Xylitol is naturally present in trace amounts in many fruits and vegetables, but it is added in larger quantities to sugar-free candy, gum, and baked goods.
High amounts of xylitol, a popular sugar substitute, can increase the risk of heart attack, stroke, and other cardiovascular diseases, according to a new study by the Cleveland Clinic.
The study, published in the European Heart Journal, focused on xylitol’s health effects. Xylitol is a natural sugar alcohol that looks and tastes like sugar but has fewer calories. Unlike regular sugar, it doesn’t raise blood sugar levels, so diabetic patients are often advised to use it for sugar replacement.
Xylitol is naturally present in trace amounts in many fruits and vegetables, such as plums, strawberries, cauliflower, and pumpkin. It is often used in dental hygiene products, such as toothpaste, to reduce the risk of dental cavities and is generally thought to have a good safety profile.
However, larger quantities of xylitol replace sugar in sugar-free candy, gums, and baked goods.
“This study again shows the immediate need for investigating sugar alcohols and artificial sweeteners, especially as they continue to be recommended in combatting conditions like obesity or diabetes,” Dr. Stanley Hazen, chair of Cardiovascular and Metabolic Sciences at Cleveland Clinic’s Lerner Research Institute and the study’s lead researcher, said in a news release.
Artificial sweeteners are often recommended for people who suffer from cardiometabolic diseases, including obesity, diabetes, and heart disease, by multiple guideline organizations, the authors wrote in the study, citing the American Heart Association and other groups in the United Kingdom, Canada, and Australia
However, xylitol “will likely confer heightened thrombosis potential,” or blood clotting risks, “in the same vulnerable patients that it is marketed towards and intended to protect (e.g. subjects with diabetes, obesity, [cardiovascular disease]),” the authors wrote.
The researchers acknowledged that further studies are needed, as their study was observational and could not prove causation.
Excess Sweetener Can Lead to Blood Clots, Stroke
In the study, Dr. Hazen and his team examined more than 3,000 U.S. and European patients, many of whom had high blood pressure, a history of heart disease, or diabetes. The researchers determined that high levels of xylitol were associated with an elevated three-year risk of cardiovascular events. One-third of patients with the highest amount of xylitol in their blood plasma were likely to experience a cardiovascular event, such as heart attack or stroke.
Xylitol reacts with blood platelets, causing them to clot. When that reaction occurs, the body is at risk of thrombosis, or blood clotting.
A second part of the study confirmed this blood clotting reaction. The research team also found that blood platelets in people who drank xylitol-sweetened beverages were more likely to clot than those in people who had beverages sweetened with glucose.
“It does not mean throw out your toothpaste if it has xylitol in it, but we should be aware that consumption of a product containing high levels could increase the risk of blood clot related events,” Dr. Hazen said in the press release.
Diabetes Increases Other Risks
People with diabetes are already at an increased risk for high blood pressure, narrowed arteries, coronary heart disease, and stroke.
The Heart and Stroke Foundation of Canada reports that people with diabetes are at risk of developing heart disease at an earlier age. More concerningly, diabetics are three times more likely to die of heart disease.
While managing blood sugar is crucial to living with diabetes, it is also essential to make healthy lifestyle choices, such as exercising, maintaining a healthy weight, avoiding smoking, managing stress, and eating well. The foundation adds that eating fewer highly processed or ultra-processed foods, like those likely to contain sugar substitutes, is one way to follow a healthier diet. It recommends the Dietary Approaches to Stop Hypertension (DASH) diet, rich in vegetables, fruit, and low-fat dairy foods.
Magnesium deficiency is widespread, affecting metabolism. Find out how this overlooked mineral could improve metabolic health.
In our pursuit of optimal health, an often-overlooked mineral has quietly emerged as a potential game-changer: magnesium.
More than half of the American population—with some estimates suggesting a staggering 75 percent—are failing to meet the recommended dietary intake of this vital nutrient, possibly hurting their metabolic health.
The Myriad Roles of Magnesium in the Body
Magnesium is essential for optimal bodily function, acting as a cofactor in numerous enzymatic reactions. It regulates cardiovascular physiology, stress responses, inflammation, and hypertension and enhances glycemic control when combined with vitamin D, making it crucial for metabolic health. Magnesium deficiency is prevalent among obese individuals.
Common symptoms of magnesium depletion include muscle cramps, headaches, eye twitches, insomnia, fatigue, irritability, and a sensation of a “lump” in the throat, Dr. Nathali Morrow-van Eck, a functional-integrative general medical practitioner in Pretoria, South Africa, told The Epoch Times. These symptoms stem from magnesium’s role in supporting the gamma-aminobutyric acid brain system, essential for relaxation and stress reduction.
Magnesium also activates the COMT gene, a protein-coding gene that helps with anxiety management and hormone metabolite detoxification (the body’s process of eliminating byproducts).
With magnesium involved in more than 300 bodily functions, deficiency signs often manifest subtly, initially affecting energy production processes, Katrina Farrell, a registered nutritional therapist, told The Epoch Times.
The Magnesium–Metabolic Syndrome Connection
A 2024 study published in the Journal of Clinical Endocrinology & Metabolism examined the link between magnesium depletion and metabolic syndrome. The analysis of 15,565 participants revealed that the likelihood of developing metabolic syndrome increased by almost one-third for every incremental rise in the magnesium depletion score.
This correlation persisted across diverse populations, regardless of behavioral or sociodemographic factors, suggesting that addressing magnesium deficiency could be a preventive measure against metabolic syndrome, whether through dietary modifications or supplementation
Magnesium plays a crucial role in various aspects of digestive health. It helps with producing digestive enzymes, nutrient absorption, and peristalsis, the wave-like motion that propels food through the digestive tract. Insufficient magnesium can lead to constipation and bloating.
Continuously low magnesium levels affect insulin function, rendering it less effective and impeding metabolism. As a result, magnesium deficiency can contribute to weight-management challenges, Type 2 diabetes, and prediabetes, according to Ms. Farrell.
Experimental magnesium deficiency in rats has been linked to inflammation, hypertriglyceridemia (high levels of triglycerides in the blood), and changes in lipoprotein metabolism, according to a scientific review published in Magnesium Research. Magnesium’s impact on intracellular calcium homeostasis may be a unifying factor connecting stress and inflammation and may be behind their potential contribution to metabolic syndrome.
Magnesium is vital for insulin and glucose metabolism because it facilitates insulin receptor function, acting as a cofactor for enzymes involved in glucose breakdown and oxidation and regulating insulin secretion. Low magnesium levels can lead to insulin resistance and impaired glucose uptake by cells, thereby disrupting overall metabolism and increasing the risk of metabolic disorders such as Type 2 diabetes.
Why Are We Not Getting Enough Magnesium?
Magnesium depletion has become increasingly prevalent, attributed to various factors in modern lifestyles, Ms. Farrell said.
Contemporary farming methods have led to declining magnesium levels in our food supply. Additionally, processed foods, ubiquitous in today’s diets, often lack sufficient magnesium content. Alcohol and certain medications, such as proton pump inhibitors (PPIs), usually prescribed for chronic acid reflux, can deplete magnesium reserves.
Excessive caffeine consumption can also deplete magnesium levels.
Stress is another major culprit behind magnesium depletion, Ms. Farrell added. During periods of stress, the body releases magnesium as part of the stress response. Consequently, whether acute or chronic, stress can rapidly deplete magnesium levels.
Research published in The Clinical Biochemist Reviews suggests that serum magnesium levels fluctuate with different types of exercise. Levels tend to increase after brief, maximal exercise but decrease following endurance exercise.
How to Increase Magnesium Intake
Diet is crucial for obtaining sufficient magnesium, Ms. Farrell said.
Grain refining and food processing diminish magnesium content, leading to up to an 85 percent reduction. Boiling magnesium-rich foods also results in significant magnesium loss. Opting for raw, whole foods provides a natural and potent source of the mineral.
Ms. Farrell advocates a “food-first” approach, emphasizing nuts, seeds, and leafy greens in daily meals to boost magnesium intake. She also recommends Epsom salt baths, magnesium body lotions for relaxation and rejuvenation, and exploring magnesium supplements tailored to people’s needs.
Dr. Morrow-van Eck recommends both oral and transdermal magnesium products. A person’s absorption of dietary magnesium from the gut can range from 24 percent to 76 percent. The absorption rate primarily depends on the individual’s magnesium status rather than their intake. When the body’s magnesium level is lower, a higher percentage of dietary magnesium is absorbed.
For oral supplementation, she prioritizes optimal doses of the most bioavailable forms, such as magnesium threonate, glycinate, and citrate. For targeted relief, she suggests applying transdermal magnesium chloride and massaging it into areas of concern for optimal absorption.
The Limitations in Assessing Magnesium Levels
Optimal health outcomes often result from a balanced and varied diet that provides a spectrum of essential vitamins, minerals, and other nutrients, Ms. Farrell said. She noted that the effects of nutrients are often enhanced or modulated by the presence of other nutrients rather than their operating independently.
An example is the relationship between vitamin D and magnesium. While vitamin D relies on magnesium for transportation and activation, magnesium plays a pivotal role in various bodily functions, including gut health, immune function, and skin health. Low magnesium levels can hinder vitamin D’s effectiveness even if one has sufficient vitamin D levels.
Regarding magnesium assessment, Ms. Farrell advises against relying solely on blood tests, as magnesium is primarily stored in organs and bones, not in the bloodstream. Blood tests, therefore, do not provide a complete picture. She suggests that considering symptoms, habitual alcohol consumption, or high levels of stress might better indicate whether more magnesium is needed.
Possible Side Effects
While magnesium from dietary sources poses no significant risks, excessive magnesium intake through dietary supplements may lead to adverse effects such as diarrhea, nausea, and abdominal cramping, according to the National Institutes of Health. Diarrhea is commonly associated with magnesium chloride, gluconate, carbonate, and oxide. People with impaired renal function or kidney failure are particularly susceptible to magnesium toxicity, which typically occurs when serum concentrations surpass 31.35 to 47.02 milligrams per deciliter (mg/dL), or 1.74 to 2.61 millimoles per liter (mmol/L). Also, several medications can influence magnesium levels or interact with magnesium supplements.
To optimize efficacy and minimize interactions, separate the intake of magnesium supplements and oral bisphosphonates by at least two hours. This precaution is essential as magnesium supplements can impede the absorption of bisphosphonates such as alendronate (Fosamax), commonly prescribed for osteoporosis treatment.
To avoid potential interaction, take specific antibiotics either two hours before or four to six hours after consuming magnesium-containing supplements. This timing is critical because magnesium can form insoluble complexes with certain antibiotics.
Cannabis can be toxic to adolescent brain functioning, increasing the risk of developing psychosis years later.
During breaks from his deployments in the Afghanistan war, Craig turned to smoking cannabis to alleviate stress, just as he had done as a teenager. However, one evening, things took a turn when he barricaded himself and his two young daughters in the master bedroom.
“He thought the house was surrounded by terrorists,” Jennifer Thomas, the girls’ mother, recounted while speaking to The Epoch Times. “That night was bad; he said they were under attack. The other times before that were mostly him seeing auras and aliens talking.”
Military police took Craig to a psychiatric hospital, where he was diagnosed with schizophrenia at 26.
Craig’s story is one among an increasing number of cases, primarily involving men, in which cannabis use has contributed to a schizophrenia diagnosis occurring in one’s 20s.
The Cannabis–Psychosis Link
New UK research shows adults who consumed high-potency cannabis between ages 16 and 18 are twice as likely to experience psychotic episodes such as hallucinations and delusions by their mid-20s compared to those using low-potency strains or abstaining. The longitudinal study, published in Addiction, highlights cannabis’s risks to adolescent brain development.
“Young people using higher-potency forms of cannabis are twice as likely to have experiences associated with psychosis, such as hallucinations and delusions,” lead author Lindsey Hines, a professor from the University of Bath Department of Psychology with a doctorate in epidemiological psychiatry, said in a statement.
Over the past several decades, illicit marijuana products have become significantly more potent. The concentration of tetrahydrocannabinol (THC)—the psychoactive compound in cannabis responsible for the “high” sensation and one linked to psychotic experiences in some people—increased to roughly 14 percent by 2019 from around 10 percent in 2009, according to a scientific review published in Biological Psychiatry: Cognitive Neuroscience and Neuroimaging
“This is the problem,” Yasmin Hurd, director of the Addiction Institute at Mount Sinai in New York, told The Epoch Times. “Many people don’t realize that the cannabis that is consumed today—the majority or all of it—is high-potency.”
The researchers examined data from the University of Bristol’s Children of the 90s (ALSPAC) study, the most comprehensive birth cohort study of its kind. The study collected information and data from about 14,000 adolescents between 16 and 18. Then, when they were 24, the participants were asked to disclose the types of cannabis they used and any psychotic experiences, such as hallucinations or delusions, they may have experienced.
The study found that 6.4 percent of young people using cannabis had new psychotic experiences, compared to 3.8 percent of nonusers. Furthermore, after starting to use cannabis, 10.1 percent of young people using higher-potency cannabis reported new psychotic experiences, while 3.8 percent using lower-potency cannabis did.
“Importantly, the young people we asked had not previously reported these experiences before starting their cannabis use,” Ms. Hines said. ”This adds to the evidence that use of higher-potency cannabis may negatively impact mental health.”
Stronger THC a Ticking Time Bomb for Mental Health
Cannabis poses a greater psychosis risk than tobacco or alcohol, according to Ms. Hurd, who noted that the new findings align with numerous studies linking cannabis use to psychosis.
A 2017 study in The American Journal of Psychiatry found that people experiencing even one cannabis-induced psychotic episode have a 47 percent higher chance of developing schizophrenia or bipolar disorder, with self-harm after such episodes indicating the highest risk. Of those experiencing substance-induced psychosis, half of them developed schizophrenia within three years, while the other half converted to bipolar disorder within almost 4 1/2 years.
Both schizophrenia and bipolar disorder are thought to involve imbalances in brain chemicals (neurotransmitters) and abnormalities in brain structure and function. These neurological factors may contribute to the development of psychotic symptoms, such as hallucinations and delusions, in both disorders.
A study published in Molecular Psychiatry analyzed genetic markers to assess the cannabis-psychosis relationship and found that “use of cannabis is causally related to the risk of schizophrenia,” meaning that cannabis is a factor influencing the occurrence of the disorder.
A 2023 Danish study reported cannabis use disorder (CUD) as a major schizophrenia risk factor for young males, estimating that 30 percent of cases among men aged 21 to 30 could be prevented by preventing CUD, a diagnosis of problematic cannabis abuse or dependence that affected 14.2 million Americans aged 12 and over in 2020.
While not all young cannabis users develop psychosis, Ms. Hurd said that factors such as starting before 16, frequent use, and higher potency increase risk, potentially triggering conditions in genetically predisposed people, as a 2018 study using 23andMe data found.
The increased psychosis risk from more potent cannabis “must be taken seriously, especially in light of the current mental health crisis,” Ms. Hurd and colleagues wrote in a 2024 commentary in The American Journal of Psychiatry.
Challenges Ahead
Despite evidence linking cannabis to psychosis, teen use soared 245 percent between 2000 and 2020, according to research published in Clinical Toxicology. The authors attributed the rise to popular edible products, with legalization making cannabis seem safer and more accessible to teens, even though it is only legal for adults in 24 states and Washington, D.C.
Tax revenue from the cannabis industry must fund prevention strategies to mitigate impacts on developing brains, Ms. Hurd and her colleagues wrote in the commentary.
The U.S. Drug Enforcement Agency (DEA) recently proposed to move cannabis to a Schedule III drug, which would reduce the penalty for selling or delivering the drug in states where it remains criminalized.
The legalization of medical marijuana in more states over the past few years has made cannabis widely accessible. However, Ms. Hurd noted that the current highly addictive strains are not benign. “The adolescent time period is a critical window for CUD risk,” she said, adding that this only makes the need for public health education and intervention more critical.
While “we should not criminalize the use,” she said, the move to make it legal and reduce penalties ignores the fact that the current strains are purposely made to be addictive because “like everything else, it’s a business, and the business is to get more customers.”
MGO, a glucose metabolite, can temporarily destroy the BRCA2 protein, reducing its levels in cells and inhibiting its tumor-preventing ability.
You may have heard that sugar feeds cancer cells, and evidence supports that. However, the missing link in this narrative has been a thorough understanding of just “how” sugar feeds cancer—until now. A recent study published in Cell in April uncovers a new mechanism linking uncontrolled blood sugar and poor diet with cancer risk.
The research, performed at the National University of Singapore’s Cancer Science Institute of Singapore, and led by professor Ashok Venkitaraman and Li Ren Kong, a senior research fellow at the University of Singapore, found a chemical released when the body breaks down sugar also suppresses a gene expression that prevents the formation of tumors.
This discovery provides valuable insights into how one’s dietary habits can impact their risk of developing cancer and forges a clear path to understanding how to reverse that risk with food choices.
Methylglyoxal–A Temporary Off Switch
It was previously believed that cancer-preventing genes must be permanently deactivated before malignant tumors can form. However, this recent discovery suggests that a chemical, methylglyoxal (MGO), released whenever the body breaks down glucose, can temporarily switch off cancer-protecting mechanisms.
Mr. Kong, first author of the study, told The Epoch Times in an email: “It has been shown that diabetic and obese individuals have a higher risk of cancer, posing as a significant societal risk. Yet, the exact cause remains debatable.
“Our study now unearthed a clue that may explain the connection between cancer risk and diet, as well as common diseases like diabetes, which arise from poor diets.
“We found that an endogenously synthesized metabolite can cause faults in our DNA that are early warning signs of cancer development, by inhibiting a cancer-preventing gene (known as the BRCA2).
BRCA2 is a gene that repairs DNA and helps make a protein that suppresses tumor growth and cancer cell proliferation. A BRCA2 gene mutation is associated primarily with a higher risk of developing breast and ovarian cancers, as well as other cancers. Those with a faulty copy of the BRCA2 gene are particularly susceptible to DNA damage from MGO.
However, the study showed that those without a predisposition to cancer also face an increased risk of developing the disease from elevated MGO levels. The study found that chronically elevated levels of blood sugar can result in a compounded increase in cancer risk.
“This study showcases the impact of methylglyoxal in inhibiting the function of tumour suppressor, such as BRCA2, suggesting that repeated episodes of poor diet or uncontrolled diabetes can ‘add up’ over time to increase cancer risk,” Mr. Kong wrote.
The Methylglyoxal and Cancer Relationship
MGO is a metabolite of glucose—a byproduct made when our cells break down sugar, mainly glucose and fructose, to create energy. MGO is capable of temporarily destroying the BRCA2 protein, leading to lower levels of the protein in the cells and thus inhibiting its ability to prevent tumor formation. The more sugar your body needs to break down, the higher the levels of this chemical, and the higher your risk of developing malignant tumors.
“Accumulation of methylglyoxal is found in cancer cells undergoing active metabolism,“ Mr. Kong said. ”People whose diet is poor may also experience higher than normal levels of methylglyoxal. The connection we unearthed may help to explain why diabetes, obesity, or poor diet can heighten cancer risk.”
MGO is challenging to measure on its own. Early detection of elevated levels is possible with a routine HbA1C blood test that measures your average blood sugar levels over the past two to three months and is typically used to diagnose diabetes. This new research may provide a mechanism for detecting early warning signs of developing cancer.
“In patients with prediabetes/diabetes, high methylglyoxal levels can usually be controlled with diet, exercise and/or medicines. We are aiming to propose the same for families with high risk of cancers, such as those with BRCA2 mutation,” Mr. Kong said.
More research is needed, but the study’s findings may open the door to new methods of mitigating cancer risk.
“It is important to take note that our work was carried out in cellular models, not in patients, so it would be premature to give specific advice to reduce risk on this basis. However, the new knowledge from our study could influence the directions of future research in this area, and eventually have implications for cancer prevention,” he said.
“For instance, poor diets rich in sugar or refined carbohydrates are known to cause blood glucose levels to spike. We are now looking at larger cancer cohorts to connect these dots.”
The Diet and Cancer Connection
Dr. Graham Simpson, medical director of Opt Health, told The Epoch Times in an email: “It’s genes loading the gun, but your lifestyle that pulls the trigger. Every bite of food you take is really information. It’s either going to turn on your longevity genes or it’s going to turn on your killer genes. So cancer is very much in large part self-induced by the individual diet.”
A 2018 study published by Cambridge University Press found an association between higher intakes of sugar-sweetened soft drinks and an increased risk of obesity-related cancers. Research published in the American Journal of Clinical Nutrition in 2020 concluded that sugars may be a risk factor for cancer, breast cancer in particular. Cancer cells are ravenous for sugar, consuming it at a rate 200 times that of normal cells.
Healthy Dietary Choices for Reducing Cancer Risk
A consensus on the best dietary approach for reducing cancer risk has yet to be determined, and further research is needed. However, the new findings of the Cell study on MGO support reducing sugar intake as a means to mitigate cancer risk. A study published in January in Diabetes & Metabolism shows that a Mediterranean diet style of eating may help reduce MGO levels.
In 2023, a study published in Cell determined that a ketogenic diet may be an effective nutritional intervention for cancer patients as it helped slow the growth of cancer cells in mice—while a review published in JAMA Oncology in 2022 found that the current evidence available supports a plant-enriched diet for reducing cancer risk.
Dr. Simpson stressed the importance of real food and healthy macronutrients with a low-carb intake for the health of our cells. “The mitochondria is the most important signaling molecule and energy-producing organelle that we have in our body. [Eat] lots of vegetables, healthy proteins, and healthy fats, fish, eggs, yogurt,” he said.
“Lots of green, above-ground vegetables, some fruits, everything that is naturally grown and is not processed.”
Question Is frontline ponatinib superior to imatinib when combined with reduced-intensity chemotherapy in adults with newly diagnosed Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL)?
Findings In this randomized clinical trial, ponatinib demonstrated a significantly higher minimal residual disease–negative complete remission rate at the end of induction (34.4% vs 16.7% with imatinib) and a comparable safety profile vs imatinib when combined with reduced-intensity chemotherapy in adults with newly diagnosed Ph+ ALL.
Meaning These efficacy and safety results support consideration of ponatinib as a frontline tyrosine kinase inhibitor in combination with chemotherapy for adults with newly diagnosed Ph+ ALL.
Abstract
Importance In newly diagnosed Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL), disease progression due to acquired resistance to first- or second-generation BCR::ABL1 tyrosine kinase inhibitors is common. Ponatinib inhibits BCR::ABL1 and all single-mutation variants, including T315I.
Objective To compare frontline ponatinib vs imatinib in adults with newly diagnosed Ph+ ALL.
Design, Setting, and Participants Global registrational, phase 3, open-label trial in adults aged 18 years or older with newly diagnosed Ph+ ALL. From January 2019 to May 2022, eligible patients at 77 sites were randomized 2:1 to ponatinib (30 mg/d) or imatinib (600 mg/d) with reduced-intensity chemotherapy, followed by single-agent ponatinib or imatinib after the cycle 20 phase of the trial. The last date of follow-up for this analysis was August 12, 2022.
Intervention Patients received ponatinib, 30 mg/d, or imatinib, 600 mg/d, with reduced-intensity chemotherapy, followed by single-agent ponatinib or imatinib after cycle 20. The ponatinib dose was reduced to 15 mg on achievement of minimal residual disease–(MRD) negative complete remission.
Main Outcomes and Measures The primary end point of this interim analysis was MRD-negative complete remission (≤0.01% BCR::ABL1 [MR4] centrally assessed by reverse transcriptase–quantitative polymerase chain reaction), with complete remission maintained for at least 4 weeks at the end of cycle 3. The key secondary end point was event-free survival.
Results Of 245 patients randomized (median age, 54 years; 133 [54.3%] female), 232 (ponatinib, n = 154; imatinib, n = 78) who had p190 or p210 dominant isoforms verified by the central laboratory were analyzed for the primary end point. The MRD-negative complete remission rate (primary end point) was significantly higher with ponatinib (34.4% [53/154]) vs imatinib (16.7% [13/78]) (risk difference, 0.18 [95% CI, 0.06-0.29]; P = .002). At the data cutoff, event-free survival had not met the prespecified number of events. Median event-free survival was not reached in the ponatinib group and was 29 months in the imatinib group. The most common adverse events were similar between treatment groups. Arterial occlusive events were infrequent and comparable between groups (ponatinib, 2.5%; imatinib, 1.2%).
Conclusions and Relevance Ponatinib demonstrated a superior rate of MRD-negative complete remission at the end of induction vs imatinib when combined with reduced-intensity chemotherapy in adults with newly diagnosed Ph+ ALL. The safety profile of ponatinib was comparable with imatinib.
Question Does the addition of inotuzumab ozogamicin (InO) to dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (DA-EPOCH) result in a safe and effective treatment for adults with relapsed or refractory B-cell acute lymphoblastic leukemia or lymphoma?
Findings In this phase 1 dose-escalation trial of 24 adult participants receiving DA-EPOCH-InO, the highest studied dose level of InO (0.6 mg/m2 on days 8 and 15) was the maximum tolerated dose. Significant severe hepatic toxic effects were rare, and there was only 1 case of sinusoidal obstructive syndrome.
Meaning The findings suggest that DA-EPOCH-InO is a safe, well-tolerated, and clinically active chemoimmunotherapy regimen warranting further clinical investigation.
Abstract
Importance Options for adults with relapsed or refractory B-cell acute lymphoblastic leukemia or lymphoma (B-ALL) are limited, and new approaches are needed. Inotuzumab ozogamicin (InO) has been combined with low-intensity chemotherapy, with modest improvements over historical controls, and dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (DA-EPOCH) treatment is safe and active for newly diagnosed ALL.
Objective To assess the safety and clinical activity of DA-EPOCH and InO in adults with relapsed or refractory B-ALL.
Design, Setting, and Participants This single-center, single-arm, nonrandomized, phase 1 dose-escalation trial included adults with relapsed or refractory CD22+ B-ALL and was conducted between September 2019 and November 2022. At least 5% blood or marrow blasts or measurable extramedullary disease (EMD) was required for enrollment.
Interventions DA-EPOCH was given on days 1 to 5, while InO was given on day 8 and day 15 of a 28-day cycle. Three dose levels were studied using a bayesian optimal interval design.
Main Outcomes and Measures The primary outcome was the maximum tolerated dose of InO when combined with DA-EPOCH, defined as the highest dose level that produced a rate of dose-limiting toxicity below 33%. Secondary objectives included response rates, survival estimates, and descriptions of toxic effects.
Results A total of 24 participants were screened and enrolled (median age, 46 [range, 28-76] years; 15 [62%] male). The median number of lines of prior therapy was 3 (range, 1-12). Three of 11 participants (27%) treated at the highest dose level (InO, 0.6 mg/m2, on day 8 and day 15) experienced dose-limiting toxicity, making this the maximum tolerated dose. No deaths occurred during the study, and only 1 patient (4%; 95% CI, 0.1%-21%) developed sinusoidal obstructive syndrome after poststudy allograft. The morphologic complete response rate was 84% (95% CI, 60%-97%), 88% (95% CI, 62%-98%) of which was measurable residual disease negative by flow cytometry. Five of 6 participants with EMD experienced treatment response. The overall response rate was 83% (95% CI, 63%-95%). Median overall survival, duration of response, and event-free survival were 17.0 (95% CI, 8.4-not reached), 15.0 (95% CI, 6.7-not reached), and 9.6 (95% CI, 4.5-not reached) months, respectively.
Conclusions In this study, adding InO to DA-EPOCH in adults with relapsed or refractory B-ALL was feasible, with high response rates and sinusoidal obstructive syndrome occurring rarely in a heavily pretreated population. Many patients were able to proceed to poststudy consolidative allogeneic hematopoietic cell transplant and/or chimeric antigen receptor T-cell therapy. Further investigation of this combination is warranted.
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