CHICAGO – The Food and Drug Administration’s updated safety warning about gadolinium-based contrast agents was dismissed as too little, too late during a postsession discussion at the annual meeting of the American College of Rheumatology.

Bruce Jancin/MDedge News

The class warning that “gadolinium is retained for months or years in brain, bone, and other organs,” a directive that a new patient medication guide be given to everyone before receiving a gadolinium-based contrast agent, and a request that manufacturers conduct human and animal studies to further assess the safety of these products, was highlighted at the FDA update session on safety issues in the treatment of rheumatic disease.

The request for further studies grew out of the FDA Advisory Committee on Medical Imaging’s Fall 2017 meeting, which concluded that, “based on available data, there is insufficient evidence of a causal relationship between adverse events and gadolinium retention and recommended the need for additional studies to inform regulatory action,” explained Rachel L. Glaser, MD, a medical officer in the agency’s division of pulmonary, allergy, and rheumatology products and a practicing rheumatologist.

Jonathan Kay, MD, rose from the audience to take the FDA to task for delegating matters related to gadolinium-based contrast agent safety to the radiologists comprising the Advisory Committee on Medical Imaging. “I think the FDA ought to bring this matter to a group of physicians who actually care for patients to get our input on this. Maybe the Arthritis Advisory Committee,” he said.

“It’s been known for more than 15 years that gadolinium deposits in the bone, and for more than 5 years that gadolinium deposits in the brain of patients who’ve received multiple magnetic resonance studies. I’m concerned that the FDA has this issue in the purview of the radiologists because radiologists administer these contrast agents and then don’t see the patients back in follow-up, whereas rheumatologists do,” noted Dr. Kay, professor of medicine and director of clinical research in rheumatology at the University of Massachusetts, Worcester.

He blasted the FDA’s call for further human and animal studies, noting “nephrogenic systemic fibrosis was the human experiment that was done with gadolinium contrast, showing that these agents, when they deposit in tissue, are extremely toxic. I can’t see other human studies being done to determine the potential consequences of these agents when they deposit long term in brain, bone, and other tissues. And the animal studies have already been done demonstrating the danger of these compounds. Might you take this out of the realm of radiologists and involve physicians who take care of patients chronically and observe the long-term consequences of these toxic effects?”

Dr. Glaser responded that the deliberations of the agency’s Advisory Committee on Medical Imaging are reviewed under the purview of the FDA’s Center for Drug Evaluation and Research. “That does include radiologists, but also other clinical reviewers of various backgrounds, including pharmacologists and toxicologists.”

Dr. Kay did not relent, further commenting that he has personally seen “over 150 patients with the devastating consequences of nephrogenic systemic fibrosis.” He added that a prominent radiologist has stated in a public forum that the risk of getting injured from crossing the street is greater than that from getting an MRI with gadolinium. “That’s completely wrong,” he declared.

Dr. Glaser and Dr. Kay reported having no financial conflicts.

[email protected]

CHICAGO – The Food and Drug Administration’s updated safety warning about gadolinium-based contrast agents was dismissed as too little, too late during a postsession discussion at the annual meeting of the American College of Rheumatology.

Bruce Jancin/MDedge News

The class warning that “gadolinium is retained for months or years in brain, bone, and other organs,” a directive that a new patient medication guide be given to everyone before receiving a gadolinium-based contrast agent, and a request that manufacturers conduct human and animal studies to further assess the safety of these products, was highlighted at the FDA update session on safety issues in the treatment of rheumatic disease.

The request for further studies grew out of the FDA Advisory Committee on Medical Imaging’s Fall 2017 meeting, which concluded that, “based on available data, there is insufficient evidence of a causal relationship between adverse events and gadolinium retention and recommended the need for additional studies to inform regulatory action,” explained Rachel L. Glaser, MD, a medical officer in the agency’s division of pulmonary, allergy, and rheumatology products and a practicing rheumatologist.

Jonathan Kay, MD, rose from the audience to take the FDA to task for delegating matters related to gadolinium-based contrast agent safety to the radiologists comprising the Advisory Committee on Medical Imaging. “I think the FDA ought to bring this matter to a group of physicians who actually care for patients to get our input on this. Maybe the Arthritis Advisory Committee,” he said.

“It’s been known for more than 15 years that gadolinium deposits in the bone, and for more than 5 years that gadolinium deposits in the brain of patients who’ve received multiple magnetic resonance studies. I’m concerned that the FDA has this issue in the purview of the radiologists because radiologists administer these contrast agents and then don’t see the patients back in follow-up, whereas rheumatologists do,” noted Dr. Kay, professor of medicine and director of clinical research in rheumatology at the University of Massachusetts, Worcester.

He blasted the FDA’s call for further human and animal studies, noting “nephrogenic systemic fibrosis was the human experiment that was done with gadolinium contrast, showing that these agents, when they deposit in tissue, are extremely toxic. I can’t see other human studies being done to determine the potential consequences of these agents when they deposit long term in brain, bone, and other tissues. And the animal studies have already been done demonstrating the danger of these compounds. Might you take this out of the realm of radiologists and involve physicians who take care of patients chronically and observe the long-term consequences of these toxic effects?”

Dr. Glaser responded that the deliberations of the agency’s Advisory Committee on Medical Imaging are reviewed under the purview of the FDA’s Center for Drug Evaluation and Research. “That does include radiologists, but also other clinical reviewers of various backgrounds, including pharmacologists and toxicologists.”

Dr. Kay did not relent, further commenting that he has personally seen “over 150 patients with the devastating consequences of nephrogenic systemic fibrosis.” He added that a prominent radiologist has stated in a public forum that the risk of getting injured from crossing the street is greater than that from getting an MRI with gadolinium. “That’s completely wrong,” he declared.

Dr. Glaser and Dr. Kay reported having no financial conflicts.

[email protected]

CHICAGO – The Food and Drug Administration’s updated safety warning about gadolinium-based contrast agents was dismissed as too little, too late during a postsession discussion at the annual meeting of the American College of Rheumatology.

Bruce Jancin/MDedge News

The class warning that “gadolinium is retained for months or years in brain, bone, and other organs,” a directive that a new patient medication guide be given to everyone before receiving a gadolinium-based contrast agent, and a request that manufacturers conduct human and animal studies to further assess the safety of these products, was highlighted at the FDA update session on safety issues in the treatment of rheumatic disease.

The request for further studies grew out of the FDA Advisory Committee on Medical Imaging’s Fall 2017 meeting, which concluded that, “based on available data, there is insufficient evidence of a causal relationship between adverse events and gadolinium retention and recommended the need for additional studies to inform regulatory action,” explained Rachel L. Glaser, MD, a medical officer in the agency’s division of pulmonary, allergy, and rheumatology products and a practicing rheumatologist.

Jonathan Kay, MD, rose from the audience to take the FDA to task for delegating matters related to gadolinium-based contrast agent safety to the radiologists comprising the Advisory Committee on Medical Imaging. “I think the FDA ought to bring this matter to a group of physicians who actually care for patients to get our input on this. Maybe the Arthritis Advisory Committee,” he said.

“It’s been known for more than 15 years that gadolinium deposits in the bone, and for more than 5 years that gadolinium deposits in the brain of patients who’ve received multiple magnetic resonance studies. I’m concerned that the FDA has this issue in the purview of the radiologists because radiologists administer these contrast agents and then don’t see the patients back in follow-up, whereas rheumatologists do,” noted Dr. Kay, professor of medicine and director of clinical research in rheumatology at the University of Massachusetts, Worcester.

He blasted the FDA’s call for further human and animal studies, noting “nephrogenic systemic fibrosis was the human experiment that was done with gadolinium contrast, showing that these agents, when they deposit in tissue, are extremely toxic. I can’t see other human studies being done to determine the potential consequences of these agents when they deposit long term in brain, bone, and other tissues. And the animal studies have already been done demonstrating the danger of these compounds. Might you take this out of the realm of radiologists and involve physicians who take care of patients chronically and observe the long-term consequences of these toxic effects?”

Dr. Glaser responded that the deliberations of the agency’s Advisory Committee on Medical Imaging are reviewed under the purview of the FDA’s Center for Drug Evaluation and Research. “That does include radiologists, but also other clinical reviewers of various backgrounds, including pharmacologists and toxicologists.”

Dr. Kay did not relent, further commenting that he has personally seen “over 150 patients with the devastating consequences of nephrogenic systemic fibrosis.” He added that a prominent radiologist has stated in a public forum that the risk of getting injured from crossing the street is greater than that from getting an MRI with gadolinium. “That’s completely wrong,” he declared.

Dr. Glaser and Dr. Kay reported having no financial conflicts.

[email protected]

Interstitial lung disease (ILD) is becoming more prevalent in patients with RA while shortening survival and leading to substantial health care costs, according to a retrospective study of RA-ILD prevalence, incidence, costs, and mortality.

“To our knowledge, this is the first study to describe the incidence and prevalence of RA-ILD among the general population and to estimate costs among U.S. patients with RA-ILD,” wrote lead author Karina Raimundo, principal health economist at Genentech, and her coauthors in the Journal of Rheumatology.

The study reviewed data from the Truven Health MarketScan Commercial and Medicare Supplemental health insurance databases, along with linking a subset of patients to the Social Security Administration Death Index to determine mortality. From 2004 to 2013, with the number of patients ranging from 892 to 3,232 per year, yearly prevalence estimates ranged from 3.2 (95% confidence interval, 3.0-3.4) to 6.0 (95% CI, 5.7-6.2) RA-ILD cases per 100,000 people. Yearly incidence ranged from 2.7 (95% CI, 2.5-2.9) to 3.8 (95% CI, 3.5-4.0) cases per 100,000 people.

While incidence was relatively stable, prevalence increased over the 10-year period. The authors noted that increased prevalence suggests improved survival of RA-ILD patients but were unable to definitively state why, with explanations ranging from more effective therapies to earlier diagnosis of the disease. “Our data do not allow more in-depth evaluation of this issue, and it merits further analysis.”

In addition, they found that average yearly costs across all study years ranged from $40,941 (standard deviation, $55,682) to $51,849 (SD, $77,125), with the main cost drivers being inpatient admissions, outpatient services, and outpatient pharmacy. By the 5-year mark of first diagnosis, 35.9% of RA-ILD patients who could be linked to the SSDI had died; those patients – with a mean age of 65 years – also had a median survival of 7.8 years (95% CI, 7.1-8.3). Generally, a 65-year-old person in the United States would be expected to live for 19 more years.

The authors acknowledged the study’s limitations, including reliance on administrative claims data, subsequent misclassification of RA-ILD status, a lack of information on cause of death, and an underestimation of mortality caused by the inability to link all patients to the Social Security Administration Death Index.

The study was funded by Genentech and F. Hoffmann–La Roche. No other conflicts of interest were reported.

SOURCE: Raimundo K et al. J Rheumatol. 2018 Nov 15. doi: 10.3899/jrheum.171315.

Interstitial lung disease (ILD) is becoming more prevalent in patients with RA while shortening survival and leading to substantial health care costs, according to a retrospective study of RA-ILD prevalence, incidence, costs, and mortality.

“To our knowledge, this is the first study to describe the incidence and prevalence of RA-ILD among the general population and to estimate costs among U.S. patients with RA-ILD,” wrote lead author Karina Raimundo, principal health economist at Genentech, and her coauthors in the Journal of Rheumatology.

The study reviewed data from the Truven Health MarketScan Commercial and Medicare Supplemental health insurance databases, along with linking a subset of patients to the Social Security Administration Death Index to determine mortality. From 2004 to 2013, with the number of patients ranging from 892 to 3,232 per year, yearly prevalence estimates ranged from 3.2 (95% confidence interval, 3.0-3.4) to 6.0 (95% CI, 5.7-6.2) RA-ILD cases per 100,000 people. Yearly incidence ranged from 2.7 (95% CI, 2.5-2.9) to 3.8 (95% CI, 3.5-4.0) cases per 100,000 people.

While incidence was relatively stable, prevalence increased over the 10-year period. The authors noted that increased prevalence suggests improved survival of RA-ILD patients but were unable to definitively state why, with explanations ranging from more effective therapies to earlier diagnosis of the disease. “Our data do not allow more in-depth evaluation of this issue, and it merits further analysis.”

In addition, they found that average yearly costs across all study years ranged from $40,941 (standard deviation, $55,682) to $51,849 (SD, $77,125), with the main cost drivers being inpatient admissions, outpatient services, and outpatient pharmacy. By the 5-year mark of first diagnosis, 35.9% of RA-ILD patients who could be linked to the SSDI had died; those patients – with a mean age of 65 years – also had a median survival of 7.8 years (95% CI, 7.1-8.3). Generally, a 65-year-old person in the United States would be expected to live for 19 more years.

The authors acknowledged the study’s limitations, including reliance on administrative claims data, subsequent misclassification of RA-ILD status, a lack of information on cause of death, and an underestimation of mortality caused by the inability to link all patients to the Social Security Administration Death Index.

The study was funded by Genentech and F. Hoffmann–La Roche. No other conflicts of interest were reported.

SOURCE: Raimundo K et al. J Rheumatol. 2018 Nov 15. doi: 10.3899/jrheum.171315.

Interstitial lung disease (ILD) is becoming more prevalent in patients with RA while shortening survival and leading to substantial health care costs, according to a retrospective study of RA-ILD prevalence, incidence, costs, and mortality.

“To our knowledge, this is the first study to describe the incidence and prevalence of RA-ILD among the general population and to estimate costs among U.S. patients with RA-ILD,” wrote lead author Karina Raimundo, principal health economist at Genentech, and her coauthors in the Journal of Rheumatology.

The study reviewed data from the Truven Health MarketScan Commercial and Medicare Supplemental health insurance databases, along with linking a subset of patients to the Social Security Administration Death Index to determine mortality. From 2004 to 2013, with the number of patients ranging from 892 to 3,232 per year, yearly prevalence estimates ranged from 3.2 (95% confidence interval, 3.0-3.4) to 6.0 (95% CI, 5.7-6.2) RA-ILD cases per 100,000 people. Yearly incidence ranged from 2.7 (95% CI, 2.5-2.9) to 3.8 (95% CI, 3.5-4.0) cases per 100,000 people.

While incidence was relatively stable, prevalence increased over the 10-year period. The authors noted that increased prevalence suggests improved survival of RA-ILD patients but were unable to definitively state why, with explanations ranging from more effective therapies to earlier diagnosis of the disease. “Our data do not allow more in-depth evaluation of this issue, and it merits further analysis.”

In addition, they found that average yearly costs across all study years ranged from $40,941 (standard deviation, $55,682) to $51,849 (SD, $77,125), with the main cost drivers being inpatient admissions, outpatient services, and outpatient pharmacy. By the 5-year mark of first diagnosis, 35.9% of RA-ILD patients who could be linked to the SSDI had died; those patients – with a mean age of 65 years – also had a median survival of 7.8 years (95% CI, 7.1-8.3). Generally, a 65-year-old person in the United States would be expected to live for 19 more years.

The authors acknowledged the study’s limitations, including reliance on administrative claims data, subsequent misclassification of RA-ILD status, a lack of information on cause of death, and an underestimation of mortality caused by the inability to link all patients to the Social Security Administration Death Index.

The study was funded by Genentech and F. Hoffmann–La Roche. No other conflicts of interest were reported.

SOURCE: Raimundo K et al. J Rheumatol. 2018 Nov 15. doi: 10.3899/jrheum.171315.

Health care is more effective when patients understand what they can do to be healthier. But many patients cannot read routine preventive information. To help busy clinicians learn more about what they can do to support patient wellness, the Indian Health Service (IHs) Health Literacy workgroup has developed a 20-minute health literacy and plain-language training module.

The IHS also is:

• Pretesting printed educational materials through focus groups and in-depth interviews to ensure messages are clear;
• Revising the IHS website;
• Hosting webinars on health literacy; and
•  Planning to refresh and promote “As Me 3” campaign, which encourages patients to ask 3 specific questions of their providers to better understand their conditions.

In addition to taking the training module, available at the Learning Management System, the IHS suggests clinicians participate in ongoing training in health literacy, plain language and culturally and linguistically appropriate services; use the “health factor” tab in the electronic health record to assess and document the patient’s level of understanding; and learn about the teach-back technique to enhance patients’ understanding.

Health care is more effective when patients understand what they can do to be healthier. But many patients cannot read routine preventive information. To help busy clinicians learn more about what they can do to support patient wellness, the Indian Health Service (IHs) Health Literacy workgroup has developed a 20-minute health literacy and plain-language training module.

The IHS also is:

• Pretesting printed educational materials through focus groups and in-depth interviews to ensure messages are clear;
• Revising the IHS website;
• Hosting webinars on health literacy; and
•  Planning to refresh and promote “As Me 3” campaign, which encourages patients to ask 3 specific questions of their providers to better understand their conditions.

In addition to taking the training module, available at the Learning Management System, the IHS suggests clinicians participate in ongoing training in health literacy, plain language and culturally and linguistically appropriate services; use the “health factor” tab in the electronic health record to assess and document the patient’s level of understanding; and learn about the teach-back technique to enhance patients’ understanding.

Health care is more effective when patients understand what they can do to be healthier. But many patients cannot read routine preventive information. To help busy clinicians learn more about what they can do to support patient wellness, the Indian Health Service (IHs) Health Literacy workgroup has developed a 20-minute health literacy and plain-language training module.

The IHS also is:

• Pretesting printed educational materials through focus groups and in-depth interviews to ensure messages are clear;
• Revising the IHS website;
• Hosting webinars on health literacy; and
•  Planning to refresh and promote “As Me 3” campaign, which encourages patients to ask 3 specific questions of their providers to better understand their conditions.

In addition to taking the training module, available at the Learning Management System, the IHS suggests clinicians participate in ongoing training in health literacy, plain language and culturally and linguistically appropriate services; use the “health factor” tab in the electronic health record to assess and document the patient’s level of understanding; and learn about the teach-back technique to enhance patients’ understanding.

Smoke-free policies are linked to lower blood pressure. Also today, bariatric surgery increases the risk for suicide and self-harm, a novel topical JAK inhibitor shows promise for atopic dermatitis, and livers infected with hepatitis C are safe for transplant.

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Smoke-free policies are linked to lower blood pressure. Also today, bariatric surgery increases the risk for suicide and self-harm, a novel topical JAK inhibitor shows promise for atopic dermatitis, and livers infected with hepatitis C are safe for transplant.

Amazon Alexa
Apple Podcasts
Google Podcasts
Spotify

Smoke-free policies are linked to lower blood pressure. Also today, bariatric surgery increases the risk for suicide and self-harm, a novel topical JAK inhibitor shows promise for atopic dermatitis, and livers infected with hepatitis C are safe for transplant.

Amazon Alexa
Apple Podcasts
Google Podcasts
Spotify

Photo by Chad McNeeley

New research suggests older individuals with clonal hematopoiesis of indeterminate potential (CHIP) are a safe donor source for allogeneic hematopoietic stem cell transplant (HSCT).

Researchers found that transplants from older donors with CHIP resulted in similar survival as transplants from older donors without CHIP.

HSCT recipients with CHIP donors had a lower risk of relapse or progression but a higher risk of chronic graft-versus-host disease (GHVD), and they were more likely to develop donor-cell malignancies.

Frederik Damm, MD, of Charité – University Medical Center Berlin in Germany, and his colleagues reported these findings in the Journal of Clinical Oncology.

Little is known about the influence of donor CHIP in allogeneic HSCT, according to the researchers.

However, an increasing number of older patients are receiving donations from older, mostly sibling, donors who may have CHIP. CHIP increases with age and is associated with a greater risk of hematologic cancers, cardiovascular disease, and death from coronary heart disease.

With this in mind, Dr. Damm and his colleagues set out to determine how donor CHIP affects the outcome of HSCT.

Between 1993 and 2017, the researchers collected blood samples from 500 healthy, related HSCT donors, age 55 or older, at 10 transplant centers in Germany and France. The researchers sequenced the samples with a 66-gene panel.

The team also assessed overall survival (OS), non-relapse mortality (NRM), cumulative incidence of relapse/progression (CIR/P), cytomegalovirus (CMV) reactivation, and acute and chronic GVHD in the HSCT recipients.

Mutation analysis

The researchers identified 92 clonal mutations in 80 (16.0%) of the 500 donors. The variant allele frequency was 5.9% (range, 2% to 43%). In 20 patients, 25 variant alleles were present at a frequency of 10% or greater.

The researchers detected a single gene mutation in 70 donors, nine donors had two mutations, and one donor had four mutations. The most frequently mutated genes were DNMT3A (40/500, 8%), TET2 (11/500, 2.2%), and ASXL1 (7/500, 1.4%).

Baseline characteristics such as age, sex, or stem cells harvested per kilogram of body weight were similar between donors with and without CHIP.

Recipient characteristics were also evenly distributed regarding donor CHIP status and baseline characteristics.

However, the researchers noted that donor CHIP was present significantly more often in donors for recipients with myeloid compared to lymphoid neoplasms—19.2% and 6.3%, respectively (P≤0.001).

The prevalence of donor CHIP increased with age, from 10.3% (ages 60 to 64) to 20.3% (ages 65 to 69), 22.5% (ages 70 to 74), and 28.6% (ages 75 to 79).

The researchers observed no statistically significant association between CHIP and age, most likely, they wrote, “because 82% of all donors in our cohort were age 60 to 69 years.”

Transplant outcome

Donor CHIP led to slightly faster leukocyte engraftment, although it did not impact thrombocyte engraftment time.

The cumulative incidence of leukocyte engraftment after 15 days was 64.1% for HSCT recipients with CHIP donors and 51.4% for those with non-CHIP donors (P=0.023).

Chronic GVHD after HSCT was more likely for recipients with CHIP donors, with a 5-year cumulative incidence of 52.9%, compared to 35.7% for patients with non-CHIP donors (P=0.008).

Multivariate analysis showed donor CHIP to be an independent risk factor for chronic GVHD when adjusted for antithymocyte globulin application and donor age.

The researchers identified donor DNMT3A mutation as the predominant CHIP factor for developing chronic GVHD. The incidence of chronic GVHD was 58.5% in patients with DNMT3A-mutated donors and 36.6% in patients with wild-type donors (P=0.006).

The researchers noted that no other CHIP mutations or characteristics affected the development of chronic GVHD.

Donor CHIP status did not impact the incidence of acute GVHD or CMV reactivation.

Transplant recipients with CHIP donors had a lower CIR/P (P=0.027) than recipients with non-CHIP donors. Patients whose donors had CHIP with a DNMT3A mutation also had a lower CIR/P (P=0.029).

Donor CHIP had no effect on NRM.

Neither donor CHIP nor donor DNMT3A mutational status impacted CIR/P or NRM in patients who underwent HSCT while they were in complete response (CR).

However, patients not in CR at the time of HSCT had a lower CIR/P when the donor was CHIP-positive (hazard ratio [HR]=0.49; 95% confidence interval [CI], 0.27 to 0.88; P=0.019) or had a DNMT3A mutation (HR=0.34; 95% CI, 0.15 to 0.81; P=0.015).

Two of 82 patients with CHIP donors developed donor-cell malignancies, but there were no donor-cell malignancies in recipients with non-CHIP donors (P=0.026).

Survival

“To our knowledge, we showed, for the first time, that donor CHIP did not affect the survival of 500 HSCT recipients,” the researchers wrote.

At a median follow-up of 3.3 years, the median OS was 2 years, and the 5-year OS was 37.6%.

The researchers observed no survival differences in patients with CHIP donors or non-CHIP donors (HR=0.88; 95% CI, 0.65 to 1.321; P=0.434). And the same was true for DNMT3A mutation (HR=0.89; 95% CI, 0.58 to 1.35; P=0.573).

The researchers pointed out that patients with myelodysplastic syndromes or acute myeloid leukemia who were not in CR when they underwent HSCT had a survival benefit with donor CHIP (HR=0.49; 95% CI, 0.28 to 0.86; P=0.011).

“This finding could implicate an important clinical potential in this difficult-to-treat subgroup,” the researchers noted.

However, this was not the case for patients with myeloproliferative neoplasia, for whom donor CHIP tended to reduce survival (P=0.077).

The research team recommended future studies be conducted in younger and unrelated donors to confirm the results of this study.

The research was funded by numerous grants and fellowships, and the researchers reported no relevant conflicts of interest.

Photo by Chad McNeeley

New research suggests older individuals with clonal hematopoiesis of indeterminate potential (CHIP) are a safe donor source for allogeneic hematopoietic stem cell transplant (HSCT).

Researchers found that transplants from older donors with CHIP resulted in similar survival as transplants from older donors without CHIP.

HSCT recipients with CHIP donors had a lower risk of relapse or progression but a higher risk of chronic graft-versus-host disease (GHVD), and they were more likely to develop donor-cell malignancies.

Frederik Damm, MD, of Charité – University Medical Center Berlin in Germany, and his colleagues reported these findings in the Journal of Clinical Oncology.

Little is known about the influence of donor CHIP in allogeneic HSCT, according to the researchers.

However, an increasing number of older patients are receiving donations from older, mostly sibling, donors who may have CHIP. CHIP increases with age and is associated with a greater risk of hematologic cancers, cardiovascular disease, and death from coronary heart disease.

With this in mind, Dr. Damm and his colleagues set out to determine how donor CHIP affects the outcome of HSCT.

Between 1993 and 2017, the researchers collected blood samples from 500 healthy, related HSCT donors, age 55 or older, at 10 transplant centers in Germany and France. The researchers sequenced the samples with a 66-gene panel.

The team also assessed overall survival (OS), non-relapse mortality (NRM), cumulative incidence of relapse/progression (CIR/P), cytomegalovirus (CMV) reactivation, and acute and chronic GVHD in the HSCT recipients.

Mutation analysis

The researchers identified 92 clonal mutations in 80 (16.0%) of the 500 donors. The variant allele frequency was 5.9% (range, 2% to 43%). In 20 patients, 25 variant alleles were present at a frequency of 10% or greater.

The researchers detected a single gene mutation in 70 donors, nine donors had two mutations, and one donor had four mutations. The most frequently mutated genes were DNMT3A (40/500, 8%), TET2 (11/500, 2.2%), and ASXL1 (7/500, 1.4%).

Baseline characteristics such as age, sex, or stem cells harvested per kilogram of body weight were similar between donors with and without CHIP.

Recipient characteristics were also evenly distributed regarding donor CHIP status and baseline characteristics.

However, the researchers noted that donor CHIP was present significantly more often in donors for recipients with myeloid compared to lymphoid neoplasms—19.2% and 6.3%, respectively (P≤0.001).

The prevalence of donor CHIP increased with age, from 10.3% (ages 60 to 64) to 20.3% (ages 65 to 69), 22.5% (ages 70 to 74), and 28.6% (ages 75 to 79).

The researchers observed no statistically significant association between CHIP and age, most likely, they wrote, “because 82% of all donors in our cohort were age 60 to 69 years.”

Transplant outcome

Donor CHIP led to slightly faster leukocyte engraftment, although it did not impact thrombocyte engraftment time.

The cumulative incidence of leukocyte engraftment after 15 days was 64.1% for HSCT recipients with CHIP donors and 51.4% for those with non-CHIP donors (P=0.023).

Chronic GVHD after HSCT was more likely for recipients with CHIP donors, with a 5-year cumulative incidence of 52.9%, compared to 35.7% for patients with non-CHIP donors (P=0.008).

Multivariate analysis showed donor CHIP to be an independent risk factor for chronic GVHD when adjusted for antithymocyte globulin application and donor age.

The researchers identified donor DNMT3A mutation as the predominant CHIP factor for developing chronic GVHD. The incidence of chronic GVHD was 58.5% in patients with DNMT3A-mutated donors and 36.6% in patients with wild-type donors (P=0.006).

The researchers noted that no other CHIP mutations or characteristics affected the development of chronic GVHD.

Donor CHIP status did not impact the incidence of acute GVHD or CMV reactivation.

Transplant recipients with CHIP donors had a lower CIR/P (P=0.027) than recipients with non-CHIP donors. Patients whose donors had CHIP with a DNMT3A mutation also had a lower CIR/P (P=0.029).

Donor CHIP had no effect on NRM.

Neither donor CHIP nor donor DNMT3A mutational status impacted CIR/P or NRM in patients who underwent HSCT while they were in complete response (CR).

However, patients not in CR at the time of HSCT had a lower CIR/P when the donor was CHIP-positive (hazard ratio [HR]=0.49; 95% confidence interval [CI], 0.27 to 0.88; P=0.019) or had a DNMT3A mutation (HR=0.34; 95% CI, 0.15 to 0.81; P=0.015).

Two of 82 patients with CHIP donors developed donor-cell malignancies, but there were no donor-cell malignancies in recipients with non-CHIP donors (P=0.026).

Survival

“To our knowledge, we showed, for the first time, that donor CHIP did not affect the survival of 500 HSCT recipients,” the researchers wrote.

At a median follow-up of 3.3 years, the median OS was 2 years, and the 5-year OS was 37.6%.

The researchers observed no survival differences in patients with CHIP donors or non-CHIP donors (HR=0.88; 95% CI, 0.65 to 1.321; P=0.434). And the same was true for DNMT3A mutation (HR=0.89; 95% CI, 0.58 to 1.35; P=0.573).

The researchers pointed out that patients with myelodysplastic syndromes or acute myeloid leukemia who were not in CR when they underwent HSCT had a survival benefit with donor CHIP (HR=0.49; 95% CI, 0.28 to 0.86; P=0.011).

“This finding could implicate an important clinical potential in this difficult-to-treat subgroup,” the researchers noted.

However, this was not the case for patients with myeloproliferative neoplasia, for whom donor CHIP tended to reduce survival (P=0.077).

The research team recommended future studies be conducted in younger and unrelated donors to confirm the results of this study.

The research was funded by numerous grants and fellowships, and the researchers reported no relevant conflicts of interest.

Photo by Chad McNeeley

New research suggests older individuals with clonal hematopoiesis of indeterminate potential (CHIP) are a safe donor source for allogeneic hematopoietic stem cell transplant (HSCT).

Researchers found that transplants from older donors with CHIP resulted in similar survival as transplants from older donors without CHIP.

HSCT recipients with CHIP donors had a lower risk of relapse or progression but a higher risk of chronic graft-versus-host disease (GHVD), and they were more likely to develop donor-cell malignancies.

Frederik Damm, MD, of Charité – University Medical Center Berlin in Germany, and his colleagues reported these findings in the Journal of Clinical Oncology.

Little is known about the influence of donor CHIP in allogeneic HSCT, according to the researchers.

However, an increasing number of older patients are receiving donations from older, mostly sibling, donors who may have CHIP. CHIP increases with age and is associated with a greater risk of hematologic cancers, cardiovascular disease, and death from coronary heart disease.

With this in mind, Dr. Damm and his colleagues set out to determine how donor CHIP affects the outcome of HSCT.

Between 1993 and 2017, the researchers collected blood samples from 500 healthy, related HSCT donors, age 55 or older, at 10 transplant centers in Germany and France. The researchers sequenced the samples with a 66-gene panel.

The team also assessed overall survival (OS), non-relapse mortality (NRM), cumulative incidence of relapse/progression (CIR/P), cytomegalovirus (CMV) reactivation, and acute and chronic GVHD in the HSCT recipients.

Mutation analysis

The researchers identified 92 clonal mutations in 80 (16.0%) of the 500 donors. The variant allele frequency was 5.9% (range, 2% to 43%). In 20 patients, 25 variant alleles were present at a frequency of 10% or greater.

The researchers detected a single gene mutation in 70 donors, nine donors had two mutations, and one donor had four mutations. The most frequently mutated genes were DNMT3A (40/500, 8%), TET2 (11/500, 2.2%), and ASXL1 (7/500, 1.4%).

Baseline characteristics such as age, sex, or stem cells harvested per kilogram of body weight were similar between donors with and without CHIP.

Recipient characteristics were also evenly distributed regarding donor CHIP status and baseline characteristics.

However, the researchers noted that donor CHIP was present significantly more often in donors for recipients with myeloid compared to lymphoid neoplasms—19.2% and 6.3%, respectively (P≤0.001).

The prevalence of donor CHIP increased with age, from 10.3% (ages 60 to 64) to 20.3% (ages 65 to 69), 22.5% (ages 70 to 74), and 28.6% (ages 75 to 79).

The researchers observed no statistically significant association between CHIP and age, most likely, they wrote, “because 82% of all donors in our cohort were age 60 to 69 years.”

Transplant outcome

Donor CHIP led to slightly faster leukocyte engraftment, although it did not impact thrombocyte engraftment time.

The cumulative incidence of leukocyte engraftment after 15 days was 64.1% for HSCT recipients with CHIP donors and 51.4% for those with non-CHIP donors (P=0.023).

Chronic GVHD after HSCT was more likely for recipients with CHIP donors, with a 5-year cumulative incidence of 52.9%, compared to 35.7% for patients with non-CHIP donors (P=0.008).

Multivariate analysis showed donor CHIP to be an independent risk factor for chronic GVHD when adjusted for antithymocyte globulin application and donor age.

The researchers identified donor DNMT3A mutation as the predominant CHIP factor for developing chronic GVHD. The incidence of chronic GVHD was 58.5% in patients with DNMT3A-mutated donors and 36.6% in patients with wild-type donors (P=0.006).

The researchers noted that no other CHIP mutations or characteristics affected the development of chronic GVHD.

Donor CHIP status did not impact the incidence of acute GVHD or CMV reactivation.

Transplant recipients with CHIP donors had a lower CIR/P (P=0.027) than recipients with non-CHIP donors. Patients whose donors had CHIP with a DNMT3A mutation also had a lower CIR/P (P=0.029).

Donor CHIP had no effect on NRM.

Neither donor CHIP nor donor DNMT3A mutational status impacted CIR/P or NRM in patients who underwent HSCT while they were in complete response (CR).

However, patients not in CR at the time of HSCT had a lower CIR/P when the donor was CHIP-positive (hazard ratio [HR]=0.49; 95% confidence interval [CI], 0.27 to 0.88; P=0.019) or had a DNMT3A mutation (HR=0.34; 95% CI, 0.15 to 0.81; P=0.015).

Two of 82 patients with CHIP donors developed donor-cell malignancies, but there were no donor-cell malignancies in recipients with non-CHIP donors (P=0.026).

Survival

“To our knowledge, we showed, for the first time, that donor CHIP did not affect the survival of 500 HSCT recipients,” the researchers wrote.

At a median follow-up of 3.3 years, the median OS was 2 years, and the 5-year OS was 37.6%.

The researchers observed no survival differences in patients with CHIP donors or non-CHIP donors (HR=0.88; 95% CI, 0.65 to 1.321; P=0.434). And the same was true for DNMT3A mutation (HR=0.89; 95% CI, 0.58 to 1.35; P=0.573).

The researchers pointed out that patients with myelodysplastic syndromes or acute myeloid leukemia who were not in CR when they underwent HSCT had a survival benefit with donor CHIP (HR=0.49; 95% CI, 0.28 to 0.86; P=0.011).

“This finding could implicate an important clinical potential in this difficult-to-treat subgroup,” the researchers noted.

However, this was not the case for patients with myeloproliferative neoplasia, for whom donor CHIP tended to reduce survival (P=0.077).

The research team recommended future studies be conducted in younger and unrelated donors to confirm the results of this study.

The research was funded by numerous grants and fellowships, and the researchers reported no relevant conflicts of interest.

Photo by Rhoda Baer

The European Commission (EC) has approved Mundipharma’s pegfilgrastim product Pelmeg, a biosimilar of Amgen’s Neulasta.

Pelmeg is approved for use in reducing the duration of neutropenia and the incidence of febrile neutropenia in adults who receive cytotoxic chemotherapy for malignancies, with the exceptions of chronic myeloid leukemia and myelodysplastic syndromes.

The approval is valid in all countries of the European Union as well as Norway, Iceland, and Liechtenstein.

The EC’s approval of Pelmeg was supported by research showing pharmacokinetic comparability between Pelmeg and Neulasta at a dose of 6 mg, pharmacodynamic comparability at doses of 6 mg and 3 mg, and no clinically meaningful differences in the safety and immunogenicity profiles of Pelmeg and Neulasta.^1,2,3

1. Roth K. et al. Demonstration of pharmacokinetic and pharmacodynamic comparability in healthy volunteers for B12019, a proposed pegfilgrastim biosimilar. ECCO 2017, abstract 241.

2. Roth K. et al. Comparability of pharmacodynamics and immunogenicity of B12019, a proposed pegfilgrastim biosimilar to Neulasta®. ASH 2017, abstract 1002.

3. Roth K. et al. Pharmacokinetic and pharmacodynamic comparability of B12019, a proposed pegfilgrastim biosimilar. ESMO 2017, poster 1573.

Photo by Rhoda Baer

The European Commission (EC) has approved Mundipharma’s pegfilgrastim product Pelmeg, a biosimilar of Amgen’s Neulasta.

Pelmeg is approved for use in reducing the duration of neutropenia and the incidence of febrile neutropenia in adults who receive cytotoxic chemotherapy for malignancies, with the exceptions of chronic myeloid leukemia and myelodysplastic syndromes.

The approval is valid in all countries of the European Union as well as Norway, Iceland, and Liechtenstein.

The EC’s approval of Pelmeg was supported by research showing pharmacokinetic comparability between Pelmeg and Neulasta at a dose of 6 mg, pharmacodynamic comparability at doses of 6 mg and 3 mg, and no clinically meaningful differences in the safety and immunogenicity profiles of Pelmeg and Neulasta.^1,2,3

1. Roth K. et al. Demonstration of pharmacokinetic and pharmacodynamic comparability in healthy volunteers for B12019, a proposed pegfilgrastim biosimilar. ECCO 2017, abstract 241.

2. Roth K. et al. Comparability of pharmacodynamics and immunogenicity of B12019, a proposed pegfilgrastim biosimilar to Neulasta®. ASH 2017, abstract 1002.

3. Roth K. et al. Pharmacokinetic and pharmacodynamic comparability of B12019, a proposed pegfilgrastim biosimilar. ESMO 2017, poster 1573.

Photo by Rhoda Baer

The European Commission (EC) has approved Mundipharma’s pegfilgrastim product Pelmeg, a biosimilar of Amgen’s Neulasta.

Pelmeg is approved for use in reducing the duration of neutropenia and the incidence of febrile neutropenia in adults who receive cytotoxic chemotherapy for malignancies, with the exceptions of chronic myeloid leukemia and myelodysplastic syndromes.

The approval is valid in all countries of the European Union as well as Norway, Iceland, and Liechtenstein.

The EC’s approval of Pelmeg was supported by research showing pharmacokinetic comparability between Pelmeg and Neulasta at a dose of 6 mg, pharmacodynamic comparability at doses of 6 mg and 3 mg, and no clinically meaningful differences in the safety and immunogenicity profiles of Pelmeg and Neulasta.^1,2,3

1. Roth K. et al. Demonstration of pharmacokinetic and pharmacodynamic comparability in healthy volunteers for B12019, a proposed pegfilgrastim biosimilar. ECCO 2017, abstract 241.

2. Roth K. et al. Comparability of pharmacodynamics and immunogenicity of B12019, a proposed pegfilgrastim biosimilar to Neulasta®. ASH 2017, abstract 1002.

3. Roth K. et al. Pharmacokinetic and pharmacodynamic comparability of B12019, a proposed pegfilgrastim biosimilar. ESMO 2017, poster 1573.

Henrique Orlandi Mourao

The U.S. Food and Drug Administration (FDA) has accepted for priority review a new drug application (NDA) for the FLT3 inhibitor quizartinib.

With this NDA, Daiichi Sankyo is seeking approval for quizartinib to treat adults with relapsed/refractory FLT3-ITD acute myeloid leukemia (AML).

The FDA grants priority review to applications for products that are expected to provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.

The FDA aims to take action on a priority review application within 6 months rather than the standard 10 months.

The FDA is expected to make a decision on the quizartinib NDA by May 25, 2019.

In addition to priority review, quizartinib has breakthrough therapy designation and fast track designation from the FDA.

Trial results

The NDA for quizartinib is supported by results from the phase 3 QuANTUM-R study. Topline results from this study were presented at the 23rd Congress of the European Hematology Association in June, and new analyses are set to be presented at the 2018 ASH Annual Meeting in December (abstract 563).

QuANTUM-R enrolled adults with FLT3-ITD AML (at least 3% FLT3-ITD allelic ratio) who had refractory disease or had relapsed within 6 months of their first complete response (CR).

Patients were randomized to receive once-daily treatment with quizartinib (n=245) or a salvage chemotherapy regimen (n=122)—low-dose cytarabine (LoDAC, n=29); combination mitoxantrone, etoposide, and cytarabine (MEC, n=40); or combination fludarabine, cytarabine, and idarubicin (FLAG-IDA, n=53).

Patients who responded to treatment could proceed to hematopoietic stem cell transplant (HSCT), and those in the quizartinib arm could resume quizartinib after HSCT.

In all, 241 patients received quizartinib, and 94 received salvage chemotherapy—LoDAC (n=22), MEC (n=25), and FLAG-IDA (n=47). Of the 28 patients in the chemotherapy group who were not treated, most withdrew consent.

Thirty-two percent of quizartinib-treated patients and 12% of the chemotherapy group went on to HSCT.

Efficacy

The median follow-up was 23.5 months. The efficacy results include all randomized patients.

The overall response rate was 69% in the quizartinib arm and 30% in the chemotherapy arm. The composite CR rate was 48% in the quizartinib arm and 27% in the chemotherapy arm. This includes:

• The CR rate (4% and 1%, respectively)
• The rate of CR with incomplete platelet recovery (4% and 0%, respectively)
• The rate of CR with incomplete hematologic recovery (40% and 26%, respectively).

The median event-free survival was 6.0 weeks in the quizartinib arm and 3.7 weeks in the chemotherapy arm (hazard ratio=0.90, P=0.1071).

The median overall survival was 6.2 months in the quizartinib arm and 4.7 months in the chemotherapy arm (hazard ratio=0.76, P=0.0177). The 1-year overall survival rate was 27% and 20%, respectively.

Safety

The safety results include only patients who received their assigned treatment.

Grade 3 or higher hematologic treatment-emergent adverse events occurring in at least 5% of patients (in the quizartinib and chemotherapy groups, respectively) included:

• Thrombocytopenia (35% and 34%)
• Anemia (30% and 29%)
• Neutropenia (32% and 25%)
• Febrile neutropenia (31% and 21%)
• Leukopenia (17% and 16%).

Grade 3 or higher non-hematologic treatment-emergent adverse events occurring in at least 5% of patients (in the quizartinib and chemotherapy groups, respectively) included:

• Sepsis/septic shock (16% and 18%)
• Hypokalemia (12% and 9%)
• Pneumonia (12% and 9%)
• Fatigue (8% and 1%)
• Dyspnea (5% for both)
• Hypophosphatemia (5% for both).

Henrique Orlandi Mourao

The U.S. Food and Drug Administration (FDA) has accepted for priority review a new drug application (NDA) for the FLT3 inhibitor quizartinib.

With this NDA, Daiichi Sankyo is seeking approval for quizartinib to treat adults with relapsed/refractory FLT3-ITD acute myeloid leukemia (AML).

The FDA grants priority review to applications for products that are expected to provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.

The FDA aims to take action on a priority review application within 6 months rather than the standard 10 months.

The FDA is expected to make a decision on the quizartinib NDA by May 25, 2019.

In addition to priority review, quizartinib has breakthrough therapy designation and fast track designation from the FDA.

Trial results

The NDA for quizartinib is supported by results from the phase 3 QuANTUM-R study. Topline results from this study were presented at the 23rd Congress of the European Hematology Association in June, and new analyses are set to be presented at the 2018 ASH Annual Meeting in December (abstract 563).

QuANTUM-R enrolled adults with FLT3-ITD AML (at least 3% FLT3-ITD allelic ratio) who had refractory disease or had relapsed within 6 months of their first complete response (CR).

Patients were randomized to receive once-daily treatment with quizartinib (n=245) or a salvage chemotherapy regimen (n=122)—low-dose cytarabine (LoDAC, n=29); combination mitoxantrone, etoposide, and cytarabine (MEC, n=40); or combination fludarabine, cytarabine, and idarubicin (FLAG-IDA, n=53).

Patients who responded to treatment could proceed to hematopoietic stem cell transplant (HSCT), and those in the quizartinib arm could resume quizartinib after HSCT.

In all, 241 patients received quizartinib, and 94 received salvage chemotherapy—LoDAC (n=22), MEC (n=25), and FLAG-IDA (n=47). Of the 28 patients in the chemotherapy group who were not treated, most withdrew consent.

Thirty-two percent of quizartinib-treated patients and 12% of the chemotherapy group went on to HSCT.

Efficacy

The median follow-up was 23.5 months. The efficacy results include all randomized patients.

The overall response rate was 69% in the quizartinib arm and 30% in the chemotherapy arm. The composite CR rate was 48% in the quizartinib arm and 27% in the chemotherapy arm. This includes:

• The CR rate (4% and 1%, respectively)
• The rate of CR with incomplete platelet recovery (4% and 0%, respectively)
• The rate of CR with incomplete hematologic recovery (40% and 26%, respectively).

The median event-free survival was 6.0 weeks in the quizartinib arm and 3.7 weeks in the chemotherapy arm (hazard ratio=0.90, P=0.1071).

The median overall survival was 6.2 months in the quizartinib arm and 4.7 months in the chemotherapy arm (hazard ratio=0.76, P=0.0177). The 1-year overall survival rate was 27% and 20%, respectively.

Safety

The safety results include only patients who received their assigned treatment.

Grade 3 or higher hematologic treatment-emergent adverse events occurring in at least 5% of patients (in the quizartinib and chemotherapy groups, respectively) included:

• Thrombocytopenia (35% and 34%)
• Anemia (30% and 29%)
• Neutropenia (32% and 25%)
• Febrile neutropenia (31% and 21%)
• Leukopenia (17% and 16%).

Grade 3 or higher non-hematologic treatment-emergent adverse events occurring in at least 5% of patients (in the quizartinib and chemotherapy groups, respectively) included:

• Sepsis/septic shock (16% and 18%)
• Hypokalemia (12% and 9%)
• Pneumonia (12% and 9%)
• Fatigue (8% and 1%)
• Dyspnea (5% for both)
• Hypophosphatemia (5% for both).

Henrique Orlandi Mourao

The U.S. Food and Drug Administration (FDA) has accepted for priority review a new drug application (NDA) for the FLT3 inhibitor quizartinib.

With this NDA, Daiichi Sankyo is seeking approval for quizartinib to treat adults with relapsed/refractory FLT3-ITD acute myeloid leukemia (AML).

The FDA grants priority review to applications for products that are expected to provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.

The FDA aims to take action on a priority review application within 6 months rather than the standard 10 months.

The FDA is expected to make a decision on the quizartinib NDA by May 25, 2019.

In addition to priority review, quizartinib has breakthrough therapy designation and fast track designation from the FDA.

Trial results

The NDA for quizartinib is supported by results from the phase 3 QuANTUM-R study. Topline results from this study were presented at the 23rd Congress of the European Hematology Association in June, and new analyses are set to be presented at the 2018 ASH Annual Meeting in December (abstract 563).

QuANTUM-R enrolled adults with FLT3-ITD AML (at least 3% FLT3-ITD allelic ratio) who had refractory disease or had relapsed within 6 months of their first complete response (CR).

Patients were randomized to receive once-daily treatment with quizartinib (n=245) or a salvage chemotherapy regimen (n=122)—low-dose cytarabine (LoDAC, n=29); combination mitoxantrone, etoposide, and cytarabine (MEC, n=40); or combination fludarabine, cytarabine, and idarubicin (FLAG-IDA, n=53).

Patients who responded to treatment could proceed to hematopoietic stem cell transplant (HSCT), and those in the quizartinib arm could resume quizartinib after HSCT.

In all, 241 patients received quizartinib, and 94 received salvage chemotherapy—LoDAC (n=22), MEC (n=25), and FLAG-IDA (n=47). Of the 28 patients in the chemotherapy group who were not treated, most withdrew consent.

Thirty-two percent of quizartinib-treated patients and 12% of the chemotherapy group went on to HSCT.

Efficacy

The median follow-up was 23.5 months. The efficacy results include all randomized patients.

The overall response rate was 69% in the quizartinib arm and 30% in the chemotherapy arm. The composite CR rate was 48% in the quizartinib arm and 27% in the chemotherapy arm. This includes:

• The CR rate (4% and 1%, respectively)
• The rate of CR with incomplete platelet recovery (4% and 0%, respectively)
• The rate of CR with incomplete hematologic recovery (40% and 26%, respectively).

The median event-free survival was 6.0 weeks in the quizartinib arm and 3.7 weeks in the chemotherapy arm (hazard ratio=0.90, P=0.1071).

The median overall survival was 6.2 months in the quizartinib arm and 4.7 months in the chemotherapy arm (hazard ratio=0.76, P=0.0177). The 1-year overall survival rate was 27% and 20%, respectively.

Safety

The safety results include only patients who received their assigned treatment.

Grade 3 or higher hematologic treatment-emergent adverse events occurring in at least 5% of patients (in the quizartinib and chemotherapy groups, respectively) included:

• Thrombocytopenia (35% and 34%)
• Anemia (30% and 29%)
• Neutropenia (32% and 25%)
• Febrile neutropenia (31% and 21%)
• Leukopenia (17% and 16%).

Grade 3 or higher non-hematologic treatment-emergent adverse events occurring in at least 5% of patients (in the quizartinib and chemotherapy groups, respectively) included:

• Sepsis/septic shock (16% and 18%)
• Hypokalemia (12% and 9%)
• Pneumonia (12% and 9%)
• Fatigue (8% and 1%)
• Dyspnea (5% for both)
• Hypophosphatemia (5% for both).

SAN DIEGO – Clinicians have few tools to monitor pain medication use and abuse in their patients. However, addiction specialist and internist Edwin Salsitz, MD, says an inexpensive and simple tool, the urine test, can provide an impressive amount of useful information.

copyright toeytoey2530/Thinkstock

“The urine drug test, or another matrix for testing, gives one of the only objective factors we have to see how a patient is doing, if they’re following the treatment plan,” said Dr. Salsitz, of Mount Sinai Beth Israel, New York, in a presentation at Pain Care for Primary Care, a symposium offered by the American Pain Society and the Global Academy for Medical Education.

Dr. Salsitz offered these tips about urine tests in pain care:
 

Consider urine tests before beginning opioid therapy

Dr. Salsitz pointed to this 2016 recommendation from the Centers for Disease Control and Prevention: “When prescribing opioids for chronic pain, clinicians should use urine drug testing before starting opioid therapy and consider urine drug testing at least annually to assess for prescribed medications as well as other controlled prescription drugs and illicit drugs.” As Dr. Salsitz puts it, these tests “can help identify misuse, which hopefully hasn’t gotten to addiction yet.”

Ask the patient what the urine test will reveal

Dr. Salsitz likes to tell patients: “If you tell me the truth, no matter what’s in the urine, it’s going to be OK. I’m not going to stop prescribing or do anything harmful to you.” But, he tells patients, if they lie, “you’re going to start breaking the trust between us. Once you do that, it becomes a problem. I don’t know what’s true or not.” In some cases, he said, patients will fess up to drug use that wouldn’t have shown up in the urine tests because it didn’t happen recently enough. “We’ll talk about whether it’s a problem,” he said.

Begin with an immunoassay panel test (IA)

The CDC recommends using an immunoassay panel first in most situations. “You can do this in the office,” Dr. Salsitz said, using a dipstick-style test. Or you can “send it out to a lab, and they’ll do the same thing.”

Understand what IA tests do and don’t do

Standard 5-drug IA screening tests detect marijuana, cocaine, amphetamine/methamphetamine, PCP, and opiates (morphine/codeine). Keep in mind, Dr. Salsitz said, that opiates and opioids aren’t the same. That means IA tests don’t pick up oxycodone use, for example, he said. More sophisticated (and more expensive) tests can distinguish between types of drugs (for example, morphine vs. codeine) and can detect drugs that aren’t included in the IA tests.

Don’t make assumptions about positive or negative tests

A positive drug test for cocaine doesn’t necessarily mean the person is addicted, Dr. Salsitz said. “It just means they used that molecule in the last 3 days. It’s up to you to figure out what it actually means.” And if a patient’s urine fails to show that he or she is taking a prescribed medication, that doesn’t necessarily indicate that the drug is being illegally diverted. The patient could have run out of the drug or lost insurance coverage, Dr. Salsitz said.
 

Be aware that patients may fake urine tests

“Cheating is a huge problem,” Dr. Salsitz said. “Is it their urine or not their urine?” Many kits promise to help people provide fake urine, and some have even provided fake penises to foil observed urine collection. What to do? Alternative tests that rely on hair, saliva, and even sweat are available, Dr. Salsitz said, and these make cheating more difficult. However, they have various limitations. Saliva, for example, only tells you what patients are using now, not what they used days ago, he said, and it’s not sensitive for marijuana.

Dr. Salsitz reported no disclosures.

The Global Academy for Medical Education, which offered the Pain Care for Primary Care symposium, and this news organization are owned by the same parent company.

SAN DIEGO – Clinicians have few tools to monitor pain medication use and abuse in their patients. However, addiction specialist and internist Edwin Salsitz, MD, says an inexpensive and simple tool, the urine test, can provide an impressive amount of useful information.

copyright toeytoey2530/Thinkstock

“The urine drug test, or another matrix for testing, gives one of the only objective factors we have to see how a patient is doing, if they’re following the treatment plan,” said Dr. Salsitz, of Mount Sinai Beth Israel, New York, in a presentation at Pain Care for Primary Care, a symposium offered by the American Pain Society and the Global Academy for Medical Education.

Dr. Salsitz offered these tips about urine tests in pain care:
 

Consider urine tests before beginning opioid therapy

Dr. Salsitz pointed to this 2016 recommendation from the Centers for Disease Control and Prevention: “When prescribing opioids for chronic pain, clinicians should use urine drug testing before starting opioid therapy and consider urine drug testing at least annually to assess for prescribed medications as well as other controlled prescription drugs and illicit drugs.” As Dr. Salsitz puts it, these tests “can help identify misuse, which hopefully hasn’t gotten to addiction yet.”

Ask the patient what the urine test will reveal

Dr. Salsitz likes to tell patients: “If you tell me the truth, no matter what’s in the urine, it’s going to be OK. I’m not going to stop prescribing or do anything harmful to you.” But, he tells patients, if they lie, “you’re going to start breaking the trust between us. Once you do that, it becomes a problem. I don’t know what’s true or not.” In some cases, he said, patients will fess up to drug use that wouldn’t have shown up in the urine tests because it didn’t happen recently enough. “We’ll talk about whether it’s a problem,” he said.

Begin with an immunoassay panel test (IA)

The CDC recommends using an immunoassay panel first in most situations. “You can do this in the office,” Dr. Salsitz said, using a dipstick-style test. Or you can “send it out to a lab, and they’ll do the same thing.”

Understand what IA tests do and don’t do

Standard 5-drug IA screening tests detect marijuana, cocaine, amphetamine/methamphetamine, PCP, and opiates (morphine/codeine). Keep in mind, Dr. Salsitz said, that opiates and opioids aren’t the same. That means IA tests don’t pick up oxycodone use, for example, he said. More sophisticated (and more expensive) tests can distinguish between types of drugs (for example, morphine vs. codeine) and can detect drugs that aren’t included in the IA tests.

Don’t make assumptions about positive or negative tests

A positive drug test for cocaine doesn’t necessarily mean the person is addicted, Dr. Salsitz said. “It just means they used that molecule in the last 3 days. It’s up to you to figure out what it actually means.” And if a patient’s urine fails to show that he or she is taking a prescribed medication, that doesn’t necessarily indicate that the drug is being illegally diverted. The patient could have run out of the drug or lost insurance coverage, Dr. Salsitz said.
 

Be aware that patients may fake urine tests

“Cheating is a huge problem,” Dr. Salsitz said. “Is it their urine or not their urine?” Many kits promise to help people provide fake urine, and some have even provided fake penises to foil observed urine collection. What to do? Alternative tests that rely on hair, saliva, and even sweat are available, Dr. Salsitz said, and these make cheating more difficult. However, they have various limitations. Saliva, for example, only tells you what patients are using now, not what they used days ago, he said, and it’s not sensitive for marijuana.

Dr. Salsitz reported no disclosures.

The Global Academy for Medical Education, which offered the Pain Care for Primary Care symposium, and this news organization are owned by the same parent company.

SAN DIEGO – Clinicians have few tools to monitor pain medication use and abuse in their patients. However, addiction specialist and internist Edwin Salsitz, MD, says an inexpensive and simple tool, the urine test, can provide an impressive amount of useful information.

copyright toeytoey2530/Thinkstock

“The urine drug test, or another matrix for testing, gives one of the only objective factors we have to see how a patient is doing, if they’re following the treatment plan,” said Dr. Salsitz, of Mount Sinai Beth Israel, New York, in a presentation at Pain Care for Primary Care, a symposium offered by the American Pain Society and the Global Academy for Medical Education.

Dr. Salsitz offered these tips about urine tests in pain care:
 

Consider urine tests before beginning opioid therapy

Dr. Salsitz pointed to this 2016 recommendation from the Centers for Disease Control and Prevention: “When prescribing opioids for chronic pain, clinicians should use urine drug testing before starting opioid therapy and consider urine drug testing at least annually to assess for prescribed medications as well as other controlled prescription drugs and illicit drugs.” As Dr. Salsitz puts it, these tests “can help identify misuse, which hopefully hasn’t gotten to addiction yet.”

Ask the patient what the urine test will reveal

Dr. Salsitz likes to tell patients: “If you tell me the truth, no matter what’s in the urine, it’s going to be OK. I’m not going to stop prescribing or do anything harmful to you.” But, he tells patients, if they lie, “you’re going to start breaking the trust between us. Once you do that, it becomes a problem. I don’t know what’s true or not.” In some cases, he said, patients will fess up to drug use that wouldn’t have shown up in the urine tests because it didn’t happen recently enough. “We’ll talk about whether it’s a problem,” he said.

Begin with an immunoassay panel test (IA)

The CDC recommends using an immunoassay panel first in most situations. “You can do this in the office,” Dr. Salsitz said, using a dipstick-style test. Or you can “send it out to a lab, and they’ll do the same thing.”

Understand what IA tests do and don’t do

Standard 5-drug IA screening tests detect marijuana, cocaine, amphetamine/methamphetamine, PCP, and opiates (morphine/codeine). Keep in mind, Dr. Salsitz said, that opiates and opioids aren’t the same. That means IA tests don’t pick up oxycodone use, for example, he said. More sophisticated (and more expensive) tests can distinguish between types of drugs (for example, morphine vs. codeine) and can detect drugs that aren’t included in the IA tests.

Don’t make assumptions about positive or negative tests

A positive drug test for cocaine doesn’t necessarily mean the person is addicted, Dr. Salsitz said. “It just means they used that molecule in the last 3 days. It’s up to you to figure out what it actually means.” And if a patient’s urine fails to show that he or she is taking a prescribed medication, that doesn’t necessarily indicate that the drug is being illegally diverted. The patient could have run out of the drug or lost insurance coverage, Dr. Salsitz said.
 

Be aware that patients may fake urine tests

“Cheating is a huge problem,” Dr. Salsitz said. “Is it their urine or not their urine?” Many kits promise to help people provide fake urine, and some have even provided fake penises to foil observed urine collection. What to do? Alternative tests that rely on hair, saliva, and even sweat are available, Dr. Salsitz said, and these make cheating more difficult. However, they have various limitations. Saliva, for example, only tells you what patients are using now, not what they used days ago, he said, and it’s not sensitive for marijuana.

Dr. Salsitz reported no disclosures.

The Global Academy for Medical Education, which offered the Pain Care for Primary Care symposium, and this news organization are owned by the same parent company.

Inflammation is a double-edged sword. Controlled and modest proinflammatory responses can enhance host immunity against viruses and decrease bacterial colonization and infection, whereas excessive uncontrolled proinflammatory responses may increase the susceptibility to bacterial colonization and secondary infection to facilitate disease pathogenesis. The immune system produces both proinflammatory and anti-inflammatory cytokines and chemokines. It is a balanced response that is key to maintaining good health.

Cynthia Goldsmith/CDC photo #10073

Viral upper respiratory tract infections (URIs) are caused by rhinoviruses, coronaviruses, enteroviruses, respiratory syncytial viruses, influenza A and B viruses, parainfluenza viruses, adenoviruses, and human metapneumoviruses. Viruses are powerful. In the nose, they induce hypersecretion of mucus, slow cilia beating, up-regulate nasal epithelial cell receptors to facilitate bacterial attachment, suppress neutrophil function, and cause increased release of proinflammatory cytokines and chemokines. All these actions by respiratory viruses promote bacterial overgrowth in the nasopharynx and thereby facilitate bacterial superinfections. In fact, progression in pathogenesis of the common bacterial respiratory infections – acute otitis media, acute sinusitis, acute conjunctivitis, and pneumonia – almost always is preceded by a viral URI. Viruses activate multiple target cells in the upper respiratory tract to produce an array of proinflammatory cytokines and chemokines. The symptoms of a viral URI resolve coinciding with an anti-inflammatory response and adaptive immunity.

In recent work, we found a higher frequency of viral URIs in children who experienced more frequent acute otitis media (AOM). We sought to understand why this might occur by comparing levels of inflammatory cytokines/chemokines in the nose during viral URI that did not precipitate AOM versus when a viral URI precipitated an AOM episode. When a child had a viral URI but did not go on to experience an AOM, the child had higher proinflammatory responses than when the viral URI precipitated an AOM. When differences of levels of proinflammatory cytokines/chemokines were compared in otitis-prone and non–otitis-prone children, lower nasal responses were associated with higher otitis-prone classification frequency (Clin Infect Dis. 2018. doi: 10.1093/cid/ciy750).

The powerful virus and the inflammatory response it can induce also play a major role in allergy and asthma. Viral URIs enhance allergic sensitization to respiratory viruses, such as influenza and respiratory syncytial virus, cause cytopathic damage to airway epithelium, promote excessive proinflammatory cytokine/chemokine production, and increase the exposure of allergens and irritants to antigen-presenting cells. Viral infections also may induce the release of epithelial mediators and cytokines that may propagate eosinophilia. Viral URIs, particularly with respiratory syncytial virus and rhinovirus, are the most common causes of wheezing in children, and they have important influences on the development of asthma. Studies have shown that viral infections trigger up to 85% of asthma exacerbations in school-aged children.

Because this column is being published during the winter, a brief discussion of influenza as a powerful virus is appropriate. Influenza occurs in winter outbreaks of varying extent every year. The severity of the influenza season reflects the changing nature of the antigenic properties of influenza viruses, and their spread depends on susceptibility of the population. Influenza outbreaks typically peak over a 2-3 week period and last for 2-3 months. Most outbreaks have attack rates of 10%-20% in children. There may be variations in disease severity caused by different influenza virus types. The symptoms are caused by excessive proinflammatory cytokine/chemokine production in the nose and lung.

Influenza and other viruses can precipitate the systemic inflammatory response syndrome (SIRS), a manifestation of extreme immune dysregulation resulting in organ dysfunction that clinically resembles bacterial sepsis. In this syndrome, tissues remote from the original insult display the cardinal signs of inflammation, including vasodilation, increased microvascular permeability, and leukocyte accumulation. SIRS is another example of the double-edged sword of inflammation.

The onset and progression of SIRS occurs because of dysregulation of the normal inflammatory response, usually with an increase in both proinflammatory and anti-inflammatory cytokines and chemokines, initiating a chain of events that leads to organ failure.

Dr. Pichichero is a specialist in pediatric infectious diseases and director of the Research Institute at Rochester (N.Y.) General Hospital. He reported having no conflicts of interest. Email him at [email protected].

Inflammation is a double-edged sword. Controlled and modest proinflammatory responses can enhance host immunity against viruses and decrease bacterial colonization and infection, whereas excessive uncontrolled proinflammatory responses may increase the susceptibility to bacterial colonization and secondary infection to facilitate disease pathogenesis. The immune system produces both proinflammatory and anti-inflammatory cytokines and chemokines. It is a balanced response that is key to maintaining good health.

Cynthia Goldsmith/CDC photo #10073

Viral upper respiratory tract infections (URIs) are caused by rhinoviruses, coronaviruses, enteroviruses, respiratory syncytial viruses, influenza A and B viruses, parainfluenza viruses, adenoviruses, and human metapneumoviruses. Viruses are powerful. In the nose, they induce hypersecretion of mucus, slow cilia beating, up-regulate nasal epithelial cell receptors to facilitate bacterial attachment, suppress neutrophil function, and cause increased release of proinflammatory cytokines and chemokines. All these actions by respiratory viruses promote bacterial overgrowth in the nasopharynx and thereby facilitate bacterial superinfections. In fact, progression in pathogenesis of the common bacterial respiratory infections – acute otitis media, acute sinusitis, acute conjunctivitis, and pneumonia – almost always is preceded by a viral URI. Viruses activate multiple target cells in the upper respiratory tract to produce an array of proinflammatory cytokines and chemokines. The symptoms of a viral URI resolve coinciding with an anti-inflammatory response and adaptive immunity.

In recent work, we found a higher frequency of viral URIs in children who experienced more frequent acute otitis media (AOM). We sought to understand why this might occur by comparing levels of inflammatory cytokines/chemokines in the nose during viral URI that did not precipitate AOM versus when a viral URI precipitated an AOM episode. When a child had a viral URI but did not go on to experience an AOM, the child had higher proinflammatory responses than when the viral URI precipitated an AOM. When differences of levels of proinflammatory cytokines/chemokines were compared in otitis-prone and non–otitis-prone children, lower nasal responses were associated with higher otitis-prone classification frequency (Clin Infect Dis. 2018. doi: 10.1093/cid/ciy750).

The powerful virus and the inflammatory response it can induce also play a major role in allergy and asthma. Viral URIs enhance allergic sensitization to respiratory viruses, such as influenza and respiratory syncytial virus, cause cytopathic damage to airway epithelium, promote excessive proinflammatory cytokine/chemokine production, and increase the exposure of allergens and irritants to antigen-presenting cells. Viral infections also may induce the release of epithelial mediators and cytokines that may propagate eosinophilia. Viral URIs, particularly with respiratory syncytial virus and rhinovirus, are the most common causes of wheezing in children, and they have important influences on the development of asthma. Studies have shown that viral infections trigger up to 85% of asthma exacerbations in school-aged children.

Because this column is being published during the winter, a brief discussion of influenza as a powerful virus is appropriate. Influenza occurs in winter outbreaks of varying extent every year. The severity of the influenza season reflects the changing nature of the antigenic properties of influenza viruses, and their spread depends on susceptibility of the population. Influenza outbreaks typically peak over a 2-3 week period and last for 2-3 months. Most outbreaks have attack rates of 10%-20% in children. There may be variations in disease severity caused by different influenza virus types. The symptoms are caused by excessive proinflammatory cytokine/chemokine production in the nose and lung.

Influenza and other viruses can precipitate the systemic inflammatory response syndrome (SIRS), a manifestation of extreme immune dysregulation resulting in organ dysfunction that clinically resembles bacterial sepsis. In this syndrome, tissues remote from the original insult display the cardinal signs of inflammation, including vasodilation, increased microvascular permeability, and leukocyte accumulation. SIRS is another example of the double-edged sword of inflammation.

The onset and progression of SIRS occurs because of dysregulation of the normal inflammatory response, usually with an increase in both proinflammatory and anti-inflammatory cytokines and chemokines, initiating a chain of events that leads to organ failure.

Dr. Pichichero is a specialist in pediatric infectious diseases and director of the Research Institute at Rochester (N.Y.) General Hospital. He reported having no conflicts of interest. Email him at [email protected].

Inflammation is a double-edged sword. Controlled and modest proinflammatory responses can enhance host immunity against viruses and decrease bacterial colonization and infection, whereas excessive uncontrolled proinflammatory responses may increase the susceptibility to bacterial colonization and secondary infection to facilitate disease pathogenesis. The immune system produces both proinflammatory and anti-inflammatory cytokines and chemokines. It is a balanced response that is key to maintaining good health.

Cynthia Goldsmith/CDC photo #10073

Viral upper respiratory tract infections (URIs) are caused by rhinoviruses, coronaviruses, enteroviruses, respiratory syncytial viruses, influenza A and B viruses, parainfluenza viruses, adenoviruses, and human metapneumoviruses. Viruses are powerful. In the nose, they induce hypersecretion of mucus, slow cilia beating, up-regulate nasal epithelial cell receptors to facilitate bacterial attachment, suppress neutrophil function, and cause increased release of proinflammatory cytokines and chemokines. All these actions by respiratory viruses promote bacterial overgrowth in the nasopharynx and thereby facilitate bacterial superinfections. In fact, progression in pathogenesis of the common bacterial respiratory infections – acute otitis media, acute sinusitis, acute conjunctivitis, and pneumonia – almost always is preceded by a viral URI. Viruses activate multiple target cells in the upper respiratory tract to produce an array of proinflammatory cytokines and chemokines. The symptoms of a viral URI resolve coinciding with an anti-inflammatory response and adaptive immunity.

In recent work, we found a higher frequency of viral URIs in children who experienced more frequent acute otitis media (AOM). We sought to understand why this might occur by comparing levels of inflammatory cytokines/chemokines in the nose during viral URI that did not precipitate AOM versus when a viral URI precipitated an AOM episode. When a child had a viral URI but did not go on to experience an AOM, the child had higher proinflammatory responses than when the viral URI precipitated an AOM. When differences of levels of proinflammatory cytokines/chemokines were compared in otitis-prone and non–otitis-prone children, lower nasal responses were associated with higher otitis-prone classification frequency (Clin Infect Dis. 2018. doi: 10.1093/cid/ciy750).

The powerful virus and the inflammatory response it can induce also play a major role in allergy and asthma. Viral URIs enhance allergic sensitization to respiratory viruses, such as influenza and respiratory syncytial virus, cause cytopathic damage to airway epithelium, promote excessive proinflammatory cytokine/chemokine production, and increase the exposure of allergens and irritants to antigen-presenting cells. Viral infections also may induce the release of epithelial mediators and cytokines that may propagate eosinophilia. Viral URIs, particularly with respiratory syncytial virus and rhinovirus, are the most common causes of wheezing in children, and they have important influences on the development of asthma. Studies have shown that viral infections trigger up to 85% of asthma exacerbations in school-aged children.

Because this column is being published during the winter, a brief discussion of influenza as a powerful virus is appropriate. Influenza occurs in winter outbreaks of varying extent every year. The severity of the influenza season reflects the changing nature of the antigenic properties of influenza viruses, and their spread depends on susceptibility of the population. Influenza outbreaks typically peak over a 2-3 week period and last for 2-3 months. Most outbreaks have attack rates of 10%-20% in children. There may be variations in disease severity caused by different influenza virus types. The symptoms are caused by excessive proinflammatory cytokine/chemokine production in the nose and lung.

Influenza and other viruses can precipitate the systemic inflammatory response syndrome (SIRS), a manifestation of extreme immune dysregulation resulting in organ dysfunction that clinically resembles bacterial sepsis. In this syndrome, tissues remote from the original insult display the cardinal signs of inflammation, including vasodilation, increased microvascular permeability, and leukocyte accumulation. SIRS is another example of the double-edged sword of inflammation.

The onset and progression of SIRS occurs because of dysregulation of the normal inflammatory response, usually with an increase in both proinflammatory and anti-inflammatory cytokines and chemokines, initiating a chain of events that leads to organ failure.

Dr. Pichichero is a specialist in pediatric infectious diseases and director of the Research Institute at Rochester (N.Y.) General Hospital. He reported having no conflicts of interest. Email him at [email protected].

Multiple myeloma is the most common plasma cell neoplasm, with an estimated 24,000 cases occurring annually.¹ Symptomatic multiple myeloma most commonly presents with one or more of the cardinal CRAB phenomena of hypercalcemia, renal dysfunction, anemia, or lytic bone lesions.² Less commonly, patients may present with plasmacytomas (focal lesions of malignant plasma cells), which may involve bony or soft tissues.¹

Plasma cell neoplasms occasionally involve the joints, including the elbows, typically as plasmacytomas. The elbow is an unusual but reported location of plasmacytomas.^3,4 A case of multiple myeloma and amyloid light-chain (AL) amyloidosis has been reported, with manifestations including pseudomyopathy, bone marrow plasmacytosis, and bilateral trochanteric bursitis.⁵Bursitis is defined as inflammation of the synovial-fluid–containing sacs that lubricate joints. The olecranon bursa is commonly affected. Etiologies include infection, inflammatory disease, trauma, and malignancy. Furthermore, there is an association between bursitis and immunosuppression.^6,7 The most common modes of therapy used to treat bursitis are nonsteroidal anti-inflammatory drugs, corticosteroid injections, and surgical management.

Trochanteric bursitis has been attributed to multiple myeloma in one previous case report, but we are not aware of any previous cases of olecranon bursitis caused by multiple myeloma. Here, we present the case of a 46-year-old man with heavily pretreated multiple myeloma and amyloidosis who developed left olecranon bursitis contemporaneously with disease relapse; flow cytometric analysis of the bursal fluid demonstrated an abnormal plasma cell population, establishing the etiology.

Case presentation and summary

A 46-year-old man with a longstanding history of multiple myeloma developed swelling of the left elbow that was initially painless in September 2016. He had been diagnosed with IgA kappa multiple myeloma and AL deposition in 2011. Over the course of his disease, he was treated with the following sequence of therapies: cyclophosphamide, bortezomib, and dexamethasone, followed by melphalan-conditioned autologous peripheral blood stem cell transplant; lenalidomide and dexamethasone; carfilzomib and dexamethasone; pomalidomide, bortezomib, and dexamethasone; and bortezomib, lenalidomide, dexamethasone, doxorubicin, cyclophosphamide, and etoposide, followed by second melphalan-conditioned autologous peripheral blood stem cell transplant. In addition to treatment with numerous novel and chemotherapeutic agents, his disease course was notable for amyloid deposition in the liver, bone marrow, and kidneys, which resulted in dialysis dependence.

After the second autologous transplant, he achieved a very good partial response and experienced about 9 months of remission, after which laboratory evaluation indicated recurrence of IgA kappa monoclonal protein and free kappa light-chains, which increased slowly over several months without focal symptoms, cytopenias, or decline in organ function (Figure 1).

Discussion

Our patient experienced left olecranon bursitis simultaneously with relapse of multiple myeloma and AL amyloidosis. Evaluation for infectious causes was negative, and the bursal fluid did not have strongly inflammatory characteristics. Furthermore, a small plasma cell population was isolated from the fluid. Imaging did not reveal an underlying dominant lytic lesion. Although we do not have direct pathologic confirmation, the clinical scenario and flow cytometry findings support our interpretation that the patient’s bursitis was caused by or at least related to underlying multiple myeloma. While reactive plasma cells are also CD38 positive and CD138 positive, they maintain the expression of CD19 and CD45 without aberrant expression of CD56 or CD117 and do not show loss of expression of CD81 or CD27. In this situation, we suspect that either a plasmacytoma involving the soft tissue of the bursa or amyloid infiltration of the synovium may have occurred. Anti-myeloma therapies and radiation therapy did not result in control of the bursitis, though it should be noted that the patient’s highly refractory disease progressed despite treatment with a combination of later-generation immunomodulatory imide and proteasome inhibitor therapies.

Cases of malignant bursitis have been reported several times in the literature, though nearly all of the instances involved connective tissue or metastatic tumors. Tumor histologies include osteochondroma,^8,9 malignant fibrous histiocytoma,¹⁰ synovial sarcoma,¹¹ and metastatic breast cancer.¹²

Hematologic malignancies are more rare causes of bursitis; our literature search identified a report of 2 cases of non-Hodgkin lymphoma mimicking rheumatoid arthritis. The joints were the knee and elbow. Synovial fluid from one case was clear and yellow, with leukocytosis with a neutrophilic predominance (similar to our case). In both cases, pathology confirmed lymphomatous infiltration of the synovium.¹³ Notably, we identified a case of a previously healthy 35-year-old woman with bilateral trochanteric bursitis. Biopsy of tissue from the right trochanteric bursa demonstrated positive birefringence, diagnostic of AL amyloidosis. The patient also had a biclonal paraprotein accompanied by calvarial lytic lesions. She was treated with a corticosteroid pulse and bisphosphonates, followed by autologous hematopoietic stem cell transplant. ⁵ Our case shares features with the above case, including the relatively young age of the patient and the presence of AL amyloidosis.

Our patient wished to avoid a surgical biopsy procedure, and therefore we utilized flow cytometry of the bursal fluid to establish that the etiology of fluid collection was consistent with his concurrent relapse of multiple myeloma. We believe that we are reporting the second case of multiple myeloma-associated bursitis and the first case associated with multiple myeloma relapse; to our knowledge, it is the first to be diagnosed with the aid of flow cytometry.

Because of our patient’s reliance on hemodialysis beginning one year prior to his presentation with olecranon bursitis, we entertain “dialysis elbow” within the differential diagnosis. Dialysis elbow is a relatively uncommon complication of dialysis, in which patients develop olecranon bursitis on the same side as the hemodialysis access after a prolonged (months to years) duration of hemodialysis. Serositis and mechanical forces are the hypothesized etiologies¹⁴; infectious and rheumatologic causes were excluded from the reported cases. Nevertheless, we favor a malignant cause based upon the flow cytometry findings indicating involvement by immunophenotypically abnormal plasma cells.

Our patient was treated initially with serial drainage and nonsteroidals, which had little impact. After diagnosis of a plasma cell population in the fluid, we offered local treatment with radiation and systemic treatment of multiple myeloma, which offered better but suboptimal control. Possible treatments for olecranon bursitis include surgery, corticosteroid injections, anti-inflammatories, and serial drainage. Nonsurgical management may be more effective than surgical management, and corticosteroid injection carries significant risks. On the other hand, serial drainage does not confer additional infection risk in cases with aseptic etiology.¹⁵ We combined conservative measures as well as treatment of the underlying disease, but we believe that our patient did not derive significant benefit because of the refractory nature of his disease; he also expressed a preference to avoid surgical intervention.
 

Conclusion

Bursitis is a rare but thought-provoking potential manifestation of multiple myeloma and AL amyloidosis; we believe that our patient’s bursitis was related to plasma cell neoplasia based upon co-occurrence with disease relapse. His bursitis turned out to be an early indicator of impending systemic relapse. In this particular case, in which the patient wished to avoid surgical intervention, flow cytometry was of great value, and we believe that our case is the first report of malignant bursitis being diagnosed by flow cytometry. Our patient’s case shares similarities with other biopsy-confirmed cases of malignant bursitis, but we were able to avoid the need for surgical biopsy or bursal stripping.

The authors thank Jennifer Wilham MT (ASCP), Pat Byrd MT (ASCP), and Darlene Mann MT (ASCP) for their technical support.

Multiple myeloma is the most common plasma cell neoplasm, with an estimated 24,000 cases occurring annually.¹ Symptomatic multiple myeloma most commonly presents with one or more of the cardinal CRAB phenomena of hypercalcemia, renal dysfunction, anemia, or lytic bone lesions.² Less commonly, patients may present with plasmacytomas (focal lesions of malignant plasma cells), which may involve bony or soft tissues.¹

Plasma cell neoplasms occasionally involve the joints, including the elbows, typically as plasmacytomas. The elbow is an unusual but reported location of plasmacytomas.^3,4 A case of multiple myeloma and amyloid light-chain (AL) amyloidosis has been reported, with manifestations including pseudomyopathy, bone marrow plasmacytosis, and bilateral trochanteric bursitis.⁵Bursitis is defined as inflammation of the synovial-fluid–containing sacs that lubricate joints. The olecranon bursa is commonly affected. Etiologies include infection, inflammatory disease, trauma, and malignancy. Furthermore, there is an association between bursitis and immunosuppression.^6,7 The most common modes of therapy used to treat bursitis are nonsteroidal anti-inflammatory drugs, corticosteroid injections, and surgical management.

Trochanteric bursitis has been attributed to multiple myeloma in one previous case report, but we are not aware of any previous cases of olecranon bursitis caused by multiple myeloma. Here, we present the case of a 46-year-old man with heavily pretreated multiple myeloma and amyloidosis who developed left olecranon bursitis contemporaneously with disease relapse; flow cytometric analysis of the bursal fluid demonstrated an abnormal plasma cell population, establishing the etiology.

Case presentation and summary

A 46-year-old man with a longstanding history of multiple myeloma developed swelling of the left elbow that was initially painless in September 2016. He had been diagnosed with IgA kappa multiple myeloma and AL deposition in 2011. Over the course of his disease, he was treated with the following sequence of therapies: cyclophosphamide, bortezomib, and dexamethasone, followed by melphalan-conditioned autologous peripheral blood stem cell transplant; lenalidomide and dexamethasone; carfilzomib and dexamethasone; pomalidomide, bortezomib, and dexamethasone; and bortezomib, lenalidomide, dexamethasone, doxorubicin, cyclophosphamide, and etoposide, followed by second melphalan-conditioned autologous peripheral blood stem cell transplant. In addition to treatment with numerous novel and chemotherapeutic agents, his disease course was notable for amyloid deposition in the liver, bone marrow, and kidneys, which resulted in dialysis dependence.

After the second autologous transplant, he achieved a very good partial response and experienced about 9 months of remission, after which laboratory evaluation indicated recurrence of IgA kappa monoclonal protein and free kappa light-chains, which increased slowly over several months without focal symptoms, cytopenias, or decline in organ function (Figure 1).

Discussion

Our patient experienced left olecranon bursitis simultaneously with relapse of multiple myeloma and AL amyloidosis. Evaluation for infectious causes was negative, and the bursal fluid did not have strongly inflammatory characteristics. Furthermore, a small plasma cell population was isolated from the fluid. Imaging did not reveal an underlying dominant lytic lesion. Although we do not have direct pathologic confirmation, the clinical scenario and flow cytometry findings support our interpretation that the patient’s bursitis was caused by or at least related to underlying multiple myeloma. While reactive plasma cells are also CD38 positive and CD138 positive, they maintain the expression of CD19 and CD45 without aberrant expression of CD56 or CD117 and do not show loss of expression of CD81 or CD27. In this situation, we suspect that either a plasmacytoma involving the soft tissue of the bursa or amyloid infiltration of the synovium may have occurred. Anti-myeloma therapies and radiation therapy did not result in control of the bursitis, though it should be noted that the patient’s highly refractory disease progressed despite treatment with a combination of later-generation immunomodulatory imide and proteasome inhibitor therapies.

Cases of malignant bursitis have been reported several times in the literature, though nearly all of the instances involved connective tissue or metastatic tumors. Tumor histologies include osteochondroma,^8,9 malignant fibrous histiocytoma,¹⁰ synovial sarcoma,¹¹ and metastatic breast cancer.¹²

Hematologic malignancies are more rare causes of bursitis; our literature search identified a report of 2 cases of non-Hodgkin lymphoma mimicking rheumatoid arthritis. The joints were the knee and elbow. Synovial fluid from one case was clear and yellow, with leukocytosis with a neutrophilic predominance (similar to our case). In both cases, pathology confirmed lymphomatous infiltration of the synovium.¹³ Notably, we identified a case of a previously healthy 35-year-old woman with bilateral trochanteric bursitis. Biopsy of tissue from the right trochanteric bursa demonstrated positive birefringence, diagnostic of AL amyloidosis. The patient also had a biclonal paraprotein accompanied by calvarial lytic lesions. She was treated with a corticosteroid pulse and bisphosphonates, followed by autologous hematopoietic stem cell transplant. ⁵ Our case shares features with the above case, including the relatively young age of the patient and the presence of AL amyloidosis.

Our patient wished to avoid a surgical biopsy procedure, and therefore we utilized flow cytometry of the bursal fluid to establish that the etiology of fluid collection was consistent with his concurrent relapse of multiple myeloma. We believe that we are reporting the second case of multiple myeloma-associated bursitis and the first case associated with multiple myeloma relapse; to our knowledge, it is the first to be diagnosed with the aid of flow cytometry.

Because of our patient’s reliance on hemodialysis beginning one year prior to his presentation with olecranon bursitis, we entertain “dialysis elbow” within the differential diagnosis. Dialysis elbow is a relatively uncommon complication of dialysis, in which patients develop olecranon bursitis on the same side as the hemodialysis access after a prolonged (months to years) duration of hemodialysis. Serositis and mechanical forces are the hypothesized etiologies¹⁴; infectious and rheumatologic causes were excluded from the reported cases. Nevertheless, we favor a malignant cause based upon the flow cytometry findings indicating involvement by immunophenotypically abnormal plasma cells.

Our patient was treated initially with serial drainage and nonsteroidals, which had little impact. After diagnosis of a plasma cell population in the fluid, we offered local treatment with radiation and systemic treatment of multiple myeloma, which offered better but suboptimal control. Possible treatments for olecranon bursitis include surgery, corticosteroid injections, anti-inflammatories, and serial drainage. Nonsurgical management may be more effective than surgical management, and corticosteroid injection carries significant risks. On the other hand, serial drainage does not confer additional infection risk in cases with aseptic etiology.¹⁵ We combined conservative measures as well as treatment of the underlying disease, but we believe that our patient did not derive significant benefit because of the refractory nature of his disease; he also expressed a preference to avoid surgical intervention.
 

Conclusion

Bursitis is a rare but thought-provoking potential manifestation of multiple myeloma and AL amyloidosis; we believe that our patient’s bursitis was related to plasma cell neoplasia based upon co-occurrence with disease relapse. His bursitis turned out to be an early indicator of impending systemic relapse. In this particular case, in which the patient wished to avoid surgical intervention, flow cytometry was of great value, and we believe that our case is the first report of malignant bursitis being diagnosed by flow cytometry. Our patient’s case shares similarities with other biopsy-confirmed cases of malignant bursitis, but we were able to avoid the need for surgical biopsy or bursal stripping.

The authors thank Jennifer Wilham MT (ASCP), Pat Byrd MT (ASCP), and Darlene Mann MT (ASCP) for their technical support.

Multiple myeloma is the most common plasma cell neoplasm, with an estimated 24,000 cases occurring annually.¹ Symptomatic multiple myeloma most commonly presents with one or more of the cardinal CRAB phenomena of hypercalcemia, renal dysfunction, anemia, or lytic bone lesions.² Less commonly, patients may present with plasmacytomas (focal lesions of malignant plasma cells), which may involve bony or soft tissues.¹

Plasma cell neoplasms occasionally involve the joints, including the elbows, typically as plasmacytomas. The elbow is an unusual but reported location of plasmacytomas.^3,4 A case of multiple myeloma and amyloid light-chain (AL) amyloidosis has been reported, with manifestations including pseudomyopathy, bone marrow plasmacytosis, and bilateral trochanteric bursitis.⁵Bursitis is defined as inflammation of the synovial-fluid–containing sacs that lubricate joints. The olecranon bursa is commonly affected. Etiologies include infection, inflammatory disease, trauma, and malignancy. Furthermore, there is an association between bursitis and immunosuppression.^6,7 The most common modes of therapy used to treat bursitis are nonsteroidal anti-inflammatory drugs, corticosteroid injections, and surgical management.

Trochanteric bursitis has been attributed to multiple myeloma in one previous case report, but we are not aware of any previous cases of olecranon bursitis caused by multiple myeloma. Here, we present the case of a 46-year-old man with heavily pretreated multiple myeloma and amyloidosis who developed left olecranon bursitis contemporaneously with disease relapse; flow cytometric analysis of the bursal fluid demonstrated an abnormal plasma cell population, establishing the etiology.

Case presentation and summary

A 46-year-old man with a longstanding history of multiple myeloma developed swelling of the left elbow that was initially painless in September 2016. He had been diagnosed with IgA kappa multiple myeloma and AL deposition in 2011. Over the course of his disease, he was treated with the following sequence of therapies: cyclophosphamide, bortezomib, and dexamethasone, followed by melphalan-conditioned autologous peripheral blood stem cell transplant; lenalidomide and dexamethasone; carfilzomib and dexamethasone; pomalidomide, bortezomib, and dexamethasone; and bortezomib, lenalidomide, dexamethasone, doxorubicin, cyclophosphamide, and etoposide, followed by second melphalan-conditioned autologous peripheral blood stem cell transplant. In addition to treatment with numerous novel and chemotherapeutic agents, his disease course was notable for amyloid deposition in the liver, bone marrow, and kidneys, which resulted in dialysis dependence.

After the second autologous transplant, he achieved a very good partial response and experienced about 9 months of remission, after which laboratory evaluation indicated recurrence of IgA kappa monoclonal protein and free kappa light-chains, which increased slowly over several months without focal symptoms, cytopenias, or decline in organ function (Figure 1).

Discussion

Our patient experienced left olecranon bursitis simultaneously with relapse of multiple myeloma and AL amyloidosis. Evaluation for infectious causes was negative, and the bursal fluid did not have strongly inflammatory characteristics. Furthermore, a small plasma cell population was isolated from the fluid. Imaging did not reveal an underlying dominant lytic lesion. Although we do not have direct pathologic confirmation, the clinical scenario and flow cytometry findings support our interpretation that the patient’s bursitis was caused by or at least related to underlying multiple myeloma. While reactive plasma cells are also CD38 positive and CD138 positive, they maintain the expression of CD19 and CD45 without aberrant expression of CD56 or CD117 and do not show loss of expression of CD81 or CD27. In this situation, we suspect that either a plasmacytoma involving the soft tissue of the bursa or amyloid infiltration of the synovium may have occurred. Anti-myeloma therapies and radiation therapy did not result in control of the bursitis, though it should be noted that the patient’s highly refractory disease progressed despite treatment with a combination of later-generation immunomodulatory imide and proteasome inhibitor therapies.

Cases of malignant bursitis have been reported several times in the literature, though nearly all of the instances involved connective tissue or metastatic tumors. Tumor histologies include osteochondroma,^8,9 malignant fibrous histiocytoma,¹⁰ synovial sarcoma,¹¹ and metastatic breast cancer.¹²

Hematologic malignancies are more rare causes of bursitis; our literature search identified a report of 2 cases of non-Hodgkin lymphoma mimicking rheumatoid arthritis. The joints were the knee and elbow. Synovial fluid from one case was clear and yellow, with leukocytosis with a neutrophilic predominance (similar to our case). In both cases, pathology confirmed lymphomatous infiltration of the synovium.¹³ Notably, we identified a case of a previously healthy 35-year-old woman with bilateral trochanteric bursitis. Biopsy of tissue from the right trochanteric bursa demonstrated positive birefringence, diagnostic of AL amyloidosis. The patient also had a biclonal paraprotein accompanied by calvarial lytic lesions. She was treated with a corticosteroid pulse and bisphosphonates, followed by autologous hematopoietic stem cell transplant. ⁵ Our case shares features with the above case, including the relatively young age of the patient and the presence of AL amyloidosis.

Our patient wished to avoid a surgical biopsy procedure, and therefore we utilized flow cytometry of the bursal fluid to establish that the etiology of fluid collection was consistent with his concurrent relapse of multiple myeloma. We believe that we are reporting the second case of multiple myeloma-associated bursitis and the first case associated with multiple myeloma relapse; to our knowledge, it is the first to be diagnosed with the aid of flow cytometry.

Because of our patient’s reliance on hemodialysis beginning one year prior to his presentation with olecranon bursitis, we entertain “dialysis elbow” within the differential diagnosis. Dialysis elbow is a relatively uncommon complication of dialysis, in which patients develop olecranon bursitis on the same side as the hemodialysis access after a prolonged (months to years) duration of hemodialysis. Serositis and mechanical forces are the hypothesized etiologies¹⁴; infectious and rheumatologic causes were excluded from the reported cases. Nevertheless, we favor a malignant cause based upon the flow cytometry findings indicating involvement by immunophenotypically abnormal plasma cells.

Our patient was treated initially with serial drainage and nonsteroidals, which had little impact. After diagnosis of a plasma cell population in the fluid, we offered local treatment with radiation and systemic treatment of multiple myeloma, which offered better but suboptimal control. Possible treatments for olecranon bursitis include surgery, corticosteroid injections, anti-inflammatories, and serial drainage. Nonsurgical management may be more effective than surgical management, and corticosteroid injection carries significant risks. On the other hand, serial drainage does not confer additional infection risk in cases with aseptic etiology.¹⁵ We combined conservative measures as well as treatment of the underlying disease, but we believe that our patient did not derive significant benefit because of the refractory nature of his disease; he also expressed a preference to avoid surgical intervention.
 

Conclusion

Bursitis is a rare but thought-provoking potential manifestation of multiple myeloma and AL amyloidosis; we believe that our patient’s bursitis was related to plasma cell neoplasia based upon co-occurrence with disease relapse. His bursitis turned out to be an early indicator of impending systemic relapse. In this particular case, in which the patient wished to avoid surgical intervention, flow cytometry was of great value, and we believe that our case is the first report of malignant bursitis being diagnosed by flow cytometry. Our patient’s case shares similarities with other biopsy-confirmed cases of malignant bursitis, but we were able to avoid the need for surgical biopsy or bursal stripping.

The authors thank Jennifer Wilham MT (ASCP), Pat Byrd MT (ASCP), and Darlene Mann MT (ASCP) for their technical support.