, including a more rational approach to treatment and better methods of measuring treatment efficacy, according to an expert speaking at the annual Coastal Dermatology Symposium, held virtually.
“By looking at rosacea in a more simple way – but a more accurate way – we are able to track what happens [to key features] over time,” explained Jerry Tan, MD, of the University of Western Ontario, London.
With the previous method of subtyping, many rosacea patients failed to fit neatly into any of the four categories, producing confusion and diverting attention from troublesome symptoms.
“Rosacea patients often present with a range of features that span multiple subtypes or progress between them,” Dr. Tan explained. The risk is not just a delay in diagnosis but a failure to focus on symptoms patients find most bothersome.
The previous diagnostic criteria for rosacea, published in 2002, identified primary and secondary symptoms within its four subtypes. The new diagnostic criteria, endorsed by the National Rosacea Society and published in 2018, rely on phenotypes defined by diagnostic, major, and minor symptoms. Rather than the four previous subtypes, which were erythematotelangiectatic, papulopustular, phymatous, and ocular, the phenotypes facilitate diagnosis in patients with mixed features.
By replacing “the old thought process of subtyping” with a newer focus on phenotypes, the updated criteria were “aimed toward accuracy, simplicity and practicality,” Dr. Tan said.
Moreover, without squeezing patients into subgroups where they do not neatly fit, the new criteria draw attention to the specific symptoms that bring patients to the clinician.
The phenotype approach to treatment strategies was reflected in a systematic review of treatments based on phenotypes that was published in 2019, not long after the new classification system became available. In this review, coauthored by Dr. Tan, the GRADE certainty-of-evidence approach was employed to identify effective therapies, matching specific symptoms with specific therapies such as low-dose isotretinoin for papules or omega-3 fatty acids for dry eyes.
Based on a patient-centric approach that emphasizes control of key symptoms, Dr. Tan also described a method of documenting the severity of major and minor symptoms at each visit. With this method, called a rosacea patient tracker, patients and physicians can determine whether therapies are effective against the signs and symptoms of disease that they find most burdensome, according to Dr. Tan, who was the first author of an article he cited as a reference to this phenotype-based methodology.
Overall, the phenotype approach to rosacea “rationalizes treatment,” he said.
Specifically, the heterogeneity of symptoms in rosacea is mirrored in the heterogeneity of underlying pathophysiology. According to Dr. Tan, the upregulation of cytokines for inflammation, of angiogenic pathways for vascular symptoms, and of matrix metalloproteinases for tissue remodeling are all implicated in rosacea but drive different types of symptoms. While appropriate skin care and efforts to identify and minimize symptom triggers is appropriate for all patients, phenotypes provide a guide to the most appropriate therapies.
He said he hopes that the focus on phenotypes will draw attention to differences in these pathophysiological mechanisms. According to Dr. Tan, evaluating rosacea from the perspective of phenotypes has represented an important paradigm shift that extends beyond diagnosis.
“The move to the phenotype approach is hopefully simpler, more accurate, and more relevant,” Dr. Tan said.
This same approach has been advocated by others, including Esther J. van Zurren, MD, professor of dermatology at Leiden University Medical Centre in the Netherlands, the lead author of the 2018 systematic review article discussed by Dr. Tan. In this review article on the phenotype approach, specific strategies were recommended for specific symptoms on the basis of grading by an international group of experts that included Dr. Tan, a coauthor.
“These strategies should be directed toward achieving improvements in general well-being by targeting those aspects most bothersome to the patient,” the article advises. Like Dr. Tan, she considers this phenotype-based approach to diagnosis and treatment to be a meaningful clinical advance over the guidelines published in 2002.
“Management strategies for people with rosacea should include phenotype-based treatments,” she agreed, adding that specific choices should be made on the basis of these phenotypes “instead of the previous subtype classification.”
The meeting was jointly presented by the University of Louisville and Global Academy for Medical Education. This publication and Global Academy for Medical Education are owned by the same parent company.
FROM COASTAL DERM
‘Practice changing’: Ruxolitinib as second-line in chronic GVHD
When chronic graft-versus-host disease (cGVHD) develops as a complication of allogeneic hematopoietic stem cell transplant (alloHSCT), treatment options are limited. New findings show that ruxolitinib (Jakafi) was superior to standard therapy in reducing symptoms of cGVHD in the second-line setting, and the results are potentially practice changing.
The new data, from the REACH3 trial, were presented at the annual meeting of the American Society of Hematology, held virtually this year.
This trial is “almost certainly a practice changer,” Robert Brodsky, MD, ASH secretary, said during a press preview webinar.
Chronic GVHD occurs in approximately 30%-70% of patients who undergo alloSCT, and “has been really hard to treat,” said Dr. Brodsky, of Johns Hopkins University, Baltimore. “Steroids are the first-line treatment, but after that, nothing else has shown any improvement and even steroids don’t work that well.”
Of the patients assessed, 50% of those who received ruxolitinib responded to therapy compared with only 25% who received standard therapies.
“This is the first multicenter randomized controlled trial for chronic GVHD that is positive,” said senior study author Robert Zeiser, PhD, of University Medical Center, Freiburg, Germany. “It shows a significant advantage for ruxolitinib. It is likely that this trial will lead to approval for this indication and change the guidelines for the treatment of this disease.”
Ruxolitinib, a JAK inhibitor first marketed for use in myelofibrosis, is already approved for acute GVHD. The Food and Drug Administration approved that indication last year on the basis of data from two previous trials, REACH 1 and REACH 2. The trials found that ruxolitinib was superior to best available therapy for treating patients with acute GVHD.
Superior to best available therapy
In the current REACH 3 study, Dr. Zeiser and colleagues compared ruxolitinib with best available therapy in 329 patients with moderate-to-severe cGVHD (both steroid dependent and steroid resistant).
All patients had undergone alloSCT and were randomly assigned to ruxolitinib (10 mg twice daily) for six 28-day cycles or investigator-selected best available therapy (BAT), of which there were 10 options. Patients continued receiving their regimen of corticosteroids, and viral prophylaxis and antibiotics were allowed as needed for infection prevention and treatment.
The study permitted crossover: Patients on BAT were allowed to start on ruxolitinib on or after cycle 7 day 1 for those who did not achieve or maintain a response, developed toxicity to BAT, or had a cGVHD flare.
The study met its primary endpoint of overall response rate (ORR), with a clear and substantial improvement among patients taking ruxolitinib (50% vs 26%; odds ratio, 2.99; P < .0001a), Dr. Zeiser noted. The complete response rate was also higher (7% vs. 3%).
Both key secondary endpoints also showed that ruxolitinib was superior to BAT. Failure-free survival was significantly longer in the ruxolitinib group (median not reached vs 5.7 months; hazard ratio, 0.370; P < .0001). There was also an improvement in symptoms based on changes in the modified Lee symptom score (mLSS; 0 [no symptoms] to 100 [worst symptoms]) at cycle 7 day 1; the results show that the mLSS responder rate was higher in patients on ruxolitinib (24% vs. 11%; odds ratio, 2.62; P = .0011).
A total of 31 patients in the ruxolitinib group died (19%) along with 27 in the BAT group (16%), with the cGVHD as the main cause of death.
Adverse events were comparable in both groups (ruxolitinib 98% [grade ≥ 3, 57%]; BAT, 92% [grade ≥ 3, 58%], with the most common being anemia (29% vs. 13%), hypertension (16% vs. 13%), pyrexia (16% vs. 9%), and ALT increase (15% vs 4%).
More options for patients
“The addition of ruxolitinib is definitely practice changing for this very difficult to treat population,” said James Essell, MD, medical director of the Blood Cancer Center at Mercy Health, Cincinnati, who was not involved in the study.
However, he added, “more options are still required, as evidenced by the continued deaths of patients despite this new option.”
Dr. Essell pointed out that ibrutinib (Imbruvica) is already approved for the treatment of cGVHD. “Ruxolitinib offers another option for treating this group of patients,” he said, and predicted that “it will be used frequently and has a different toxicity profile, ultimately improving the care for patients with cGVHD.”
It is likely that ruxolitinib will be considered earlier in the treatment of cGVHD to avoid the toxicity of chronic steroid use, he added, but price is a consideration. “The cost of ruxolitinib is over 200 times more than prednisone, limiting the adoption front line without a clinical trial.”
Another expert approached for comment was enthusiastic. “The abstract gave good evidence and efficacy with chronic GVHD,” said Ryotaro Nakamura, MD, associate professor of hematology & hematopoietic cell transplantation at City of Hope, Duarte, Calif. He noted that there have been two previous REACH trials which showed a benefit for ruxolitinib in acute GVHD.
What this means is that there is now global evidence that ruxolitinib is better than anything else so far, he said, and this latest trial is just part of the “practice-changing data,” from the three studies. “It is practice changing in that it is providing options now for these patients,” he said.
Dr. Zeiser has disclosed relationships with Incyte, Novartis and Mallinckrodt; other authors disclosed relationships with industry as noted in the abstract. Dr. Essell and Dr. Nakamura have disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
When chronic graft-versus-host disease (cGVHD) develops as a complication of allogeneic hematopoietic stem cell transplant (alloHSCT), treatment options are limited. New findings show that ruxolitinib (Jakafi) was superior to standard therapy in reducing symptoms of cGVHD in the second-line setting, and the results are potentially practice changing.
The new data, from the REACH3 trial, were presented at the annual meeting of the American Society of Hematology, held virtually this year.
This trial is “almost certainly a practice changer,” Robert Brodsky, MD, ASH secretary, said during a press preview webinar.
Chronic GVHD occurs in approximately 30%-70% of patients who undergo alloSCT, and “has been really hard to treat,” said Dr. Brodsky, of Johns Hopkins University, Baltimore. “Steroids are the first-line treatment, but after that, nothing else has shown any improvement and even steroids don’t work that well.”
Of the patients assessed, 50% of those who received ruxolitinib responded to therapy compared with only 25% who received standard therapies.
“This is the first multicenter randomized controlled trial for chronic GVHD that is positive,” said senior study author Robert Zeiser, PhD, of University Medical Center, Freiburg, Germany. “It shows a significant advantage for ruxolitinib. It is likely that this trial will lead to approval for this indication and change the guidelines for the treatment of this disease.”
Ruxolitinib, a JAK inhibitor first marketed for use in myelofibrosis, is already approved for acute GVHD. The Food and Drug Administration approved that indication last year on the basis of data from two previous trials, REACH 1 and REACH 2. The trials found that ruxolitinib was superior to best available therapy for treating patients with acute GVHD.
Superior to best available therapy
In the current REACH 3 study, Dr. Zeiser and colleagues compared ruxolitinib with best available therapy in 329 patients with moderate-to-severe cGVHD (both steroid dependent and steroid resistant).
All patients had undergone alloSCT and were randomly assigned to ruxolitinib (10 mg twice daily) for six 28-day cycles or investigator-selected best available therapy (BAT), of which there were 10 options. Patients continued receiving their regimen of corticosteroids, and viral prophylaxis and antibiotics were allowed as needed for infection prevention and treatment.
The study permitted crossover: Patients on BAT were allowed to start on ruxolitinib on or after cycle 7 day 1 for those who did not achieve or maintain a response, developed toxicity to BAT, or had a cGVHD flare.
The study met its primary endpoint of overall response rate (ORR), with a clear and substantial improvement among patients taking ruxolitinib (50% vs 26%; odds ratio, 2.99; P < .0001a), Dr. Zeiser noted. The complete response rate was also higher (7% vs. 3%).
Both key secondary endpoints also showed that ruxolitinib was superior to BAT. Failure-free survival was significantly longer in the ruxolitinib group (median not reached vs 5.7 months; hazard ratio, 0.370; P < .0001). There was also an improvement in symptoms based on changes in the modified Lee symptom score (mLSS; 0 [no symptoms] to 100 [worst symptoms]) at cycle 7 day 1; the results show that the mLSS responder rate was higher in patients on ruxolitinib (24% vs. 11%; odds ratio, 2.62; P = .0011).
A total of 31 patients in the ruxolitinib group died (19%) along with 27 in the BAT group (16%), with the cGVHD as the main cause of death.
Adverse events were comparable in both groups (ruxolitinib 98% [grade ≥ 3, 57%]; BAT, 92% [grade ≥ 3, 58%], with the most common being anemia (29% vs. 13%), hypertension (16% vs. 13%), pyrexia (16% vs. 9%), and ALT increase (15% vs 4%).
More options for patients
“The addition of ruxolitinib is definitely practice changing for this very difficult to treat population,” said James Essell, MD, medical director of the Blood Cancer Center at Mercy Health, Cincinnati, who was not involved in the study.
However, he added, “more options are still required, as evidenced by the continued deaths of patients despite this new option.”
Dr. Essell pointed out that ibrutinib (Imbruvica) is already approved for the treatment of cGVHD. “Ruxolitinib offers another option for treating this group of patients,” he said, and predicted that “it will be used frequently and has a different toxicity profile, ultimately improving the care for patients with cGVHD.”
It is likely that ruxolitinib will be considered earlier in the treatment of cGVHD to avoid the toxicity of chronic steroid use, he added, but price is a consideration. “The cost of ruxolitinib is over 200 times more than prednisone, limiting the adoption front line without a clinical trial.”
Another expert approached for comment was enthusiastic. “The abstract gave good evidence and efficacy with chronic GVHD,” said Ryotaro Nakamura, MD, associate professor of hematology & hematopoietic cell transplantation at City of Hope, Duarte, Calif. He noted that there have been two previous REACH trials which showed a benefit for ruxolitinib in acute GVHD.
What this means is that there is now global evidence that ruxolitinib is better than anything else so far, he said, and this latest trial is just part of the “practice-changing data,” from the three studies. “It is practice changing in that it is providing options now for these patients,” he said.
Dr. Zeiser has disclosed relationships with Incyte, Novartis and Mallinckrodt; other authors disclosed relationships with industry as noted in the abstract. Dr. Essell and Dr. Nakamura have disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
When chronic graft-versus-host disease (cGVHD) develops as a complication of allogeneic hematopoietic stem cell transplant (alloHSCT), treatment options are limited. New findings show that ruxolitinib (Jakafi) was superior to standard therapy in reducing symptoms of cGVHD in the second-line setting, and the results are potentially practice changing.
The new data, from the REACH3 trial, were presented at the annual meeting of the American Society of Hematology, held virtually this year.
This trial is “almost certainly a practice changer,” Robert Brodsky, MD, ASH secretary, said during a press preview webinar.
Chronic GVHD occurs in approximately 30%-70% of patients who undergo alloSCT, and “has been really hard to treat,” said Dr. Brodsky, of Johns Hopkins University, Baltimore. “Steroids are the first-line treatment, but after that, nothing else has shown any improvement and even steroids don’t work that well.”
Of the patients assessed, 50% of those who received ruxolitinib responded to therapy compared with only 25% who received standard therapies.
“This is the first multicenter randomized controlled trial for chronic GVHD that is positive,” said senior study author Robert Zeiser, PhD, of University Medical Center, Freiburg, Germany. “It shows a significant advantage for ruxolitinib. It is likely that this trial will lead to approval for this indication and change the guidelines for the treatment of this disease.”
Ruxolitinib, a JAK inhibitor first marketed for use in myelofibrosis, is already approved for acute GVHD. The Food and Drug Administration approved that indication last year on the basis of data from two previous trials, REACH 1 and REACH 2. The trials found that ruxolitinib was superior to best available therapy for treating patients with acute GVHD.
Superior to best available therapy
In the current REACH 3 study, Dr. Zeiser and colleagues compared ruxolitinib with best available therapy in 329 patients with moderate-to-severe cGVHD (both steroid dependent and steroid resistant).
All patients had undergone alloSCT and were randomly assigned to ruxolitinib (10 mg twice daily) for six 28-day cycles or investigator-selected best available therapy (BAT), of which there were 10 options. Patients continued receiving their regimen of corticosteroids, and viral prophylaxis and antibiotics were allowed as needed for infection prevention and treatment.
The study permitted crossover: Patients on BAT were allowed to start on ruxolitinib on or after cycle 7 day 1 for those who did not achieve or maintain a response, developed toxicity to BAT, or had a cGVHD flare.
The study met its primary endpoint of overall response rate (ORR), with a clear and substantial improvement among patients taking ruxolitinib (50% vs 26%; odds ratio, 2.99; P < .0001a), Dr. Zeiser noted. The complete response rate was also higher (7% vs. 3%).
Both key secondary endpoints also showed that ruxolitinib was superior to BAT. Failure-free survival was significantly longer in the ruxolitinib group (median not reached vs 5.7 months; hazard ratio, 0.370; P < .0001). There was also an improvement in symptoms based on changes in the modified Lee symptom score (mLSS; 0 [no symptoms] to 100 [worst symptoms]) at cycle 7 day 1; the results show that the mLSS responder rate was higher in patients on ruxolitinib (24% vs. 11%; odds ratio, 2.62; P = .0011).
A total of 31 patients in the ruxolitinib group died (19%) along with 27 in the BAT group (16%), with the cGVHD as the main cause of death.
Adverse events were comparable in both groups (ruxolitinib 98% [grade ≥ 3, 57%]; BAT, 92% [grade ≥ 3, 58%], with the most common being anemia (29% vs. 13%), hypertension (16% vs. 13%), pyrexia (16% vs. 9%), and ALT increase (15% vs 4%).
More options for patients
“The addition of ruxolitinib is definitely practice changing for this very difficult to treat population,” said James Essell, MD, medical director of the Blood Cancer Center at Mercy Health, Cincinnati, who was not involved in the study.
However, he added, “more options are still required, as evidenced by the continued deaths of patients despite this new option.”
Dr. Essell pointed out that ibrutinib (Imbruvica) is already approved for the treatment of cGVHD. “Ruxolitinib offers another option for treating this group of patients,” he said, and predicted that “it will be used frequently and has a different toxicity profile, ultimately improving the care for patients with cGVHD.”
It is likely that ruxolitinib will be considered earlier in the treatment of cGVHD to avoid the toxicity of chronic steroid use, he added, but price is a consideration. “The cost of ruxolitinib is over 200 times more than prednisone, limiting the adoption front line without a clinical trial.”
Another expert approached for comment was enthusiastic. “The abstract gave good evidence and efficacy with chronic GVHD,” said Ryotaro Nakamura, MD, associate professor of hematology & hematopoietic cell transplantation at City of Hope, Duarte, Calif. He noted that there have been two previous REACH trials which showed a benefit for ruxolitinib in acute GVHD.
What this means is that there is now global evidence that ruxolitinib is better than anything else so far, he said, and this latest trial is just part of the “practice-changing data,” from the three studies. “It is practice changing in that it is providing options now for these patients,” he said.
Dr. Zeiser has disclosed relationships with Incyte, Novartis and Mallinckrodt; other authors disclosed relationships with industry as noted in the abstract. Dr. Essell and Dr. Nakamura have disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
Duvelisib response rate encouraging in phase 2 PRIMO trial of patients with r/r PTCL
Duvelisib is demonstrating encouraging activity and manageable toxicities among patients with relapsed/refractory peripheral T-cell lymphoma (PTCL) in a phase 2 trial, an investigator said.
The overall response rate in the dose-optimization phase of the PRIMO trial was more than 60% among patients receiving 75 mg of duvelisib twice daily, with a median duration of response exceeding 12 months, said investigator Barbara Pro, MD, of Northwestern University, Chicago.
In the ongoing dose-expansion phase, in which patients start on 75 mg twice daily and then transition to a lower dose, the ORR is over 50%, including complete responses (CRs) in about one-third of patients, Dr. Pro reported at the annual meeting of the American Society of Hematology.
Most previously approved treatments for relapsed/refractory PTCL are associated with ORRs of less than 30%, low rates of CR, and median progression-free survival of less than 4 months, Dr. Pro said in her presentation.
There have been no unexpected toxicities in the dose-expansion phase, and the adverse event profile is consistent with what has been observed previously for this oral phosphatidylinositol 3-kinase (PI3K) inhibitor, according to Dr. Pro.
Based on results to date, Dr. Pro said she and coinvestigators are hopeful that duvelisib will have a place in the treatment armamentarium for relapsed/refractory PTCL in the future.
“This is one of the most effective agents in T-cell lymphoma, and hopefully will be approved and available for treatment soon,” she said in remarks following her presentation of PRIMO study data.
“The next question would be how to try to move this agent up front,” she added. “We’ll have to try to see what could be the possible combinations and evaluate the possible overlapping toxicity with alternative treatments.”
The PRIMO trial provides “very exciting numbers” that include roughly half of relapsed/refractory PTCL patients are responding to the oral therapy, said Andrei R. Shustov, MD, professor of medicine in the division of hematology at the University of Washington, Seattle.
Perhaps more importantly, at least half of those responses have been CRs, Dr. Shustov noted in an interview: “We haven’t seen this yet in T-cell lymphomas, short of brentuximab vedotin targeting CD30,” he said, referring to the 2018 Food and Drug Administration approval of brentuximab vedotin for previously untreated CD30-expressing PTCL.
If duvelisib is approved, it would be the first oral agent with an indication for relapsed/refractory PTCL, which could have important implications for patient quality of life, Dr. Shustov added.
“The fact that you can take a pill at home, and don’t have to be in clinic once a week, or have the port device, or be infused every week would be an incredible change in quality of life,” he said, “and this is really amplified in the older population where quality of life is so important.”
Duvelisib was FDA approved in 2018, at a dose of 25 mg orally twice daily, for the treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma, and follicular lymphoma, following at least two previous treatments.
In relapsed/refractory PTCL, results of a phase 1 study previously published in Blood showed that duvelisib demonstrated an ORR of 50%, or 8 out of 16 patients treated with 25 or 75 mg twice daily continuously.
The phase 2 study described by Dr. Pro at this year’s ASH meeting included 33 patients with relapsed/refractory PTCL treated with duvelisib 25 mg or 75 mg twice daily as part of a dose-optimization phase, and 25 patients treated in an expansion phase at 75 mg twice daily for two 28-day cycles, followed by treatment at 25 mg twice daily.
Starting at the higher dose of 75 mg twice daily is intended to achieve rapid tumor control, while switching to the lower 25-mg twice-daily dose is to maintain long-term control of the disease while mitigating potential for later toxicities, according to the published abstract for the PRIMO trial.
Results of the dose-optimization phase included an ORR by independent review committee of 62% for patients treated at the 75-mg twice-daily dose, and 40% for those treated at 25 mg twice daily. The median duration of response in the 75-mg twice-daily group was 12.2 months, which Dr. Pro said was significantly higher than what was observed for the lower dose.
In the ongoing dose-expansion phase, the ORR by investigator was 52% (13 of 25 patients), with a CR rate of 36% (9 of 25 patients). The reported data show that with a median duration of follow-up of 3.78 months, the median duration of response thus far is 4.1 months.
The most common grade 3 or higher adverse events were increases in ALT and AST, seen in 24% and 20% of patients, respectively. The most common grade 3 or greater hematologic toxicity was decreased lymphocyte count, seen in 16%.
Three serious treatment-emergent adverse events thought to be related to duvelisib occurred in two patients, including grade 5 pneumonitis in one patient, and skin lesion plus posttransplant lymphoproliferative disorder in the other patient, according to Dr. Pro. Serious treatment-emergent adverse events leading to duvelisib discontinuation included increased ALT/AST in 2 patients and pneumonitis in one patient.
Grade 1-2 adverse events reported at ASH included hypertension, nausea, anemia, fatigue, diarrhea, constipation and pyrexia, among others.
Enrollment in the dose-expansion phase of PRIMO is ongoing and should be complete in February, according to Dr. Pro.
Support for the study came from Verastem Oncology and Secura Bio. Dr. Pro reported research funding from Verastem Oncology, Takeda, and other pharmaceutical companies and honoraria from Takeda and Seattle Genetics.
SOURCE: Pro B et al. ASH 2020, Abstract 44.
Duvelisib is demonstrating encouraging activity and manageable toxicities among patients with relapsed/refractory peripheral T-cell lymphoma (PTCL) in a phase 2 trial, an investigator said.
The overall response rate in the dose-optimization phase of the PRIMO trial was more than 60% among patients receiving 75 mg of duvelisib twice daily, with a median duration of response exceeding 12 months, said investigator Barbara Pro, MD, of Northwestern University, Chicago.
In the ongoing dose-expansion phase, in which patients start on 75 mg twice daily and then transition to a lower dose, the ORR is over 50%, including complete responses (CRs) in about one-third of patients, Dr. Pro reported at the annual meeting of the American Society of Hematology.
Most previously approved treatments for relapsed/refractory PTCL are associated with ORRs of less than 30%, low rates of CR, and median progression-free survival of less than 4 months, Dr. Pro said in her presentation.
There have been no unexpected toxicities in the dose-expansion phase, and the adverse event profile is consistent with what has been observed previously for this oral phosphatidylinositol 3-kinase (PI3K) inhibitor, according to Dr. Pro.
Based on results to date, Dr. Pro said she and coinvestigators are hopeful that duvelisib will have a place in the treatment armamentarium for relapsed/refractory PTCL in the future.
“This is one of the most effective agents in T-cell lymphoma, and hopefully will be approved and available for treatment soon,” she said in remarks following her presentation of PRIMO study data.
“The next question would be how to try to move this agent up front,” she added. “We’ll have to try to see what could be the possible combinations and evaluate the possible overlapping toxicity with alternative treatments.”
The PRIMO trial provides “very exciting numbers” that include roughly half of relapsed/refractory PTCL patients are responding to the oral therapy, said Andrei R. Shustov, MD, professor of medicine in the division of hematology at the University of Washington, Seattle.
Perhaps more importantly, at least half of those responses have been CRs, Dr. Shustov noted in an interview: “We haven’t seen this yet in T-cell lymphomas, short of brentuximab vedotin targeting CD30,” he said, referring to the 2018 Food and Drug Administration approval of brentuximab vedotin for previously untreated CD30-expressing PTCL.
If duvelisib is approved, it would be the first oral agent with an indication for relapsed/refractory PTCL, which could have important implications for patient quality of life, Dr. Shustov added.
“The fact that you can take a pill at home, and don’t have to be in clinic once a week, or have the port device, or be infused every week would be an incredible change in quality of life,” he said, “and this is really amplified in the older population where quality of life is so important.”
Duvelisib was FDA approved in 2018, at a dose of 25 mg orally twice daily, for the treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma, and follicular lymphoma, following at least two previous treatments.
In relapsed/refractory PTCL, results of a phase 1 study previously published in Blood showed that duvelisib demonstrated an ORR of 50%, or 8 out of 16 patients treated with 25 or 75 mg twice daily continuously.
The phase 2 study described by Dr. Pro at this year’s ASH meeting included 33 patients with relapsed/refractory PTCL treated with duvelisib 25 mg or 75 mg twice daily as part of a dose-optimization phase, and 25 patients treated in an expansion phase at 75 mg twice daily for two 28-day cycles, followed by treatment at 25 mg twice daily.
Starting at the higher dose of 75 mg twice daily is intended to achieve rapid tumor control, while switching to the lower 25-mg twice-daily dose is to maintain long-term control of the disease while mitigating potential for later toxicities, according to the published abstract for the PRIMO trial.
Results of the dose-optimization phase included an ORR by independent review committee of 62% for patients treated at the 75-mg twice-daily dose, and 40% for those treated at 25 mg twice daily. The median duration of response in the 75-mg twice-daily group was 12.2 months, which Dr. Pro said was significantly higher than what was observed for the lower dose.
In the ongoing dose-expansion phase, the ORR by investigator was 52% (13 of 25 patients), with a CR rate of 36% (9 of 25 patients). The reported data show that with a median duration of follow-up of 3.78 months, the median duration of response thus far is 4.1 months.
The most common grade 3 or higher adverse events were increases in ALT and AST, seen in 24% and 20% of patients, respectively. The most common grade 3 or greater hematologic toxicity was decreased lymphocyte count, seen in 16%.
Three serious treatment-emergent adverse events thought to be related to duvelisib occurred in two patients, including grade 5 pneumonitis in one patient, and skin lesion plus posttransplant lymphoproliferative disorder in the other patient, according to Dr. Pro. Serious treatment-emergent adverse events leading to duvelisib discontinuation included increased ALT/AST in 2 patients and pneumonitis in one patient.
Grade 1-2 adverse events reported at ASH included hypertension, nausea, anemia, fatigue, diarrhea, constipation and pyrexia, among others.
Enrollment in the dose-expansion phase of PRIMO is ongoing and should be complete in February, according to Dr. Pro.
Support for the study came from Verastem Oncology and Secura Bio. Dr. Pro reported research funding from Verastem Oncology, Takeda, and other pharmaceutical companies and honoraria from Takeda and Seattle Genetics.
SOURCE: Pro B et al. ASH 2020, Abstract 44.
Duvelisib is demonstrating encouraging activity and manageable toxicities among patients with relapsed/refractory peripheral T-cell lymphoma (PTCL) in a phase 2 trial, an investigator said.
The overall response rate in the dose-optimization phase of the PRIMO trial was more than 60% among patients receiving 75 mg of duvelisib twice daily, with a median duration of response exceeding 12 months, said investigator Barbara Pro, MD, of Northwestern University, Chicago.
In the ongoing dose-expansion phase, in which patients start on 75 mg twice daily and then transition to a lower dose, the ORR is over 50%, including complete responses (CRs) in about one-third of patients, Dr. Pro reported at the annual meeting of the American Society of Hematology.
Most previously approved treatments for relapsed/refractory PTCL are associated with ORRs of less than 30%, low rates of CR, and median progression-free survival of less than 4 months, Dr. Pro said in her presentation.
There have been no unexpected toxicities in the dose-expansion phase, and the adverse event profile is consistent with what has been observed previously for this oral phosphatidylinositol 3-kinase (PI3K) inhibitor, according to Dr. Pro.
Based on results to date, Dr. Pro said she and coinvestigators are hopeful that duvelisib will have a place in the treatment armamentarium for relapsed/refractory PTCL in the future.
“This is one of the most effective agents in T-cell lymphoma, and hopefully will be approved and available for treatment soon,” she said in remarks following her presentation of PRIMO study data.
“The next question would be how to try to move this agent up front,” she added. “We’ll have to try to see what could be the possible combinations and evaluate the possible overlapping toxicity with alternative treatments.”
The PRIMO trial provides “very exciting numbers” that include roughly half of relapsed/refractory PTCL patients are responding to the oral therapy, said Andrei R. Shustov, MD, professor of medicine in the division of hematology at the University of Washington, Seattle.
Perhaps more importantly, at least half of those responses have been CRs, Dr. Shustov noted in an interview: “We haven’t seen this yet in T-cell lymphomas, short of brentuximab vedotin targeting CD30,” he said, referring to the 2018 Food and Drug Administration approval of brentuximab vedotin for previously untreated CD30-expressing PTCL.
If duvelisib is approved, it would be the first oral agent with an indication for relapsed/refractory PTCL, which could have important implications for patient quality of life, Dr. Shustov added.
“The fact that you can take a pill at home, and don’t have to be in clinic once a week, or have the port device, or be infused every week would be an incredible change in quality of life,” he said, “and this is really amplified in the older population where quality of life is so important.”
Duvelisib was FDA approved in 2018, at a dose of 25 mg orally twice daily, for the treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma, and follicular lymphoma, following at least two previous treatments.
In relapsed/refractory PTCL, results of a phase 1 study previously published in Blood showed that duvelisib demonstrated an ORR of 50%, or 8 out of 16 patients treated with 25 or 75 mg twice daily continuously.
The phase 2 study described by Dr. Pro at this year’s ASH meeting included 33 patients with relapsed/refractory PTCL treated with duvelisib 25 mg or 75 mg twice daily as part of a dose-optimization phase, and 25 patients treated in an expansion phase at 75 mg twice daily for two 28-day cycles, followed by treatment at 25 mg twice daily.
Starting at the higher dose of 75 mg twice daily is intended to achieve rapid tumor control, while switching to the lower 25-mg twice-daily dose is to maintain long-term control of the disease while mitigating potential for later toxicities, according to the published abstract for the PRIMO trial.
Results of the dose-optimization phase included an ORR by independent review committee of 62% for patients treated at the 75-mg twice-daily dose, and 40% for those treated at 25 mg twice daily. The median duration of response in the 75-mg twice-daily group was 12.2 months, which Dr. Pro said was significantly higher than what was observed for the lower dose.
In the ongoing dose-expansion phase, the ORR by investigator was 52% (13 of 25 patients), with a CR rate of 36% (9 of 25 patients). The reported data show that with a median duration of follow-up of 3.78 months, the median duration of response thus far is 4.1 months.
The most common grade 3 or higher adverse events were increases in ALT and AST, seen in 24% and 20% of patients, respectively. The most common grade 3 or greater hematologic toxicity was decreased lymphocyte count, seen in 16%.
Three serious treatment-emergent adverse events thought to be related to duvelisib occurred in two patients, including grade 5 pneumonitis in one patient, and skin lesion plus posttransplant lymphoproliferative disorder in the other patient, according to Dr. Pro. Serious treatment-emergent adverse events leading to duvelisib discontinuation included increased ALT/AST in 2 patients and pneumonitis in one patient.
Grade 1-2 adverse events reported at ASH included hypertension, nausea, anemia, fatigue, diarrhea, constipation and pyrexia, among others.
Enrollment in the dose-expansion phase of PRIMO is ongoing and should be complete in February, according to Dr. Pro.
Support for the study came from Verastem Oncology and Secura Bio. Dr. Pro reported research funding from Verastem Oncology, Takeda, and other pharmaceutical companies and honoraria from Takeda and Seattle Genetics.
SOURCE: Pro B et al. ASH 2020, Abstract 44.
FROM ASH 2020
Cost is the main hurdle to broad use of caplacizumab for TTP
As hematologists debated the role of the anti–von Willebrand factor agent caplacizumab for acquired thrombotic thrombocytopenic purpura (TTP), an investigator on the phase 3 trial that led to its approval had a message.
,” said hematologist Spero Cataland, MD, of the department of internal medicine at Ohio State University in Columbus.
If cost is going to be a factor, and it “has to be in our world these days, it’s more of a discussion,” he said during his presentation at the 2020 Update in Nonneoplastic Hematology virtual conference.
The HERCULES trial Dr. Cataland helped conduct found a median time to platelet count normalization of 2.69 days when caplacizumab was started during plasma exchange versus 2.88 days for placebo; 12% of patients had a TTP recurrence while they continued caplacizumab for 30 days past their last exchange and were followed for an additional 28 days versus 38% randomized to placebo. Caplacizumab subjects needed an average of 5.8 days of plasma exchange versus 9.4 days in the placebo arm (N Engl J Med. 2019 Jan 24;380(4):335-46).
Based on the results, the Food and Drug Administration approved the agent for acquired TTP in combination with plasma exchange and immunosuppressives in Feb. 2019 for 30 days beyond the last plasma exchange, with up to 28 additional days if ADAMTS13 activity remains suppressed. Labeling notes a risk of severe bleeding.
“The data on refractory disease and mortality aren’t quite there yet, but there’s a suggestion [caplacizumab] might impact that as well,” Dr. Cataland said. In its recent TTP guidelines, the International Society on Thrombosis and Haemostasis gave the agent only a conditional recommendation, in part because it’s backed up only by HERCULES and a phase 2 trial.
Also, the group noted that in the phase 2 study caplacizumab patients had a clinically and statistically significant increase in the number of relapses at 12 months: 31% versus 8% placebo. “Caplacizumab may leave patients prone to experience a later recurrence owing to the unresolved ADAMTS13 deficiency and inhibitors,” Dr. Cataland said.
“We do see some early recurrence” when caplacizumab is stopped, suggesting that when the agent’s “protective effect is removed, the risk is still there,” said Dr. Cataland, who was also an author on the ISTH guidelines, as well as the phase 2 trial.
It raises the question of how long patients should be kept on caplacizumab. There are few data on the issue, “but the consensus has been to stop caplacizumab when two consecutive ADAMTS13 measurements show 20% or greater activity,” or perhaps with one reading above 20% in a patient trending in the right direction. “With a bleeding complication, you might stop it sooner,” he said.
Dr. Cataland anticipates TTP management will eventually move away from plasma exchange to more directed therapies, including caplacizumab and perhaps recombinant ADAMTS13, which is in development.
There have been a few reports of TTP patients who refuse plasma exchange on religious grounds being successfully treated with caplacizumab. Dr. Cataland also noted a patient of his with relapsing TTP who didn’t want to be admitted yet again for plasma exchange and steroids at the start of a new episode.
“We managed her with caplacizumab and rituximab, and in a couple weeks she had recovered her ADAMTS13 activity and was able to stop the caplacizumab.” She was a motivated, knowledgeable person, “someone I trusted, so I was comfortable with the approach. I think that may be where we are headed in the future, hopefully,” he said.
Dr. Cataland disclosed research funding and consulting fees from Alexion, caplacizumab’s maker, Sanofi Genzyme, and Takeda,. The conference was sponsored by MedscapeLive. MedscapeLive and this news organization are owned by the same parent company.
As hematologists debated the role of the anti–von Willebrand factor agent caplacizumab for acquired thrombotic thrombocytopenic purpura (TTP), an investigator on the phase 3 trial that led to its approval had a message.
,” said hematologist Spero Cataland, MD, of the department of internal medicine at Ohio State University in Columbus.
If cost is going to be a factor, and it “has to be in our world these days, it’s more of a discussion,” he said during his presentation at the 2020 Update in Nonneoplastic Hematology virtual conference.
The HERCULES trial Dr. Cataland helped conduct found a median time to platelet count normalization of 2.69 days when caplacizumab was started during plasma exchange versus 2.88 days for placebo; 12% of patients had a TTP recurrence while they continued caplacizumab for 30 days past their last exchange and were followed for an additional 28 days versus 38% randomized to placebo. Caplacizumab subjects needed an average of 5.8 days of plasma exchange versus 9.4 days in the placebo arm (N Engl J Med. 2019 Jan 24;380(4):335-46).
Based on the results, the Food and Drug Administration approved the agent for acquired TTP in combination with plasma exchange and immunosuppressives in Feb. 2019 for 30 days beyond the last plasma exchange, with up to 28 additional days if ADAMTS13 activity remains suppressed. Labeling notes a risk of severe bleeding.
“The data on refractory disease and mortality aren’t quite there yet, but there’s a suggestion [caplacizumab] might impact that as well,” Dr. Cataland said. In its recent TTP guidelines, the International Society on Thrombosis and Haemostasis gave the agent only a conditional recommendation, in part because it’s backed up only by HERCULES and a phase 2 trial.
Also, the group noted that in the phase 2 study caplacizumab patients had a clinically and statistically significant increase in the number of relapses at 12 months: 31% versus 8% placebo. “Caplacizumab may leave patients prone to experience a later recurrence owing to the unresolved ADAMTS13 deficiency and inhibitors,” Dr. Cataland said.
“We do see some early recurrence” when caplacizumab is stopped, suggesting that when the agent’s “protective effect is removed, the risk is still there,” said Dr. Cataland, who was also an author on the ISTH guidelines, as well as the phase 2 trial.
It raises the question of how long patients should be kept on caplacizumab. There are few data on the issue, “but the consensus has been to stop caplacizumab when two consecutive ADAMTS13 measurements show 20% or greater activity,” or perhaps with one reading above 20% in a patient trending in the right direction. “With a bleeding complication, you might stop it sooner,” he said.
Dr. Cataland anticipates TTP management will eventually move away from plasma exchange to more directed therapies, including caplacizumab and perhaps recombinant ADAMTS13, which is in development.
There have been a few reports of TTP patients who refuse plasma exchange on religious grounds being successfully treated with caplacizumab. Dr. Cataland also noted a patient of his with relapsing TTP who didn’t want to be admitted yet again for plasma exchange and steroids at the start of a new episode.
“We managed her with caplacizumab and rituximab, and in a couple weeks she had recovered her ADAMTS13 activity and was able to stop the caplacizumab.” She was a motivated, knowledgeable person, “someone I trusted, so I was comfortable with the approach. I think that may be where we are headed in the future, hopefully,” he said.
Dr. Cataland disclosed research funding and consulting fees from Alexion, caplacizumab’s maker, Sanofi Genzyme, and Takeda,. The conference was sponsored by MedscapeLive. MedscapeLive and this news organization are owned by the same parent company.
As hematologists debated the role of the anti–von Willebrand factor agent caplacizumab for acquired thrombotic thrombocytopenic purpura (TTP), an investigator on the phase 3 trial that led to its approval had a message.
,” said hematologist Spero Cataland, MD, of the department of internal medicine at Ohio State University in Columbus.
If cost is going to be a factor, and it “has to be in our world these days, it’s more of a discussion,” he said during his presentation at the 2020 Update in Nonneoplastic Hematology virtual conference.
The HERCULES trial Dr. Cataland helped conduct found a median time to platelet count normalization of 2.69 days when caplacizumab was started during plasma exchange versus 2.88 days for placebo; 12% of patients had a TTP recurrence while they continued caplacizumab for 30 days past their last exchange and were followed for an additional 28 days versus 38% randomized to placebo. Caplacizumab subjects needed an average of 5.8 days of plasma exchange versus 9.4 days in the placebo arm (N Engl J Med. 2019 Jan 24;380(4):335-46).
Based on the results, the Food and Drug Administration approved the agent for acquired TTP in combination with plasma exchange and immunosuppressives in Feb. 2019 for 30 days beyond the last plasma exchange, with up to 28 additional days if ADAMTS13 activity remains suppressed. Labeling notes a risk of severe bleeding.
“The data on refractory disease and mortality aren’t quite there yet, but there’s a suggestion [caplacizumab] might impact that as well,” Dr. Cataland said. In its recent TTP guidelines, the International Society on Thrombosis and Haemostasis gave the agent only a conditional recommendation, in part because it’s backed up only by HERCULES and a phase 2 trial.
Also, the group noted that in the phase 2 study caplacizumab patients had a clinically and statistically significant increase in the number of relapses at 12 months: 31% versus 8% placebo. “Caplacizumab may leave patients prone to experience a later recurrence owing to the unresolved ADAMTS13 deficiency and inhibitors,” Dr. Cataland said.
“We do see some early recurrence” when caplacizumab is stopped, suggesting that when the agent’s “protective effect is removed, the risk is still there,” said Dr. Cataland, who was also an author on the ISTH guidelines, as well as the phase 2 trial.
It raises the question of how long patients should be kept on caplacizumab. There are few data on the issue, “but the consensus has been to stop caplacizumab when two consecutive ADAMTS13 measurements show 20% or greater activity,” or perhaps with one reading above 20% in a patient trending in the right direction. “With a bleeding complication, you might stop it sooner,” he said.
Dr. Cataland anticipates TTP management will eventually move away from plasma exchange to more directed therapies, including caplacizumab and perhaps recombinant ADAMTS13, which is in development.
There have been a few reports of TTP patients who refuse plasma exchange on religious grounds being successfully treated with caplacizumab. Dr. Cataland also noted a patient of his with relapsing TTP who didn’t want to be admitted yet again for plasma exchange and steroids at the start of a new episode.
“We managed her with caplacizumab and rituximab, and in a couple weeks she had recovered her ADAMTS13 activity and was able to stop the caplacizumab.” She was a motivated, knowledgeable person, “someone I trusted, so I was comfortable with the approach. I think that may be where we are headed in the future, hopefully,” he said.
Dr. Cataland disclosed research funding and consulting fees from Alexion, caplacizumab’s maker, Sanofi Genzyme, and Takeda,. The conference was sponsored by MedscapeLive. MedscapeLive and this news organization are owned by the same parent company.
FROM 2020 UNNH
No benefit from tranexamic acid prophylaxis in blood cancers
Despite being routinely used in clinical settings, prophylactic use of tranexamic acid, an antifibrinolytic agent administered with platelet transfusions, did not reduce bleeding among patients with blood cancers and severe thrombocytopenia, according to a new study.
The study compared tranexamic acid to placebo and found no significant differences in terms of the number of bleeding events, the number of red blood cell transfusions, or the number of platelet transfusions that were required.
However, the rate of occlusions in the central venous line was significantly higher for patients in the tranexamic acid group, although there was no difference between groups for other types of thrombotic events.
The findings were presented at the annual meeting of the American Society of Hematology, which was held online.
The study was highlighted as potentially practice changing at a press preview webinar by ASH Secretary Robert Brodsky, MD.
“They found absolutely no difference in bleeding or need for transfusion,” said Brodsky. “What they did find was more catheter-associated blood clots in the tranexamic acid group. This is a practice changer in that it probably should not be given prophylactically to patients with thrombocytopenia.”
Senior author Terry B. Gernsheimer, MD, of the University of Washington, Seattle, noted that tranexamic acid has been found to be effective in the treatment of bleeding related to childbirth, surgery, and inherited blood disorders.
It is also used for patients with blood cancers and severe thrombocytopenia. There is little evidence to support this use, which is why the researchers decided to investigate.
“Clearly patients with low platelet counts and blood cancers have a different kind of bleeding than the bleeding experienced by patients who have suffered some kind of trauma or surgery,” Dr. Gernsheimer said in a statement.
“Their bleeding likely is due to endothelial damage – damage to the lining of blood vessels – that tranexamic acid would not treat,” she added.
“To prevent bleeding in these patients, we may need to look at ways to speed the healing of the endothelium that occurs with chemotherapy, radiation, and graft-vs-host disease in patients receiving a transplant,” Dr. Gernsheimer commented.
Temper enthusiasm
“Overall, I think these results will temper enthusiasm for using tranexamic acid in this setting,” said Mitul Gandhi, MD, a medical oncologist with Virginia Cancer Specialists, who was approached for comment.
These data do not support the routine use of prophylactic tranexamic acid in chemotherapy-induced thrombocytopenia for patients with platelet counts lower than 30,000/μL, he added.
“The primary objective was not met, and there was an observed increased rate of catheter-associated thrombosis,” he said. “Continued use of judicious transfusion support and correction of a concomitant coagulopathy remains the main clinical approach to these patients.”
Dr. Gandhi commented that tranexamic acid “remains a potentially useful adjunct agent in certain cases of recalcitrant bleeding related to thrombocytopenia or coagulopathy.
“While there is no uniform scenario, it is typically reserved on a case-by-case basis after addressing vascular defects, utilization of platelet, fresh frozen plasma, cryoprecipitate transfusions, vitamin K repletion, and of course excluding any antiplatelet or anticoagulant therapy,» he told this news organization. “For persistent bleeding in spite of all corrective measures or hemorrhage into noncompressible vascular beds, such as with intracranial bleeds, antifibrinolytic therapy may assist in mitigating further blood loss.”
However, this has to be balanced with the potential increased risk for thrombosis after correction of the hemostatic insult.
At present, tranexamic acid “only has an FDA indication for uterine bleeding, but it is frequently used in trauma settings and obstetrical emergencies,” said Douglas Tremblay, MD, an internist at the Icahn School of Medicine at Mount Sinai, New York, who was also approached for comment.
“There is evidence from prior studies that were done 20 or 30 years ago that it may help in this setting, so it is used in some institutions, although we don’t give it prophylactically for patients with a hematologic malignancy.”
Although this was a negative study, Dr. Tremblay pointed out that one thing that may come out of it is that there may be subgroups who can benefit from the prophylactic use of tranexamic acid. “There is very wide inclusion criteria for the study – any type of hematologic malignancy in patients undergoing chemotherapy or stem cell transplant,” he said in an interview. “Even among chemotherapy and transplant patients, there are different risks for bleeding.”
For example, patients undergoing induction chemotherapy for acute myeloid leukemia are at an increased risk of bleeding in comparison with patients with other hematologic malignancies, and those undergoing allogeneic transplant are at an increased risk of bleeding in comparison with patients undergoing autologous transplant. “So while its unclear if a subgroup may benefit from this strategy, lumped together, it doesn’t appear it is of any benefit and potentially harmful, in terms of line occlusions,” he said. “While that may seem to be a nuisance, it can delay chemotherapy or supportive infusions, and that can be a big deal.”
No evidence of benefit
Dr. Gernsheimer and colleagues conducted the American Trial Using Tranexamic Acid in Thrombocytopenia (A-TREAT), which evaluated the effects of prophylactic tranexamic acid as an adjunct to routine transfusion therapy on bleeding and transfusion requirements.
A total of 330 patients were randomly assigned to receive either tranexamic acid 1,000 mg IV or 1,300 mg or placebo. Randomization was stratified by site and therapy: chemotherapy, allogeneic transplant, or autologous transplant. It was anticipated that all patients had hypoproliferative thrombocytopenia (expected platelet count, 10,000/µL for at least 5 days).
Treatment continued for 30 days or platelet count recovery (>30,000/µL), diagnosis of thrombosis or veno-occlusive disease, recurrent line occlusion, visible hematuria, or physician or patient request.
The primary endpoint of the study was the proportion of patients with bleeding of World Health Organization grade 2 or above over 30 days after beginning therapy. Secondary endpoints included the number of transfusions and the number of days alive without WHO grade 2+ bleeding during the first 30 days post activation of study drug.
The time to first WHO 2+ bleeding was “remarkably similar” between the tranexamic acid groups and the placebo group, said Dr. Gernsheimer.
In the cohort as a whole, 48.8% in the placebo group experienced a grade 2+ bleed vs. 45.4% in the tranexamic group (odds ratio, 0.86).
Similar results were observed across subgroups: allogeneic transplant, 57.3% vs. 58.8% (OR, 0.94); autologous transplant, 19.9% vs. 24.7% ( OR, 0.71); or chemotherapy, 48% vs. 52.1% (OR, 0.84).
There were no significant differences in mean number of transfusions (difference, 0.1; 95% confidence interval, –1.9 to 2) or days alive without grade 2 or higher bleeding (difference, 0.1; 95% CI, –1.4 to 1.5).
“A post hoc analysis of WHO 3+ bleeding showed these events to be rare and without any improvement with tranexamic acid,” she said.
A higher percentage of patients in the tranexamic acid group experienced thrombotic events (19.5% vs. 11%). “But importantly, in both groups, it was primarily due to central line occlusions without an associated thrombus,” said Dr. Gernsheimer. “This was statistically significant.”
Fewer non–catheter related thrombotic events occurred in the tranexamic acid group (3.7% vs. 5.5%), but the difference was not statistically significant.
There was also no significant difference between groups in veno-occlusive disease after 30 days (1.8% vs. 1.2%) or all-cause mortality at 30 days (2.4% vs. 3%) or 100 days (11.5% vs. 11.5%). No deaths associated with thrombosis had occurred in either group at 120 days.
The study was supported by the University of Washington and the National Heart, Lung, and Blood Institute. Dr. Gernsheimer has relationships with Amgen, Cellphire, Dova Pharmaceuticals, Novartis, Principia, Rigel, Sanofi, and Vertex. Dr. Tremblay and Dr. Gandhi have disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
Despite being routinely used in clinical settings, prophylactic use of tranexamic acid, an antifibrinolytic agent administered with platelet transfusions, did not reduce bleeding among patients with blood cancers and severe thrombocytopenia, according to a new study.
The study compared tranexamic acid to placebo and found no significant differences in terms of the number of bleeding events, the number of red blood cell transfusions, or the number of platelet transfusions that were required.
However, the rate of occlusions in the central venous line was significantly higher for patients in the tranexamic acid group, although there was no difference between groups for other types of thrombotic events.
The findings were presented at the annual meeting of the American Society of Hematology, which was held online.
The study was highlighted as potentially practice changing at a press preview webinar by ASH Secretary Robert Brodsky, MD.
“They found absolutely no difference in bleeding or need for transfusion,” said Brodsky. “What they did find was more catheter-associated blood clots in the tranexamic acid group. This is a practice changer in that it probably should not be given prophylactically to patients with thrombocytopenia.”
Senior author Terry B. Gernsheimer, MD, of the University of Washington, Seattle, noted that tranexamic acid has been found to be effective in the treatment of bleeding related to childbirth, surgery, and inherited blood disorders.
It is also used for patients with blood cancers and severe thrombocytopenia. There is little evidence to support this use, which is why the researchers decided to investigate.
“Clearly patients with low platelet counts and blood cancers have a different kind of bleeding than the bleeding experienced by patients who have suffered some kind of trauma or surgery,” Dr. Gernsheimer said in a statement.
“Their bleeding likely is due to endothelial damage – damage to the lining of blood vessels – that tranexamic acid would not treat,” she added.
“To prevent bleeding in these patients, we may need to look at ways to speed the healing of the endothelium that occurs with chemotherapy, radiation, and graft-vs-host disease in patients receiving a transplant,” Dr. Gernsheimer commented.
Temper enthusiasm
“Overall, I think these results will temper enthusiasm for using tranexamic acid in this setting,” said Mitul Gandhi, MD, a medical oncologist with Virginia Cancer Specialists, who was approached for comment.
These data do not support the routine use of prophylactic tranexamic acid in chemotherapy-induced thrombocytopenia for patients with platelet counts lower than 30,000/μL, he added.
“The primary objective was not met, and there was an observed increased rate of catheter-associated thrombosis,” he said. “Continued use of judicious transfusion support and correction of a concomitant coagulopathy remains the main clinical approach to these patients.”
Dr. Gandhi commented that tranexamic acid “remains a potentially useful adjunct agent in certain cases of recalcitrant bleeding related to thrombocytopenia or coagulopathy.
“While there is no uniform scenario, it is typically reserved on a case-by-case basis after addressing vascular defects, utilization of platelet, fresh frozen plasma, cryoprecipitate transfusions, vitamin K repletion, and of course excluding any antiplatelet or anticoagulant therapy,» he told this news organization. “For persistent bleeding in spite of all corrective measures or hemorrhage into noncompressible vascular beds, such as with intracranial bleeds, antifibrinolytic therapy may assist in mitigating further blood loss.”
However, this has to be balanced with the potential increased risk for thrombosis after correction of the hemostatic insult.
At present, tranexamic acid “only has an FDA indication for uterine bleeding, but it is frequently used in trauma settings and obstetrical emergencies,” said Douglas Tremblay, MD, an internist at the Icahn School of Medicine at Mount Sinai, New York, who was also approached for comment.
“There is evidence from prior studies that were done 20 or 30 years ago that it may help in this setting, so it is used in some institutions, although we don’t give it prophylactically for patients with a hematologic malignancy.”
Although this was a negative study, Dr. Tremblay pointed out that one thing that may come out of it is that there may be subgroups who can benefit from the prophylactic use of tranexamic acid. “There is very wide inclusion criteria for the study – any type of hematologic malignancy in patients undergoing chemotherapy or stem cell transplant,” he said in an interview. “Even among chemotherapy and transplant patients, there are different risks for bleeding.”
For example, patients undergoing induction chemotherapy for acute myeloid leukemia are at an increased risk of bleeding in comparison with patients with other hematologic malignancies, and those undergoing allogeneic transplant are at an increased risk of bleeding in comparison with patients undergoing autologous transplant. “So while its unclear if a subgroup may benefit from this strategy, lumped together, it doesn’t appear it is of any benefit and potentially harmful, in terms of line occlusions,” he said. “While that may seem to be a nuisance, it can delay chemotherapy or supportive infusions, and that can be a big deal.”
No evidence of benefit
Dr. Gernsheimer and colleagues conducted the American Trial Using Tranexamic Acid in Thrombocytopenia (A-TREAT), which evaluated the effects of prophylactic tranexamic acid as an adjunct to routine transfusion therapy on bleeding and transfusion requirements.
A total of 330 patients were randomly assigned to receive either tranexamic acid 1,000 mg IV or 1,300 mg or placebo. Randomization was stratified by site and therapy: chemotherapy, allogeneic transplant, or autologous transplant. It was anticipated that all patients had hypoproliferative thrombocytopenia (expected platelet count, 10,000/µL for at least 5 days).
Treatment continued for 30 days or platelet count recovery (>30,000/µL), diagnosis of thrombosis or veno-occlusive disease, recurrent line occlusion, visible hematuria, or physician or patient request.
The primary endpoint of the study was the proportion of patients with bleeding of World Health Organization grade 2 or above over 30 days after beginning therapy. Secondary endpoints included the number of transfusions and the number of days alive without WHO grade 2+ bleeding during the first 30 days post activation of study drug.
The time to first WHO 2+ bleeding was “remarkably similar” between the tranexamic acid groups and the placebo group, said Dr. Gernsheimer.
In the cohort as a whole, 48.8% in the placebo group experienced a grade 2+ bleed vs. 45.4% in the tranexamic group (odds ratio, 0.86).
Similar results were observed across subgroups: allogeneic transplant, 57.3% vs. 58.8% (OR, 0.94); autologous transplant, 19.9% vs. 24.7% ( OR, 0.71); or chemotherapy, 48% vs. 52.1% (OR, 0.84).
There were no significant differences in mean number of transfusions (difference, 0.1; 95% confidence interval, –1.9 to 2) or days alive without grade 2 or higher bleeding (difference, 0.1; 95% CI, –1.4 to 1.5).
“A post hoc analysis of WHO 3+ bleeding showed these events to be rare and without any improvement with tranexamic acid,” she said.
A higher percentage of patients in the tranexamic acid group experienced thrombotic events (19.5% vs. 11%). “But importantly, in both groups, it was primarily due to central line occlusions without an associated thrombus,” said Dr. Gernsheimer. “This was statistically significant.”
Fewer non–catheter related thrombotic events occurred in the tranexamic acid group (3.7% vs. 5.5%), but the difference was not statistically significant.
There was also no significant difference between groups in veno-occlusive disease after 30 days (1.8% vs. 1.2%) or all-cause mortality at 30 days (2.4% vs. 3%) or 100 days (11.5% vs. 11.5%). No deaths associated with thrombosis had occurred in either group at 120 days.
The study was supported by the University of Washington and the National Heart, Lung, and Blood Institute. Dr. Gernsheimer has relationships with Amgen, Cellphire, Dova Pharmaceuticals, Novartis, Principia, Rigel, Sanofi, and Vertex. Dr. Tremblay and Dr. Gandhi have disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
Despite being routinely used in clinical settings, prophylactic use of tranexamic acid, an antifibrinolytic agent administered with platelet transfusions, did not reduce bleeding among patients with blood cancers and severe thrombocytopenia, according to a new study.
The study compared tranexamic acid to placebo and found no significant differences in terms of the number of bleeding events, the number of red blood cell transfusions, or the number of platelet transfusions that were required.
However, the rate of occlusions in the central venous line was significantly higher for patients in the tranexamic acid group, although there was no difference between groups for other types of thrombotic events.
The findings were presented at the annual meeting of the American Society of Hematology, which was held online.
The study was highlighted as potentially practice changing at a press preview webinar by ASH Secretary Robert Brodsky, MD.
“They found absolutely no difference in bleeding or need for transfusion,” said Brodsky. “What they did find was more catheter-associated blood clots in the tranexamic acid group. This is a practice changer in that it probably should not be given prophylactically to patients with thrombocytopenia.”
Senior author Terry B. Gernsheimer, MD, of the University of Washington, Seattle, noted that tranexamic acid has been found to be effective in the treatment of bleeding related to childbirth, surgery, and inherited blood disorders.
It is also used for patients with blood cancers and severe thrombocytopenia. There is little evidence to support this use, which is why the researchers decided to investigate.
“Clearly patients with low platelet counts and blood cancers have a different kind of bleeding than the bleeding experienced by patients who have suffered some kind of trauma or surgery,” Dr. Gernsheimer said in a statement.
“Their bleeding likely is due to endothelial damage – damage to the lining of blood vessels – that tranexamic acid would not treat,” she added.
“To prevent bleeding in these patients, we may need to look at ways to speed the healing of the endothelium that occurs with chemotherapy, radiation, and graft-vs-host disease in patients receiving a transplant,” Dr. Gernsheimer commented.
Temper enthusiasm
“Overall, I think these results will temper enthusiasm for using tranexamic acid in this setting,” said Mitul Gandhi, MD, a medical oncologist with Virginia Cancer Specialists, who was approached for comment.
These data do not support the routine use of prophylactic tranexamic acid in chemotherapy-induced thrombocytopenia for patients with platelet counts lower than 30,000/μL, he added.
“The primary objective was not met, and there was an observed increased rate of catheter-associated thrombosis,” he said. “Continued use of judicious transfusion support and correction of a concomitant coagulopathy remains the main clinical approach to these patients.”
Dr. Gandhi commented that tranexamic acid “remains a potentially useful adjunct agent in certain cases of recalcitrant bleeding related to thrombocytopenia or coagulopathy.
“While there is no uniform scenario, it is typically reserved on a case-by-case basis after addressing vascular defects, utilization of platelet, fresh frozen plasma, cryoprecipitate transfusions, vitamin K repletion, and of course excluding any antiplatelet or anticoagulant therapy,» he told this news organization. “For persistent bleeding in spite of all corrective measures or hemorrhage into noncompressible vascular beds, such as with intracranial bleeds, antifibrinolytic therapy may assist in mitigating further blood loss.”
However, this has to be balanced with the potential increased risk for thrombosis after correction of the hemostatic insult.
At present, tranexamic acid “only has an FDA indication for uterine bleeding, but it is frequently used in trauma settings and obstetrical emergencies,” said Douglas Tremblay, MD, an internist at the Icahn School of Medicine at Mount Sinai, New York, who was also approached for comment.
“There is evidence from prior studies that were done 20 or 30 years ago that it may help in this setting, so it is used in some institutions, although we don’t give it prophylactically for patients with a hematologic malignancy.”
Although this was a negative study, Dr. Tremblay pointed out that one thing that may come out of it is that there may be subgroups who can benefit from the prophylactic use of tranexamic acid. “There is very wide inclusion criteria for the study – any type of hematologic malignancy in patients undergoing chemotherapy or stem cell transplant,” he said in an interview. “Even among chemotherapy and transplant patients, there are different risks for bleeding.”
For example, patients undergoing induction chemotherapy for acute myeloid leukemia are at an increased risk of bleeding in comparison with patients with other hematologic malignancies, and those undergoing allogeneic transplant are at an increased risk of bleeding in comparison with patients undergoing autologous transplant. “So while its unclear if a subgroup may benefit from this strategy, lumped together, it doesn’t appear it is of any benefit and potentially harmful, in terms of line occlusions,” he said. “While that may seem to be a nuisance, it can delay chemotherapy or supportive infusions, and that can be a big deal.”
No evidence of benefit
Dr. Gernsheimer and colleagues conducted the American Trial Using Tranexamic Acid in Thrombocytopenia (A-TREAT), which evaluated the effects of prophylactic tranexamic acid as an adjunct to routine transfusion therapy on bleeding and transfusion requirements.
A total of 330 patients were randomly assigned to receive either tranexamic acid 1,000 mg IV or 1,300 mg or placebo. Randomization was stratified by site and therapy: chemotherapy, allogeneic transplant, or autologous transplant. It was anticipated that all patients had hypoproliferative thrombocytopenia (expected platelet count, 10,000/µL for at least 5 days).
Treatment continued for 30 days or platelet count recovery (>30,000/µL), diagnosis of thrombosis or veno-occlusive disease, recurrent line occlusion, visible hematuria, or physician or patient request.
The primary endpoint of the study was the proportion of patients with bleeding of World Health Organization grade 2 or above over 30 days after beginning therapy. Secondary endpoints included the number of transfusions and the number of days alive without WHO grade 2+ bleeding during the first 30 days post activation of study drug.
The time to first WHO 2+ bleeding was “remarkably similar” between the tranexamic acid groups and the placebo group, said Dr. Gernsheimer.
In the cohort as a whole, 48.8% in the placebo group experienced a grade 2+ bleed vs. 45.4% in the tranexamic group (odds ratio, 0.86).
Similar results were observed across subgroups: allogeneic transplant, 57.3% vs. 58.8% (OR, 0.94); autologous transplant, 19.9% vs. 24.7% ( OR, 0.71); or chemotherapy, 48% vs. 52.1% (OR, 0.84).
There were no significant differences in mean number of transfusions (difference, 0.1; 95% confidence interval, –1.9 to 2) or days alive without grade 2 or higher bleeding (difference, 0.1; 95% CI, –1.4 to 1.5).
“A post hoc analysis of WHO 3+ bleeding showed these events to be rare and without any improvement with tranexamic acid,” she said.
A higher percentage of patients in the tranexamic acid group experienced thrombotic events (19.5% vs. 11%). “But importantly, in both groups, it was primarily due to central line occlusions without an associated thrombus,” said Dr. Gernsheimer. “This was statistically significant.”
Fewer non–catheter related thrombotic events occurred in the tranexamic acid group (3.7% vs. 5.5%), but the difference was not statistically significant.
There was also no significant difference between groups in veno-occlusive disease after 30 days (1.8% vs. 1.2%) or all-cause mortality at 30 days (2.4% vs. 3%) or 100 days (11.5% vs. 11.5%). No deaths associated with thrombosis had occurred in either group at 120 days.
The study was supported by the University of Washington and the National Heart, Lung, and Blood Institute. Dr. Gernsheimer has relationships with Amgen, Cellphire, Dova Pharmaceuticals, Novartis, Principia, Rigel, Sanofi, and Vertex. Dr. Tremblay and Dr. Gandhi have disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
Childhood Hodgkin survivors have neurocognitive impairment
More than 2 decades on, adult survivors of childhood Hodgkin lymphoma report significantly more neurocognitive impairment than their siblings, but the differences may be related to risk factors in adulthood rather than to treatment in childhood, investigators say.
Among adults with a history of childhood Hodgkin lymphoma and their siblings as controls, the survivors reported significantly worse functioning than their brothers or sisters in four domains of neurocognitive functioning.
In multivariate analysis, however, while sex, race, activity level and smoking status were all significant predictors for worse neurocognitive impairment, there were no significant associations between chemotherapy drugs or chest radiation and neurocognitive impairment, said Annalynn M. Williams, PhD, from St. Jude Children’s Research Hospital in Memphis.
“Hodgkin lymphoma is the most common cancer diagnosed in adolescents, and for many years we’ve had high cure rates, resulting in a growing population of survivors who are now, unfortunately, at an increased risk for cardiovascular, respiratory, endocrine and neurologic late morbidity. The neurocognitive morbidity in this population, however, is unknown,” she said in oral abstract presented at the annual meeting of the American Society of Hematology.
Survivors and sibs
To better characterize the potential late neurocognitive effects of intensive Hodgkin lymphoma therapy in childhood, Dr. Williams and colleagues polled survivors of childhood Hodgkin lymphoma and randomly selected sibling controls who were participants in the Childhood Cancer Survivor Study (CCSS).
Participants were asked to complete questionnaires regarding four domains of neurocognitive impairment: task efficiency, emotional regulation, organization, and memory. The investigators defined impairment in each domain as a score lower than that of the 90th percentile of community controls from the St. Jude Lifetime Cohort.
A total of 1,564 survivors and 725 controls completed the questionnaires and were included in the study.
The median age at follow-up was slightly higher among survivors, at 37 versus 32 years. The median age at diagnosis was 14, and the median time since diagnosis was 23 years.
In all, 10.8% of survivors reported impaired task efficiency, compared with 7.7% of controls. Problems with emotional regulation were reported by 16.6% of survivors versus 11.5% of siblings, and difficulties with organization and memory were reported by 12.1% versus10.3%, and 8.1% versus 5.7%, respectively.
In a model adjusted for age, sex, and race, the relative risks for neurocognitive impairment among survivors versus siblings, were as follows: task efficiency (RR,1.37); emotional regulation (RR, 1.56); organization (RR, 1.32); memory (RR, 1.72) (all significant by confidence interval).
In a model adjusted for sex, race, smoking status, exercise, age, time since diagnosis, and treatment exposures, risk factors for neurocognitive impairment among survivors included female versus male sex (significant for emotional regulation and memory deficits); non-White versus White (significant for task efficiency); former smoker versus never (significant for all domains except organization); current smoker versus never (significant for task efficiency and emotional regulation); and meeting Centers for Disease Control and Prevention exercise criteria versus not (negatively significant for task efficiency and organization); (P < .05 for all above comparisons).
However, in a model adjusted for relapse, second malignancy, treatment exposures, age, sex, race, time since diagnosis, smoking status and physical activity, only relapse or second malignancy – surrogates for additional treatment exposures – were significantly associated with neurocognitive impairment, and then only in the domain of task efficiency.
Chronic conditions significantly associated with risk for impairment included cardiovascular disease (significant across all domains), respiratory comorbidities (significant for task efficiency), endocrine disorders (significant for task efficiency), and neurologic disorders (significant in all domains except organization).
“While these analyses give us a sense of the presence of neurocognitive impairment in a large sample of Hodgkin lymphoma survivors from across the U.S., these analyses are limited by the self-reported nature of the data,” Dr. Williams acknowledged.
“Because survivors self-report impairments, these likely represent overt, symptomatic neurocognitive impairments. Many more survivors may experience more subtle neurocognitive impairments, and additional research with objective measures of both chronic health conditions and neurocognitive functioning are warranted,” she added.
Smoking gun?
In the question-and-answer session following the presentation, session comoderator Pallawi Torka, MD, from Roswell Park Comprehensive Cancer Center in Buffalo, N.Y., who was not involved in the research, commented that the finding regarding a link between current and former smoking as risk factors for neurocognitive impairment was “intriguing.”
“Do you think that smoking is a cause or an effect of having that impairment in childhood survivors of Hodgkin lymphoma?” she asked.
“That’s a great question, and actually one we have spent a great deal of time discussing, and we’re still trying to tease that apart. We’re still not really sure where that association is coming from,” Dr. Williams replied.
She noted that, in a different sample of CCSS participants from whom biospecimens were collected, the investigators plan to see whether smoking drives inflammation and oxidative stress mechanisms that may be contributing to neurocognitive impairment, or whether smoking is a coping mechanism related to anxiety and depression, which have also been seen in survivors.
Kara Kelly, MD, a pediatric oncologist at Roswell Park, commented that some survivors report symptoms of cognitive dysfunction shortly after treatment, and asked whether there might be a relationship to Hodgkin-specific factors such as B symptoms, in which cytokine-mediated inflammation may play a role.
Dr. Williams said that, “unfortunately, in CCSS these survivors had to be at least 5 years from diagnosis, but in many cases were recruited years after their diagnosis and treatment, so we don’t have data on B symptoms.”
The CCSS is funded by the National Cancer Institute. Dr. Williams, Dr. Palawi, and Dr. Kelly all reported no relevant conflicts of interest to disclose.
SOURCE: Williams AM et al. ASH 2020, Abstract 370.
More than 2 decades on, adult survivors of childhood Hodgkin lymphoma report significantly more neurocognitive impairment than their siblings, but the differences may be related to risk factors in adulthood rather than to treatment in childhood, investigators say.
Among adults with a history of childhood Hodgkin lymphoma and their siblings as controls, the survivors reported significantly worse functioning than their brothers or sisters in four domains of neurocognitive functioning.
In multivariate analysis, however, while sex, race, activity level and smoking status were all significant predictors for worse neurocognitive impairment, there were no significant associations between chemotherapy drugs or chest radiation and neurocognitive impairment, said Annalynn M. Williams, PhD, from St. Jude Children’s Research Hospital in Memphis.
“Hodgkin lymphoma is the most common cancer diagnosed in adolescents, and for many years we’ve had high cure rates, resulting in a growing population of survivors who are now, unfortunately, at an increased risk for cardiovascular, respiratory, endocrine and neurologic late morbidity. The neurocognitive morbidity in this population, however, is unknown,” she said in oral abstract presented at the annual meeting of the American Society of Hematology.
Survivors and sibs
To better characterize the potential late neurocognitive effects of intensive Hodgkin lymphoma therapy in childhood, Dr. Williams and colleagues polled survivors of childhood Hodgkin lymphoma and randomly selected sibling controls who were participants in the Childhood Cancer Survivor Study (CCSS).
Participants were asked to complete questionnaires regarding four domains of neurocognitive impairment: task efficiency, emotional regulation, organization, and memory. The investigators defined impairment in each domain as a score lower than that of the 90th percentile of community controls from the St. Jude Lifetime Cohort.
A total of 1,564 survivors and 725 controls completed the questionnaires and were included in the study.
The median age at follow-up was slightly higher among survivors, at 37 versus 32 years. The median age at diagnosis was 14, and the median time since diagnosis was 23 years.
In all, 10.8% of survivors reported impaired task efficiency, compared with 7.7% of controls. Problems with emotional regulation were reported by 16.6% of survivors versus 11.5% of siblings, and difficulties with organization and memory were reported by 12.1% versus10.3%, and 8.1% versus 5.7%, respectively.
In a model adjusted for age, sex, and race, the relative risks for neurocognitive impairment among survivors versus siblings, were as follows: task efficiency (RR,1.37); emotional regulation (RR, 1.56); organization (RR, 1.32); memory (RR, 1.72) (all significant by confidence interval).
In a model adjusted for sex, race, smoking status, exercise, age, time since diagnosis, and treatment exposures, risk factors for neurocognitive impairment among survivors included female versus male sex (significant for emotional regulation and memory deficits); non-White versus White (significant for task efficiency); former smoker versus never (significant for all domains except organization); current smoker versus never (significant for task efficiency and emotional regulation); and meeting Centers for Disease Control and Prevention exercise criteria versus not (negatively significant for task efficiency and organization); (P < .05 for all above comparisons).
However, in a model adjusted for relapse, second malignancy, treatment exposures, age, sex, race, time since diagnosis, smoking status and physical activity, only relapse or second malignancy – surrogates for additional treatment exposures – were significantly associated with neurocognitive impairment, and then only in the domain of task efficiency.
Chronic conditions significantly associated with risk for impairment included cardiovascular disease (significant across all domains), respiratory comorbidities (significant for task efficiency), endocrine disorders (significant for task efficiency), and neurologic disorders (significant in all domains except organization).
“While these analyses give us a sense of the presence of neurocognitive impairment in a large sample of Hodgkin lymphoma survivors from across the U.S., these analyses are limited by the self-reported nature of the data,” Dr. Williams acknowledged.
“Because survivors self-report impairments, these likely represent overt, symptomatic neurocognitive impairments. Many more survivors may experience more subtle neurocognitive impairments, and additional research with objective measures of both chronic health conditions and neurocognitive functioning are warranted,” she added.
Smoking gun?
In the question-and-answer session following the presentation, session comoderator Pallawi Torka, MD, from Roswell Park Comprehensive Cancer Center in Buffalo, N.Y., who was not involved in the research, commented that the finding regarding a link between current and former smoking as risk factors for neurocognitive impairment was “intriguing.”
“Do you think that smoking is a cause or an effect of having that impairment in childhood survivors of Hodgkin lymphoma?” she asked.
“That’s a great question, and actually one we have spent a great deal of time discussing, and we’re still trying to tease that apart. We’re still not really sure where that association is coming from,” Dr. Williams replied.
She noted that, in a different sample of CCSS participants from whom biospecimens were collected, the investigators plan to see whether smoking drives inflammation and oxidative stress mechanisms that may be contributing to neurocognitive impairment, or whether smoking is a coping mechanism related to anxiety and depression, which have also been seen in survivors.
Kara Kelly, MD, a pediatric oncologist at Roswell Park, commented that some survivors report symptoms of cognitive dysfunction shortly after treatment, and asked whether there might be a relationship to Hodgkin-specific factors such as B symptoms, in which cytokine-mediated inflammation may play a role.
Dr. Williams said that, “unfortunately, in CCSS these survivors had to be at least 5 years from diagnosis, but in many cases were recruited years after their diagnosis and treatment, so we don’t have data on B symptoms.”
The CCSS is funded by the National Cancer Institute. Dr. Williams, Dr. Palawi, and Dr. Kelly all reported no relevant conflicts of interest to disclose.
SOURCE: Williams AM et al. ASH 2020, Abstract 370.
More than 2 decades on, adult survivors of childhood Hodgkin lymphoma report significantly more neurocognitive impairment than their siblings, but the differences may be related to risk factors in adulthood rather than to treatment in childhood, investigators say.
Among adults with a history of childhood Hodgkin lymphoma and their siblings as controls, the survivors reported significantly worse functioning than their brothers or sisters in four domains of neurocognitive functioning.
In multivariate analysis, however, while sex, race, activity level and smoking status were all significant predictors for worse neurocognitive impairment, there were no significant associations between chemotherapy drugs or chest radiation and neurocognitive impairment, said Annalynn M. Williams, PhD, from St. Jude Children’s Research Hospital in Memphis.
“Hodgkin lymphoma is the most common cancer diagnosed in adolescents, and for many years we’ve had high cure rates, resulting in a growing population of survivors who are now, unfortunately, at an increased risk for cardiovascular, respiratory, endocrine and neurologic late morbidity. The neurocognitive morbidity in this population, however, is unknown,” she said in oral abstract presented at the annual meeting of the American Society of Hematology.
Survivors and sibs
To better characterize the potential late neurocognitive effects of intensive Hodgkin lymphoma therapy in childhood, Dr. Williams and colleagues polled survivors of childhood Hodgkin lymphoma and randomly selected sibling controls who were participants in the Childhood Cancer Survivor Study (CCSS).
Participants were asked to complete questionnaires regarding four domains of neurocognitive impairment: task efficiency, emotional regulation, organization, and memory. The investigators defined impairment in each domain as a score lower than that of the 90th percentile of community controls from the St. Jude Lifetime Cohort.
A total of 1,564 survivors and 725 controls completed the questionnaires and were included in the study.
The median age at follow-up was slightly higher among survivors, at 37 versus 32 years. The median age at diagnosis was 14, and the median time since diagnosis was 23 years.
In all, 10.8% of survivors reported impaired task efficiency, compared with 7.7% of controls. Problems with emotional regulation were reported by 16.6% of survivors versus 11.5% of siblings, and difficulties with organization and memory were reported by 12.1% versus10.3%, and 8.1% versus 5.7%, respectively.
In a model adjusted for age, sex, and race, the relative risks for neurocognitive impairment among survivors versus siblings, were as follows: task efficiency (RR,1.37); emotional regulation (RR, 1.56); organization (RR, 1.32); memory (RR, 1.72) (all significant by confidence interval).
In a model adjusted for sex, race, smoking status, exercise, age, time since diagnosis, and treatment exposures, risk factors for neurocognitive impairment among survivors included female versus male sex (significant for emotional regulation and memory deficits); non-White versus White (significant for task efficiency); former smoker versus never (significant for all domains except organization); current smoker versus never (significant for task efficiency and emotional regulation); and meeting Centers for Disease Control and Prevention exercise criteria versus not (negatively significant for task efficiency and organization); (P < .05 for all above comparisons).
However, in a model adjusted for relapse, second malignancy, treatment exposures, age, sex, race, time since diagnosis, smoking status and physical activity, only relapse or second malignancy – surrogates for additional treatment exposures – were significantly associated with neurocognitive impairment, and then only in the domain of task efficiency.
Chronic conditions significantly associated with risk for impairment included cardiovascular disease (significant across all domains), respiratory comorbidities (significant for task efficiency), endocrine disorders (significant for task efficiency), and neurologic disorders (significant in all domains except organization).
“While these analyses give us a sense of the presence of neurocognitive impairment in a large sample of Hodgkin lymphoma survivors from across the U.S., these analyses are limited by the self-reported nature of the data,” Dr. Williams acknowledged.
“Because survivors self-report impairments, these likely represent overt, symptomatic neurocognitive impairments. Many more survivors may experience more subtle neurocognitive impairments, and additional research with objective measures of both chronic health conditions and neurocognitive functioning are warranted,” she added.
Smoking gun?
In the question-and-answer session following the presentation, session comoderator Pallawi Torka, MD, from Roswell Park Comprehensive Cancer Center in Buffalo, N.Y., who was not involved in the research, commented that the finding regarding a link between current and former smoking as risk factors for neurocognitive impairment was “intriguing.”
“Do you think that smoking is a cause or an effect of having that impairment in childhood survivors of Hodgkin lymphoma?” she asked.
“That’s a great question, and actually one we have spent a great deal of time discussing, and we’re still trying to tease that apart. We’re still not really sure where that association is coming from,” Dr. Williams replied.
She noted that, in a different sample of CCSS participants from whom biospecimens were collected, the investigators plan to see whether smoking drives inflammation and oxidative stress mechanisms that may be contributing to neurocognitive impairment, or whether smoking is a coping mechanism related to anxiety and depression, which have also been seen in survivors.
Kara Kelly, MD, a pediatric oncologist at Roswell Park, commented that some survivors report symptoms of cognitive dysfunction shortly after treatment, and asked whether there might be a relationship to Hodgkin-specific factors such as B symptoms, in which cytokine-mediated inflammation may play a role.
Dr. Williams said that, “unfortunately, in CCSS these survivors had to be at least 5 years from diagnosis, but in many cases were recruited years after their diagnosis and treatment, so we don’t have data on B symptoms.”
The CCSS is funded by the National Cancer Institute. Dr. Williams, Dr. Palawi, and Dr. Kelly all reported no relevant conflicts of interest to disclose.
SOURCE: Williams AM et al. ASH 2020, Abstract 370.
FROM ASH 2020