ATLANTA – Patients with acute myeloid leukemia (AML) bearing mutations in IDH1 who could not withstand the rigors of intensive therapy had improved event-free and overall survival when they were treated with the combination of ivosidenib (Tibsovo) and azacitidine (Onureg, Vidaza), compared with azacitidine alone.

The results come from the phase 3 AGILE trial. The ivosidenib-azacitidine (IVO-AZA) combination was associated with a 67% reduction in the risk of treatment failure, relapse, or death, and 56% improvement in overall survival, reported Hartmut Döhner, MD, from Ulm (Germany) University Hospital.

Median overall survival was 24 months with the combination, compared with 7.9 months for azacitidine-placebo, translating into a hazard ratio for death with the IVO-AZA of 0.44 (P = .0005).

“The IVO-AZA combination was safe and tolerable, with fewer infections reported relative to placebo plus AZA. Additionally, the clinical benefit of the combination was supported by favorable health-related quality of life,” he said.

Dr. Döhner spoke at a press briefing prior to the presentation of the trial results at the annual meeting of the American Society of Hematology.

“I’m really excited by the results from the AGILE trial,” commented Mikkael A. Sekeres, MD, chief of the division of hematology at the University of Miami’s Sylvester Comprehensive Cancer Center, who moderated the briefing.

The results show “survival that’s three times longer for a combination of ivosidenib plus azacitidine versus azacitidine alone in a very distinct population of patients who have an IDH1 mutation,” he said.

“The question that will arise is, if the standard of care is now to give azacitidine and venetoclax [Venclexta] to patients who don’t receive intensive chemotherapy in the inpatient setting, where does this trial end? And I would answer [by saying] that the combination of azacitidine is not truly nonintensive therapy, and it’s probably on a spectrum between nonintensive and intensive therapy, and probably closer to seven plus three than a lot of people recognize,” Dr. Sekeres said.

The combination of ivosidenib and azacitidine may therefore be a better choice for treatment of older patients with IDH1-mutated AML – particularly those with comorbidities – who may not be able to tolerate venetoclax plus azacitidine, he added.
 

AGILE results

For the analysis presented at the meeting, there was a data cutoff in March 2021, at which point 146 patients out of a planned 200 had been enrolled and randomly assigned. They received treatment with either oral ivosidenib 500 mg daily plus azacitidine 75 mg/m², delivered subcutaneously or intravenously, or azacitidine plus placebo.

In May 2021, after an interim analysis, the independent data-monitoring committee recommended a halt to the trial because of significant improvements in outcomes among patients assigned to the combination, and those data are reported at the meeting.

The median patient age was about 76 years in each group. Approximately 75% of patients in each arm had de novo AML, and about 25% had AML secondary to treatment, myelodysplastic syndrome, or myeloproliferative neoplasms. The majority of patients in each group had intermediate cytogenetic risk disease.

The analysis was by intention to treat, with patients who did not have complete remission (CR) by week 24 considered to have had an event on day 1 of randomization.

At the time of the interim analysis, with the longest follow-up out to 29 months (the investigators did not report median follow-up time for the study), there were significantly fewer study events – defined as treatment failure by week 24, relapse from remission, or death from any cause – in the ivosidenib/azacitidine combination, with a hazard ratio of 0.33 (P = .0011).

The EFS benefit and the overall survival benefit were consistent across subgroups, the researchers noted, including in patients with de novo disease, demographics, baseline cytogenetic risk status, World Health Organization AML classification, baseline white blood cell count, and baseline percentage of bone marrow blasts.

Clinical and hematologic responses also favored the combination, with a complete response (CR) rate of 34%, compared with 11% for azacitidine alone (odds ratio, 4.8; P < .0001), and respective overall response rates of 45% versus 14% (odds ratio, 7.2; P < .0001).

Health-related quality of life measures also trended better with the combination across all subscales, and were significantly better at day 1 of cycle 5 in the diarrhea and appetite loss domains.

Treatment-emergent adverse events included grade 2 or higher differentiation syndrome, which occurred in 14.1% of patients treated with IVO-AZA versus 8.2% treated with AZA alone. Grade 3 or higher QT interval prolongation was also more frequent with the combination, at 9.9% versus 4.1%.

Any-grade infections were less common with IVO-AZA, however, at 28.2% versus 49.3% with AZA alone. At the briefing, this news organization asked coinvestigator Stephane de Botton, MD, Gustave Roussy Cancer Center, Villejuif, France, whether he could explain this seemingly paradoxical result.

He replied that the combination results in greater production of neutrophils and therefore better protection against infections, compared with azacitidine alone.

The study was funded by Agios Pharmaceuticals, now a part of Servier Pharmaceuticals. Dr. Döhner disclosed consultancy and other relationships with various companies. Dr. Sekeres disclosed consulting/advising for Novartis, Takea/Millennium, and Bristol-Myers Squibb.

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

ATLANTA – Patients with acute myeloid leukemia (AML) bearing mutations in IDH1 who could not withstand the rigors of intensive therapy had improved event-free and overall survival when they were treated with the combination of ivosidenib (Tibsovo) and azacitidine (Onureg, Vidaza), compared with azacitidine alone.

The results come from the phase 3 AGILE trial. The ivosidenib-azacitidine (IVO-AZA) combination was associated with a 67% reduction in the risk of treatment failure, relapse, or death, and 56% improvement in overall survival, reported Hartmut Döhner, MD, from Ulm (Germany) University Hospital.

Median overall survival was 24 months with the combination, compared with 7.9 months for azacitidine-placebo, translating into a hazard ratio for death with the IVO-AZA of 0.44 (P = .0005).

“The IVO-AZA combination was safe and tolerable, with fewer infections reported relative to placebo plus AZA. Additionally, the clinical benefit of the combination was supported by favorable health-related quality of life,” he said.

Dr. Döhner spoke at a press briefing prior to the presentation of the trial results at the annual meeting of the American Society of Hematology.

“I’m really excited by the results from the AGILE trial,” commented Mikkael A. Sekeres, MD, chief of the division of hematology at the University of Miami’s Sylvester Comprehensive Cancer Center, who moderated the briefing.

The results show “survival that’s three times longer for a combination of ivosidenib plus azacitidine versus azacitidine alone in a very distinct population of patients who have an IDH1 mutation,” he said.

“The question that will arise is, if the standard of care is now to give azacitidine and venetoclax [Venclexta] to patients who don’t receive intensive chemotherapy in the inpatient setting, where does this trial end? And I would answer [by saying] that the combination of azacitidine is not truly nonintensive therapy, and it’s probably on a spectrum between nonintensive and intensive therapy, and probably closer to seven plus three than a lot of people recognize,” Dr. Sekeres said.

The combination of ivosidenib and azacitidine may therefore be a better choice for treatment of older patients with IDH1-mutated AML – particularly those with comorbidities – who may not be able to tolerate venetoclax plus azacitidine, he added.
 

AGILE results

For the analysis presented at the meeting, there was a data cutoff in March 2021, at which point 146 patients out of a planned 200 had been enrolled and randomly assigned. They received treatment with either oral ivosidenib 500 mg daily plus azacitidine 75 mg/m², delivered subcutaneously or intravenously, or azacitidine plus placebo.

In May 2021, after an interim analysis, the independent data-monitoring committee recommended a halt to the trial because of significant improvements in outcomes among patients assigned to the combination, and those data are reported at the meeting.

The median patient age was about 76 years in each group. Approximately 75% of patients in each arm had de novo AML, and about 25% had AML secondary to treatment, myelodysplastic syndrome, or myeloproliferative neoplasms. The majority of patients in each group had intermediate cytogenetic risk disease.

The analysis was by intention to treat, with patients who did not have complete remission (CR) by week 24 considered to have had an event on day 1 of randomization.

At the time of the interim analysis, with the longest follow-up out to 29 months (the investigators did not report median follow-up time for the study), there were significantly fewer study events – defined as treatment failure by week 24, relapse from remission, or death from any cause – in the ivosidenib/azacitidine combination, with a hazard ratio of 0.33 (P = .0011).

The EFS benefit and the overall survival benefit were consistent across subgroups, the researchers noted, including in patients with de novo disease, demographics, baseline cytogenetic risk status, World Health Organization AML classification, baseline white blood cell count, and baseline percentage of bone marrow blasts.

Clinical and hematologic responses also favored the combination, with a complete response (CR) rate of 34%, compared with 11% for azacitidine alone (odds ratio, 4.8; P < .0001), and respective overall response rates of 45% versus 14% (odds ratio, 7.2; P < .0001).

Health-related quality of life measures also trended better with the combination across all subscales, and were significantly better at day 1 of cycle 5 in the diarrhea and appetite loss domains.

Treatment-emergent adverse events included grade 2 or higher differentiation syndrome, which occurred in 14.1% of patients treated with IVO-AZA versus 8.2% treated with AZA alone. Grade 3 or higher QT interval prolongation was also more frequent with the combination, at 9.9% versus 4.1%.

Any-grade infections were less common with IVO-AZA, however, at 28.2% versus 49.3% with AZA alone. At the briefing, this news organization asked coinvestigator Stephane de Botton, MD, Gustave Roussy Cancer Center, Villejuif, France, whether he could explain this seemingly paradoxical result.

He replied that the combination results in greater production of neutrophils and therefore better protection against infections, compared with azacitidine alone.

The study was funded by Agios Pharmaceuticals, now a part of Servier Pharmaceuticals. Dr. Döhner disclosed consultancy and other relationships with various companies. Dr. Sekeres disclosed consulting/advising for Novartis, Takea/Millennium, and Bristol-Myers Squibb.

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

ATLANTA – Patients with acute myeloid leukemia (AML) bearing mutations in IDH1 who could not withstand the rigors of intensive therapy had improved event-free and overall survival when they were treated with the combination of ivosidenib (Tibsovo) and azacitidine (Onureg, Vidaza), compared with azacitidine alone.

The results come from the phase 3 AGILE trial. The ivosidenib-azacitidine (IVO-AZA) combination was associated with a 67% reduction in the risk of treatment failure, relapse, or death, and 56% improvement in overall survival, reported Hartmut Döhner, MD, from Ulm (Germany) University Hospital.

Median overall survival was 24 months with the combination, compared with 7.9 months for azacitidine-placebo, translating into a hazard ratio for death with the IVO-AZA of 0.44 (P = .0005).

“The IVO-AZA combination was safe and tolerable, with fewer infections reported relative to placebo plus AZA. Additionally, the clinical benefit of the combination was supported by favorable health-related quality of life,” he said.

Dr. Döhner spoke at a press briefing prior to the presentation of the trial results at the annual meeting of the American Society of Hematology.

“I’m really excited by the results from the AGILE trial,” commented Mikkael A. Sekeres, MD, chief of the division of hematology at the University of Miami’s Sylvester Comprehensive Cancer Center, who moderated the briefing.

The results show “survival that’s three times longer for a combination of ivosidenib plus azacitidine versus azacitidine alone in a very distinct population of patients who have an IDH1 mutation,” he said.

“The question that will arise is, if the standard of care is now to give azacitidine and venetoclax [Venclexta] to patients who don’t receive intensive chemotherapy in the inpatient setting, where does this trial end? And I would answer [by saying] that the combination of azacitidine is not truly nonintensive therapy, and it’s probably on a spectrum between nonintensive and intensive therapy, and probably closer to seven plus three than a lot of people recognize,” Dr. Sekeres said.

The combination of ivosidenib and azacitidine may therefore be a better choice for treatment of older patients with IDH1-mutated AML – particularly those with comorbidities – who may not be able to tolerate venetoclax plus azacitidine, he added.
 

AGILE results

For the analysis presented at the meeting, there was a data cutoff in March 2021, at which point 146 patients out of a planned 200 had been enrolled and randomly assigned. They received treatment with either oral ivosidenib 500 mg daily plus azacitidine 75 mg/m², delivered subcutaneously or intravenously, or azacitidine plus placebo.

In May 2021, after an interim analysis, the independent data-monitoring committee recommended a halt to the trial because of significant improvements in outcomes among patients assigned to the combination, and those data are reported at the meeting.

The median patient age was about 76 years in each group. Approximately 75% of patients in each arm had de novo AML, and about 25% had AML secondary to treatment, myelodysplastic syndrome, or myeloproliferative neoplasms. The majority of patients in each group had intermediate cytogenetic risk disease.

The analysis was by intention to treat, with patients who did not have complete remission (CR) by week 24 considered to have had an event on day 1 of randomization.

At the time of the interim analysis, with the longest follow-up out to 29 months (the investigators did not report median follow-up time for the study), there were significantly fewer study events – defined as treatment failure by week 24, relapse from remission, or death from any cause – in the ivosidenib/azacitidine combination, with a hazard ratio of 0.33 (P = .0011).

The EFS benefit and the overall survival benefit were consistent across subgroups, the researchers noted, including in patients with de novo disease, demographics, baseline cytogenetic risk status, World Health Organization AML classification, baseline white blood cell count, and baseline percentage of bone marrow blasts.

Clinical and hematologic responses also favored the combination, with a complete response (CR) rate of 34%, compared with 11% for azacitidine alone (odds ratio, 4.8; P < .0001), and respective overall response rates of 45% versus 14% (odds ratio, 7.2; P < .0001).

Health-related quality of life measures also trended better with the combination across all subscales, and were significantly better at day 1 of cycle 5 in the diarrhea and appetite loss domains.

Treatment-emergent adverse events included grade 2 or higher differentiation syndrome, which occurred in 14.1% of patients treated with IVO-AZA versus 8.2% treated with AZA alone. Grade 3 or higher QT interval prolongation was also more frequent with the combination, at 9.9% versus 4.1%.

Any-grade infections were less common with IVO-AZA, however, at 28.2% versus 49.3% with AZA alone. At the briefing, this news organization asked coinvestigator Stephane de Botton, MD, Gustave Roussy Cancer Center, Villejuif, France, whether he could explain this seemingly paradoxical result.

He replied that the combination results in greater production of neutrophils and therefore better protection against infections, compared with azacitidine alone.

The study was funded by Agios Pharmaceuticals, now a part of Servier Pharmaceuticals. Dr. Döhner disclosed consultancy and other relationships with various companies. Dr. Sekeres disclosed consulting/advising for Novartis, Takea/Millennium, and Bristol-Myers Squibb.

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

In a field of poor outcomes, few standards of care, and small populations of patients scattered across the world, investigators studying rare genitourinary (GU) cancers are gaining ground through international collaboration and novel trial design.

Fundamental clinical questions in the area remain unanswered, including the value of conventional treatments, such as chemotherapy and surgery, vs. emerging immunotherapy combinations.

Managing patients with rare GU cancers presents a variety of challenges, as does conducting research in the field, according to Philippe E. Spiess, MD, MS, FACS, assistant chief of surgical services and senior member in the department of GU oncology at Moffitt Cancer Center, Tampa.

“Unfortunately, there are limited resources for patients – from an education, from a patient advocacy, and ultimately also from a research standpoint,” Dr. Spiess said in an interview, noting difficulties in attaining funding and reaching meaningful endpoints.

The Global Society of Rare Genitourinary Tumors

Last year Dr. Spiess teamed up with Andrea Necchi, MD, of the department of medical oncology at Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, to found the Global Society of Rare Genitourinary Tumors (GSRGT), the first organization of its kind.

“We’ve formally established a society and gotten some of the world leaders [in the field] … to work with us in developing educational tools and patient advocacy efforts to really promote and improve the care of patients impacted with rare cancers,” Dr. Spiess said.

He went on to highlight the truly global makeup of GSRGT, which includes members from leading centers in North America, South America, Europe, and India, and described it as a “grass-roots” organization that he and Dr. Necchi privately funded without financial backing from pharmaceutical companies.

The first GSRGT summit took place in 2020; it focused on penile and testis cancers and was attended by more than 350 participants. The second summit, planned for March 2022, in a virtual format, will focus on rare kidney cancers and upper tract cancers.

“We’ll definitely be having a lot of important conversations about important unmet needs, and some of the important clinical trials that patients and clinicians should be aware of,” Dr. Spiess said.

Dr. Spiess is currently involved in the International Penile Advanced Cancer Trial(InPACT), which is aiming to enroll 200 patients with squamous cell carcinoma of the penis. The randomized study will compare outcomes across patients treated with standard surgery alone, neoadjuvant chemotherapy plus surgery, and neoadjuvant chemoradiotherapy plus surgery.

“I think this is going to be a landmark study because it’s going to give really baseline high-quality data on the effectiveness of these therapies,” Dr. Spiess said.

Results are expected in 2024.

Basket trials open doors for patients in need

Other investigators are testing immunotherapy combinations in patients with rare GU tumors via nonrandomized basket trials, which widen inclusion criteria and improve local availability.

According to Bradley McGregor, MD, clinical director of the Lank Center for GU Oncology at the Dana-Farber Cancer Institute in Boston, early results from these trials are promising, both in terms of therapeutic efficacy and the approach itself.

“Patients [with rare GU tumors] would come to us saying, ‘Well, what can we do? What trial?’,” Dr. McGregor said. “But really, there was no trial to get them on.”Basket trials are therefore needed, he said, as they accelerate progress in the field and help meet patient needs.

“For some of these relatively rare diseases … there is no standard of care,” Dr. McGregor said. “And low incidence makes it challenging to conduct a dedicated clinical trial. Those patients are left with minimal therapeutic options. … We look to provide care for that unmet need.”Andrea B. Apolo, MD, described similar experiences as head of the bladder cancer section of the GU malignancies branch of the National Cancer Institute (NCI), Bethesda, Md.

“I’ve been at the NCI for the past 10 years and I’ve gotten a lot of referrals for rare tumors,” Dr. Apolo said. “[These patients] have tried all available standard of care options, and therefore are often looking for clinical trials and new drugs – any kind of therapy that may be effective for their disease.”This call for help, along with a growing scientific curiosity, motivated Dr. Apolo to design trials that would include patients who had nowhere else to go.

“I became very interested in … understanding more about the mechanism of tumorigenesis and understanding rare tumors, biologically, within the lab,” she said, “but also clinically, in terms of finding more effective therapies.”

Both Dr. McGregor and Dr. Apolo are currently conducting basket trials for patients with rare GU tumors. While Dr. McGregor is testing a combination of PD-1 inhibitor nivolumab and CTLA-4 inhibitor ipilimumab, Dr. Apolo is exploring the benefit of cabozantinib, a targeted therapy, given with either nivolumab or nivolumab plus ipilimumab.

When asked about these trials, Dr. Spiess said that “basket trials are important because they may give us an understanding of some potentially useful therapies or combinations;” however, he also pointed out their limitations, noting that they may inaccurately characterize the efficacy of given therapies over a broad array of disease entities even if they are of similar histology. As an example, he noted “very different” genomic profiles across squamous cell carcinomas of the pelvis depending on exact anatomical location, suggesting that these differences may affect responses to therapy, citing a recent study in European Urology that he conducted with Dr. Necchi.¹

“[Basket trials] are probably not going to be the be-all-end-all,” Dr. Spiess said. “It really requires a global initiative to do these types of studies, which the Global Society of Rare Genitourinary Tumors will allow.”

Exploring immunotherapy combinations

Despite the potential limitations, recent basket trials involving immunotherapy regimens have been associated with overall response rates, in some subgroups, that exceed 35%.^2,3

In comparison with previous trials, many of which had response rates in the single digits, or no responses at all, these results are, in Dr. McGregor’s words, “very thought provoking.”Most rare GU malignancies fall into one of four categories: bladder cancer variant histology (BCVH), adrenal tumors, penile squamous cell carcinoma (PSCC), and chemotherapy-refractory germ cell tumors (CRGCT). Among these, BCVH has the strongest evidence supporting clinical use of immunotherapy, based on U.S. approval for urothelial histology, according to Dr. McGregor.⁴Data supporting immunotherapy for the remaining disease subtypes are scarce. Although pembrolizumab is approved for patients with solid tumors that exhibit microsatellite instability (MSI), MSI is uncommon among patients with rare GU cancers; estimated incidence rates are less than 10%.⁴

“As such, clinical trials to address this unmet need are imperative,” Dr. McGregor wrote in a recent review article.⁴

According to Dr. McGregor, programmed death ligand 1 (PD-L1) expression in rare GU tumors may be relatively common in some disease subtypes, such as PSCC, which has a PD-L1 expression rate of up to 60%.⁴

But rare GU tumor trials involving a single checkpoint inhibitor have produced limited results, if any.

The largest trial for adrenocortical carcinoma (ACC), for example, which included 50 patients, showed that avelumab resulted in an objective response rate (ORR) of just 6%.⁵

Pembrolizumab was slightly more effective for ACC, based on a trial involving 39 patients, which returned an ORR of 23%, and another trial involving 15 patients that had a 15% ORR.^6,7

Two other trials, which tested single-agent pembrolizumab or durvalumab in patients with CRGCT, resulted in no responses at all, whereas a trial testing pembrolizumab alone for penile squamous cell carcinoma was terminated in 2020, citing poor accrual.^8,9 Still, the durvalumab trial for CRGCT, led by Dr. Necchi, did offer a glimpse at what might be possible with a combination of immunotherapies. Although no responses were observed among 11 patients who received durvalumab alone, an efficacy signal was observed in a second cohort of 11 patients who were given durvalumab in combination with the CTLA-4 inhibitor tremilimumab.⁹

Out of those 11 patients, 1 had a partial response, and another achieved stable disease.

In light of these findings, and more that have been published since then, the clinical trial landscape for rare GU tumors is shifting toward a combination immunotherapy approach, according to Dr. McGregor.⁴

Nivolumab and ipilimumab

Dr. McGregor is leading a phase II trial (NCT03333616) testing a combination of nivolumab and ipilimumab in patients with a variety of advanced rare GU malignancies, including bladder and upper tract carcinoma of variant histology (BUTCVH), adrenal tumors, CRGCT, PSCC, and prostate cancer of variant histology (PCVH).

“When trials are designed, these patients are often forgotten,” Dr. McGregor noted. “We said, let’s do a trial for all rare GU tumors and just sort of assess and look for a signal, and, hopefully, find a signal that we can then take to the next level.”

Along with appropriate disease phenotype, trial eligibility depended upon an ECOG performance status of 0-2 and no prior exposure to checkpoint inhibitors. Treatment-naive patients were allowed. All participants received nivolumab 3 mg/kg and ipilimumab 1 mg/kg IV every 3 weeks for four doses, followed by maintenance nivolumab at a dose of 480 mg every 4 weeks.

Most recent results, published in Cancer, included data from 55 patients, including 19 with BUTCVH, 18 with adrenal tumors, and 18 with other tumors.³ After a median follow-up of 9.9 months, 28 patients (51%) received all four doses of the regimen, 25 of whom received maintenance therapy with a median of four cycles.

Overall, nine patients (16%) responded to therapy, six of whom (67%) maintained their response for at least 9 months. Two responses were complete, and seven were partial. Median progression-free survival was 2.8 months.

Twenty-two patients (39%) had grade 3 or higher treatment-related adverse events, approximately one-quarter (23%) needed high-dose steroids, and a slightly greater proportion (27%) discontinued the regimen because of adverse events. Three patients exhibited grade 5 toxicity, and one patient death was treatment related. A closer look at the efficacy data suggested that one disease subgroup benefited much more than the others. The overall response rate among 19 patients with BUTCVH was 37%, compared with 6% in the other two cohorts.

“A response rate of 37% compares quite favorably to anything we’ve seen to date,” Dr. McGregor said. “It’s remarkable that [this response] was seen across histologies – we saw this in urachal, we saw this in adenocarcinoma – we really saw this across the board. This is very, very, very intriguing data.”

The phase II trial is ongoing at multiple centers across the country, including the Dana-Farber/Harvard Cancer Center, Boston, the University of Texas MD Anderson Cancer Center, Houston, the Moores Cancer Center at University of California Health, San Diego, the Ohio State University Comprehensive Cancer Center, Columbus, and the Winship Cancer Institute of Emory University, Atlanta.

“We accrued this trial in just under 18 months,” Dr. McGregor said. “I think this shows that with a well-designed trial, we can actually study these diseases and improve outcomes in these patients.” According to Dr. McGregor, the current findings deserve further investigation, potentially including expansion of the BUTCVH cohort. Recruitment is ongoing for a fourth cohort involving patients with tumors that exhibit neuroendocrine differentiation.

Cabozantinib and nivolumab with or without ipilimumab

Dr. Apolo is leading a similar basket trial (NCT02496208) that is testing cabozantinib plus nivolumab with or without ipilimumab.

“What we’re doing is using immunotherapy and a targeted therapy that work in standard urothelial carcinoma and renal cell carcinoma,” Dr. Apolo said. “But really, we don’t know the activity in these rare GU tumors. … There’s still so much we don’t understand about what the driving mutations are, and how we can best target them.”

Most recent data, published in Journal of Clinical Oncology, include 122 patients with metastatic GU tumors, including urothelial carcinoma, clear cell renal cell carcinoma, bladder adenocarcinoma, and other rare GU cancers.²

Among these patients, 54 were in the phase I dose-finding cohort (eight escalating doses) and 64 were in the dose-expansion cohorts.

After a median follow-up of 40.4 months, 64 patients received the dual combination, whereas 56 received the triplet regimen. The ORR for 108 evaluable patients was 38%, including 12 complete responses (11.1%) and 29 partial responses (26.9%). The largest disease cohort, for urothelial carcinoma, included 33 patients and was associated with an ORR of 42.4%, with a complete response rate of 21.2%. Objective response rate was highest for squamous bladder cancer (85.7%; n = 7), followed by clear cell renal carcinoma (62.5%; n = 16), renal medullary cancer (50%; n = 2), penile cancer (44.4%; n = 9), small cell bladder cancer (33.1%; n = 3), bladder adenocarcinoma (20%; n = 15), and prostate cancer (11.1%; n = 9). No responses were seen in six patients with germ cell tumors.

Adding ipilimumab appeared to have a minimal impact on toxicity. Grade 3 or 4 treatment-related adverse events (AEs) occurred in 84% of patients in the dual combination group, compared with 80% receiving the triplet regimen. Most common AEs were hypophosphatemia (16-25%), lipase elevation (20%), fatigue (18-20%), ALT elevation (5-14%), AST elevation (9-11%), diarrhea (9-11%), and thromboembolic event (4-11%). One patient taking the triplet regimen had grade 5 pneumonitis.

These positive phase I results have paved the way for the phase II ICONIC trial (NCT03866382), a national study available through the Alliance Cooperative Group. The trial is currently recruiting, with an estimated enrollment of 224 patients with rare GU tumors.

The ICONIC trial is just one of several studies that Dr. Apolo is conducting for patients with rare GU cancer. “I have several bladder cancer trials where I’m accepting rare GU tumors to enroll,” she said, noting that efficacy signals in these exploratory cohorts may be pursued with expansion studies like ICONIC.

This inclusive strategy is uncovering promising new treatments for some rare GU malignancies, but the rarest of the rare tumor types remain challenging to study, Dr. Apolo said, because very small sample sizes can preclude significant data. “Although we do have the referral base at the NCI, we still get a small number of a lot of rare tumors,” Dr. Apolo said. “What I end up having, a lot of time, are small subsets of rare tumors – I’ll have 4 of one kind, 10 of another.” This situation means that sometimes, time and resources must be focused where they are needed most.

“Sometimes I actually have to decide which are the more common rare tumors so I can study them in a larger cohort,” Dr. Apolo said. “It can have more clinical impact within the community of that rare tumor.” Dr. Apolo described the inherent conflict involved in this decision, but also, its ultimate necessity.

“It’s what you don’t want to do, but you end up doing,” she said. “Because you want to be inclusive and include the rare, rare tumor, but sometimes you just can’t get enough numbers to see if there’s actually a difference [in efficacy]. If it doesn’t work in one patient, does that mean it doesn’t work at all? You need more numbers to really test the efficacy of therapy.”

From clinical trials to clinical practice

To accrue the number of patients needed for practice-altering findings, both Dr. McGregor and Dr. Apolo emphasized the importance of institutional support and collaborative trial designs.

“The FDA is a great ally,” Dr. McGregor said. “They’re acutely aware of the challenges facing patients with rare malignancies – not just GU malignancies. They’re continuing to evaluate the best way to move these drugs forward for those patients. … They’re constantly working with investigators, with industry, looking at data and trying to determine at what threshold these will be practice-changing studies.”

Dr. McGregor suggested that larger trials could shift national guideline recommendations toward combination immunotherapies for patients with rare GU tumors, which would lead to inclusion in compendia, and from there, broader clinical usage.

“At end of the day, luckily, we’re not dealing with drugs that aren’t available,” Dr. McGregor said. “These are drugs that are readily available, approved by the FDA in other settings.”

Dr. Apolo also described strong support from the NCI.

“The NCI really encourages the conduction and enrollment of these rare GU tumor trials, because they understand that the NCI is a really good place to study these rare tumors,” she said. “We have unique resources that make it feasible to conduct some of these trials.”

Dr. Apolo also praised the Alliance Cooperative Group for helping expand patient access to rare GU tumor trials.

“[The Alliance Cooperative Group] makes trials available at community centers across the country,” Dr. Apolo said. “Patients don’t have to travel to the NCI, and they can get the same therapies.”

Still, Dr. Apolo recommended that, when possible, clinicians refer patients with newly diagnosed, rare GU tumors to centers that see a higher number of such cases.

“It’s hard to keep up with all the different treatments that are available right now for different cancers,” Dr. Apolo said. “And sometimes for the rare tumors, there may be great opportunities within a clinical trial that a cancer center may have available that may not be available locally in the community.”

For patients who would like to learn more about rare bladder cancers, Dr. Apolo recommended a visit to the Bladder Cancer Advocacy Network (BCAN) website (bcan.org).

“I’m a big fan of these patient-centered advocacy networks,” Dr. Apolo said. “I like BCAN a lot. It’s a patient-run organization for patients with bladder cancer. With them, I have done a couple of webinars for rare bladder tumors that Ive had some patients tell me are very helpful. They’re a terrific organization that really provides not only emotional support but also educational support for patients that have a diagnosis of bladder cancer and now, rare bladder tumors.” Dr. Spiess offered similar advice for clinicians managing patients with rare GU tumors. He emphasized the key role played by patient advocacy groups, and recommended referral to institutions specializing in specific GU tumor types. For example, he recommended that patients with penile cancer be treated at Moffitt (Tampa) or MD Anderson (Houston), as these centers have the greatest relevant experience. Dr. McGregor disclosed relationships with Bayer, Astellas, Nektar, and others. Dr. Apolo and Dr. Spiess disclosed no conflicts of interest.
 

References

1.Necchi A et al. Eur Urol. 2021 June;79:S929-30.

2.Apolo AB et al. J Clin Oncol. 2021;39(6_suppl):3.

3.McGregor BA et al. Cancer. 2021 Mar 15;127(6):840-9.

4.McGregor BA and Sonpavde GP. Eur Urol Focus. 2020;6(1):14-16.5.Le Tourneau C et al. J Immunother Cancer. 2018 Oct 22;6(1):111.6.Naing A et al. J Immunother Cancer. 2020;8(1).

7.Raj N et al. J Clin Oncol. 2020;38(1):71-80.

8.Adra N et al. Ann Oncol. 2018;29(1):209-14.

9.Necchi A et al. Eur Urol. 2019;75(1):201-3.

In a field of poor outcomes, few standards of care, and small populations of patients scattered across the world, investigators studying rare genitourinary (GU) cancers are gaining ground through international collaboration and novel trial design.

Fundamental clinical questions in the area remain unanswered, including the value of conventional treatments, such as chemotherapy and surgery, vs. emerging immunotherapy combinations.

Managing patients with rare GU cancers presents a variety of challenges, as does conducting research in the field, according to Philippe E. Spiess, MD, MS, FACS, assistant chief of surgical services and senior member in the department of GU oncology at Moffitt Cancer Center, Tampa.

“Unfortunately, there are limited resources for patients – from an education, from a patient advocacy, and ultimately also from a research standpoint,” Dr. Spiess said in an interview, noting difficulties in attaining funding and reaching meaningful endpoints.

The Global Society of Rare Genitourinary Tumors

Last year Dr. Spiess teamed up with Andrea Necchi, MD, of the department of medical oncology at Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, to found the Global Society of Rare Genitourinary Tumors (GSRGT), the first organization of its kind.

“We’ve formally established a society and gotten some of the world leaders [in the field] … to work with us in developing educational tools and patient advocacy efforts to really promote and improve the care of patients impacted with rare cancers,” Dr. Spiess said.

He went on to highlight the truly global makeup of GSRGT, which includes members from leading centers in North America, South America, Europe, and India, and described it as a “grass-roots” organization that he and Dr. Necchi privately funded without financial backing from pharmaceutical companies.

The first GSRGT summit took place in 2020; it focused on penile and testis cancers and was attended by more than 350 participants. The second summit, planned for March 2022, in a virtual format, will focus on rare kidney cancers and upper tract cancers.

“We’ll definitely be having a lot of important conversations about important unmet needs, and some of the important clinical trials that patients and clinicians should be aware of,” Dr. Spiess said.

Dr. Spiess is currently involved in the International Penile Advanced Cancer Trial(InPACT), which is aiming to enroll 200 patients with squamous cell carcinoma of the penis. The randomized study will compare outcomes across patients treated with standard surgery alone, neoadjuvant chemotherapy plus surgery, and neoadjuvant chemoradiotherapy plus surgery.

“I think this is going to be a landmark study because it’s going to give really baseline high-quality data on the effectiveness of these therapies,” Dr. Spiess said.

Results are expected in 2024.

Basket trials open doors for patients in need

Other investigators are testing immunotherapy combinations in patients with rare GU tumors via nonrandomized basket trials, which widen inclusion criteria and improve local availability.

According to Bradley McGregor, MD, clinical director of the Lank Center for GU Oncology at the Dana-Farber Cancer Institute in Boston, early results from these trials are promising, both in terms of therapeutic efficacy and the approach itself.

“Patients [with rare GU tumors] would come to us saying, ‘Well, what can we do? What trial?’,” Dr. McGregor said. “But really, there was no trial to get them on.”Basket trials are therefore needed, he said, as they accelerate progress in the field and help meet patient needs.

“For some of these relatively rare diseases … there is no standard of care,” Dr. McGregor said. “And low incidence makes it challenging to conduct a dedicated clinical trial. Those patients are left with minimal therapeutic options. … We look to provide care for that unmet need.”Andrea B. Apolo, MD, described similar experiences as head of the bladder cancer section of the GU malignancies branch of the National Cancer Institute (NCI), Bethesda, Md.

“I’ve been at the NCI for the past 10 years and I’ve gotten a lot of referrals for rare tumors,” Dr. Apolo said. “[These patients] have tried all available standard of care options, and therefore are often looking for clinical trials and new drugs – any kind of therapy that may be effective for their disease.”This call for help, along with a growing scientific curiosity, motivated Dr. Apolo to design trials that would include patients who had nowhere else to go.

“I became very interested in … understanding more about the mechanism of tumorigenesis and understanding rare tumors, biologically, within the lab,” she said, “but also clinically, in terms of finding more effective therapies.”

Both Dr. McGregor and Dr. Apolo are currently conducting basket trials for patients with rare GU tumors. While Dr. McGregor is testing a combination of PD-1 inhibitor nivolumab and CTLA-4 inhibitor ipilimumab, Dr. Apolo is exploring the benefit of cabozantinib, a targeted therapy, given with either nivolumab or nivolumab plus ipilimumab.

When asked about these trials, Dr. Spiess said that “basket trials are important because they may give us an understanding of some potentially useful therapies or combinations;” however, he also pointed out their limitations, noting that they may inaccurately characterize the efficacy of given therapies over a broad array of disease entities even if they are of similar histology. As an example, he noted “very different” genomic profiles across squamous cell carcinomas of the pelvis depending on exact anatomical location, suggesting that these differences may affect responses to therapy, citing a recent study in European Urology that he conducted with Dr. Necchi.¹

“[Basket trials] are probably not going to be the be-all-end-all,” Dr. Spiess said. “It really requires a global initiative to do these types of studies, which the Global Society of Rare Genitourinary Tumors will allow.”

Exploring immunotherapy combinations

Despite the potential limitations, recent basket trials involving immunotherapy regimens have been associated with overall response rates, in some subgroups, that exceed 35%.^2,3

In comparison with previous trials, many of which had response rates in the single digits, or no responses at all, these results are, in Dr. McGregor’s words, “very thought provoking.”Most rare GU malignancies fall into one of four categories: bladder cancer variant histology (BCVH), adrenal tumors, penile squamous cell carcinoma (PSCC), and chemotherapy-refractory germ cell tumors (CRGCT). Among these, BCVH has the strongest evidence supporting clinical use of immunotherapy, based on U.S. approval for urothelial histology, according to Dr. McGregor.⁴Data supporting immunotherapy for the remaining disease subtypes are scarce. Although pembrolizumab is approved for patients with solid tumors that exhibit microsatellite instability (MSI), MSI is uncommon among patients with rare GU cancers; estimated incidence rates are less than 10%.⁴

“As such, clinical trials to address this unmet need are imperative,” Dr. McGregor wrote in a recent review article.⁴

According to Dr. McGregor, programmed death ligand 1 (PD-L1) expression in rare GU tumors may be relatively common in some disease subtypes, such as PSCC, which has a PD-L1 expression rate of up to 60%.⁴

But rare GU tumor trials involving a single checkpoint inhibitor have produced limited results, if any.

The largest trial for adrenocortical carcinoma (ACC), for example, which included 50 patients, showed that avelumab resulted in an objective response rate (ORR) of just 6%.⁵

Pembrolizumab was slightly more effective for ACC, based on a trial involving 39 patients, which returned an ORR of 23%, and another trial involving 15 patients that had a 15% ORR.^6,7

Two other trials, which tested single-agent pembrolizumab or durvalumab in patients with CRGCT, resulted in no responses at all, whereas a trial testing pembrolizumab alone for penile squamous cell carcinoma was terminated in 2020, citing poor accrual.^8,9 Still, the durvalumab trial for CRGCT, led by Dr. Necchi, did offer a glimpse at what might be possible with a combination of immunotherapies. Although no responses were observed among 11 patients who received durvalumab alone, an efficacy signal was observed in a second cohort of 11 patients who were given durvalumab in combination with the CTLA-4 inhibitor tremilimumab.⁹

Out of those 11 patients, 1 had a partial response, and another achieved stable disease.

In light of these findings, and more that have been published since then, the clinical trial landscape for rare GU tumors is shifting toward a combination immunotherapy approach, according to Dr. McGregor.⁴

Nivolumab and ipilimumab

Dr. McGregor is leading a phase II trial (NCT03333616) testing a combination of nivolumab and ipilimumab in patients with a variety of advanced rare GU malignancies, including bladder and upper tract carcinoma of variant histology (BUTCVH), adrenal tumors, CRGCT, PSCC, and prostate cancer of variant histology (PCVH).

“When trials are designed, these patients are often forgotten,” Dr. McGregor noted. “We said, let’s do a trial for all rare GU tumors and just sort of assess and look for a signal, and, hopefully, find a signal that we can then take to the next level.”

Along with appropriate disease phenotype, trial eligibility depended upon an ECOG performance status of 0-2 and no prior exposure to checkpoint inhibitors. Treatment-naive patients were allowed. All participants received nivolumab 3 mg/kg and ipilimumab 1 mg/kg IV every 3 weeks for four doses, followed by maintenance nivolumab at a dose of 480 mg every 4 weeks.

Most recent results, published in Cancer, included data from 55 patients, including 19 with BUTCVH, 18 with adrenal tumors, and 18 with other tumors.³ After a median follow-up of 9.9 months, 28 patients (51%) received all four doses of the regimen, 25 of whom received maintenance therapy with a median of four cycles.

Overall, nine patients (16%) responded to therapy, six of whom (67%) maintained their response for at least 9 months. Two responses were complete, and seven were partial. Median progression-free survival was 2.8 months.

Twenty-two patients (39%) had grade 3 or higher treatment-related adverse events, approximately one-quarter (23%) needed high-dose steroids, and a slightly greater proportion (27%) discontinued the regimen because of adverse events. Three patients exhibited grade 5 toxicity, and one patient death was treatment related. A closer look at the efficacy data suggested that one disease subgroup benefited much more than the others. The overall response rate among 19 patients with BUTCVH was 37%, compared with 6% in the other two cohorts.

“A response rate of 37% compares quite favorably to anything we’ve seen to date,” Dr. McGregor said. “It’s remarkable that [this response] was seen across histologies – we saw this in urachal, we saw this in adenocarcinoma – we really saw this across the board. This is very, very, very intriguing data.”

The phase II trial is ongoing at multiple centers across the country, including the Dana-Farber/Harvard Cancer Center, Boston, the University of Texas MD Anderson Cancer Center, Houston, the Moores Cancer Center at University of California Health, San Diego, the Ohio State University Comprehensive Cancer Center, Columbus, and the Winship Cancer Institute of Emory University, Atlanta.

“We accrued this trial in just under 18 months,” Dr. McGregor said. “I think this shows that with a well-designed trial, we can actually study these diseases and improve outcomes in these patients.” According to Dr. McGregor, the current findings deserve further investigation, potentially including expansion of the BUTCVH cohort. Recruitment is ongoing for a fourth cohort involving patients with tumors that exhibit neuroendocrine differentiation.

Cabozantinib and nivolumab with or without ipilimumab

Dr. Apolo is leading a similar basket trial (NCT02496208) that is testing cabozantinib plus nivolumab with or without ipilimumab.

“What we’re doing is using immunotherapy and a targeted therapy that work in standard urothelial carcinoma and renal cell carcinoma,” Dr. Apolo said. “But really, we don’t know the activity in these rare GU tumors. … There’s still so much we don’t understand about what the driving mutations are, and how we can best target them.”

Most recent data, published in Journal of Clinical Oncology, include 122 patients with metastatic GU tumors, including urothelial carcinoma, clear cell renal cell carcinoma, bladder adenocarcinoma, and other rare GU cancers.²

Among these patients, 54 were in the phase I dose-finding cohort (eight escalating doses) and 64 were in the dose-expansion cohorts.

After a median follow-up of 40.4 months, 64 patients received the dual combination, whereas 56 received the triplet regimen. The ORR for 108 evaluable patients was 38%, including 12 complete responses (11.1%) and 29 partial responses (26.9%). The largest disease cohort, for urothelial carcinoma, included 33 patients and was associated with an ORR of 42.4%, with a complete response rate of 21.2%. Objective response rate was highest for squamous bladder cancer (85.7%; n = 7), followed by clear cell renal carcinoma (62.5%; n = 16), renal medullary cancer (50%; n = 2), penile cancer (44.4%; n = 9), small cell bladder cancer (33.1%; n = 3), bladder adenocarcinoma (20%; n = 15), and prostate cancer (11.1%; n = 9). No responses were seen in six patients with germ cell tumors.

Adding ipilimumab appeared to have a minimal impact on toxicity. Grade 3 or 4 treatment-related adverse events (AEs) occurred in 84% of patients in the dual combination group, compared with 80% receiving the triplet regimen. Most common AEs were hypophosphatemia (16-25%), lipase elevation (20%), fatigue (18-20%), ALT elevation (5-14%), AST elevation (9-11%), diarrhea (9-11%), and thromboembolic event (4-11%). One patient taking the triplet regimen had grade 5 pneumonitis.

These positive phase I results have paved the way for the phase II ICONIC trial (NCT03866382), a national study available through the Alliance Cooperative Group. The trial is currently recruiting, with an estimated enrollment of 224 patients with rare GU tumors.

The ICONIC trial is just one of several studies that Dr. Apolo is conducting for patients with rare GU cancer. “I have several bladder cancer trials where I’m accepting rare GU tumors to enroll,” she said, noting that efficacy signals in these exploratory cohorts may be pursued with expansion studies like ICONIC.

This inclusive strategy is uncovering promising new treatments for some rare GU malignancies, but the rarest of the rare tumor types remain challenging to study, Dr. Apolo said, because very small sample sizes can preclude significant data. “Although we do have the referral base at the NCI, we still get a small number of a lot of rare tumors,” Dr. Apolo said. “What I end up having, a lot of time, are small subsets of rare tumors – I’ll have 4 of one kind, 10 of another.” This situation means that sometimes, time and resources must be focused where they are needed most.

“Sometimes I actually have to decide which are the more common rare tumors so I can study them in a larger cohort,” Dr. Apolo said. “It can have more clinical impact within the community of that rare tumor.” Dr. Apolo described the inherent conflict involved in this decision, but also, its ultimate necessity.

“It’s what you don’t want to do, but you end up doing,” she said. “Because you want to be inclusive and include the rare, rare tumor, but sometimes you just can’t get enough numbers to see if there’s actually a difference [in efficacy]. If it doesn’t work in one patient, does that mean it doesn’t work at all? You need more numbers to really test the efficacy of therapy.”

From clinical trials to clinical practice

To accrue the number of patients needed for practice-altering findings, both Dr. McGregor and Dr. Apolo emphasized the importance of institutional support and collaborative trial designs.

“The FDA is a great ally,” Dr. McGregor said. “They’re acutely aware of the challenges facing patients with rare malignancies – not just GU malignancies. They’re continuing to evaluate the best way to move these drugs forward for those patients. … They’re constantly working with investigators, with industry, looking at data and trying to determine at what threshold these will be practice-changing studies.”

Dr. McGregor suggested that larger trials could shift national guideline recommendations toward combination immunotherapies for patients with rare GU tumors, which would lead to inclusion in compendia, and from there, broader clinical usage.

“At end of the day, luckily, we’re not dealing with drugs that aren’t available,” Dr. McGregor said. “These are drugs that are readily available, approved by the FDA in other settings.”

Dr. Apolo also described strong support from the NCI.

“The NCI really encourages the conduction and enrollment of these rare GU tumor trials, because they understand that the NCI is a really good place to study these rare tumors,” she said. “We have unique resources that make it feasible to conduct some of these trials.”

Dr. Apolo also praised the Alliance Cooperative Group for helping expand patient access to rare GU tumor trials.

“[The Alliance Cooperative Group] makes trials available at community centers across the country,” Dr. Apolo said. “Patients don’t have to travel to the NCI, and they can get the same therapies.”

Still, Dr. Apolo recommended that, when possible, clinicians refer patients with newly diagnosed, rare GU tumors to centers that see a higher number of such cases.

“It’s hard to keep up with all the different treatments that are available right now for different cancers,” Dr. Apolo said. “And sometimes for the rare tumors, there may be great opportunities within a clinical trial that a cancer center may have available that may not be available locally in the community.”

For patients who would like to learn more about rare bladder cancers, Dr. Apolo recommended a visit to the Bladder Cancer Advocacy Network (BCAN) website (bcan.org).

“I’m a big fan of these patient-centered advocacy networks,” Dr. Apolo said. “I like BCAN a lot. It’s a patient-run organization for patients with bladder cancer. With them, I have done a couple of webinars for rare bladder tumors that Ive had some patients tell me are very helpful. They’re a terrific organization that really provides not only emotional support but also educational support for patients that have a diagnosis of bladder cancer and now, rare bladder tumors.” Dr. Spiess offered similar advice for clinicians managing patients with rare GU tumors. He emphasized the key role played by patient advocacy groups, and recommended referral to institutions specializing in specific GU tumor types. For example, he recommended that patients with penile cancer be treated at Moffitt (Tampa) or MD Anderson (Houston), as these centers have the greatest relevant experience. Dr. McGregor disclosed relationships with Bayer, Astellas, Nektar, and others. Dr. Apolo and Dr. Spiess disclosed no conflicts of interest.
 

References

1.Necchi A et al. Eur Urol. 2021 June;79:S929-30.

2.Apolo AB et al. J Clin Oncol. 2021;39(6_suppl):3.

3.McGregor BA et al. Cancer. 2021 Mar 15;127(6):840-9.

4.McGregor BA and Sonpavde GP. Eur Urol Focus. 2020;6(1):14-16.5.Le Tourneau C et al. J Immunother Cancer. 2018 Oct 22;6(1):111.6.Naing A et al. J Immunother Cancer. 2020;8(1).

7.Raj N et al. J Clin Oncol. 2020;38(1):71-80.

8.Adra N et al. Ann Oncol. 2018;29(1):209-14.

9.Necchi A et al. Eur Urol. 2019;75(1):201-3.

In a field of poor outcomes, few standards of care, and small populations of patients scattered across the world, investigators studying rare genitourinary (GU) cancers are gaining ground through international collaboration and novel trial design.

Fundamental clinical questions in the area remain unanswered, including the value of conventional treatments, such as chemotherapy and surgery, vs. emerging immunotherapy combinations.

Managing patients with rare GU cancers presents a variety of challenges, as does conducting research in the field, according to Philippe E. Spiess, MD, MS, FACS, assistant chief of surgical services and senior member in the department of GU oncology at Moffitt Cancer Center, Tampa.

“Unfortunately, there are limited resources for patients – from an education, from a patient advocacy, and ultimately also from a research standpoint,” Dr. Spiess said in an interview, noting difficulties in attaining funding and reaching meaningful endpoints.

The Global Society of Rare Genitourinary Tumors

Last year Dr. Spiess teamed up with Andrea Necchi, MD, of the department of medical oncology at Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, to found the Global Society of Rare Genitourinary Tumors (GSRGT), the first organization of its kind.

“We’ve formally established a society and gotten some of the world leaders [in the field] … to work with us in developing educational tools and patient advocacy efforts to really promote and improve the care of patients impacted with rare cancers,” Dr. Spiess said.

He went on to highlight the truly global makeup of GSRGT, which includes members from leading centers in North America, South America, Europe, and India, and described it as a “grass-roots” organization that he and Dr. Necchi privately funded without financial backing from pharmaceutical companies.

The first GSRGT summit took place in 2020; it focused on penile and testis cancers and was attended by more than 350 participants. The second summit, planned for March 2022, in a virtual format, will focus on rare kidney cancers and upper tract cancers.

“We’ll definitely be having a lot of important conversations about important unmet needs, and some of the important clinical trials that patients and clinicians should be aware of,” Dr. Spiess said.

Dr. Spiess is currently involved in the International Penile Advanced Cancer Trial(InPACT), which is aiming to enroll 200 patients with squamous cell carcinoma of the penis. The randomized study will compare outcomes across patients treated with standard surgery alone, neoadjuvant chemotherapy plus surgery, and neoadjuvant chemoradiotherapy plus surgery.

“I think this is going to be a landmark study because it’s going to give really baseline high-quality data on the effectiveness of these therapies,” Dr. Spiess said.

Results are expected in 2024.

Basket trials open doors for patients in need

Other investigators are testing immunotherapy combinations in patients with rare GU tumors via nonrandomized basket trials, which widen inclusion criteria and improve local availability.

According to Bradley McGregor, MD, clinical director of the Lank Center for GU Oncology at the Dana-Farber Cancer Institute in Boston, early results from these trials are promising, both in terms of therapeutic efficacy and the approach itself.

“Patients [with rare GU tumors] would come to us saying, ‘Well, what can we do? What trial?’,” Dr. McGregor said. “But really, there was no trial to get them on.”Basket trials are therefore needed, he said, as they accelerate progress in the field and help meet patient needs.

“For some of these relatively rare diseases … there is no standard of care,” Dr. McGregor said. “And low incidence makes it challenging to conduct a dedicated clinical trial. Those patients are left with minimal therapeutic options. … We look to provide care for that unmet need.”Andrea B. Apolo, MD, described similar experiences as head of the bladder cancer section of the GU malignancies branch of the National Cancer Institute (NCI), Bethesda, Md.

“I’ve been at the NCI for the past 10 years and I’ve gotten a lot of referrals for rare tumors,” Dr. Apolo said. “[These patients] have tried all available standard of care options, and therefore are often looking for clinical trials and new drugs – any kind of therapy that may be effective for their disease.”This call for help, along with a growing scientific curiosity, motivated Dr. Apolo to design trials that would include patients who had nowhere else to go.

“I became very interested in … understanding more about the mechanism of tumorigenesis and understanding rare tumors, biologically, within the lab,” she said, “but also clinically, in terms of finding more effective therapies.”

Both Dr. McGregor and Dr. Apolo are currently conducting basket trials for patients with rare GU tumors. While Dr. McGregor is testing a combination of PD-1 inhibitor nivolumab and CTLA-4 inhibitor ipilimumab, Dr. Apolo is exploring the benefit of cabozantinib, a targeted therapy, given with either nivolumab or nivolumab plus ipilimumab.

When asked about these trials, Dr. Spiess said that “basket trials are important because they may give us an understanding of some potentially useful therapies or combinations;” however, he also pointed out their limitations, noting that they may inaccurately characterize the efficacy of given therapies over a broad array of disease entities even if they are of similar histology. As an example, he noted “very different” genomic profiles across squamous cell carcinomas of the pelvis depending on exact anatomical location, suggesting that these differences may affect responses to therapy, citing a recent study in European Urology that he conducted with Dr. Necchi.¹

“[Basket trials] are probably not going to be the be-all-end-all,” Dr. Spiess said. “It really requires a global initiative to do these types of studies, which the Global Society of Rare Genitourinary Tumors will allow.”

Exploring immunotherapy combinations

Despite the potential limitations, recent basket trials involving immunotherapy regimens have been associated with overall response rates, in some subgroups, that exceed 35%.^2,3

In comparison with previous trials, many of which had response rates in the single digits, or no responses at all, these results are, in Dr. McGregor’s words, “very thought provoking.”Most rare GU malignancies fall into one of four categories: bladder cancer variant histology (BCVH), adrenal tumors, penile squamous cell carcinoma (PSCC), and chemotherapy-refractory germ cell tumors (CRGCT). Among these, BCVH has the strongest evidence supporting clinical use of immunotherapy, based on U.S. approval for urothelial histology, according to Dr. McGregor.⁴Data supporting immunotherapy for the remaining disease subtypes are scarce. Although pembrolizumab is approved for patients with solid tumors that exhibit microsatellite instability (MSI), MSI is uncommon among patients with rare GU cancers; estimated incidence rates are less than 10%.⁴

“As such, clinical trials to address this unmet need are imperative,” Dr. McGregor wrote in a recent review article.⁴

According to Dr. McGregor, programmed death ligand 1 (PD-L1) expression in rare GU tumors may be relatively common in some disease subtypes, such as PSCC, which has a PD-L1 expression rate of up to 60%.⁴

But rare GU tumor trials involving a single checkpoint inhibitor have produced limited results, if any.

The largest trial for adrenocortical carcinoma (ACC), for example, which included 50 patients, showed that avelumab resulted in an objective response rate (ORR) of just 6%.⁵

Pembrolizumab was slightly more effective for ACC, based on a trial involving 39 patients, which returned an ORR of 23%, and another trial involving 15 patients that had a 15% ORR.^6,7

Two other trials, which tested single-agent pembrolizumab or durvalumab in patients with CRGCT, resulted in no responses at all, whereas a trial testing pembrolizumab alone for penile squamous cell carcinoma was terminated in 2020, citing poor accrual.^8,9 Still, the durvalumab trial for CRGCT, led by Dr. Necchi, did offer a glimpse at what might be possible with a combination of immunotherapies. Although no responses were observed among 11 patients who received durvalumab alone, an efficacy signal was observed in a second cohort of 11 patients who were given durvalumab in combination with the CTLA-4 inhibitor tremilimumab.⁹

Out of those 11 patients, 1 had a partial response, and another achieved stable disease.

In light of these findings, and more that have been published since then, the clinical trial landscape for rare GU tumors is shifting toward a combination immunotherapy approach, according to Dr. McGregor.⁴

Nivolumab and ipilimumab

Dr. McGregor is leading a phase II trial (NCT03333616) testing a combination of nivolumab and ipilimumab in patients with a variety of advanced rare GU malignancies, including bladder and upper tract carcinoma of variant histology (BUTCVH), adrenal tumors, CRGCT, PSCC, and prostate cancer of variant histology (PCVH).

“When trials are designed, these patients are often forgotten,” Dr. McGregor noted. “We said, let’s do a trial for all rare GU tumors and just sort of assess and look for a signal, and, hopefully, find a signal that we can then take to the next level.”

Along with appropriate disease phenotype, trial eligibility depended upon an ECOG performance status of 0-2 and no prior exposure to checkpoint inhibitors. Treatment-naive patients were allowed. All participants received nivolumab 3 mg/kg and ipilimumab 1 mg/kg IV every 3 weeks for four doses, followed by maintenance nivolumab at a dose of 480 mg every 4 weeks.

Most recent results, published in Cancer, included data from 55 patients, including 19 with BUTCVH, 18 with adrenal tumors, and 18 with other tumors.³ After a median follow-up of 9.9 months, 28 patients (51%) received all four doses of the regimen, 25 of whom received maintenance therapy with a median of four cycles.

Overall, nine patients (16%) responded to therapy, six of whom (67%) maintained their response for at least 9 months. Two responses were complete, and seven were partial. Median progression-free survival was 2.8 months.

Twenty-two patients (39%) had grade 3 or higher treatment-related adverse events, approximately one-quarter (23%) needed high-dose steroids, and a slightly greater proportion (27%) discontinued the regimen because of adverse events. Three patients exhibited grade 5 toxicity, and one patient death was treatment related. A closer look at the efficacy data suggested that one disease subgroup benefited much more than the others. The overall response rate among 19 patients with BUTCVH was 37%, compared with 6% in the other two cohorts.

“A response rate of 37% compares quite favorably to anything we’ve seen to date,” Dr. McGregor said. “It’s remarkable that [this response] was seen across histologies – we saw this in urachal, we saw this in adenocarcinoma – we really saw this across the board. This is very, very, very intriguing data.”

The phase II trial is ongoing at multiple centers across the country, including the Dana-Farber/Harvard Cancer Center, Boston, the University of Texas MD Anderson Cancer Center, Houston, the Moores Cancer Center at University of California Health, San Diego, the Ohio State University Comprehensive Cancer Center, Columbus, and the Winship Cancer Institute of Emory University, Atlanta.

“We accrued this trial in just under 18 months,” Dr. McGregor said. “I think this shows that with a well-designed trial, we can actually study these diseases and improve outcomes in these patients.” According to Dr. McGregor, the current findings deserve further investigation, potentially including expansion of the BUTCVH cohort. Recruitment is ongoing for a fourth cohort involving patients with tumors that exhibit neuroendocrine differentiation.

Cabozantinib and nivolumab with or without ipilimumab

Dr. Apolo is leading a similar basket trial (NCT02496208) that is testing cabozantinib plus nivolumab with or without ipilimumab.

“What we’re doing is using immunotherapy and a targeted therapy that work in standard urothelial carcinoma and renal cell carcinoma,” Dr. Apolo said. “But really, we don’t know the activity in these rare GU tumors. … There’s still so much we don’t understand about what the driving mutations are, and how we can best target them.”

Most recent data, published in Journal of Clinical Oncology, include 122 patients with metastatic GU tumors, including urothelial carcinoma, clear cell renal cell carcinoma, bladder adenocarcinoma, and other rare GU cancers.²

Among these patients, 54 were in the phase I dose-finding cohort (eight escalating doses) and 64 were in the dose-expansion cohorts.

After a median follow-up of 40.4 months, 64 patients received the dual combination, whereas 56 received the triplet regimen. The ORR for 108 evaluable patients was 38%, including 12 complete responses (11.1%) and 29 partial responses (26.9%). The largest disease cohort, for urothelial carcinoma, included 33 patients and was associated with an ORR of 42.4%, with a complete response rate of 21.2%. Objective response rate was highest for squamous bladder cancer (85.7%; n = 7), followed by clear cell renal carcinoma (62.5%; n = 16), renal medullary cancer (50%; n = 2), penile cancer (44.4%; n = 9), small cell bladder cancer (33.1%; n = 3), bladder adenocarcinoma (20%; n = 15), and prostate cancer (11.1%; n = 9). No responses were seen in six patients with germ cell tumors.

Adding ipilimumab appeared to have a minimal impact on toxicity. Grade 3 or 4 treatment-related adverse events (AEs) occurred in 84% of patients in the dual combination group, compared with 80% receiving the triplet regimen. Most common AEs were hypophosphatemia (16-25%), lipase elevation (20%), fatigue (18-20%), ALT elevation (5-14%), AST elevation (9-11%), diarrhea (9-11%), and thromboembolic event (4-11%). One patient taking the triplet regimen had grade 5 pneumonitis.

These positive phase I results have paved the way for the phase II ICONIC trial (NCT03866382), a national study available through the Alliance Cooperative Group. The trial is currently recruiting, with an estimated enrollment of 224 patients with rare GU tumors.

The ICONIC trial is just one of several studies that Dr. Apolo is conducting for patients with rare GU cancer. “I have several bladder cancer trials where I’m accepting rare GU tumors to enroll,” she said, noting that efficacy signals in these exploratory cohorts may be pursued with expansion studies like ICONIC.

This inclusive strategy is uncovering promising new treatments for some rare GU malignancies, but the rarest of the rare tumor types remain challenging to study, Dr. Apolo said, because very small sample sizes can preclude significant data. “Although we do have the referral base at the NCI, we still get a small number of a lot of rare tumors,” Dr. Apolo said. “What I end up having, a lot of time, are small subsets of rare tumors – I’ll have 4 of one kind, 10 of another.” This situation means that sometimes, time and resources must be focused where they are needed most.

“Sometimes I actually have to decide which are the more common rare tumors so I can study them in a larger cohort,” Dr. Apolo said. “It can have more clinical impact within the community of that rare tumor.” Dr. Apolo described the inherent conflict involved in this decision, but also, its ultimate necessity.

“It’s what you don’t want to do, but you end up doing,” she said. “Because you want to be inclusive and include the rare, rare tumor, but sometimes you just can’t get enough numbers to see if there’s actually a difference [in efficacy]. If it doesn’t work in one patient, does that mean it doesn’t work at all? You need more numbers to really test the efficacy of therapy.”

From clinical trials to clinical practice

To accrue the number of patients needed for practice-altering findings, both Dr. McGregor and Dr. Apolo emphasized the importance of institutional support and collaborative trial designs.

“The FDA is a great ally,” Dr. McGregor said. “They’re acutely aware of the challenges facing patients with rare malignancies – not just GU malignancies. They’re continuing to evaluate the best way to move these drugs forward for those patients. … They’re constantly working with investigators, with industry, looking at data and trying to determine at what threshold these will be practice-changing studies.”

Dr. McGregor suggested that larger trials could shift national guideline recommendations toward combination immunotherapies for patients with rare GU tumors, which would lead to inclusion in compendia, and from there, broader clinical usage.

“At end of the day, luckily, we’re not dealing with drugs that aren’t available,” Dr. McGregor said. “These are drugs that are readily available, approved by the FDA in other settings.”

Dr. Apolo also described strong support from the NCI.

“The NCI really encourages the conduction and enrollment of these rare GU tumor trials, because they understand that the NCI is a really good place to study these rare tumors,” she said. “We have unique resources that make it feasible to conduct some of these trials.”

Dr. Apolo also praised the Alliance Cooperative Group for helping expand patient access to rare GU tumor trials.

“[The Alliance Cooperative Group] makes trials available at community centers across the country,” Dr. Apolo said. “Patients don’t have to travel to the NCI, and they can get the same therapies.”

Still, Dr. Apolo recommended that, when possible, clinicians refer patients with newly diagnosed, rare GU tumors to centers that see a higher number of such cases.

“It’s hard to keep up with all the different treatments that are available right now for different cancers,” Dr. Apolo said. “And sometimes for the rare tumors, there may be great opportunities within a clinical trial that a cancer center may have available that may not be available locally in the community.”

For patients who would like to learn more about rare bladder cancers, Dr. Apolo recommended a visit to the Bladder Cancer Advocacy Network (BCAN) website (bcan.org).

“I’m a big fan of these patient-centered advocacy networks,” Dr. Apolo said. “I like BCAN a lot. It’s a patient-run organization for patients with bladder cancer. With them, I have done a couple of webinars for rare bladder tumors that Ive had some patients tell me are very helpful. They’re a terrific organization that really provides not only emotional support but also educational support for patients that have a diagnosis of bladder cancer and now, rare bladder tumors.” Dr. Spiess offered similar advice for clinicians managing patients with rare GU tumors. He emphasized the key role played by patient advocacy groups, and recommended referral to institutions specializing in specific GU tumor types. For example, he recommended that patients with penile cancer be treated at Moffitt (Tampa) or MD Anderson (Houston), as these centers have the greatest relevant experience. Dr. McGregor disclosed relationships with Bayer, Astellas, Nektar, and others. Dr. Apolo and Dr. Spiess disclosed no conflicts of interest.
 

References

1.Necchi A et al. Eur Urol. 2021 June;79:S929-30.

2.Apolo AB et al. J Clin Oncol. 2021;39(6_suppl):3.

3.McGregor BA et al. Cancer. 2021 Mar 15;127(6):840-9.

4.McGregor BA and Sonpavde GP. Eur Urol Focus. 2020;6(1):14-16.5.Le Tourneau C et al. J Immunother Cancer. 2018 Oct 22;6(1):111.6.Naing A et al. J Immunother Cancer. 2020;8(1).

7.Raj N et al. J Clin Oncol. 2020;38(1):71-80.

8.Adra N et al. Ann Oncol. 2018;29(1):209-14.

9.Necchi A et al. Eur Urol. 2019;75(1):201-3.

Adapted D-dimer thresholds based on pretest probability were effective for ruling out pulmonary embolism (PE) in subgroups of high-risk individuals without the use of imaging in a review of data.

In a patient suspected to have a PE, “diagnosis is made radiographically, usually with CT pulmonary angiogram, or V/Q scan,” Suman Pal, MD, of the University of New Mexico, Albuquerque, said in an interview.

“Validated clinical decision tools such as Wells’ score or Geneva score may be used to identify patients at low pretest probability of PE who may initially get a D-dimer level check, followed by imaging only if D-dimer level is elevated,” explained Dr. Pal, who was not involved with the new research, which was published in the Annals of Internal Medicine.

According to the authors of the new paper, while current diagnostic strategies in patients with suspected PE include use of a validated clinical decision rule (CDR) and D-dimer testing to rule out PE without imaging tests, the effectiveness of D-dimer tests in older patients, inpatients, cancer patients, and other high-risk groups has not been well-studied.

Lead author of the paper, Milou A.M. Stals, MD, and colleagues said their goal was to evaluate the safety and efficiency of the Wells rule and revised Geneva score in combination with D-dimer tests, and also the YEARS algorithm for D-dimer thresholds, in their paper.

Dr. Stals, of Leiden (the Netherlands) University Medical Center, and the coinvestigators conducted an international systemic review and individual patient data meta-analysis that included 16 studies and 20,553 patients, with all studies having been published between Jan. 1, 1995, and Jan. 1, 2021. Their primary outcomes were the safety and efficiency of each of these three strategies.

In the review, the researchers defined safety as the 3-month incidence of venous thromboembolism after PE was ruled out without imaging at baseline. They defined efficiency as the proportion patients for whom PE was ruled out based on D-dimer thresholds without imaging.

Overall, efficiency was highest in the subset of patients aged younger than 40 years, ranging from 47% to 68% in this group. Efficiency was lowest in patients aged 80 years and older (6.0%-23%), and in patients with cancer (9.6%-26%).

The efficiency was higher when D-dimer thresholds based on pretest probability were used, compared with when fixed or age-adjusted D-dimer thresholds were used.

The key finding was the significant variability in performance of the diagnostic strategies, the researchers said.

“The predicted failure rate was generally highest for strategies incorporating adapted D-dimer thresholds. However, at the same time, predicted overall efficiency was substantially higher with these strategies versus strategies with a fixed D-dimer threshold as well,” they said. Given that the benefits of each of the three diagnostic strategies depends on their correct application, the researchers recommended that an individual hospitalist choose one strategy for their institution.

“Whether clinicians should rely on the Wells rule, the YEARS algorithm, or the revised Geneva score becomes a matter of local preference and experience,” Dr. Stals and colleagues wrote.

The study findings were limited by several factors including between-study differences in scoring predictors and D-dimer assays. Another limitation was that differential verification biases for classifying fatal events and PE may have contributed to overestimation of failure rates of the adapted D-dimer thresholds.

Strengths of the study included its large sample size and original data on pretest probability, and that data support the use of any of the three strategies for ruling out PE in the identified subgroups without the need for imaging tests, the authors wrote.

“Pending the results of ongoing diagnostic randomized trials, physicians and guideline committees should balance the interlink between safety and efficiency of available diagnostic strategies,” they concluded.

Adapted D-dimer benefits some patients

“Clearly, increasing the D-dimer cutoff will lower the number of patients who require radiographic imaging (improved specificity), but this comes with a risk for missing PE (lower sensitivity). Is this risk worth taking?” Daniel J. Brotman, MD, of Johns Hopkins University, Baltimore, asked in an editorial accompanying the new study.

Dr. Brotman was not surprised by the study findings.

“Conditions that predispose to thrombosis through activated hemostasis – such as advanced age, cancer, inflammation, prolonged hospitalization, and trauma – drive D-dimer levels higher independent of the presence or absence of radiographically apparent thrombosis,” he said. However, these patients are unlikely to have normal D-dimer levels regardless of the cutoff used.

Adapted D-dimer cutoffs may benefit some patients, including those with contraindications or limited access to imaging, said Dr. Brotman. D-dimer may be used for risk stratification regardless of PE, since patients with marginally elevated D-dimers have better prognoses than those with higher D-dimer elevations, even if a small PE is missed.

Dr. Brotman wrote that increasing D-dimer cutoffs for high-risk patients in the subgroups analyzed may spare some patients radiographic testing, but doing so carries an increased risk for diagnostic failure. Overall, “the important work by Stals and colleagues offers reassurance that modifying D-dimer thresholds according to age or pretest probability is safe enough for widespread practice, even in high-risk groups.”
 

Focus on single strategy ‘based on local needs’

“Several validated clinical decision tools, along with age or pretest probability adjusted D-dimer threshold are currently in use as diagnostic strategies for ruling out pulmonary embolism,” Dr. Pal said in an interview.

The current study is important because of limited data on the performance of these strategies in specific subgroups of patients whose risk of PE may differ from the overall patient population, he noted.

“Different diagnostic strategies for PE have a variable performance in patients with differences of age, active cancer, and history of VTE,” said Dr. Pal. “However, in this study, no clear preference for one strategy over others could be established for these subgroups, and clinicians should continue to follow institution-specific guidance.

“A single strategy should be adopted at each institution based on local needs and used as the standard of care until further data are available,” he said.

“The use of D-dimer to rule out PE, either with fixed threshold or age-adjusted thresholds, can be confounded in clinical settings by other comorbid conditions such as sepsis, recent surgery, and more recently, COVID-19,” he said.

“Since the findings of this study do not show a clear benefit of one diagnostic strategy over others in the analyzed subgroups of patients, further prospective head-to-head comparison among the subgroups of interest would be helpful to guide clinical decision making,” Dr. Pal added.
 

YEARS-specific study supports D-dimer safety and value

A recent paper published in JAMA supported the results of the meta-analysis. In that study, Yonathan Freund, MD, of Sorbonne Université, Paris, and colleagues focused on the YEARS strategy combined with age-adjusted D-dimer thresholds as a way to rule out PE in PERC-positive ED patients.

The authors of this paper randomized 18 EDs to either a protocol of intervention followed by control, or control followed by intervention. The study population included 726 patients in the intervention group and 688 in the control group.

The intervention strategy to rule out PE consisted of assessing the YEARS criteria and D-dimer testing. PE was ruled out in patients with no YEARS criteria and a D-dimer level below 1,000 ng/mL and in patients with one or more YEARS criteria and D-dimers below an age-adjusted threshold (defined as age times 10 ng/mL in patients aged 50 years and older).

The control strategy consisted of D-dimer testing for all patients with the threshold at age-adjusted levels; D-dimers about these levels prompted chest imaging.

Overall, the risk of a missed VTE at 3 months was noninferior between the groups (0.15% in the intervention group and 0.80% in the controls).

“The intervention was associated with a statistically significant reduction in chest imaging use,” the researchers wrote.

This study’s findings were limited by randomization at the center level, rather than the patient level, and the use of imaging on some patients despite negative D-dimer tests, the researchers wrote. However, their findings support those of previous studies and especially support the safety of the intervention, in an emergency medicine setting, as no PEs occurred in patients with a YEARS score of zero who underwent the intervention.
 

Downsides to applying algorithms to every patient explained

In an editorial accompanying the JAMA study, Marcel Levi, MD, and Nick van Es, MD, of Amsterdam University Medical Center, emphasized the challenges of diagnosing PE given that many patients present with nonspecific clinical manifestations and without typical signs and symptoms. High-resolution CT pulmonary angiography allows for a fast and easy diagnosis in an emergency setting. However, efforts are ongoing to develop alternative strategies that avoid unnecessary scanning for potential PE patients, many of whom have alternative diagnoses such as pulmonary infections, cardiac conditions, pleural disease, or musculoskeletal problems.

On review of the JAMA study using the YEARS rule with adjusted D-dimer thresholds, the editorialists noted that the data were robust and indicated a 10% reduction in chest imaging. They also emphasized the potential to overwhelm busy clinicians with more algorithms.

“Blindly applying algorithms to every patient may be less appropriate or even undesirable in specific situations in which deviation from the rules on clinical grounds is indicated,” but a complex imaging approach may be time consuming and challenging in the acute setting, and a simple algorithm may be safe and efficient in many cases, they wrote. “From a patient perspective, a negative diagnostic algorithm for pulmonary embolism does not diminish the physician’s obligation to consider other diagnoses that explain the symptoms, for which chest CT scans may still be needed and helpful.”

The Annals of Internal Medicine study was supported by the Dutch Research Council. The JAMA study was supported by the French Health Ministry. Dr. Stals, Dr. Freund, Dr. Pal, Dr. Levi, and Dr. van Es had no financial conflicts to disclose.

Adapted D-dimer thresholds based on pretest probability were effective for ruling out pulmonary embolism (PE) in subgroups of high-risk individuals without the use of imaging in a review of data.

In a patient suspected to have a PE, “diagnosis is made radiographically, usually with CT pulmonary angiogram, or V/Q scan,” Suman Pal, MD, of the University of New Mexico, Albuquerque, said in an interview.

“Validated clinical decision tools such as Wells’ score or Geneva score may be used to identify patients at low pretest probability of PE who may initially get a D-dimer level check, followed by imaging only if D-dimer level is elevated,” explained Dr. Pal, who was not involved with the new research, which was published in the Annals of Internal Medicine.

According to the authors of the new paper, while current diagnostic strategies in patients with suspected PE include use of a validated clinical decision rule (CDR) and D-dimer testing to rule out PE without imaging tests, the effectiveness of D-dimer tests in older patients, inpatients, cancer patients, and other high-risk groups has not been well-studied.

Lead author of the paper, Milou A.M. Stals, MD, and colleagues said their goal was to evaluate the safety and efficiency of the Wells rule and revised Geneva score in combination with D-dimer tests, and also the YEARS algorithm for D-dimer thresholds, in their paper.

Dr. Stals, of Leiden (the Netherlands) University Medical Center, and the coinvestigators conducted an international systemic review and individual patient data meta-analysis that included 16 studies and 20,553 patients, with all studies having been published between Jan. 1, 1995, and Jan. 1, 2021. Their primary outcomes were the safety and efficiency of each of these three strategies.

In the review, the researchers defined safety as the 3-month incidence of venous thromboembolism after PE was ruled out without imaging at baseline. They defined efficiency as the proportion patients for whom PE was ruled out based on D-dimer thresholds without imaging.

Overall, efficiency was highest in the subset of patients aged younger than 40 years, ranging from 47% to 68% in this group. Efficiency was lowest in patients aged 80 years and older (6.0%-23%), and in patients with cancer (9.6%-26%).

The efficiency was higher when D-dimer thresholds based on pretest probability were used, compared with when fixed or age-adjusted D-dimer thresholds were used.

The key finding was the significant variability in performance of the diagnostic strategies, the researchers said.

“The predicted failure rate was generally highest for strategies incorporating adapted D-dimer thresholds. However, at the same time, predicted overall efficiency was substantially higher with these strategies versus strategies with a fixed D-dimer threshold as well,” they said. Given that the benefits of each of the three diagnostic strategies depends on their correct application, the researchers recommended that an individual hospitalist choose one strategy for their institution.

“Whether clinicians should rely on the Wells rule, the YEARS algorithm, or the revised Geneva score becomes a matter of local preference and experience,” Dr. Stals and colleagues wrote.

The study findings were limited by several factors including between-study differences in scoring predictors and D-dimer assays. Another limitation was that differential verification biases for classifying fatal events and PE may have contributed to overestimation of failure rates of the adapted D-dimer thresholds.

Strengths of the study included its large sample size and original data on pretest probability, and that data support the use of any of the three strategies for ruling out PE in the identified subgroups without the need for imaging tests, the authors wrote.

“Pending the results of ongoing diagnostic randomized trials, physicians and guideline committees should balance the interlink between safety and efficiency of available diagnostic strategies,” they concluded.

Adapted D-dimer benefits some patients

“Clearly, increasing the D-dimer cutoff will lower the number of patients who require radiographic imaging (improved specificity), but this comes with a risk for missing PE (lower sensitivity). Is this risk worth taking?” Daniel J. Brotman, MD, of Johns Hopkins University, Baltimore, asked in an editorial accompanying the new study.

Dr. Brotman was not surprised by the study findings.

“Conditions that predispose to thrombosis through activated hemostasis – such as advanced age, cancer, inflammation, prolonged hospitalization, and trauma – drive D-dimer levels higher independent of the presence or absence of radiographically apparent thrombosis,” he said. However, these patients are unlikely to have normal D-dimer levels regardless of the cutoff used.

Adapted D-dimer cutoffs may benefit some patients, including those with contraindications or limited access to imaging, said Dr. Brotman. D-dimer may be used for risk stratification regardless of PE, since patients with marginally elevated D-dimers have better prognoses than those with higher D-dimer elevations, even if a small PE is missed.

Dr. Brotman wrote that increasing D-dimer cutoffs for high-risk patients in the subgroups analyzed may spare some patients radiographic testing, but doing so carries an increased risk for diagnostic failure. Overall, “the important work by Stals and colleagues offers reassurance that modifying D-dimer thresholds according to age or pretest probability is safe enough for widespread practice, even in high-risk groups.”
 

Focus on single strategy ‘based on local needs’

“Several validated clinical decision tools, along with age or pretest probability adjusted D-dimer threshold are currently in use as diagnostic strategies for ruling out pulmonary embolism,” Dr. Pal said in an interview.

The current study is important because of limited data on the performance of these strategies in specific subgroups of patients whose risk of PE may differ from the overall patient population, he noted.

“Different diagnostic strategies for PE have a variable performance in patients with differences of age, active cancer, and history of VTE,” said Dr. Pal. “However, in this study, no clear preference for one strategy over others could be established for these subgroups, and clinicians should continue to follow institution-specific guidance.

“A single strategy should be adopted at each institution based on local needs and used as the standard of care until further data are available,” he said.

“The use of D-dimer to rule out PE, either with fixed threshold or age-adjusted thresholds, can be confounded in clinical settings by other comorbid conditions such as sepsis, recent surgery, and more recently, COVID-19,” he said.

“Since the findings of this study do not show a clear benefit of one diagnostic strategy over others in the analyzed subgroups of patients, further prospective head-to-head comparison among the subgroups of interest would be helpful to guide clinical decision making,” Dr. Pal added.
 

YEARS-specific study supports D-dimer safety and value

A recent paper published in JAMA supported the results of the meta-analysis. In that study, Yonathan Freund, MD, of Sorbonne Université, Paris, and colleagues focused on the YEARS strategy combined with age-adjusted D-dimer thresholds as a way to rule out PE in PERC-positive ED patients.

The authors of this paper randomized 18 EDs to either a protocol of intervention followed by control, or control followed by intervention. The study population included 726 patients in the intervention group and 688 in the control group.

The intervention strategy to rule out PE consisted of assessing the YEARS criteria and D-dimer testing. PE was ruled out in patients with no YEARS criteria and a D-dimer level below 1,000 ng/mL and in patients with one or more YEARS criteria and D-dimers below an age-adjusted threshold (defined as age times 10 ng/mL in patients aged 50 years and older).

The control strategy consisted of D-dimer testing for all patients with the threshold at age-adjusted levels; D-dimers about these levels prompted chest imaging.

Overall, the risk of a missed VTE at 3 months was noninferior between the groups (0.15% in the intervention group and 0.80% in the controls).

“The intervention was associated with a statistically significant reduction in chest imaging use,” the researchers wrote.

This study’s findings were limited by randomization at the center level, rather than the patient level, and the use of imaging on some patients despite negative D-dimer tests, the researchers wrote. However, their findings support those of previous studies and especially support the safety of the intervention, in an emergency medicine setting, as no PEs occurred in patients with a YEARS score of zero who underwent the intervention.
 

Downsides to applying algorithms to every patient explained

In an editorial accompanying the JAMA study, Marcel Levi, MD, and Nick van Es, MD, of Amsterdam University Medical Center, emphasized the challenges of diagnosing PE given that many patients present with nonspecific clinical manifestations and without typical signs and symptoms. High-resolution CT pulmonary angiography allows for a fast and easy diagnosis in an emergency setting. However, efforts are ongoing to develop alternative strategies that avoid unnecessary scanning for potential PE patients, many of whom have alternative diagnoses such as pulmonary infections, cardiac conditions, pleural disease, or musculoskeletal problems.

On review of the JAMA study using the YEARS rule with adjusted D-dimer thresholds, the editorialists noted that the data were robust and indicated a 10% reduction in chest imaging. They also emphasized the potential to overwhelm busy clinicians with more algorithms.

“Blindly applying algorithms to every patient may be less appropriate or even undesirable in specific situations in which deviation from the rules on clinical grounds is indicated,” but a complex imaging approach may be time consuming and challenging in the acute setting, and a simple algorithm may be safe and efficient in many cases, they wrote. “From a patient perspective, a negative diagnostic algorithm for pulmonary embolism does not diminish the physician’s obligation to consider other diagnoses that explain the symptoms, for which chest CT scans may still be needed and helpful.”

The Annals of Internal Medicine study was supported by the Dutch Research Council. The JAMA study was supported by the French Health Ministry. Dr. Stals, Dr. Freund, Dr. Pal, Dr. Levi, and Dr. van Es had no financial conflicts to disclose.

Adapted D-dimer thresholds based on pretest probability were effective for ruling out pulmonary embolism (PE) in subgroups of high-risk individuals without the use of imaging in a review of data.

In a patient suspected to have a PE, “diagnosis is made radiographically, usually with CT pulmonary angiogram, or V/Q scan,” Suman Pal, MD, of the University of New Mexico, Albuquerque, said in an interview.

“Validated clinical decision tools such as Wells’ score or Geneva score may be used to identify patients at low pretest probability of PE who may initially get a D-dimer level check, followed by imaging only if D-dimer level is elevated,” explained Dr. Pal, who was not involved with the new research, which was published in the Annals of Internal Medicine.

According to the authors of the new paper, while current diagnostic strategies in patients with suspected PE include use of a validated clinical decision rule (CDR) and D-dimer testing to rule out PE without imaging tests, the effectiveness of D-dimer tests in older patients, inpatients, cancer patients, and other high-risk groups has not been well-studied.

Lead author of the paper, Milou A.M. Stals, MD, and colleagues said their goal was to evaluate the safety and efficiency of the Wells rule and revised Geneva score in combination with D-dimer tests, and also the YEARS algorithm for D-dimer thresholds, in their paper.

Dr. Stals, of Leiden (the Netherlands) University Medical Center, and the coinvestigators conducted an international systemic review and individual patient data meta-analysis that included 16 studies and 20,553 patients, with all studies having been published between Jan. 1, 1995, and Jan. 1, 2021. Their primary outcomes were the safety and efficiency of each of these three strategies.

In the review, the researchers defined safety as the 3-month incidence of venous thromboembolism after PE was ruled out without imaging at baseline. They defined efficiency as the proportion patients for whom PE was ruled out based on D-dimer thresholds without imaging.

Overall, efficiency was highest in the subset of patients aged younger than 40 years, ranging from 47% to 68% in this group. Efficiency was lowest in patients aged 80 years and older (6.0%-23%), and in patients with cancer (9.6%-26%).

The efficiency was higher when D-dimer thresholds based on pretest probability were used, compared with when fixed or age-adjusted D-dimer thresholds were used.

The key finding was the significant variability in performance of the diagnostic strategies, the researchers said.

“The predicted failure rate was generally highest for strategies incorporating adapted D-dimer thresholds. However, at the same time, predicted overall efficiency was substantially higher with these strategies versus strategies with a fixed D-dimer threshold as well,” they said. Given that the benefits of each of the three diagnostic strategies depends on their correct application, the researchers recommended that an individual hospitalist choose one strategy for their institution.

“Whether clinicians should rely on the Wells rule, the YEARS algorithm, or the revised Geneva score becomes a matter of local preference and experience,” Dr. Stals and colleagues wrote.

The study findings were limited by several factors including between-study differences in scoring predictors and D-dimer assays. Another limitation was that differential verification biases for classifying fatal events and PE may have contributed to overestimation of failure rates of the adapted D-dimer thresholds.

Strengths of the study included its large sample size and original data on pretest probability, and that data support the use of any of the three strategies for ruling out PE in the identified subgroups without the need for imaging tests, the authors wrote.

“Pending the results of ongoing diagnostic randomized trials, physicians and guideline committees should balance the interlink between safety and efficiency of available diagnostic strategies,” they concluded.

Adapted D-dimer benefits some patients

“Clearly, increasing the D-dimer cutoff will lower the number of patients who require radiographic imaging (improved specificity), but this comes with a risk for missing PE (lower sensitivity). Is this risk worth taking?” Daniel J. Brotman, MD, of Johns Hopkins University, Baltimore, asked in an editorial accompanying the new study.

Dr. Brotman was not surprised by the study findings.

“Conditions that predispose to thrombosis through activated hemostasis – such as advanced age, cancer, inflammation, prolonged hospitalization, and trauma – drive D-dimer levels higher independent of the presence or absence of radiographically apparent thrombosis,” he said. However, these patients are unlikely to have normal D-dimer levels regardless of the cutoff used.

Adapted D-dimer cutoffs may benefit some patients, including those with contraindications or limited access to imaging, said Dr. Brotman. D-dimer may be used for risk stratification regardless of PE, since patients with marginally elevated D-dimers have better prognoses than those with higher D-dimer elevations, even if a small PE is missed.

Dr. Brotman wrote that increasing D-dimer cutoffs for high-risk patients in the subgroups analyzed may spare some patients radiographic testing, but doing so carries an increased risk for diagnostic failure. Overall, “the important work by Stals and colleagues offers reassurance that modifying D-dimer thresholds according to age or pretest probability is safe enough for widespread practice, even in high-risk groups.”
 

Focus on single strategy ‘based on local needs’

“Several validated clinical decision tools, along with age or pretest probability adjusted D-dimer threshold are currently in use as diagnostic strategies for ruling out pulmonary embolism,” Dr. Pal said in an interview.

The current study is important because of limited data on the performance of these strategies in specific subgroups of patients whose risk of PE may differ from the overall patient population, he noted.

“Different diagnostic strategies for PE have a variable performance in patients with differences of age, active cancer, and history of VTE,” said Dr. Pal. “However, in this study, no clear preference for one strategy over others could be established for these subgroups, and clinicians should continue to follow institution-specific guidance.

“A single strategy should be adopted at each institution based on local needs and used as the standard of care until further data are available,” he said.

“The use of D-dimer to rule out PE, either with fixed threshold or age-adjusted thresholds, can be confounded in clinical settings by other comorbid conditions such as sepsis, recent surgery, and more recently, COVID-19,” he said.

“Since the findings of this study do not show a clear benefit of one diagnostic strategy over others in the analyzed subgroups of patients, further prospective head-to-head comparison among the subgroups of interest would be helpful to guide clinical decision making,” Dr. Pal added.
 

YEARS-specific study supports D-dimer safety and value

A recent paper published in JAMA supported the results of the meta-analysis. In that study, Yonathan Freund, MD, of Sorbonne Université, Paris, and colleagues focused on the YEARS strategy combined with age-adjusted D-dimer thresholds as a way to rule out PE in PERC-positive ED patients.

The authors of this paper randomized 18 EDs to either a protocol of intervention followed by control, or control followed by intervention. The study population included 726 patients in the intervention group and 688 in the control group.

The intervention strategy to rule out PE consisted of assessing the YEARS criteria and D-dimer testing. PE was ruled out in patients with no YEARS criteria and a D-dimer level below 1,000 ng/mL and in patients with one or more YEARS criteria and D-dimers below an age-adjusted threshold (defined as age times 10 ng/mL in patients aged 50 years and older).

The control strategy consisted of D-dimer testing for all patients with the threshold at age-adjusted levels; D-dimers about these levels prompted chest imaging.

Overall, the risk of a missed VTE at 3 months was noninferior between the groups (0.15% in the intervention group and 0.80% in the controls).

“The intervention was associated with a statistically significant reduction in chest imaging use,” the researchers wrote.

This study’s findings were limited by randomization at the center level, rather than the patient level, and the use of imaging on some patients despite negative D-dimer tests, the researchers wrote. However, their findings support those of previous studies and especially support the safety of the intervention, in an emergency medicine setting, as no PEs occurred in patients with a YEARS score of zero who underwent the intervention.
 

Downsides to applying algorithms to every patient explained

In an editorial accompanying the JAMA study, Marcel Levi, MD, and Nick van Es, MD, of Amsterdam University Medical Center, emphasized the challenges of diagnosing PE given that many patients present with nonspecific clinical manifestations and without typical signs and symptoms. High-resolution CT pulmonary angiography allows for a fast and easy diagnosis in an emergency setting. However, efforts are ongoing to develop alternative strategies that avoid unnecessary scanning for potential PE patients, many of whom have alternative diagnoses such as pulmonary infections, cardiac conditions, pleural disease, or musculoskeletal problems.

On review of the JAMA study using the YEARS rule with adjusted D-dimer thresholds, the editorialists noted that the data were robust and indicated a 10% reduction in chest imaging. They also emphasized the potential to overwhelm busy clinicians with more algorithms.

“Blindly applying algorithms to every patient may be less appropriate or even undesirable in specific situations in which deviation from the rules on clinical grounds is indicated,” but a complex imaging approach may be time consuming and challenging in the acute setting, and a simple algorithm may be safe and efficient in many cases, they wrote. “From a patient perspective, a negative diagnostic algorithm for pulmonary embolism does not diminish the physician’s obligation to consider other diagnoses that explain the symptoms, for which chest CT scans may still be needed and helpful.”

The Annals of Internal Medicine study was supported by the Dutch Research Council. The JAMA study was supported by the French Health Ministry. Dr. Stals, Dr. Freund, Dr. Pal, Dr. Levi, and Dr. van Es had no financial conflicts to disclose.

What the Future May Hold for Covid-19 Survivors

More than 3 million Americans¹ have been hospitalized with Covid-19, and 770,000 of them have died. ² As of this writing,  49,000 Americans are hospitalized, with 12,000 remaining in intensive care units.³ With growing numbers of patients being discharged from extensive stays in the ICU for severe Covid, it remains to be seen what the long-term impact will be on these patients, their families and on society writ large.

And these are just the patients with severe Covid: those who were never hospitalized are also showing deleterious effects from the effects of their illness.

Covid in the ICU

 What we know is that prior to Covid, 10% of all patients were admitted to ICU with acute respiratory distress syndrome⁴ (ARDS), despite receiving such life-saving measures as mechanical ventilation, medication, and supportive nutrition. Those who do survive face a long journey.⁴ Besides the specific respiratory recovery needed in those with ARDS, patients who have spent time in the ICU can develop multiple non-respiratory complications, including muscle wasting, generalized weakness, and delirium. The physical, cognitive, and psychological impairments that follow an ICU stay are termed postintensive care syndrome (PICS). PICS is an underrecognized phenomenon that describes the immense complications of an ICU stay for any reason. Recognition of this entity, and education of patients, is particularly important now as we face an ongoing pandemic which is creating a burgeoning number of ICU graduates.

PICS

Cognitive dysfunction is one hallmark of PICS. Delirium is a common complication of any hospitalization, with critically ill patients particularly susceptible given the severity of their illness and their exposure to medications such as sedatives. However, persistent global cognitive impairment is unique to PICS. Up to 40% ⁴ of ICU survivors have been found to have cognitive test results similar to those with moderate traumatic brain injury 3 months after discharge;  approximately 34% were still affected at 1 year. Similar findings were seen in a different study of ARDS patients.⁵ Hopkins et al. found that in these patients the rate of neurocognitive deficit persisted in 47% of patients at their 2-year follow-up. Patients describe being unable to re-enter their prior lives, troubled by difficulties with complex thinking and activities of daily living.

The second aspect of PICS is its psychological component. In the Hopkins study,⁵  23% ultimately reported persistent symptoms of depression and/or anxiety two years afterwards. Some patients have described intrusive distorted memories from their time in ICU; one patient detailed a recurring memory of an hallucination in which the nurses were transformed into demons hovering over his bed. Others have described feelings akin to depression, anxiety, and posttraumatic stress syndrome (PTSD).

The final component of PICS is physical impairment. Those who are critically ill commonly suffer intensive care unit-acquired weakness,⁶ which is a term to describe generalized limb and diaphragmatic weakness with no other medical cause. Risk factors for this entity include sepsis, multi-organ failure, mechanical ventilation, hyperglycemia, extensive immobilization, and exposure to steroids and neuromuscular blocking agents. ICU-acquired weakness can resolve within weeks to months but in some studies can persist for years. It has been observed that survivors of ARDS experience persistent physical limitations, even 5 years later.

Covid in the ICU

Estimates of the incidence of PICS due to Covid are evolving. A report on 1700 Covid hospitalized patients in Wuhan, China demonstrated a large prevalence of residual symptoms at 6 months. The most common symptoms were fatigue and weakness (63%), insomnia (26%), and anxiety or depression (23%).⁷ Furthermore, one-fourth to one-third of those with severe illness fell below the lower limit of normal for a 6-minute walk test. An Italian study demonstrated decreased global quality of life indices for Covid ICU survivors⁸ 3 months from discharge, particularly with mobility, eating, and resuming usual activities. In a Michigan observational⁹ study, which included all hospitalized patients with Covid including those never in ICU, one-third of respondents said they continued to cough or have shortness of breath. Only one-fourth had returned to work, with many of them having to modify activities or reduce hours due to their health. Nearly half reported being negatively emotionally impacted by their health issues. Last, a single French hospital¹⁰ discovered that Covid patients 4 months after hospital discharge experienced numerous, persistent symptoms. 38% of patients confirmed some form of cognitive impairment, with 17% reporting memory difficulties, 10% mental slowness, and 10% concentration problems. Of patients who were intubated, one-third still reported subjective dyspnea. Nearly a third still struggled with weakness.

As more centers track the progress of their ICU graduates over time, we can better understand the profound impact of critical illness on our Covid patients and better educate our patients and families on what to expect. One might be able to gain some clues from what is known regarding the prior coronavirus epidemics, severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS). In these diseases, a meta-analysis showed significant rates of      lung function abnormalities,¹¹ physical deconditioning, and mental health disorders during the 6 months after discharge. It might be that the impact of SARS-CoV2 is even more profound on survivors; additional studies need to be done.

Additional issues

What is particularly unique to Covid is the prevalence of long-term symptoms in those who were never hospitalized for Covid. Recent estimates of non-hospitalized patients who had Covid are showing at least 25% of them have had long-lasting effects, including stomach pain and respiratory issues.¹² We are continuing to learn more about what is described as “long-haul syndrome.” It has been described in both hospitalized and non-hospitalized patients, and therefore it can be hard to distinguish which symptoms are attributable to long-term effects of Covid infection versus the critical illness/PICS itself. These long-haul symptoms range from persistent lack of smell and taste, cognitive dysfunction, fatigue, decreased exercise endurance, and an increase in mental health disorders. The prognosis and spectrum of disease, as well as treatment, have yet to be determined, and the NIH is initiating a multicenter research study, RECOVER, to better characterize this syndrome.¹³  Patients who are interested in enrolling can fill out an interest form at recoverCovid.org.

Financially 1/3¹⁴ of patients were impacted by their hospitalization for Covid, with nearly 10% using most or all their savings, despite many being covered by cost-sharing waivers for Covid care. A study reviewing Medicare data noted that the mean cost of a hospitalization for Covid is $21,752,¹⁵ increasing to nearly $50,000 if mechanical ventilation is needed. This does not account for the cost of rehabilitative care, as 40%¹⁶ of patients are discharged either to home with additional services or to other facilities (skilled nursing facility, hospice). As insurance companies increasingly lift the cost-sharing waivers and patients assume more responsibility for paying more of this cost, the financial burden on individual patients will increase. Furthermore, given a prolonged course of mental and physical disabilities after severe Covid, patients may lose their ability to return to work, their medical insurance, or their ability to provide childcare, further compounding their family’s financial woes.

Conclusion

The long-term effects of hospitalization from Covid argues further for continued work on increasing the vaccination rate of our population. Even with Delta variant, vaccines decrease the risk of hospitalization and death by more than a factor of 10.¹⁷ The profound medical and financial effects of severe Covid, and the repercussions on their family, should compel us as health care practitioners to inform those who are vaccine hesitant and to inform patients that they are eligible for vaccine boosters. The combination of colder weather and loosening of social distancing has already led to another surge of Covid infections and makes expedient vaccination the priority.

What the Future May Hold for Covid-19 Survivors

More than 3 million Americans¹ have been hospitalized with Covid-19, and 770,000 of them have died. ² As of this writing,  49,000 Americans are hospitalized, with 12,000 remaining in intensive care units.³ With growing numbers of patients being discharged from extensive stays in the ICU for severe Covid, it remains to be seen what the long-term impact will be on these patients, their families and on society writ large.

And these are just the patients with severe Covid: those who were never hospitalized are also showing deleterious effects from the effects of their illness.

Covid in the ICU

 What we know is that prior to Covid, 10% of all patients were admitted to ICU with acute respiratory distress syndrome⁴ (ARDS), despite receiving such life-saving measures as mechanical ventilation, medication, and supportive nutrition. Those who do survive face a long journey.⁴ Besides the specific respiratory recovery needed in those with ARDS, patients who have spent time in the ICU can develop multiple non-respiratory complications, including muscle wasting, generalized weakness, and delirium. The physical, cognitive, and psychological impairments that follow an ICU stay are termed postintensive care syndrome (PICS). PICS is an underrecognized phenomenon that describes the immense complications of an ICU stay for any reason. Recognition of this entity, and education of patients, is particularly important now as we face an ongoing pandemic which is creating a burgeoning number of ICU graduates.

PICS

Cognitive dysfunction is one hallmark of PICS. Delirium is a common complication of any hospitalization, with critically ill patients particularly susceptible given the severity of their illness and their exposure to medications such as sedatives. However, persistent global cognitive impairment is unique to PICS. Up to 40% ⁴ of ICU survivors have been found to have cognitive test results similar to those with moderate traumatic brain injury 3 months after discharge;  approximately 34% were still affected at 1 year. Similar findings were seen in a different study of ARDS patients.⁵ Hopkins et al. found that in these patients the rate of neurocognitive deficit persisted in 47% of patients at their 2-year follow-up. Patients describe being unable to re-enter their prior lives, troubled by difficulties with complex thinking and activities of daily living.

The second aspect of PICS is its psychological component. In the Hopkins study,⁵  23% ultimately reported persistent symptoms of depression and/or anxiety two years afterwards. Some patients have described intrusive distorted memories from their time in ICU; one patient detailed a recurring memory of an hallucination in which the nurses were transformed into demons hovering over his bed. Others have described feelings akin to depression, anxiety, and posttraumatic stress syndrome (PTSD).

The final component of PICS is physical impairment. Those who are critically ill commonly suffer intensive care unit-acquired weakness,⁶ which is a term to describe generalized limb and diaphragmatic weakness with no other medical cause. Risk factors for this entity include sepsis, multi-organ failure, mechanical ventilation, hyperglycemia, extensive immobilization, and exposure to steroids and neuromuscular blocking agents. ICU-acquired weakness can resolve within weeks to months but in some studies can persist for years. It has been observed that survivors of ARDS experience persistent physical limitations, even 5 years later.

Covid in the ICU

Estimates of the incidence of PICS due to Covid are evolving. A report on 1700 Covid hospitalized patients in Wuhan, China demonstrated a large prevalence of residual symptoms at 6 months. The most common symptoms were fatigue and weakness (63%), insomnia (26%), and anxiety or depression (23%).⁷ Furthermore, one-fourth to one-third of those with severe illness fell below the lower limit of normal for a 6-minute walk test. An Italian study demonstrated decreased global quality of life indices for Covid ICU survivors⁸ 3 months from discharge, particularly with mobility, eating, and resuming usual activities. In a Michigan observational⁹ study, which included all hospitalized patients with Covid including those never in ICU, one-third of respondents said they continued to cough or have shortness of breath. Only one-fourth had returned to work, with many of them having to modify activities or reduce hours due to their health. Nearly half reported being negatively emotionally impacted by their health issues. Last, a single French hospital¹⁰ discovered that Covid patients 4 months after hospital discharge experienced numerous, persistent symptoms. 38% of patients confirmed some form of cognitive impairment, with 17% reporting memory difficulties, 10% mental slowness, and 10% concentration problems. Of patients who were intubated, one-third still reported subjective dyspnea. Nearly a third still struggled with weakness.

As more centers track the progress of their ICU graduates over time, we can better understand the profound impact of critical illness on our Covid patients and better educate our patients and families on what to expect. One might be able to gain some clues from what is known regarding the prior coronavirus epidemics, severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS). In these diseases, a meta-analysis showed significant rates of      lung function abnormalities,¹¹ physical deconditioning, and mental health disorders during the 6 months after discharge. It might be that the impact of SARS-CoV2 is even more profound on survivors; additional studies need to be done.

Additional issues

What is particularly unique to Covid is the prevalence of long-term symptoms in those who were never hospitalized for Covid. Recent estimates of non-hospitalized patients who had Covid are showing at least 25% of them have had long-lasting effects, including stomach pain and respiratory issues.¹² We are continuing to learn more about what is described as “long-haul syndrome.” It has been described in both hospitalized and non-hospitalized patients, and therefore it can be hard to distinguish which symptoms are attributable to long-term effects of Covid infection versus the critical illness/PICS itself. These long-haul symptoms range from persistent lack of smell and taste, cognitive dysfunction, fatigue, decreased exercise endurance, and an increase in mental health disorders. The prognosis and spectrum of disease, as well as treatment, have yet to be determined, and the NIH is initiating a multicenter research study, RECOVER, to better characterize this syndrome.¹³  Patients who are interested in enrolling can fill out an interest form at recoverCovid.org.

Financially 1/3¹⁴ of patients were impacted by their hospitalization for Covid, with nearly 10% using most or all their savings, despite many being covered by cost-sharing waivers for Covid care. A study reviewing Medicare data noted that the mean cost of a hospitalization for Covid is $21,752,¹⁵ increasing to nearly $50,000 if mechanical ventilation is needed. This does not account for the cost of rehabilitative care, as 40%¹⁶ of patients are discharged either to home with additional services or to other facilities (skilled nursing facility, hospice). As insurance companies increasingly lift the cost-sharing waivers and patients assume more responsibility for paying more of this cost, the financial burden on individual patients will increase. Furthermore, given a prolonged course of mental and physical disabilities after severe Covid, patients may lose their ability to return to work, their medical insurance, or their ability to provide childcare, further compounding their family’s financial woes.

Conclusion

The long-term effects of hospitalization from Covid argues further for continued work on increasing the vaccination rate of our population. Even with Delta variant, vaccines decrease the risk of hospitalization and death by more than a factor of 10.¹⁷ The profound medical and financial effects of severe Covid, and the repercussions on their family, should compel us as health care practitioners to inform those who are vaccine hesitant and to inform patients that they are eligible for vaccine boosters. The combination of colder weather and loosening of social distancing has already led to another surge of Covid infections and makes expedient vaccination the priority.

What the Future May Hold for Covid-19 Survivors

More than 3 million Americans¹ have been hospitalized with Covid-19, and 770,000 of them have died. ² As of this writing,  49,000 Americans are hospitalized, with 12,000 remaining in intensive care units.³ With growing numbers of patients being discharged from extensive stays in the ICU for severe Covid, it remains to be seen what the long-term impact will be on these patients, their families and on society writ large.

And these are just the patients with severe Covid: those who were never hospitalized are also showing deleterious effects from the effects of their illness.

Covid in the ICU

 What we know is that prior to Covid, 10% of all patients were admitted to ICU with acute respiratory distress syndrome⁴ (ARDS), despite receiving such life-saving measures as mechanical ventilation, medication, and supportive nutrition. Those who do survive face a long journey.⁴ Besides the specific respiratory recovery needed in those with ARDS, patients who have spent time in the ICU can develop multiple non-respiratory complications, including muscle wasting, generalized weakness, and delirium. The physical, cognitive, and psychological impairments that follow an ICU stay are termed postintensive care syndrome (PICS). PICS is an underrecognized phenomenon that describes the immense complications of an ICU stay for any reason. Recognition of this entity, and education of patients, is particularly important now as we face an ongoing pandemic which is creating a burgeoning number of ICU graduates.

PICS

Cognitive dysfunction is one hallmark of PICS. Delirium is a common complication of any hospitalization, with critically ill patients particularly susceptible given the severity of their illness and their exposure to medications such as sedatives. However, persistent global cognitive impairment is unique to PICS. Up to 40% ⁴ of ICU survivors have been found to have cognitive test results similar to those with moderate traumatic brain injury 3 months after discharge;  approximately 34% were still affected at 1 year. Similar findings were seen in a different study of ARDS patients.⁵ Hopkins et al. found that in these patients the rate of neurocognitive deficit persisted in 47% of patients at their 2-year follow-up. Patients describe being unable to re-enter their prior lives, troubled by difficulties with complex thinking and activities of daily living.

The second aspect of PICS is its psychological component. In the Hopkins study,⁵  23% ultimately reported persistent symptoms of depression and/or anxiety two years afterwards. Some patients have described intrusive distorted memories from their time in ICU; one patient detailed a recurring memory of an hallucination in which the nurses were transformed into demons hovering over his bed. Others have described feelings akin to depression, anxiety, and posttraumatic stress syndrome (PTSD).

The final component of PICS is physical impairment. Those who are critically ill commonly suffer intensive care unit-acquired weakness,⁶ which is a term to describe generalized limb and diaphragmatic weakness with no other medical cause. Risk factors for this entity include sepsis, multi-organ failure, mechanical ventilation, hyperglycemia, extensive immobilization, and exposure to steroids and neuromuscular blocking agents. ICU-acquired weakness can resolve within weeks to months but in some studies can persist for years. It has been observed that survivors of ARDS experience persistent physical limitations, even 5 years later.

Covid in the ICU

Estimates of the incidence of PICS due to Covid are evolving. A report on 1700 Covid hospitalized patients in Wuhan, China demonstrated a large prevalence of residual symptoms at 6 months. The most common symptoms were fatigue and weakness (63%), insomnia (26%), and anxiety or depression (23%).⁷ Furthermore, one-fourth to one-third of those with severe illness fell below the lower limit of normal for a 6-minute walk test. An Italian study demonstrated decreased global quality of life indices for Covid ICU survivors⁸ 3 months from discharge, particularly with mobility, eating, and resuming usual activities. In a Michigan observational⁹ study, which included all hospitalized patients with Covid including those never in ICU, one-third of respondents said they continued to cough or have shortness of breath. Only one-fourth had returned to work, with many of them having to modify activities or reduce hours due to their health. Nearly half reported being negatively emotionally impacted by their health issues. Last, a single French hospital¹⁰ discovered that Covid patients 4 months after hospital discharge experienced numerous, persistent symptoms. 38% of patients confirmed some form of cognitive impairment, with 17% reporting memory difficulties, 10% mental slowness, and 10% concentration problems. Of patients who were intubated, one-third still reported subjective dyspnea. Nearly a third still struggled with weakness.

As more centers track the progress of their ICU graduates over time, we can better understand the profound impact of critical illness on our Covid patients and better educate our patients and families on what to expect. One might be able to gain some clues from what is known regarding the prior coronavirus epidemics, severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS). In these diseases, a meta-analysis showed significant rates of      lung function abnormalities,¹¹ physical deconditioning, and mental health disorders during the 6 months after discharge. It might be that the impact of SARS-CoV2 is even more profound on survivors; additional studies need to be done.

Additional issues

What is particularly unique to Covid is the prevalence of long-term symptoms in those who were never hospitalized for Covid. Recent estimates of non-hospitalized patients who had Covid are showing at least 25% of them have had long-lasting effects, including stomach pain and respiratory issues.¹² We are continuing to learn more about what is described as “long-haul syndrome.” It has been described in both hospitalized and non-hospitalized patients, and therefore it can be hard to distinguish which symptoms are attributable to long-term effects of Covid infection versus the critical illness/PICS itself. These long-haul symptoms range from persistent lack of smell and taste, cognitive dysfunction, fatigue, decreased exercise endurance, and an increase in mental health disorders. The prognosis and spectrum of disease, as well as treatment, have yet to be determined, and the NIH is initiating a multicenter research study, RECOVER, to better characterize this syndrome.¹³  Patients who are interested in enrolling can fill out an interest form at recoverCovid.org.

Financially 1/3¹⁴ of patients were impacted by their hospitalization for Covid, with nearly 10% using most or all their savings, despite many being covered by cost-sharing waivers for Covid care. A study reviewing Medicare data noted that the mean cost of a hospitalization for Covid is $21,752,¹⁵ increasing to nearly $50,000 if mechanical ventilation is needed. This does not account for the cost of rehabilitative care, as 40%¹⁶ of patients are discharged either to home with additional services or to other facilities (skilled nursing facility, hospice). As insurance companies increasingly lift the cost-sharing waivers and patients assume more responsibility for paying more of this cost, the financial burden on individual patients will increase. Furthermore, given a prolonged course of mental and physical disabilities after severe Covid, patients may lose their ability to return to work, their medical insurance, or their ability to provide childcare, further compounding their family’s financial woes.

Conclusion

The long-term effects of hospitalization from Covid argues further for continued work on increasing the vaccination rate of our population. Even with Delta variant, vaccines decrease the risk of hospitalization and death by more than a factor of 10.¹⁷ The profound medical and financial effects of severe Covid, and the repercussions on their family, should compel us as health care practitioners to inform those who are vaccine hesitant and to inform patients that they are eligible for vaccine boosters. The combination of colder weather and loosening of social distancing has already led to another surge of Covid infections and makes expedient vaccination the priority.

Yoga added to conventional therapy for vasovagal syncope (VVS), when patients faint after a sudden drop in heart rate and blood pressure, can reduce symptoms and improve quality of life, new research suggests. 

AndiP/pixabay.com

A small, open-label trial conducted in New Delhi showed that participants practicing yoga reported an improvement in VVS symptoms after only 6 weeks, with a reduction of 1.82 events at 12 months. All those practicing yoga also showed significantly improved quality of life (QoL) scores by the end of the trial.

“Yoga as add-on therapy in VVS is superior to medical therapy in reducing syncopal and presyncopal events and in improving the QoL,” report Gautam Sharma, MD, DM, Centre for Integrative Medicine and Research, All India Institute of Medical Sciences, New Delhi, and colleagues. “It may be useful to integrate a cost-effective and safe intervention such as yoga into the management of VVS.”

Results of the LIVE-Yoga study were published online in JACC: Clinical Electrophysiology.

Vasovagal syncope is a common and non–life-threatening condition, but given the severity and frequency of recurrence it can result in significant deterioration in a patient’s quality of life, the authors note. “Existing management therapies have been largely ineffective,” they write.

Recent trials have suggested some efficacy for yoga in diseases of autonomic imbalance, suggesting a possible use in VVS. To find out, the researchers enrolled adults with VVS between the ages of 15-70 years who had a positive head-up tilt test (HUTT) and at least two syncope or presyncope events within 3 months of enrollment. They also needed to be willing and able to practice yoga. Those with structural heart disease, accelerated hypertension, and underlying neurologic disorders were not included in the study.

A total of 55 patients were randomly assigned to receive either a specialized yoga training program in addition to guideline-based therapy, or guideline-based therapy alone. Standard care included physical counterpressure maneuvers, avoidance of known triggers, increased salt and water intake, and drug therapy or pacing at the discretion of the treating physician.

The primary outcome was a composite of the number of episodes of syncope and presyncope at 12 months.    

Secondary outcomes including QoL, assessed using the World Health Organization Quality of Life Brief Field questionnaire (WHOQoL-BREF) and the Syncope Functional Status Questionnaire (SFSQ) at 12 months, a head-up tilt test, and heart rate variability at 6 weeks.

For the first 2 weeks, patients in the intervention group were enrolled in eight supervised yoga sessions conducted at the Centre for Integrative Medicine and Research at the All India Institute of Medical Sciences. For the remainder of the trial, they continued a daily yoga practice at home at least 5 days a week.

The yoga module created for participants was designed with a view to the pathophysiology of VVS and featured postures, breathing, and relaxation techniques. Yoga classes were taught by qualified therapists under the guidance of physicians.

In addition to a booklet with a pictorial of the yoga regimen, participants received twice-monthly calls from the yoga center to encourage compliance. Results show that all participants adhered to their yoga routine for more than 80% of the 12-month trial.

At 12 months, the mean number of syncopal or presyncopal events was 0.7 ± 0.7 with the yoga intervention versus 2.52 ± 1.93 among patients in the control arm (P < .05). The reduction in events started as early as 6 weeks and continued to separate out to 12 months, the researchers note.

Thirteen of 30 (43.3%) intervention patients and 4 of 25 (16%) control patients remained event-free at 12 months, a statistically significant difference (P = .02). There was a trend toward fewer positive head-up tilt tests between groups that did not reach significance, and there was no difference in heart rate variability at 6 weeks.

No adverse events as a result of the yoga practice were reported, and no patient started drug therapy or received pacing therapy during the trial, they note.

The researchers point out that yoga postures can enhance vascular and muscle tone, especially in the lower limbs.

“Yoga breathing and relaxation techniques have been shown to increase vagal tone and improve autonomic balance, which could potentially curtail the sympathetic overdrive phase and interrupt the activation of the c-mechanoreceptors, which is a critical step in the syncope cascade,” they note.

“We postulate that positive effects of yoga in this study could be related to a multidimensional effect of this intervention acting through both central and peripheral mechanisms, including physical, psychological, and autonomic pathways,” the authors conclude.
 

Comprehensive regimen

Dhanunjaya Lakkireddy, MD, medical director for the Kansas City Heart Rhythm Institute, Overland Park, Kansas, says these results are in line with previous research indicating the benefits of yoga in improving cardiovascular function.

“All of this clearly shows that when you [include] a systematic diet of yoga for a reasonable amount of time to improve the plasticity of parasympathetic inputs into the chest and thereby the cardiovascular system ... you can help patients to improve their symptoms,” he said in an interview.  

He already prescribes yoga in his own practice as part of a comprehensive therapeutic regimen, he said. “We have a handful of practitioners all around the city who work with us,” Dr. Lakkireddy said.

Both he and the study authors point the economic burden of VVS both in management and in loss of patient productivity. “A low-cost intervention in the form of yoga, which essentially requires only a mat, can reduce both direct and indirect costs significantly,” note the authors.

The trial was supported under the extramural research (EMR) scheme by the Ministry of AYUSH, Government of India. The authors have disclosed no relevant financial relationships.

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

Yoga added to conventional therapy for vasovagal syncope (VVS), when patients faint after a sudden drop in heart rate and blood pressure, can reduce symptoms and improve quality of life, new research suggests. 

AndiP/pixabay.com

A small, open-label trial conducted in New Delhi showed that participants practicing yoga reported an improvement in VVS symptoms after only 6 weeks, with a reduction of 1.82 events at 12 months. All those practicing yoga also showed significantly improved quality of life (QoL) scores by the end of the trial.

“Yoga as add-on therapy in VVS is superior to medical therapy in reducing syncopal and presyncopal events and in improving the QoL,” report Gautam Sharma, MD, DM, Centre for Integrative Medicine and Research, All India Institute of Medical Sciences, New Delhi, and colleagues. “It may be useful to integrate a cost-effective and safe intervention such as yoga into the management of VVS.”

Results of the LIVE-Yoga study were published online in JACC: Clinical Electrophysiology.

Vasovagal syncope is a common and non–life-threatening condition, but given the severity and frequency of recurrence it can result in significant deterioration in a patient’s quality of life, the authors note. “Existing management therapies have been largely ineffective,” they write.

Recent trials have suggested some efficacy for yoga in diseases of autonomic imbalance, suggesting a possible use in VVS. To find out, the researchers enrolled adults with VVS between the ages of 15-70 years who had a positive head-up tilt test (HUTT) and at least two syncope or presyncope events within 3 months of enrollment. They also needed to be willing and able to practice yoga. Those with structural heart disease, accelerated hypertension, and underlying neurologic disorders were not included in the study.

A total of 55 patients were randomly assigned to receive either a specialized yoga training program in addition to guideline-based therapy, or guideline-based therapy alone. Standard care included physical counterpressure maneuvers, avoidance of known triggers, increased salt and water intake, and drug therapy or pacing at the discretion of the treating physician.

The primary outcome was a composite of the number of episodes of syncope and presyncope at 12 months.    

Secondary outcomes including QoL, assessed using the World Health Organization Quality of Life Brief Field questionnaire (WHOQoL-BREF) and the Syncope Functional Status Questionnaire (SFSQ) at 12 months, a head-up tilt test, and heart rate variability at 6 weeks.

For the first 2 weeks, patients in the intervention group were enrolled in eight supervised yoga sessions conducted at the Centre for Integrative Medicine and Research at the All India Institute of Medical Sciences. For the remainder of the trial, they continued a daily yoga practice at home at least 5 days a week.

The yoga module created for participants was designed with a view to the pathophysiology of VVS and featured postures, breathing, and relaxation techniques. Yoga classes were taught by qualified therapists under the guidance of physicians.

In addition to a booklet with a pictorial of the yoga regimen, participants received twice-monthly calls from the yoga center to encourage compliance. Results show that all participants adhered to their yoga routine for more than 80% of the 12-month trial.

At 12 months, the mean number of syncopal or presyncopal events was 0.7 ± 0.7 with the yoga intervention versus 2.52 ± 1.93 among patients in the control arm (P < .05). The reduction in events started as early as 6 weeks and continued to separate out to 12 months, the researchers note.

Thirteen of 30 (43.3%) intervention patients and 4 of 25 (16%) control patients remained event-free at 12 months, a statistically significant difference (P = .02). There was a trend toward fewer positive head-up tilt tests between groups that did not reach significance, and there was no difference in heart rate variability at 6 weeks.

No adverse events as a result of the yoga practice were reported, and no patient started drug therapy or received pacing therapy during the trial, they note.

The researchers point out that yoga postures can enhance vascular and muscle tone, especially in the lower limbs.

“Yoga breathing and relaxation techniques have been shown to increase vagal tone and improve autonomic balance, which could potentially curtail the sympathetic overdrive phase and interrupt the activation of the c-mechanoreceptors, which is a critical step in the syncope cascade,” they note.

“We postulate that positive effects of yoga in this study could be related to a multidimensional effect of this intervention acting through both central and peripheral mechanisms, including physical, psychological, and autonomic pathways,” the authors conclude.
 

Comprehensive regimen

Dhanunjaya Lakkireddy, MD, medical director for the Kansas City Heart Rhythm Institute, Overland Park, Kansas, says these results are in line with previous research indicating the benefits of yoga in improving cardiovascular function.

“All of this clearly shows that when you [include] a systematic diet of yoga for a reasonable amount of time to improve the plasticity of parasympathetic inputs into the chest and thereby the cardiovascular system ... you can help patients to improve their symptoms,” he said in an interview.  

He already prescribes yoga in his own practice as part of a comprehensive therapeutic regimen, he said. “We have a handful of practitioners all around the city who work with us,” Dr. Lakkireddy said.

Both he and the study authors point the economic burden of VVS both in management and in loss of patient productivity. “A low-cost intervention in the form of yoga, which essentially requires only a mat, can reduce both direct and indirect costs significantly,” note the authors.

The trial was supported under the extramural research (EMR) scheme by the Ministry of AYUSH, Government of India. The authors have disclosed no relevant financial relationships.

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

Yoga added to conventional therapy for vasovagal syncope (VVS), when patients faint after a sudden drop in heart rate and blood pressure, can reduce symptoms and improve quality of life, new research suggests. 

AndiP/pixabay.com

A small, open-label trial conducted in New Delhi showed that participants practicing yoga reported an improvement in VVS symptoms after only 6 weeks, with a reduction of 1.82 events at 12 months. All those practicing yoga also showed significantly improved quality of life (QoL) scores by the end of the trial.

“Yoga as add-on therapy in VVS is superior to medical therapy in reducing syncopal and presyncopal events and in improving the QoL,” report Gautam Sharma, MD, DM, Centre for Integrative Medicine and Research, All India Institute of Medical Sciences, New Delhi, and colleagues. “It may be useful to integrate a cost-effective and safe intervention such as yoga into the management of VVS.”

Results of the LIVE-Yoga study were published online in JACC: Clinical Electrophysiology.

Vasovagal syncope is a common and non–life-threatening condition, but given the severity and frequency of recurrence it can result in significant deterioration in a patient’s quality of life, the authors note. “Existing management therapies have been largely ineffective,” they write.

Recent trials have suggested some efficacy for yoga in diseases of autonomic imbalance, suggesting a possible use in VVS. To find out, the researchers enrolled adults with VVS between the ages of 15-70 years who had a positive head-up tilt test (HUTT) and at least two syncope or presyncope events within 3 months of enrollment. They also needed to be willing and able to practice yoga. Those with structural heart disease, accelerated hypertension, and underlying neurologic disorders were not included in the study.

A total of 55 patients were randomly assigned to receive either a specialized yoga training program in addition to guideline-based therapy, or guideline-based therapy alone. Standard care included physical counterpressure maneuvers, avoidance of known triggers, increased salt and water intake, and drug therapy or pacing at the discretion of the treating physician.

The primary outcome was a composite of the number of episodes of syncope and presyncope at 12 months.    

Secondary outcomes including QoL, assessed using the World Health Organization Quality of Life Brief Field questionnaire (WHOQoL-BREF) and the Syncope Functional Status Questionnaire (SFSQ) at 12 months, a head-up tilt test, and heart rate variability at 6 weeks.

For the first 2 weeks, patients in the intervention group were enrolled in eight supervised yoga sessions conducted at the Centre for Integrative Medicine and Research at the All India Institute of Medical Sciences. For the remainder of the trial, they continued a daily yoga practice at home at least 5 days a week.

The yoga module created for participants was designed with a view to the pathophysiology of VVS and featured postures, breathing, and relaxation techniques. Yoga classes were taught by qualified therapists under the guidance of physicians.

In addition to a booklet with a pictorial of the yoga regimen, participants received twice-monthly calls from the yoga center to encourage compliance. Results show that all participants adhered to their yoga routine for more than 80% of the 12-month trial.

At 12 months, the mean number of syncopal or presyncopal events was 0.7 ± 0.7 with the yoga intervention versus 2.52 ± 1.93 among patients in the control arm (P < .05). The reduction in events started as early as 6 weeks and continued to separate out to 12 months, the researchers note.

Thirteen of 30 (43.3%) intervention patients and 4 of 25 (16%) control patients remained event-free at 12 months, a statistically significant difference (P = .02). There was a trend toward fewer positive head-up tilt tests between groups that did not reach significance, and there was no difference in heart rate variability at 6 weeks.

No adverse events as a result of the yoga practice were reported, and no patient started drug therapy or received pacing therapy during the trial, they note.

The researchers point out that yoga postures can enhance vascular and muscle tone, especially in the lower limbs.

“Yoga breathing and relaxation techniques have been shown to increase vagal tone and improve autonomic balance, which could potentially curtail the sympathetic overdrive phase and interrupt the activation of the c-mechanoreceptors, which is a critical step in the syncope cascade,” they note.

“We postulate that positive effects of yoga in this study could be related to a multidimensional effect of this intervention acting through both central and peripheral mechanisms, including physical, psychological, and autonomic pathways,” the authors conclude.
 

Comprehensive regimen

Dhanunjaya Lakkireddy, MD, medical director for the Kansas City Heart Rhythm Institute, Overland Park, Kansas, says these results are in line with previous research indicating the benefits of yoga in improving cardiovascular function.

“All of this clearly shows that when you [include] a systematic diet of yoga for a reasonable amount of time to improve the plasticity of parasympathetic inputs into the chest and thereby the cardiovascular system ... you can help patients to improve their symptoms,” he said in an interview.  

He already prescribes yoga in his own practice as part of a comprehensive therapeutic regimen, he said. “We have a handful of practitioners all around the city who work with us,” Dr. Lakkireddy said.

Both he and the study authors point the economic burden of VVS both in management and in loss of patient productivity. “A low-cost intervention in the form of yoga, which essentially requires only a mat, can reduce both direct and indirect costs significantly,” note the authors.

The trial was supported under the extramural research (EMR) scheme by the Ministry of AYUSH, Government of India. The authors have disclosed no relevant financial relationships.

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

To the Editor:

Dermatomyositis (DM) is an idiopathic inflammatory myopathy characterized by bilateral, symmetrical, proximal muscle weakness and classic cutaneous manifestations.¹ Patients with antibodies directed against melanoma differentiation–associated gene 5, MDA5, have a distinct presentation due to vasculopathy with more severe cutaneous ulcerations, palmar papules, alopecia, and an elevated risk of rapidly progressive interstitial lung disease.² A ferritin level greater than 1600 ng/mL portends an increased risk for pulmonary disease and therefore can be of prognostic value.³ Further, patients with anti-MDA5 DM are at a lower risk of malignancy and are more likely to test negative for antinuclear antibodies in comparison to other patients with DM.^2,4

Hemophagocytic lymphohistiocytosis (HLH), also known as hemophagocytic syndrome, is a potentially lethal condition whereby uncontrolled activation of histiocytes in the reticuloendothelial system causes hemophagocytosis and a hyperinflammatory state. Patients present with fever, splenomegaly, cytopenia, and hyperferritinemia.⁵ Autoimmune‐associated hemophagocytic syndrome (AAHS) describes HLH that develops in association with autoimmune conditions, most commonly systemic lupus erythematosus and adult-onset Still disease. Cases reported in association with DM exist but are few in number, and there is no standard-of-care treatment.⁶ We report a case of a woman with anti-MDA5 DM complicated by HLH and DM-associated liver injury.

A 50-year-old woman presented as a direct admit from the rheumatology clinic for diffuse muscle weakness of 8 months’ duration, 40-pound unintentional weight loss, pruritic rash, bilateral joint pains, dry eyes, dry mouth, and altered mental status. Four months prior, she presented to an outside hospital and was given a diagnosis of probable Sjögren syndrome and autoimmune hepatitis vs drug-induced liver injury. At that time, a workup was notable for antibodies against Sjögren syndrome–related antigen A, anti–smooth muscle antibodies, and transaminitis. Ultrasonography of the right upper quadrant revealed hepatic steatosis. The patient was started on oral prednisone and pilocarpine but had been off all medications for 1 month when she presented to our hospital.

On hospital admission, physical examination revealed a violaceous heliotrope rash; a v-sign on the chest; shawl sign; palmar papules with pits at the fingertips; and periungual erythema and ulcerations along the metacarpophalangeal joints, elbows, lateral feet, and upper eyelids (Figure 1). Laboratory workup showed the following results: white blood cell count, 4100/μL (reference range, 4000–11,000/μL); hemoglobin, 11.6 g/dL (reference range, 12–16 g/dL); platelet count, 100,000/μL (reference range, 150,000–450,000/μL); lactate dehydrogenase, 510 U/L (reference range, 80–225 U/L); alkaline phosphatase (ALP), 766 U/L (reference range, 30–120 U/L); alanine aminotransferase (ALT), 88 U/L (reference range, 10–40 U/L); aspartate aminotransferase (AST), 544 U/L (reference range, 10–40 U/L); total bilirubin, 4.2 mg/dL (reference range, 0.3–1.0 mg/dL); direct bilirubin, 3.7 mg/dL (reference range, 0.1–0.3 mg/dL); aldolase, 20.2 U/L (reference range, 1–7.5 U/L), creatine kinase, 180 U/L (reference range, 30–135 U/L); γ-glutamyltransferase (GGT), 2743 U/L (reference range, 8–40 U/L); high sensitivity C-reactive protein, 122.9 mg/L (low-risk reference range, <1.0 mg/L); triglycerides, 534 mg/dL (reference range, <150 mg/dL); ferritin, 3784 ng/mL (reference range, 24–307 ng/mL); antinuclear antibody, negative titer; antimitochondrial antibody, negative titer; soluble IL-2 receptor (CD25), 7000 U/mL (reference range, 189–846 U/mL); anti-Sjögren syndrome–related antigen A antibody, positive.

To the Editor:

Dermatomyositis (DM) is an idiopathic inflammatory myopathy characterized by bilateral, symmetrical, proximal muscle weakness and classic cutaneous manifestations.¹ Patients with antibodies directed against melanoma differentiation–associated gene 5, MDA5, have a distinct presentation due to vasculopathy with more severe cutaneous ulcerations, palmar papules, alopecia, and an elevated risk of rapidly progressive interstitial lung disease.² A ferritin level greater than 1600 ng/mL portends an increased risk for pulmonary disease and therefore can be of prognostic value.³ Further, patients with anti-MDA5 DM are at a lower risk of malignancy and are more likely to test negative for antinuclear antibodies in comparison to other patients with DM.^2,4

Hemophagocytic lymphohistiocytosis (HLH), also known as hemophagocytic syndrome, is a potentially lethal condition whereby uncontrolled activation of histiocytes in the reticuloendothelial system causes hemophagocytosis and a hyperinflammatory state. Patients present with fever, splenomegaly, cytopenia, and hyperferritinemia.⁵ Autoimmune‐associated hemophagocytic syndrome (AAHS) describes HLH that develops in association with autoimmune conditions, most commonly systemic lupus erythematosus and adult-onset Still disease. Cases reported in association with DM exist but are few in number, and there is no standard-of-care treatment.⁶ We report a case of a woman with anti-MDA5 DM complicated by HLH and DM-associated liver injury.

A 50-year-old woman presented as a direct admit from the rheumatology clinic for diffuse muscle weakness of 8 months’ duration, 40-pound unintentional weight loss, pruritic rash, bilateral joint pains, dry eyes, dry mouth, and altered mental status. Four months prior, she presented to an outside hospital and was given a diagnosis of probable Sjögren syndrome and autoimmune hepatitis vs drug-induced liver injury. At that time, a workup was notable for antibodies against Sjögren syndrome–related antigen A, anti–smooth muscle antibodies, and transaminitis. Ultrasonography of the right upper quadrant revealed hepatic steatosis. The patient was started on oral prednisone and pilocarpine but had been off all medications for 1 month when she presented to our hospital.

On hospital admission, physical examination revealed a violaceous heliotrope rash; a v-sign on the chest; shawl sign; palmar papules with pits at the fingertips; and periungual erythema and ulcerations along the metacarpophalangeal joints, elbows, lateral feet, and upper eyelids (Figure 1). Laboratory workup showed the following results: white blood cell count, 4100/μL (reference range, 4000–11,000/μL); hemoglobin, 11.6 g/dL (reference range, 12–16 g/dL); platelet count, 100,000/μL (reference range, 150,000–450,000/μL); lactate dehydrogenase, 510 U/L (reference range, 80–225 U/L); alkaline phosphatase (ALP), 766 U/L (reference range, 30–120 U/L); alanine aminotransferase (ALT), 88 U/L (reference range, 10–40 U/L); aspartate aminotransferase (AST), 544 U/L (reference range, 10–40 U/L); total bilirubin, 4.2 mg/dL (reference range, 0.3–1.0 mg/dL); direct bilirubin, 3.7 mg/dL (reference range, 0.1–0.3 mg/dL); aldolase, 20.2 U/L (reference range, 1–7.5 U/L), creatine kinase, 180 U/L (reference range, 30–135 U/L); γ-glutamyltransferase (GGT), 2743 U/L (reference range, 8–40 U/L); high sensitivity C-reactive protein, 122.9 mg/L (low-risk reference range, <1.0 mg/L); triglycerides, 534 mg/dL (reference range, <150 mg/dL); ferritin, 3784 ng/mL (reference range, 24–307 ng/mL); antinuclear antibody, negative titer; antimitochondrial antibody, negative titer; soluble IL-2 receptor (CD25), 7000 U/mL (reference range, 189–846 U/mL); anti-Sjögren syndrome–related antigen A antibody, positive.

To the Editor:

Dermatomyositis (DM) is an idiopathic inflammatory myopathy characterized by bilateral, symmetrical, proximal muscle weakness and classic cutaneous manifestations.¹ Patients with antibodies directed against melanoma differentiation–associated gene 5, MDA5, have a distinct presentation due to vasculopathy with more severe cutaneous ulcerations, palmar papules, alopecia, and an elevated risk of rapidly progressive interstitial lung disease.² A ferritin level greater than 1600 ng/mL portends an increased risk for pulmonary disease and therefore can be of prognostic value.³ Further, patients with anti-MDA5 DM are at a lower risk of malignancy and are more likely to test negative for antinuclear antibodies in comparison to other patients with DM.^2,4

Hemophagocytic lymphohistiocytosis (HLH), also known as hemophagocytic syndrome, is a potentially lethal condition whereby uncontrolled activation of histiocytes in the reticuloendothelial system causes hemophagocytosis and a hyperinflammatory state. Patients present with fever, splenomegaly, cytopenia, and hyperferritinemia.⁵ Autoimmune‐associated hemophagocytic syndrome (AAHS) describes HLH that develops in association with autoimmune conditions, most commonly systemic lupus erythematosus and adult-onset Still disease. Cases reported in association with DM exist but are few in number, and there is no standard-of-care treatment.⁶ We report a case of a woman with anti-MDA5 DM complicated by HLH and DM-associated liver injury.

A 50-year-old woman presented as a direct admit from the rheumatology clinic for diffuse muscle weakness of 8 months’ duration, 40-pound unintentional weight loss, pruritic rash, bilateral joint pains, dry eyes, dry mouth, and altered mental status. Four months prior, she presented to an outside hospital and was given a diagnosis of probable Sjögren syndrome and autoimmune hepatitis vs drug-induced liver injury. At that time, a workup was notable for antibodies against Sjögren syndrome–related antigen A, anti–smooth muscle antibodies, and transaminitis. Ultrasonography of the right upper quadrant revealed hepatic steatosis. The patient was started on oral prednisone and pilocarpine but had been off all medications for 1 month when she presented to our hospital.

On hospital admission, physical examination revealed a violaceous heliotrope rash; a v-sign on the chest; shawl sign; palmar papules with pits at the fingertips; and periungual erythema and ulcerations along the metacarpophalangeal joints, elbows, lateral feet, and upper eyelids (Figure 1). Laboratory workup showed the following results: white blood cell count, 4100/μL (reference range, 4000–11,000/μL); hemoglobin, 11.6 g/dL (reference range, 12–16 g/dL); platelet count, 100,000/μL (reference range, 150,000–450,000/μL); lactate dehydrogenase, 510 U/L (reference range, 80–225 U/L); alkaline phosphatase (ALP), 766 U/L (reference range, 30–120 U/L); alanine aminotransferase (ALT), 88 U/L (reference range, 10–40 U/L); aspartate aminotransferase (AST), 544 U/L (reference range, 10–40 U/L); total bilirubin, 4.2 mg/dL (reference range, 0.3–1.0 mg/dL); direct bilirubin, 3.7 mg/dL (reference range, 0.1–0.3 mg/dL); aldolase, 20.2 U/L (reference range, 1–7.5 U/L), creatine kinase, 180 U/L (reference range, 30–135 U/L); γ-glutamyltransferase (GGT), 2743 U/L (reference range, 8–40 U/L); high sensitivity C-reactive protein, 122.9 mg/L (low-risk reference range, <1.0 mg/L); triglycerides, 534 mg/dL (reference range, <150 mg/dL); ferritin, 3784 ng/mL (reference range, 24–307 ng/mL); antinuclear antibody, negative titer; antimitochondrial antibody, negative titer; soluble IL-2 receptor (CD25), 7000 U/mL (reference range, 189–846 U/mL); anti-Sjögren syndrome–related antigen A antibody, positive.

As compared with White individuals, minorities often face higher barriers to cancer care. Racial and ethnic disparities in patients with solid tumors, particularly those of the prostate and breast, have been well documented. Hematologic malignancies are less common, but an increasing number of studies have documented disparities within this subgroup of cancer, particularly among Black and non-White Hispanics. An increasing armamentarium of therapeutics, including novel chemotherapy agents and targeted molecular, cellular, and immunologic therapies, has highlighted the need for understanding and exploring the differences in care as well as biology, which may lead to disparate outcomes.

Courtesy NIAID

Overall, an estimated 186,400 people living in the United States are expected to be diagnosed with leukemia, lymphoma, or myeloma in 2021, and new cases of hematologic malignancies are expected to account for 9.8% of the estimated 1,898,160 new cancer cases diagnosed this year.¹

The underlying reasons for disparities are highly complex and multifactorial, and clinicians must consider how the biologic, clinical, demographic, and socioeconomic characteristics of their patients interact. All of these factors can play a role in prognosis and/or access to care.

Disparities in leukemia

Leukemia is a heterogeneous group of diseases affecting both children and adults, but during the past few decades survival rates have steadily improved, particularly among children. Response to therapy and prognosis do vary among leukemia types, but one large analysis reported that there were overall improvements in survival seen across racial/ethnic groups, most age groups, and genders during a 40-year period.²

From 1973 through 2014, survival trends were assessed across four leukemia types: acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and chronic lymphoid leukemia (CLL). After stratifying survival for each leukemia type by race/ethnicity, improvement rates were not uniform among all groups.

For example, there were substantial improvements of leukemia-specific survival in 2010-2014 among Black (81.0%) and Asian (80.0%) patients with CML, as well as younger patients (20-49 years) with CLL (96.0%). But in contrast, Black patients, those with AML, and individuals over the age of 75 years experienced the lowest improvement in survival.

Studies have found that Hispanics have increased rates of ALL and acute promyelocytic leukemia (APL), but lower rates of AML, as compared to Whites. They also tend to be diagnosed at a younger age and have poorer overall survival.³

Demographics may also play a role, as Hispanics born outside the United States had a higher incidence rate of APL versus U.S.-born Hispanics (incidence rate ratio, 1.79; 1.11-2.94). Thus, the higher incidence rates of increased B-cell ALL may be due to heritable genetic factors, while APL may also be attributable to environmental exposures.⁴

Hispanics living on the Texas-Mexico border were also found to have a higher incidence of chronic myeloid leukemia (RR, 1.28; 95% CI, 1.07-1.51; P = .02) and acute myeloid leukemia (RR, 1.17; 95% CI, 1.04-1.33; P = .0009) as compared with Hispanics living elsewhere in Texas⁵ AML and CML were more likely to be observed in patients who resided in this border region, and those with ALL, AML, and CML had worse outcomes compared with Hispanics living elsewhere in Texas. In addition, both Hispanic and non-Hispanic patients along the border have a worse prognosis for ALL than patients in other areas of Texas.

“We don’t yet understand if the differences are due to nonbiologic factors, or if biology plays a role because of the more aggressive disease that we’re seeing,” said study author Anna Eiring, PhD, an assistant professor at Texas Tech University, El Paso. “This is a medically underserved region, and even though we are a safety net hospital, many of the Hispanic patients don’t have health insurance.”

They also tend to have worse socioeconomic status compared with non-Hispanic populations, and there may also be lifestyle and environmental factors. “Exposure to environmental toxins may also play a role, as many work in jobs that could put them at risk,” she said. “Lifestyle factors may also play a role.”

AML is a hematopoietic disorder that is characterized by numerous cytogenetic and molecular aberrations, with poor overall survival. Researchers found that Black patients had shorter survival than White patients, based on an analysis of Surveillance Epidemiology and End Results (SEER) Program data, and performing and performed mutational profiling of 1,339 patients with AML treated on frontline Alliance for Clinical Trials in Oncology (Alliance) protocols.⁶ The disparity was especially pronounced in Black patients under 60 years old, after adjustment for socioeconomic (SEER) and molecular (Alliance) factors. Black race was an independent prognosticator of poor survival.

“Based on our analyses in Black and White AML patients under the age of 60 years, we believe that a differential impact of molecular aberrations, specifically AML-associated gene mutations, contribute to the observed survival disparities,” said study author Ann-Kathrin Eisfeld, MD, an assistant professor in the division of hematology at the Ohio State University, Columbus, and a member of the leukemia research program at the university’s comprehensive cancer center, the James. “For example, NPM1 mutations seem to lack the known positive prognostic impact we are used to seeing in previous studies with White AML patients.”

HRaun/E+

Disparities in lymphoma

Similar to leukemia, lymphomas are a heterogenous and diverse group of malignancies that range from indolent to highly aggressive. The two main types are listed below:

Non-Hodgkin lymphoma (NHL), the most common subtype, with about 80,000 new cases a year in the United States. There are more than 90 types of NHL, the most common being B-cell lymphomas, which include diffuse large B cell, primary mediastinal B cell, follicular, small lymphocytic lymphoma, and chronic lymphocytic leukemia; marginal zone, mantle zone, and Burkitt lymphomas; and Waldenström macroglobulinemia.

Hodgkin lymphoma (HL), less common than NHL, with about 9,000 people diagnosed every year. There are five types of HL, and it is primarily seen in children and young adults.

Disparities in incidence, age at diagnosis, and overall survival have been observed in lymphoma, which, aside from marginal zone and follicular lymphoma, are more common among men. The incidence of most lymphoma subtypes is generally lower in racial and ethnic minority groups, although Black and Hispanic patients tend to be diagnosed at a younger age, and in Black patients, at a more advanced stage and the lymphomas have higher risk features at initial presentation.⁷

One study that looked at racial disparities in Hodgkin lymphoma found that HL was significantly more common in Hispanics versus Whites under the age of 65 years. The 5-, 10-, and 15-year overall survival rates were also inferior for Blacks and Hispanics compared with Whites (P less than 0.005 and P less than 0.001, respectively).⁸

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma in the United States, comprising approximately one-third of lymphomas diagnosed in adults (Lee et al. 2020). In one study that examined ancestry and tumor genomics, recurrent somatic mutations in established driver genes, such as ATM, MGA, SETD2, TET2, DNMT3A, and MLL3, were observed more frequently in patients with African ancestry versus those of European ancestry.⁹ Other data suggest a variety of disparities in receipt of treatment. For example, patients with localized disease who were Black, uninsured/Medicaid insured, or of lower socioeconomic status were less likely to receive any form of chemotherapy (all P less than 0.0001), and Black race was also associated with being less likely to receive chemoimmunotherapy.

Leveling the field of disparities is complex and requires a multifaceted approach. But one facility found that they could help minority patients overcome some of the hurdles related to nonbiologic factors by the support of a nurse navigator in addition to therapy.¹⁰ Their study included 204 patients with DLBCL (47 minority patients and 157 White patients) and following the initiation of the nurse navigator program, virtually all patients received frontline chemotherapy (98% versus 96%). The incidence of relapsed/refractory disease was similar (40% versus 38%) and in the relapsed/refractory population, similar proportions of patients underwent hematopoietic stem cell transplantation (32% versus 29%) or received chimeric antigen receptor T-cell therapy (16% versus 19%). The 2-year overall survival rates were 81% and 76% for minorities and Whites, respectively, and 2-year progression-free survival rates were 62% and 65%, respectively.

“We found that the minority patients often needed more help to get care, and they utilized the nurse navigator more intensively,” said study author Bei Hu, MD, who is with the department of hematologic oncology and blood disorders, Levine Cancer Institute/Atrium Health, Charlotte, N.C. “The nurse navigator was able to help them with things like finances, transportation, and insurance.”

Minorities tended to face more barriers than White patients. “Even something as simple as needing money for gas to get to the clinic can be a barrier to care,” said Dr. Hu. “And many of the patients are often uncomfortable discussing these things with their physician – plus a lot is covered in our appointments and we focus on the cancer. So, they may be more comfortable discussing these issues with the nurse.”

Disparities in multiple myeloma

Multiple myeloma is the malignant clonal proliferation of plasma B cells in the bone marrow and, despite the advent of new therapies, remains incurable and generally fatal. It progresses from the more common but often subclinical precursor states of monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) to overt and symptomatic multiple myeloma. Racial disparities have been observed in all stages of the disease, and as compared with Whites, individuals who are Black have a higher risk of MGUS and myeloma and a higher mortality rate.¹¹ They have not experienced the same survival gains seen in White patients.

Some research suggests that these disparities may be more related to socioeconomic status as opposed to race. One analysis of 562 patients found that those with higher socioeconomic status had a median overall survival of 62.8 months compared with 53.7 and 48.6 months for middle and low socioeconomic status (P = 0.015).¹²

After controlling for confounders including race, patients with low socioeconomic status had a 54% increase in mortality rate relative to those with high status. The authors then performed a similar analysis of 45,505 patients with multiple myeloma from the Surveillance, Epidemiology and End Results-18 database to support their analysis, and that also showed low socioeconomic status to be independently associated with poorer overall survival.

“In some homogeneous health systems, such as the VA, we are seeing that Black patients do as well or better than White patients,” said Catherine Marinac, PhD, an assistant professor of medicine, Harvard Medical School, Boston. “Survival is equal or better, as long as treatment is not delayed and they receive the standard of care.”

Black patients generally have a more indolent disease subtype and may experience less aggressive disease, but they have not experienced the same magnitude in survival as White patients following the introduction of new therapeutics. This disparity lends support to the influence of socioeconomic factors, such as unequal access to novel therapies and/or differences in treatment response, and lower rates of autologous stem cell transplantation.¹³

However, there are racial/ethnic differences in risk for both myeloma and its premalignant conditions, as well as incidence. Blacks have a twofold increased risk of myeloma compared with White individuals and are diagnosed at younger ages. Differences in myeloma incidence is less marked in other racial/ethnic groups, such as Hispanics, where it is only slightly higher than in Whites at 6.7 per 100,00.¹¹ In contrast, the incidence of myeloma is markedly lower in Asians as compared with non-Hispanic Whites (incidence rate of 3.8 versus 6.2 per 100,000). Black persons also have a markedly higher prevalence of MGUS, and these differences suggest that biology, and clinical characteristics, differ by race or ancestry.

“Mortality among Black patients is also higher,” said Dr. Marinac, who is also on the faculty in the division of population sciences at the Dana Farber Cancer Institute, also in Boston. “The higher mortality rate is driven by the higher incidence.”

There are also differences in the prevalence of immunoglobulin isotypes observed across racial/ethnic groups of MGUS patients, Dr. Marinac explained, which is consistent with the hypothesis that there is a biological basis for disparities arising in precursor lesions.

“What we are looking at now is cancer prevention and early intervention,” she said. “There are well-defined precursors to myeloma, and Blacks are three times more likely to have a precursor condition.”

Early detection of precursors followed by preventing progression to full-blown multiple myeloma is one way of addressing disparities, but right now, there are no real screening guidelines. “Most patients now are diagnosed incidentally, and then the only intervention is to monitor them,” Dr. Marinac said. “At Dana Farber, we are now looking to see if we can refine screening, and then see who may need additional monitoring.”

The Promise study, being conducted at Dana Farber, is recruiting participants to examine the molecular changes that occur when precursor conditions develop into full-blown multiple myeloma and is open to individuals considered to be at high risk: Black race and/or have a first-degree relative with multiple myeloma or one of its precursor conditions.

Dr. Marinac also pointed out that there are ongoing clinical trials that are looking at low-risk early interventions in patients with precursor conditions. “We are now looking at lifestyle and metformin,” she said. “The thought is that if we treat them now, we can prevent myeloma from developing.”

Lessening barriers to care

When trying to tease out the strongest/most prominent reasons for the disparities that have been observed in the care of patients with blood cancers, Stephanie Lee, M.D., M.P.H, professor and associate director of the clinical research division at Fred Hutchinson Cancer Research Center, Seattle, thinks that the problem is truly multifactorial.

“Access has been cited many times because some studies show that if access is equitable, sometimes racial/ethnic minorities do the same as non-Hispanic Whites,” she said. “Same thing with quality of care – if all people are treated on clinical trials, sometimes the outcomes are the same.”

That said, many things have to go right to get the best outcomes, and if one factor isn’t optimal, then treatment may never achieve the success that is possible, she noted.

Considering how complex the issue of disparities is, addressing it can seem daunting. Dr. Lee points out that the place to begin is with clinical trials. “I would like to see more studies that test interventions to correct disparities,” said Dr. Lee. “But I have actually seen in my own work that racial and ethnic minorities are less likely to participate in studies, even survey and observational studies where physical risks are low or nonexistent.”

People are studying how to increase minority participation in clinical trials, but thus far, there isn’t one solution. “As with routine care, there are probably a lot of logistical barriers to trial participation that disproportionately affect minority populations,” she noted. “There is also greater distrust of studies.”

But for now, there are some steps that clinicians can take to start to improve these disparities. “I think we can start inquiring about and documenting barriers to care and clinical trial participation, just like we document other aspects of the social history,” Dr. Lee explained. “Truly understanding the problem is the first step toward trying to solve it.”

References

1. Leukemia & Lymphoma Society. 2021. www.lls.org/facts-and-statistics/facts-and-statistics-overview.

2. Utuama O et al. PLoS One. 2019 Aug 19;14(8):e0220864.

3. Pollyea DA et al. J Cancer Prev Curr Res. 2014;1(1):14-19.

4. Bencomo-Alvarez AE et al. Cancer. 2021 Apr 1;127(7):1068-79.

5. Nabhan C et al. Cancer. 2012 Oct 1;118(19):4842-50.

6. Bhatnagar B et al. Blood. 2020;136(Suppl 1):5-7.

7. Shenoy PJ et al. Cancer. 2011;117:2530-40.

8. Evens AM et al. Ann Oncol. 2012 Aug 1;23(8):2128-37.

9. Lee MJ et al. Cancer. 2020;126:3493-3503.

10. Hu B et al. Cancer. 2021 Jul 21. doi: 10.1002/cncr.33779.

11. Marinac CR et al. Blood Cancer J. 2020 Feb 17;10(2):19.

12. Fiala MA et al. Leuk Lymphoma. 2015;56(9):2643-9.

13. Costa LJ et al. Biol Blood Marrow Transplant. 2015 Apr;21(4):701-6.

As compared with White individuals, minorities often face higher barriers to cancer care. Racial and ethnic disparities in patients with solid tumors, particularly those of the prostate and breast, have been well documented. Hematologic malignancies are less common, but an increasing number of studies have documented disparities within this subgroup of cancer, particularly among Black and non-White Hispanics. An increasing armamentarium of therapeutics, including novel chemotherapy agents and targeted molecular, cellular, and immunologic therapies, has highlighted the need for understanding and exploring the differences in care as well as biology, which may lead to disparate outcomes.

Courtesy NIAID

Overall, an estimated 186,400 people living in the United States are expected to be diagnosed with leukemia, lymphoma, or myeloma in 2021, and new cases of hematologic malignancies are expected to account for 9.8% of the estimated 1,898,160 new cancer cases diagnosed this year.¹

The underlying reasons for disparities are highly complex and multifactorial, and clinicians must consider how the biologic, clinical, demographic, and socioeconomic characteristics of their patients interact. All of these factors can play a role in prognosis and/or access to care.

Disparities in leukemia

Leukemia is a heterogeneous group of diseases affecting both children and adults, but during the past few decades survival rates have steadily improved, particularly among children. Response to therapy and prognosis do vary among leukemia types, but one large analysis reported that there were overall improvements in survival seen across racial/ethnic groups, most age groups, and genders during a 40-year period.²

From 1973 through 2014, survival trends were assessed across four leukemia types: acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and chronic lymphoid leukemia (CLL). After stratifying survival for each leukemia type by race/ethnicity, improvement rates were not uniform among all groups.

For example, there were substantial improvements of leukemia-specific survival in 2010-2014 among Black (81.0%) and Asian (80.0%) patients with CML, as well as younger patients (20-49 years) with CLL (96.0%). But in contrast, Black patients, those with AML, and individuals over the age of 75 years experienced the lowest improvement in survival.

Studies have found that Hispanics have increased rates of ALL and acute promyelocytic leukemia (APL), but lower rates of AML, as compared to Whites. They also tend to be diagnosed at a younger age and have poorer overall survival.³

Demographics may also play a role, as Hispanics born outside the United States had a higher incidence rate of APL versus U.S.-born Hispanics (incidence rate ratio, 1.79; 1.11-2.94). Thus, the higher incidence rates of increased B-cell ALL may be due to heritable genetic factors, while APL may also be attributable to environmental exposures.⁴

Hispanics living on the Texas-Mexico border were also found to have a higher incidence of chronic myeloid leukemia (RR, 1.28; 95% CI, 1.07-1.51; P = .02) and acute myeloid leukemia (RR, 1.17; 95% CI, 1.04-1.33; P = .0009) as compared with Hispanics living elsewhere in Texas⁵ AML and CML were more likely to be observed in patients who resided in this border region, and those with ALL, AML, and CML had worse outcomes compared with Hispanics living elsewhere in Texas. In addition, both Hispanic and non-Hispanic patients along the border have a worse prognosis for ALL than patients in other areas of Texas.

“We don’t yet understand if the differences are due to nonbiologic factors, or if biology plays a role because of the more aggressive disease that we’re seeing,” said study author Anna Eiring, PhD, an assistant professor at Texas Tech University, El Paso. “This is a medically underserved region, and even though we are a safety net hospital, many of the Hispanic patients don’t have health insurance.”

They also tend to have worse socioeconomic status compared with non-Hispanic populations, and there may also be lifestyle and environmental factors. “Exposure to environmental toxins may also play a role, as many work in jobs that could put them at risk,” she said. “Lifestyle factors may also play a role.”

AML is a hematopoietic disorder that is characterized by numerous cytogenetic and molecular aberrations, with poor overall survival. Researchers found that Black patients had shorter survival than White patients, based on an analysis of Surveillance Epidemiology and End Results (SEER) Program data, and performing and performed mutational profiling of 1,339 patients with AML treated on frontline Alliance for Clinical Trials in Oncology (Alliance) protocols.⁶ The disparity was especially pronounced in Black patients under 60 years old, after adjustment for socioeconomic (SEER) and molecular (Alliance) factors. Black race was an independent prognosticator of poor survival.

“Based on our analyses in Black and White AML patients under the age of 60 years, we believe that a differential impact of molecular aberrations, specifically AML-associated gene mutations, contribute to the observed survival disparities,” said study author Ann-Kathrin Eisfeld, MD, an assistant professor in the division of hematology at the Ohio State University, Columbus, and a member of the leukemia research program at the university’s comprehensive cancer center, the James. “For example, NPM1 mutations seem to lack the known positive prognostic impact we are used to seeing in previous studies with White AML patients.”

HRaun/E+

Disparities in lymphoma

Similar to leukemia, lymphomas are a heterogenous and diverse group of malignancies that range from indolent to highly aggressive. The two main types are listed below:

Non-Hodgkin lymphoma (NHL), the most common subtype, with about 80,000 new cases a year in the United States. There are more than 90 types of NHL, the most common being B-cell lymphomas, which include diffuse large B cell, primary mediastinal B cell, follicular, small lymphocytic lymphoma, and chronic lymphocytic leukemia; marginal zone, mantle zone, and Burkitt lymphomas; and Waldenström macroglobulinemia.

Hodgkin lymphoma (HL), less common than NHL, with about 9,000 people diagnosed every year. There are five types of HL, and it is primarily seen in children and young adults.

Disparities in incidence, age at diagnosis, and overall survival have been observed in lymphoma, which, aside from marginal zone and follicular lymphoma, are more common among men. The incidence of most lymphoma subtypes is generally lower in racial and ethnic minority groups, although Black and Hispanic patients tend to be diagnosed at a younger age, and in Black patients, at a more advanced stage and the lymphomas have higher risk features at initial presentation.⁷

One study that looked at racial disparities in Hodgkin lymphoma found that HL was significantly more common in Hispanics versus Whites under the age of 65 years. The 5-, 10-, and 15-year overall survival rates were also inferior for Blacks and Hispanics compared with Whites (P less than 0.005 and P less than 0.001, respectively).⁸

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma in the United States, comprising approximately one-third of lymphomas diagnosed in adults (Lee et al. 2020). In one study that examined ancestry and tumor genomics, recurrent somatic mutations in established driver genes, such as ATM, MGA, SETD2, TET2, DNMT3A, and MLL3, were observed more frequently in patients with African ancestry versus those of European ancestry.⁹ Other data suggest a variety of disparities in receipt of treatment. For example, patients with localized disease who were Black, uninsured/Medicaid insured, or of lower socioeconomic status were less likely to receive any form of chemotherapy (all P less than 0.0001), and Black race was also associated with being less likely to receive chemoimmunotherapy.

Leveling the field of disparities is complex and requires a multifaceted approach. But one facility found that they could help minority patients overcome some of the hurdles related to nonbiologic factors by the support of a nurse navigator in addition to therapy.¹⁰ Their study included 204 patients with DLBCL (47 minority patients and 157 White patients) and following the initiation of the nurse navigator program, virtually all patients received frontline chemotherapy (98% versus 96%). The incidence of relapsed/refractory disease was similar (40% versus 38%) and in the relapsed/refractory population, similar proportions of patients underwent hematopoietic stem cell transplantation (32% versus 29%) or received chimeric antigen receptor T-cell therapy (16% versus 19%). The 2-year overall survival rates were 81% and 76% for minorities and Whites, respectively, and 2-year progression-free survival rates were 62% and 65%, respectively.

“We found that the minority patients often needed more help to get care, and they utilized the nurse navigator more intensively,” said study author Bei Hu, MD, who is with the department of hematologic oncology and blood disorders, Levine Cancer Institute/Atrium Health, Charlotte, N.C. “The nurse navigator was able to help them with things like finances, transportation, and insurance.”

Minorities tended to face more barriers than White patients. “Even something as simple as needing money for gas to get to the clinic can be a barrier to care,” said Dr. Hu. “And many of the patients are often uncomfortable discussing these things with their physician – plus a lot is covered in our appointments and we focus on the cancer. So, they may be more comfortable discussing these issues with the nurse.”

Disparities in multiple myeloma

Multiple myeloma is the malignant clonal proliferation of plasma B cells in the bone marrow and, despite the advent of new therapies, remains incurable and generally fatal. It progresses from the more common but often subclinical precursor states of monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) to overt and symptomatic multiple myeloma. Racial disparities have been observed in all stages of the disease, and as compared with Whites, individuals who are Black have a higher risk of MGUS and myeloma and a higher mortality rate.¹¹ They have not experienced the same survival gains seen in White patients.

Some research suggests that these disparities may be more related to socioeconomic status as opposed to race. One analysis of 562 patients found that those with higher socioeconomic status had a median overall survival of 62.8 months compared with 53.7 and 48.6 months for middle and low socioeconomic status (P = 0.015).¹²

After controlling for confounders including race, patients with low socioeconomic status had a 54% increase in mortality rate relative to those with high status. The authors then performed a similar analysis of 45,505 patients with multiple myeloma from the Surveillance, Epidemiology and End Results-18 database to support their analysis, and that also showed low socioeconomic status to be independently associated with poorer overall survival.

“In some homogeneous health systems, such as the VA, we are seeing that Black patients do as well or better than White patients,” said Catherine Marinac, PhD, an assistant professor of medicine, Harvard Medical School, Boston. “Survival is equal or better, as long as treatment is not delayed and they receive the standard of care.”

Black patients generally have a more indolent disease subtype and may experience less aggressive disease, but they have not experienced the same magnitude in survival as White patients following the introduction of new therapeutics. This disparity lends support to the influence of socioeconomic factors, such as unequal access to novel therapies and/or differences in treatment response, and lower rates of autologous stem cell transplantation.¹³

However, there are racial/ethnic differences in risk for both myeloma and its premalignant conditions, as well as incidence. Blacks have a twofold increased risk of myeloma compared with White individuals and are diagnosed at younger ages. Differences in myeloma incidence is less marked in other racial/ethnic groups, such as Hispanics, where it is only slightly higher than in Whites at 6.7 per 100,00.¹¹ In contrast, the incidence of myeloma is markedly lower in Asians as compared with non-Hispanic Whites (incidence rate of 3.8 versus 6.2 per 100,000). Black persons also have a markedly higher prevalence of MGUS, and these differences suggest that biology, and clinical characteristics, differ by race or ancestry.

“Mortality among Black patients is also higher,” said Dr. Marinac, who is also on the faculty in the division of population sciences at the Dana Farber Cancer Institute, also in Boston. “The higher mortality rate is driven by the higher incidence.”

There are also differences in the prevalence of immunoglobulin isotypes observed across racial/ethnic groups of MGUS patients, Dr. Marinac explained, which is consistent with the hypothesis that there is a biological basis for disparities arising in precursor lesions.

“What we are looking at now is cancer prevention and early intervention,” she said. “There are well-defined precursors to myeloma, and Blacks are three times more likely to have a precursor condition.”

Early detection of precursors followed by preventing progression to full-blown multiple myeloma is one way of addressing disparities, but right now, there are no real screening guidelines. “Most patients now are diagnosed incidentally, and then the only intervention is to monitor them,” Dr. Marinac said. “At Dana Farber, we are now looking to see if we can refine screening, and then see who may need additional monitoring.”

The Promise study, being conducted at Dana Farber, is recruiting participants to examine the molecular changes that occur when precursor conditions develop into full-blown multiple myeloma and is open to individuals considered to be at high risk: Black race and/or have a first-degree relative with multiple myeloma or one of its precursor conditions.

Dr. Marinac also pointed out that there are ongoing clinical trials that are looking at low-risk early interventions in patients with precursor conditions. “We are now looking at lifestyle and metformin,” she said. “The thought is that if we treat them now, we can prevent myeloma from developing.”

Lessening barriers to care

When trying to tease out the strongest/most prominent reasons for the disparities that have been observed in the care of patients with blood cancers, Stephanie Lee, M.D., M.P.H, professor and associate director of the clinical research division at Fred Hutchinson Cancer Research Center, Seattle, thinks that the problem is truly multifactorial.

“Access has been cited many times because some studies show that if access is equitable, sometimes racial/ethnic minorities do the same as non-Hispanic Whites,” she said. “Same thing with quality of care – if all people are treated on clinical trials, sometimes the outcomes are the same.”

That said, many things have to go right to get the best outcomes, and if one factor isn’t optimal, then treatment may never achieve the success that is possible, she noted.

Considering how complex the issue of disparities is, addressing it can seem daunting. Dr. Lee points out that the place to begin is with clinical trials. “I would like to see more studies that test interventions to correct disparities,” said Dr. Lee. “But I have actually seen in my own work that racial and ethnic minorities are less likely to participate in studies, even survey and observational studies where physical risks are low or nonexistent.”

People are studying how to increase minority participation in clinical trials, but thus far, there isn’t one solution. “As with routine care, there are probably a lot of logistical barriers to trial participation that disproportionately affect minority populations,” she noted. “There is also greater distrust of studies.”

But for now, there are some steps that clinicians can take to start to improve these disparities. “I think we can start inquiring about and documenting barriers to care and clinical trial participation, just like we document other aspects of the social history,” Dr. Lee explained. “Truly understanding the problem is the first step toward trying to solve it.”

References

1. Leukemia & Lymphoma Society. 2021. www.lls.org/facts-and-statistics/facts-and-statistics-overview.

2. Utuama O et al. PLoS One. 2019 Aug 19;14(8):e0220864.

3. Pollyea DA et al. J Cancer Prev Curr Res. 2014;1(1):14-19.

4. Bencomo-Alvarez AE et al. Cancer. 2021 Apr 1;127(7):1068-79.

5. Nabhan C et al. Cancer. 2012 Oct 1;118(19):4842-50.

6. Bhatnagar B et al. Blood. 2020;136(Suppl 1):5-7.

7. Shenoy PJ et al. Cancer. 2011;117:2530-40.

8. Evens AM et al. Ann Oncol. 2012 Aug 1;23(8):2128-37.

9. Lee MJ et al. Cancer. 2020;126:3493-3503.

10. Hu B et al. Cancer. 2021 Jul 21. doi: 10.1002/cncr.33779.

11. Marinac CR et al. Blood Cancer J. 2020 Feb 17;10(2):19.

12. Fiala MA et al. Leuk Lymphoma. 2015;56(9):2643-9.

13. Costa LJ et al. Biol Blood Marrow Transplant. 2015 Apr;21(4):701-6.

As compared with White individuals, minorities often face higher barriers to cancer care. Racial and ethnic disparities in patients with solid tumors, particularly those of the prostate and breast, have been well documented. Hematologic malignancies are less common, but an increasing number of studies have documented disparities within this subgroup of cancer, particularly among Black and non-White Hispanics. An increasing armamentarium of therapeutics, including novel chemotherapy agents and targeted molecular, cellular, and immunologic therapies, has highlighted the need for understanding and exploring the differences in care as well as biology, which may lead to disparate outcomes.

Courtesy NIAID

Overall, an estimated 186,400 people living in the United States are expected to be diagnosed with leukemia, lymphoma, or myeloma in 2021, and new cases of hematologic malignancies are expected to account for 9.8% of the estimated 1,898,160 new cancer cases diagnosed this year.¹

The underlying reasons for disparities are highly complex and multifactorial, and clinicians must consider how the biologic, clinical, demographic, and socioeconomic characteristics of their patients interact. All of these factors can play a role in prognosis and/or access to care.

Disparities in leukemia

Leukemia is a heterogeneous group of diseases affecting both children and adults, but during the past few decades survival rates have steadily improved, particularly among children. Response to therapy and prognosis do vary among leukemia types, but one large analysis reported that there were overall improvements in survival seen across racial/ethnic groups, most age groups, and genders during a 40-year period.²

From 1973 through 2014, survival trends were assessed across four leukemia types: acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and chronic lymphoid leukemia (CLL). After stratifying survival for each leukemia type by race/ethnicity, improvement rates were not uniform among all groups.

For example, there were substantial improvements of leukemia-specific survival in 2010-2014 among Black (81.0%) and Asian (80.0%) patients with CML, as well as younger patients (20-49 years) with CLL (96.0%). But in contrast, Black patients, those with AML, and individuals over the age of 75 years experienced the lowest improvement in survival.

Studies have found that Hispanics have increased rates of ALL and acute promyelocytic leukemia (APL), but lower rates of AML, as compared to Whites. They also tend to be diagnosed at a younger age and have poorer overall survival.³

Demographics may also play a role, as Hispanics born outside the United States had a higher incidence rate of APL versus U.S.-born Hispanics (incidence rate ratio, 1.79; 1.11-2.94). Thus, the higher incidence rates of increased B-cell ALL may be due to heritable genetic factors, while APL may also be attributable to environmental exposures.⁴

Hispanics living on the Texas-Mexico border were also found to have a higher incidence of chronic myeloid leukemia (RR, 1.28; 95% CI, 1.07-1.51; P = .02) and acute myeloid leukemia (RR, 1.17; 95% CI, 1.04-1.33; P = .0009) as compared with Hispanics living elsewhere in Texas⁵ AML and CML were more likely to be observed in patients who resided in this border region, and those with ALL, AML, and CML had worse outcomes compared with Hispanics living elsewhere in Texas. In addition, both Hispanic and non-Hispanic patients along the border have a worse prognosis for ALL than patients in other areas of Texas.

“We don’t yet understand if the differences are due to nonbiologic factors, or if biology plays a role because of the more aggressive disease that we’re seeing,” said study author Anna Eiring, PhD, an assistant professor at Texas Tech University, El Paso. “This is a medically underserved region, and even though we are a safety net hospital, many of the Hispanic patients don’t have health insurance.”

They also tend to have worse socioeconomic status compared with non-Hispanic populations, and there may also be lifestyle and environmental factors. “Exposure to environmental toxins may also play a role, as many work in jobs that could put them at risk,” she said. “Lifestyle factors may also play a role.”

AML is a hematopoietic disorder that is characterized by numerous cytogenetic and molecular aberrations, with poor overall survival. Researchers found that Black patients had shorter survival than White patients, based on an analysis of Surveillance Epidemiology and End Results (SEER) Program data, and performing and performed mutational profiling of 1,339 patients with AML treated on frontline Alliance for Clinical Trials in Oncology (Alliance) protocols.⁶ The disparity was especially pronounced in Black patients under 60 years old, after adjustment for socioeconomic (SEER) and molecular (Alliance) factors. Black race was an independent prognosticator of poor survival.

“Based on our analyses in Black and White AML patients under the age of 60 years, we believe that a differential impact of molecular aberrations, specifically AML-associated gene mutations, contribute to the observed survival disparities,” said study author Ann-Kathrin Eisfeld, MD, an assistant professor in the division of hematology at the Ohio State University, Columbus, and a member of the leukemia research program at the university’s comprehensive cancer center, the James. “For example, NPM1 mutations seem to lack the known positive prognostic impact we are used to seeing in previous studies with White AML patients.”

HRaun/E+

Disparities in lymphoma

Similar to leukemia, lymphomas are a heterogenous and diverse group of malignancies that range from indolent to highly aggressive. The two main types are listed below:

Non-Hodgkin lymphoma (NHL), the most common subtype, with about 80,000 new cases a year in the United States. There are more than 90 types of NHL, the most common being B-cell lymphomas, which include diffuse large B cell, primary mediastinal B cell, follicular, small lymphocytic lymphoma, and chronic lymphocytic leukemia; marginal zone, mantle zone, and Burkitt lymphomas; and Waldenström macroglobulinemia.

Hodgkin lymphoma (HL), less common than NHL, with about 9,000 people diagnosed every year. There are five types of HL, and it is primarily seen in children and young adults.

Disparities in incidence, age at diagnosis, and overall survival have been observed in lymphoma, which, aside from marginal zone and follicular lymphoma, are more common among men. The incidence of most lymphoma subtypes is generally lower in racial and ethnic minority groups, although Black and Hispanic patients tend to be diagnosed at a younger age, and in Black patients, at a more advanced stage and the lymphomas have higher risk features at initial presentation.⁷

One study that looked at racial disparities in Hodgkin lymphoma found that HL was significantly more common in Hispanics versus Whites under the age of 65 years. The 5-, 10-, and 15-year overall survival rates were also inferior for Blacks and Hispanics compared with Whites (P less than 0.005 and P less than 0.001, respectively).⁸

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma in the United States, comprising approximately one-third of lymphomas diagnosed in adults (Lee et al. 2020). In one study that examined ancestry and tumor genomics, recurrent somatic mutations in established driver genes, such as ATM, MGA, SETD2, TET2, DNMT3A, and MLL3, were observed more frequently in patients with African ancestry versus those of European ancestry.⁹ Other data suggest a variety of disparities in receipt of treatment. For example, patients with localized disease who were Black, uninsured/Medicaid insured, or of lower socioeconomic status were less likely to receive any form of chemotherapy (all P less than 0.0001), and Black race was also associated with being less likely to receive chemoimmunotherapy.

Leveling the field of disparities is complex and requires a multifaceted approach. But one facility found that they could help minority patients overcome some of the hurdles related to nonbiologic factors by the support of a nurse navigator in addition to therapy.¹⁰ Their study included 204 patients with DLBCL (47 minority patients and 157 White patients) and following the initiation of the nurse navigator program, virtually all patients received frontline chemotherapy (98% versus 96%). The incidence of relapsed/refractory disease was similar (40% versus 38%) and in the relapsed/refractory population, similar proportions of patients underwent hematopoietic stem cell transplantation (32% versus 29%) or received chimeric antigen receptor T-cell therapy (16% versus 19%). The 2-year overall survival rates were 81% and 76% for minorities and Whites, respectively, and 2-year progression-free survival rates were 62% and 65%, respectively.

“We found that the minority patients often needed more help to get care, and they utilized the nurse navigator more intensively,” said study author Bei Hu, MD, who is with the department of hematologic oncology and blood disorders, Levine Cancer Institute/Atrium Health, Charlotte, N.C. “The nurse navigator was able to help them with things like finances, transportation, and insurance.”

Minorities tended to face more barriers than White patients. “Even something as simple as needing money for gas to get to the clinic can be a barrier to care,” said Dr. Hu. “And many of the patients are often uncomfortable discussing these things with their physician – plus a lot is covered in our appointments and we focus on the cancer. So, they may be more comfortable discussing these issues with the nurse.”

Disparities in multiple myeloma

Multiple myeloma is the malignant clonal proliferation of plasma B cells in the bone marrow and, despite the advent of new therapies, remains incurable and generally fatal. It progresses from the more common but often subclinical precursor states of monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) to overt and symptomatic multiple myeloma. Racial disparities have been observed in all stages of the disease, and as compared with Whites, individuals who are Black have a higher risk of MGUS and myeloma and a higher mortality rate.¹¹ They have not experienced the same survival gains seen in White patients.

Some research suggests that these disparities may be more related to socioeconomic status as opposed to race. One analysis of 562 patients found that those with higher socioeconomic status had a median overall survival of 62.8 months compared with 53.7 and 48.6 months for middle and low socioeconomic status (P = 0.015).¹²

After controlling for confounders including race, patients with low socioeconomic status had a 54% increase in mortality rate relative to those with high status. The authors then performed a similar analysis of 45,505 patients with multiple myeloma from the Surveillance, Epidemiology and End Results-18 database to support their analysis, and that also showed low socioeconomic status to be independently associated with poorer overall survival.

“In some homogeneous health systems, such as the VA, we are seeing that Black patients do as well or better than White patients,” said Catherine Marinac, PhD, an assistant professor of medicine, Harvard Medical School, Boston. “Survival is equal or better, as long as treatment is not delayed and they receive the standard of care.”

Black patients generally have a more indolent disease subtype and may experience less aggressive disease, but they have not experienced the same magnitude in survival as White patients following the introduction of new therapeutics. This disparity lends support to the influence of socioeconomic factors, such as unequal access to novel therapies and/or differences in treatment response, and lower rates of autologous stem cell transplantation.¹³

However, there are racial/ethnic differences in risk for both myeloma and its premalignant conditions, as well as incidence. Blacks have a twofold increased risk of myeloma compared with White individuals and are diagnosed at younger ages. Differences in myeloma incidence is less marked in other racial/ethnic groups, such as Hispanics, where it is only slightly higher than in Whites at 6.7 per 100,00.¹¹ In contrast, the incidence of myeloma is markedly lower in Asians as compared with non-Hispanic Whites (incidence rate of 3.8 versus 6.2 per 100,000). Black persons also have a markedly higher prevalence of MGUS, and these differences suggest that biology, and clinical characteristics, differ by race or ancestry.

“Mortality among Black patients is also higher,” said Dr. Marinac, who is also on the faculty in the division of population sciences at the Dana Farber Cancer Institute, also in Boston. “The higher mortality rate is driven by the higher incidence.”

There are also differences in the prevalence of immunoglobulin isotypes observed across racial/ethnic groups of MGUS patients, Dr. Marinac explained, which is consistent with the hypothesis that there is a biological basis for disparities arising in precursor lesions.

“What we are looking at now is cancer prevention and early intervention,” she said. “There are well-defined precursors to myeloma, and Blacks are three times more likely to have a precursor condition.”

Early detection of precursors followed by preventing progression to full-blown multiple myeloma is one way of addressing disparities, but right now, there are no real screening guidelines. “Most patients now are diagnosed incidentally, and then the only intervention is to monitor them,” Dr. Marinac said. “At Dana Farber, we are now looking to see if we can refine screening, and then see who may need additional monitoring.”

The Promise study, being conducted at Dana Farber, is recruiting participants to examine the molecular changes that occur when precursor conditions develop into full-blown multiple myeloma and is open to individuals considered to be at high risk: Black race and/or have a first-degree relative with multiple myeloma or one of its precursor conditions.

Dr. Marinac also pointed out that there are ongoing clinical trials that are looking at low-risk early interventions in patients with precursor conditions. “We are now looking at lifestyle and metformin,” she said. “The thought is that if we treat them now, we can prevent myeloma from developing.”

Lessening barriers to care

When trying to tease out the strongest/most prominent reasons for the disparities that have been observed in the care of patients with blood cancers, Stephanie Lee, M.D., M.P.H, professor and associate director of the clinical research division at Fred Hutchinson Cancer Research Center, Seattle, thinks that the problem is truly multifactorial.

“Access has been cited many times because some studies show that if access is equitable, sometimes racial/ethnic minorities do the same as non-Hispanic Whites,” she said. “Same thing with quality of care – if all people are treated on clinical trials, sometimes the outcomes are the same.”

That said, many things have to go right to get the best outcomes, and if one factor isn’t optimal, then treatment may never achieve the success that is possible, she noted.

Considering how complex the issue of disparities is, addressing it can seem daunting. Dr. Lee points out that the place to begin is with clinical trials. “I would like to see more studies that test interventions to correct disparities,” said Dr. Lee. “But I have actually seen in my own work that racial and ethnic minorities are less likely to participate in studies, even survey and observational studies where physical risks are low or nonexistent.”

People are studying how to increase minority participation in clinical trials, but thus far, there isn’t one solution. “As with routine care, there are probably a lot of logistical barriers to trial participation that disproportionately affect minority populations,” she noted. “There is also greater distrust of studies.”

But for now, there are some steps that clinicians can take to start to improve these disparities. “I think we can start inquiring about and documenting barriers to care and clinical trial participation, just like we document other aspects of the social history,” Dr. Lee explained. “Truly understanding the problem is the first step toward trying to solve it.”

References

1. Leukemia & Lymphoma Society. 2021. www.lls.org/facts-and-statistics/facts-and-statistics-overview.

2. Utuama O et al. PLoS One. 2019 Aug 19;14(8):e0220864.

3. Pollyea DA et al. J Cancer Prev Curr Res. 2014;1(1):14-19.

4. Bencomo-Alvarez AE et al. Cancer. 2021 Apr 1;127(7):1068-79.

5. Nabhan C et al. Cancer. 2012 Oct 1;118(19):4842-50.

6. Bhatnagar B et al. Blood. 2020;136(Suppl 1):5-7.

7. Shenoy PJ et al. Cancer. 2011;117:2530-40.

8. Evens AM et al. Ann Oncol. 2012 Aug 1;23(8):2128-37.

9. Lee MJ et al. Cancer. 2020;126:3493-3503.

10. Hu B et al. Cancer. 2021 Jul 21. doi: 10.1002/cncr.33779.

11. Marinac CR et al. Blood Cancer J. 2020 Feb 17;10(2):19.

12. Fiala MA et al. Leuk Lymphoma. 2015;56(9):2643-9.

13. Costa LJ et al. Biol Blood Marrow Transplant. 2015 Apr;21(4):701-6.

The season of conception does not affect whether more boys than girls are born, nor do temperatures in the environment, a large study reveals. Similarly, researchers found no connection with a location’s violent crime level, unemployment rate, or major events like Hurricane Katrina.

But certain chemical pollutants were related to fewer boys being born compared to girls when researchers looked at data for more than 3 million newborns over 8 years in the U.S. and another 3 million born over 30 years in Sweden.

“With data on births in 150 million people in the U.S. over 8 years and 9 million Swedes over 9 years, this is almost surely the largest study to date on the question of environmental factors and their influence on sex ratio at birth,” says Shanna Swan, PhD, who was not affiliated with the research

Variations in the annual sex birth ratio (SRB) – the number of boys born compared to the total birth rate – are well-accepted. Less clear is what things drive these changes.

Although not the first study to look for connections between major events or pollutants in the air, water, and land and the SRB, it is the first to mine two very large electronic medical record databases for answers, senior study author Andrey Rzhetsky, PhD, a professor of medicine and human genetics at the University of Chicago, tells this news organization.

The findings were published Dec. 2, 2021, in PLOS Computational Biology.

And even though the SRB did not vary significantly after Hurricane Katrina in 2005, it did after the 2007 shooting at Virginia Tech, Dr. Rzhetsky and colleagues found. The SRB was lower than expected 34 weeks after the mass shooting.
 

Location, location, location

The researchers also found the levels of chemical pollutants “varied remarkably” across different regions of the country. For example, lead in the land was elevated in the Northeast, Southwest, and Mideastern U.S. but not in the South. Also, the highest levels of total mercury in water samples was found mostly in Eastern states, especially in the Northeast.

Dr. Rzhetsky and colleagues mapped these regional differences in many factors, including hydrazine. Hydrazine is a foaming agent used to make pharmaceuticals, agrochemicals, and as a propellant for spacecraft.

“Hydrazine appears to follow capricious, blotch-like shapes in the eastern U.S., each blotch likely centered at a factory emitting this pollutant,” the authors wrote.

To get a more complete picture, the investigators also compared changes in the SRB to data from the U.S. National Oceanic and Atmospheric Administration, U.S. Environmental Protection Agency, Swedish Meteorological and Hydrological Institute, and Statistics Sweden.

They found that aluminium in air, chromium in water, and total mercury levels drove the SRB up. By comparison, lead in soil and areas with a higher renter occupancy were linked to a lower SRB, or a higher proportion of girls being born.

Dr. Rzhetsky and colleagues also add to the evidence for a link between polychlorinated biphenyls (PCBs) and the SRB. Previous findings conflict, the authors noted.

“Since the sample sizes of the studies published thus far were very small, our PCBs result would have substantially larger statistical power,” they said.

Several pollutants had no significant link to SRB in the study, including levels of lead or chromium in the air, arsenic in the soil, and cadmium in the air or water.
 

Consistent findings

That said, the research had limits.

“The magnitude is new in terms of number of births, and the statistical methods are unusually sophisticated, but the conclusions don’t really differ from much of what has been published,” says Dr. Swan, a professor of environmental medicine and public health at the Icahn School of Medicine at Mount Sinai, New York.

“The takeaway message that many examined exposures are associated with lower – and some with higher – SRBs is not new but consistent with other, smaller studies,” says Dr. Swan, who co-authored a Sept. 2021 study evaluating endocrine-disrupting chemicals and lower birth rates in Asia.

The data on environmental exposures “is, however, quite uneven, and only known at the ecologic and not the individual level,” she says. “We learn, for example, that SRB was significantly reduced ... among families living in areas with the highest septile of lead exposure but also in those among the highest septile of percent renter occupancy.”

“Evaluating these as to mechanism and plausibility is difficult,” Dr. Swan says.
 

More research warranted

The mechanism remains unknown, but the investigators suggested that female embryo pregnancies may end early in development, driving the SRB up. Also, male embryo deaths are more common in the late second or third trimester, at which point they would drive the SRB down. A third factor, maternal hormone levels around the time of conception, could also alter the SRB.

The associations between individual factors and SRB changes are just that – associations – not intended to be interpreted as “sex-specific selection mechanisms” causing the differences at this point, the authors noted. Further studies to confirm the associations are needed.

The research is a good stepping off point for future studies to look closer at the contribution of pollutants like arsenic, lead, cadmium, and more, Dr. Rzhetsky says.

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

The season of conception does not affect whether more boys than girls are born, nor do temperatures in the environment, a large study reveals. Similarly, researchers found no connection with a location’s violent crime level, unemployment rate, or major events like Hurricane Katrina.

But certain chemical pollutants were related to fewer boys being born compared to girls when researchers looked at data for more than 3 million newborns over 8 years in the U.S. and another 3 million born over 30 years in Sweden.

“With data on births in 150 million people in the U.S. over 8 years and 9 million Swedes over 9 years, this is almost surely the largest study to date on the question of environmental factors and their influence on sex ratio at birth,” says Shanna Swan, PhD, who was not affiliated with the research

Variations in the annual sex birth ratio (SRB) – the number of boys born compared to the total birth rate – are well-accepted. Less clear is what things drive these changes.

Although not the first study to look for connections between major events or pollutants in the air, water, and land and the SRB, it is the first to mine two very large electronic medical record databases for answers, senior study author Andrey Rzhetsky, PhD, a professor of medicine and human genetics at the University of Chicago, tells this news organization.

The findings were published Dec. 2, 2021, in PLOS Computational Biology.

And even though the SRB did not vary significantly after Hurricane Katrina in 2005, it did after the 2007 shooting at Virginia Tech, Dr. Rzhetsky and colleagues found. The SRB was lower than expected 34 weeks after the mass shooting.
 

Location, location, location

The researchers also found the levels of chemical pollutants “varied remarkably” across different regions of the country. For example, lead in the land was elevated in the Northeast, Southwest, and Mideastern U.S. but not in the South. Also, the highest levels of total mercury in water samples was found mostly in Eastern states, especially in the Northeast.

Dr. Rzhetsky and colleagues mapped these regional differences in many factors, including hydrazine. Hydrazine is a foaming agent used to make pharmaceuticals, agrochemicals, and as a propellant for spacecraft.

“Hydrazine appears to follow capricious, blotch-like shapes in the eastern U.S., each blotch likely centered at a factory emitting this pollutant,” the authors wrote.

To get a more complete picture, the investigators also compared changes in the SRB to data from the U.S. National Oceanic and Atmospheric Administration, U.S. Environmental Protection Agency, Swedish Meteorological and Hydrological Institute, and Statistics Sweden.

They found that aluminium in air, chromium in water, and total mercury levels drove the SRB up. By comparison, lead in soil and areas with a higher renter occupancy were linked to a lower SRB, or a higher proportion of girls being born.

Dr. Rzhetsky and colleagues also add to the evidence for a link between polychlorinated biphenyls (PCBs) and the SRB. Previous findings conflict, the authors noted.

“Since the sample sizes of the studies published thus far were very small, our PCBs result would have substantially larger statistical power,” they said.

Several pollutants had no significant link to SRB in the study, including levels of lead or chromium in the air, arsenic in the soil, and cadmium in the air or water.
 

Consistent findings

That said, the research had limits.

“The magnitude is new in terms of number of births, and the statistical methods are unusually sophisticated, but the conclusions don’t really differ from much of what has been published,” says Dr. Swan, a professor of environmental medicine and public health at the Icahn School of Medicine at Mount Sinai, New York.

“The takeaway message that many examined exposures are associated with lower – and some with higher – SRBs is not new but consistent with other, smaller studies,” says Dr. Swan, who co-authored a Sept. 2021 study evaluating endocrine-disrupting chemicals and lower birth rates in Asia.

The data on environmental exposures “is, however, quite uneven, and only known at the ecologic and not the individual level,” she says. “We learn, for example, that SRB was significantly reduced ... among families living in areas with the highest septile of lead exposure but also in those among the highest septile of percent renter occupancy.”

“Evaluating these as to mechanism and plausibility is difficult,” Dr. Swan says.
 

More research warranted

The mechanism remains unknown, but the investigators suggested that female embryo pregnancies may end early in development, driving the SRB up. Also, male embryo deaths are more common in the late second or third trimester, at which point they would drive the SRB down. A third factor, maternal hormone levels around the time of conception, could also alter the SRB.

The associations between individual factors and SRB changes are just that – associations – not intended to be interpreted as “sex-specific selection mechanisms” causing the differences at this point, the authors noted. Further studies to confirm the associations are needed.

The research is a good stepping off point for future studies to look closer at the contribution of pollutants like arsenic, lead, cadmium, and more, Dr. Rzhetsky says.

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

The season of conception does not affect whether more boys than girls are born, nor do temperatures in the environment, a large study reveals. Similarly, researchers found no connection with a location’s violent crime level, unemployment rate, or major events like Hurricane Katrina.

But certain chemical pollutants were related to fewer boys being born compared to girls when researchers looked at data for more than 3 million newborns over 8 years in the U.S. and another 3 million born over 30 years in Sweden.

“With data on births in 150 million people in the U.S. over 8 years and 9 million Swedes over 9 years, this is almost surely the largest study to date on the question of environmental factors and their influence on sex ratio at birth,” says Shanna Swan, PhD, who was not affiliated with the research

Variations in the annual sex birth ratio (SRB) – the number of boys born compared to the total birth rate – are well-accepted. Less clear is what things drive these changes.

Although not the first study to look for connections between major events or pollutants in the air, water, and land and the SRB, it is the first to mine two very large electronic medical record databases for answers, senior study author Andrey Rzhetsky, PhD, a professor of medicine and human genetics at the University of Chicago, tells this news organization.

The findings were published Dec. 2, 2021, in PLOS Computational Biology.

And even though the SRB did not vary significantly after Hurricane Katrina in 2005, it did after the 2007 shooting at Virginia Tech, Dr. Rzhetsky and colleagues found. The SRB was lower than expected 34 weeks after the mass shooting.
 

Location, location, location

The researchers also found the levels of chemical pollutants “varied remarkably” across different regions of the country. For example, lead in the land was elevated in the Northeast, Southwest, and Mideastern U.S. but not in the South. Also, the highest levels of total mercury in water samples was found mostly in Eastern states, especially in the Northeast.

Dr. Rzhetsky and colleagues mapped these regional differences in many factors, including hydrazine. Hydrazine is a foaming agent used to make pharmaceuticals, agrochemicals, and as a propellant for spacecraft.

“Hydrazine appears to follow capricious, blotch-like shapes in the eastern U.S., each blotch likely centered at a factory emitting this pollutant,” the authors wrote.

To get a more complete picture, the investigators also compared changes in the SRB to data from the U.S. National Oceanic and Atmospheric Administration, U.S. Environmental Protection Agency, Swedish Meteorological and Hydrological Institute, and Statistics Sweden.

They found that aluminium in air, chromium in water, and total mercury levels drove the SRB up. By comparison, lead in soil and areas with a higher renter occupancy were linked to a lower SRB, or a higher proportion of girls being born.

Dr. Rzhetsky and colleagues also add to the evidence for a link between polychlorinated biphenyls (PCBs) and the SRB. Previous findings conflict, the authors noted.

“Since the sample sizes of the studies published thus far were very small, our PCBs result would have substantially larger statistical power,” they said.

Several pollutants had no significant link to SRB in the study, including levels of lead or chromium in the air, arsenic in the soil, and cadmium in the air or water.
 

Consistent findings

That said, the research had limits.

“The magnitude is new in terms of number of births, and the statistical methods are unusually sophisticated, but the conclusions don’t really differ from much of what has been published,” says Dr. Swan, a professor of environmental medicine and public health at the Icahn School of Medicine at Mount Sinai, New York.

“The takeaway message that many examined exposures are associated with lower – and some with higher – SRBs is not new but consistent with other, smaller studies,” says Dr. Swan, who co-authored a Sept. 2021 study evaluating endocrine-disrupting chemicals and lower birth rates in Asia.

The data on environmental exposures “is, however, quite uneven, and only known at the ecologic and not the individual level,” she says. “We learn, for example, that SRB was significantly reduced ... among families living in areas with the highest septile of lead exposure but also in those among the highest septile of percent renter occupancy.”

“Evaluating these as to mechanism and plausibility is difficult,” Dr. Swan says.
 

More research warranted

The mechanism remains unknown, but the investigators suggested that female embryo pregnancies may end early in development, driving the SRB up. Also, male embryo deaths are more common in the late second or third trimester, at which point they would drive the SRB down. A third factor, maternal hormone levels around the time of conception, could also alter the SRB.

The associations between individual factors and SRB changes are just that – associations – not intended to be interpreted as “sex-specific selection mechanisms” causing the differences at this point, the authors noted. Further studies to confirm the associations are needed.

The research is a good stepping off point for future studies to look closer at the contribution of pollutants like arsenic, lead, cadmium, and more, Dr. Rzhetsky says.

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

Azelaic acid is a bit of a forgotten acid, often in the shadows of glycolic acid and trichloroacetic acid (TCA). However, it has many positive qualities, including being gentle enough to use daily and is safe to use in pregnancy. It is antibacterial, comedolytic, keratolytic, and has antioxidant activity. Unfortunately, in the last decade the formulations of azelaic acid have not been changed considerably. The 20% cream, 15% gel, and 15% foam vehicles are often too irritating and drying to be used in the population it is intended for: those with rosacea, or with inflamed or sensitive skin.

Azelaic acid is a dicarboxylic acid produced by Pityrosporum ovale. It inhibits the synthesis of cellular proteins and is bactericidal against Propionibacterium acnes and Staphylococcus epidermidis. Azelaic acid is both keratolytic and comedolytic by decreasing keratohyalin granules and reducing filaggrin in the epidermis. It not only scavenges free oxygen radicals, thereby reducing inflammation, but is also a tyrosinase inhibitor – making it a safe, non–hydroquinone-based alternative to skin lightening.

Azelaic acid has little toxicity, it is ingested regularly as it is found in wheat, barley, and rye. Topical side effects are usually mild and can subside with increased use. The most common side effects include erythema, local stinging, pruritus, scaling, and a burning sensation. It is considered safe in pregnancy and a great alternative to medications for acne in pregnant or nursing patients.

The largest constraint with azelaic acid preparations on the market – and most likely the reason it has not been more widely used for acne, rosacea, antiaging, and hyperpigmentation – is the formulation. The foam and gel preparations are irritating and difficult to use on dry or sensitive skin. The 20% cream preparations are slightly better tolerated; however, in vitro skin-penetration studies have shown that cutaneous penetration of azelaic acid is greater after application of a 15% gel (aqueous-based vehicle) and 15% foam (hydrophilic oil-in-water emulsion) as compared with the 20% cream formulations.

In my clinical experience, azelaic acid can only be used in rosacea patients with oily or nonsensitive skin. The majority of my rosacea patients cannot tolerate the burning sensation, albeit transient and mild. Acne patients who do not have dry skin and pregnant patients with mild acne are a great population for integrating azelaic acid into an acne regimen. I also use azelaic acid as an alternative for mild melasma and lentigines in patients who are tapering off hydroquinone or cannot use hydroquinone. In the future, we need better, creamier, nonirritating formulations to be developed and more studies of higher concentrations of this acid for both prescription/patient at-home use, as well as more elegant in-office localized peel systems using azelaic acid.

Dr. Talakoub and Dr. Wesley are cocontributors to this column. Dr. Talakoub is in private practice in McLean, Va. Dr. Wesley practices dermatology in Beverly Hills, Calif. This month’s column is by Dr. Talakoub. Write to them at [email protected]. They had no relevant disclosures.

References

Fitton A and Goa KL. Drugs. 1991 May;41(5):780-98.

Del Rosso JQ. J Clin Aesthet Dermatol. 2017 Mar;10(3):37-40.

Breathnach AC et al. Clin Dermatol. Apr-Jun 1989;7(2):106-19.
 

Azelaic acid is a bit of a forgotten acid, often in the shadows of glycolic acid and trichloroacetic acid (TCA). However, it has many positive qualities, including being gentle enough to use daily and is safe to use in pregnancy. It is antibacterial, comedolytic, keratolytic, and has antioxidant activity. Unfortunately, in the last decade the formulations of azelaic acid have not been changed considerably. The 20% cream, 15% gel, and 15% foam vehicles are often too irritating and drying to be used in the population it is intended for: those with rosacea, or with inflamed or sensitive skin.

Azelaic acid is a dicarboxylic acid produced by Pityrosporum ovale. It inhibits the synthesis of cellular proteins and is bactericidal against Propionibacterium acnes and Staphylococcus epidermidis. Azelaic acid is both keratolytic and comedolytic by decreasing keratohyalin granules and reducing filaggrin in the epidermis. It not only scavenges free oxygen radicals, thereby reducing inflammation, but is also a tyrosinase inhibitor – making it a safe, non–hydroquinone-based alternative to skin lightening.

Azelaic acid has little toxicity, it is ingested regularly as it is found in wheat, barley, and rye. Topical side effects are usually mild and can subside with increased use. The most common side effects include erythema, local stinging, pruritus, scaling, and a burning sensation. It is considered safe in pregnancy and a great alternative to medications for acne in pregnant or nursing patients.

The largest constraint with azelaic acid preparations on the market – and most likely the reason it has not been more widely used for acne, rosacea, antiaging, and hyperpigmentation – is the formulation. The foam and gel preparations are irritating and difficult to use on dry or sensitive skin. The 20% cream preparations are slightly better tolerated; however, in vitro skin-penetration studies have shown that cutaneous penetration of azelaic acid is greater after application of a 15% gel (aqueous-based vehicle) and 15% foam (hydrophilic oil-in-water emulsion) as compared with the 20% cream formulations.

In my clinical experience, azelaic acid can only be used in rosacea patients with oily or nonsensitive skin. The majority of my rosacea patients cannot tolerate the burning sensation, albeit transient and mild. Acne patients who do not have dry skin and pregnant patients with mild acne are a great population for integrating azelaic acid into an acne regimen. I also use azelaic acid as an alternative for mild melasma and lentigines in patients who are tapering off hydroquinone or cannot use hydroquinone. In the future, we need better, creamier, nonirritating formulations to be developed and more studies of higher concentrations of this acid for both prescription/patient at-home use, as well as more elegant in-office localized peel systems using azelaic acid.

Dr. Talakoub and Dr. Wesley are cocontributors to this column. Dr. Talakoub is in private practice in McLean, Va. Dr. Wesley practices dermatology in Beverly Hills, Calif. This month’s column is by Dr. Talakoub. Write to them at [email protected]. They had no relevant disclosures.

References

Fitton A and Goa KL. Drugs. 1991 May;41(5):780-98.

Del Rosso JQ. J Clin Aesthet Dermatol. 2017 Mar;10(3):37-40.

Breathnach AC et al. Clin Dermatol. Apr-Jun 1989;7(2):106-19.
 

Azelaic acid is a bit of a forgotten acid, often in the shadows of glycolic acid and trichloroacetic acid (TCA). However, it has many positive qualities, including being gentle enough to use daily and is safe to use in pregnancy. It is antibacterial, comedolytic, keratolytic, and has antioxidant activity. Unfortunately, in the last decade the formulations of azelaic acid have not been changed considerably. The 20% cream, 15% gel, and 15% foam vehicles are often too irritating and drying to be used in the population it is intended for: those with rosacea, or with inflamed or sensitive skin.

Azelaic acid is a dicarboxylic acid produced by Pityrosporum ovale. It inhibits the synthesis of cellular proteins and is bactericidal against Propionibacterium acnes and Staphylococcus epidermidis. Azelaic acid is both keratolytic and comedolytic by decreasing keratohyalin granules and reducing filaggrin in the epidermis. It not only scavenges free oxygen radicals, thereby reducing inflammation, but is also a tyrosinase inhibitor – making it a safe, non–hydroquinone-based alternative to skin lightening.

Azelaic acid has little toxicity, it is ingested regularly as it is found in wheat, barley, and rye. Topical side effects are usually mild and can subside with increased use. The most common side effects include erythema, local stinging, pruritus, scaling, and a burning sensation. It is considered safe in pregnancy and a great alternative to medications for acne in pregnant or nursing patients.

The largest constraint with azelaic acid preparations on the market – and most likely the reason it has not been more widely used for acne, rosacea, antiaging, and hyperpigmentation – is the formulation. The foam and gel preparations are irritating and difficult to use on dry or sensitive skin. The 20% cream preparations are slightly better tolerated; however, in vitro skin-penetration studies have shown that cutaneous penetration of azelaic acid is greater after application of a 15% gel (aqueous-based vehicle) and 15% foam (hydrophilic oil-in-water emulsion) as compared with the 20% cream formulations.

In my clinical experience, azelaic acid can only be used in rosacea patients with oily or nonsensitive skin. The majority of my rosacea patients cannot tolerate the burning sensation, albeit transient and mild. Acne patients who do not have dry skin and pregnant patients with mild acne are a great population for integrating azelaic acid into an acne regimen. I also use azelaic acid as an alternative for mild melasma and lentigines in patients who are tapering off hydroquinone or cannot use hydroquinone. In the future, we need better, creamier, nonirritating formulations to be developed and more studies of higher concentrations of this acid for both prescription/patient at-home use, as well as more elegant in-office localized peel systems using azelaic acid.

Dr. Talakoub and Dr. Wesley are cocontributors to this column. Dr. Talakoub is in private practice in McLean, Va. Dr. Wesley practices dermatology in Beverly Hills, Calif. This month’s column is by Dr. Talakoub. Write to them at [email protected]. They had no relevant disclosures.

References

Fitton A and Goa KL. Drugs. 1991 May;41(5):780-98.

Del Rosso JQ. J Clin Aesthet Dermatol. 2017 Mar;10(3):37-40.

Breathnach AC et al. Clin Dermatol. Apr-Jun 1989;7(2):106-19.
 

Two distinct gut microbiota subtypes showed an enhanced clinical response to a low FODMAP diet in an analysis of 41 adults with irritable bowel syndrome and household controls.

Irritable bowel syndrome (IBS) has a significant impact on quality of life, and some patients find relief on a low FODMAP (fermentable oligosaccharides, disaccharides, monosaccharides and polyols) diet, wrote Kevin Vervier, PhD, of Wellcome Sanger Institute, Hinxton, England, and colleagues. However, the mechanism of action for the success of low FODMAP diets remains unclear, the diet is hard for many patients to follow, and the long-term impact on health is unknown. Therefore, research is needed to identify patients who would derive the most benefit, they said.

In a study published in Gut, the researchers used metagenomics and functional analysis to identify potential biomarkers of response to a low FODMAP diet. They analyzed stool samples from 41 pairs of IBS patients and household contacts. Stool samples were collected at baseline while on usual diets, and again after 4 weeks and 12 weeks on a low FODMAP diet. The patients were divided into two groups based on microbiota clusters; baseline demographics and clinical characteristics were similar between the clusters. In addition, symptom severity was measured using the IBS Severity Scoring System (IBS-SSS).

Cluster 1 was referred to as IBS^P microbiome type because of its pathogenic properties, and cluster 2 as IBS^H microbiome type because of its resemblance to the microbiome of healthy household controls, the researchers wrote.

“We found a significant enrichment of 109 functional pathways and significant depletion of 13 functional pathways in IBS^P microbiomes compared with IBS^H microbiomes,” the researchers said.

More specifically, the IBS^P microbiomes were enriched in Firmicutes and in genes for amino acid and carbohydrate metabolism, at baseline, while the IBS^H microbiomes were similar to healthy controls.

After 4 weeks on the low FODMAP diet, the IBS^P microbiomes normalized, with increased levels of Bacterioides and decreased levels of pathobionts (including Clostridium difficile, Streptococcus parasanguinis, and Paeniclostridium sordellii) to create a microbiome profile resembling the IBSH microbiomes and healthy controls. The taxonomic profile of microbiomes observed in IBS^H and healthy controls did not demonstrate a significant shift.

Although both microbiome groups showed improvement in IBS-SSS scores from baseline on the low FODMAP diet, decreasing from a mean baseline score of 278 to a diet score of 128, the improvement was greater in the IBS^P group than the IBS^H group (delta, 194 vs. 114, respectively; P = .02), the researchers noted. “The shift in the IBS^P microbiota to a healthy profile appeared stable for at least 3 months and correlated with continuing symptomatic well-being,” they wrote.

The distinct responses of the IBS^P and IBS^H microbiomes to the low FODMAP diet suggest a potential mode of action, the researchers said in their discussion. Based on their findings, “it is possible that removal of the eliciting dietary component starves the pathobionts, leading to reduction in their growth and metabolism and a consequent decrease in symptoms, accompanied by an expansion of commensal or symbiotic species leading to a health-associated microbiome,” but more research is needed to prove causality, they said.

The study findings were limited by several factors, including the relatively small sample size, strict inclusion criteria, restriction of medications, and need for participation by household controls, the researchers noted. Other limitations include the inability to control for other factors that could have impacted the gut microbiota, such as the placebo effect and psychological factors, they said.

However, the findings provide a foundation for more research and should be validated in other populations involving different geographical regions and dietary habits, they said. “The identification of a microbial signature ‘biomarker’ that correlates with improved response to a low FODMAP diet may, if validated, allow better stratification and selection of patients likely to benefit from the diet,” they concluded.
 

Setting the stage for focused studies

The low FODMAP diet has demonstrated effectiveness for symptom relief in IBS, although potential risks include exacerbation of disordered eating, nutrition deficiencies, and disrupting gut microbiota, wrote Peter R. Gibson, MD, and Emma P. Halmos, MD, of Monash University and Alfred Health, Melbourne, in an accompanying editorial. However, the current study takes a new step on the journey to identifying patients most likely to respond to a low FODMAP diet, they said.

The editorialists noted three key takeaway points. First, the fecal microbiome may predict response to a low FODMAP diet. Second, the correction of the microbiome through the low FODMAP diet appeared to continue even after the diet was discontinued. “The other intriguing finding was that trehalose metabolic pathways were ‘activated’ in those with dysbiosis,” suggesting that trehalose might be an unrecognized FODMAP, the researchers noted. Trehalose has not been well studied but has been associated with pathogenicity, they said.

Although the study may overemphasize the impact of the low FODMAP diet given the relatively poor assessment of FODMAP intake, “the beauty of Vervier’s work is not in its definitive nature but in that it enables the creation of feasible innovative hypotheses that can be examined by focused studies,” they concluded.

The current study is important because IBS and related disorders of gut-brain interaction are common and greatly impact the quality of life of affected individuals, Jatin Roper, MD, of Duke University in Durham, N.C., said in an interview. Although the mechanisms for improvement are unknown, he said, “The low FODMAP diet is widely used to treat IBS, based on the hypothesis that this diet modifies the gut microbiome in a beneficial way.”

The study authors made two important discoveries, said Dr. Roper. “First, they found that they were able to distinguish IBS versus household controls based on their gut microbial signatures as well expression of key metabolic genes,” he said. “Second, they identified a unique microbiota subtype that was associated with a significant clinical response to the low FODMAP diet in IBS patients; IBS patients with a ‘pathogenic’ microbiome consisting of high Firmicutes and low Bacteroidetes responded to a greater degree to the low FODMAP diet compared to IBS patients with a ‘healthy’ microbiome that was similar to controls,” he explained. “Furthermore, after time on the low FODMAP diet, the IBS patients with pathogenic microbiome signatures developed a microbiome with low Firmicutes and high Bacteroidetes, which is thought to be healthy,” he added.

“These findings are exciting because they suggest that a patient’s microbial signature might be used clinically to predict response to the low FODMAP diet,” said Dr. Roper. “The surprising aspect of these results is that the microbial signature alone was able to predict response to a low FODMAP diet, despite the complex effects of the diet on host physiology and metabolism and the multifactorial etiology of IBS,” he noted. 

However, larger clinical studies are needed to confirm the study findings results in larger patient cohorts and to show that standardized clinical assays can be used to prospectively predict response to dietary interventions such as low FODMAP in IBS, Dr. Roper emphasized.

“This paper provides preliminary and provocative findings that suggest that gut microbiota metabolites may play a role in the pathogenesis of IBS,” said Dr. Roper. “Future basic science and translational research is needed to study the mechanisms by which specific bacterial metabolites regulate intestinal function and disorders such as IBS. I hope that this research will eventually lead to metabolite-based therapies for IBS and other gastrointestinal disorders,” he said.

The study received no outside funding. Lead author Dr. Vervier had no financial conflicts to disclose. Dr. Gibson disclosed authoring two educational/recipe books on the low FODMAP diet, and Monash University financially benefits from the sales of a digital application, booklets, and online courses on the low FODMAP diet. Dr. Halmos had no financial conflicts to disclose. Dr. Roper had no financial conflicts to disclose.

Two distinct gut microbiota subtypes showed an enhanced clinical response to a low FODMAP diet in an analysis of 41 adults with irritable bowel syndrome and household controls.

Irritable bowel syndrome (IBS) has a significant impact on quality of life, and some patients find relief on a low FODMAP (fermentable oligosaccharides, disaccharides, monosaccharides and polyols) diet, wrote Kevin Vervier, PhD, of Wellcome Sanger Institute, Hinxton, England, and colleagues. However, the mechanism of action for the success of low FODMAP diets remains unclear, the diet is hard for many patients to follow, and the long-term impact on health is unknown. Therefore, research is needed to identify patients who would derive the most benefit, they said.

In a study published in Gut, the researchers used metagenomics and functional analysis to identify potential biomarkers of response to a low FODMAP diet. They analyzed stool samples from 41 pairs of IBS patients and household contacts. Stool samples were collected at baseline while on usual diets, and again after 4 weeks and 12 weeks on a low FODMAP diet. The patients were divided into two groups based on microbiota clusters; baseline demographics and clinical characteristics were similar between the clusters. In addition, symptom severity was measured using the IBS Severity Scoring System (IBS-SSS).

Cluster 1 was referred to as IBS^P microbiome type because of its pathogenic properties, and cluster 2 as IBS^H microbiome type because of its resemblance to the microbiome of healthy household controls, the researchers wrote.

“We found a significant enrichment of 109 functional pathways and significant depletion of 13 functional pathways in IBS^P microbiomes compared with IBS^H microbiomes,” the researchers said.

More specifically, the IBS^P microbiomes were enriched in Firmicutes and in genes for amino acid and carbohydrate metabolism, at baseline, while the IBS^H microbiomes were similar to healthy controls.

After 4 weeks on the low FODMAP diet, the IBS^P microbiomes normalized, with increased levels of Bacterioides and decreased levels of pathobionts (including Clostridium difficile, Streptococcus parasanguinis, and Paeniclostridium sordellii) to create a microbiome profile resembling the IBSH microbiomes and healthy controls. The taxonomic profile of microbiomes observed in IBS^H and healthy controls did not demonstrate a significant shift.

Although both microbiome groups showed improvement in IBS-SSS scores from baseline on the low FODMAP diet, decreasing from a mean baseline score of 278 to a diet score of 128, the improvement was greater in the IBS^P group than the IBS^H group (delta, 194 vs. 114, respectively; P = .02), the researchers noted. “The shift in the IBS^P microbiota to a healthy profile appeared stable for at least 3 months and correlated with continuing symptomatic well-being,” they wrote.

The distinct responses of the IBS^P and IBS^H microbiomes to the low FODMAP diet suggest a potential mode of action, the researchers said in their discussion. Based on their findings, “it is possible that removal of the eliciting dietary component starves the pathobionts, leading to reduction in their growth and metabolism and a consequent decrease in symptoms, accompanied by an expansion of commensal or symbiotic species leading to a health-associated microbiome,” but more research is needed to prove causality, they said.

The study findings were limited by several factors, including the relatively small sample size, strict inclusion criteria, restriction of medications, and need for participation by household controls, the researchers noted. Other limitations include the inability to control for other factors that could have impacted the gut microbiota, such as the placebo effect and psychological factors, they said.

However, the findings provide a foundation for more research and should be validated in other populations involving different geographical regions and dietary habits, they said. “The identification of a microbial signature ‘biomarker’ that correlates with improved response to a low FODMAP diet may, if validated, allow better stratification and selection of patients likely to benefit from the diet,” they concluded.
 

Setting the stage for focused studies

The low FODMAP diet has demonstrated effectiveness for symptom relief in IBS, although potential risks include exacerbation of disordered eating, nutrition deficiencies, and disrupting gut microbiota, wrote Peter R. Gibson, MD, and Emma P. Halmos, MD, of Monash University and Alfred Health, Melbourne, in an accompanying editorial. However, the current study takes a new step on the journey to identifying patients most likely to respond to a low FODMAP diet, they said.

The editorialists noted three key takeaway points. First, the fecal microbiome may predict response to a low FODMAP diet. Second, the correction of the microbiome through the low FODMAP diet appeared to continue even after the diet was discontinued. “The other intriguing finding was that trehalose metabolic pathways were ‘activated’ in those with dysbiosis,” suggesting that trehalose might be an unrecognized FODMAP, the researchers noted. Trehalose has not been well studied but has been associated with pathogenicity, they said.

Although the study may overemphasize the impact of the low FODMAP diet given the relatively poor assessment of FODMAP intake, “the beauty of Vervier’s work is not in its definitive nature but in that it enables the creation of feasible innovative hypotheses that can be examined by focused studies,” they concluded.

The current study is important because IBS and related disorders of gut-brain interaction are common and greatly impact the quality of life of affected individuals, Jatin Roper, MD, of Duke University in Durham, N.C., said in an interview. Although the mechanisms for improvement are unknown, he said, “The low FODMAP diet is widely used to treat IBS, based on the hypothesis that this diet modifies the gut microbiome in a beneficial way.”

The study authors made two important discoveries, said Dr. Roper. “First, they found that they were able to distinguish IBS versus household controls based on their gut microbial signatures as well expression of key metabolic genes,” he said. “Second, they identified a unique microbiota subtype that was associated with a significant clinical response to the low FODMAP diet in IBS patients; IBS patients with a ‘pathogenic’ microbiome consisting of high Firmicutes and low Bacteroidetes responded to a greater degree to the low FODMAP diet compared to IBS patients with a ‘healthy’ microbiome that was similar to controls,” he explained. “Furthermore, after time on the low FODMAP diet, the IBS patients with pathogenic microbiome signatures developed a microbiome with low Firmicutes and high Bacteroidetes, which is thought to be healthy,” he added.

“These findings are exciting because they suggest that a patient’s microbial signature might be used clinically to predict response to the low FODMAP diet,” said Dr. Roper. “The surprising aspect of these results is that the microbial signature alone was able to predict response to a low FODMAP diet, despite the complex effects of the diet on host physiology and metabolism and the multifactorial etiology of IBS,” he noted. 

However, larger clinical studies are needed to confirm the study findings results in larger patient cohorts and to show that standardized clinical assays can be used to prospectively predict response to dietary interventions such as low FODMAP in IBS, Dr. Roper emphasized.

“This paper provides preliminary and provocative findings that suggest that gut microbiota metabolites may play a role in the pathogenesis of IBS,” said Dr. Roper. “Future basic science and translational research is needed to study the mechanisms by which specific bacterial metabolites regulate intestinal function and disorders such as IBS. I hope that this research will eventually lead to metabolite-based therapies for IBS and other gastrointestinal disorders,” he said.

The study received no outside funding. Lead author Dr. Vervier had no financial conflicts to disclose. Dr. Gibson disclosed authoring two educational/recipe books on the low FODMAP diet, and Monash University financially benefits from the sales of a digital application, booklets, and online courses on the low FODMAP diet. Dr. Halmos had no financial conflicts to disclose. Dr. Roper had no financial conflicts to disclose.

Two distinct gut microbiota subtypes showed an enhanced clinical response to a low FODMAP diet in an analysis of 41 adults with irritable bowel syndrome and household controls.

Irritable bowel syndrome (IBS) has a significant impact on quality of life, and some patients find relief on a low FODMAP (fermentable oligosaccharides, disaccharides, monosaccharides and polyols) diet, wrote Kevin Vervier, PhD, of Wellcome Sanger Institute, Hinxton, England, and colleagues. However, the mechanism of action for the success of low FODMAP diets remains unclear, the diet is hard for many patients to follow, and the long-term impact on health is unknown. Therefore, research is needed to identify patients who would derive the most benefit, they said.

In a study published in Gut, the researchers used metagenomics and functional analysis to identify potential biomarkers of response to a low FODMAP diet. They analyzed stool samples from 41 pairs of IBS patients and household contacts. Stool samples were collected at baseline while on usual diets, and again after 4 weeks and 12 weeks on a low FODMAP diet. The patients were divided into two groups based on microbiota clusters; baseline demographics and clinical characteristics were similar between the clusters. In addition, symptom severity was measured using the IBS Severity Scoring System (IBS-SSS).

Cluster 1 was referred to as IBS^P microbiome type because of its pathogenic properties, and cluster 2 as IBS^H microbiome type because of its resemblance to the microbiome of healthy household controls, the researchers wrote.

“We found a significant enrichment of 109 functional pathways and significant depletion of 13 functional pathways in IBS^P microbiomes compared with IBS^H microbiomes,” the researchers said.

More specifically, the IBS^P microbiomes were enriched in Firmicutes and in genes for amino acid and carbohydrate metabolism, at baseline, while the IBS^H microbiomes were similar to healthy controls.

After 4 weeks on the low FODMAP diet, the IBS^P microbiomes normalized, with increased levels of Bacterioides and decreased levels of pathobionts (including Clostridium difficile, Streptococcus parasanguinis, and Paeniclostridium sordellii) to create a microbiome profile resembling the IBSH microbiomes and healthy controls. The taxonomic profile of microbiomes observed in IBS^H and healthy controls did not demonstrate a significant shift.

Although both microbiome groups showed improvement in IBS-SSS scores from baseline on the low FODMAP diet, decreasing from a mean baseline score of 278 to a diet score of 128, the improvement was greater in the IBS^P group than the IBS^H group (delta, 194 vs. 114, respectively; P = .02), the researchers noted. “The shift in the IBS^P microbiota to a healthy profile appeared stable for at least 3 months and correlated with continuing symptomatic well-being,” they wrote.

The distinct responses of the IBS^P and IBS^H microbiomes to the low FODMAP diet suggest a potential mode of action, the researchers said in their discussion. Based on their findings, “it is possible that removal of the eliciting dietary component starves the pathobionts, leading to reduction in their growth and metabolism and a consequent decrease in symptoms, accompanied by an expansion of commensal or symbiotic species leading to a health-associated microbiome,” but more research is needed to prove causality, they said.

The study findings were limited by several factors, including the relatively small sample size, strict inclusion criteria, restriction of medications, and need for participation by household controls, the researchers noted. Other limitations include the inability to control for other factors that could have impacted the gut microbiota, such as the placebo effect and psychological factors, they said.

However, the findings provide a foundation for more research and should be validated in other populations involving different geographical regions and dietary habits, they said. “The identification of a microbial signature ‘biomarker’ that correlates with improved response to a low FODMAP diet may, if validated, allow better stratification and selection of patients likely to benefit from the diet,” they concluded.
 

Setting the stage for focused studies

The low FODMAP diet has demonstrated effectiveness for symptom relief in IBS, although potential risks include exacerbation of disordered eating, nutrition deficiencies, and disrupting gut microbiota, wrote Peter R. Gibson, MD, and Emma P. Halmos, MD, of Monash University and Alfred Health, Melbourne, in an accompanying editorial. However, the current study takes a new step on the journey to identifying patients most likely to respond to a low FODMAP diet, they said.

The editorialists noted three key takeaway points. First, the fecal microbiome may predict response to a low FODMAP diet. Second, the correction of the microbiome through the low FODMAP diet appeared to continue even after the diet was discontinued. “The other intriguing finding was that trehalose metabolic pathways were ‘activated’ in those with dysbiosis,” suggesting that trehalose might be an unrecognized FODMAP, the researchers noted. Trehalose has not been well studied but has been associated with pathogenicity, they said.

Although the study may overemphasize the impact of the low FODMAP diet given the relatively poor assessment of FODMAP intake, “the beauty of Vervier’s work is not in its definitive nature but in that it enables the creation of feasible innovative hypotheses that can be examined by focused studies,” they concluded.

The current study is important because IBS and related disorders of gut-brain interaction are common and greatly impact the quality of life of affected individuals, Jatin Roper, MD, of Duke University in Durham, N.C., said in an interview. Although the mechanisms for improvement are unknown, he said, “The low FODMAP diet is widely used to treat IBS, based on the hypothesis that this diet modifies the gut microbiome in a beneficial way.”

The study authors made two important discoveries, said Dr. Roper. “First, they found that they were able to distinguish IBS versus household controls based on their gut microbial signatures as well expression of key metabolic genes,” he said. “Second, they identified a unique microbiota subtype that was associated with a significant clinical response to the low FODMAP diet in IBS patients; IBS patients with a ‘pathogenic’ microbiome consisting of high Firmicutes and low Bacteroidetes responded to a greater degree to the low FODMAP diet compared to IBS patients with a ‘healthy’ microbiome that was similar to controls,” he explained. “Furthermore, after time on the low FODMAP diet, the IBS patients with pathogenic microbiome signatures developed a microbiome with low Firmicutes and high Bacteroidetes, which is thought to be healthy,” he added.

“These findings are exciting because they suggest that a patient’s microbial signature might be used clinically to predict response to the low FODMAP diet,” said Dr. Roper. “The surprising aspect of these results is that the microbial signature alone was able to predict response to a low FODMAP diet, despite the complex effects of the diet on host physiology and metabolism and the multifactorial etiology of IBS,” he noted. 

However, larger clinical studies are needed to confirm the study findings results in larger patient cohorts and to show that standardized clinical assays can be used to prospectively predict response to dietary interventions such as low FODMAP in IBS, Dr. Roper emphasized.

“This paper provides preliminary and provocative findings that suggest that gut microbiota metabolites may play a role in the pathogenesis of IBS,” said Dr. Roper. “Future basic science and translational research is needed to study the mechanisms by which specific bacterial metabolites regulate intestinal function and disorders such as IBS. I hope that this research will eventually lead to metabolite-based therapies for IBS and other gastrointestinal disorders,” he said.

The study received no outside funding. Lead author Dr. Vervier had no financial conflicts to disclose. Dr. Gibson disclosed authoring two educational/recipe books on the low FODMAP diet, and Monash University financially benefits from the sales of a digital application, booklets, and online courses on the low FODMAP diet. Dr. Halmos had no financial conflicts to disclose. Dr. Roper had no financial conflicts to disclose.