Remission

Cancer Trial Using Monoclonal Antibody Finds Remission in Every Patient

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A vial of Regeneron's monoclonal antibody treatment sits on a medical table next to a patient at the Sarasota Memorial Urgent Care Center in Sarasota, Fla., on Sept. 23, 2021. (Shannon Stapleton/Reuters)

A vial of Regeneron’s monoclonal antibody treatment sits on a medical table next to a patient at the Sarasota Memorial Urgent Care Center in Sarasota, Fla., on Sept. 23, 2021.

A cancer trial has reportedly become the first in the world to completely remove the disease in every patient, according to a study published on June 5 in The New England Journal of Medicine.

The study, “PD-1 Blockade in Mismatch Repair—Deficient, Locally Advanced Rectal Cancer,” was conducted among 12 rectal cancer patients, all of whom had a “clinical complete response,” according to the authors, led by Dr. Andrea Cercek of the Memorial Sloan Kettering Cancer Center in New York.

Doctors have been unable to see any evidence of tumors among the patients when using magnetic resonance imaging, fludeoxyglucose F 18 injections, physical examinations, or endoscopic evaluations, according to researchers.

The patients also continued to show no signs of cancer during follow-ups ranging from six months to 25 months and haven’t had to undergo surgery or receive radiation and chemotherapy.

“No adverse events of grade 3 or higher have been reported,” the study authors noted.

Specifically, the rectal cancer patients were given dostarlimab, a monoclonal antibody, every three weeks for six months. The patients had mismatch repair-deficient stage two or three rectal adenocarcinomas, a type of cancer.

The median age of the patients enrolled was 54 years old and 62 percent of them were women.

Typically, such cancer patients would have needed to undergo often debilitating treatments such as chemotherapy, radiation, or surgery, and in extreme cases be fitted with colostomy bags.

However, after taking dostarlimab, which is sold under the brand name Jemperli, no cases of progression or recurrence were reported in the patients who underwent the study.

Dostarlimab is already approved by the U.S. Food and Drug Administration for use in the treatment of adult patients with mismatch repair-deficient recurrent or advanced solid tumors. Rectal cancer is an off-label use, according to Medscape.

According to drugs.com, the cost of Jemperli intravenous solution (500 milligrams/10 milliliters) is around $11,201 for a supply of 10 milliliters.

The results of the study were also presented at the American Society of Clinical Oncology 2022 annual meeting.

“Mismatch repair-deficient, locally advanced rectal cancer was highly sensitive to single-agent PD-1 blockade,” the authors wrote, acknowledging that extended follow-up is needed to assess the duration of response.

Dr. Luis A. Diaz Jr. of Memorial Sloan Kettering Cancer Center, author of the study, told The New York Times that he believes this is the “first time this has happened in the history of cancer.”

“The implications for quality of life are substantial, especially among patients in whom standard treatment would affect child-bearing potential [and] given that the incidence of rectal cancer is rising among young adults of childbearing age, the use of PD-1 blockade to eliminate the need for chemoradiotherapy and surgery may confer a particular benefit in that age group,” the authors wrote.

The study was supported by the Simon and Eve Colin Foundation, GlaxoSmithKline, Stand Up to Cancer, Swim Across America, and the National Cancer Institute of the National Institutes of Health.

About one-third of the 145,000 cases of colorectal cancers diagnosed each year are found in the rectum, according to the Cancer Treatment Centers of America, and the risk of this specific type of cancer increases with age, although men are typically at a higher risk than women.

Nearly half of adults with type 2 diabetes saw remission with calorie restriction, timing

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Nearly half of a cohort of adults with type 2 diabetes participating in a calorie-restricted intermittent fasting intervention achieved diabetes remission, according to findings from a randomized controlled trial in China.

In a study published in The Journal of Clinical Endocrinology & Metabolism, adults who participated in the Chinese Medical Nutrition Therapy dietary approach that encompassed 5 days of intermittent fasting followed by 10 days of eating ad libitum had greater reductions in fasting blood glucose and HbA1c than adults eating an ad libitum diet alone 3 and 12 months after the trial ended.

A calroie-restricted intermittent fasting intervention led to diabetes remission in more than 40%
Data were derived from Yang E, et al. J Clin Endocrinol Metab. 2022;doi:10.1210/clinem/dgac661.

“This study was performed under real-life conditions, and the intervention was delivered by trained nurses in primary care rather than by specialized staff at a research institute, making it a more practical and achievable way to manage type 2 diabetes,” Dongbo Liu, PhD, director of the Subhealth Intervention Technology Laboratory at the State Administration of Traditional Chinese Medicine, China, told Healio. “It could be a shift in the paradigm of management goals in diabetes care.”

Dongbo Liu

Liu and colleagues conducted a parallel-design, open-label, randomized controlled trial in which 72 adults aged 18 to 75 years diagnosed with type 2 diabetes and taking at least one diabetes medication were enrolled. Half the participants were randomly assigned to a control group eating an ad libitum diet for the entire trial. The rest were randomly assigned to eat about 840 kcal per day in an intermittent fasting regime with breakfast between 6:30 and 8:30 a.m., lunch between 11 a.m. and 1 p.m., and dinner between 5 and 7 p.m. The intervention group completed 5 days of intermittent fasting followed by 10 days of an ad libitum diet. The intervention cycle was completed six times in 90 days.

“The Chinese Medical Nutrition Therapy diet is a food-based diet instead of meal replacement products,” Liu said. “It allowed the participants to follow their habitual social eating patterns, which avoided discontinuing treatment due to difficulty in maintenance. The trial was designed to be pragmatic in nature and could be beneficial for implementing similar interventions in the community.”

Diabetes medications were adjusted during the trial based on blood glucose levels. The primary outcome was diabetes remission, defined as a stable HbA1c of less than 6.5% for at least 3 months without taking a diabetes medication. Anthropometric measures, blood pressure and biochemical assessments were performed at baseline, the end of the intervention and at follow-up 3 and 12 months after the intervention concluded.

At the end of the trial, 50% of the intervention group had stopped using diabetes medications, and 68.4% reduced their medication dose compared with 2.8% of the control group. The intervention group had a lower FBG (6.3 vs. 7.66 mmol/L; P < .0001) and a greater body weight reduction (5.93 kg vs. 0.27 kg; P < .0001) than the control group.

At the 3-month follow-up, 47.2% of the intervention group achieved diabetes remission compared with 2.8% of the control group (P < .0001). The intervention group had a lower HbA1c (5.66% vs. 7.87%; P < .0001) and FBG (5.84 mmol/L vs. 7.64 mmol/L; P < .0001) than controls.

At the 12-month follow-up, 44.4% of the intervention group achieved diabetes remission compared with none in the control group. The intervention group continued to maintain a lower HbA1c (6.33% vs. 7.76%; P < .0001) and FBG (6.17 mmol/L vs. 7.47 mmol/L; P < .0001) than the control group.

“These participants have been followed up for 1 year and a follow-up of 5 years or more is ongoing to explore the stability of the Chinese Medical Nutrition Therapy diet and its impact on complications,” Liu said. “An experiment with more participants and a wider area is being pushed forward to further explore the effectiveness.”

Even Leaner People with Type 2 Diabetes Can Achieve Remission

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A new study has demonstrated that weight loss can lead to remission from type 2 diabetes even for people that are not overweight.

We already know that some people with type 2 diabetes can achieve remission, but most research suggests that it generally requires dramatic weight loss. So where does that leave patients with type 2 diabetes that have less weight to lose?

Contrary to the stereotypes, sometimes even lean adults develop type 2 diabetes. According to the CDC’s National Diabetes Statistics Report (PDF), about 11% of the United States’ estimated 34 million adults with diabetes have a BMI under 25 kg/m2, indicating “normal” weight. (An additional 27.6% are classed as “overweight,” but not obese.)

The ReTUNE trial, out of the UK’s Newcastle University, suggests that even comparatively lean patients with diabetes can put their conditions into remission. And the method is the just same: cutting calories and losing weight.

The trial enrolled adults with type 2 diabetes that had a BMI near 25 kg/m2, the official border between “normal” and “overweight.” Participants were asked to follow a strict 800-calorie per day diet consisting of “formula meal replacements and non-starchy vegetables.” They would alternate between 2-4 weeks of the crash diet and 4-6 weeks of a weight-loss maintenance diet, repeating the cycle up to three times.

In results shared at the recent 2022 Diabetes UK Professional Conference , an incredible 70% of ReTUNE participants were said to achieve remission. These lucky patients lost an average of 8% of their bodyweight, and enjoyed significant improvements to their A1C despite ceasing the use of glucose-lowering medications.

The results are impressive, but a few warnings are in order:

  • The study was extremely small (only 20 participants).
  • All participants had been diagnosed with type 2 in the previous five years. There’s reason to doubt that intervention would be as effective for people with long-standing diabetes.
  • We don’t know what will happen to these participants in the future. Most experts believe that losing weight in the first place is actually the easy part. Maintaining weight loss is the real struggle. Does a crash diet set patients up for sustainable success?

This isn’t the first time the same research team has shown that very low-calorie diets can make a big difference. Dr. Roy Taylor also led the DIRECT trial, which placed adults with type 2 diabetes on a very low-calorie diet for 3-5 months and then offered significant weight management training and support for up to two years. An impressive 36% of those participants achieved diabetes remission by the end of the second year. Among those that lost at least 10kg (about 22 lbs.), a majority (64%) achieved remission.

Dr. Taylor’s unifying theory of diabetes is the personal fat threshold, which argues that every individual has a unique level of excess fat accumulation that they can handle. Some people may develop type 2 diabetes after gaining only a little weight, while others can sustain extreme obesity without ever becoming diabetic. As Dr. Taylor told the Guardian, “The bottom line is, a person will develop type 2 diabetes when they’ve become too heavy for their own body. It doesn’t matter if their BMI is within the ‘normal’ range. They’ve crossed their personal threshold and become unhealthy.”

Although leaner people with diabetes have less weight to lose, the theory goes, they have just as much to gain from losing it.

Dr. Taylor is eager to spread the word. On his university webpage, you can find links to his books and Youtube talks, and even a list of approved meal-replacement shakes. Last year the Guardian published a profile of Dr. Taylor and his methods, another resource for curious readers.

Other trials unrelated to Dr. Taylor’s research have similarly shown that very low-calorie diets can be effective in reversing the progression of type 2 diabetes. But those should perhaps be weighed against the fact that most dieting authorities caution against crash diets, believing that they do not prepare dieters for the type of sustainable healthy adjustments that they’ll need to maintain weight loss for years into the future.

It should go without saying that anyone contemplating an extreme diet should speak to their doctor first.

Brother’s Stem Cells Make Remission Possible for Pediatric Leukemia Patient

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How do you repay someone who has given you the gift of life? Eight-year-old Emma Duffin of Enfield, Connecticut, started by giving a kiss and cuddle to her brother, Alexander, who donated his bone marrow stem cells to Emma to reboot her immune system and send her rare form of leukemia into remission.

Emma’s journey to a stem cell transplant began in April 2014, when her usual energetic demeanor began to change. “Emma was very vibrant, very active, and she did not like to rest,” says her father, Brian Duffin. But suddenly his go-go daughter was exhausted all the time. She was diagnosed with strep throat, then foot-and-mouth disease, but neither medication nor time brought any improvement.

During yet another trip to the emergency room, a blood draw revealed Emma had an alarmingly low level of hemoglobin – a 3 instead of the normal range for a juvenile of 11 or higher.

“For an adult, such low levels would have been fatal,” Brian says. Emma was rushed to Connecticut Children’s Medical Center (CCMC), where she was diagnosed a few days later with acute undifferentiated leukemia.

Most leukemias fall into two types: acute lymphocytic leukemia (ALL) or acute myeloid leukemia (AML). Each type is treated with a distinct protocol. Acute undifferentiated leukemia is a subset of the disease that shows markers of both types.

“As a result, part of the leukemia is often resistant to one protocol or the other,” explains Steven Margossian, MD, PhD, a senior physician of pediatric hematology and oncology at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center. “In this circumstance, the best approach is often a bone marrow stem cell transplant. The bone marrow is the factory where leukemia cells are made. By using strong chemotherapy to destroy the existing bone marrow cells, you can then replace those with normal, healthy cells from a donor as closely matched to the patient as possible.”

In Emma’s case, Alexander ended up being her perfect match.

Emma’s oncologist at CCMC trained under Dr. Margossian and referred the family to her mentor.

“When your doctor tells you the number one pediatric stem cell transplant hospital in the world is only 90 minutes from your house, you don’t question it,” says Allyson Duffin, Emma’s mom.

After Emma completed three rounds of chemotherapy at CCMC, the Duffin family traveled to Boston to prepare for “zero day”: the day Dr. Margossian would perform the stem cell transplant. Prior to the transplant, Emma had one last round of high-dose chemotherapy and radiation – a typical pre-transplant treatment called conditioning therapy – to wipe out any remaining malignant stem cells. Then, on zero day, Margossian’s team harvested and processed Alexander’s stem cells and prepared Emma for the infusion. Brian had the privilege of pushing the button that began the infusion, transferring this gift of life from his son to his daughter.

Emma remained at Boston Children’s Hospital for about a month until engraftment, or the point at which the new stem cells produce enough neutrophils, a specific kind of white blood cell, to provide protection against bacterial infection.

“She was still energetic during that time; she has a zest for life that is unquestionable,” Brian says.

On Halloween, Emma dressed as Elsa and enjoyed “reverse trick-or-treating,” as doctors and nurses brought candy to her on their rounds.

Still, the month of recovery had its challenges. The conditioning therapy often causes the onset of mucositis, an extremely painful inflammation of the mucous membranes that line the digestive tract. Emma’s case was especially severe; she had to be fed through a nasal tube.

“For 95 percent of stem cell patients, the pain of mucositis is what they remember the most about their transplant,” Margossian says.

Emma also endured graft-versus-host disease (GVHD), another expected side effect of a stem cell transplant in which the donor’s white blood cells (the “graft”) attack the host’s cells, which can cause skin rashes and irritate the digestive system and liver.

“Emma’s nurses were very proactive about it,” Allyson says. “They gave her Benadryl and used every lotion known to man to soothe her skin.”

After Emma was released from the hospital, she remained in quarantine at home for nine months, allowing her fragile immune system to gradually rebuild itself without unnecessary exposure to germs in indoor public places. She entertained plenty of visitors on her front porch, relished rides around town with her family, and enjoyed the occasional meal on the outside patio at her favorite restaurant.

When Emma’s quarantine restrictions were lifted on June 1, 2015, “she celebrated by doing anything and everything,” Brian says with a laugh. “She shopped, she visited friends, she ate inside at her favorite restaurant – and she was excited to go back to school.”

Today, Emma remains healthy. “You would never know she had been so sick,” Allyson says. Now 11, Emma is in a dance troupe and involved in acting. She plays trumpet in her school band. And yes, she and Alexander are back to the usual sibling antics.

“Kids often bounce back more easily, physically and psychologically, because they are more resilient,” Margossian said. “Emma is spunky, and her energetic attitude went a long way in positively influencing her recovery.”

Source:http://www.dana-farber.org

 

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AML: Conjugate Produces High Remission Rates in Older Patients

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Early promising results for antibody-drug conjugate delivered with hypomethylating agents.

Older adults who are newly diagnosed with acute myeloid leukemia (AML) are often not sufficiently fit to withstand the rigors of remission induction therapy with cytarabine and an anthracycline such as daunorubicin or idarubicin. Other patients may decline to have intensive therapy due to frailty or concerns about toxicities. For these patients, clinicians in the United States often prescribe lower-intensity therapy with the hypomethylating agents decitabine and/or azacitdine, but these agents are both associated with low response rates and limited clinical benefits, according to treatment information from theNational Cancer Institute.

However, an investigational therapy consisting of a conjugated monoclonal antibody combined with hypomethylating agents (HMAs) has been shown in early clinical trials to induce high complete or near-complete remission rates in older adults with AML.

At the 2016 annual congress of the European Hematology Association, Amir T. Fathi, MD, from Massachusetts General Hospital Cancer Center in Boston, reported data from a phase I study of older adults with AML who were treated with a combination of the monoclonal antibody drug conjugate vadastuximab talirine (33A; Seattle Genetics) and either azacitdine or decitabine.

Among 49 patients evaluable for efficacy, the combined rate of complete remissions (CR) or CR with incomplete recovery of counts (CRi) was 71%.

“The high remission rate in this traditionally high-risk group and difficult-to-treat population is very compelling,” Fathi said. “Response rates were higher, and were achieved more quickly than would be expected from historical data associated with HMA therapy alone.”

Target: CD33

33A is a highly potent antibody-drug conjugate designed to deliver a cytotoxic agent to myeloid leukemia cells. The agent is targeted to CD33 receptors that are expressed on leukemic blasts in nearly all cases of AML. The antibody is conjugated to two molecules of a pyrrolobenzodiazepine (PBD) dimer. Upon binding to the receptors, the conjugate is internalized and transported to cellular lysosomes where the PBD dimer is released via proteolytic cleavage of the linker, resulting in a crosslinking of DNA, and leading to cell death.

The cell-killing activity of this agent had been shown in preclinical studies to be enhanced when delivered in combination with hypomethylating therapy, Fathi noted.

For the phase I trial, the combination of 33A and a hypomethylating agent was tested in 53 adults with a median age of 75. The patients all had CD33-positive AML, and all had declined to undergo an intensive chemotherapy induction regimen. Five patients had previously received low-intensity therapy for myelodysplastic syndromes, and the remaining 48 patients had not received any prior therapy for AML.

Enrollment criteria included an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1. Nineteen of the patients had adverse cytogenetic-risk disease, and 30 had intermediate-risk disease.

The patients received 33A in intravenous infusions of 10 mcg/kg delivered in an outpatient setting every 4 weeks on the last day of a hypomethylating therapy regimen — either azacitidine at 75 mg/m2 for 7 days, or decitabine at 20 mg/m2 for 5 days. Patients who had clinical benefit could be continued on treatment until disease relapse or unacceptable toxicity.

Responses were assessed by investigators according to the International Working Groupfor Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia (IWG). CRi was defined as either a platelet count of ≥100,000/µL or neutrophils of ≥1,000/µL.

The combined CR/CRi rate among the 49 patients evaluable for response at the time of data cutoff was 71%, with no difference in the rate of complete or near-complete remissions between patients treated with azacitidine or decitabine.

The overall response rate (CR, CRi, and partial responses) was 76%. Encouragingly, Fathi said, many higher-risk patients had responses, including 15 of 18 patients with adverse cytogenetics, and 16 of 22 with underlying myelodysplasia.

Eight of the 19 patients who had a CR met the criteria for minimal residual disease, as did 5 of 15 who achieved a CRi.

The overall survival results were ongoing at the time of the presentation. After a median follow-up of 12.58 months, the estimated median overall survival for the first 25 patients enrolled in the study was 12.75 months; and as of the most recent follow-up, 27 were alive and remained on study.

The median relapse-free survival was 7.7 months; 30- and 60-day mortality rates were 2% and 8%, respectively. There were no treatment-related deaths reported.

Safety Profile

Patients generally tolerated the therapy well, Fathi said. Grade 3 or greater adverse events reported in at least 20% of patients included, in order of frequency, febrile neutropenia (47% of patients), thrombocytopenia (42%), anemia (34%), and neutropenia (28%).

Other common treatment-emergent adverse events were fatigue, nausea, constipation, decreased appetite, and peripheral edema.

Fathi noted that a phase III trial to evaluate 33A in combination with hypomethylating agents in previously untreated older AML patients is now open for enrollment.