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Real-World Data Question Low-Dose Steroid Use in ANCA Vasculitis
TOPLINE:
Compared with a standard dosing regimen, a reduced-dose glucocorticoid regimen is associated with an increased risk for disease progression, relapse, death, or kidney failure in antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis, particularly affecting patients receiving rituximab or those with elevated creatinine levels.
METHODOLOGY:
- The PEXIVAS trial demonstrated that a reduced-dose glucocorticoid regimen was noninferior to standard dosing in terms of death or end-stage kidney disease in ANCA-associated vasculitis. However, the trial did not include disease progression or relapse as a primary endpoint, and cyclophosphamide was the primary induction therapy.
- Researchers conducted this retrospective study across 19 hospitals (18 in France and one in Luxembourg) between January 2018 and November 2022 to compare the effectiveness of a reduced-dose glucocorticoid regimen, as used in the PEXIVAS trial, with a standard-dose regimen in patients with ANCA-associated vasculitis in the real-world setting.
- They included 234 patients aged > 15 years (51% men) with severe granulomatosis with polyangiitis (n = 141) or microscopic polyangiitis (n = 93) who received induction therapy with rituximab or cyclophosphamide; 126 and 108 patients received reduced-dose and standard-dose glucocorticoid regimens, respectively.
- Most patients (70%) had severe renal involvement.
- The primary composite outcome encompassed minor relapse, major relapse, disease progression before remission, end-stage kidney disease requiring dialysis for > 12 weeks or transplantation, and death within 12 months post-induction.
TAKEAWAY:
- The primary composite outcome occurred in a higher proportion of patients receiving reduced-dose glucocorticoid therapy than in those receiving standard-dose therapy (33.3% vs 18.5%; hazard ratio [HR], 2.20; 95% CI, 1.23-3.94).
- However, no significant association was found between reduced-dose glucocorticoids and the risk for death or end-stage kidney disease or the occurrence of serious infections.
- Among patients receiving reduced-dose glucocorticoids, serum creatinine levels > 300 μmol/L were associated with an increased risk for the primary composite outcome (adjusted HR, 3.02; 95% CI, 1.28-7.11).
- In the rituximab induction subgroup, reduced-dose glucocorticoid was associated with an increased risk for the primary composite outcome (adjusted HR, 2.36; 95% CI, 1.18-4.71), compared with standard-dose glucocorticoids.
IN PRACTICE:
“Our data suggest increased vigilance when using the [reduced-dose glucocorticoid] regimen, especially in the two subgroups of patients at higher risk of failure, that is, those receiving [rituximab] as induction therapy and those with a baseline serum creatinine greater than 300 μmol/L,” the authors wrote.
SOURCE:
The study was led by Sophie Nagle, MD, National Referral Centre for Rare Autoimmune and Systemic Diseases, Department of Internal Medicine, Hôpital Cochin, Paris, France. It was published online on November 20, 2024, in Annals of the Rheumatic Diseases.
LIMITATIONS:
The retrospective nature of this study may have introduced inherent limitations and potential selection bias. The study lacked data on patient comorbidities, which could have influenced treatment choice and outcomes. Additionally, about a quarter of patients did not receive methylprednisolone pulses prior to oral glucocorticoids, unlike the PEXIVAS trial protocol. The group receiving standard-dose glucocorticoids showed heterogeneity in glucocorticoid regimens, and the minimum follow-up was only 6 months.
DISCLOSURES:
This study did not report any source of funding. The authors reported no relevant conflicts of interest.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.
TOPLINE:
Compared with a standard dosing regimen, a reduced-dose glucocorticoid regimen is associated with an increased risk for disease progression, relapse, death, or kidney failure in antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis, particularly affecting patients receiving rituximab or those with elevated creatinine levels.
METHODOLOGY:
- The PEXIVAS trial demonstrated that a reduced-dose glucocorticoid regimen was noninferior to standard dosing in terms of death or end-stage kidney disease in ANCA-associated vasculitis. However, the trial did not include disease progression or relapse as a primary endpoint, and cyclophosphamide was the primary induction therapy.
- Researchers conducted this retrospective study across 19 hospitals (18 in France and one in Luxembourg) between January 2018 and November 2022 to compare the effectiveness of a reduced-dose glucocorticoid regimen, as used in the PEXIVAS trial, with a standard-dose regimen in patients with ANCA-associated vasculitis in the real-world setting.
- They included 234 patients aged > 15 years (51% men) with severe granulomatosis with polyangiitis (n = 141) or microscopic polyangiitis (n = 93) who received induction therapy with rituximab or cyclophosphamide; 126 and 108 patients received reduced-dose and standard-dose glucocorticoid regimens, respectively.
- Most patients (70%) had severe renal involvement.
- The primary composite outcome encompassed minor relapse, major relapse, disease progression before remission, end-stage kidney disease requiring dialysis for > 12 weeks or transplantation, and death within 12 months post-induction.
TAKEAWAY:
- The primary composite outcome occurred in a higher proportion of patients receiving reduced-dose glucocorticoid therapy than in those receiving standard-dose therapy (33.3% vs 18.5%; hazard ratio [HR], 2.20; 95% CI, 1.23-3.94).
- However, no significant association was found between reduced-dose glucocorticoids and the risk for death or end-stage kidney disease or the occurrence of serious infections.
- Among patients receiving reduced-dose glucocorticoids, serum creatinine levels > 300 μmol/L were associated with an increased risk for the primary composite outcome (adjusted HR, 3.02; 95% CI, 1.28-7.11).
- In the rituximab induction subgroup, reduced-dose glucocorticoid was associated with an increased risk for the primary composite outcome (adjusted HR, 2.36; 95% CI, 1.18-4.71), compared with standard-dose glucocorticoids.
IN PRACTICE:
“Our data suggest increased vigilance when using the [reduced-dose glucocorticoid] regimen, especially in the two subgroups of patients at higher risk of failure, that is, those receiving [rituximab] as induction therapy and those with a baseline serum creatinine greater than 300 μmol/L,” the authors wrote.
SOURCE:
The study was led by Sophie Nagle, MD, National Referral Centre for Rare Autoimmune and Systemic Diseases, Department of Internal Medicine, Hôpital Cochin, Paris, France. It was published online on November 20, 2024, in Annals of the Rheumatic Diseases.
LIMITATIONS:
The retrospective nature of this study may have introduced inherent limitations and potential selection bias. The study lacked data on patient comorbidities, which could have influenced treatment choice and outcomes. Additionally, about a quarter of patients did not receive methylprednisolone pulses prior to oral glucocorticoids, unlike the PEXIVAS trial protocol. The group receiving standard-dose glucocorticoids showed heterogeneity in glucocorticoid regimens, and the minimum follow-up was only 6 months.
DISCLOSURES:
This study did not report any source of funding. The authors reported no relevant conflicts of interest.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.
TOPLINE:
Compared with a standard dosing regimen, a reduced-dose glucocorticoid regimen is associated with an increased risk for disease progression, relapse, death, or kidney failure in antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis, particularly affecting patients receiving rituximab or those with elevated creatinine levels.
METHODOLOGY:
- The PEXIVAS trial demonstrated that a reduced-dose glucocorticoid regimen was noninferior to standard dosing in terms of death or end-stage kidney disease in ANCA-associated vasculitis. However, the trial did not include disease progression or relapse as a primary endpoint, and cyclophosphamide was the primary induction therapy.
- Researchers conducted this retrospective study across 19 hospitals (18 in France and one in Luxembourg) between January 2018 and November 2022 to compare the effectiveness of a reduced-dose glucocorticoid regimen, as used in the PEXIVAS trial, with a standard-dose regimen in patients with ANCA-associated vasculitis in the real-world setting.
- They included 234 patients aged > 15 years (51% men) with severe granulomatosis with polyangiitis (n = 141) or microscopic polyangiitis (n = 93) who received induction therapy with rituximab or cyclophosphamide; 126 and 108 patients received reduced-dose and standard-dose glucocorticoid regimens, respectively.
- Most patients (70%) had severe renal involvement.
- The primary composite outcome encompassed minor relapse, major relapse, disease progression before remission, end-stage kidney disease requiring dialysis for > 12 weeks or transplantation, and death within 12 months post-induction.
TAKEAWAY:
- The primary composite outcome occurred in a higher proportion of patients receiving reduced-dose glucocorticoid therapy than in those receiving standard-dose therapy (33.3% vs 18.5%; hazard ratio [HR], 2.20; 95% CI, 1.23-3.94).
- However, no significant association was found between reduced-dose glucocorticoids and the risk for death or end-stage kidney disease or the occurrence of serious infections.
- Among patients receiving reduced-dose glucocorticoids, serum creatinine levels > 300 μmol/L were associated with an increased risk for the primary composite outcome (adjusted HR, 3.02; 95% CI, 1.28-7.11).
- In the rituximab induction subgroup, reduced-dose glucocorticoid was associated with an increased risk for the primary composite outcome (adjusted HR, 2.36; 95% CI, 1.18-4.71), compared with standard-dose glucocorticoids.
IN PRACTICE:
“Our data suggest increased vigilance when using the [reduced-dose glucocorticoid] regimen, especially in the two subgroups of patients at higher risk of failure, that is, those receiving [rituximab] as induction therapy and those with a baseline serum creatinine greater than 300 μmol/L,” the authors wrote.
SOURCE:
The study was led by Sophie Nagle, MD, National Referral Centre for Rare Autoimmune and Systemic Diseases, Department of Internal Medicine, Hôpital Cochin, Paris, France. It was published online on November 20, 2024, in Annals of the Rheumatic Diseases.
LIMITATIONS:
The retrospective nature of this study may have introduced inherent limitations and potential selection bias. The study lacked data on patient comorbidities, which could have influenced treatment choice and outcomes. Additionally, about a quarter of patients did not receive methylprednisolone pulses prior to oral glucocorticoids, unlike the PEXIVAS trial protocol. The group receiving standard-dose glucocorticoids showed heterogeneity in glucocorticoid regimens, and the minimum follow-up was only 6 months.
DISCLOSURES:
This study did not report any source of funding. The authors reported no relevant conflicts of interest.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.
With Chemo, Blinatumomab Boosts DFS in Pediatric B-ALL
Among pediatric patients with B-ALL followed for a mean of 2.5 years (1.6-3.2 years), 718 patients in the blinatumomab-plus-chemotherapy group had a 3-year DFS of 96.0 ± 1.2%, compared with 87.9 ± 2.1% of the 722 patients in the chemotherapy-only group, researchers reported at the American Society of Hematology (ASH) 2024 Annual Meeting.
“Our results demonstrate that blinatumomab added to chemotherapy represents a new treatment standard for most patients with NCI [National Cancer Institute] standard-risk [B-ALL],” said first author Rachel E. Rau, MD, Seattle Children’s Hospital, University of Washington, during a news briefing.
As Cynthia E. Dunbar, MD, chief of the Translational Stem Cell Biology Branch at the National Heart, Lung, and Blood Institute, noted in a news briefing: “B-cell ALL is the most common childhood cancer and one of the most treatable. However, some children still relapse following standard chemotherapy treatments and then have a much grimmer outcome.”
The AALL1731 study was initiated in 2019 with a recruitment goal of 2245 participants. The patients were over age 1 and less than 10 years, with an initial white blood cell count of < 50,000/μL and were considered to be standard risk–high or standard risk–average.
The control group received standard-intensity chemotherapy (standard risk–average patients) or augmented Berlin-Frankfurt-Münster–based chemotherapy (standard risk–high patients). In addition, the blinatumomab groups received two cycles of the drug.
Randomization was terminated in 2024 at 1440 patients because of the positive results. Patients had a median age of 4.3 years (2.8-6.4), 52.6% were boys, 26% were Hispanic, and 5% were non-Hispanic Black.
The addition of blinatumomab improved DFS by 61% (hazard ratio, 0.39; 95% CI, 0.24-0.64; P < .0001).
In the group of standard risk–average patients, 3-year DFS was 97.5±1.3% in the blinatumomab group vs 90.2±2.3% in the control group (HR, 0.33; 95% CI, 0.15-0.69). For standard risk–high patients, 3-year DFS was 94.1 ± 2.5% and 84.8 ± 3.8%, respectively.
Six deaths occurred in remission, all in standard risk–high patients and none during blinatumomab cycles. Out of first courses of blinatumomab, 0.3% were associated with Grade 3 or higher cytokine release syndrome and 0.7% with seizures.
“We did note higher rates of subsequent sepsis and catheter-related infections in our standard risk–average patients who received blinatumomab,” Rau said.
“The improvement in disease survival was secondary to significant reduction in bone marrow relapse,” Rau added. “We did not see a similar reduction in the more rare event of an isolated central nervous system relapse. This finding was not surprising given blinatumomab’s known limited activity in the central nervous system.”
Rau noted that there are two challenges in terms of access to blinatumomab: its cost, at about $225,000 per a 2023 report, and its administration. The drug is administered via 4-week-long infusions. “The delivery method is very cumbersome,” she said.
“These are big problems that are going to take the combined efforts of pediatric oncologist cancer consortia and pharmaceutical industry partners as well as government agencies,” she said. Fortunately, she said, in June 2024 the Food and Drug Administration approved blinatumomab for adult and pediatric patients 1 month and older with CD19-positive Philadelphia chromosome–negative B-ALL in the consolidation phase of multiphase chemotherapy.
“So it’s relatively easy, at least, to prescribe blinatumomab in the United States for our patients that we feel would benefit from it,” she said.
As for method of delivery, Rau said easier-to-deliver formulations are in development.
Rau has disclosed spousal employment (AbbVie), serving on advisory boards (Servier, Jazz), consulting, and receiving honoraria (Jazz). Other study authors report various disclosures including ties with Amgen, the maker of blinatumomab. Dunbar has reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Among pediatric patients with B-ALL followed for a mean of 2.5 years (1.6-3.2 years), 718 patients in the blinatumomab-plus-chemotherapy group had a 3-year DFS of 96.0 ± 1.2%, compared with 87.9 ± 2.1% of the 722 patients in the chemotherapy-only group, researchers reported at the American Society of Hematology (ASH) 2024 Annual Meeting.
“Our results demonstrate that blinatumomab added to chemotherapy represents a new treatment standard for most patients with NCI [National Cancer Institute] standard-risk [B-ALL],” said first author Rachel E. Rau, MD, Seattle Children’s Hospital, University of Washington, during a news briefing.
As Cynthia E. Dunbar, MD, chief of the Translational Stem Cell Biology Branch at the National Heart, Lung, and Blood Institute, noted in a news briefing: “B-cell ALL is the most common childhood cancer and one of the most treatable. However, some children still relapse following standard chemotherapy treatments and then have a much grimmer outcome.”
The AALL1731 study was initiated in 2019 with a recruitment goal of 2245 participants. The patients were over age 1 and less than 10 years, with an initial white blood cell count of < 50,000/μL and were considered to be standard risk–high or standard risk–average.
The control group received standard-intensity chemotherapy (standard risk–average patients) or augmented Berlin-Frankfurt-Münster–based chemotherapy (standard risk–high patients). In addition, the blinatumomab groups received two cycles of the drug.
Randomization was terminated in 2024 at 1440 patients because of the positive results. Patients had a median age of 4.3 years (2.8-6.4), 52.6% were boys, 26% were Hispanic, and 5% were non-Hispanic Black.
The addition of blinatumomab improved DFS by 61% (hazard ratio, 0.39; 95% CI, 0.24-0.64; P < .0001).
In the group of standard risk–average patients, 3-year DFS was 97.5±1.3% in the blinatumomab group vs 90.2±2.3% in the control group (HR, 0.33; 95% CI, 0.15-0.69). For standard risk–high patients, 3-year DFS was 94.1 ± 2.5% and 84.8 ± 3.8%, respectively.
Six deaths occurred in remission, all in standard risk–high patients and none during blinatumomab cycles. Out of first courses of blinatumomab, 0.3% were associated with Grade 3 or higher cytokine release syndrome and 0.7% with seizures.
“We did note higher rates of subsequent sepsis and catheter-related infections in our standard risk–average patients who received blinatumomab,” Rau said.
“The improvement in disease survival was secondary to significant reduction in bone marrow relapse,” Rau added. “We did not see a similar reduction in the more rare event of an isolated central nervous system relapse. This finding was not surprising given blinatumomab’s known limited activity in the central nervous system.”
Rau noted that there are two challenges in terms of access to blinatumomab: its cost, at about $225,000 per a 2023 report, and its administration. The drug is administered via 4-week-long infusions. “The delivery method is very cumbersome,” she said.
“These are big problems that are going to take the combined efforts of pediatric oncologist cancer consortia and pharmaceutical industry partners as well as government agencies,” she said. Fortunately, she said, in June 2024 the Food and Drug Administration approved blinatumomab for adult and pediatric patients 1 month and older with CD19-positive Philadelphia chromosome–negative B-ALL in the consolidation phase of multiphase chemotherapy.
“So it’s relatively easy, at least, to prescribe blinatumomab in the United States for our patients that we feel would benefit from it,” she said.
As for method of delivery, Rau said easier-to-deliver formulations are in development.
Rau has disclosed spousal employment (AbbVie), serving on advisory boards (Servier, Jazz), consulting, and receiving honoraria (Jazz). Other study authors report various disclosures including ties with Amgen, the maker of blinatumomab. Dunbar has reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Among pediatric patients with B-ALL followed for a mean of 2.5 years (1.6-3.2 years), 718 patients in the blinatumomab-plus-chemotherapy group had a 3-year DFS of 96.0 ± 1.2%, compared with 87.9 ± 2.1% of the 722 patients in the chemotherapy-only group, researchers reported at the American Society of Hematology (ASH) 2024 Annual Meeting.
“Our results demonstrate that blinatumomab added to chemotherapy represents a new treatment standard for most patients with NCI [National Cancer Institute] standard-risk [B-ALL],” said first author Rachel E. Rau, MD, Seattle Children’s Hospital, University of Washington, during a news briefing.
As Cynthia E. Dunbar, MD, chief of the Translational Stem Cell Biology Branch at the National Heart, Lung, and Blood Institute, noted in a news briefing: “B-cell ALL is the most common childhood cancer and one of the most treatable. However, some children still relapse following standard chemotherapy treatments and then have a much grimmer outcome.”
The AALL1731 study was initiated in 2019 with a recruitment goal of 2245 participants. The patients were over age 1 and less than 10 years, with an initial white blood cell count of < 50,000/μL and were considered to be standard risk–high or standard risk–average.
The control group received standard-intensity chemotherapy (standard risk–average patients) or augmented Berlin-Frankfurt-Münster–based chemotherapy (standard risk–high patients). In addition, the blinatumomab groups received two cycles of the drug.
Randomization was terminated in 2024 at 1440 patients because of the positive results. Patients had a median age of 4.3 years (2.8-6.4), 52.6% were boys, 26% were Hispanic, and 5% were non-Hispanic Black.
The addition of blinatumomab improved DFS by 61% (hazard ratio, 0.39; 95% CI, 0.24-0.64; P < .0001).
In the group of standard risk–average patients, 3-year DFS was 97.5±1.3% in the blinatumomab group vs 90.2±2.3% in the control group (HR, 0.33; 95% CI, 0.15-0.69). For standard risk–high patients, 3-year DFS was 94.1 ± 2.5% and 84.8 ± 3.8%, respectively.
Six deaths occurred in remission, all in standard risk–high patients and none during blinatumomab cycles. Out of first courses of blinatumomab, 0.3% were associated with Grade 3 or higher cytokine release syndrome and 0.7% with seizures.
“We did note higher rates of subsequent sepsis and catheter-related infections in our standard risk–average patients who received blinatumomab,” Rau said.
“The improvement in disease survival was secondary to significant reduction in bone marrow relapse,” Rau added. “We did not see a similar reduction in the more rare event of an isolated central nervous system relapse. This finding was not surprising given blinatumomab’s known limited activity in the central nervous system.”
Rau noted that there are two challenges in terms of access to blinatumomab: its cost, at about $225,000 per a 2023 report, and its administration. The drug is administered via 4-week-long infusions. “The delivery method is very cumbersome,” she said.
“These are big problems that are going to take the combined efforts of pediatric oncologist cancer consortia and pharmaceutical industry partners as well as government agencies,” she said. Fortunately, she said, in June 2024 the Food and Drug Administration approved blinatumomab for adult and pediatric patients 1 month and older with CD19-positive Philadelphia chromosome–negative B-ALL in the consolidation phase of multiphase chemotherapy.
“So it’s relatively easy, at least, to prescribe blinatumomab in the United States for our patients that we feel would benefit from it,” she said.
As for method of delivery, Rau said easier-to-deliver formulations are in development.
Rau has disclosed spousal employment (AbbVie), serving on advisory boards (Servier, Jazz), consulting, and receiving honoraria (Jazz). Other study authors report various disclosures including ties with Amgen, the maker of blinatumomab. Dunbar has reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM ASH 2024
High-Fiber Diet Linked to Improved Stem Cell Transplant, GvHD Outcomes
Importantly, the findings suggest standard recommendations for patients of a low-fiber diet following allo-HCT may run counter to the potential benefits.
“Significant decrease of fiber intake during transplantation is detrimental. It’s a lost opportunity to promote a healthy gut microbiome, recover from treatment-related microbiota injury, and protect against GVHD,” first author Jenny Paredes, PhD, a staff scientist at City of Hope National Medical Center in Duarte, California, said in a press statement for the study presented at the American Society of Hematology (ASH) 2024 Annual Meeting.
Although the health benefits of dietary fiber on the gut microbiome are well-documented, the effects have recently been shown to extend to outcomes after allo-HCT in general, with researchers finding increased overall survival when there is higher diversity in the gut microbiome, including a higher abundance of butyrate producers and lower abundance of enterococcus, explained Paredes when presenting the findings.
Acute GvHD, a common and potentially life-threatening complication of allo-HCT, can have symptoms that mimic irritable bowel disease (IBD), including abdominal pain or cramps, nausea, vomiting, and diarrhea. The low-fiber diet recommendations, including avoidance of raw vegetables and fruits before and after the allo-HCT procedure, are designed to counter those effects, as well as reduce exposure to bacteria.
However, with data suggesting the potential benefits of dietary fiber could extend to the prevention of GvHD, Paredes and colleagues further investigated.
For the observational study, they evaluated all dietary data on 173 allo-HCT recipients at Memorial Sloan Kettering Cancer Center (MSKCC) from 10 days prior to transplantation to 30 days post-transplantation, representing 3837 patient-days in total.
Data collected from the patients also included rRNA sequencing of fecal samples and fecal short-chain fatty acid concentration.
Participants had a median age of 60, and 45% were female. The most common diseases being treated were leukemia (50%), myelodysplastic syndrome (25%), and non-Hodgkin’s lymphoma (8.7%).
After stratifying patients based on high- or low-fiber intake, those with high-fiber intake were found to have significantly higher rates of microbial α-diversity (P = .009), a higher abundance of butyrate producers (P = .03), and a higher concentration of butyrate (P = .02), a short-chain fatty acid that plays a key role in gut health.
Furthermore, the high-fiber group had significantly higher overall survival in an analysis extending to 24 months relative to day 12 of the study (P = .04).
Focusing on GvHD outcomes, the authors further evaluated data on 101 non-T-cell–depleted patients, and identified 29 patients without GvHD and 24 who developed lower gastrointestinal (GI) GvHD.
Patients with lower GI GvHD had significantly lower fecal concentrations of butyrate (P = .03) and acetate (P = .02).
However, patients among those in the high-fiber intake group had a significantly lower cumulative incidence of developing GvHD at day 100 (P = .034) and a lower incidence of lower GI GvHD (P = .04).
A separate preclinical analysis of a mouse model with GvHD further showed that a fiber-rich diet (12% cellulose) significantly increased the expression of genes associated with reduced GvHD, including IDO1 and CEACAM1, and those associated with enrichment of the bile acid pathway.
The findings suggest an opportunity to improve outcomes with relatively small dietary changes, Paredes said.
“Strategies to increase the fiber concentration in these diets paired with the safety that these patients need is what makes this study exciting,” she said in an interview.
“Increasing the fiber intake by 10 to 20 grams/day could potentially increase the microbiome diversity and abundance of butyrate producers, which have been correlated with higher overall survival rates post allo-HCT,” she continued.
“[For instance], that could be an avocado per day, or it could be a small salad per day, or a small vegetable soup per day,” she added. “I would encourage institutions to re-evaluate their menu planning and see how to include more fiber into the meals in a safe way.”
Ultimately, “I think that a dietary intervention outweighs the risks of a pharmacological intervention,” Paredes added.
The necessary duration of a high-fiber diet to produce the beneficial effects on allo-HCT outcomes would likely be over the course of the pre- and post-transplant periods, Paredes added.
“With the survival analysis extending from 5 days before transplantation to 12 days post, we are looking at an intervention that potentially could be around 20 days,” she said.
“We would love to take advantage of the pretransplantation window, in particular, and we can see that just increasing the fiber intake by about 20 grams during this window was shown to improve overall survival after 24 months,” Paredes added.
Importantly, however, some patients may not be appropriate for high-fiber dietary changes, Paredes cautioned.
“Patients that have developed IBD-like symptoms and severe GvHD patients, for example, or with lower GI-GvHD grades 3 and 4 would be not appropriate candidates for a high-fiber diet,” she said.
High-Fiber Diet Slows MM Disease Progression?
The potential important benefits of a high-fiber diet in blood diseases were further demonstrated in a separate study also by MSKCC researchers presented at the meeting, which showed encouraging signs that a plant-based diet rich in fiber could potentially slow disease progression in multiple myeloma (MM).
NUTRIVENTION included 20 patients with the two precancerous MM conditions, monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM), which can last for years without progressing to MM and which researchers have speculated could be a potential opportunity to intervene to prevent progression to cancer.
Patients were provided with a 12-week controlled diet plus health coaching for another 3 months; no meals or coaching were provided for the rest of the 1-year study period. Participants had a median age of 62 and, with being overweight/obesity a risk factor for MM, had a body mass index (BMI) of 25 kg/m2 or higher.
The trial met its endpoint of feasibility, with 91% adherence in the first 3 months. The rate of consumption of unprocessed plant foods increased from 20% at baseline to 92% on the intervention. Overall adherence was 58%. Insulin and anti-inflammatory markers also improved and, despite no calorie restriction, there was a 7% sustained reduction in BMI.
Notably, two patients in the study had stabilization of disease progression.
“We saw improvements in all spheres, including metabolism, microbiome, and immune system markers, and we also saw that two patients with progressive disease had the progression stabilize and slow down on the intervention,” principal investigator Urvi A. Shah, MD, said in a press statement.
“Even though it’s just two cases, to our knowledge, it has not been shown before in an intervention setting that you can improve diet and lifestyle and actually slow or change the trajectory of the disease,” she noted.
The researchers caution that findings in mice do not necessarily translate to humans but note another experiment in mice with SMM that showed animals fed a normal diet had progression to MM after a median of 12 weeks, compared with a median of 30 weeks among those fed a high-fiber diet.
Notably, all mice in the normal-diet group progressed to MM, whereas 40% of mice in the high-fiber group did not.
“We found that a high-fiber plant-based diet can improve BMI, improve insulin resistance [and] the microbiome through diversity and butyrate producers, and with the production of short-chain fatty acids, can have effects on inflammation, immunity, innate and adaptive antitumor immunity, and tumor cells or plasma cells,” Shah said during her presentation.
The study was supported by funding from the National Cancer Institute and private foundations. Paredes has reported no relevant financial relationships. Shah has reported relationships with Sanofi, Bristol Myers Squibb, and Janssen.
A version of this article first appeared on Medscape.com.
Importantly, the findings suggest standard recommendations for patients of a low-fiber diet following allo-HCT may run counter to the potential benefits.
“Significant decrease of fiber intake during transplantation is detrimental. It’s a lost opportunity to promote a healthy gut microbiome, recover from treatment-related microbiota injury, and protect against GVHD,” first author Jenny Paredes, PhD, a staff scientist at City of Hope National Medical Center in Duarte, California, said in a press statement for the study presented at the American Society of Hematology (ASH) 2024 Annual Meeting.
Although the health benefits of dietary fiber on the gut microbiome are well-documented, the effects have recently been shown to extend to outcomes after allo-HCT in general, with researchers finding increased overall survival when there is higher diversity in the gut microbiome, including a higher abundance of butyrate producers and lower abundance of enterococcus, explained Paredes when presenting the findings.
Acute GvHD, a common and potentially life-threatening complication of allo-HCT, can have symptoms that mimic irritable bowel disease (IBD), including abdominal pain or cramps, nausea, vomiting, and diarrhea. The low-fiber diet recommendations, including avoidance of raw vegetables and fruits before and after the allo-HCT procedure, are designed to counter those effects, as well as reduce exposure to bacteria.
However, with data suggesting the potential benefits of dietary fiber could extend to the prevention of GvHD, Paredes and colleagues further investigated.
For the observational study, they evaluated all dietary data on 173 allo-HCT recipients at Memorial Sloan Kettering Cancer Center (MSKCC) from 10 days prior to transplantation to 30 days post-transplantation, representing 3837 patient-days in total.
Data collected from the patients also included rRNA sequencing of fecal samples and fecal short-chain fatty acid concentration.
Participants had a median age of 60, and 45% were female. The most common diseases being treated were leukemia (50%), myelodysplastic syndrome (25%), and non-Hodgkin’s lymphoma (8.7%).
After stratifying patients based on high- or low-fiber intake, those with high-fiber intake were found to have significantly higher rates of microbial α-diversity (P = .009), a higher abundance of butyrate producers (P = .03), and a higher concentration of butyrate (P = .02), a short-chain fatty acid that plays a key role in gut health.
Furthermore, the high-fiber group had significantly higher overall survival in an analysis extending to 24 months relative to day 12 of the study (P = .04).
Focusing on GvHD outcomes, the authors further evaluated data on 101 non-T-cell–depleted patients, and identified 29 patients without GvHD and 24 who developed lower gastrointestinal (GI) GvHD.
Patients with lower GI GvHD had significantly lower fecal concentrations of butyrate (P = .03) and acetate (P = .02).
However, patients among those in the high-fiber intake group had a significantly lower cumulative incidence of developing GvHD at day 100 (P = .034) and a lower incidence of lower GI GvHD (P = .04).
A separate preclinical analysis of a mouse model with GvHD further showed that a fiber-rich diet (12% cellulose) significantly increased the expression of genes associated with reduced GvHD, including IDO1 and CEACAM1, and those associated with enrichment of the bile acid pathway.
The findings suggest an opportunity to improve outcomes with relatively small dietary changes, Paredes said.
“Strategies to increase the fiber concentration in these diets paired with the safety that these patients need is what makes this study exciting,” she said in an interview.
“Increasing the fiber intake by 10 to 20 grams/day could potentially increase the microbiome diversity and abundance of butyrate producers, which have been correlated with higher overall survival rates post allo-HCT,” she continued.
“[For instance], that could be an avocado per day, or it could be a small salad per day, or a small vegetable soup per day,” she added. “I would encourage institutions to re-evaluate their menu planning and see how to include more fiber into the meals in a safe way.”
Ultimately, “I think that a dietary intervention outweighs the risks of a pharmacological intervention,” Paredes added.
The necessary duration of a high-fiber diet to produce the beneficial effects on allo-HCT outcomes would likely be over the course of the pre- and post-transplant periods, Paredes added.
“With the survival analysis extending from 5 days before transplantation to 12 days post, we are looking at an intervention that potentially could be around 20 days,” she said.
“We would love to take advantage of the pretransplantation window, in particular, and we can see that just increasing the fiber intake by about 20 grams during this window was shown to improve overall survival after 24 months,” Paredes added.
Importantly, however, some patients may not be appropriate for high-fiber dietary changes, Paredes cautioned.
“Patients that have developed IBD-like symptoms and severe GvHD patients, for example, or with lower GI-GvHD grades 3 and 4 would be not appropriate candidates for a high-fiber diet,” she said.
High-Fiber Diet Slows MM Disease Progression?
The potential important benefits of a high-fiber diet in blood diseases were further demonstrated in a separate study also by MSKCC researchers presented at the meeting, which showed encouraging signs that a plant-based diet rich in fiber could potentially slow disease progression in multiple myeloma (MM).
NUTRIVENTION included 20 patients with the two precancerous MM conditions, monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM), which can last for years without progressing to MM and which researchers have speculated could be a potential opportunity to intervene to prevent progression to cancer.
Patients were provided with a 12-week controlled diet plus health coaching for another 3 months; no meals or coaching were provided for the rest of the 1-year study period. Participants had a median age of 62 and, with being overweight/obesity a risk factor for MM, had a body mass index (BMI) of 25 kg/m2 or higher.
The trial met its endpoint of feasibility, with 91% adherence in the first 3 months. The rate of consumption of unprocessed plant foods increased from 20% at baseline to 92% on the intervention. Overall adherence was 58%. Insulin and anti-inflammatory markers also improved and, despite no calorie restriction, there was a 7% sustained reduction in BMI.
Notably, two patients in the study had stabilization of disease progression.
“We saw improvements in all spheres, including metabolism, microbiome, and immune system markers, and we also saw that two patients with progressive disease had the progression stabilize and slow down on the intervention,” principal investigator Urvi A. Shah, MD, said in a press statement.
“Even though it’s just two cases, to our knowledge, it has not been shown before in an intervention setting that you can improve diet and lifestyle and actually slow or change the trajectory of the disease,” she noted.
The researchers caution that findings in mice do not necessarily translate to humans but note another experiment in mice with SMM that showed animals fed a normal diet had progression to MM after a median of 12 weeks, compared with a median of 30 weeks among those fed a high-fiber diet.
Notably, all mice in the normal-diet group progressed to MM, whereas 40% of mice in the high-fiber group did not.
“We found that a high-fiber plant-based diet can improve BMI, improve insulin resistance [and] the microbiome through diversity and butyrate producers, and with the production of short-chain fatty acids, can have effects on inflammation, immunity, innate and adaptive antitumor immunity, and tumor cells or plasma cells,” Shah said during her presentation.
The study was supported by funding from the National Cancer Institute and private foundations. Paredes has reported no relevant financial relationships. Shah has reported relationships with Sanofi, Bristol Myers Squibb, and Janssen.
A version of this article first appeared on Medscape.com.
Importantly, the findings suggest standard recommendations for patients of a low-fiber diet following allo-HCT may run counter to the potential benefits.
“Significant decrease of fiber intake during transplantation is detrimental. It’s a lost opportunity to promote a healthy gut microbiome, recover from treatment-related microbiota injury, and protect against GVHD,” first author Jenny Paredes, PhD, a staff scientist at City of Hope National Medical Center in Duarte, California, said in a press statement for the study presented at the American Society of Hematology (ASH) 2024 Annual Meeting.
Although the health benefits of dietary fiber on the gut microbiome are well-documented, the effects have recently been shown to extend to outcomes after allo-HCT in general, with researchers finding increased overall survival when there is higher diversity in the gut microbiome, including a higher abundance of butyrate producers and lower abundance of enterococcus, explained Paredes when presenting the findings.
Acute GvHD, a common and potentially life-threatening complication of allo-HCT, can have symptoms that mimic irritable bowel disease (IBD), including abdominal pain or cramps, nausea, vomiting, and diarrhea. The low-fiber diet recommendations, including avoidance of raw vegetables and fruits before and after the allo-HCT procedure, are designed to counter those effects, as well as reduce exposure to bacteria.
However, with data suggesting the potential benefits of dietary fiber could extend to the prevention of GvHD, Paredes and colleagues further investigated.
For the observational study, they evaluated all dietary data on 173 allo-HCT recipients at Memorial Sloan Kettering Cancer Center (MSKCC) from 10 days prior to transplantation to 30 days post-transplantation, representing 3837 patient-days in total.
Data collected from the patients also included rRNA sequencing of fecal samples and fecal short-chain fatty acid concentration.
Participants had a median age of 60, and 45% were female. The most common diseases being treated were leukemia (50%), myelodysplastic syndrome (25%), and non-Hodgkin’s lymphoma (8.7%).
After stratifying patients based on high- or low-fiber intake, those with high-fiber intake were found to have significantly higher rates of microbial α-diversity (P = .009), a higher abundance of butyrate producers (P = .03), and a higher concentration of butyrate (P = .02), a short-chain fatty acid that plays a key role in gut health.
Furthermore, the high-fiber group had significantly higher overall survival in an analysis extending to 24 months relative to day 12 of the study (P = .04).
Focusing on GvHD outcomes, the authors further evaluated data on 101 non-T-cell–depleted patients, and identified 29 patients without GvHD and 24 who developed lower gastrointestinal (GI) GvHD.
Patients with lower GI GvHD had significantly lower fecal concentrations of butyrate (P = .03) and acetate (P = .02).
However, patients among those in the high-fiber intake group had a significantly lower cumulative incidence of developing GvHD at day 100 (P = .034) and a lower incidence of lower GI GvHD (P = .04).
A separate preclinical analysis of a mouse model with GvHD further showed that a fiber-rich diet (12% cellulose) significantly increased the expression of genes associated with reduced GvHD, including IDO1 and CEACAM1, and those associated with enrichment of the bile acid pathway.
The findings suggest an opportunity to improve outcomes with relatively small dietary changes, Paredes said.
“Strategies to increase the fiber concentration in these diets paired with the safety that these patients need is what makes this study exciting,” she said in an interview.
“Increasing the fiber intake by 10 to 20 grams/day could potentially increase the microbiome diversity and abundance of butyrate producers, which have been correlated with higher overall survival rates post allo-HCT,” she continued.
“[For instance], that could be an avocado per day, or it could be a small salad per day, or a small vegetable soup per day,” she added. “I would encourage institutions to re-evaluate their menu planning and see how to include more fiber into the meals in a safe way.”
Ultimately, “I think that a dietary intervention outweighs the risks of a pharmacological intervention,” Paredes added.
The necessary duration of a high-fiber diet to produce the beneficial effects on allo-HCT outcomes would likely be over the course of the pre- and post-transplant periods, Paredes added.
“With the survival analysis extending from 5 days before transplantation to 12 days post, we are looking at an intervention that potentially could be around 20 days,” she said.
“We would love to take advantage of the pretransplantation window, in particular, and we can see that just increasing the fiber intake by about 20 grams during this window was shown to improve overall survival after 24 months,” Paredes added.
Importantly, however, some patients may not be appropriate for high-fiber dietary changes, Paredes cautioned.
“Patients that have developed IBD-like symptoms and severe GvHD patients, for example, or with lower GI-GvHD grades 3 and 4 would be not appropriate candidates for a high-fiber diet,” she said.
High-Fiber Diet Slows MM Disease Progression?
The potential important benefits of a high-fiber diet in blood diseases were further demonstrated in a separate study also by MSKCC researchers presented at the meeting, which showed encouraging signs that a plant-based diet rich in fiber could potentially slow disease progression in multiple myeloma (MM).
NUTRIVENTION included 20 patients with the two precancerous MM conditions, monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM), which can last for years without progressing to MM and which researchers have speculated could be a potential opportunity to intervene to prevent progression to cancer.
Patients were provided with a 12-week controlled diet plus health coaching for another 3 months; no meals or coaching were provided for the rest of the 1-year study period. Participants had a median age of 62 and, with being overweight/obesity a risk factor for MM, had a body mass index (BMI) of 25 kg/m2 or higher.
The trial met its endpoint of feasibility, with 91% adherence in the first 3 months. The rate of consumption of unprocessed plant foods increased from 20% at baseline to 92% on the intervention. Overall adherence was 58%. Insulin and anti-inflammatory markers also improved and, despite no calorie restriction, there was a 7% sustained reduction in BMI.
Notably, two patients in the study had stabilization of disease progression.
“We saw improvements in all spheres, including metabolism, microbiome, and immune system markers, and we also saw that two patients with progressive disease had the progression stabilize and slow down on the intervention,” principal investigator Urvi A. Shah, MD, said in a press statement.
“Even though it’s just two cases, to our knowledge, it has not been shown before in an intervention setting that you can improve diet and lifestyle and actually slow or change the trajectory of the disease,” she noted.
The researchers caution that findings in mice do not necessarily translate to humans but note another experiment in mice with SMM that showed animals fed a normal diet had progression to MM after a median of 12 weeks, compared with a median of 30 weeks among those fed a high-fiber diet.
Notably, all mice in the normal-diet group progressed to MM, whereas 40% of mice in the high-fiber group did not.
“We found that a high-fiber plant-based diet can improve BMI, improve insulin resistance [and] the microbiome through diversity and butyrate producers, and with the production of short-chain fatty acids, can have effects on inflammation, immunity, innate and adaptive antitumor immunity, and tumor cells or plasma cells,” Shah said during her presentation.
The study was supported by funding from the National Cancer Institute and private foundations. Paredes has reported no relevant financial relationships. Shah has reported relationships with Sanofi, Bristol Myers Squibb, and Janssen.
A version of this article first appeared on Medscape.com.
FROM ASH 2024
24-Hour Urine Testing in Multiple Myeloma: Time to Stop?
Overall, evaluating patients’ responses using urine-free and traditional criteria led to nearly identical assessments. When comparing the two criteria, only 7 of 645 patients evaluated had discordant results.
The findings, presented at the American Society of Hematology (ASH) 2024 Annual Meeting, add weight to the push to drop the requirement to perform routine urine tests from International Myeloma Working Group (IMWG) response criteria for multiple myeloma, said the study’s lead author, Rahul Banerjee, MD, from Fred Hutch Cancer Center, University of Washington School of Medicine, Seattle.
“International guidelines for multiple myeloma, which haven’t been updated in almost a decade, currently recommend these refrigerated 24-hour urine assessments, which are cumbersome for patients and can create substantial disparities,” Banerjee said in an interview.
“The international community is actually in the midst of updating its guidelines (I am part of this effort), and our work will hopefully help lead the way for future guidelines that de-emphasize the need for 24-hour urine testing to only a few rare scenarios, such as AL amyloidosis,” Banerjee added.
Urine tests can help detect the presence of abnormal proteins, which can indicate the level of myeloma tumor burden. Performing these tests routinely can help physicians monitor the effectiveness of patients’ treatment in practice and clinical trials.
Some recent data, however, suggest that dropping urine testing from the response criteria would change the response assessment in fewer than 5% of patients. Still, it’s not clear how urine-free criteria would impact assessments of progression free survival.
In the current study, Banerjee and colleagues performed a secondary analysis of the STaMINA trial. In the original trial, patients were randomized to lenalidomide maintenance, tandem autologous hematopoietic cell transplantation followed by lenalidomide maintenance, or consolidation therapy (lenalidomide, bortezomib, and dexamethasone) followed by lenalidomide maintenance until disease progression.
The secondary analysis included 645 patients from the original trial who were evaluable 56 days following autologous hematopoietic cell transplantation. The analysis looked at patients across all groups, but excluded those with progressive disease, and compared patients’ responses using traditional IMWG criteria, which includes 24-hour urine assessments, and urine-free criteria. Response measurements included complete response, very good partial response, partial response, and stable disease.
Patients were a median age of 56 years, 41% were female, 17% were Black, and 7% were Hispanic; 26% had light-chain only disease. About half (49%) had received lenalidomide alone, 28% had received post-autologous stem cell transplantation consolidation followed by lenalidomide, and 24% had received tandem transplantation followed by lenalidomide.
The analysis showed that “urine-free response criteria worked just fine in terms of their prognostic value,” Banerjee said while presenting the findings.
Specifically, the complete response rate was 29.4% using the traditional criteria vs 29.7% using the urine-free criteria. The very good partial response rate was 37.0% with the traditional approach vs 36.6% with the urine-free approach. The partial response rate was 30.7% for both and the stable disease rate was 3.0% for both.
Achieving a complete response based on the urine-free criteria was highly prognostic for progression-free survival (P = .005) while achieving a very good partial response by either criterion was borderline prognostic for progression-free survival (P = .102).
Only 1.1% of patients — seven patients altogether — had discordant responses between traditional and urine-free response criteria, Banerjee noted. One patient, for instance, was downgraded from a very good partial response with traditional criteria to a partial response with urine-free criteria “because current response criteria rate urine [as] more important than serum-free light chains,” Banerjee explained. Two other patients who met all other stringent criteria for a complete response but still had urine paraprotein at Day 56 were classified as having a very good partial response using traditional criteria but as a complete response with the urine-free criteria.
The other four patients with discordant results were the most important, Banerjee said. These patients were missing urine protein electrophoresis values, which made them non-evaluable using traditional criteria, but became evaluable when using urine-free criteria. “This is, I think, the bane of our existence, right? We ask our patients to put their blood, soul, sweat, and tears into being in a clinical trial, and then they’re not evaluable,” he said.
Overall, these results strongly support the de-emphasis of 24-hour urine requirements in updated IMWG response criteria, said Banerjee. However, he noted, 24-hour urine testing still has a very important place in the screening process and in patients with monoclonal gammopathy of renal significance or AL amyloidosis.
“This study provides reassurance to those of us already not repeating urine tests that urine testing is unnecessary for tracking responses,” said Manni Mohyuddin, MD, from the Multiple Myeloma Program at Huntsman Cancer Institute and assistant professor at the University of Utah, Salt Lake City. “These assessments aren’t done consistently in practice outside of trials anyway, and I hope that this study will lead to a formal change in criteria and the omission of urine assessments in clinical trials.”
Funding for the study was provided by the National Heart, Lung, and Blood Institute; National Cancer Institute; Alliance for Clinical Trials in Oncology; ECOG-ACRIN Cancer Research Group; and SWOG; and contributions were provided by Celgene and Millennium Pharmaceuticals. Banerjee has reported consulting for Adaptive Biotechnologies, Bristol-Myers Squibb, Caribou Biosciences, Genentech, GSK, Johnson & Johnson/Janssen, Karyopharm, Legend Biotech, Pfizer, Sanofi, and SparkCures, and receiving research funding from AbbVie, Johnson & Johnson, Novartis, Pack Health, Prothena, and Sanofi. Mohyuddin has disclosed no personal payments and no consultation for industry. His institution has received research funding from Janssen for his role as a principal investigator on a trial.
A version of this article first appeared on Medscape.com.
Overall, evaluating patients’ responses using urine-free and traditional criteria led to nearly identical assessments. When comparing the two criteria, only 7 of 645 patients evaluated had discordant results.
The findings, presented at the American Society of Hematology (ASH) 2024 Annual Meeting, add weight to the push to drop the requirement to perform routine urine tests from International Myeloma Working Group (IMWG) response criteria for multiple myeloma, said the study’s lead author, Rahul Banerjee, MD, from Fred Hutch Cancer Center, University of Washington School of Medicine, Seattle.
“International guidelines for multiple myeloma, which haven’t been updated in almost a decade, currently recommend these refrigerated 24-hour urine assessments, which are cumbersome for patients and can create substantial disparities,” Banerjee said in an interview.
“The international community is actually in the midst of updating its guidelines (I am part of this effort), and our work will hopefully help lead the way for future guidelines that de-emphasize the need for 24-hour urine testing to only a few rare scenarios, such as AL amyloidosis,” Banerjee added.
Urine tests can help detect the presence of abnormal proteins, which can indicate the level of myeloma tumor burden. Performing these tests routinely can help physicians monitor the effectiveness of patients’ treatment in practice and clinical trials.
Some recent data, however, suggest that dropping urine testing from the response criteria would change the response assessment in fewer than 5% of patients. Still, it’s not clear how urine-free criteria would impact assessments of progression free survival.
In the current study, Banerjee and colleagues performed a secondary analysis of the STaMINA trial. In the original trial, patients were randomized to lenalidomide maintenance, tandem autologous hematopoietic cell transplantation followed by lenalidomide maintenance, or consolidation therapy (lenalidomide, bortezomib, and dexamethasone) followed by lenalidomide maintenance until disease progression.
The secondary analysis included 645 patients from the original trial who were evaluable 56 days following autologous hematopoietic cell transplantation. The analysis looked at patients across all groups, but excluded those with progressive disease, and compared patients’ responses using traditional IMWG criteria, which includes 24-hour urine assessments, and urine-free criteria. Response measurements included complete response, very good partial response, partial response, and stable disease.
Patients were a median age of 56 years, 41% were female, 17% were Black, and 7% were Hispanic; 26% had light-chain only disease. About half (49%) had received lenalidomide alone, 28% had received post-autologous stem cell transplantation consolidation followed by lenalidomide, and 24% had received tandem transplantation followed by lenalidomide.
The analysis showed that “urine-free response criteria worked just fine in terms of their prognostic value,” Banerjee said while presenting the findings.
Specifically, the complete response rate was 29.4% using the traditional criteria vs 29.7% using the urine-free criteria. The very good partial response rate was 37.0% with the traditional approach vs 36.6% with the urine-free approach. The partial response rate was 30.7% for both and the stable disease rate was 3.0% for both.
Achieving a complete response based on the urine-free criteria was highly prognostic for progression-free survival (P = .005) while achieving a very good partial response by either criterion was borderline prognostic for progression-free survival (P = .102).
Only 1.1% of patients — seven patients altogether — had discordant responses between traditional and urine-free response criteria, Banerjee noted. One patient, for instance, was downgraded from a very good partial response with traditional criteria to a partial response with urine-free criteria “because current response criteria rate urine [as] more important than serum-free light chains,” Banerjee explained. Two other patients who met all other stringent criteria for a complete response but still had urine paraprotein at Day 56 were classified as having a very good partial response using traditional criteria but as a complete response with the urine-free criteria.
The other four patients with discordant results were the most important, Banerjee said. These patients were missing urine protein electrophoresis values, which made them non-evaluable using traditional criteria, but became evaluable when using urine-free criteria. “This is, I think, the bane of our existence, right? We ask our patients to put their blood, soul, sweat, and tears into being in a clinical trial, and then they’re not evaluable,” he said.
Overall, these results strongly support the de-emphasis of 24-hour urine requirements in updated IMWG response criteria, said Banerjee. However, he noted, 24-hour urine testing still has a very important place in the screening process and in patients with monoclonal gammopathy of renal significance or AL amyloidosis.
“This study provides reassurance to those of us already not repeating urine tests that urine testing is unnecessary for tracking responses,” said Manni Mohyuddin, MD, from the Multiple Myeloma Program at Huntsman Cancer Institute and assistant professor at the University of Utah, Salt Lake City. “These assessments aren’t done consistently in practice outside of trials anyway, and I hope that this study will lead to a formal change in criteria and the omission of urine assessments in clinical trials.”
Funding for the study was provided by the National Heart, Lung, and Blood Institute; National Cancer Institute; Alliance for Clinical Trials in Oncology; ECOG-ACRIN Cancer Research Group; and SWOG; and contributions were provided by Celgene and Millennium Pharmaceuticals. Banerjee has reported consulting for Adaptive Biotechnologies, Bristol-Myers Squibb, Caribou Biosciences, Genentech, GSK, Johnson & Johnson/Janssen, Karyopharm, Legend Biotech, Pfizer, Sanofi, and SparkCures, and receiving research funding from AbbVie, Johnson & Johnson, Novartis, Pack Health, Prothena, and Sanofi. Mohyuddin has disclosed no personal payments and no consultation for industry. His institution has received research funding from Janssen for his role as a principal investigator on a trial.
A version of this article first appeared on Medscape.com.
Overall, evaluating patients’ responses using urine-free and traditional criteria led to nearly identical assessments. When comparing the two criteria, only 7 of 645 patients evaluated had discordant results.
The findings, presented at the American Society of Hematology (ASH) 2024 Annual Meeting, add weight to the push to drop the requirement to perform routine urine tests from International Myeloma Working Group (IMWG) response criteria for multiple myeloma, said the study’s lead author, Rahul Banerjee, MD, from Fred Hutch Cancer Center, University of Washington School of Medicine, Seattle.
“International guidelines for multiple myeloma, which haven’t been updated in almost a decade, currently recommend these refrigerated 24-hour urine assessments, which are cumbersome for patients and can create substantial disparities,” Banerjee said in an interview.
“The international community is actually in the midst of updating its guidelines (I am part of this effort), and our work will hopefully help lead the way for future guidelines that de-emphasize the need for 24-hour urine testing to only a few rare scenarios, such as AL amyloidosis,” Banerjee added.
Urine tests can help detect the presence of abnormal proteins, which can indicate the level of myeloma tumor burden. Performing these tests routinely can help physicians monitor the effectiveness of patients’ treatment in practice and clinical trials.
Some recent data, however, suggest that dropping urine testing from the response criteria would change the response assessment in fewer than 5% of patients. Still, it’s not clear how urine-free criteria would impact assessments of progression free survival.
In the current study, Banerjee and colleagues performed a secondary analysis of the STaMINA trial. In the original trial, patients were randomized to lenalidomide maintenance, tandem autologous hematopoietic cell transplantation followed by lenalidomide maintenance, or consolidation therapy (lenalidomide, bortezomib, and dexamethasone) followed by lenalidomide maintenance until disease progression.
The secondary analysis included 645 patients from the original trial who were evaluable 56 days following autologous hematopoietic cell transplantation. The analysis looked at patients across all groups, but excluded those with progressive disease, and compared patients’ responses using traditional IMWG criteria, which includes 24-hour urine assessments, and urine-free criteria. Response measurements included complete response, very good partial response, partial response, and stable disease.
Patients were a median age of 56 years, 41% were female, 17% were Black, and 7% were Hispanic; 26% had light-chain only disease. About half (49%) had received lenalidomide alone, 28% had received post-autologous stem cell transplantation consolidation followed by lenalidomide, and 24% had received tandem transplantation followed by lenalidomide.
The analysis showed that “urine-free response criteria worked just fine in terms of their prognostic value,” Banerjee said while presenting the findings.
Specifically, the complete response rate was 29.4% using the traditional criteria vs 29.7% using the urine-free criteria. The very good partial response rate was 37.0% with the traditional approach vs 36.6% with the urine-free approach. The partial response rate was 30.7% for both and the stable disease rate was 3.0% for both.
Achieving a complete response based on the urine-free criteria was highly prognostic for progression-free survival (P = .005) while achieving a very good partial response by either criterion was borderline prognostic for progression-free survival (P = .102).
Only 1.1% of patients — seven patients altogether — had discordant responses between traditional and urine-free response criteria, Banerjee noted. One patient, for instance, was downgraded from a very good partial response with traditional criteria to a partial response with urine-free criteria “because current response criteria rate urine [as] more important than serum-free light chains,” Banerjee explained. Two other patients who met all other stringent criteria for a complete response but still had urine paraprotein at Day 56 were classified as having a very good partial response using traditional criteria but as a complete response with the urine-free criteria.
The other four patients with discordant results were the most important, Banerjee said. These patients were missing urine protein electrophoresis values, which made them non-evaluable using traditional criteria, but became evaluable when using urine-free criteria. “This is, I think, the bane of our existence, right? We ask our patients to put their blood, soul, sweat, and tears into being in a clinical trial, and then they’re not evaluable,” he said.
Overall, these results strongly support the de-emphasis of 24-hour urine requirements in updated IMWG response criteria, said Banerjee. However, he noted, 24-hour urine testing still has a very important place in the screening process and in patients with monoclonal gammopathy of renal significance or AL amyloidosis.
“This study provides reassurance to those of us already not repeating urine tests that urine testing is unnecessary for tracking responses,” said Manni Mohyuddin, MD, from the Multiple Myeloma Program at Huntsman Cancer Institute and assistant professor at the University of Utah, Salt Lake City. “These assessments aren’t done consistently in practice outside of trials anyway, and I hope that this study will lead to a formal change in criteria and the omission of urine assessments in clinical trials.”
Funding for the study was provided by the National Heart, Lung, and Blood Institute; National Cancer Institute; Alliance for Clinical Trials in Oncology; ECOG-ACRIN Cancer Research Group; and SWOG; and contributions were provided by Celgene and Millennium Pharmaceuticals. Banerjee has reported consulting for Adaptive Biotechnologies, Bristol-Myers Squibb, Caribou Biosciences, Genentech, GSK, Johnson & Johnson/Janssen, Karyopharm, Legend Biotech, Pfizer, Sanofi, and SparkCures, and receiving research funding from AbbVie, Johnson & Johnson, Novartis, Pack Health, Prothena, and Sanofi. Mohyuddin has disclosed no personal payments and no consultation for industry. His institution has received research funding from Janssen for his role as a principal investigator on a trial.
A version of this article first appeared on Medscape.com.
FROM ASH 2024
IVIG Prophylaxis in Multiple Myeloma Cuts Infections, Boosts Survival
Among 225 consecutive patients who received at least one treatment for relapsed and/or refractory multiple myeloma, those who received IVIG prophylaxis experienced a significantly longer duration of infection-free survival and an almost threefold longer median overall survival, compared with patients who did not receive IVIG prophylaxis.
IVIG supplementation has been shown to prevent severe infections in patients with multiple myeloma, but evidence on the best time to initiate IVIG prophylaxis among those receiving teclistamab remains less clear.
“Our institutional practice is to start IVIG about cycle 2 of therapy, which ended up being around 39 days,” but a key takeaway from the current findings is to “start IVIG within 30 days,” said lead investigator Heloise Cheruvalath, BA, a medical student at Medical College of Wisconsin, Milwaukee, who presented the findings.
The 225 patients included in the study had received at least one dose of standard-of-care teclistamab or an investigational B-cell maturation antigen (BCMA)–directed bispecific antibody (bsAb). IVIG was given as prophylaxis to 92 patients (41%) in the primary arm. The remaining 133 patients (59%) did not receive IVIG prophylaxis, but 29% received IVIG after a documented infection.
In total, there were 288 infections in 136 patients, and about 61% of infections required hospitalization. Median time to infection was 97 days, with the 12-month cumulative incidence of all-grade infections reaching 73% and the incidence of grade 3 or higher infections totaling 53%. Respiratory tract infections were the most common infection type, with COVID-19 accounting for 11% of cases, Cheruvalath noted.
Comparing patients who did and did not receive IVIG prophylaxis, median infection-free survival was significantly longer in the prophylaxis group — a median of 7.7 months vs 3 months — as was grade 3 or higher infection-free survival — a median of 14 months vs 7.5 months.
IVIG prophylaxis also led to a higher rate of 2-year progression free survival in the prophylaxis vs nonprophylaxis group — at 38% vs 32% — as well as longer median progression-free survival — at 15 months vs 8 months.
After multivariate analysis, IVIG prophylaxis was no longer significantly associated with improved progression-free survival.
However, median overall survival did remain significantly better in the IVIG prophylaxis than the nonprophylaxis group after multivariate analysis — 44 months vs 16 months. The presence of high-risk and extramedullary disease was independently associated with worse overall survival.
The effects of IVIG prophylaxis were stronger for bacterial infections at earlier (30 days or sooner) vs later (31 days or later) time points, but timing of IVIG therapy did not appear to affect the incidence of viral infections.
A study limitation was lack of randomization; IVIG prophylaxis was given at the physician’s discretion. In addition, multiple myeloma treatment was not standardized, with 15% of IVIG patients and 38% of non-IVIG patients receiving investigational BCMA bsAB.
“However, the majority of those who received primary IVIG prophylaxis were treated with standard-of-care teclistamab, making our results generalizable to current clinical practice,” Cheruvalath said.
Rahul Banerjee, MD, who was not involved with the research, noted he has already started providing routine IVIG prophylaxis based on earlier research from this group. “Before I did, my patients would often get very rare infections requiring protracted courses of antibiotics,” Banerjee, from Fred Hutch Cancer Center, University of Washington School of Medicine, Seattle, said in an interview. “Moving to IVIG before the infections start makes much more sense.”
Banerjee also commented that, in general, “the myeloma field has been moving from IV treatments to subcutaneous treatments to lower ‘time toxicity’ and IVIG is a notable exception to that trend, but perhaps it won’t be this way forever.”
Many patients with rheumatologic conditions receive subcutaneous immunoglobulin, in some cases, with kits they can self-administer at home, Banerjee said, and “I know some groups are starting to work on moving subcutaneous immunoglobulin to the oncologic setting.”
Funding was provided by the Advancing Healthier Wisconsin Endowment. Cheruvalath has reported no relevant disclosures. Banerjee has reported consulting for Adaptive Biotechnologies, Bristol Myers Squibb, Caribou Biosciences, Genentech, GSK, Johnson & Johnson/Janssen, Karyopharm, Legend Biotech, Pfizer, Sanofi, and SparkCures; and receiving research funding from AbbVie, Johnson & Johnson, Novartis, Pack Health, Prothena, and Sanofi.
A version of this article first appeared on Medscape.com.
Among 225 consecutive patients who received at least one treatment for relapsed and/or refractory multiple myeloma, those who received IVIG prophylaxis experienced a significantly longer duration of infection-free survival and an almost threefold longer median overall survival, compared with patients who did not receive IVIG prophylaxis.
IVIG supplementation has been shown to prevent severe infections in patients with multiple myeloma, but evidence on the best time to initiate IVIG prophylaxis among those receiving teclistamab remains less clear.
“Our institutional practice is to start IVIG about cycle 2 of therapy, which ended up being around 39 days,” but a key takeaway from the current findings is to “start IVIG within 30 days,” said lead investigator Heloise Cheruvalath, BA, a medical student at Medical College of Wisconsin, Milwaukee, who presented the findings.
The 225 patients included in the study had received at least one dose of standard-of-care teclistamab or an investigational B-cell maturation antigen (BCMA)–directed bispecific antibody (bsAb). IVIG was given as prophylaxis to 92 patients (41%) in the primary arm. The remaining 133 patients (59%) did not receive IVIG prophylaxis, but 29% received IVIG after a documented infection.
In total, there were 288 infections in 136 patients, and about 61% of infections required hospitalization. Median time to infection was 97 days, with the 12-month cumulative incidence of all-grade infections reaching 73% and the incidence of grade 3 or higher infections totaling 53%. Respiratory tract infections were the most common infection type, with COVID-19 accounting for 11% of cases, Cheruvalath noted.
Comparing patients who did and did not receive IVIG prophylaxis, median infection-free survival was significantly longer in the prophylaxis group — a median of 7.7 months vs 3 months — as was grade 3 or higher infection-free survival — a median of 14 months vs 7.5 months.
IVIG prophylaxis also led to a higher rate of 2-year progression free survival in the prophylaxis vs nonprophylaxis group — at 38% vs 32% — as well as longer median progression-free survival — at 15 months vs 8 months.
After multivariate analysis, IVIG prophylaxis was no longer significantly associated with improved progression-free survival.
However, median overall survival did remain significantly better in the IVIG prophylaxis than the nonprophylaxis group after multivariate analysis — 44 months vs 16 months. The presence of high-risk and extramedullary disease was independently associated with worse overall survival.
The effects of IVIG prophylaxis were stronger for bacterial infections at earlier (30 days or sooner) vs later (31 days or later) time points, but timing of IVIG therapy did not appear to affect the incidence of viral infections.
A study limitation was lack of randomization; IVIG prophylaxis was given at the physician’s discretion. In addition, multiple myeloma treatment was not standardized, with 15% of IVIG patients and 38% of non-IVIG patients receiving investigational BCMA bsAB.
“However, the majority of those who received primary IVIG prophylaxis were treated with standard-of-care teclistamab, making our results generalizable to current clinical practice,” Cheruvalath said.
Rahul Banerjee, MD, who was not involved with the research, noted he has already started providing routine IVIG prophylaxis based on earlier research from this group. “Before I did, my patients would often get very rare infections requiring protracted courses of antibiotics,” Banerjee, from Fred Hutch Cancer Center, University of Washington School of Medicine, Seattle, said in an interview. “Moving to IVIG before the infections start makes much more sense.”
Banerjee also commented that, in general, “the myeloma field has been moving from IV treatments to subcutaneous treatments to lower ‘time toxicity’ and IVIG is a notable exception to that trend, but perhaps it won’t be this way forever.”
Many patients with rheumatologic conditions receive subcutaneous immunoglobulin, in some cases, with kits they can self-administer at home, Banerjee said, and “I know some groups are starting to work on moving subcutaneous immunoglobulin to the oncologic setting.”
Funding was provided by the Advancing Healthier Wisconsin Endowment. Cheruvalath has reported no relevant disclosures. Banerjee has reported consulting for Adaptive Biotechnologies, Bristol Myers Squibb, Caribou Biosciences, Genentech, GSK, Johnson & Johnson/Janssen, Karyopharm, Legend Biotech, Pfizer, Sanofi, and SparkCures; and receiving research funding from AbbVie, Johnson & Johnson, Novartis, Pack Health, Prothena, and Sanofi.
A version of this article first appeared on Medscape.com.
Among 225 consecutive patients who received at least one treatment for relapsed and/or refractory multiple myeloma, those who received IVIG prophylaxis experienced a significantly longer duration of infection-free survival and an almost threefold longer median overall survival, compared with patients who did not receive IVIG prophylaxis.
IVIG supplementation has been shown to prevent severe infections in patients with multiple myeloma, but evidence on the best time to initiate IVIG prophylaxis among those receiving teclistamab remains less clear.
“Our institutional practice is to start IVIG about cycle 2 of therapy, which ended up being around 39 days,” but a key takeaway from the current findings is to “start IVIG within 30 days,” said lead investigator Heloise Cheruvalath, BA, a medical student at Medical College of Wisconsin, Milwaukee, who presented the findings.
The 225 patients included in the study had received at least one dose of standard-of-care teclistamab or an investigational B-cell maturation antigen (BCMA)–directed bispecific antibody (bsAb). IVIG was given as prophylaxis to 92 patients (41%) in the primary arm. The remaining 133 patients (59%) did not receive IVIG prophylaxis, but 29% received IVIG after a documented infection.
In total, there were 288 infections in 136 patients, and about 61% of infections required hospitalization. Median time to infection was 97 days, with the 12-month cumulative incidence of all-grade infections reaching 73% and the incidence of grade 3 or higher infections totaling 53%. Respiratory tract infections were the most common infection type, with COVID-19 accounting for 11% of cases, Cheruvalath noted.
Comparing patients who did and did not receive IVIG prophylaxis, median infection-free survival was significantly longer in the prophylaxis group — a median of 7.7 months vs 3 months — as was grade 3 or higher infection-free survival — a median of 14 months vs 7.5 months.
IVIG prophylaxis also led to a higher rate of 2-year progression free survival in the prophylaxis vs nonprophylaxis group — at 38% vs 32% — as well as longer median progression-free survival — at 15 months vs 8 months.
After multivariate analysis, IVIG prophylaxis was no longer significantly associated with improved progression-free survival.
However, median overall survival did remain significantly better in the IVIG prophylaxis than the nonprophylaxis group after multivariate analysis — 44 months vs 16 months. The presence of high-risk and extramedullary disease was independently associated with worse overall survival.
The effects of IVIG prophylaxis were stronger for bacterial infections at earlier (30 days or sooner) vs later (31 days or later) time points, but timing of IVIG therapy did not appear to affect the incidence of viral infections.
A study limitation was lack of randomization; IVIG prophylaxis was given at the physician’s discretion. In addition, multiple myeloma treatment was not standardized, with 15% of IVIG patients and 38% of non-IVIG patients receiving investigational BCMA bsAB.
“However, the majority of those who received primary IVIG prophylaxis were treated with standard-of-care teclistamab, making our results generalizable to current clinical practice,” Cheruvalath said.
Rahul Banerjee, MD, who was not involved with the research, noted he has already started providing routine IVIG prophylaxis based on earlier research from this group. “Before I did, my patients would often get very rare infections requiring protracted courses of antibiotics,” Banerjee, from Fred Hutch Cancer Center, University of Washington School of Medicine, Seattle, said in an interview. “Moving to IVIG before the infections start makes much more sense.”
Banerjee also commented that, in general, “the myeloma field has been moving from IV treatments to subcutaneous treatments to lower ‘time toxicity’ and IVIG is a notable exception to that trend, but perhaps it won’t be this way forever.”
Many patients with rheumatologic conditions receive subcutaneous immunoglobulin, in some cases, with kits they can self-administer at home, Banerjee said, and “I know some groups are starting to work on moving subcutaneous immunoglobulin to the oncologic setting.”
Funding was provided by the Advancing Healthier Wisconsin Endowment. Cheruvalath has reported no relevant disclosures. Banerjee has reported consulting for Adaptive Biotechnologies, Bristol Myers Squibb, Caribou Biosciences, Genentech, GSK, Johnson & Johnson/Janssen, Karyopharm, Legend Biotech, Pfizer, Sanofi, and SparkCures; and receiving research funding from AbbVie, Johnson & Johnson, Novartis, Pack Health, Prothena, and Sanofi.
A version of this article first appeared on Medscape.com.
FROM ASH 2024
LBCL: Bispecific Antibodies Fare Less Well in Real-World Analysis
In a presentation at the American Society of Hematology (ASH) 2024 Annual Meeting, researchers reported that of 172 patients treated with the drugs who had evaluable responses over a median follow-up of 5 months, median progression-free survival was 2.7 months (95% CI, 2.0-3.9) and median overall survival was 7.2 months (95% CI, 6.1–not reached).
It’s important to consider the real-world nature of the study’s patient population, said first author Taylor R. Brooks, MD, of Cleveland Clinic, Ohio, in an interview. “Compared to pivotal trials, our cohort was enriched for patients with high-risk features, with almost three quarters having some comorbidity that would’ve excluded them from one of the [earlier] studies.”
He added that “though individuals eligible to receive these medicines may be more sick with high-risk disease, a sizable fraction will respond, and some will maintain remissions.’”
According to Brooks, about one third of patients with diffuse LBCL relapse after standard front-line R-CHOP therapy. “The prognosis is poor for patients who are not candidates for aggressive salvage chemotherapy and for those who relapse after two or more lines,” Brooks said. “T cell–engaging bispecific antibodies have emerged as a promising option for patients with relapsed or refractory large B-cell lymphoma, given their favorable rates and duration of responses as well as their manageable rates of toxicities.”
The Food and Drug Administration (FDA) granted accelerated approval for epcoritamab and glofitamab in 2023.
“With increasing uptake into clinical practice following the FDA approvals, there is increasing interest in assessing the efficacy and safety of these drugs in real-world, nontrial settings,” Brooks said. “The goal of our study was to investigate outcomes and identify clinical factors associated with outcomes.”
The multicenter, retrospective, observational REALBiTE study tracked 209 patients with relapsed/refractory diffuse LBCL at 19 US centers (epcoritamab, n = 139; glofitamab, n = 70; median age at start of treatment, 67 years [58-76]; 62.2% male; 74.2% diffuse LBCL). The median number of lines of therapy was three (range, 1-12).
“Patients who received epcoritamab tended to be slightly older, were more likely to have a history of indolent non-Hodgkin lymphoma prior to their diagnosis of aggressive B-cell lymphoma and were more likely to have an elevated International Prognostic Index score at the start of bispecific therapy, suggesting that these patients may have been slightly older with higher-risk disease compared to those who received glofitamab,” Brooks said.
In total, 172 patients were response-evaluable. The overall response rate was 50.6% (complete response, 23.8%; partial response, 26.7%; stable disease, 5.8%; progressive disease, 43.6%).
The overall and complete response rates were “somewhat lower that what has been published in the pivotal trials of these medicines,” Brooks said. The low progression-free and overall survival rates “highlight the difficulty in managing this group of patients.”
Cytokine release syndrome (CRS) of any grade occurred in 39.2% of patients: 51% in the epcoritamab group and 28.6% in the glofitamab group. Grade ≥3 CRS occurred in 4.3% of patients, who were all taking epcoritamab.
“For epcoritamab, CRS was almost entirely of low grade, and most CRS events occurred around administration of the first full dose of the drug on day 15,” Brooks said. “Similarly, the CRS events for glofitamab were mostly of low grade, though events were observed to occur throughout the step-up dosing. Tocilizumab was administered in about one fifth of the patients.”
In addition, Brooks said, “we found that, among the 19 individuals with paired biopsy samples before and after bispecific therapy, nearly all — 89% — were found to have lost CD20 expression. We expected some patients to experience loss of this important target, but the rate at which we found this to be the case was surprisingly high.”
Brooks added that “clinicians should be acquainted with CRS, ICANS [immune effector cell-associated neurotoxicity syndrome], and mitigation strategies if they are prescribing these medicines. Appropriate and timely management using tocilizumab, steroids, and other adjunctive measures can effectively manage these complications and hopefully allow for the continued delivery of therapy.”
In an interview, Matthew Lunning, DO, associate professor at the University of Nebraska Medical Center/Fred & Pamela Buffett Cancer Center, Omaha, who didn’t take part in the new study, said the findings aren’t bad news. Instead, they’re “practical news,” because they offer insight into how the drugs work.
“The big lesson from this and other trials is the importance of assessing for CD20 expression prior to taking a bispecific off the shelf, “ he said. “These are learnings that often come after approval.”
He added that it’s clear that, “in more heavily pretreated patients, more disease led to less optimal results and higher risk for toxicities.”
Lunning also noted that both epcoritamab and glofitamab “entered into a crowded and chaotic relapsed/refractory LBCL space based high complete response rates with the opportunity for durability in those complete responses.”
Academic institutions were especially interested, as they can manage CRS and ICANS, but “significantly less enthusiasm has been seen in community practices that expect CRS/ICANS to be in the rear-view mirror if they are going to deliver any bispecific,” he said. “It is not that they don’t have the clinical acumen to manage CRS/ICANS. I believe it is the perception of the lack of supportive infrastructure necessary to manage these toxicities.”
There was no study funding. Brooks has reported no disclosures. Other authors have reported various disclosures including relationships with Novartis, AbbVie, Genentech, Genmab, Biogen, Amgen, and others. Lunning has disclosed ties with AbbVie, Genmab, Kite, Bristol-Myers Squibb, Regeneron, and ADC Therapeutics.
A version of this article first appeared on Medscape.com.
In a presentation at the American Society of Hematology (ASH) 2024 Annual Meeting, researchers reported that of 172 patients treated with the drugs who had evaluable responses over a median follow-up of 5 months, median progression-free survival was 2.7 months (95% CI, 2.0-3.9) and median overall survival was 7.2 months (95% CI, 6.1–not reached).
It’s important to consider the real-world nature of the study’s patient population, said first author Taylor R. Brooks, MD, of Cleveland Clinic, Ohio, in an interview. “Compared to pivotal trials, our cohort was enriched for patients with high-risk features, with almost three quarters having some comorbidity that would’ve excluded them from one of the [earlier] studies.”
He added that “though individuals eligible to receive these medicines may be more sick with high-risk disease, a sizable fraction will respond, and some will maintain remissions.’”
According to Brooks, about one third of patients with diffuse LBCL relapse after standard front-line R-CHOP therapy. “The prognosis is poor for patients who are not candidates for aggressive salvage chemotherapy and for those who relapse after two or more lines,” Brooks said. “T cell–engaging bispecific antibodies have emerged as a promising option for patients with relapsed or refractory large B-cell lymphoma, given their favorable rates and duration of responses as well as their manageable rates of toxicities.”
The Food and Drug Administration (FDA) granted accelerated approval for epcoritamab and glofitamab in 2023.
“With increasing uptake into clinical practice following the FDA approvals, there is increasing interest in assessing the efficacy and safety of these drugs in real-world, nontrial settings,” Brooks said. “The goal of our study was to investigate outcomes and identify clinical factors associated with outcomes.”
The multicenter, retrospective, observational REALBiTE study tracked 209 patients with relapsed/refractory diffuse LBCL at 19 US centers (epcoritamab, n = 139; glofitamab, n = 70; median age at start of treatment, 67 years [58-76]; 62.2% male; 74.2% diffuse LBCL). The median number of lines of therapy was three (range, 1-12).
“Patients who received epcoritamab tended to be slightly older, were more likely to have a history of indolent non-Hodgkin lymphoma prior to their diagnosis of aggressive B-cell lymphoma and were more likely to have an elevated International Prognostic Index score at the start of bispecific therapy, suggesting that these patients may have been slightly older with higher-risk disease compared to those who received glofitamab,” Brooks said.
In total, 172 patients were response-evaluable. The overall response rate was 50.6% (complete response, 23.8%; partial response, 26.7%; stable disease, 5.8%; progressive disease, 43.6%).
The overall and complete response rates were “somewhat lower that what has been published in the pivotal trials of these medicines,” Brooks said. The low progression-free and overall survival rates “highlight the difficulty in managing this group of patients.”
Cytokine release syndrome (CRS) of any grade occurred in 39.2% of patients: 51% in the epcoritamab group and 28.6% in the glofitamab group. Grade ≥3 CRS occurred in 4.3% of patients, who were all taking epcoritamab.
“For epcoritamab, CRS was almost entirely of low grade, and most CRS events occurred around administration of the first full dose of the drug on day 15,” Brooks said. “Similarly, the CRS events for glofitamab were mostly of low grade, though events were observed to occur throughout the step-up dosing. Tocilizumab was administered in about one fifth of the patients.”
In addition, Brooks said, “we found that, among the 19 individuals with paired biopsy samples before and after bispecific therapy, nearly all — 89% — were found to have lost CD20 expression. We expected some patients to experience loss of this important target, but the rate at which we found this to be the case was surprisingly high.”
Brooks added that “clinicians should be acquainted with CRS, ICANS [immune effector cell-associated neurotoxicity syndrome], and mitigation strategies if they are prescribing these medicines. Appropriate and timely management using tocilizumab, steroids, and other adjunctive measures can effectively manage these complications and hopefully allow for the continued delivery of therapy.”
In an interview, Matthew Lunning, DO, associate professor at the University of Nebraska Medical Center/Fred & Pamela Buffett Cancer Center, Omaha, who didn’t take part in the new study, said the findings aren’t bad news. Instead, they’re “practical news,” because they offer insight into how the drugs work.
“The big lesson from this and other trials is the importance of assessing for CD20 expression prior to taking a bispecific off the shelf, “ he said. “These are learnings that often come after approval.”
He added that it’s clear that, “in more heavily pretreated patients, more disease led to less optimal results and higher risk for toxicities.”
Lunning also noted that both epcoritamab and glofitamab “entered into a crowded and chaotic relapsed/refractory LBCL space based high complete response rates with the opportunity for durability in those complete responses.”
Academic institutions were especially interested, as they can manage CRS and ICANS, but “significantly less enthusiasm has been seen in community practices that expect CRS/ICANS to be in the rear-view mirror if they are going to deliver any bispecific,” he said. “It is not that they don’t have the clinical acumen to manage CRS/ICANS. I believe it is the perception of the lack of supportive infrastructure necessary to manage these toxicities.”
There was no study funding. Brooks has reported no disclosures. Other authors have reported various disclosures including relationships with Novartis, AbbVie, Genentech, Genmab, Biogen, Amgen, and others. Lunning has disclosed ties with AbbVie, Genmab, Kite, Bristol-Myers Squibb, Regeneron, and ADC Therapeutics.
A version of this article first appeared on Medscape.com.
In a presentation at the American Society of Hematology (ASH) 2024 Annual Meeting, researchers reported that of 172 patients treated with the drugs who had evaluable responses over a median follow-up of 5 months, median progression-free survival was 2.7 months (95% CI, 2.0-3.9) and median overall survival was 7.2 months (95% CI, 6.1–not reached).
It’s important to consider the real-world nature of the study’s patient population, said first author Taylor R. Brooks, MD, of Cleveland Clinic, Ohio, in an interview. “Compared to pivotal trials, our cohort was enriched for patients with high-risk features, with almost three quarters having some comorbidity that would’ve excluded them from one of the [earlier] studies.”
He added that “though individuals eligible to receive these medicines may be more sick with high-risk disease, a sizable fraction will respond, and some will maintain remissions.’”
According to Brooks, about one third of patients with diffuse LBCL relapse after standard front-line R-CHOP therapy. “The prognosis is poor for patients who are not candidates for aggressive salvage chemotherapy and for those who relapse after two or more lines,” Brooks said. “T cell–engaging bispecific antibodies have emerged as a promising option for patients with relapsed or refractory large B-cell lymphoma, given their favorable rates and duration of responses as well as their manageable rates of toxicities.”
The Food and Drug Administration (FDA) granted accelerated approval for epcoritamab and glofitamab in 2023.
“With increasing uptake into clinical practice following the FDA approvals, there is increasing interest in assessing the efficacy and safety of these drugs in real-world, nontrial settings,” Brooks said. “The goal of our study was to investigate outcomes and identify clinical factors associated with outcomes.”
The multicenter, retrospective, observational REALBiTE study tracked 209 patients with relapsed/refractory diffuse LBCL at 19 US centers (epcoritamab, n = 139; glofitamab, n = 70; median age at start of treatment, 67 years [58-76]; 62.2% male; 74.2% diffuse LBCL). The median number of lines of therapy was three (range, 1-12).
“Patients who received epcoritamab tended to be slightly older, were more likely to have a history of indolent non-Hodgkin lymphoma prior to their diagnosis of aggressive B-cell lymphoma and were more likely to have an elevated International Prognostic Index score at the start of bispecific therapy, suggesting that these patients may have been slightly older with higher-risk disease compared to those who received glofitamab,” Brooks said.
In total, 172 patients were response-evaluable. The overall response rate was 50.6% (complete response, 23.8%; partial response, 26.7%; stable disease, 5.8%; progressive disease, 43.6%).
The overall and complete response rates were “somewhat lower that what has been published in the pivotal trials of these medicines,” Brooks said. The low progression-free and overall survival rates “highlight the difficulty in managing this group of patients.”
Cytokine release syndrome (CRS) of any grade occurred in 39.2% of patients: 51% in the epcoritamab group and 28.6% in the glofitamab group. Grade ≥3 CRS occurred in 4.3% of patients, who were all taking epcoritamab.
“For epcoritamab, CRS was almost entirely of low grade, and most CRS events occurred around administration of the first full dose of the drug on day 15,” Brooks said. “Similarly, the CRS events for glofitamab were mostly of low grade, though events were observed to occur throughout the step-up dosing. Tocilizumab was administered in about one fifth of the patients.”
In addition, Brooks said, “we found that, among the 19 individuals with paired biopsy samples before and after bispecific therapy, nearly all — 89% — were found to have lost CD20 expression. We expected some patients to experience loss of this important target, but the rate at which we found this to be the case was surprisingly high.”
Brooks added that “clinicians should be acquainted with CRS, ICANS [immune effector cell-associated neurotoxicity syndrome], and mitigation strategies if they are prescribing these medicines. Appropriate and timely management using tocilizumab, steroids, and other adjunctive measures can effectively manage these complications and hopefully allow for the continued delivery of therapy.”
In an interview, Matthew Lunning, DO, associate professor at the University of Nebraska Medical Center/Fred & Pamela Buffett Cancer Center, Omaha, who didn’t take part in the new study, said the findings aren’t bad news. Instead, they’re “practical news,” because they offer insight into how the drugs work.
“The big lesson from this and other trials is the importance of assessing for CD20 expression prior to taking a bispecific off the shelf, “ he said. “These are learnings that often come after approval.”
He added that it’s clear that, “in more heavily pretreated patients, more disease led to less optimal results and higher risk for toxicities.”
Lunning also noted that both epcoritamab and glofitamab “entered into a crowded and chaotic relapsed/refractory LBCL space based high complete response rates with the opportunity for durability in those complete responses.”
Academic institutions were especially interested, as they can manage CRS and ICANS, but “significantly less enthusiasm has been seen in community practices that expect CRS/ICANS to be in the rear-view mirror if they are going to deliver any bispecific,” he said. “It is not that they don’t have the clinical acumen to manage CRS/ICANS. I believe it is the perception of the lack of supportive infrastructure necessary to manage these toxicities.”
There was no study funding. Brooks has reported no disclosures. Other authors have reported various disclosures including relationships with Novartis, AbbVie, Genentech, Genmab, Biogen, Amgen, and others. Lunning has disclosed ties with AbbVie, Genmab, Kite, Bristol-Myers Squibb, Regeneron, and ADC Therapeutics.
A version of this article first appeared on Medscape.com.
FROM ASH 2024
ASH 2024: New Leukemia Txs, Fewer Blood Clots With GLP-1 Rxs
Children’s Disorders: Major Progress in B-Cell Acute Lymphoblastic Leukemia (B-ALL), Immune Thrombocytopenic Purpura (ITP)
While B-ALL is the most common childhood cancer and one of the most treatable, some patients face grim outcomes after they relapse following chemotherapy, said Cynthia E. Dunbar, MD, chief of the Translational Stem Cell Biology Branch at the National Heart, Lung, and Blood Institute.
A new study reports that adding the targeted cancer drug blinatumomab (Blincyto) to chemotherapy boosted disease-free survival in standard-risk pediatric patients. “They definitively demonstrate a benefit with the addition of this immunotherapeutic drug, achieving 97% disease-free survival at 3 years on the blinatumomab plus chemotherapy arm compared to 90% for the control arm with standard therapies alone,” Dunbar said. “This trial will establish the addition of blinatumomab for childhood B-ALL as standard of care.”
A reporter asked Dunbar about the risk for severe immune activation syndrome. “These immune cell engagers can result in cytokine release syndrome and other severe immune activation consequences,” she said. “However, it appears that children seem to be less susceptible to those, at least in terms of severity, than adults. In this study, the complications that occurred didn’t result in mortality and were easily treatable. So that was not a major drawback to the addition of this drug.”
The blinatumomab study is sponsored by Children’s Oncology Group.
In ITP, thrombopoietin (TPO) agonists such as eltrombopag (Promacta) are a mainstay of second- or third-line treatment in children and adults with severe cases, Dunbar said. “However, TPO agonists are generally only given after months to years of failures of corticosteroids, IVIG [intravenous immunoglobulin], or splenectomy.”
In the phase 3, randomized, controlled PINES trial, researchers explored whether the drug could improve outcomes in children with untreated or very recent-onset severe ITP vs standard of care.
“The children treated with eltrombopag had double the response rate with a much lower need for rescue therapies,” Dunbar said. The percentage of patients who received rescue therapy was 19% in the eltrombopag arm (15/78) vs 46% in the control arm (18/39, P = .002).
“Given the potential short- and long-term consequences of corticosteroids and other standard treatments in children, this study is encouraging and will likely result in a change in the standard of care for pediatric ITP,” Dunbar said.
The eltrombopag study is sponsored by the ITP Consortium of North America and funded by Novartis.
Fewer Blood Clots: Another Big Benefit for Weight Loss Drugs?
Mikkael A. Sekeres, MD, MS, of the Sylvester Comprehensive Cancer Center at the University of Miami in Florida, highlighted an analysis of whether GLP-1 receptor agonists, initially approved as type 2 diabetes treatments, affect the risk for VTE.
Researchers tracked patients with type 2 diabetes — 366,369 who received the drugs and 290,219 who took dipeptidyl peptidase 4 inhibitors. The patients who took GLP-1 agonists “had lower rates of venous thromboembolic events after 1 year,” Sekeres said. “The risk reduction was actually pretty substantial.”
In these patients, the risk for VTE was 18% lower (hazard ratio [HR], 0.82; 95% CI, 0.77-0.88), and there were 22% and 15% reductions in pulmonary embolisms and deep venous thrombosis, respectively (HR, 0.78; 95% CI, 0.71-0.86 and HR, 0.85; 95% CI, 0.79-0.92).
Drug Regimen Improves Outcomes in Chronic Lymphocytic Leukemia (CLL)
An interim analysis of an open-label, randomized, phase 3 trial of patients with untreated CLL “demonstrated superior progression-free survival with acalabrutinib and venetoclax versus what we consider more classic chemotherapy of fludarabine, Cytoxan [cyclophosphamide], and rituximab or bendamustine and rituximab,” Sekeres said. “Similar findings were seen with acalabrutinib, venetoclax, and obinutuzumab vs that classic chemotherapy.”
Overall response rates were 93% for both the acalabrutinib/venetoclax regimens vs 75% for bendamustine/rituximab, Sekeres noted, and overall survival was higher for acalabrutinib/venetoclax vs the two classic chemotherapy regimens (HR, 0.33; P < .0001).
However, Sekeres questioned the value of comparing acalabrutinib/venetoclax with classical chemotherapy regimens. “A lot of times we have a lot of new, really good, really effective therapy to offer to patients that isn’t as toxic as previous chemotherapy.”
In contrast, fludarabine, cyclophosphamide, and rituximab are “your grandmother’s or your grandfather’s chemotherapy. It’s pretty toxic stuff,” he said.
Sekeres said it would have been better to compare acalabrutinib/venetoclax with a Bruton tyrosine kinase inhibitor–based regimen.
The German CLL Study Group is listed as the trial’s sponsor, and AstraZeneca is a collaborator. Dunbar disclosed research funding from Novartis. Sekeres had no relevant disclosures.
A version of this article appeared on Medscape.com.
Children’s Disorders: Major Progress in B-Cell Acute Lymphoblastic Leukemia (B-ALL), Immune Thrombocytopenic Purpura (ITP)
While B-ALL is the most common childhood cancer and one of the most treatable, some patients face grim outcomes after they relapse following chemotherapy, said Cynthia E. Dunbar, MD, chief of the Translational Stem Cell Biology Branch at the National Heart, Lung, and Blood Institute.
A new study reports that adding the targeted cancer drug blinatumomab (Blincyto) to chemotherapy boosted disease-free survival in standard-risk pediatric patients. “They definitively demonstrate a benefit with the addition of this immunotherapeutic drug, achieving 97% disease-free survival at 3 years on the blinatumomab plus chemotherapy arm compared to 90% for the control arm with standard therapies alone,” Dunbar said. “This trial will establish the addition of blinatumomab for childhood B-ALL as standard of care.”
A reporter asked Dunbar about the risk for severe immune activation syndrome. “These immune cell engagers can result in cytokine release syndrome and other severe immune activation consequences,” she said. “However, it appears that children seem to be less susceptible to those, at least in terms of severity, than adults. In this study, the complications that occurred didn’t result in mortality and were easily treatable. So that was not a major drawback to the addition of this drug.”
The blinatumomab study is sponsored by Children’s Oncology Group.
In ITP, thrombopoietin (TPO) agonists such as eltrombopag (Promacta) are a mainstay of second- or third-line treatment in children and adults with severe cases, Dunbar said. “However, TPO agonists are generally only given after months to years of failures of corticosteroids, IVIG [intravenous immunoglobulin], or splenectomy.”
In the phase 3, randomized, controlled PINES trial, researchers explored whether the drug could improve outcomes in children with untreated or very recent-onset severe ITP vs standard of care.
“The children treated with eltrombopag had double the response rate with a much lower need for rescue therapies,” Dunbar said. The percentage of patients who received rescue therapy was 19% in the eltrombopag arm (15/78) vs 46% in the control arm (18/39, P = .002).
“Given the potential short- and long-term consequences of corticosteroids and other standard treatments in children, this study is encouraging and will likely result in a change in the standard of care for pediatric ITP,” Dunbar said.
The eltrombopag study is sponsored by the ITP Consortium of North America and funded by Novartis.
Fewer Blood Clots: Another Big Benefit for Weight Loss Drugs?
Mikkael A. Sekeres, MD, MS, of the Sylvester Comprehensive Cancer Center at the University of Miami in Florida, highlighted an analysis of whether GLP-1 receptor agonists, initially approved as type 2 diabetes treatments, affect the risk for VTE.
Researchers tracked patients with type 2 diabetes — 366,369 who received the drugs and 290,219 who took dipeptidyl peptidase 4 inhibitors. The patients who took GLP-1 agonists “had lower rates of venous thromboembolic events after 1 year,” Sekeres said. “The risk reduction was actually pretty substantial.”
In these patients, the risk for VTE was 18% lower (hazard ratio [HR], 0.82; 95% CI, 0.77-0.88), and there were 22% and 15% reductions in pulmonary embolisms and deep venous thrombosis, respectively (HR, 0.78; 95% CI, 0.71-0.86 and HR, 0.85; 95% CI, 0.79-0.92).
Drug Regimen Improves Outcomes in Chronic Lymphocytic Leukemia (CLL)
An interim analysis of an open-label, randomized, phase 3 trial of patients with untreated CLL “demonstrated superior progression-free survival with acalabrutinib and venetoclax versus what we consider more classic chemotherapy of fludarabine, Cytoxan [cyclophosphamide], and rituximab or bendamustine and rituximab,” Sekeres said. “Similar findings were seen with acalabrutinib, venetoclax, and obinutuzumab vs that classic chemotherapy.”
Overall response rates were 93% for both the acalabrutinib/venetoclax regimens vs 75% for bendamustine/rituximab, Sekeres noted, and overall survival was higher for acalabrutinib/venetoclax vs the two classic chemotherapy regimens (HR, 0.33; P < .0001).
However, Sekeres questioned the value of comparing acalabrutinib/venetoclax with classical chemotherapy regimens. “A lot of times we have a lot of new, really good, really effective therapy to offer to patients that isn’t as toxic as previous chemotherapy.”
In contrast, fludarabine, cyclophosphamide, and rituximab are “your grandmother’s or your grandfather’s chemotherapy. It’s pretty toxic stuff,” he said.
Sekeres said it would have been better to compare acalabrutinib/venetoclax with a Bruton tyrosine kinase inhibitor–based regimen.
The German CLL Study Group is listed as the trial’s sponsor, and AstraZeneca is a collaborator. Dunbar disclosed research funding from Novartis. Sekeres had no relevant disclosures.
A version of this article appeared on Medscape.com.
Children’s Disorders: Major Progress in B-Cell Acute Lymphoblastic Leukemia (B-ALL), Immune Thrombocytopenic Purpura (ITP)
While B-ALL is the most common childhood cancer and one of the most treatable, some patients face grim outcomes after they relapse following chemotherapy, said Cynthia E. Dunbar, MD, chief of the Translational Stem Cell Biology Branch at the National Heart, Lung, and Blood Institute.
A new study reports that adding the targeted cancer drug blinatumomab (Blincyto) to chemotherapy boosted disease-free survival in standard-risk pediatric patients. “They definitively demonstrate a benefit with the addition of this immunotherapeutic drug, achieving 97% disease-free survival at 3 years on the blinatumomab plus chemotherapy arm compared to 90% for the control arm with standard therapies alone,” Dunbar said. “This trial will establish the addition of blinatumomab for childhood B-ALL as standard of care.”
A reporter asked Dunbar about the risk for severe immune activation syndrome. “These immune cell engagers can result in cytokine release syndrome and other severe immune activation consequences,” she said. “However, it appears that children seem to be less susceptible to those, at least in terms of severity, than adults. In this study, the complications that occurred didn’t result in mortality and were easily treatable. So that was not a major drawback to the addition of this drug.”
The blinatumomab study is sponsored by Children’s Oncology Group.
In ITP, thrombopoietin (TPO) agonists such as eltrombopag (Promacta) are a mainstay of second- or third-line treatment in children and adults with severe cases, Dunbar said. “However, TPO agonists are generally only given after months to years of failures of corticosteroids, IVIG [intravenous immunoglobulin], or splenectomy.”
In the phase 3, randomized, controlled PINES trial, researchers explored whether the drug could improve outcomes in children with untreated or very recent-onset severe ITP vs standard of care.
“The children treated with eltrombopag had double the response rate with a much lower need for rescue therapies,” Dunbar said. The percentage of patients who received rescue therapy was 19% in the eltrombopag arm (15/78) vs 46% in the control arm (18/39, P = .002).
“Given the potential short- and long-term consequences of corticosteroids and other standard treatments in children, this study is encouraging and will likely result in a change in the standard of care for pediatric ITP,” Dunbar said.
The eltrombopag study is sponsored by the ITP Consortium of North America and funded by Novartis.
Fewer Blood Clots: Another Big Benefit for Weight Loss Drugs?
Mikkael A. Sekeres, MD, MS, of the Sylvester Comprehensive Cancer Center at the University of Miami in Florida, highlighted an analysis of whether GLP-1 receptor agonists, initially approved as type 2 diabetes treatments, affect the risk for VTE.
Researchers tracked patients with type 2 diabetes — 366,369 who received the drugs and 290,219 who took dipeptidyl peptidase 4 inhibitors. The patients who took GLP-1 agonists “had lower rates of venous thromboembolic events after 1 year,” Sekeres said. “The risk reduction was actually pretty substantial.”
In these patients, the risk for VTE was 18% lower (hazard ratio [HR], 0.82; 95% CI, 0.77-0.88), and there were 22% and 15% reductions in pulmonary embolisms and deep venous thrombosis, respectively (HR, 0.78; 95% CI, 0.71-0.86 and HR, 0.85; 95% CI, 0.79-0.92).
Drug Regimen Improves Outcomes in Chronic Lymphocytic Leukemia (CLL)
An interim analysis of an open-label, randomized, phase 3 trial of patients with untreated CLL “demonstrated superior progression-free survival with acalabrutinib and venetoclax versus what we consider more classic chemotherapy of fludarabine, Cytoxan [cyclophosphamide], and rituximab or bendamustine and rituximab,” Sekeres said. “Similar findings were seen with acalabrutinib, venetoclax, and obinutuzumab vs that classic chemotherapy.”
Overall response rates were 93% for both the acalabrutinib/venetoclax regimens vs 75% for bendamustine/rituximab, Sekeres noted, and overall survival was higher for acalabrutinib/venetoclax vs the two classic chemotherapy regimens (HR, 0.33; P < .0001).
However, Sekeres questioned the value of comparing acalabrutinib/venetoclax with classical chemotherapy regimens. “A lot of times we have a lot of new, really good, really effective therapy to offer to patients that isn’t as toxic as previous chemotherapy.”
In contrast, fludarabine, cyclophosphamide, and rituximab are “your grandmother’s or your grandfather’s chemotherapy. It’s pretty toxic stuff,” he said.
Sekeres said it would have been better to compare acalabrutinib/venetoclax with a Bruton tyrosine kinase inhibitor–based regimen.
The German CLL Study Group is listed as the trial’s sponsor, and AstraZeneca is a collaborator. Dunbar disclosed research funding from Novartis. Sekeres had no relevant disclosures.
A version of this article appeared on Medscape.com.
FROM ASH 2024
Human Milk Boosts Intestinal Growth, Immune Health of Fetal Organoids
These findings suggest an important role for human milk in supporting intestinal health, and may inform strategies for reducing the risk of necrotizing enterocolitis (NEC) in preterm infants, lead author Lauren Smith, MD, of Yale School of Medicine, New Haven, Connecticut, and colleagues, reported.
“Compelling evidence has revealed that the largest risk factor for NEC apart from prematurity is formula feeding, while conversely, parental milk (PM) confers protection, with a 6- to 10-fold lower incidence of NEC among PM-fed infants compared to formula,” the investigators wrote in Gastro Hep Advances. “It is unknown whether this is due to the many known protective factors in PM or as a result of an injurious component present in formula or a combination of both.”
To learn more, the investigators studied organoids cultured in a three-dimensional matrix and exposed to one of four dietary conditions: PM, donor human milk (DHM), standard formula (SF), or extensively hydrolyzed formula (HF). Organoids were grown in growth media supplemented with these diets for 5 days, followed by differentiation media for an additional 5 days. Growth, differentiation, and immune-related factors were analyzed using advanced imaging, RNA sequencing, and cytokine profiling.
The results demonstrated that human milk–fed organoids significantly outperformed formula-fed organoids in several measures. By the fifth day of growth media exposure, organoids supplemented with PM or DHM were larger and exhibited higher rates of proliferation, as evidenced by Ki67 staining. Organoids exposed to SF were the smallest and had the lowest proliferation and highest levels of apoptosis, while HF-fed organoids showed intermediate growth performance.
During the differentiation phase, organoids exposed to human milk developed more complex structures, forming buds with greater length and diameter compared to formula-fed organoids. PM was particularly effective, though DHM also promoted substantial differentiation. RNA sequencing revealed that organoids cultured with human milk upregulated genes involved in fatty acid metabolism and Wnt signaling, which are critical for cellular energy production and epithelial proliferation. In contrast, formula-fed organoids exhibited downregulation of cell-cycle-promoting genes and showed an inflammatory gene signature.
Cytokine profiling further underscored the benefits of human milk. Organoids exposed to PM and DHM secreted higher levels of immune-regulating cytokines, such as thymic stromal lymphopoietin (TSLP) and macrophage colony-stimulating factor (M-CSF). In contrast, formula-fed organoids produced lower levels of these beneficial cytokines and higher levels of pro-inflammatory markers, including interleukin-18 (IL-18).
These findings suggest that human milk supports intestinal growth, differentiation, and immune regulation in ways that formula does not, and the investigators emphasized the importance of identifying specific bioactive factors in human milk.
“If the factors responsible for this effect can be identified, there could be significant clinical value in supplementing these components in DHM and formula to help prevent NEC and foster normal intestinal development in preterm infants,” they concluded.
Future research will aim to isolate and supplement key components of human milk to enhance the nutritional and protective value of donor milk and formula. In addition, the investigators noted the need to explore potential sex-based differences in intestinal development, as the current study used only male-derived samples.The research was supported by the Yale School of Medicine Medical Student Research Fellowship. The investigators disclosed no conflicts of interest.
These findings suggest an important role for human milk in supporting intestinal health, and may inform strategies for reducing the risk of necrotizing enterocolitis (NEC) in preterm infants, lead author Lauren Smith, MD, of Yale School of Medicine, New Haven, Connecticut, and colleagues, reported.
“Compelling evidence has revealed that the largest risk factor for NEC apart from prematurity is formula feeding, while conversely, parental milk (PM) confers protection, with a 6- to 10-fold lower incidence of NEC among PM-fed infants compared to formula,” the investigators wrote in Gastro Hep Advances. “It is unknown whether this is due to the many known protective factors in PM or as a result of an injurious component present in formula or a combination of both.”
To learn more, the investigators studied organoids cultured in a three-dimensional matrix and exposed to one of four dietary conditions: PM, donor human milk (DHM), standard formula (SF), or extensively hydrolyzed formula (HF). Organoids were grown in growth media supplemented with these diets for 5 days, followed by differentiation media for an additional 5 days. Growth, differentiation, and immune-related factors were analyzed using advanced imaging, RNA sequencing, and cytokine profiling.
The results demonstrated that human milk–fed organoids significantly outperformed formula-fed organoids in several measures. By the fifth day of growth media exposure, organoids supplemented with PM or DHM were larger and exhibited higher rates of proliferation, as evidenced by Ki67 staining. Organoids exposed to SF were the smallest and had the lowest proliferation and highest levels of apoptosis, while HF-fed organoids showed intermediate growth performance.
During the differentiation phase, organoids exposed to human milk developed more complex structures, forming buds with greater length and diameter compared to formula-fed organoids. PM was particularly effective, though DHM also promoted substantial differentiation. RNA sequencing revealed that organoids cultured with human milk upregulated genes involved in fatty acid metabolism and Wnt signaling, which are critical for cellular energy production and epithelial proliferation. In contrast, formula-fed organoids exhibited downregulation of cell-cycle-promoting genes and showed an inflammatory gene signature.
Cytokine profiling further underscored the benefits of human milk. Organoids exposed to PM and DHM secreted higher levels of immune-regulating cytokines, such as thymic stromal lymphopoietin (TSLP) and macrophage colony-stimulating factor (M-CSF). In contrast, formula-fed organoids produced lower levels of these beneficial cytokines and higher levels of pro-inflammatory markers, including interleukin-18 (IL-18).
These findings suggest that human milk supports intestinal growth, differentiation, and immune regulation in ways that formula does not, and the investigators emphasized the importance of identifying specific bioactive factors in human milk.
“If the factors responsible for this effect can be identified, there could be significant clinical value in supplementing these components in DHM and formula to help prevent NEC and foster normal intestinal development in preterm infants,” they concluded.
Future research will aim to isolate and supplement key components of human milk to enhance the nutritional and protective value of donor milk and formula. In addition, the investigators noted the need to explore potential sex-based differences in intestinal development, as the current study used only male-derived samples.The research was supported by the Yale School of Medicine Medical Student Research Fellowship. The investigators disclosed no conflicts of interest.
These findings suggest an important role for human milk in supporting intestinal health, and may inform strategies for reducing the risk of necrotizing enterocolitis (NEC) in preterm infants, lead author Lauren Smith, MD, of Yale School of Medicine, New Haven, Connecticut, and colleagues, reported.
“Compelling evidence has revealed that the largest risk factor for NEC apart from prematurity is formula feeding, while conversely, parental milk (PM) confers protection, with a 6- to 10-fold lower incidence of NEC among PM-fed infants compared to formula,” the investigators wrote in Gastro Hep Advances. “It is unknown whether this is due to the many known protective factors in PM or as a result of an injurious component present in formula or a combination of both.”
To learn more, the investigators studied organoids cultured in a three-dimensional matrix and exposed to one of four dietary conditions: PM, donor human milk (DHM), standard formula (SF), or extensively hydrolyzed formula (HF). Organoids were grown in growth media supplemented with these diets for 5 days, followed by differentiation media for an additional 5 days. Growth, differentiation, and immune-related factors were analyzed using advanced imaging, RNA sequencing, and cytokine profiling.
The results demonstrated that human milk–fed organoids significantly outperformed formula-fed organoids in several measures. By the fifth day of growth media exposure, organoids supplemented with PM or DHM were larger and exhibited higher rates of proliferation, as evidenced by Ki67 staining. Organoids exposed to SF were the smallest and had the lowest proliferation and highest levels of apoptosis, while HF-fed organoids showed intermediate growth performance.
During the differentiation phase, organoids exposed to human milk developed more complex structures, forming buds with greater length and diameter compared to formula-fed organoids. PM was particularly effective, though DHM also promoted substantial differentiation. RNA sequencing revealed that organoids cultured with human milk upregulated genes involved in fatty acid metabolism and Wnt signaling, which are critical for cellular energy production and epithelial proliferation. In contrast, formula-fed organoids exhibited downregulation of cell-cycle-promoting genes and showed an inflammatory gene signature.
Cytokine profiling further underscored the benefits of human milk. Organoids exposed to PM and DHM secreted higher levels of immune-regulating cytokines, such as thymic stromal lymphopoietin (TSLP) and macrophage colony-stimulating factor (M-CSF). In contrast, formula-fed organoids produced lower levels of these beneficial cytokines and higher levels of pro-inflammatory markers, including interleukin-18 (IL-18).
These findings suggest that human milk supports intestinal growth, differentiation, and immune regulation in ways that formula does not, and the investigators emphasized the importance of identifying specific bioactive factors in human milk.
“If the factors responsible for this effect can be identified, there could be significant clinical value in supplementing these components in DHM and formula to help prevent NEC and foster normal intestinal development in preterm infants,” they concluded.
Future research will aim to isolate and supplement key components of human milk to enhance the nutritional and protective value of donor milk and formula. In addition, the investigators noted the need to explore potential sex-based differences in intestinal development, as the current study used only male-derived samples.The research was supported by the Yale School of Medicine Medical Student Research Fellowship. The investigators disclosed no conflicts of interest.
FROM GASTRO HEP ADVANCES
Biomarkers Predict Villous Atrophy in Potential Celiac Disease Patients
according to investigators.
Given that PCD patients present with positive serology and intact duodenal architecture, these findings may provide a much-needed tool for identifying patients who are more likely to benefit from early dietary interventions, lead author Renata Auricchio, MD, PhD, of the University of Naples Federico II, Italy, and colleagues reported.
“PCD offers the unique opportunity to observe the progression of gluten-induced tissue damage in celiac disease,” the investigators wrote in Gastroenterology. “These patients recognize gluten and produce specific autoantibodies, but have not developed intestinal damage.”
The study included 31 children with asymptomatic PCD who were eating a gluten-containing diet. Serum samples from each child were analyzed for the relative abundance of 92 inflammation-linked proteins using a proximity extension immunoassay. Statistical analyses, including partial least squares discriminant and linear discriminant analyses, were then applied to identify which proteins were associated with the development of VA.
After a mean follow-up period of 5.85 years, 14 participants developed VA (ie, celiac disease), while the remaining 17 remained asymptomatic.
Panel analysis revealed that specific inflammatory proteins, including interleukin (IL)–20, IL-2, sirtuin 2 (SIRT2), leukemia inhibitory factor (LIF), IL-22 receptor subunit a1, cystatin D (CST5), IL-17 receptor A, IL-15 receptor subunit a (RA), CUB domain–containing protein 1 (CDCP1), and IL-14, were 1.23- to 1.76-fold higher in children who developed VA. Among these, seven proteins — CDCP1, IL-2, LIF, IL10RA, SIRT2, CST5, and IL-4 — were able to significantly distinguish between symptomatic and asymptomatic cases in a linear discriminant model. This panel of seven proteins achieved a predictive accuracy of 96.8% in identifying children at risk of VA.
Additionally, bioinformatics pathway analysis confirmed that the broader set of proteins is involved in the positive regulation of JAK-STAT signaling (involving IL-22 receptor subunit a1, IL-4, IL-20, IL10RA, LIF, and IL-2), inflammatory responses (IL-4, IL-20, LIF, and IL-2), and processes such as tyrosine phosphorylation, leukocyte differentiation, IgG isotype switching, and protein phosphorylation regulation. These findings suggest that gluten-induced inflammation may already be active in early stages of the disease, including the initial phases of leukocyte differentiation, according to the investigators.
“Over a long follow-up on a gluten-containing diet, only 40% of these patients progressed to VA,” Dr. Auricchio and colleagues wrote. “Notably, 25%-30% of children with PCD even stop producing anti–tissue transglutaminase antibodies, and the others keep on producing autoantibodies but preserve a normal intestinal mucosa. Considering these data, the decision to address a patient with PCD on a gluten-free diet at time of diagnosis is quite critical.”
The researchers noted that this new model, with accuracy exceeding 95%, is well suited for routine use because of its practicality and reliability.
“Our previous model, based mainly on small intestinal mucosa features, moved a step toward the prediction of outcome but still required a mucosal biopsy, and the accuracy of prediction was not greater than 80%, which is somewhat uncertain for a lifelong clinical decision,” they wrote. In contrast, the present model “appears to be sufficient to immediately suggest a gluten-free diet in children with PCD, who are almost certainly committed to developing VA.”
The investigators called for long-term studies to validate their findings in other cohorts, including adult populations.This study was supported by the TIMID project and Inflammation in Human Early Life: Targeting Impacts on Life Course Health (INITIALISE) by the Horizon Europe Program of the European Union. The investigators disclosed no conflicts of interest.
Patients with positive celiac serologies but normal villous architecture on biopsy are considered to have potential celiac disease (PCD). While the prevalence of PCD is not well-established, it is estimated to be around 1%. This study by Auricchio and colleagues investigates seven serum proteomic biomarkers that could help predict whether asymptomatic patients with PCD are at risk of developing villous atrophy (VA).
The study also identifies specific inflammatory proteins present in PCD patients who are likely to develop VA. These biomarkers provide valuable insights into the pathogenesis of celiac disease and the development of VA in genetically predisposed individuals.
As celiac disease is increasingly diagnosed without biopsies, serum proteomic biomarkers could be crucial in identifying patients who may benefit from starting a gluten-free diet (GFD) earlier, potentially preventing complications. According to the European Society of Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) guidelines, children can be diagnosed with celiac disease if their tissue transglutaminase IgA level is 10 times the upper limit of normal, confirmed by a positive endomysial antibody test. However, this approach may lead to many patients committing to a lifelong GFD despite having only PCD, as biopsies may not have been performed. In this study, 60% of patients with PCD did not progress to VA, suggesting that biomarkers could help prevent unnecessary long-term GFD commitments.
Stephanie M. Moleski, MD, is the director of the Jefferson Celiac Center and associate professor in the division of gastroenterology at Thomas Jefferson University Hospital in Philadelphia. She reported no conflicts of interest.
Patients with positive celiac serologies but normal villous architecture on biopsy are considered to have potential celiac disease (PCD). While the prevalence of PCD is not well-established, it is estimated to be around 1%. This study by Auricchio and colleagues investigates seven serum proteomic biomarkers that could help predict whether asymptomatic patients with PCD are at risk of developing villous atrophy (VA).
The study also identifies specific inflammatory proteins present in PCD patients who are likely to develop VA. These biomarkers provide valuable insights into the pathogenesis of celiac disease and the development of VA in genetically predisposed individuals.
As celiac disease is increasingly diagnosed without biopsies, serum proteomic biomarkers could be crucial in identifying patients who may benefit from starting a gluten-free diet (GFD) earlier, potentially preventing complications. According to the European Society of Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) guidelines, children can be diagnosed with celiac disease if their tissue transglutaminase IgA level is 10 times the upper limit of normal, confirmed by a positive endomysial antibody test. However, this approach may lead to many patients committing to a lifelong GFD despite having only PCD, as biopsies may not have been performed. In this study, 60% of patients with PCD did not progress to VA, suggesting that biomarkers could help prevent unnecessary long-term GFD commitments.
Stephanie M. Moleski, MD, is the director of the Jefferson Celiac Center and associate professor in the division of gastroenterology at Thomas Jefferson University Hospital in Philadelphia. She reported no conflicts of interest.
Patients with positive celiac serologies but normal villous architecture on biopsy are considered to have potential celiac disease (PCD). While the prevalence of PCD is not well-established, it is estimated to be around 1%. This study by Auricchio and colleagues investigates seven serum proteomic biomarkers that could help predict whether asymptomatic patients with PCD are at risk of developing villous atrophy (VA).
The study also identifies specific inflammatory proteins present in PCD patients who are likely to develop VA. These biomarkers provide valuable insights into the pathogenesis of celiac disease and the development of VA in genetically predisposed individuals.
As celiac disease is increasingly diagnosed without biopsies, serum proteomic biomarkers could be crucial in identifying patients who may benefit from starting a gluten-free diet (GFD) earlier, potentially preventing complications. According to the European Society of Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) guidelines, children can be diagnosed with celiac disease if their tissue transglutaminase IgA level is 10 times the upper limit of normal, confirmed by a positive endomysial antibody test. However, this approach may lead to many patients committing to a lifelong GFD despite having only PCD, as biopsies may not have been performed. In this study, 60% of patients with PCD did not progress to VA, suggesting that biomarkers could help prevent unnecessary long-term GFD commitments.
Stephanie M. Moleski, MD, is the director of the Jefferson Celiac Center and associate professor in the division of gastroenterology at Thomas Jefferson University Hospital in Philadelphia. She reported no conflicts of interest.
according to investigators.
Given that PCD patients present with positive serology and intact duodenal architecture, these findings may provide a much-needed tool for identifying patients who are more likely to benefit from early dietary interventions, lead author Renata Auricchio, MD, PhD, of the University of Naples Federico II, Italy, and colleagues reported.
“PCD offers the unique opportunity to observe the progression of gluten-induced tissue damage in celiac disease,” the investigators wrote in Gastroenterology. “These patients recognize gluten and produce specific autoantibodies, but have not developed intestinal damage.”
The study included 31 children with asymptomatic PCD who were eating a gluten-containing diet. Serum samples from each child were analyzed for the relative abundance of 92 inflammation-linked proteins using a proximity extension immunoassay. Statistical analyses, including partial least squares discriminant and linear discriminant analyses, were then applied to identify which proteins were associated with the development of VA.
After a mean follow-up period of 5.85 years, 14 participants developed VA (ie, celiac disease), while the remaining 17 remained asymptomatic.
Panel analysis revealed that specific inflammatory proteins, including interleukin (IL)–20, IL-2, sirtuin 2 (SIRT2), leukemia inhibitory factor (LIF), IL-22 receptor subunit a1, cystatin D (CST5), IL-17 receptor A, IL-15 receptor subunit a (RA), CUB domain–containing protein 1 (CDCP1), and IL-14, were 1.23- to 1.76-fold higher in children who developed VA. Among these, seven proteins — CDCP1, IL-2, LIF, IL10RA, SIRT2, CST5, and IL-4 — were able to significantly distinguish between symptomatic and asymptomatic cases in a linear discriminant model. This panel of seven proteins achieved a predictive accuracy of 96.8% in identifying children at risk of VA.
Additionally, bioinformatics pathway analysis confirmed that the broader set of proteins is involved in the positive regulation of JAK-STAT signaling (involving IL-22 receptor subunit a1, IL-4, IL-20, IL10RA, LIF, and IL-2), inflammatory responses (IL-4, IL-20, LIF, and IL-2), and processes such as tyrosine phosphorylation, leukocyte differentiation, IgG isotype switching, and protein phosphorylation regulation. These findings suggest that gluten-induced inflammation may already be active in early stages of the disease, including the initial phases of leukocyte differentiation, according to the investigators.
“Over a long follow-up on a gluten-containing diet, only 40% of these patients progressed to VA,” Dr. Auricchio and colleagues wrote. “Notably, 25%-30% of children with PCD even stop producing anti–tissue transglutaminase antibodies, and the others keep on producing autoantibodies but preserve a normal intestinal mucosa. Considering these data, the decision to address a patient with PCD on a gluten-free diet at time of diagnosis is quite critical.”
The researchers noted that this new model, with accuracy exceeding 95%, is well suited for routine use because of its practicality and reliability.
“Our previous model, based mainly on small intestinal mucosa features, moved a step toward the prediction of outcome but still required a mucosal biopsy, and the accuracy of prediction was not greater than 80%, which is somewhat uncertain for a lifelong clinical decision,” they wrote. In contrast, the present model “appears to be sufficient to immediately suggest a gluten-free diet in children with PCD, who are almost certainly committed to developing VA.”
The investigators called for long-term studies to validate their findings in other cohorts, including adult populations.This study was supported by the TIMID project and Inflammation in Human Early Life: Targeting Impacts on Life Course Health (INITIALISE) by the Horizon Europe Program of the European Union. The investigators disclosed no conflicts of interest.
according to investigators.
Given that PCD patients present with positive serology and intact duodenal architecture, these findings may provide a much-needed tool for identifying patients who are more likely to benefit from early dietary interventions, lead author Renata Auricchio, MD, PhD, of the University of Naples Federico II, Italy, and colleagues reported.
“PCD offers the unique opportunity to observe the progression of gluten-induced tissue damage in celiac disease,” the investigators wrote in Gastroenterology. “These patients recognize gluten and produce specific autoantibodies, but have not developed intestinal damage.”
The study included 31 children with asymptomatic PCD who were eating a gluten-containing diet. Serum samples from each child were analyzed for the relative abundance of 92 inflammation-linked proteins using a proximity extension immunoassay. Statistical analyses, including partial least squares discriminant and linear discriminant analyses, were then applied to identify which proteins were associated with the development of VA.
After a mean follow-up period of 5.85 years, 14 participants developed VA (ie, celiac disease), while the remaining 17 remained asymptomatic.
Panel analysis revealed that specific inflammatory proteins, including interleukin (IL)–20, IL-2, sirtuin 2 (SIRT2), leukemia inhibitory factor (LIF), IL-22 receptor subunit a1, cystatin D (CST5), IL-17 receptor A, IL-15 receptor subunit a (RA), CUB domain–containing protein 1 (CDCP1), and IL-14, were 1.23- to 1.76-fold higher in children who developed VA. Among these, seven proteins — CDCP1, IL-2, LIF, IL10RA, SIRT2, CST5, and IL-4 — were able to significantly distinguish between symptomatic and asymptomatic cases in a linear discriminant model. This panel of seven proteins achieved a predictive accuracy of 96.8% in identifying children at risk of VA.
Additionally, bioinformatics pathway analysis confirmed that the broader set of proteins is involved in the positive regulation of JAK-STAT signaling (involving IL-22 receptor subunit a1, IL-4, IL-20, IL10RA, LIF, and IL-2), inflammatory responses (IL-4, IL-20, LIF, and IL-2), and processes such as tyrosine phosphorylation, leukocyte differentiation, IgG isotype switching, and protein phosphorylation regulation. These findings suggest that gluten-induced inflammation may already be active in early stages of the disease, including the initial phases of leukocyte differentiation, according to the investigators.
“Over a long follow-up on a gluten-containing diet, only 40% of these patients progressed to VA,” Dr. Auricchio and colleagues wrote. “Notably, 25%-30% of children with PCD even stop producing anti–tissue transglutaminase antibodies, and the others keep on producing autoantibodies but preserve a normal intestinal mucosa. Considering these data, the decision to address a patient with PCD on a gluten-free diet at time of diagnosis is quite critical.”
The researchers noted that this new model, with accuracy exceeding 95%, is well suited for routine use because of its practicality and reliability.
“Our previous model, based mainly on small intestinal mucosa features, moved a step toward the prediction of outcome but still required a mucosal biopsy, and the accuracy of prediction was not greater than 80%, which is somewhat uncertain for a lifelong clinical decision,” they wrote. In contrast, the present model “appears to be sufficient to immediately suggest a gluten-free diet in children with PCD, who are almost certainly committed to developing VA.”
The investigators called for long-term studies to validate their findings in other cohorts, including adult populations.This study was supported by the TIMID project and Inflammation in Human Early Life: Targeting Impacts on Life Course Health (INITIALISE) by the Horizon Europe Program of the European Union. The investigators disclosed no conflicts of interest.
FROM GASTROENTEROLOGY
Intratumoral Dendritic Cell Therapy Shows Promise in Early-Stage ERBB2-Positive Breast Cancer
TOPLINE:
The higher dose (100 million cells) shows enhanced immune effector recruitment and significant tumor regression before chemotherapy initiation.
METHODOLOGY:
- ERBB2-positive breast cancer survival has improved with anti-ERBB2 antibodies trastuzumab and pertuzumab, but for a pathologic complete response, chemotherapy remains necessary, which comes with significant toxic effects.
- A phase 1, nonrandomized clinical trial enrolled 12 patients with early-stage ERBB2-positive breast cancer in Tampa, Florida, from October 2021 to October 2022.
- Participants received intratumoral (IT) cDC1 injections weekly for 6 weeks at two dose levels (50 million cells for dose level 1 and 100 million cells for dose level 2), with six patients in each group.
- Starting from day 1 of the cDC1 injections, treatment included trastuzumab (8-mg/kg loading dose, then 6 mg/kg) and pertuzumab (840-mg loading dose, then 420 mg) administered intravenously every 3 weeks for six cycles, followed by paclitaxel (80 mg/m2) weekly for 12 weeks and surgery with lumpectomy or mastectomy.
- Primary outcomes measured safety and immune response of increasing doses of cDC1 combined with anti-ERBB2 antibodies before neoadjuvant chemotherapy; secondary outcomes assessed antitumor efficacy through breast MRI and residual cancer burden at surgery.
TAKEAWAY:
- IT delivery of ERBB2 cDC1 was safe and not associated with any dose-limiting toxic effects. The most frequent adverse events attributed to cDC1 were grade 1-2 chills (50%), fatigue (41.7%), headache (33%), and injection-site reactions (33%).
- Dose level 2 showed enhanced recruitment of adaptive CD3, CD4, and CD8 T cells and B cells within the tumor microenvironment (TME), along with increased innate gamma delta T cells and natural killer T cells.
- Breast MRI revealed nine objective responses, including six partial responses and three complete responses, with three cases of stable disease.
- Following surgery, 7 of 12 patients (58%) achieved a pathologic complete response, including all 3 hormone receptor–negative patients and 4 of the 9 hormone receptor–positive patients.
IN PRACTICE:
“Overall, the clinical data shown here demonstrate the effects of combining ERBB2 antibodies with IT [intratumoral] delivery of targeted cDC1 to enhance immune cell infiltration within the TME [tumor microenvironment] and subsequently induce tumor regression before chemotherapy,” wrote the authors, who noted they will be testing the higher dose for an ongoing phase 2 trial with an additional 41 patients.
SOURCE:
The study was led by Hyo S. Han, MD, of H. Lee Moffitt Cancer Center and Research Institute in Tampa, Florida. It was published online on December 5, 2024, in JAMA Oncology.
LIMITATIONS:
Because only two dose levels of cDC1 were tested, it remains unclear whether higher doses or different administration schedules could further enhance immune response. Additionally, the nonrandomized design prevents definitive conclusions about whether the clinical benefits were solely from the anti-ERBB2 antibodies. The small sample size also makes it difficult to determine if the pathologic complete responses were primarily due to the 12 weeks of trastuzumab/pertuzumab/paclitaxel treatment.
DISCLOSURES:
This study was funded by the Moffitt Breast Cancer Research Fund, Shula Fund, and Pennies in Action. Several authors reported research support and personal and consulting fees from US funding agencies and multiple pharmaceutical companies outside of the submitted work, as well as related intellectual property and patents.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.
TOPLINE:
The higher dose (100 million cells) shows enhanced immune effector recruitment and significant tumor regression before chemotherapy initiation.
METHODOLOGY:
- ERBB2-positive breast cancer survival has improved with anti-ERBB2 antibodies trastuzumab and pertuzumab, but for a pathologic complete response, chemotherapy remains necessary, which comes with significant toxic effects.
- A phase 1, nonrandomized clinical trial enrolled 12 patients with early-stage ERBB2-positive breast cancer in Tampa, Florida, from October 2021 to October 2022.
- Participants received intratumoral (IT) cDC1 injections weekly for 6 weeks at two dose levels (50 million cells for dose level 1 and 100 million cells for dose level 2), with six patients in each group.
- Starting from day 1 of the cDC1 injections, treatment included trastuzumab (8-mg/kg loading dose, then 6 mg/kg) and pertuzumab (840-mg loading dose, then 420 mg) administered intravenously every 3 weeks for six cycles, followed by paclitaxel (80 mg/m2) weekly for 12 weeks and surgery with lumpectomy or mastectomy.
- Primary outcomes measured safety and immune response of increasing doses of cDC1 combined with anti-ERBB2 antibodies before neoadjuvant chemotherapy; secondary outcomes assessed antitumor efficacy through breast MRI and residual cancer burden at surgery.
TAKEAWAY:
- IT delivery of ERBB2 cDC1 was safe and not associated with any dose-limiting toxic effects. The most frequent adverse events attributed to cDC1 were grade 1-2 chills (50%), fatigue (41.7%), headache (33%), and injection-site reactions (33%).
- Dose level 2 showed enhanced recruitment of adaptive CD3, CD4, and CD8 T cells and B cells within the tumor microenvironment (TME), along with increased innate gamma delta T cells and natural killer T cells.
- Breast MRI revealed nine objective responses, including six partial responses and three complete responses, with three cases of stable disease.
- Following surgery, 7 of 12 patients (58%) achieved a pathologic complete response, including all 3 hormone receptor–negative patients and 4 of the 9 hormone receptor–positive patients.
IN PRACTICE:
“Overall, the clinical data shown here demonstrate the effects of combining ERBB2 antibodies with IT [intratumoral] delivery of targeted cDC1 to enhance immune cell infiltration within the TME [tumor microenvironment] and subsequently induce tumor regression before chemotherapy,” wrote the authors, who noted they will be testing the higher dose for an ongoing phase 2 trial with an additional 41 patients.
SOURCE:
The study was led by Hyo S. Han, MD, of H. Lee Moffitt Cancer Center and Research Institute in Tampa, Florida. It was published online on December 5, 2024, in JAMA Oncology.
LIMITATIONS:
Because only two dose levels of cDC1 were tested, it remains unclear whether higher doses or different administration schedules could further enhance immune response. Additionally, the nonrandomized design prevents definitive conclusions about whether the clinical benefits were solely from the anti-ERBB2 antibodies. The small sample size also makes it difficult to determine if the pathologic complete responses were primarily due to the 12 weeks of trastuzumab/pertuzumab/paclitaxel treatment.
DISCLOSURES:
This study was funded by the Moffitt Breast Cancer Research Fund, Shula Fund, and Pennies in Action. Several authors reported research support and personal and consulting fees from US funding agencies and multiple pharmaceutical companies outside of the submitted work, as well as related intellectual property and patents.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.
TOPLINE:
The higher dose (100 million cells) shows enhanced immune effector recruitment and significant tumor regression before chemotherapy initiation.
METHODOLOGY:
- ERBB2-positive breast cancer survival has improved with anti-ERBB2 antibodies trastuzumab and pertuzumab, but for a pathologic complete response, chemotherapy remains necessary, which comes with significant toxic effects.
- A phase 1, nonrandomized clinical trial enrolled 12 patients with early-stage ERBB2-positive breast cancer in Tampa, Florida, from October 2021 to October 2022.
- Participants received intratumoral (IT) cDC1 injections weekly for 6 weeks at two dose levels (50 million cells for dose level 1 and 100 million cells for dose level 2), with six patients in each group.
- Starting from day 1 of the cDC1 injections, treatment included trastuzumab (8-mg/kg loading dose, then 6 mg/kg) and pertuzumab (840-mg loading dose, then 420 mg) administered intravenously every 3 weeks for six cycles, followed by paclitaxel (80 mg/m2) weekly for 12 weeks and surgery with lumpectomy or mastectomy.
- Primary outcomes measured safety and immune response of increasing doses of cDC1 combined with anti-ERBB2 antibodies before neoadjuvant chemotherapy; secondary outcomes assessed antitumor efficacy through breast MRI and residual cancer burden at surgery.
TAKEAWAY:
- IT delivery of ERBB2 cDC1 was safe and not associated with any dose-limiting toxic effects. The most frequent adverse events attributed to cDC1 were grade 1-2 chills (50%), fatigue (41.7%), headache (33%), and injection-site reactions (33%).
- Dose level 2 showed enhanced recruitment of adaptive CD3, CD4, and CD8 T cells and B cells within the tumor microenvironment (TME), along with increased innate gamma delta T cells and natural killer T cells.
- Breast MRI revealed nine objective responses, including six partial responses and three complete responses, with three cases of stable disease.
- Following surgery, 7 of 12 patients (58%) achieved a pathologic complete response, including all 3 hormone receptor–negative patients and 4 of the 9 hormone receptor–positive patients.
IN PRACTICE:
“Overall, the clinical data shown here demonstrate the effects of combining ERBB2 antibodies with IT [intratumoral] delivery of targeted cDC1 to enhance immune cell infiltration within the TME [tumor microenvironment] and subsequently induce tumor regression before chemotherapy,” wrote the authors, who noted they will be testing the higher dose for an ongoing phase 2 trial with an additional 41 patients.
SOURCE:
The study was led by Hyo S. Han, MD, of H. Lee Moffitt Cancer Center and Research Institute in Tampa, Florida. It was published online on December 5, 2024, in JAMA Oncology.
LIMITATIONS:
Because only two dose levels of cDC1 were tested, it remains unclear whether higher doses or different administration schedules could further enhance immune response. Additionally, the nonrandomized design prevents definitive conclusions about whether the clinical benefits were solely from the anti-ERBB2 antibodies. The small sample size also makes it difficult to determine if the pathologic complete responses were primarily due to the 12 weeks of trastuzumab/pertuzumab/paclitaxel treatment.
DISCLOSURES:
This study was funded by the Moffitt Breast Cancer Research Fund, Shula Fund, and Pennies in Action. Several authors reported research support and personal and consulting fees from US funding agencies and multiple pharmaceutical companies outside of the submitted work, as well as related intellectual property and patents.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.