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Sharon Worcester is an award-winning medical journalist for MDedge News. She has been with the company since 1996, first as the Southeast Bureau Chief (1996-2009) when the company was known as International Medical News Group, then as a freelance writer (2010-2015) before returning as a reporter in 2015. She previously worked as a daily newspaper reporter covering health and local government. Sharon currently reports primarily on oncology and hematology. She has a BA from Eckerd College and an MA in Mass Communication/Print Journalism from the University of Florida. Connect with her via LinkedIn and follow her on twitter @SW_MedReporter.
Lymphopenia linked to worse response in RCC, bladder cancer patients on checkpoint inhibitors
ORLANDO – treated in a real-world setting.
In a retrospective study of 20 patients, those with lower pALCs and higher pNLRs were less likely to respond to checkpoint inhibitors.
Tonjeh Bah, MD, of Feist-Weiller Cancer Center at LSU Health Shreveport in Louisiana, and colleagues reported these results in a poster at the ASCO-SITC Clinical Immuno-Oncology Symposium.
Response rates were 75% in patients with pALC greater than 1,000 and 25% in patients with pALC less than 1,000. This difference was statistically significant (P = .027), Dr. Bah noted, adding that the groups were comparable with respect to age, sex, race, and type of checkpoint inhibitors used.
Similarly, response rates were 80% in patients with pNLR less than 3 (the established upper limit of normal) and 30% in patients with pNLR greater than 3 (P = .024).
Checkpoint inhibitors targeting cytotoxic T-lymphocyte-associated protein 4 and programmed death-1 and its ligand are essential components of therapy across multiple cancer types, Dr. Bah noted in an interview. She explained that prior studies – mostly in patients with lung cancer and head and neck cancers – have also shown pALC and pNLR to be independently associated with poor checkpoint inhibitor response and worse progression-free survival.
“But this is the first study to look at the connection in kidney and bladder cancer in a real-world setting,” she said.
Dr. Bah and colleagues conducted the study to test the hypothesis that “lymphopenia is a marker of immune exhaustion, which is characterized by dysfunctional T cells that have a limited antitumor effect even in the presence of [checkpoint inhibitors] and by the eventual depletion of antitumor lymphocytes,” they wrote in the poster.
Patients included in the study were all those with renal cell carcinoma (n = 13) or bladder-urothelial cancers (n = 7) who received checkpoint inhibitors at one of two medical centers in Louisiana during 2015-2019 and who had outcomes reported. Patients who attained stable disease or had partial or complete responses were categorized as responders. Patients who progressed on checkpoint inhibitors were considered nonresponders.
“Our findings were not a surprise, but they do document, for the first time and in a real-world setting, that pALC and pNLR may have prognostic utility in patients with kidney and bladder cancers who are treated with [checkpoint inhibitors],” Dr. Bah said.
She added that the findings could help determine which patients are candidates for checkpoint inhibitors, but the results require confirmation in a large, prospective study. Dr. Bah reported having no disclosures, and there was no sponsor for this study.
SOURCE: Bah T et al. ASCO-SITC 2020. Abstract 31.
ORLANDO – treated in a real-world setting.
In a retrospective study of 20 patients, those with lower pALCs and higher pNLRs were less likely to respond to checkpoint inhibitors.
Tonjeh Bah, MD, of Feist-Weiller Cancer Center at LSU Health Shreveport in Louisiana, and colleagues reported these results in a poster at the ASCO-SITC Clinical Immuno-Oncology Symposium.
Response rates were 75% in patients with pALC greater than 1,000 and 25% in patients with pALC less than 1,000. This difference was statistically significant (P = .027), Dr. Bah noted, adding that the groups were comparable with respect to age, sex, race, and type of checkpoint inhibitors used.
Similarly, response rates were 80% in patients with pNLR less than 3 (the established upper limit of normal) and 30% in patients with pNLR greater than 3 (P = .024).
Checkpoint inhibitors targeting cytotoxic T-lymphocyte-associated protein 4 and programmed death-1 and its ligand are essential components of therapy across multiple cancer types, Dr. Bah noted in an interview. She explained that prior studies – mostly in patients with lung cancer and head and neck cancers – have also shown pALC and pNLR to be independently associated with poor checkpoint inhibitor response and worse progression-free survival.
“But this is the first study to look at the connection in kidney and bladder cancer in a real-world setting,” she said.
Dr. Bah and colleagues conducted the study to test the hypothesis that “lymphopenia is a marker of immune exhaustion, which is characterized by dysfunctional T cells that have a limited antitumor effect even in the presence of [checkpoint inhibitors] and by the eventual depletion of antitumor lymphocytes,” they wrote in the poster.
Patients included in the study were all those with renal cell carcinoma (n = 13) or bladder-urothelial cancers (n = 7) who received checkpoint inhibitors at one of two medical centers in Louisiana during 2015-2019 and who had outcomes reported. Patients who attained stable disease or had partial or complete responses were categorized as responders. Patients who progressed on checkpoint inhibitors were considered nonresponders.
“Our findings were not a surprise, but they do document, for the first time and in a real-world setting, that pALC and pNLR may have prognostic utility in patients with kidney and bladder cancers who are treated with [checkpoint inhibitors],” Dr. Bah said.
She added that the findings could help determine which patients are candidates for checkpoint inhibitors, but the results require confirmation in a large, prospective study. Dr. Bah reported having no disclosures, and there was no sponsor for this study.
SOURCE: Bah T et al. ASCO-SITC 2020. Abstract 31.
ORLANDO – treated in a real-world setting.
In a retrospective study of 20 patients, those with lower pALCs and higher pNLRs were less likely to respond to checkpoint inhibitors.
Tonjeh Bah, MD, of Feist-Weiller Cancer Center at LSU Health Shreveport in Louisiana, and colleagues reported these results in a poster at the ASCO-SITC Clinical Immuno-Oncology Symposium.
Response rates were 75% in patients with pALC greater than 1,000 and 25% in patients with pALC less than 1,000. This difference was statistically significant (P = .027), Dr. Bah noted, adding that the groups were comparable with respect to age, sex, race, and type of checkpoint inhibitors used.
Similarly, response rates were 80% in patients with pNLR less than 3 (the established upper limit of normal) and 30% in patients with pNLR greater than 3 (P = .024).
Checkpoint inhibitors targeting cytotoxic T-lymphocyte-associated protein 4 and programmed death-1 and its ligand are essential components of therapy across multiple cancer types, Dr. Bah noted in an interview. She explained that prior studies – mostly in patients with lung cancer and head and neck cancers – have also shown pALC and pNLR to be independently associated with poor checkpoint inhibitor response and worse progression-free survival.
“But this is the first study to look at the connection in kidney and bladder cancer in a real-world setting,” she said.
Dr. Bah and colleagues conducted the study to test the hypothesis that “lymphopenia is a marker of immune exhaustion, which is characterized by dysfunctional T cells that have a limited antitumor effect even in the presence of [checkpoint inhibitors] and by the eventual depletion of antitumor lymphocytes,” they wrote in the poster.
Patients included in the study were all those with renal cell carcinoma (n = 13) or bladder-urothelial cancers (n = 7) who received checkpoint inhibitors at one of two medical centers in Louisiana during 2015-2019 and who had outcomes reported. Patients who attained stable disease or had partial or complete responses were categorized as responders. Patients who progressed on checkpoint inhibitors were considered nonresponders.
“Our findings were not a surprise, but they do document, for the first time and in a real-world setting, that pALC and pNLR may have prognostic utility in patients with kidney and bladder cancers who are treated with [checkpoint inhibitors],” Dr. Bah said.
She added that the findings could help determine which patients are candidates for checkpoint inhibitors, but the results require confirmation in a large, prospective study. Dr. Bah reported having no disclosures, and there was no sponsor for this study.
SOURCE: Bah T et al. ASCO-SITC 2020. Abstract 31.
REPORTING FROM THE CLINICAL IMMUNO-ONCOLOGY SYMPOSIUM
Review reveals shorter OS, RFS in young colorectal cancer patients
Colorectal cancer patients aged 10-25 years have significantly worse survival rates than those of older patients, findings from a retrospective review suggest.
Overall survival (OS) at 3 years was 42% among patients aged 10-25 years and 90% among patients older than 25 years of age (P less than .0001). Recurrence-free survival (RFS) rates were 32% and 78%, respectively (P less than .0001).
Andrea A. Hayes-Jordan, MD, of the University of North Carolina at Chapel Hill, and colleagues reported these findings in the Journal of the American College of Surgeons.
The researchers reviewed patients treated at MD Anderson Cancer Center in Houston between 1991 and 2017 who were part of a prospectively maintained database. The cohort comprised 94 patients ages 10-25 years and 765 patients who were older than 25 years of age.
RFS and OS data were available for all of the older patients. For the younger group, RFS data were available for 77 patients, and OS data were available for 80 patients.
Five-year OS rates by disease stage in the younger and older groups, respectively, were:
100% and 96% for stage 1.
64% and 90% for stage 2 (P less than .0001).
58% and 85% for stage 3 (P less than .0001).
16% and 55% for stage 4 (P less than .0001).
Five-year RFS rates by disease stage in the younger and older groups, respectively, were:
100% and 95% for stage 1.
55% and 85% for stage 2 (P = .0002).
31% and 73% for stage 3 (P less than .0001).
5% and 27% for stage 4 (P less than .0001).
On multivariate analysis, patients aged 10-25 years had a significantly higher risk of recurrence or death (hazard ratio, 2.312; P less than .0001) and a higher risk of death (HR, 3.592; P less than .0001) compared with older patients.
Of note, peritoneal metastasis occurred significantly more often in the younger group (P = .00001), but predisposing conditions such as polyposis or congenital colon disease did not account for this difference.
“Besides age, mucinous and signet ring histology, poorly differentiated histology, [and] microsatellite instability were statistically significantly more prevalent in this [young] population,” the researchers wrote. “Although other authors have noted similar differences, none have identified peritoneal metastasis to be statistically significantly more prevalent in patients under 25 years.”
The reason for this finding “most certainly lies in the biology in this age group and propensity to develop peritoneal metastasis based on a yet unknown genetic factor,” the researchers added. They reported having no disclosures.
SOURCE: Hayes-Jordan A et al. J Am Coll Surg. 2020 Feb 21. doi: 10.1016/j.jamcollsurg.2019.12.043.
Colorectal cancer patients aged 10-25 years have significantly worse survival rates than those of older patients, findings from a retrospective review suggest.
Overall survival (OS) at 3 years was 42% among patients aged 10-25 years and 90% among patients older than 25 years of age (P less than .0001). Recurrence-free survival (RFS) rates were 32% and 78%, respectively (P less than .0001).
Andrea A. Hayes-Jordan, MD, of the University of North Carolina at Chapel Hill, and colleagues reported these findings in the Journal of the American College of Surgeons.
The researchers reviewed patients treated at MD Anderson Cancer Center in Houston between 1991 and 2017 who were part of a prospectively maintained database. The cohort comprised 94 patients ages 10-25 years and 765 patients who were older than 25 years of age.
RFS and OS data were available for all of the older patients. For the younger group, RFS data were available for 77 patients, and OS data were available for 80 patients.
Five-year OS rates by disease stage in the younger and older groups, respectively, were:
100% and 96% for stage 1.
64% and 90% for stage 2 (P less than .0001).
58% and 85% for stage 3 (P less than .0001).
16% and 55% for stage 4 (P less than .0001).
Five-year RFS rates by disease stage in the younger and older groups, respectively, were:
100% and 95% for stage 1.
55% and 85% for stage 2 (P = .0002).
31% and 73% for stage 3 (P less than .0001).
5% and 27% for stage 4 (P less than .0001).
On multivariate analysis, patients aged 10-25 years had a significantly higher risk of recurrence or death (hazard ratio, 2.312; P less than .0001) and a higher risk of death (HR, 3.592; P less than .0001) compared with older patients.
Of note, peritoneal metastasis occurred significantly more often in the younger group (P = .00001), but predisposing conditions such as polyposis or congenital colon disease did not account for this difference.
“Besides age, mucinous and signet ring histology, poorly differentiated histology, [and] microsatellite instability were statistically significantly more prevalent in this [young] population,” the researchers wrote. “Although other authors have noted similar differences, none have identified peritoneal metastasis to be statistically significantly more prevalent in patients under 25 years.”
The reason for this finding “most certainly lies in the biology in this age group and propensity to develop peritoneal metastasis based on a yet unknown genetic factor,” the researchers added. They reported having no disclosures.
SOURCE: Hayes-Jordan A et al. J Am Coll Surg. 2020 Feb 21. doi: 10.1016/j.jamcollsurg.2019.12.043.
Colorectal cancer patients aged 10-25 years have significantly worse survival rates than those of older patients, findings from a retrospective review suggest.
Overall survival (OS) at 3 years was 42% among patients aged 10-25 years and 90% among patients older than 25 years of age (P less than .0001). Recurrence-free survival (RFS) rates were 32% and 78%, respectively (P less than .0001).
Andrea A. Hayes-Jordan, MD, of the University of North Carolina at Chapel Hill, and colleagues reported these findings in the Journal of the American College of Surgeons.
The researchers reviewed patients treated at MD Anderson Cancer Center in Houston between 1991 and 2017 who were part of a prospectively maintained database. The cohort comprised 94 patients ages 10-25 years and 765 patients who were older than 25 years of age.
RFS and OS data were available for all of the older patients. For the younger group, RFS data were available for 77 patients, and OS data were available for 80 patients.
Five-year OS rates by disease stage in the younger and older groups, respectively, were:
100% and 96% for stage 1.
64% and 90% for stage 2 (P less than .0001).
58% and 85% for stage 3 (P less than .0001).
16% and 55% for stage 4 (P less than .0001).
Five-year RFS rates by disease stage in the younger and older groups, respectively, were:
100% and 95% for stage 1.
55% and 85% for stage 2 (P = .0002).
31% and 73% for stage 3 (P less than .0001).
5% and 27% for stage 4 (P less than .0001).
On multivariate analysis, patients aged 10-25 years had a significantly higher risk of recurrence or death (hazard ratio, 2.312; P less than .0001) and a higher risk of death (HR, 3.592; P less than .0001) compared with older patients.
Of note, peritoneal metastasis occurred significantly more often in the younger group (P = .00001), but predisposing conditions such as polyposis or congenital colon disease did not account for this difference.
“Besides age, mucinous and signet ring histology, poorly differentiated histology, [and] microsatellite instability were statistically significantly more prevalent in this [young] population,” the researchers wrote. “Although other authors have noted similar differences, none have identified peritoneal metastasis to be statistically significantly more prevalent in patients under 25 years.”
The reason for this finding “most certainly lies in the biology in this age group and propensity to develop peritoneal metastasis based on a yet unknown genetic factor,” the researchers added. They reported having no disclosures.
SOURCE: Hayes-Jordan A et al. J Am Coll Surg. 2020 Feb 21. doi: 10.1016/j.jamcollsurg.2019.12.043.
FROM JOURNAL OF THE AMERICAN COLLEGE OF SURGEONS
Late effects in young cancer survivors underscore importance of high-risk screening
according to data from the Childhood Cancer Survivor Study.
At a median follow-up of 21 years, the SMR for all-cause mortality was 5.9 among survivors aged 15-20 years and 6.2 among diagnosis-matched children under 15 years, compared with expected rates at the same ages in the general population. For health-related causes – excluding primary cancer recurrence or progression but including late effects of cancer therapy – the SMRs were 4.8 in the older group and 6.8 in the younger group.
Eugene Suh, MD, of Loyola University Chicago Medical Center, Maywood, Ill., and colleagues reported these results in Lancet Oncology.
The difference between the older and younger survivors (n = 5,804 in each group) was most evident at least 20 years after cancer diagnosis, the authors noted.
For both groups, but more so for childhood cancer survivors, the risk of developing any chronic health condition and any grade 3-5 health condition was greater than for siblings of the same age who did not have cancer (hazard ratios, 4.2 for adolescents/young adults and 5.6 for childhood survivors). The same was true for grade 3-5 cardiac conditions (HRs, 4.3 and 5.6, respectively), endocrine conditions (HRs, 3.9 and 6.4, respectively), and musculoskeletal conditions (HRs, 6.5 and 8.0, respectively).
These findings, which confirm those of previous studies suggesting that younger children might be more vulnerable to the adverse effects of cancer treatment, “underscore that focused efforts are needed to ensure early-adolescent and young adult cancer survivors are receiving recommended risk-based care, with a focus on high-risk cancer screening, to reduce morbidity and premature mortality,” the researchers concluded, noting that “studies to date indicate that adherence to such high-risk screening is poor.”
In a related editorial, Päivi Lähteenmäki, MD, PhD, of University of Turku (Finland) and Turku University Hospital, wrote that these findings warrant long-term follow-up of adolescent and young adult cancer survivors. She also argued that the results “might not be fully generalizable to patients treated today who might be on different treatment regimens to those treated in previous decades” and that “[m]ore prospectively collected objective data focusing on survivors ... are needed.”
Accurate characterization of patients at high risk who would benefit from a tailored screening program is most important, and identifying underlying genetic or molecular factors that confer higher risk for late sequelae would be useful for “planning approaches to survivorship,” Dr. Lähteenmäki added.
This study was funded by the National Cancer Institute and American Lebanese-Syrian Associated Charities. Dr. Suh and Dr. Lähteenmäki reported having no competing interests.
SOURCES: Suh E et al. Lancet Oncology. 2020 Feb 14. doi: 10.1016/S1470-2045(19)30800-9;Lähteenmäki P. Lancet Oncol. 2020 Feb 14. doi: 10.106/S1470-2045(19)30858-7.
according to data from the Childhood Cancer Survivor Study.
At a median follow-up of 21 years, the SMR for all-cause mortality was 5.9 among survivors aged 15-20 years and 6.2 among diagnosis-matched children under 15 years, compared with expected rates at the same ages in the general population. For health-related causes – excluding primary cancer recurrence or progression but including late effects of cancer therapy – the SMRs were 4.8 in the older group and 6.8 in the younger group.
Eugene Suh, MD, of Loyola University Chicago Medical Center, Maywood, Ill., and colleagues reported these results in Lancet Oncology.
The difference between the older and younger survivors (n = 5,804 in each group) was most evident at least 20 years after cancer diagnosis, the authors noted.
For both groups, but more so for childhood cancer survivors, the risk of developing any chronic health condition and any grade 3-5 health condition was greater than for siblings of the same age who did not have cancer (hazard ratios, 4.2 for adolescents/young adults and 5.6 for childhood survivors). The same was true for grade 3-5 cardiac conditions (HRs, 4.3 and 5.6, respectively), endocrine conditions (HRs, 3.9 and 6.4, respectively), and musculoskeletal conditions (HRs, 6.5 and 8.0, respectively).
These findings, which confirm those of previous studies suggesting that younger children might be more vulnerable to the adverse effects of cancer treatment, “underscore that focused efforts are needed to ensure early-adolescent and young adult cancer survivors are receiving recommended risk-based care, with a focus on high-risk cancer screening, to reduce morbidity and premature mortality,” the researchers concluded, noting that “studies to date indicate that adherence to such high-risk screening is poor.”
In a related editorial, Päivi Lähteenmäki, MD, PhD, of University of Turku (Finland) and Turku University Hospital, wrote that these findings warrant long-term follow-up of adolescent and young adult cancer survivors. She also argued that the results “might not be fully generalizable to patients treated today who might be on different treatment regimens to those treated in previous decades” and that “[m]ore prospectively collected objective data focusing on survivors ... are needed.”
Accurate characterization of patients at high risk who would benefit from a tailored screening program is most important, and identifying underlying genetic or molecular factors that confer higher risk for late sequelae would be useful for “planning approaches to survivorship,” Dr. Lähteenmäki added.
This study was funded by the National Cancer Institute and American Lebanese-Syrian Associated Charities. Dr. Suh and Dr. Lähteenmäki reported having no competing interests.
SOURCES: Suh E et al. Lancet Oncology. 2020 Feb 14. doi: 10.1016/S1470-2045(19)30800-9;Lähteenmäki P. Lancet Oncol. 2020 Feb 14. doi: 10.106/S1470-2045(19)30858-7.
according to data from the Childhood Cancer Survivor Study.
At a median follow-up of 21 years, the SMR for all-cause mortality was 5.9 among survivors aged 15-20 years and 6.2 among diagnosis-matched children under 15 years, compared with expected rates at the same ages in the general population. For health-related causes – excluding primary cancer recurrence or progression but including late effects of cancer therapy – the SMRs were 4.8 in the older group and 6.8 in the younger group.
Eugene Suh, MD, of Loyola University Chicago Medical Center, Maywood, Ill., and colleagues reported these results in Lancet Oncology.
The difference between the older and younger survivors (n = 5,804 in each group) was most evident at least 20 years after cancer diagnosis, the authors noted.
For both groups, but more so for childhood cancer survivors, the risk of developing any chronic health condition and any grade 3-5 health condition was greater than for siblings of the same age who did not have cancer (hazard ratios, 4.2 for adolescents/young adults and 5.6 for childhood survivors). The same was true for grade 3-5 cardiac conditions (HRs, 4.3 and 5.6, respectively), endocrine conditions (HRs, 3.9 and 6.4, respectively), and musculoskeletal conditions (HRs, 6.5 and 8.0, respectively).
These findings, which confirm those of previous studies suggesting that younger children might be more vulnerable to the adverse effects of cancer treatment, “underscore that focused efforts are needed to ensure early-adolescent and young adult cancer survivors are receiving recommended risk-based care, with a focus on high-risk cancer screening, to reduce morbidity and premature mortality,” the researchers concluded, noting that “studies to date indicate that adherence to such high-risk screening is poor.”
In a related editorial, Päivi Lähteenmäki, MD, PhD, of University of Turku (Finland) and Turku University Hospital, wrote that these findings warrant long-term follow-up of adolescent and young adult cancer survivors. She also argued that the results “might not be fully generalizable to patients treated today who might be on different treatment regimens to those treated in previous decades” and that “[m]ore prospectively collected objective data focusing on survivors ... are needed.”
Accurate characterization of patients at high risk who would benefit from a tailored screening program is most important, and identifying underlying genetic or molecular factors that confer higher risk for late sequelae would be useful for “planning approaches to survivorship,” Dr. Lähteenmäki added.
This study was funded by the National Cancer Institute and American Lebanese-Syrian Associated Charities. Dr. Suh and Dr. Lähteenmäki reported having no competing interests.
SOURCES: Suh E et al. Lancet Oncology. 2020 Feb 14. doi: 10.1016/S1470-2045(19)30800-9;Lähteenmäki P. Lancet Oncol. 2020 Feb 14. doi: 10.106/S1470-2045(19)30858-7.
FROM LANCET ONCOLOGY
Adolescent obesity linked with midlife cancer risk
Obesity during adolescence is associated with increased midlife cancer risk, according to findings from a large population-based cohort of Israeli teens examined between 1967 and 2010.
The association, which was stronger in individuals in the later period of the cohort than in those in the earlier years, suggests that the burden of obesity-related cancers might increase over time, given the increasing prevalence of adolescent obesity, wrote Ariel Furer, MD, of Israel Defense Forces Medical Corps, Ramat Gan, and colleagues. Their report is in The Lancet.
Obesity is a known causal factor for several types of cancer, but most studies have looked at middle-age or older individuals and had relatively short follow-up, and period effects are rarely assessed, the investigators said, noting that “the attributable burden of obesity-related cancer was previously calculated with an unverified assumption that the association remained unchanged over time.
“In contrast to this paucity of knowledge, the prevalence of youth obesity – particularly severe obesity – has increased worldwide, which parallels the rise in youth cancer incidence,” they wrote.
To address this paucity of data, the researchers reviewed medical and sociodemographic data for adolescents who were assessed at age 17 years for medical eligibility for mandatory military service, and linked that information with data from the National Cancer Registry to create a unified file. The primary study outcome was any cancer diagnosis between Jan. 1, 1967, and Dec. 31, 2012, and a secondary endpoint was all-cause mortality through Dec. 31, 2017, among those who developed cancer.
Among nearly 2.3 million participating adolescents who were evaluated for associations between body mass index at age 17 years and later cancer incidence, 1,370,020 were men with more than 29.5 million person-years of follow-up, and 928,110 were women with more than 18 million person-years of follow-up. The numbers of incident cancer cases in the men and women were 26,353 and 29,488, and the mean ages at diagnosis were 43.2 and 40.0 years, respectively, the investigators reported (Lancet. 2020 Feb 3. doi: 10.1016/S2213-8587(20)30019-X).
Adolescent obesity in men was significantly associated with midlife cancer incidence (hazard ratio, 1.26), but in women, no association was seen due to the previously reported inverse associations between obesity and cervical and breast cancers, they said.
However, when those cancers were excluded for women, the adjusted hazard ratio was similar to that for men (HR, 1.27).
Cancer incidence in both men and women increased gradually across BMI percentiles, and for both sexes, overweight BMI was associated with an increased cancer risk after 10 years of follow-up (HR, 1.14 for men, 1.22 for women after exclusion of cervical and breast cancer). Therefore, in some cases the increased cancer risk in those who were overweight as teens was evident before age 30 years, the authors noted.
Further, BMI was positively associated with greater mortality risk. For men, 5-year survival rates were 75.2% in those with adolescent BMI in the 5th-49th percentile, compared with 72.2% in those with BMI in the obesity range (95th percentile or greater), and the corresponding rates in women were 89.3% and 83.1% (HR, 1.33 and 1.89, respectively).
Of note, the investigators identified a period effect. That is, after stratification by enrollment period/cancer recording period (1967-1981/1982-1996 vs. 1982-1996/1997-2011), a stronger association was noted in individuals who entered the study during the later period, compared with those who entered in the early period (HR, 1.36 vs. 1.13; adjusted HR, 1.11 vs. 1.07 per 5 kg/m2). Possible mechanisms for this finding include environmental and nutritional factors, increased use of medical services, and changes in early cancer screening techniques, but further study is needed to verify the trend and “refine the exact nature of carcinogenic elements, compared with earlier periods,” they said.
Also of note, some cancers that were not associated with BMI in the early period, including stomach cancer, non-Hodgkin lymphoma, thyroid cancer, and colorectal and oral cavity cancers, became significantly associated with BMI in the late period.
“The projected population attributable risk percentage, using 2017 prevalence data of high BMI, was 5.1% for any cancer in men and 5.7% for cancers other than breast and cervical in women,” the researchers wrote, noting that this “is probably an underestimation, given the accentuation of the BMI-cancer association and the rapid increase in adolescent obesity prevalence within the past decade in Israel and worldwide.”
In an accompanying editorial, the journal editors noted that the findings by Dr. Furer and colleagues highlight the need to tackle obesity early in life and the need for obesity prevention strategies to reduce cancer incidence and mortality for those cancers that can be prevented by lifestyle modifications. They added, however, that care would be needed to avoid stigmatizing those with obesity, as obesity itself is a “multifactorial condition driven by social injustice and health inequalities” that most often affect those who are least able to implement lifestyle change (Lancet. 2020 Feb 3. doi: 10.106/S2213-8587(20)30031-0).
They also emphasized that the links between obesity and cancer, like those between obesity and other diseases such as diabetes, underscore the fact that noncommunicable diseases do not exist in isolation, and that tackling them requires bold action, a consolidated approach, and elimination of the environmental and social factors driving the epidemic.
The study was limited by a number of factors, including the lack of data on lifestyle factors, underrepresentation of some ethnicities, and lack of data on BMI and medical comorbidities at the time of cancer diagnosis. However, strengths of the study include the systematic data collection, narrow range of age at study entry, strict control of coexisting conditions, and high statistical power, which strengthen the generalizability of the results, the investigators said, concluding, therefore, that “[c]urrent trends of rising BMI among adolescents could constitute an important intervention target for cancer prevention.”
The authors reported having no disclosures.
SOURCE: Furer A et al. Lancet Diabetes Endocrinol. 2020 Feb 3. doi: 10.1016/S2213-8587(20)30019-X.
Obesity during adolescence is associated with increased midlife cancer risk, according to findings from a large population-based cohort of Israeli teens examined between 1967 and 2010.
The association, which was stronger in individuals in the later period of the cohort than in those in the earlier years, suggests that the burden of obesity-related cancers might increase over time, given the increasing prevalence of adolescent obesity, wrote Ariel Furer, MD, of Israel Defense Forces Medical Corps, Ramat Gan, and colleagues. Their report is in The Lancet.
Obesity is a known causal factor for several types of cancer, but most studies have looked at middle-age or older individuals and had relatively short follow-up, and period effects are rarely assessed, the investigators said, noting that “the attributable burden of obesity-related cancer was previously calculated with an unverified assumption that the association remained unchanged over time.
“In contrast to this paucity of knowledge, the prevalence of youth obesity – particularly severe obesity – has increased worldwide, which parallels the rise in youth cancer incidence,” they wrote.
To address this paucity of data, the researchers reviewed medical and sociodemographic data for adolescents who were assessed at age 17 years for medical eligibility for mandatory military service, and linked that information with data from the National Cancer Registry to create a unified file. The primary study outcome was any cancer diagnosis between Jan. 1, 1967, and Dec. 31, 2012, and a secondary endpoint was all-cause mortality through Dec. 31, 2017, among those who developed cancer.
Among nearly 2.3 million participating adolescents who were evaluated for associations between body mass index at age 17 years and later cancer incidence, 1,370,020 were men with more than 29.5 million person-years of follow-up, and 928,110 were women with more than 18 million person-years of follow-up. The numbers of incident cancer cases in the men and women were 26,353 and 29,488, and the mean ages at diagnosis were 43.2 and 40.0 years, respectively, the investigators reported (Lancet. 2020 Feb 3. doi: 10.1016/S2213-8587(20)30019-X).
Adolescent obesity in men was significantly associated with midlife cancer incidence (hazard ratio, 1.26), but in women, no association was seen due to the previously reported inverse associations between obesity and cervical and breast cancers, they said.
However, when those cancers were excluded for women, the adjusted hazard ratio was similar to that for men (HR, 1.27).
Cancer incidence in both men and women increased gradually across BMI percentiles, and for both sexes, overweight BMI was associated with an increased cancer risk after 10 years of follow-up (HR, 1.14 for men, 1.22 for women after exclusion of cervical and breast cancer). Therefore, in some cases the increased cancer risk in those who were overweight as teens was evident before age 30 years, the authors noted.
Further, BMI was positively associated with greater mortality risk. For men, 5-year survival rates were 75.2% in those with adolescent BMI in the 5th-49th percentile, compared with 72.2% in those with BMI in the obesity range (95th percentile or greater), and the corresponding rates in women were 89.3% and 83.1% (HR, 1.33 and 1.89, respectively).
Of note, the investigators identified a period effect. That is, after stratification by enrollment period/cancer recording period (1967-1981/1982-1996 vs. 1982-1996/1997-2011), a stronger association was noted in individuals who entered the study during the later period, compared with those who entered in the early period (HR, 1.36 vs. 1.13; adjusted HR, 1.11 vs. 1.07 per 5 kg/m2). Possible mechanisms for this finding include environmental and nutritional factors, increased use of medical services, and changes in early cancer screening techniques, but further study is needed to verify the trend and “refine the exact nature of carcinogenic elements, compared with earlier periods,” they said.
Also of note, some cancers that were not associated with BMI in the early period, including stomach cancer, non-Hodgkin lymphoma, thyroid cancer, and colorectal and oral cavity cancers, became significantly associated with BMI in the late period.
“The projected population attributable risk percentage, using 2017 prevalence data of high BMI, was 5.1% for any cancer in men and 5.7% for cancers other than breast and cervical in women,” the researchers wrote, noting that this “is probably an underestimation, given the accentuation of the BMI-cancer association and the rapid increase in adolescent obesity prevalence within the past decade in Israel and worldwide.”
In an accompanying editorial, the journal editors noted that the findings by Dr. Furer and colleagues highlight the need to tackle obesity early in life and the need for obesity prevention strategies to reduce cancer incidence and mortality for those cancers that can be prevented by lifestyle modifications. They added, however, that care would be needed to avoid stigmatizing those with obesity, as obesity itself is a “multifactorial condition driven by social injustice and health inequalities” that most often affect those who are least able to implement lifestyle change (Lancet. 2020 Feb 3. doi: 10.106/S2213-8587(20)30031-0).
They also emphasized that the links between obesity and cancer, like those between obesity and other diseases such as diabetes, underscore the fact that noncommunicable diseases do not exist in isolation, and that tackling them requires bold action, a consolidated approach, and elimination of the environmental and social factors driving the epidemic.
The study was limited by a number of factors, including the lack of data on lifestyle factors, underrepresentation of some ethnicities, and lack of data on BMI and medical comorbidities at the time of cancer diagnosis. However, strengths of the study include the systematic data collection, narrow range of age at study entry, strict control of coexisting conditions, and high statistical power, which strengthen the generalizability of the results, the investigators said, concluding, therefore, that “[c]urrent trends of rising BMI among adolescents could constitute an important intervention target for cancer prevention.”
The authors reported having no disclosures.
SOURCE: Furer A et al. Lancet Diabetes Endocrinol. 2020 Feb 3. doi: 10.1016/S2213-8587(20)30019-X.
Obesity during adolescence is associated with increased midlife cancer risk, according to findings from a large population-based cohort of Israeli teens examined between 1967 and 2010.
The association, which was stronger in individuals in the later period of the cohort than in those in the earlier years, suggests that the burden of obesity-related cancers might increase over time, given the increasing prevalence of adolescent obesity, wrote Ariel Furer, MD, of Israel Defense Forces Medical Corps, Ramat Gan, and colleagues. Their report is in The Lancet.
Obesity is a known causal factor for several types of cancer, but most studies have looked at middle-age or older individuals and had relatively short follow-up, and period effects are rarely assessed, the investigators said, noting that “the attributable burden of obesity-related cancer was previously calculated with an unverified assumption that the association remained unchanged over time.
“In contrast to this paucity of knowledge, the prevalence of youth obesity – particularly severe obesity – has increased worldwide, which parallels the rise in youth cancer incidence,” they wrote.
To address this paucity of data, the researchers reviewed medical and sociodemographic data for adolescents who were assessed at age 17 years for medical eligibility for mandatory military service, and linked that information with data from the National Cancer Registry to create a unified file. The primary study outcome was any cancer diagnosis between Jan. 1, 1967, and Dec. 31, 2012, and a secondary endpoint was all-cause mortality through Dec. 31, 2017, among those who developed cancer.
Among nearly 2.3 million participating adolescents who were evaluated for associations between body mass index at age 17 years and later cancer incidence, 1,370,020 were men with more than 29.5 million person-years of follow-up, and 928,110 were women with more than 18 million person-years of follow-up. The numbers of incident cancer cases in the men and women were 26,353 and 29,488, and the mean ages at diagnosis were 43.2 and 40.0 years, respectively, the investigators reported (Lancet. 2020 Feb 3. doi: 10.1016/S2213-8587(20)30019-X).
Adolescent obesity in men was significantly associated with midlife cancer incidence (hazard ratio, 1.26), but in women, no association was seen due to the previously reported inverse associations between obesity and cervical and breast cancers, they said.
However, when those cancers were excluded for women, the adjusted hazard ratio was similar to that for men (HR, 1.27).
Cancer incidence in both men and women increased gradually across BMI percentiles, and for both sexes, overweight BMI was associated with an increased cancer risk after 10 years of follow-up (HR, 1.14 for men, 1.22 for women after exclusion of cervical and breast cancer). Therefore, in some cases the increased cancer risk in those who were overweight as teens was evident before age 30 years, the authors noted.
Further, BMI was positively associated with greater mortality risk. For men, 5-year survival rates were 75.2% in those with adolescent BMI in the 5th-49th percentile, compared with 72.2% in those with BMI in the obesity range (95th percentile or greater), and the corresponding rates in women were 89.3% and 83.1% (HR, 1.33 and 1.89, respectively).
Of note, the investigators identified a period effect. That is, after stratification by enrollment period/cancer recording period (1967-1981/1982-1996 vs. 1982-1996/1997-2011), a stronger association was noted in individuals who entered the study during the later period, compared with those who entered in the early period (HR, 1.36 vs. 1.13; adjusted HR, 1.11 vs. 1.07 per 5 kg/m2). Possible mechanisms for this finding include environmental and nutritional factors, increased use of medical services, and changes in early cancer screening techniques, but further study is needed to verify the trend and “refine the exact nature of carcinogenic elements, compared with earlier periods,” they said.
Also of note, some cancers that were not associated with BMI in the early period, including stomach cancer, non-Hodgkin lymphoma, thyroid cancer, and colorectal and oral cavity cancers, became significantly associated with BMI in the late period.
“The projected population attributable risk percentage, using 2017 prevalence data of high BMI, was 5.1% for any cancer in men and 5.7% for cancers other than breast and cervical in women,” the researchers wrote, noting that this “is probably an underestimation, given the accentuation of the BMI-cancer association and the rapid increase in adolescent obesity prevalence within the past decade in Israel and worldwide.”
In an accompanying editorial, the journal editors noted that the findings by Dr. Furer and colleagues highlight the need to tackle obesity early in life and the need for obesity prevention strategies to reduce cancer incidence and mortality for those cancers that can be prevented by lifestyle modifications. They added, however, that care would be needed to avoid stigmatizing those with obesity, as obesity itself is a “multifactorial condition driven by social injustice and health inequalities” that most often affect those who are least able to implement lifestyle change (Lancet. 2020 Feb 3. doi: 10.106/S2213-8587(20)30031-0).
They also emphasized that the links between obesity and cancer, like those between obesity and other diseases such as diabetes, underscore the fact that noncommunicable diseases do not exist in isolation, and that tackling them requires bold action, a consolidated approach, and elimination of the environmental and social factors driving the epidemic.
The study was limited by a number of factors, including the lack of data on lifestyle factors, underrepresentation of some ethnicities, and lack of data on BMI and medical comorbidities at the time of cancer diagnosis. However, strengths of the study include the systematic data collection, narrow range of age at study entry, strict control of coexisting conditions, and high statistical power, which strengthen the generalizability of the results, the investigators said, concluding, therefore, that “[c]urrent trends of rising BMI among adolescents could constitute an important intervention target for cancer prevention.”
The authors reported having no disclosures.
SOURCE: Furer A et al. Lancet Diabetes Endocrinol. 2020 Feb 3. doi: 10.1016/S2213-8587(20)30019-X.
FROM THE LANCET
Synovial biopsy findings drive precision medicine for RA closer to the clinic
Researchers are mining the synovium for potential treasure: robust markers to bring precision medicine to the rheumatoid arthritis (RA) arena. The signs, according to a number of recent reports, point toward a gold strike via synovial tissue biopsy.
“I have no doubt about that – I am very confident that this concept of going straight to the tissue and using functional genomics will help us stratify our patients and will be a predictive model for patients with respect to therapy,” Harris R. Perlman, PhD, the Mabel Greene Myers Professor of Medicine and chief of the division of rheumatology at Northwestern University, Chicago, said in an interview.
Dr. Perlman is the principle investigator for the REASON (Rheumatoid Arthritis Synovial Tissue Network) study, and in a 2018 report on the network’s efforts to train participants across the United States in ultrasound-guided joint biopsy techniques and to collect and analyze synovial tissue samples submitted by the six participating centers, he and the coinvestigators explained why a precision approach can’t come soon enough.
“Currently, the standard of care for RA is to prescribe biologic therapy through a costly and time‐consuming trial‐and‐error process. Therefore, the utility of a biomarker to identify how a patient will respond to a particular therapy cannot be overstated,” they wrote (Arthritis Rheumatol. 2018 Jun;70[6]:841-54).
Since that REASON report was published, efforts by the investigators and others, such as those involved with the Accelerating Medicines Partnership (AMP) in RA and Lupus Network, to identify such biomarkers have continued to yield encouraging results.
In fact, data from the phase 4 R4-RA (Response, Relapse and Resistance to Rituximab Therapy in patients with RA) trial – the first randomized, controlled, biopsy-driven trial in RA – were reported in November 2019 at the annual meeting of the American College of Rheumatology. R4-RA demonstrated that patients with B cell–poor RA identified on synovial tissue biopsy (STB) responded better to tocilizumab (Actemra) than to rituximab (Rituxan), whereas those with B cell–rich RA on STB did not, Constantino Pitzalis, MD, head of the Centre for Experimental Medicine & Rheumatology at Queen Mary University of London said, noting that the findings could have “massive implications” for RA management and outcomes.
Numerous treatments exist for RA, but methods for determining which to use for a given patient are sorely lacking and the field of rheumatology lags behind others, like oncology, in bringing individualized medicine to the clinic, he explained.
Why STB?
Despite extensive efforts, blood testing has failed to yield markers sufficient for guiding RA treatment, and although the synovium has long been considered a potentially better source of information to guide treatment given the damage it sustains from RA, biopsies have generally been accessible only during arthroscopic or joint replacement surgery in patients with severe disease, which doesn’t reflect the population of patients who could benefit from early intervention, Dr. Perlman and colleagues explained in their 2018 report.
Musculoskeletal ultrasound (US) technology, however, has advanced dramatically over the past decade, is available and used by rheumatologists in clinical practice, and has brought US-guided joint biopsies to the forefront of research. Such techniques have been used in Europe for years, and as a result, an extensive catalog of literature supports the safety, feasibility, and tolerability of the approach.
A recent study in Portugal by Romao et al., for example, showed “remarkably high” patient tolerability (70%) with 64 US-guided procedures, including 52 in clinical practice and 12 for research purposes. No major adverse events occurred, and biopsy usefulness was high, with 37% having a direct diagnostic impact and with 100% and 95% positive- and negative-predictive values for infection. Further, synovial tissues were retrieved in 88% of biopsies and a median of 75% of samples were gradable (Arthritis Care Res. 2019 Aug 17. doi: 10.1002/acr.24050).
A 2018 study of 524 synovial biopsies, including 402 performed using US-guided needle biopsy, performed at five centers across Europe similarly demonstrated safety and patient tolerability (RMD Open. 2018;4[2]:e000799. doi: 10.1136/mdopen-2018-000799).
Building on the work in Europe, investigators at Northwestern launched the REASON study, assembling a consortium of academic rheumatology groups across the United States, training participants in minimally invasive US-guided joint biopsy techniques, and collecting and analyzing synovial tissue samples submitted by the participating centers.
Laura B. Hughes, MD, a professor at the University of Alabama at Birmingham and an investigator in both the REASON study and AMP, said in an interview that her experience with patients is similar.
“It has been very, very well tolerated,” she said of the biopsy procedure used in the course of the studies – and that’s despite the time and commitment required, she added, explaining that 12 samples, each requiring a separate injection, are obtained over a 30- to 45-minute visit.
“We’ve had no problems, no complications,” she said, also noting the importance of careful patient selection.
Patients are altruistic; they want to be a part of moving things forward and helping other patients, and they have been more than willing to participate, both she and Dr. Perlman noted.
In fact, the REASON study investigators reported that performance of STB by rheumatologists in the United States is feasible and generates high-quality samples.
Further, the transcriptional profiles of isolated RA synovial macrophages identified from samples submitted by Dr. Hughes and others in the network characterized subpopulations of patients and identified six novel transcriptional modules associated with disease activity and therapy, underscoring the potential for precision medicine in RA.
“We posit that transcriptional signatures in macrophages ... will predict responsiveness to specific nonbiologic and/or biologic therapies,” they wrote, adding that future studies will “entail collection of synovial biopsy specimens from a larger cohort longitudinally, prior to, and following therapy.”
The ongoing National Institutes of Health–funded AMP Network research is also using synovial biopsies, but more for identification of molecular pathways with a focus on potential drug development.
A 2019 report from the AMP investigators described their integrated use of single-cell transcriptomics and mass cytometry to reveal cell states expanded in RA synovia and the mapping of inflammatory mediators to their source cell populations, which may be key mediators of RA pathogenesis.
“We observed upregulation of chemokines (CXCL8, CXCL9, and CXCL13), cytokines (IFNG and IL15), and surface receptors (PDGFRB and SMAMF7) in distinct immune and stromal cell populations, suggesting potential novel targets,” they wrote (Nat Immunol. 2019 Jul;20[7]:928-42).
Next steps
These reports, along with the thousands of papers published over the past few decades describing phenotypic and functional abnormalities in synovial tissue obtained from RA patients undergoing joint replacement surgery or, more recently, via STB early in the course of disease, have provided a wealth of information, Helen Michelle McGettrick, MD, noted in an editorial addressing the potential of STB analysis for “unlocking the hidden secrets to personalized medicine.”
The question, however, is whether they have moved the field closer to “translating this discovery science into new biomarkers or drugs to improve diagnosis or prognosis,” she wrote (Arthritis Res Ther. 2019;21[90]. doi: 10.1186/s13075-019-1871-5).
“Three sides of our square are in place: clinical expertise, technology, and patient willingness,” she said, arguing that the fourth side is “standardization in the handling, evaluation, and interpretation of STB.”
In fact, her editorial focused on a joint consensus of the European League Against Rheumatism Synovitis Study Group and the OMERACT Synovial Tissue Biopsy Group (Arthritis Res Ther. 2018;20[265]. doi: 10.1186/s13075-018-1762-1).
The groups, based on member survey responses, proposed a “consensual set of analysis items” to be used for synovial biopsies in clinical practice and translational research, including matters such as biopsy sampling, histologic criteria, and biopsy interpretation. Their work, according to Dr. McGettrick and the authors themselves, marked a step forward, but provided only a foundation for a standardization framework.
One particular area of synovial research that has received recent attention and which illustrates the need for standardization involves the role of synovial B cells in RA. The R4-RA researchers, in conjunction with the Pathobiology of Early Arthritis Cohort, are working to better define the relationship of synovial B cells to clinical RA phenotypes at various disease stages and drug exposures as a potential source of predictive and prognostic biomarkers, and in an article accepted for publication in Arthritis & Rheumatology, they describe a “robust semiquantitative histological B cell score that closely replicates the quantification of B cells by digital or molecular analyses.”
In their study of 329 patients, they demonstrated an ongoing B cell–rich synovitis more prevalent in patients with established RA who had inadequate response to tumor necrosis factor inhibitor therapy than in those with early RA (47.4% vs. 35%), but which does not appear to be captured by standard clinimetric assessment (Arthritis Rheumatol. 2019 Nov 29. doi: 10.1002/art.41184).
“Overall, our study confirms the relevance of synovial B cells in RA and suggests that the classification of patients into B cell–rich/–poor can contribute to patient stratification,” they concluded.
In a related editorial, Dana E. Orange, MD, and Laura T. Donlin, PhD, of the Hospital for Special Surgery, New York, note that previously discrepant findings with respect to the value of B cell infiltrate scores for predicting RA treatment response may relate to the lack of a standardized scoring system (Arthritis Rheumatol. 2019 Nov 29. doi: 10.1002/art.41185).
Together, these emerging findings are “advancing our understanding of the transcriptional and cellular characteristics of the synovium in RA,” they wrote, concluding that incorporation of synovial assessments into clinical management of patients is “the next step in empowering clinicians to apply advances in molecular immunology to better tailor treatment decisions.”
Indeed, an important goal is empowering rheumatologists to become adept in obtaining synovial biopsies in clinical practice, much like gastroenterologists collect tissue for biopsy via colonoscopy, Dr. Pitzalis said in an interview following his R4-RA presentation at the ACR meeting.
Dr. Hughes predicts that a subset will embrace the concept, but not all rheumatologists are interested and not all use musculoskeletal US in their practice.
“It requires a lot of training, there is a credentialing exam, and it’s not necessary for practicing rheumatology, but there is a lot of growth,” she said, noting that training is being promoted through the ACR and other organizations, and Europeans who are well-versed in US-guided STB have served as mentors. “It’s been a nice collaboration, and I think it’s just going to push the field forward ... it really is exciting – I think synovial biopsies will yield a lot of information and really, hopefully, help us target therapy and find new therapeutic targets that we haven’t even thought of.”
However, Dr. Pitzalis stressed that there remains much work to do.
“It’s important to understand this is early data and will require validation in larger and target-driven and biopsy-driven treatment clinical trials,” he said of the R4-RA findings.
Those efforts are underway; the REASON study, for example, is moving forward, having recently been awarded a National Institutes of Health Research Project Grant, Dr. Perlman said, explaining that the latest goal is to determine whether the transcription modules the investigators have identified to date can be predictive of treatment response.
He expects to report outcomes at ACR 2020, and noted that preliminary findings suggest that “we can tell, by 4 weeks, which patients will respond or not.”
Dr. Pitzalis and his colleagues are also working on their “next set of trials,” which are using biopsies for treatment allocation (B cell–poor patients get one drug, B cell–rich patients, another, for example), and he, too said he expects to have additional data to present at ACR 2020.
“If we are to demonstrate clinical utility, I think rheumatology will be ready to implement this methodology in clinical practice,” he said.
The authors interviewed for this article reported having no relevant financial disclosures.
Researchers are mining the synovium for potential treasure: robust markers to bring precision medicine to the rheumatoid arthritis (RA) arena. The signs, according to a number of recent reports, point toward a gold strike via synovial tissue biopsy.
“I have no doubt about that – I am very confident that this concept of going straight to the tissue and using functional genomics will help us stratify our patients and will be a predictive model for patients with respect to therapy,” Harris R. Perlman, PhD, the Mabel Greene Myers Professor of Medicine and chief of the division of rheumatology at Northwestern University, Chicago, said in an interview.
Dr. Perlman is the principle investigator for the REASON (Rheumatoid Arthritis Synovial Tissue Network) study, and in a 2018 report on the network’s efforts to train participants across the United States in ultrasound-guided joint biopsy techniques and to collect and analyze synovial tissue samples submitted by the six participating centers, he and the coinvestigators explained why a precision approach can’t come soon enough.
“Currently, the standard of care for RA is to prescribe biologic therapy through a costly and time‐consuming trial‐and‐error process. Therefore, the utility of a biomarker to identify how a patient will respond to a particular therapy cannot be overstated,” they wrote (Arthritis Rheumatol. 2018 Jun;70[6]:841-54).
Since that REASON report was published, efforts by the investigators and others, such as those involved with the Accelerating Medicines Partnership (AMP) in RA and Lupus Network, to identify such biomarkers have continued to yield encouraging results.
In fact, data from the phase 4 R4-RA (Response, Relapse and Resistance to Rituximab Therapy in patients with RA) trial – the first randomized, controlled, biopsy-driven trial in RA – were reported in November 2019 at the annual meeting of the American College of Rheumatology. R4-RA demonstrated that patients with B cell–poor RA identified on synovial tissue biopsy (STB) responded better to tocilizumab (Actemra) than to rituximab (Rituxan), whereas those with B cell–rich RA on STB did not, Constantino Pitzalis, MD, head of the Centre for Experimental Medicine & Rheumatology at Queen Mary University of London said, noting that the findings could have “massive implications” for RA management and outcomes.
Numerous treatments exist for RA, but methods for determining which to use for a given patient are sorely lacking and the field of rheumatology lags behind others, like oncology, in bringing individualized medicine to the clinic, he explained.
Why STB?
Despite extensive efforts, blood testing has failed to yield markers sufficient for guiding RA treatment, and although the synovium has long been considered a potentially better source of information to guide treatment given the damage it sustains from RA, biopsies have generally been accessible only during arthroscopic or joint replacement surgery in patients with severe disease, which doesn’t reflect the population of patients who could benefit from early intervention, Dr. Perlman and colleagues explained in their 2018 report.
Musculoskeletal ultrasound (US) technology, however, has advanced dramatically over the past decade, is available and used by rheumatologists in clinical practice, and has brought US-guided joint biopsies to the forefront of research. Such techniques have been used in Europe for years, and as a result, an extensive catalog of literature supports the safety, feasibility, and tolerability of the approach.
A recent study in Portugal by Romao et al., for example, showed “remarkably high” patient tolerability (70%) with 64 US-guided procedures, including 52 in clinical practice and 12 for research purposes. No major adverse events occurred, and biopsy usefulness was high, with 37% having a direct diagnostic impact and with 100% and 95% positive- and negative-predictive values for infection. Further, synovial tissues were retrieved in 88% of biopsies and a median of 75% of samples were gradable (Arthritis Care Res. 2019 Aug 17. doi: 10.1002/acr.24050).
A 2018 study of 524 synovial biopsies, including 402 performed using US-guided needle biopsy, performed at five centers across Europe similarly demonstrated safety and patient tolerability (RMD Open. 2018;4[2]:e000799. doi: 10.1136/mdopen-2018-000799).
Building on the work in Europe, investigators at Northwestern launched the REASON study, assembling a consortium of academic rheumatology groups across the United States, training participants in minimally invasive US-guided joint biopsy techniques, and collecting and analyzing synovial tissue samples submitted by the participating centers.
Laura B. Hughes, MD, a professor at the University of Alabama at Birmingham and an investigator in both the REASON study and AMP, said in an interview that her experience with patients is similar.
“It has been very, very well tolerated,” she said of the biopsy procedure used in the course of the studies – and that’s despite the time and commitment required, she added, explaining that 12 samples, each requiring a separate injection, are obtained over a 30- to 45-minute visit.
“We’ve had no problems, no complications,” she said, also noting the importance of careful patient selection.
Patients are altruistic; they want to be a part of moving things forward and helping other patients, and they have been more than willing to participate, both she and Dr. Perlman noted.
In fact, the REASON study investigators reported that performance of STB by rheumatologists in the United States is feasible and generates high-quality samples.
Further, the transcriptional profiles of isolated RA synovial macrophages identified from samples submitted by Dr. Hughes and others in the network characterized subpopulations of patients and identified six novel transcriptional modules associated with disease activity and therapy, underscoring the potential for precision medicine in RA.
“We posit that transcriptional signatures in macrophages ... will predict responsiveness to specific nonbiologic and/or biologic therapies,” they wrote, adding that future studies will “entail collection of synovial biopsy specimens from a larger cohort longitudinally, prior to, and following therapy.”
The ongoing National Institutes of Health–funded AMP Network research is also using synovial biopsies, but more for identification of molecular pathways with a focus on potential drug development.
A 2019 report from the AMP investigators described their integrated use of single-cell transcriptomics and mass cytometry to reveal cell states expanded in RA synovia and the mapping of inflammatory mediators to their source cell populations, which may be key mediators of RA pathogenesis.
“We observed upregulation of chemokines (CXCL8, CXCL9, and CXCL13), cytokines (IFNG and IL15), and surface receptors (PDGFRB and SMAMF7) in distinct immune and stromal cell populations, suggesting potential novel targets,” they wrote (Nat Immunol. 2019 Jul;20[7]:928-42).
Next steps
These reports, along with the thousands of papers published over the past few decades describing phenotypic and functional abnormalities in synovial tissue obtained from RA patients undergoing joint replacement surgery or, more recently, via STB early in the course of disease, have provided a wealth of information, Helen Michelle McGettrick, MD, noted in an editorial addressing the potential of STB analysis for “unlocking the hidden secrets to personalized medicine.”
The question, however, is whether they have moved the field closer to “translating this discovery science into new biomarkers or drugs to improve diagnosis or prognosis,” she wrote (Arthritis Res Ther. 2019;21[90]. doi: 10.1186/s13075-019-1871-5).
“Three sides of our square are in place: clinical expertise, technology, and patient willingness,” she said, arguing that the fourth side is “standardization in the handling, evaluation, and interpretation of STB.”
In fact, her editorial focused on a joint consensus of the European League Against Rheumatism Synovitis Study Group and the OMERACT Synovial Tissue Biopsy Group (Arthritis Res Ther. 2018;20[265]. doi: 10.1186/s13075-018-1762-1).
The groups, based on member survey responses, proposed a “consensual set of analysis items” to be used for synovial biopsies in clinical practice and translational research, including matters such as biopsy sampling, histologic criteria, and biopsy interpretation. Their work, according to Dr. McGettrick and the authors themselves, marked a step forward, but provided only a foundation for a standardization framework.
One particular area of synovial research that has received recent attention and which illustrates the need for standardization involves the role of synovial B cells in RA. The R4-RA researchers, in conjunction with the Pathobiology of Early Arthritis Cohort, are working to better define the relationship of synovial B cells to clinical RA phenotypes at various disease stages and drug exposures as a potential source of predictive and prognostic biomarkers, and in an article accepted for publication in Arthritis & Rheumatology, they describe a “robust semiquantitative histological B cell score that closely replicates the quantification of B cells by digital or molecular analyses.”
In their study of 329 patients, they demonstrated an ongoing B cell–rich synovitis more prevalent in patients with established RA who had inadequate response to tumor necrosis factor inhibitor therapy than in those with early RA (47.4% vs. 35%), but which does not appear to be captured by standard clinimetric assessment (Arthritis Rheumatol. 2019 Nov 29. doi: 10.1002/art.41184).
“Overall, our study confirms the relevance of synovial B cells in RA and suggests that the classification of patients into B cell–rich/–poor can contribute to patient stratification,” they concluded.
In a related editorial, Dana E. Orange, MD, and Laura T. Donlin, PhD, of the Hospital for Special Surgery, New York, note that previously discrepant findings with respect to the value of B cell infiltrate scores for predicting RA treatment response may relate to the lack of a standardized scoring system (Arthritis Rheumatol. 2019 Nov 29. doi: 10.1002/art.41185).
Together, these emerging findings are “advancing our understanding of the transcriptional and cellular characteristics of the synovium in RA,” they wrote, concluding that incorporation of synovial assessments into clinical management of patients is “the next step in empowering clinicians to apply advances in molecular immunology to better tailor treatment decisions.”
Indeed, an important goal is empowering rheumatologists to become adept in obtaining synovial biopsies in clinical practice, much like gastroenterologists collect tissue for biopsy via colonoscopy, Dr. Pitzalis said in an interview following his R4-RA presentation at the ACR meeting.
Dr. Hughes predicts that a subset will embrace the concept, but not all rheumatologists are interested and not all use musculoskeletal US in their practice.
“It requires a lot of training, there is a credentialing exam, and it’s not necessary for practicing rheumatology, but there is a lot of growth,” she said, noting that training is being promoted through the ACR and other organizations, and Europeans who are well-versed in US-guided STB have served as mentors. “It’s been a nice collaboration, and I think it’s just going to push the field forward ... it really is exciting – I think synovial biopsies will yield a lot of information and really, hopefully, help us target therapy and find new therapeutic targets that we haven’t even thought of.”
However, Dr. Pitzalis stressed that there remains much work to do.
“It’s important to understand this is early data and will require validation in larger and target-driven and biopsy-driven treatment clinical trials,” he said of the R4-RA findings.
Those efforts are underway; the REASON study, for example, is moving forward, having recently been awarded a National Institutes of Health Research Project Grant, Dr. Perlman said, explaining that the latest goal is to determine whether the transcription modules the investigators have identified to date can be predictive of treatment response.
He expects to report outcomes at ACR 2020, and noted that preliminary findings suggest that “we can tell, by 4 weeks, which patients will respond or not.”
Dr. Pitzalis and his colleagues are also working on their “next set of trials,” which are using biopsies for treatment allocation (B cell–poor patients get one drug, B cell–rich patients, another, for example), and he, too said he expects to have additional data to present at ACR 2020.
“If we are to demonstrate clinical utility, I think rheumatology will be ready to implement this methodology in clinical practice,” he said.
The authors interviewed for this article reported having no relevant financial disclosures.
Researchers are mining the synovium for potential treasure: robust markers to bring precision medicine to the rheumatoid arthritis (RA) arena. The signs, according to a number of recent reports, point toward a gold strike via synovial tissue biopsy.
“I have no doubt about that – I am very confident that this concept of going straight to the tissue and using functional genomics will help us stratify our patients and will be a predictive model for patients with respect to therapy,” Harris R. Perlman, PhD, the Mabel Greene Myers Professor of Medicine and chief of the division of rheumatology at Northwestern University, Chicago, said in an interview.
Dr. Perlman is the principle investigator for the REASON (Rheumatoid Arthritis Synovial Tissue Network) study, and in a 2018 report on the network’s efforts to train participants across the United States in ultrasound-guided joint biopsy techniques and to collect and analyze synovial tissue samples submitted by the six participating centers, he and the coinvestigators explained why a precision approach can’t come soon enough.
“Currently, the standard of care for RA is to prescribe biologic therapy through a costly and time‐consuming trial‐and‐error process. Therefore, the utility of a biomarker to identify how a patient will respond to a particular therapy cannot be overstated,” they wrote (Arthritis Rheumatol. 2018 Jun;70[6]:841-54).
Since that REASON report was published, efforts by the investigators and others, such as those involved with the Accelerating Medicines Partnership (AMP) in RA and Lupus Network, to identify such biomarkers have continued to yield encouraging results.
In fact, data from the phase 4 R4-RA (Response, Relapse and Resistance to Rituximab Therapy in patients with RA) trial – the first randomized, controlled, biopsy-driven trial in RA – were reported in November 2019 at the annual meeting of the American College of Rheumatology. R4-RA demonstrated that patients with B cell–poor RA identified on synovial tissue biopsy (STB) responded better to tocilizumab (Actemra) than to rituximab (Rituxan), whereas those with B cell–rich RA on STB did not, Constantino Pitzalis, MD, head of the Centre for Experimental Medicine & Rheumatology at Queen Mary University of London said, noting that the findings could have “massive implications” for RA management and outcomes.
Numerous treatments exist for RA, but methods for determining which to use for a given patient are sorely lacking and the field of rheumatology lags behind others, like oncology, in bringing individualized medicine to the clinic, he explained.
Why STB?
Despite extensive efforts, blood testing has failed to yield markers sufficient for guiding RA treatment, and although the synovium has long been considered a potentially better source of information to guide treatment given the damage it sustains from RA, biopsies have generally been accessible only during arthroscopic or joint replacement surgery in patients with severe disease, which doesn’t reflect the population of patients who could benefit from early intervention, Dr. Perlman and colleagues explained in their 2018 report.
Musculoskeletal ultrasound (US) technology, however, has advanced dramatically over the past decade, is available and used by rheumatologists in clinical practice, and has brought US-guided joint biopsies to the forefront of research. Such techniques have been used in Europe for years, and as a result, an extensive catalog of literature supports the safety, feasibility, and tolerability of the approach.
A recent study in Portugal by Romao et al., for example, showed “remarkably high” patient tolerability (70%) with 64 US-guided procedures, including 52 in clinical practice and 12 for research purposes. No major adverse events occurred, and biopsy usefulness was high, with 37% having a direct diagnostic impact and with 100% and 95% positive- and negative-predictive values for infection. Further, synovial tissues were retrieved in 88% of biopsies and a median of 75% of samples were gradable (Arthritis Care Res. 2019 Aug 17. doi: 10.1002/acr.24050).
A 2018 study of 524 synovial biopsies, including 402 performed using US-guided needle biopsy, performed at five centers across Europe similarly demonstrated safety and patient tolerability (RMD Open. 2018;4[2]:e000799. doi: 10.1136/mdopen-2018-000799).
Building on the work in Europe, investigators at Northwestern launched the REASON study, assembling a consortium of academic rheumatology groups across the United States, training participants in minimally invasive US-guided joint biopsy techniques, and collecting and analyzing synovial tissue samples submitted by the participating centers.
Laura B. Hughes, MD, a professor at the University of Alabama at Birmingham and an investigator in both the REASON study and AMP, said in an interview that her experience with patients is similar.
“It has been very, very well tolerated,” she said of the biopsy procedure used in the course of the studies – and that’s despite the time and commitment required, she added, explaining that 12 samples, each requiring a separate injection, are obtained over a 30- to 45-minute visit.
“We’ve had no problems, no complications,” she said, also noting the importance of careful patient selection.
Patients are altruistic; they want to be a part of moving things forward and helping other patients, and they have been more than willing to participate, both she and Dr. Perlman noted.
In fact, the REASON study investigators reported that performance of STB by rheumatologists in the United States is feasible and generates high-quality samples.
Further, the transcriptional profiles of isolated RA synovial macrophages identified from samples submitted by Dr. Hughes and others in the network characterized subpopulations of patients and identified six novel transcriptional modules associated with disease activity and therapy, underscoring the potential for precision medicine in RA.
“We posit that transcriptional signatures in macrophages ... will predict responsiveness to specific nonbiologic and/or biologic therapies,” they wrote, adding that future studies will “entail collection of synovial biopsy specimens from a larger cohort longitudinally, prior to, and following therapy.”
The ongoing National Institutes of Health–funded AMP Network research is also using synovial biopsies, but more for identification of molecular pathways with a focus on potential drug development.
A 2019 report from the AMP investigators described their integrated use of single-cell transcriptomics and mass cytometry to reveal cell states expanded in RA synovia and the mapping of inflammatory mediators to their source cell populations, which may be key mediators of RA pathogenesis.
“We observed upregulation of chemokines (CXCL8, CXCL9, and CXCL13), cytokines (IFNG and IL15), and surface receptors (PDGFRB and SMAMF7) in distinct immune and stromal cell populations, suggesting potential novel targets,” they wrote (Nat Immunol. 2019 Jul;20[7]:928-42).
Next steps
These reports, along with the thousands of papers published over the past few decades describing phenotypic and functional abnormalities in synovial tissue obtained from RA patients undergoing joint replacement surgery or, more recently, via STB early in the course of disease, have provided a wealth of information, Helen Michelle McGettrick, MD, noted in an editorial addressing the potential of STB analysis for “unlocking the hidden secrets to personalized medicine.”
The question, however, is whether they have moved the field closer to “translating this discovery science into new biomarkers or drugs to improve diagnosis or prognosis,” she wrote (Arthritis Res Ther. 2019;21[90]. doi: 10.1186/s13075-019-1871-5).
“Three sides of our square are in place: clinical expertise, technology, and patient willingness,” she said, arguing that the fourth side is “standardization in the handling, evaluation, and interpretation of STB.”
In fact, her editorial focused on a joint consensus of the European League Against Rheumatism Synovitis Study Group and the OMERACT Synovial Tissue Biopsy Group (Arthritis Res Ther. 2018;20[265]. doi: 10.1186/s13075-018-1762-1).
The groups, based on member survey responses, proposed a “consensual set of analysis items” to be used for synovial biopsies in clinical practice and translational research, including matters such as biopsy sampling, histologic criteria, and biopsy interpretation. Their work, according to Dr. McGettrick and the authors themselves, marked a step forward, but provided only a foundation for a standardization framework.
One particular area of synovial research that has received recent attention and which illustrates the need for standardization involves the role of synovial B cells in RA. The R4-RA researchers, in conjunction with the Pathobiology of Early Arthritis Cohort, are working to better define the relationship of synovial B cells to clinical RA phenotypes at various disease stages and drug exposures as a potential source of predictive and prognostic biomarkers, and in an article accepted for publication in Arthritis & Rheumatology, they describe a “robust semiquantitative histological B cell score that closely replicates the quantification of B cells by digital or molecular analyses.”
In their study of 329 patients, they demonstrated an ongoing B cell–rich synovitis more prevalent in patients with established RA who had inadequate response to tumor necrosis factor inhibitor therapy than in those with early RA (47.4% vs. 35%), but which does not appear to be captured by standard clinimetric assessment (Arthritis Rheumatol. 2019 Nov 29. doi: 10.1002/art.41184).
“Overall, our study confirms the relevance of synovial B cells in RA and suggests that the classification of patients into B cell–rich/–poor can contribute to patient stratification,” they concluded.
In a related editorial, Dana E. Orange, MD, and Laura T. Donlin, PhD, of the Hospital for Special Surgery, New York, note that previously discrepant findings with respect to the value of B cell infiltrate scores for predicting RA treatment response may relate to the lack of a standardized scoring system (Arthritis Rheumatol. 2019 Nov 29. doi: 10.1002/art.41185).
Together, these emerging findings are “advancing our understanding of the transcriptional and cellular characteristics of the synovium in RA,” they wrote, concluding that incorporation of synovial assessments into clinical management of patients is “the next step in empowering clinicians to apply advances in molecular immunology to better tailor treatment decisions.”
Indeed, an important goal is empowering rheumatologists to become adept in obtaining synovial biopsies in clinical practice, much like gastroenterologists collect tissue for biopsy via colonoscopy, Dr. Pitzalis said in an interview following his R4-RA presentation at the ACR meeting.
Dr. Hughes predicts that a subset will embrace the concept, but not all rheumatologists are interested and not all use musculoskeletal US in their practice.
“It requires a lot of training, there is a credentialing exam, and it’s not necessary for practicing rheumatology, but there is a lot of growth,” she said, noting that training is being promoted through the ACR and other organizations, and Europeans who are well-versed in US-guided STB have served as mentors. “It’s been a nice collaboration, and I think it’s just going to push the field forward ... it really is exciting – I think synovial biopsies will yield a lot of information and really, hopefully, help us target therapy and find new therapeutic targets that we haven’t even thought of.”
However, Dr. Pitzalis stressed that there remains much work to do.
“It’s important to understand this is early data and will require validation in larger and target-driven and biopsy-driven treatment clinical trials,” he said of the R4-RA findings.
Those efforts are underway; the REASON study, for example, is moving forward, having recently been awarded a National Institutes of Health Research Project Grant, Dr. Perlman said, explaining that the latest goal is to determine whether the transcription modules the investigators have identified to date can be predictive of treatment response.
He expects to report outcomes at ACR 2020, and noted that preliminary findings suggest that “we can tell, by 4 weeks, which patients will respond or not.”
Dr. Pitzalis and his colleagues are also working on their “next set of trials,” which are using biopsies for treatment allocation (B cell–poor patients get one drug, B cell–rich patients, another, for example), and he, too said he expects to have additional data to present at ACR 2020.
“If we are to demonstrate clinical utility, I think rheumatology will be ready to implement this methodology in clinical practice,” he said.
The authors interviewed for this article reported having no relevant financial disclosures.
Tramadol use for noncancer pain linked with increased hip fracture risk
The risk of hip fracture was higher among patients treated with tramadol for chronic noncancer pain than among those treated with other commonly used NSAIDs in a large population-based cohort in the United Kingdom.
The incidence of hip fracture over a 12-month period among 293,912 propensity score-matched tramadol and codeine recipients in The Health Improvement Network (THIN) database during 2000-2017 was 3.7 vs. 2.9 per 1,000 person-years, respectively (hazard ratio for hip fracture, 1.28), Jie Wei, PhD, of Xiangya Hospital, Central South University, Changsha, China, and colleagues reported in the Journal of Bone and Mineral Research.
Hip fracture incidence per 1,000 person-years was also higher in propensity score–matched cohorts of patients receiving tramadol vs. naproxen (2.9 vs. 1.7; HR, 1.69), ibuprofen (3.4 vs. 2.0; HR, 1.65), celecoxib (3.4 vs. 1.8; HR, 1.85), or etoricoxib (2.9 vs. 1.5; HR, 1.96), the investigators found.
Tramadol is considered a weak opioid and is commonly used for the treatment of pain based on a lower perceived risk of serious cardiovascular and gastrointestinal effects versus NSAIDs, and of addiction and respiratory depression versus traditional opioids, they explained. Several professional organizations also have “strongly or conditionally recommended tramadol” as a first- or second-line treatment for conditions such as osteoarthritis, fibromyalgia, and chronic low back pain.
The potential mechanisms for the association between tramadol and hip fracture require further study, but “[c]onsidering the significant impact of hip fracture on morbidity, mortality, and health care costs, our results point to the need to consider tramadol’s associated risk of fracture in clinical practice and treatment guidelines,” they concluded.
This study was supported by the National Institutes of Health, the National Natural Science Foundation of China, and the Postdoctoral Science Foundation of Central South University. The authors reported having no conflicts of interest.
SOURCE: Wei J et al. J Bone Miner Res. 2019 Feb 5. doi: 10.1002/jbmr.3935.
The risk of hip fracture was higher among patients treated with tramadol for chronic noncancer pain than among those treated with other commonly used NSAIDs in a large population-based cohort in the United Kingdom.
The incidence of hip fracture over a 12-month period among 293,912 propensity score-matched tramadol and codeine recipients in The Health Improvement Network (THIN) database during 2000-2017 was 3.7 vs. 2.9 per 1,000 person-years, respectively (hazard ratio for hip fracture, 1.28), Jie Wei, PhD, of Xiangya Hospital, Central South University, Changsha, China, and colleagues reported in the Journal of Bone and Mineral Research.
Hip fracture incidence per 1,000 person-years was also higher in propensity score–matched cohorts of patients receiving tramadol vs. naproxen (2.9 vs. 1.7; HR, 1.69), ibuprofen (3.4 vs. 2.0; HR, 1.65), celecoxib (3.4 vs. 1.8; HR, 1.85), or etoricoxib (2.9 vs. 1.5; HR, 1.96), the investigators found.
Tramadol is considered a weak opioid and is commonly used for the treatment of pain based on a lower perceived risk of serious cardiovascular and gastrointestinal effects versus NSAIDs, and of addiction and respiratory depression versus traditional opioids, they explained. Several professional organizations also have “strongly or conditionally recommended tramadol” as a first- or second-line treatment for conditions such as osteoarthritis, fibromyalgia, and chronic low back pain.
The potential mechanisms for the association between tramadol and hip fracture require further study, but “[c]onsidering the significant impact of hip fracture on morbidity, mortality, and health care costs, our results point to the need to consider tramadol’s associated risk of fracture in clinical practice and treatment guidelines,” they concluded.
This study was supported by the National Institutes of Health, the National Natural Science Foundation of China, and the Postdoctoral Science Foundation of Central South University. The authors reported having no conflicts of interest.
SOURCE: Wei J et al. J Bone Miner Res. 2019 Feb 5. doi: 10.1002/jbmr.3935.
The risk of hip fracture was higher among patients treated with tramadol for chronic noncancer pain than among those treated with other commonly used NSAIDs in a large population-based cohort in the United Kingdom.
The incidence of hip fracture over a 12-month period among 293,912 propensity score-matched tramadol and codeine recipients in The Health Improvement Network (THIN) database during 2000-2017 was 3.7 vs. 2.9 per 1,000 person-years, respectively (hazard ratio for hip fracture, 1.28), Jie Wei, PhD, of Xiangya Hospital, Central South University, Changsha, China, and colleagues reported in the Journal of Bone and Mineral Research.
Hip fracture incidence per 1,000 person-years was also higher in propensity score–matched cohorts of patients receiving tramadol vs. naproxen (2.9 vs. 1.7; HR, 1.69), ibuprofen (3.4 vs. 2.0; HR, 1.65), celecoxib (3.4 vs. 1.8; HR, 1.85), or etoricoxib (2.9 vs. 1.5; HR, 1.96), the investigators found.
Tramadol is considered a weak opioid and is commonly used for the treatment of pain based on a lower perceived risk of serious cardiovascular and gastrointestinal effects versus NSAIDs, and of addiction and respiratory depression versus traditional opioids, they explained. Several professional organizations also have “strongly or conditionally recommended tramadol” as a first- or second-line treatment for conditions such as osteoarthritis, fibromyalgia, and chronic low back pain.
The potential mechanisms for the association between tramadol and hip fracture require further study, but “[c]onsidering the significant impact of hip fracture on morbidity, mortality, and health care costs, our results point to the need to consider tramadol’s associated risk of fracture in clinical practice and treatment guidelines,” they concluded.
This study was supported by the National Institutes of Health, the National Natural Science Foundation of China, and the Postdoctoral Science Foundation of Central South University. The authors reported having no conflicts of interest.
SOURCE: Wei J et al. J Bone Miner Res. 2019 Feb 5. doi: 10.1002/jbmr.3935.
FROM THE JOURNAL OF BONE AND MINERAL RESEARCH
IFN-activated monocytes show early promise for ovarian cancer
ORLANDO –
The best response observed in the open-label, dose-escalation study was a partial response in 2 of 11 evaluable patients, with about a 30% reduction in target lesion size in both patients. An additional six patients had stable disease, and three had progressive disease.
Christopher Browning Cole, MD, PhD, of the National Cancer Institute, Bethesda, Md., reported these results at the ASCO-SITC Clinical Immuno-Oncology Symposium.
The primary objective of this study was to determine safety and identify the maximum tolerated dose (MTD). The study enrolled 18 patients with metastatic or unresectable ovarian cancer that was platinum resistant or refractory. They had a median age of 61 years and had received a median of five prior therapies.
The patients were enrolled in four dose cohorts in which they were treated every 28 days with intraperitoneal peginterferon alfa-2b (Sylatron) at doses of 25-250 mcg and interferon gamma-1b (Actimmune) at doses of 5-50 mcg, with or without autologous monocytes (75-750 x 106 cells).
In all, 15 patients were assigned to dose levels that included monocytes (dose levels 2, 3, and 4). Two of these patients were unable to tolerate apheresis and were reallocated, after two to four cycles of therapy, to “dose level 3-b,” which included 250 mcg of peginterferon alfa-2b, 50 mcg of interferon gamma-1b, and no monocytes, Dr. Cole said.
Results
Based on overall safety and tolerability, the highest dose (250 mcg of peginterferon alfa-2b, 50 mcg of interferon gamma-1b, and 750 x 106 autologous monocytes) was the MTD. Six patients received this dose.
One of the partial responders received one cycle of the MTD, and the other received eight cycles of the lowest dose (25 mcg of peginterferon alfa-2b, 5 mcg of interferon gamma-1b, and no monocytes).
The median number of cycles patients received was 3.2, but “several patients stayed on treatment much longer than that,” Dr. Cole said. Two patients are still on study, one of whom has received 10 cycles to date.
Toxicities were “largely expected” based on prior studies, and included fatigue, nausea, and abdominal pain, Dr. Cole said. He added that monocyte collection by apheresis was “tolerated pretty well” by all but the two patients reallocated to dose level 3-b, and no grade 4 or 5 toxicities occurred.
There was one grade 3 peritoneal infection associated with a catheter used for monocyte administration. After a switch to port access for administration, no other such complications occurred, Dr. Cole noted.
Rationale and next steps
“There were three sets of studies that really provided the basis for [this trial],” Dr. Cole said, explaining that the first involves the “long-standing observation that ovarian cancer is really a peritoneal disease.”
“This has led to a lot of interest in directing therapies directly to the tumor in the peritoneum ... and many of these trials have shown some really impressive results in terms of [overall survival] advantage in long-term follow up,” he added.
The second set includes pioneering studies using interferons, which are capable of activating innate immune cells, intraperitoneally to treat ovarian cancer. Interferon-gamma and interferon-alfa showed particular promise.
The third set of studies, including extensive preclinical data, shows that autologous monocytes can be activated by interferon-gamma and interferon-alfa to become tumoricidal, Dr. Cole said.
The findings of the current study support further assessment of this approach, he said, adding that exploratory analyses are ongoing to measure plasma cytokines at baseline and after therapy, specifically looking for cytokines secreted by activated monocytes.
In addition to interferon-gamma, several cytokines were present at detectable levels in the blood, including interleukin-6 and tumor necrosis factor–alpha, Dr. Cole noted.
He and colleagues seek to understand changes in immune cell populations induced by the therapy. They have developed a comprehensive set of panels to look at ligands and markers reflective of immune system activation, and “markers which might be targets for future therapies, potentially allowing us to develop some rational combinations, such as [programmed death-1, programmed death-ligand 1, and cytotoxic T-lymphocyte-associated antigen 4],” he added.
“What we’d like to do next is enroll an expansion cohort at the MTD to learn more about efficacy and immunomodulatory effects of this regimen, particularly ... what’s happening with the immune system in the tumor microenvironment, so we’re going to perform tumor biopsies before and after therapy to learn a little more about that,” Dr. Cole said. “What we ultimately envision this regimen becoming is a platform to combine intraperitoneal cellular immune therapies in the innate immune system with other immunotherapies, such as systemic therapy targeting the adaptive immune system.”
The National Institutes of Health funded the study. Dr. Cole reported having no disclosures.
SOURCE: Cole C et al. ASCO-SITC: Abstract 1.
ORLANDO –
The best response observed in the open-label, dose-escalation study was a partial response in 2 of 11 evaluable patients, with about a 30% reduction in target lesion size in both patients. An additional six patients had stable disease, and three had progressive disease.
Christopher Browning Cole, MD, PhD, of the National Cancer Institute, Bethesda, Md., reported these results at the ASCO-SITC Clinical Immuno-Oncology Symposium.
The primary objective of this study was to determine safety and identify the maximum tolerated dose (MTD). The study enrolled 18 patients with metastatic or unresectable ovarian cancer that was platinum resistant or refractory. They had a median age of 61 years and had received a median of five prior therapies.
The patients were enrolled in four dose cohorts in which they were treated every 28 days with intraperitoneal peginterferon alfa-2b (Sylatron) at doses of 25-250 mcg and interferon gamma-1b (Actimmune) at doses of 5-50 mcg, with or without autologous monocytes (75-750 x 106 cells).
In all, 15 patients were assigned to dose levels that included monocytes (dose levels 2, 3, and 4). Two of these patients were unable to tolerate apheresis and were reallocated, after two to four cycles of therapy, to “dose level 3-b,” which included 250 mcg of peginterferon alfa-2b, 50 mcg of interferon gamma-1b, and no monocytes, Dr. Cole said.
Results
Based on overall safety and tolerability, the highest dose (250 mcg of peginterferon alfa-2b, 50 mcg of interferon gamma-1b, and 750 x 106 autologous monocytes) was the MTD. Six patients received this dose.
One of the partial responders received one cycle of the MTD, and the other received eight cycles of the lowest dose (25 mcg of peginterferon alfa-2b, 5 mcg of interferon gamma-1b, and no monocytes).
The median number of cycles patients received was 3.2, but “several patients stayed on treatment much longer than that,” Dr. Cole said. Two patients are still on study, one of whom has received 10 cycles to date.
Toxicities were “largely expected” based on prior studies, and included fatigue, nausea, and abdominal pain, Dr. Cole said. He added that monocyte collection by apheresis was “tolerated pretty well” by all but the two patients reallocated to dose level 3-b, and no grade 4 or 5 toxicities occurred.
There was one grade 3 peritoneal infection associated with a catheter used for monocyte administration. After a switch to port access for administration, no other such complications occurred, Dr. Cole noted.
Rationale and next steps
“There were three sets of studies that really provided the basis for [this trial],” Dr. Cole said, explaining that the first involves the “long-standing observation that ovarian cancer is really a peritoneal disease.”
“This has led to a lot of interest in directing therapies directly to the tumor in the peritoneum ... and many of these trials have shown some really impressive results in terms of [overall survival] advantage in long-term follow up,” he added.
The second set includes pioneering studies using interferons, which are capable of activating innate immune cells, intraperitoneally to treat ovarian cancer. Interferon-gamma and interferon-alfa showed particular promise.
The third set of studies, including extensive preclinical data, shows that autologous monocytes can be activated by interferon-gamma and interferon-alfa to become tumoricidal, Dr. Cole said.
The findings of the current study support further assessment of this approach, he said, adding that exploratory analyses are ongoing to measure plasma cytokines at baseline and after therapy, specifically looking for cytokines secreted by activated monocytes.
In addition to interferon-gamma, several cytokines were present at detectable levels in the blood, including interleukin-6 and tumor necrosis factor–alpha, Dr. Cole noted.
He and colleagues seek to understand changes in immune cell populations induced by the therapy. They have developed a comprehensive set of panels to look at ligands and markers reflective of immune system activation, and “markers which might be targets for future therapies, potentially allowing us to develop some rational combinations, such as [programmed death-1, programmed death-ligand 1, and cytotoxic T-lymphocyte-associated antigen 4],” he added.
“What we’d like to do next is enroll an expansion cohort at the MTD to learn more about efficacy and immunomodulatory effects of this regimen, particularly ... what’s happening with the immune system in the tumor microenvironment, so we’re going to perform tumor biopsies before and after therapy to learn a little more about that,” Dr. Cole said. “What we ultimately envision this regimen becoming is a platform to combine intraperitoneal cellular immune therapies in the innate immune system with other immunotherapies, such as systemic therapy targeting the adaptive immune system.”
The National Institutes of Health funded the study. Dr. Cole reported having no disclosures.
SOURCE: Cole C et al. ASCO-SITC: Abstract 1.
ORLANDO –
The best response observed in the open-label, dose-escalation study was a partial response in 2 of 11 evaluable patients, with about a 30% reduction in target lesion size in both patients. An additional six patients had stable disease, and three had progressive disease.
Christopher Browning Cole, MD, PhD, of the National Cancer Institute, Bethesda, Md., reported these results at the ASCO-SITC Clinical Immuno-Oncology Symposium.
The primary objective of this study was to determine safety and identify the maximum tolerated dose (MTD). The study enrolled 18 patients with metastatic or unresectable ovarian cancer that was platinum resistant or refractory. They had a median age of 61 years and had received a median of five prior therapies.
The patients were enrolled in four dose cohorts in which they were treated every 28 days with intraperitoneal peginterferon alfa-2b (Sylatron) at doses of 25-250 mcg and interferon gamma-1b (Actimmune) at doses of 5-50 mcg, with or without autologous monocytes (75-750 x 106 cells).
In all, 15 patients were assigned to dose levels that included monocytes (dose levels 2, 3, and 4). Two of these patients were unable to tolerate apheresis and were reallocated, after two to four cycles of therapy, to “dose level 3-b,” which included 250 mcg of peginterferon alfa-2b, 50 mcg of interferon gamma-1b, and no monocytes, Dr. Cole said.
Results
Based on overall safety and tolerability, the highest dose (250 mcg of peginterferon alfa-2b, 50 mcg of interferon gamma-1b, and 750 x 106 autologous monocytes) was the MTD. Six patients received this dose.
One of the partial responders received one cycle of the MTD, and the other received eight cycles of the lowest dose (25 mcg of peginterferon alfa-2b, 5 mcg of interferon gamma-1b, and no monocytes).
The median number of cycles patients received was 3.2, but “several patients stayed on treatment much longer than that,” Dr. Cole said. Two patients are still on study, one of whom has received 10 cycles to date.
Toxicities were “largely expected” based on prior studies, and included fatigue, nausea, and abdominal pain, Dr. Cole said. He added that monocyte collection by apheresis was “tolerated pretty well” by all but the two patients reallocated to dose level 3-b, and no grade 4 or 5 toxicities occurred.
There was one grade 3 peritoneal infection associated with a catheter used for monocyte administration. After a switch to port access for administration, no other such complications occurred, Dr. Cole noted.
Rationale and next steps
“There were three sets of studies that really provided the basis for [this trial],” Dr. Cole said, explaining that the first involves the “long-standing observation that ovarian cancer is really a peritoneal disease.”
“This has led to a lot of interest in directing therapies directly to the tumor in the peritoneum ... and many of these trials have shown some really impressive results in terms of [overall survival] advantage in long-term follow up,” he added.
The second set includes pioneering studies using interferons, which are capable of activating innate immune cells, intraperitoneally to treat ovarian cancer. Interferon-gamma and interferon-alfa showed particular promise.
The third set of studies, including extensive preclinical data, shows that autologous monocytes can be activated by interferon-gamma and interferon-alfa to become tumoricidal, Dr. Cole said.
The findings of the current study support further assessment of this approach, he said, adding that exploratory analyses are ongoing to measure plasma cytokines at baseline and after therapy, specifically looking for cytokines secreted by activated monocytes.
In addition to interferon-gamma, several cytokines were present at detectable levels in the blood, including interleukin-6 and tumor necrosis factor–alpha, Dr. Cole noted.
He and colleagues seek to understand changes in immune cell populations induced by the therapy. They have developed a comprehensive set of panels to look at ligands and markers reflective of immune system activation, and “markers which might be targets for future therapies, potentially allowing us to develop some rational combinations, such as [programmed death-1, programmed death-ligand 1, and cytotoxic T-lymphocyte-associated antigen 4],” he added.
“What we’d like to do next is enroll an expansion cohort at the MTD to learn more about efficacy and immunomodulatory effects of this regimen, particularly ... what’s happening with the immune system in the tumor microenvironment, so we’re going to perform tumor biopsies before and after therapy to learn a little more about that,” Dr. Cole said. “What we ultimately envision this regimen becoming is a platform to combine intraperitoneal cellular immune therapies in the innate immune system with other immunotherapies, such as systemic therapy targeting the adaptive immune system.”
The National Institutes of Health funded the study. Dr. Cole reported having no disclosures.
SOURCE: Cole C et al. ASCO-SITC: Abstract 1.
REPORTING FROM THE CLINICAL IMMUNO-ONCOLOGY SYMPOSIUM
Model reveals genes associated with prognosis in ER+, HER2– breast cancer
ORLANDO – , according to new research.
Yara Abdou, MD, of Roswell Park Comprehensive Cancer Center in Buffalo, N.Y., and colleagues presented this work in a poster at the ASCO-SITC Clinical Immuno-Oncology Symposium.
The model used 50 cycles of machine learning to cluster 98 patients from The Cancer Genome Atlas Program into high- and low-risk groups based on mRNA expression of 26 gene groups.
The gene groups consisted of 191 genes enriched in cellular and noncellular elements of the tumor microenvironment. Mutational burden and clinical outcomes data for the patients also were considered, Dr. Abdou explained in an interview.
Kaplan-Meier curves were created for each group by K-means clustering, survival differences between the two groups were assessed, and correlations among the various gene groups were analyzed.
Five identified genes were associated with poor prognosis: LOXL2, PHEX, ACTA2, MEGF9, and TNFSF4. Fifteen genes were associated with good prognosis: CD8A, CD8B, FCRL3, GZMK, CD3E, CCL5, TP53, ICAM3, CD247, IFNG, IFNGR1, ICAM4, SHH, HLA-DOB, and CXCR3.
The Kaplan-Meier curves showed a significant difference in survival between the two groups (hazard ratio, 2.878; P = .05), confirming the validity of the risk score modeling, Dr. Abdou said.
Immune profiling showed that expression of genes associated with desmoplastic reaction, neutrophils, and immunosuppressive cytokines were higher in the high-risk group, whereas expression of genes related to immune system activation were higher in the low-risk group (P less than .05).
Stroma in the tumor microenvironment is known to affect prognosis and response to therapy in patients with breast cancer, but few mathematical models exist to determine prognosis based on mRNA expressivity in the tumor microenvironment, Dr. Abdou said, explaining the rationale for the study.
The findings suggest that when genomic profile information is available for a given patient in the clinic, this machine learning–assisted risk scoring approach could have prognostic value, she said, noting that the model also will be assessed in patients with other types of breast cancer.
Dr. Abdou reported having no disclosures.
SOURCE: Abdou Y et al. ASCO-SITC. Poster A3.
ORLANDO – , according to new research.
Yara Abdou, MD, of Roswell Park Comprehensive Cancer Center in Buffalo, N.Y., and colleagues presented this work in a poster at the ASCO-SITC Clinical Immuno-Oncology Symposium.
The model used 50 cycles of machine learning to cluster 98 patients from The Cancer Genome Atlas Program into high- and low-risk groups based on mRNA expression of 26 gene groups.
The gene groups consisted of 191 genes enriched in cellular and noncellular elements of the tumor microenvironment. Mutational burden and clinical outcomes data for the patients also were considered, Dr. Abdou explained in an interview.
Kaplan-Meier curves were created for each group by K-means clustering, survival differences between the two groups were assessed, and correlations among the various gene groups were analyzed.
Five identified genes were associated with poor prognosis: LOXL2, PHEX, ACTA2, MEGF9, and TNFSF4. Fifteen genes were associated with good prognosis: CD8A, CD8B, FCRL3, GZMK, CD3E, CCL5, TP53, ICAM3, CD247, IFNG, IFNGR1, ICAM4, SHH, HLA-DOB, and CXCR3.
The Kaplan-Meier curves showed a significant difference in survival between the two groups (hazard ratio, 2.878; P = .05), confirming the validity of the risk score modeling, Dr. Abdou said.
Immune profiling showed that expression of genes associated with desmoplastic reaction, neutrophils, and immunosuppressive cytokines were higher in the high-risk group, whereas expression of genes related to immune system activation were higher in the low-risk group (P less than .05).
Stroma in the tumor microenvironment is known to affect prognosis and response to therapy in patients with breast cancer, but few mathematical models exist to determine prognosis based on mRNA expressivity in the tumor microenvironment, Dr. Abdou said, explaining the rationale for the study.
The findings suggest that when genomic profile information is available for a given patient in the clinic, this machine learning–assisted risk scoring approach could have prognostic value, she said, noting that the model also will be assessed in patients with other types of breast cancer.
Dr. Abdou reported having no disclosures.
SOURCE: Abdou Y et al. ASCO-SITC. Poster A3.
ORLANDO – , according to new research.
Yara Abdou, MD, of Roswell Park Comprehensive Cancer Center in Buffalo, N.Y., and colleagues presented this work in a poster at the ASCO-SITC Clinical Immuno-Oncology Symposium.
The model used 50 cycles of machine learning to cluster 98 patients from The Cancer Genome Atlas Program into high- and low-risk groups based on mRNA expression of 26 gene groups.
The gene groups consisted of 191 genes enriched in cellular and noncellular elements of the tumor microenvironment. Mutational burden and clinical outcomes data for the patients also were considered, Dr. Abdou explained in an interview.
Kaplan-Meier curves were created for each group by K-means clustering, survival differences between the two groups were assessed, and correlations among the various gene groups were analyzed.
Five identified genes were associated with poor prognosis: LOXL2, PHEX, ACTA2, MEGF9, and TNFSF4. Fifteen genes were associated with good prognosis: CD8A, CD8B, FCRL3, GZMK, CD3E, CCL5, TP53, ICAM3, CD247, IFNG, IFNGR1, ICAM4, SHH, HLA-DOB, and CXCR3.
The Kaplan-Meier curves showed a significant difference in survival between the two groups (hazard ratio, 2.878; P = .05), confirming the validity of the risk score modeling, Dr. Abdou said.
Immune profiling showed that expression of genes associated with desmoplastic reaction, neutrophils, and immunosuppressive cytokines were higher in the high-risk group, whereas expression of genes related to immune system activation were higher in the low-risk group (P less than .05).
Stroma in the tumor microenvironment is known to affect prognosis and response to therapy in patients with breast cancer, but few mathematical models exist to determine prognosis based on mRNA expressivity in the tumor microenvironment, Dr. Abdou said, explaining the rationale for the study.
The findings suggest that when genomic profile information is available for a given patient in the clinic, this machine learning–assisted risk scoring approach could have prognostic value, she said, noting that the model also will be assessed in patients with other types of breast cancer.
Dr. Abdou reported having no disclosures.
SOURCE: Abdou Y et al. ASCO-SITC. Poster A3.
REPORTING FROM THE CLINICAL IMMUNO-ONCOLOGY SYMPOSIUM
Phase 2 data: Inotuzumab, approved in adults with B-ALL, shows promise in kids, too
ORLANDO – Inotuzumab ozogamicin (InO), a CD22-targeted antibody approved for adults with relapsed/refractory B-cell acute lymphoblastic leukemia (R/R B-ALL), showed promising safety and efficacy in children and young adults with R/R B-ALL in a phase 2 trial.
Of 48 patients aged 1-21 years enrolled in the Children’s Oncology Group (COG) Protocol AALL1621 and evaluable for response and toxicity after treatment with the approved adult InO dose, 19 achieved a complete response (CR) and 9 achieved a complete response with incomplete count recovery (CRi) after the first treatment cycle, for an overall CR/CRi rate of 58.3%, Maureen M. O’Brien, MD, reported at the annual meeting of the American Society of Hematology.
Of those with CR/CRi, 19 (65.5%) achieved minimal residual disease less than 0.01%, said Dr. O’Brien, a pediatric hematologist and medical director of the Leukemia/Lymphoma Program at the Cancer and Blood Diseases Institute, Cincinnati Children’s Hospital Medical Center.
Three patients had a partial response (PR), nine had stable disease (SD), and eight had progressive disease (PD), and one of each with PR and SD achieved CR/CRi after a second treatment cycle.
“Of note, two patients who were characterized as [having] progressive disease actually had marrow complete response with incomplete count recovery, but had progressive CNS disease,” she said.
Patients included in the single-arm trial had CD22-positive B-ALL, defined as B-ALL with greater than 20% of blasts expressing CD22, and were in at least their second relapse, were refractory to two prior induction regimens, or had a relapse after hematopoietic stem cell transplantation (HSCT). One exception was that patients with Down syndrome were allowed inclusion after a first relapse, she noted.
Median patient age was 9 years, four patients had CNS 3 status, three had Down syndrome, and most were heavily pretreated, with 32 in at least their second relapse.
“Most patients had significant marrow disease burden, with a median marrow blast percentage of 81%,” Dr. O’Brien said. “In terms of prior therapy, 23% had prior transplant, 23% had prior CD19 [chimeric antigen receptor (CAR)] T-cell therapy – including two patients with prior CD22 CAR T, and 29% of patients had received prior blinatumomab.”
All patients received one cycle of InO at a dose of 1.8mg/m2, with .8mg/m2 given on day 1 and 0.5mg/m2 given on days 8 and 15. Intrathecal therapy was determined based on CNS status.
Patients with at least stable disease at day 28 were eligible for a second cycle; those with CR or CRi received InO at a dose of 0.5 mg/m2 on days 1, 8, and 15 in cycle 2, and those without CR/CRi received the same fractionated dose as in cycle 1. Patients with CR/CRi after two cycles were eligible for up to six total cycles at investigator discretion, Dr. O’Brien explained, adding that 26 of 40 patients eligible for cycle 2 proceeded, including 13 of 18 with MRD less than .01%, 6 of 10 with MRD of 0.01% or greater, and 7 of 12 with PR/SD.
After cycle 2, all 13 with MRD less than .01% maintained that MRD level, 3 of 6 with MRD of .01% or greater achieved MRD less than .01%, 2 of 7 with PR/SD achieved CRi with MRD of .01% or greater – and one of those 2 was MRD negative after a third cycle.
Seven patients received three or more cycles.
“Therapy was extremely well tolerated,” Dr. O’Brien said, noting that the most common nonhematological grade 3 or higher adverse events occurring in at least 5% of patients in cycle 1 were febrile neutropenia and infection, occurring in 27.1% and 16.7% of patients, respectively. “But toxicity was quite minimal.”
Hepatic toxicity included four cases of grade 3 alanine transaminase and one grade 3 bilirubin toxicity in cycle 1, and one grade 3 ALT in cycle 2.
“Importantly, there were no inotuzumab dose modifications or delays due to hepatic toxicity,” she said.
Nine patients experienced 11 dose-limiting toxicities in cycle 1, including 7 involving prolonged count recovery beyond day 42, which was not attributable to disease, and 4 nonhematologic events, including drug reaction with eosinophilia and systemic symptoms, bronchopulmonary hemorrhage, respiratory distress, and a postintrathecal methotrexate stroke.
Sinusoidal obstruction syndrome (SOS) developed in 5 of the 48 patients, all in patients who underwent transplant after InO treatment. Only one of the five had undergone a prior transplant. All SOS cases were grade 3 and were treated with defibrotide; four cases resolved quickly, and one was resolving at the time of death from other causes, she said.
“We found no evidence of association with age, conditioning regimen, SOS prophylaxis, cumulative InO exposure, or time from InO to transplant, bearing in mind that it is a small number of cases, so analysis is limited,” she added.
Central CD22 evaluation in 27 patients with pre– and post–cycle 1 samples showed that 11 of those patients had residual disease at the end of cycle 1.
“There is clearly a subset of patients for whom the resistance mechanism does not seem to have any bearing on CD22, as it was still highly expressed at the time of relapse, but there are a significant number of patients who have downregulation of CD22 expression or a subset of blasts that were CD22 negative at the time of relapse,” she said. “Notably, two of three patients with baseline partial CD22 expression – so less than 90% ... did not achieve a morphologic complete response, and both of these patients had KMT2A rearrangements.”
The findings are important, because 10%-20% of children and young adults with B-ALL will relapse, and therapies that can bridge patients to HSCT or CAR T-cell therapy are critical for improving outcomes, Dr. O’Brien said, explaining that InO, a humanized CD22 IgG4 antibody conjugated to calicheamicin, was approved in adults based on “the impressive results from the INNOVATE trial, compared with chemotherapy,” but prospective data on its efficacy and safety in pediatric patients are lacking.
Retrospective data from a compassionate use program in children demonstrated a response rate of 67% in a heavily pretreated population, and phase 1 data from the ITCC-059 trial presented in a poster at the ASH meeting also showed “quite impressive results,” but a major concern has been hepatic toxicity, including SOS, she said.
Given the observed safety and efficacy in the current phase 2 trial, investigation in children will continue, she said, explaining that “COG is now undertaking a phase 3 trial – AALL1732 – which will randomize patients to chemotherapy [with or without] inotuzumab for patients aged 1-25 with newly diagnosed high-risk B-ALL.”
COG AALL1621 was funded by NCTN grants, St. Baldrick’s Foundation, and Pfizer. Dr. O’Brien reported research funding from Pfizer, Celgene, AbbVie, Amgen, Bristol-Myers Squibb, and BTG.
SOURCE: O’Brien M et al. ASH 2019, Abstract 741.
ORLANDO – Inotuzumab ozogamicin (InO), a CD22-targeted antibody approved for adults with relapsed/refractory B-cell acute lymphoblastic leukemia (R/R B-ALL), showed promising safety and efficacy in children and young adults with R/R B-ALL in a phase 2 trial.
Of 48 patients aged 1-21 years enrolled in the Children’s Oncology Group (COG) Protocol AALL1621 and evaluable for response and toxicity after treatment with the approved adult InO dose, 19 achieved a complete response (CR) and 9 achieved a complete response with incomplete count recovery (CRi) after the first treatment cycle, for an overall CR/CRi rate of 58.3%, Maureen M. O’Brien, MD, reported at the annual meeting of the American Society of Hematology.
Of those with CR/CRi, 19 (65.5%) achieved minimal residual disease less than 0.01%, said Dr. O’Brien, a pediatric hematologist and medical director of the Leukemia/Lymphoma Program at the Cancer and Blood Diseases Institute, Cincinnati Children’s Hospital Medical Center.
Three patients had a partial response (PR), nine had stable disease (SD), and eight had progressive disease (PD), and one of each with PR and SD achieved CR/CRi after a second treatment cycle.
“Of note, two patients who were characterized as [having] progressive disease actually had marrow complete response with incomplete count recovery, but had progressive CNS disease,” she said.
Patients included in the single-arm trial had CD22-positive B-ALL, defined as B-ALL with greater than 20% of blasts expressing CD22, and were in at least their second relapse, were refractory to two prior induction regimens, or had a relapse after hematopoietic stem cell transplantation (HSCT). One exception was that patients with Down syndrome were allowed inclusion after a first relapse, she noted.
Median patient age was 9 years, four patients had CNS 3 status, three had Down syndrome, and most were heavily pretreated, with 32 in at least their second relapse.
“Most patients had significant marrow disease burden, with a median marrow blast percentage of 81%,” Dr. O’Brien said. “In terms of prior therapy, 23% had prior transplant, 23% had prior CD19 [chimeric antigen receptor (CAR)] T-cell therapy – including two patients with prior CD22 CAR T, and 29% of patients had received prior blinatumomab.”
All patients received one cycle of InO at a dose of 1.8mg/m2, with .8mg/m2 given on day 1 and 0.5mg/m2 given on days 8 and 15. Intrathecal therapy was determined based on CNS status.
Patients with at least stable disease at day 28 were eligible for a second cycle; those with CR or CRi received InO at a dose of 0.5 mg/m2 on days 1, 8, and 15 in cycle 2, and those without CR/CRi received the same fractionated dose as in cycle 1. Patients with CR/CRi after two cycles were eligible for up to six total cycles at investigator discretion, Dr. O’Brien explained, adding that 26 of 40 patients eligible for cycle 2 proceeded, including 13 of 18 with MRD less than .01%, 6 of 10 with MRD of 0.01% or greater, and 7 of 12 with PR/SD.
After cycle 2, all 13 with MRD less than .01% maintained that MRD level, 3 of 6 with MRD of .01% or greater achieved MRD less than .01%, 2 of 7 with PR/SD achieved CRi with MRD of .01% or greater – and one of those 2 was MRD negative after a third cycle.
Seven patients received three or more cycles.
“Therapy was extremely well tolerated,” Dr. O’Brien said, noting that the most common nonhematological grade 3 or higher adverse events occurring in at least 5% of patients in cycle 1 were febrile neutropenia and infection, occurring in 27.1% and 16.7% of patients, respectively. “But toxicity was quite minimal.”
Hepatic toxicity included four cases of grade 3 alanine transaminase and one grade 3 bilirubin toxicity in cycle 1, and one grade 3 ALT in cycle 2.
“Importantly, there were no inotuzumab dose modifications or delays due to hepatic toxicity,” she said.
Nine patients experienced 11 dose-limiting toxicities in cycle 1, including 7 involving prolonged count recovery beyond day 42, which was not attributable to disease, and 4 nonhematologic events, including drug reaction with eosinophilia and systemic symptoms, bronchopulmonary hemorrhage, respiratory distress, and a postintrathecal methotrexate stroke.
Sinusoidal obstruction syndrome (SOS) developed in 5 of the 48 patients, all in patients who underwent transplant after InO treatment. Only one of the five had undergone a prior transplant. All SOS cases were grade 3 and were treated with defibrotide; four cases resolved quickly, and one was resolving at the time of death from other causes, she said.
“We found no evidence of association with age, conditioning regimen, SOS prophylaxis, cumulative InO exposure, or time from InO to transplant, bearing in mind that it is a small number of cases, so analysis is limited,” she added.
Central CD22 evaluation in 27 patients with pre– and post–cycle 1 samples showed that 11 of those patients had residual disease at the end of cycle 1.
“There is clearly a subset of patients for whom the resistance mechanism does not seem to have any bearing on CD22, as it was still highly expressed at the time of relapse, but there are a significant number of patients who have downregulation of CD22 expression or a subset of blasts that were CD22 negative at the time of relapse,” she said. “Notably, two of three patients with baseline partial CD22 expression – so less than 90% ... did not achieve a morphologic complete response, and both of these patients had KMT2A rearrangements.”
The findings are important, because 10%-20% of children and young adults with B-ALL will relapse, and therapies that can bridge patients to HSCT or CAR T-cell therapy are critical for improving outcomes, Dr. O’Brien said, explaining that InO, a humanized CD22 IgG4 antibody conjugated to calicheamicin, was approved in adults based on “the impressive results from the INNOVATE trial, compared with chemotherapy,” but prospective data on its efficacy and safety in pediatric patients are lacking.
Retrospective data from a compassionate use program in children demonstrated a response rate of 67% in a heavily pretreated population, and phase 1 data from the ITCC-059 trial presented in a poster at the ASH meeting also showed “quite impressive results,” but a major concern has been hepatic toxicity, including SOS, she said.
Given the observed safety and efficacy in the current phase 2 trial, investigation in children will continue, she said, explaining that “COG is now undertaking a phase 3 trial – AALL1732 – which will randomize patients to chemotherapy [with or without] inotuzumab for patients aged 1-25 with newly diagnosed high-risk B-ALL.”
COG AALL1621 was funded by NCTN grants, St. Baldrick’s Foundation, and Pfizer. Dr. O’Brien reported research funding from Pfizer, Celgene, AbbVie, Amgen, Bristol-Myers Squibb, and BTG.
SOURCE: O’Brien M et al. ASH 2019, Abstract 741.
ORLANDO – Inotuzumab ozogamicin (InO), a CD22-targeted antibody approved for adults with relapsed/refractory B-cell acute lymphoblastic leukemia (R/R B-ALL), showed promising safety and efficacy in children and young adults with R/R B-ALL in a phase 2 trial.
Of 48 patients aged 1-21 years enrolled in the Children’s Oncology Group (COG) Protocol AALL1621 and evaluable for response and toxicity after treatment with the approved adult InO dose, 19 achieved a complete response (CR) and 9 achieved a complete response with incomplete count recovery (CRi) after the first treatment cycle, for an overall CR/CRi rate of 58.3%, Maureen M. O’Brien, MD, reported at the annual meeting of the American Society of Hematology.
Of those with CR/CRi, 19 (65.5%) achieved minimal residual disease less than 0.01%, said Dr. O’Brien, a pediatric hematologist and medical director of the Leukemia/Lymphoma Program at the Cancer and Blood Diseases Institute, Cincinnati Children’s Hospital Medical Center.
Three patients had a partial response (PR), nine had stable disease (SD), and eight had progressive disease (PD), and one of each with PR and SD achieved CR/CRi after a second treatment cycle.
“Of note, two patients who were characterized as [having] progressive disease actually had marrow complete response with incomplete count recovery, but had progressive CNS disease,” she said.
Patients included in the single-arm trial had CD22-positive B-ALL, defined as B-ALL with greater than 20% of blasts expressing CD22, and were in at least their second relapse, were refractory to two prior induction regimens, or had a relapse after hematopoietic stem cell transplantation (HSCT). One exception was that patients with Down syndrome were allowed inclusion after a first relapse, she noted.
Median patient age was 9 years, four patients had CNS 3 status, three had Down syndrome, and most were heavily pretreated, with 32 in at least their second relapse.
“Most patients had significant marrow disease burden, with a median marrow blast percentage of 81%,” Dr. O’Brien said. “In terms of prior therapy, 23% had prior transplant, 23% had prior CD19 [chimeric antigen receptor (CAR)] T-cell therapy – including two patients with prior CD22 CAR T, and 29% of patients had received prior blinatumomab.”
All patients received one cycle of InO at a dose of 1.8mg/m2, with .8mg/m2 given on day 1 and 0.5mg/m2 given on days 8 and 15. Intrathecal therapy was determined based on CNS status.
Patients with at least stable disease at day 28 were eligible for a second cycle; those with CR or CRi received InO at a dose of 0.5 mg/m2 on days 1, 8, and 15 in cycle 2, and those without CR/CRi received the same fractionated dose as in cycle 1. Patients with CR/CRi after two cycles were eligible for up to six total cycles at investigator discretion, Dr. O’Brien explained, adding that 26 of 40 patients eligible for cycle 2 proceeded, including 13 of 18 with MRD less than .01%, 6 of 10 with MRD of 0.01% or greater, and 7 of 12 with PR/SD.
After cycle 2, all 13 with MRD less than .01% maintained that MRD level, 3 of 6 with MRD of .01% or greater achieved MRD less than .01%, 2 of 7 with PR/SD achieved CRi with MRD of .01% or greater – and one of those 2 was MRD negative after a third cycle.
Seven patients received three or more cycles.
“Therapy was extremely well tolerated,” Dr. O’Brien said, noting that the most common nonhematological grade 3 or higher adverse events occurring in at least 5% of patients in cycle 1 were febrile neutropenia and infection, occurring in 27.1% and 16.7% of patients, respectively. “But toxicity was quite minimal.”
Hepatic toxicity included four cases of grade 3 alanine transaminase and one grade 3 bilirubin toxicity in cycle 1, and one grade 3 ALT in cycle 2.
“Importantly, there were no inotuzumab dose modifications or delays due to hepatic toxicity,” she said.
Nine patients experienced 11 dose-limiting toxicities in cycle 1, including 7 involving prolonged count recovery beyond day 42, which was not attributable to disease, and 4 nonhematologic events, including drug reaction with eosinophilia and systemic symptoms, bronchopulmonary hemorrhage, respiratory distress, and a postintrathecal methotrexate stroke.
Sinusoidal obstruction syndrome (SOS) developed in 5 of the 48 patients, all in patients who underwent transplant after InO treatment. Only one of the five had undergone a prior transplant. All SOS cases were grade 3 and were treated with defibrotide; four cases resolved quickly, and one was resolving at the time of death from other causes, she said.
“We found no evidence of association with age, conditioning regimen, SOS prophylaxis, cumulative InO exposure, or time from InO to transplant, bearing in mind that it is a small number of cases, so analysis is limited,” she added.
Central CD22 evaluation in 27 patients with pre– and post–cycle 1 samples showed that 11 of those patients had residual disease at the end of cycle 1.
“There is clearly a subset of patients for whom the resistance mechanism does not seem to have any bearing on CD22, as it was still highly expressed at the time of relapse, but there are a significant number of patients who have downregulation of CD22 expression or a subset of blasts that were CD22 negative at the time of relapse,” she said. “Notably, two of three patients with baseline partial CD22 expression – so less than 90% ... did not achieve a morphologic complete response, and both of these patients had KMT2A rearrangements.”
The findings are important, because 10%-20% of children and young adults with B-ALL will relapse, and therapies that can bridge patients to HSCT or CAR T-cell therapy are critical for improving outcomes, Dr. O’Brien said, explaining that InO, a humanized CD22 IgG4 antibody conjugated to calicheamicin, was approved in adults based on “the impressive results from the INNOVATE trial, compared with chemotherapy,” but prospective data on its efficacy and safety in pediatric patients are lacking.
Retrospective data from a compassionate use program in children demonstrated a response rate of 67% in a heavily pretreated population, and phase 1 data from the ITCC-059 trial presented in a poster at the ASH meeting also showed “quite impressive results,” but a major concern has been hepatic toxicity, including SOS, she said.
Given the observed safety and efficacy in the current phase 2 trial, investigation in children will continue, she said, explaining that “COG is now undertaking a phase 3 trial – AALL1732 – which will randomize patients to chemotherapy [with or without] inotuzumab for patients aged 1-25 with newly diagnosed high-risk B-ALL.”
COG AALL1621 was funded by NCTN grants, St. Baldrick’s Foundation, and Pfizer. Dr. O’Brien reported research funding from Pfizer, Celgene, AbbVie, Amgen, Bristol-Myers Squibb, and BTG.
SOURCE: O’Brien M et al. ASH 2019, Abstract 741.
REPORTING FROM ASH 2019
Adding ilixadencel improved outcomes in metastatic renal cell carcinoma
ORLANDO –
The confirmed overall response rate was 42.2% (19/45) in patients who received ilixadencel plus sunitinib and 24.0% (6/25) in patients who received sunitinib monotherapy. Magnus Lindskog, MD, PhD, of Uppsala (Sweden) University Hospital, reported these results at the ASCO-SITC Immuno-Oncology Symposium.
The complete response rate was 11.1% with ilixadencel plus sunitinib and 4% with sunitinib monotherapy. The confirmed complete response rates were 6.7% and 0%, respectively.
The median duration of response was 7.1 months with ilixadencel plus sunitinib and 2.9 months with sunitinib monotherapy. The median progression-free survival was 11.8 months and 11.0 months, respectively.
There was no difference in median overall survival – a coprimary endpoint – at 18 months, nor was there a difference in progression-free survival at that time. “We do find it interesting that there is a late separation of both [survival] curves like we see in many immunotherapy trials,” Dr. Lindskog said, noting that all five complete responders in the combination therapy arm were alive at 33 months, whereas the single patient with a complete response in the monotherapy group died after 41 months.
“So far, we have 54% versus 37% still alive in the ilixadencel versus sunitinib groups,” Dr. Lindskog said, adding that the observed activity of ilixadencel appears to be driven by responses in patients with intermediate risk.
The overall survival data in the intermediate-risk patients is not mature. The overall survival in poor-risk patients was 11.6 months in the combination group and 9.3 months in the monotherapy group.
MERECA study participants were adults with a mean age of 62-64 years who were considered surgical candidates. They were enrolled from eight centers in Europe and the United States between April 2014 and January 2017 and randomized 2:1 to the combination and monotherapy arms. In all, 45 patients received their assigned treatment in the combination arm, and 25 patients received their assigned treatment in the monotherapy arm.
Patients in the ilixadencel arm were injected twice, 2 weeks apart, at the primary tumor site using CT guidance. Patients in the monotherapy arm were observed until nephrectomy. Both groups received sunitinib after nephrectomy, which was performed within 6 weeks, and all were followed for 18 months.
Treatment was well tolerated. Ilixadencel did not add any clinically meaningful treatment-related grade 3-4 adverse events or serious adverse events, Dr. Lindskog said. He noted that the most common ilixadencel-related adverse event was uncomplicated pyrexia.
There were no signs of induced autoimmunity, and although 57% of patients in the combination therapy group developed ilixadencel-specific alloantibodies, this had no relationship to responses, Dr. Lindskog said.
“From this phase 2 study, we have confirmed the feasibility and safety of ilixadencel and sunitinib combined in newly diagnosed synchronous metastatic renal cell carcinoma patients,” he said.
He added that longer follow-up is needed to understand the late divergence in survival curves between the groups. Survival follow-up will continue for 5 years.
This study was funded by Immunicum. Dr. Lindskog disclosed relationships with Pfizer, Bristol-Myers Squibb, and Ipsen.
SOURCE: Lindskog M et al. ASCO-SITC 2020, Abstract 11.
ORLANDO –
The confirmed overall response rate was 42.2% (19/45) in patients who received ilixadencel plus sunitinib and 24.0% (6/25) in patients who received sunitinib monotherapy. Magnus Lindskog, MD, PhD, of Uppsala (Sweden) University Hospital, reported these results at the ASCO-SITC Immuno-Oncology Symposium.
The complete response rate was 11.1% with ilixadencel plus sunitinib and 4% with sunitinib monotherapy. The confirmed complete response rates were 6.7% and 0%, respectively.
The median duration of response was 7.1 months with ilixadencel plus sunitinib and 2.9 months with sunitinib monotherapy. The median progression-free survival was 11.8 months and 11.0 months, respectively.
There was no difference in median overall survival – a coprimary endpoint – at 18 months, nor was there a difference in progression-free survival at that time. “We do find it interesting that there is a late separation of both [survival] curves like we see in many immunotherapy trials,” Dr. Lindskog said, noting that all five complete responders in the combination therapy arm were alive at 33 months, whereas the single patient with a complete response in the monotherapy group died after 41 months.
“So far, we have 54% versus 37% still alive in the ilixadencel versus sunitinib groups,” Dr. Lindskog said, adding that the observed activity of ilixadencel appears to be driven by responses in patients with intermediate risk.
The overall survival data in the intermediate-risk patients is not mature. The overall survival in poor-risk patients was 11.6 months in the combination group and 9.3 months in the monotherapy group.
MERECA study participants were adults with a mean age of 62-64 years who were considered surgical candidates. They were enrolled from eight centers in Europe and the United States between April 2014 and January 2017 and randomized 2:1 to the combination and monotherapy arms. In all, 45 patients received their assigned treatment in the combination arm, and 25 patients received their assigned treatment in the monotherapy arm.
Patients in the ilixadencel arm were injected twice, 2 weeks apart, at the primary tumor site using CT guidance. Patients in the monotherapy arm were observed until nephrectomy. Both groups received sunitinib after nephrectomy, which was performed within 6 weeks, and all were followed for 18 months.
Treatment was well tolerated. Ilixadencel did not add any clinically meaningful treatment-related grade 3-4 adverse events or serious adverse events, Dr. Lindskog said. He noted that the most common ilixadencel-related adverse event was uncomplicated pyrexia.
There were no signs of induced autoimmunity, and although 57% of patients in the combination therapy group developed ilixadencel-specific alloantibodies, this had no relationship to responses, Dr. Lindskog said.
“From this phase 2 study, we have confirmed the feasibility and safety of ilixadencel and sunitinib combined in newly diagnosed synchronous metastatic renal cell carcinoma patients,” he said.
He added that longer follow-up is needed to understand the late divergence in survival curves between the groups. Survival follow-up will continue for 5 years.
This study was funded by Immunicum. Dr. Lindskog disclosed relationships with Pfizer, Bristol-Myers Squibb, and Ipsen.
SOURCE: Lindskog M et al. ASCO-SITC 2020, Abstract 11.
ORLANDO –
The confirmed overall response rate was 42.2% (19/45) in patients who received ilixadencel plus sunitinib and 24.0% (6/25) in patients who received sunitinib monotherapy. Magnus Lindskog, MD, PhD, of Uppsala (Sweden) University Hospital, reported these results at the ASCO-SITC Immuno-Oncology Symposium.
The complete response rate was 11.1% with ilixadencel plus sunitinib and 4% with sunitinib monotherapy. The confirmed complete response rates were 6.7% and 0%, respectively.
The median duration of response was 7.1 months with ilixadencel plus sunitinib and 2.9 months with sunitinib monotherapy. The median progression-free survival was 11.8 months and 11.0 months, respectively.
There was no difference in median overall survival – a coprimary endpoint – at 18 months, nor was there a difference in progression-free survival at that time. “We do find it interesting that there is a late separation of both [survival] curves like we see in many immunotherapy trials,” Dr. Lindskog said, noting that all five complete responders in the combination therapy arm were alive at 33 months, whereas the single patient with a complete response in the monotherapy group died after 41 months.
“So far, we have 54% versus 37% still alive in the ilixadencel versus sunitinib groups,” Dr. Lindskog said, adding that the observed activity of ilixadencel appears to be driven by responses in patients with intermediate risk.
The overall survival data in the intermediate-risk patients is not mature. The overall survival in poor-risk patients was 11.6 months in the combination group and 9.3 months in the monotherapy group.
MERECA study participants were adults with a mean age of 62-64 years who were considered surgical candidates. They were enrolled from eight centers in Europe and the United States between April 2014 and January 2017 and randomized 2:1 to the combination and monotherapy arms. In all, 45 patients received their assigned treatment in the combination arm, and 25 patients received their assigned treatment in the monotherapy arm.
Patients in the ilixadencel arm were injected twice, 2 weeks apart, at the primary tumor site using CT guidance. Patients in the monotherapy arm were observed until nephrectomy. Both groups received sunitinib after nephrectomy, which was performed within 6 weeks, and all were followed for 18 months.
Treatment was well tolerated. Ilixadencel did not add any clinically meaningful treatment-related grade 3-4 adverse events or serious adverse events, Dr. Lindskog said. He noted that the most common ilixadencel-related adverse event was uncomplicated pyrexia.
There were no signs of induced autoimmunity, and although 57% of patients in the combination therapy group developed ilixadencel-specific alloantibodies, this had no relationship to responses, Dr. Lindskog said.
“From this phase 2 study, we have confirmed the feasibility and safety of ilixadencel and sunitinib combined in newly diagnosed synchronous metastatic renal cell carcinoma patients,” he said.
He added that longer follow-up is needed to understand the late divergence in survival curves between the groups. Survival follow-up will continue for 5 years.
This study was funded by Immunicum. Dr. Lindskog disclosed relationships with Pfizer, Bristol-Myers Squibb, and Ipsen.
SOURCE: Lindskog M et al. ASCO-SITC 2020, Abstract 11.
REPORTING FROM THE CLINICAL IMMUNO-ONCOLOGY SYMPOSIUM