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Studies highlight interactions among lifestyle factors, disease development, and response to treatment

(SAN DIEGO—Dec. 7, 2024) — Five studies presented during the 66th ��ѻ��ý (ASH) Annual Meeting and Exposition reveal new linkages between blood disorders and the foods and substances we are exposed to. By illuminating how diet and other lifestyle factors may affect a person’s likelihood of developing a blood disorder as well as disease progression and response to treatment, the studies point to possible opportunities to intervene through lifestyle modifications.

“When someone is facing a diagnosis of cancer or some other blood disorder, the emotional response to that is to ask, what did I do to be in this situation, or what can I do to resolve this situation?” said Chancellor Donald, MD, assistant professor of medicine, hematology, and medical oncology at Tulane University School of Medicine in New Orleans. “One of the things we have greatest control over is our overall lifestyle and diet. This research speaks directly to that idea of lifestyle modification as you face different issues.”

The first study points to potential benefits of taking glucagon-like peptide 1 (GLP-1) receptor agonists for diabetes, suggesting that these drugs could help reduce the risk of dangerous blood clots in addition to their known benefits for weight loss.

Two studies offer evidence that consuming a high-fiber diet may help to reduce complications and disease progression by improving the health of the gut microbiome. Another study speaks to the role of tobacco exposure in cancer development and bolsters the evidence that quitting smoking could help to reduce or delay disease progression.

The final study suggests that a substance associated with a ketogenic diet could improve the effectiveness of chimeric antigen receptor (CAR) T-cell therapy, pointing to new opportunities to improve the success rate of this curative therapy.

GLP-1 Agonists May Reduce Risk of Dangerous Blood Clots in People with Diabetes
: Glucagon-like Peptide 1 Receptor Agonists Reduce the Risk of Venous Thromboembolism in Patients with Diabetes Irrespective of Obesity: A Propensity Score-Matched Multicenter Database Analysis

Regardless of their weight status, people taking GLP-1 receptor agonists for diabetes were 20% less likely to suffer venous thromboembolism (VTE) compared with a similar group of patients taking a different type of diabetes drug, according to a large retrospective study. The findings suggest that lowering the risk of dangerous blood clots could represent another previously unrecognized benefit of GLP-1 agonists, a class of medications widely known for their effectiveness as a weight loss agent and diabetes treatment.

“Our study showed that the use of a GLP-1 receptor agonist is associated with lower incidence of VTE over one year,” said Rushad Patell, MD, the study’s lead author and assistant professor of medicine at Harvard Medical School in Boston. “If you’re selecting an antidiabetic agent for a patient and thrombotic risk comes into play, this data suggests that there may be some advantage to choosing a GLP-1 receptor agonist.”

VTEs, which occur when a blood clot forms in a vein, are a leading cause of preventable in-hospital deaths in the United States, according to the Centers for Disease Control and Prevention. Deep vein thrombosis (DVT, when a clot forms in a deep vein, typically in the legs) and pulmonary embolism (PE, when a clot travels to the lungs) are the two types of VTE and can cause serious complications, prolonged hospitalization, and death.

GLP-1 receptor agonists were initially approved by the U.S. Food and Drug Administration (FDA) to improve insulin production in people with diabetes; some drugs in this class have also been approved for weight control in people with obesity. Studies have suggested they can also reduce the risk of cardiovascular disease, but no previous study has examined their potential impacts on VTE risk.

Researchers analyzed data from over 558,128 patients with type 2 diabetes in a large global database of electronic health records from over 120 health care institutions. Using a statistical technique known as propensity-score matching, they created two groups, each containing nearly 279,064 patients, who were similar in terms of demographics, health conditions, and medications, with one exception: patients in one group were prescribed a GLP-1 drug, while patients in the other group were prescribed a dipeptidyl peptidase-4 inhibitor (DPP4i), a type of diabetes drug that works through a different mechanism and does not cause weight loss.

During the first year after patients were prescribed their diabetes drug, the incidence rate of VTE per 1,000 patient-years (a metric used to assess the rate of relatively rare health events over a short period of time) was 6.5 for those prescribed GLP-1 drugs and 7.9 for those prescribed a DPP4i, amounting to a 20% reduced risk for those taking GLP-1 receptor agonists. This reduction reflected decreases in risk for both DVT and PE. The results were similar among patients who were obese up to a year before starting their diabetes medication and those who were not obese.

Because obesity is a known risk factor for VTE, weight loss could be one potential mechanism through which GLP-1 drugs lower VTE risk. However, the study does not offer definitive evidence that the VTE risk reduction is achieved through the effects of the GLP-1 agonists on weight loss. Researchers also noted that the differences between the two study groups began to emerge within weeks of when patients started taking their prescribed drug, which may suggest that other factors are involved since weight loss takes time. “We would need additional studies to determine the potential mechanism, whether through weight loss or some other means,” Dr. Patell said.

The large number of patients included in the study strengthens the evidence it provides, but as a retrospective study, researchers cautioned that it is not as definitive as a randomized controlled trial. They suggested that future studies could further illuminate the potential impacts of GLP-1 drugs in people without diabetes, people taking these drugs specifically for weight loss purposes, and people who have elevated risk of VTEs due to cancer, heart conditions, or other factors.

“From a public health perspective, given how prevalent these drugs are, there is potential to see if the overall burden of VTE might be reduced at a national or population level,” said Dr. Patell. “VTE risk seems to continuously go up; maybe this will bring the curve down.”

This study received funding support from the Conquer Cancer Foundation and the National Blood Clot Alliance.

Cho Han Chiang, MD, of Mount Auburn Hospital, will present this study during an oral presentation on Sunday, December 8, 2024, at 5:30 p.m. Pacific time in Room 6CF in the San Diego Convention Center.

A Fiber-Rich Diet May Help Prevent Complications after Stem Cell Transplant
: Increased Fiber Intake Results in Better Overall Survival and Lower GI-aGVHD in Allo-HCT Recipients and Pre-Clinical Gvhd Models

Consuming a high-fiber diet after undergoing stem cell transplantation could help to reduce the risk of graft-versus-host disease (GVHD) by cultivating a healthy gut microbiome, according to studies conducted in patients and mice.

The findings add to a growing body of evidence highlighting the benefits of a high-fiber diet for maintaining microbiome health and suggest that dietary restrictions commonly recommended after a stem cell transplant – which typically result in low fiber intake – may be counterproductive for some patients.

“Our study reaffirms data [on the benefits of dietary fiber] that have been captured outside the GVHD world, and we’re now demonstrating that those ‘rules’ also apply to GVHD,” said Jenny Paredes, PhD, staff scientist at City of Hope National Medical Center in Duarte, California, and the study’s lead author. “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.”

GVHD is the most common complication of allogeneic stem cell transplantation, a procedure in which a person’s cancerous or abnormal blood stem cells are removed and replaced with healthy cells from a donor. GVHD occurs when the donated cells attack the patient’s own tissues and can cause a variety of symptoms ranging from mild to life-threatening.

Because patients with GVHD often exhibit symptoms similar to irritable bowel disease (IBD) and the process of stem cell transplantation depletes the immune system, patients are encouraged to avoid eating raw vegetables and fruits without a removable peel for about 10 days before their procedure and 30 days after, when most patients stay in an isolation room in the hospital. The goal of these dietary restrictions is to minimize their exposure to pathogenic bacteria and reduce IBD-like symptoms. However, the cooked and processed foods that most patients consume during this period tend to have lower fiber content, Dr. Paredes explained. This can alter the makeup of the gut microbiome and deplete gut microbes that thrive through fermentation of dietary fiber, a process which produces beneficial short-chain fatty acids linked with gut health and immunity.

To examine the potential benefits of maintaining high fiber intake during stem cell transplantation to avoid GVHD, the researchers worked in collaboration with investigators at Memorial Sloan Kettering Cancer Center to analyze the diets of 173 patients undergoing the procedure. To measure fiber intake, they tracked all foods and beverages participants consumed and used food databases from the FDA to calculate the amount of fiber and other nutrients in their diets from 10 days before their transplant until 30 days afterward.

Dr. Paredes and her colleagues found that a low-fiber diet was linked with reduced gut microbiome diversity, which can also increase susceptibility to infection by intestinal pathogens. They conversely found that a high-fiber diet was associated with better overall survival, reduced risk of acute GVHD affecting the lower gastrointestinal tract, and higher microbial diversity in the gut. “The microbiome is protective if it’s in the right balance; if not, it could be a source of infection and increase the risk of mortality,” she said.

Patients with higher fiber intake also had higher levels of butyrate – a product of dietary fiber fermentation – and more gut microbes that produce butyrate. Previous studies have demonstrated that people with more butyrate producers in their gut are less likely to die from GVHD than those with lower levels of these microbes.

The researchers also studied the mechanisms involved in these effects through a companion study of GVHD and the dietary fiber source cellulose, a type of fiber that mammals cannot digest without the help of gut microbiota, in mouse models. Mice fed a diet high in cellulose during stem cell transplantation had a reduced rate of death from GVHD and other markers of reduced GVHD risk, as well as higher microbial diversity and butyrate concentrations in the gut. According to Dr. Paredes, these findings bolster the evidence for the health benefits of butyrate and other products of fiber fermentation, including improved colon health, digestive support, and reduced inflammation.

Dr. Paredes cautioned that a high-fiber diet may not be best for all patients. Since the process of fiber fermentation can lead to gas and bloating, reducing fiber intake can help to alleviate discomfort if patients develop IBD-like symptoms. Further study could help clarify the optimal way to increase fiber without triggering these symptoms.

Taken together, the findings suggest that plant-based, high-fiber foods could help to maintain a healthy gut microbiome and reduce the risk of GVHD, Dr. Paredes said. She is now working to implement new nutrition protocols at City of Hope and noted that hospitals can support patients undergoing stem cell transplantation by offering them diverse food choices. “The more diverse our diet is, the more diverse our microbiome will be, and that applies to the clinic as well,” said Dr. Paredes.

This study was supported by funding from the National Cancer Institute and private foundations.

Jenny Paredes, PhD, of City of Hope National Medical Center, will present this study during an oral presentation on Saturday, December 7, 2024, at 2:00 p.m. Pacific time in Room 6B in the San Diego Convention Center.

High-Fiber Diet May Slow Disease Progression to Multiple Myeloma
A High-Fiber Dietary Intervention (NUTRIVENTION) in Precursor Plasma Cell Disorders Improves Biomarkers of Disease and May Delay Progression to Myeloma 

New data suggest that a plant-based diet rich in fiber could help to improve the outlook for people with precursor conditions that can lead to multiple myeloma (MM). The research, which involved a 12-week controlled diet with additional health coaching for 20 patients as well as experiments in mice, is the first interventional study to demonstrate that fiber-focused dietary modifications have the potential to slow the progression of blood cancers.

MM is a cancer affecting plasma cells, a type of white blood cell. It typically develops gradually starting with one of two precursor conditions known as monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM). Since these conditions can last for many years without progressing to MM, researchers have sought ways to intercede and prevent patients with MGUS or SMM from developing cancer, but there is currently no cure for MM.

“As we’re detecting cancers earlier – during the precancerous state – there is a greater opportunity to understand how lifestyle can modify the course of the disease and help patients live better,” said Urvi A. Shah, MD, principal investigator of the NUTRIVENTION trial and assistant attending physician at Memorial Sloan Kettering Cancer Center in New York. “It is very anxiety-provoking when someone is told they have a precancerous state and there is nothing they can do. Our motivation is to see if we can empower patients to take steps to lower their risk.”

People who are overweight face an increased risk of MM, and previous studies have suggested that factors such as diet and the health of the gut microbiome may influence disease progression. Dr. Shah and her team conducted a pilot clinical trial involving 20 participants (median age of 62 years, 11 female and nine from underrepresented racial and ethnic populations) with MGUS or SMM and a body mass index of 25 or more to determine whether adopting a high-fiber, plant-based diet could be feasible and potentially slow disease progression.

The trial lasted for one year. During the first three months, participants received ready-made meals consisting of six lunches and dinners per week coupled with virtual nutritional coaching to help them adopt a diet rich in beans and legumes, whole grains, fruits, and vegetables, and avoid animal products and processed foods. For the second three-month period, participants continued their nutritional coaching sessions but were responsible for preparing all of their own meals. No meals or coaching sessions were provided for the remainder of the year.

The trial met its primary endpoints for feasibility, with participants showing high adherence and significant weight loss. The median overall adherence to the high-fiber, plant-based diet was 91% during the first three months and 58% at the end of the year, substantially higher than the 20% adherence rate before the study. Participants lost a median of 7% of their body weight over the first three months and this was sustained throughout the course of the year. Participants also showed improvements in quality of life and a variety of biochemical markers, including those related to insulin resistance, fecal microbiome diversity, and inflammation.

“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,” said Dr. Shah. “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 trajectory of the disease.”

Researchers at the Bellone laboratory at IRCSS San Rafaele Hospital in Milan, Italy conducted a similar experiment on SMM in a mouse model. In the mice, consuming a high-fiber diet delayed the progression to MM from a median of 12 weeks among those fed a normal diet to 30 weeks among those fed a high-fiber diet. All mice in the control arm developed MM during the study, while 40% of those fed a high-fiber diet did not.

“Mechanistically, we saw that the beneficial effects of a high-fiber diet were similar in overweight and lean mice even in more advanced phases of the disease,” said Dr. Shah. “Efficacy of the diet also appears independent from calorie intake and was not just a matter of how much body weight was lost.” Biochemical analyses pointed to increased microbial diversity and particular substances produced by gut microbes as potential mechanisms for slowing disease progression by slowing the growth of abnormal plasma cells, reducing inflammation, and improving immune functioning.

Researchers cautioned that findings in mice do not necessarily translate to humans and that the clinical trial was limited by its small size, making it challenging to understand why some participants saw a change in their disease progression while others did not. A follow-up study is now underway to investigate the potential impacts of dietary changes and/or dietary supplements on the progression to MM in a larger patient group.

This research was supported by funding from the ��ѻ��ý, the National Cancer Institute, the Allen Foundation Inc, the Paula and Rodger Riney Foundation, the Solomon Fund, the AIRC Foundation for Cancer Research, and the Leukemia and Lymphoma Society.

Urvi Shah, MD, of the Memorial Sloan Kettering Cancer Center, will present this study during an oral presentation on Sunday, December 8, 2024, at 5:30 p.m. Pacific time in Pacific ballrooms 24-26 in the Marriott Marquis San Diego Marina.

Smoking Linked with Genetic Mutations that Worsen Myelodysplastic Syndromes
: Association between Smoking Intensity, Genetic Mutations, and Disease Progression in Myelodysplastic Syndromes 

For the first time, researchers have illuminated how smoking – a known risk factor for many types of cancer – may lead to a group of blood cancers known as myelodysplastic syndromes (MDS) by way of specific genetic mutations. The new findings indicate that these potentially harmful mutations accumulate over time, helping to explain why people who smoke more heavily and for a longer period of time can experience worse outcomes with MDS.

“We have shown that tobacco smoking is associated with specific genetic mutations related to MDS, and when someone smokes for a longer time, they accumulate more mutations and are more likely to progress to MDS,” said Sangeetha Venugopal, MD, the study’s lead author and a physician at Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine. “Our results show that there is definitely a dose-response relationship and also an association between disease progression and overall survival.”

MDS develop gradually from several precursor conditions and affect the bone marrow’s ability to produce healthy blood cells. MDS are considered a form of cancer and can also progress to acute myeloid leukemia, a more aggressive type of blood cancer. Numerous studies have linked smoking with lung cancer and other solid tumors, but the genetic mechanisms linking smoking with blood cancers such as MDS are not well understood.

Researchers analyzed genetic data, smoking history, and disease progression among nearly 1,900 participants in the National MDS Study, the largest national prospective study of people diagnosed with MDS or one of its precursor conditions. About half of the participants had a history of smoking and 18% still smoked at the time of their diagnosis. Among those with any history of smoking, many were heavy tobacco users, reporting smoking about 16 cigarettes per day for nearly 30 years, on average. Over two-thirds of those with a history of smoking were male, and nearly half were in their seventies.

Comparing smokers and non-smokers after adjusting for age, sex, and type of disease, the researchers found that smokers had significantly more genetic mutations, with the difference being most pronounced among the heaviest smokers. Those in the 75th and 90th percentiles for pack-years (a metric that accounts for smoking intensity as well as the total number of years smoked) had 1.8 and 3.5 times the number of mutations, respectively, compared with non-smokers.

People who had smoked for longer periods of time were also significantly more likely to experience disease progression compared with those who smoked for a shorter period or not at all, with 27% of long-term smokers showing disease progression compared with 18% among nonsmokers and those with a short smoking history. Some of the genetic mutations implicated in the study, such as ASXL1, had previously been associated with smoking, while several others had not.

Since the study showed a clear dose-response relationship, meaning that more smoking led to more mutations, researchers said the findings suggest that quitting smoking can potentially help to reduce MDS risk for those with precursor diagnoses, and may lower the risk of MDS progressing to a more aggressive cancer. Doctors can support patients by broaching the topic multiple times – recognizing that quitting can be especially challenging for lifelong smokers – and helping patients access tobacco cessation aids.

“This study can give doctors more reason to have a discussion with patients who may be still smoking at the time of their diagnosis, to let them know that the progression can be worse and encourage them to consider tobacco cessation,” said Dr. Venugopal. “I don’t want to encourage patients to blame themselves for their blood cancer, but I also don’t want them to have an unhealthy habit that may affect their disease progression, so we have to strike a balance.”
Since the research was based on data from a study of people with MDS or precursor conditions, it is unclear whether some of the same mutations identified in the study are also present in people with a history of smoking who do not have these conditions. Researchers suggested that future studies involving smokers without MDS or related conditions could help to further clarify the genetic mechanisms and risk factors involved.

This study was funded by the National Heart, Lung, and Blood Institute.

Sangeeta Venugopal, MD, MS, of the University of Miami Miller School of Medicine, will present this study in a poster on Monday, December 9, 2024, at 6:00 p.m. Pacific time in Halls G-H in the San Diego Convention Center.

Ketogenic Diet Boosts CAR T-Cell Function for Better Tumor Control
: Ketogenic Diet Enhances CAR T Cell Antitumor Function Via β-Hydroxybutyrate

Findings from a series of studies conducted in mice, human tissues, and healthy volunteers suggest that a ketogenic diet can enhance the effectiveness of CAR T-cell therapy. The results point to β-hydroxybutyrate (BHB), a substance our bodies produce when we consume a ketogenic diet, as a driver of increased CAR T-cell function against cancer.

In CAR-T therapies, a patient’s own immune cells are removed, genetically engineered, and infused back into the body where they recognize and kill cancer cells. The FDA has approved several CAR-T therapies for treating a variety of blood cancer types.

“Our research found that a ketogenic diet can enhance CAR T-cell function, and we further found that BHB, one of the important metabolites produced in response to a ketogenic diet, plays a major role in mediating this effect,” said Shan Liu, PhD, a postdoctoral researcher in the Perelman School of Medicine at the University of Pennsylvania in Philadelphia and one of the study’s lead authors. “Given that about two-thirds of patients who undergo CAR-T therapy either do not see a response or eventually relapse, a dietary intervention that could be implemented relatively easily along with CAR-T therapy would be very attractive.”

Diet is known to influence health in general, as well as patients’ responses to various cancer treatments. For example, previous studies have shown that a high-fiber diet can affect the efficacy of a type of immunotherapy called immune checkpoint blockade. The new study is the first to examine how specific dietary interventions modulate the anti-tumor effect of CAR T-cell immunotherapy.

Researchers first tested several different types of diets including high-fiber, high-fat, high-protein, and ketogenic diets in mice with B-cell lymphoma, and found that mice fed a ketogenic diet showed the best tumor control and overall survival after CAR-T therapy. They then found that BHB was the key metabolite enriched following ketogenic diet feeding and that mice fed a normal diet but given BHB supplementation showed improved CAR T-cell expansion and better tumor control than mice that were not given BHB supplementation.

Additional studies suggested that BHB increases CAR T-cell function by providing a more efficient source of energy compared with glucose, the typical fuel source for most cells. When the researchers used T cells from patients with lymphoma to manufacture CAR T cells, they found that BHB added to cell culture medium increased T-cell expansion and function of mitochondria, the energy factory of the cell. In addition, the team retrospectively analyzed the BHB levels in blood samples from 17 patients who received CAR-T treatment for large B-cell lymphoma and found that higher BHB levels were correlated with greater CAR T-cell expansion.

To assess the potential impacts of taking BHB supplements, the researchers recruited healthy volunteers and analyzed their T-cell function before and after consuming a BHB supplement. The results suggested that BHB enhances the function of T-cell mitochondria, further bolstering the hypothesis that BHB enhances T-cell activity through its effects on energy processing.

Since the research was largely conducted in the laboratory and in mice and did not involve interventions with any patients undergoing CAR-T therapy, researchers caution that further studies will be required to determine the clinical significance of the findings. “At this point, we do not recommend adopting a ketogenic diet or taking BHB supplements during CAR-T therapy,” said Dr. Liu. The research team will soon start a clinical trial in patients with lymphoma receiving CAR-T therapy to study the effect of BHB supplementation in the clinic.

Shan Liu, PhD, of the University of Pennsylvania, will present this study in a plenary session on Sunday, December 8, 2024, at 2:00 p.m. PT in Hall B in the San Diego Convention Center.

The ��ѻ��ý (ASH) (hematology.org) is the world’s largest professional society of hematologists dedicated to furthering the understanding, diagnosis, treatment, and prevention of disorders affecting the blood. Since 1958, the Society has led the development of hematology as a discipline by promoting research, patient care, education, training, and advocacy in hematology.

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Claire Whetzel, 202-629-5085
[email protected]