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Studies Highlight Novel Approaches to Screening for and Treating Blood Disorders

Emerging research also highlights possible association between blood abnormality and Alzheimer’s disease

(WASHINGTON, Dec. 11, 2021) – Three studies being presented during the 63rd American Society of Hematology (ASH) Annual Meeting and Exposition throw a spotlight on novel approaches to screening for and treating blood diseases, as well as an unexpected, potential association between a blood abnormality and Alzheimer’s disease.

The first study demonstrates how the use of high-sensitivity screening techniques for the early detection of blood abnormalities may identify people at high risk for multiple myeloma earlier – especially Black patients and those with a first-degree relative with the disease – giving them more timely access to treatment. The second reveals a surprising possible association between a fairly common blood abnormality in older adults and a reduced risk for Alzheimer’s disease, the most common cause of dementia. And in the third – the largest study to date of gene therapy for a blood disorder – investigators report on a novel treatment strategy with the potential to dramatically improve both the quality and quantity of life for patients with a severe form of an inherited blood disease.

“Each of these studies is compelling in its own way,” said press briefing moderator Joseph Mikhael, MD, of the Translational Genomics Research Institute. “The first presents a strong case for screening people at high risk for multiple myeloma. This could have important health equity implications because multiple myeloma is twice as common among African Americans as in the general population. In the second study, the possible association with Alzheimer’s disease is intriguing and, of course, any new approach that might alter the course of this terrible disease is desirable. Last, but not least, the third study offers a welcome new approach that could lighten the burden of a devastating blood disease, beta thalassemia.”

This press briefing will take place on Saturday, December 11, at 10:30 a.m. Eastern time in press briefing room A315.

Older Adults at High Risk for Multiple Myeloma Precursor Condition May Benefit from Screening

152: High Prevalence of Monoclonal Gammopathy in a Population at Risk: The First Results of the Promise Study

The first results from the largest screening study yet conducted in the United States of people at high risk for the blood cancer multiple myeloma show that older adults who are Black or who have an immediate family member with a current or past blood cancer have higher rates of multiple myeloma precursor conditions and may benefit from periodic screening and early intervention that might prevent the disease.

“We know that in cancers such as breast cancer and lung cancer, screening, early detection, and early intervention can make a difference in patient survival,” said Irene M. Ghobrial, MD, of the Dana-Farber Cancer Institute in Boston. “We have shown for the first time that with highly sensitive screening techniques it may eventually be possible to make a difference in the survival of people at elevated risk for multiple myeloma.”

A precancerous condition called monoclonal gammopathy of undetermined significance (MGUS) carries a 1%-per-year risk of progressing to multiple myeloma. The defining feature of MGUS is a moderately elevated blood level of protein known as monoclonal, or M protein, which is made by plasma cells, a type of white blood cell. MGUS has no signs or symptoms and currently doctors do not routinely screen patients for it, Dr. Ghobrial said.

A previous study estimated that 3% of Americans ages 50 and older have MGUS, but that study was conducted in people predominantly of European descent. Although studies have shown that people of African descent and those with a family history of blood cancers are at increased risk for multiple myeloma, no previous study had looked at the prevalence of MGUS in a prospectively followed high-risk population.

The PROMISE study, launched in 2019, aims to enroll 30,000 people ages 40 to 75 who are at above-average risk for multiple myeloma because they are Black or have a parent, sibling, or child with a history of multiple myeloma or another blood cancer. Study participants provide a blood sample that is tested for MGUS using both conventional and newer high-sensitivity techniques. All PROMISE study participants who test positive for MGUS are referred to a medical specialist in the treatment of blood cancers for further testing and follow-up.

To ensure adequate representation of people of African descent in the study population, Dr. Ghobrial and colleagues also identified and screened Black people who had contributed blood samples to a large biological specimen repository, the Mass General Brigham Biobank in Boston. For this cohort, up to 10 years of follow-up data were available.

In the current study, the investigators report interim screening findings for 7,622 participants, including 2,439 Black people.

“Ours is the largest cohort of Black people to be recruited for a myeloma screening study and the first prospective study to actively recruit people at high risk for multiple myeloma, follow them over time to accurately estimate the prevalence of MGUS, and explore outcomes for patients with this precursor condition,” said Dr. Ghobrial.

“Using screening techniques that are currently available in doctors’ offices, we show that the prevalence of MGUS in a high-risk population over age 50 – Black people and people who have a first-degree relative with a blood cancer – is twice as high as in the general United States population,” she said. “Using a novel, high-sensitivity screening technique (mass spectrometry), we detected MGUS in 14% of participants. And when we fully employ the capability of mass spectrometry to detect even minute amounts of M-protein in the blood, we can detect the protein in 42% of the high-risk population over age 50.”

When the investigators examined the follow-up data for participants whose samples came from the Biobank, they found that, after a median of 4.5 years of follow-up, those with any level of M-protein had negative health effects, seen as a slightly higher mortality rate from any cause than people who had no M-protein in their blood.

“This suggests that people with M-protein are at risk of not only multiple myeloma but also of other conditions, including other blood cancers and heart attacks,” said Dr. Ghobrial. “We believe these results make a strong case that older adults who are Black or who have a first-degree relative with a blood cancer could benefit from regular, high-sensitivity screening, and early intervention.”

In the future, Dr. Ghobrial and her research team hope that the PROMISE study will help identify the factors that contribute to the development of MGUS, cause MGUS to progress to overt cancer in some people but not others, and result in negative health effects for people who have any level of M-protein in their blood.

Habib El-Khoury, Dana-Farber Cancer Center, will present this study during an oral presentation on Saturday, December 11, at 12:00 noon Eastern time in Georgia Ballroom 1-3.

Mutations that Heighten the Risk for Blood Cancers and Heart Disease Are Associated with Lower Odds of Alzheimer’s Disease

5: Clonal Hematopoiesis Is Associated with Reduced Risk of Alzheimer’s Disease

Random changes in certain genes that cause blood-forming stem cells to accumulate unchecked, and that have been shown to increase tenfold the risk of developing a blood cancer, may be associated with a reduced risk of Alzheimer’s disease.

“We found the opposite of what we were expecting,” said Siddhartha Jaiswal, MD, of Stanford University. “Our hypothesis was that these mutations would be associated with an increased risk of Alzheimer’s disease, but we found an overall 35% to 40% reduced risk for Alzheimer’s, although this is an association and does not address causality.”

The mutations, known collectively as clonal hematopoiesis of indeterminate potential (CHIP), are increasingly common with aging, and are acquired (i.e., they develop during a person’s lifetime) rather than inherited. CHIP is found in at least 10% to 20% of people over age 70. Previous studies have shown that people with CHIP have about a 1% per year chance of developing leukemia or another blood cancer and are at nearly double the average risk for heart disease. CHIP itself has no signs or symptoms and is generally detected only when a person undergoes genetic testing for another condition (e.g., for a solid tumor or an unexplained low blood count).

According to the Alzheimer’s Association, an estimated 6.2 million Americans ages 65 and older are currently living with Alzheimer’s disease, a progressive neurodegenerative disease that is now thought to begin with changes in the brain that start at least 20 years before symptoms appear. Most people who develop the disease have the late-onset form, in which symptoms become noticeable in their mid-60s or later. Currently available treatments may temporarily improve symptoms such as memory loss, but do not stop the brain damage that causes the disease to get worse over time. While no specific gene has been identified as the cause of late-onset Alzheimer’s disease, carrying a variant form of a gene known as APOE affects a person’s risk for developing the disease.

“APOE has several different forms,” said Dr. Jaiswal. “The ones most relevant to Alzheimer’s are e2, which decreases risk; e3, which has a neutral effect on risk; and e4, which significantly increases risk. In our study, if people had the protective e2 form of the gene, CHIP did not seem to have any effect. But for carriers of e3 and e4, the risk reduction associated with CHIP was comparable to or greater than that of APOE e2.”

Dr. Jaiswal and his colleagues analyzed anonymized data from 5,730 people who had contributed blood samples to one of two large, ongoing precision medicine studies: Trans-Omics for Precision Medicine or TOPMed, sponsored by the National Heart, Lung, and Blood Institute, and the Alzheimer's Disease Sequencing Project, sponsored by the National Human Genome Research Institute and the National Institute on Aging. They matched data on whether or not people carried a CHIP mutation and an APOE mutation. The two cohorts were about 60% female, with an average age ranging from 60 to 80, and were predominantly white. They found an association between CHIP mutations and a lower likelihood of developing Alzheimer’s disease or changes in the brain typically seen in people with Alzheimer’s disease.

The investigators also examined brain tissue samples from autopsies performed on eight donors who had CHIP, six of whom were cognitively normal when they died. They identified the CHIP mutation in cells known as microglia, which are “the immune cells of the brain,” said Dr. Jaiswal.

“Previous studies have shown that Alzheimer’s disease is largely a disease of the microglia,” he said. “Other studies – by our group and others – have shown that the mutations that cause CHIP dysregulate the body’s immune response, resulting in inflammation, which we think is the underlying cause of the increased heart-disease risk seen in carriers of CHIP.”

There is also a long-standing suspicion that inflammation plays a role in the development of Alzheimer’s disease, Dr. Jaiswal added.

“Our thinking now is that the job of the microglia may be to clear out the toxic lumps of protein that accumulate in the brains of people with Alzheimer’s. As we age, normal microglia may do this less well, but something about the CHIP mutation may allow the mutated microglia to continue effectively performing this task. Proving this – and figuring out what it is about the CHIP mutation that exerts this protective effect – could ultimately lead to the development of new treatments for Alzheimer’s disease,” he explained.

Dr. Jaiswal cautioned that while the current findings show an association between the presence of the CHIP mutation and a reduced risk for Alzheimer’s disease, he and his team have not proven that the mutation directly explains the potential for reduced risk.

Hind Bouzid, Stanford University School of Medicine, will present this study during a plenary presentation on Sunday, December 12, at 2:00 p.m. Eastern time in Hall B211-B212.

Patients with Beta Thalassemia Major Achieve Transfusion Independence After Gene Therapy

573: Restoring Iron Homeostasis in Pts Who Achieved Transfusion Independence after Treatment with Betibeglogene Autotemcel Gene Therapy: Results from up to 7 Years of Follow-up

In an international study, the largest to date of gene therapy for a blood disorder, patients with a severe genetic disorder who had previously been dependent on regular blood transfusions to stay alive were able to go for a median of 32 months without a transfusion after receiving a single infusion of their own blood-forming stem cells that had been altered to correct the genetic mutation that caused their disease.

“For these patients – many of whom have been transfusion dependent for decades – being able to discontinue chronic transfusions is an extraordinary, almost unthinkable accomplishment,” said study author Alexis A. Thompson, MD, MPH, of the Ann & Robert H. Lurie Children’s Hospital of Chicago. “While there is not yet consensus to say that these patients are cured, we are hopeful that – with seven years of follow-up to date – we have demonstrated the durability of this gene therapy approach.”The patients have a severe form of beta thalassemia (beta thal), an inherited disease in which the body makes too little hemoglobin, a substance in red blood cells that carries oxygen to the body’s cells. The disease is caused by a mutation in the beta-globin gene, which carries the instructions for the body to manufacture one of the proteins that make up hemoglobin. A shortage of hemoglobin leads to a shortage of healthy red blood cells, causing anemia, symptoms of which include fatigue, weakness, shortness of breath, dizziness or headaches, and susceptibility to infections.

People with the most severe form of beta thal, known as beta thal major, need lifelong regular blood transfusions, an adverse effect of which is iron overload, or excess levels of iron in the body. Over time, iron overload can cause severe damage to multiple organs. Although patients take drugs to reduce their iron levels (known as chelation therapy), many nevertheless develop chronic diseases such as heart disease, diabetes, and osteoarthritis.

While relatively rare in the United States, beta thal is common in other parts of the world, including the eastern Mediterranean region, Middle East, Africa, and South Asia. It affects men and women about equally, and symptoms typically appear by age two.

In the study, 51 patients (55% female, median age 19) first underwent a procedure to harvest their blood-forming stem cells. Each patient’s cells were sent to a laboratory, where a healthy copy of the beta-globin gene was inserted into them. Then the cells were frozen, shipped back, thawed, and re-infused into the patient.

After completing two years of follow-up, patients had the option to enroll in a long-term study in which they would be followed for up to an additional 13 years. The current study reports results for patients with up to seven years of follow-up since they received their genetically modified stem cells.

After a median of 44 months of follow-up, 40 patients (78%) had achieved transfusion independence, which was defined in the study as not needing a transfusion of red blood cells for at least one year while maintaining a safe hemoglobin level.

Patients stopped iron chelation therapy at least seven days before infusion of their genetically modified stem cells. “Many patients will still have iron overload after stem cell transplant that warrants resumption of chelation treatment,” said Dr. Thompson. The current study shows that thalassemia patients who achieved transfusion independence after gene therapy experienced reductions in iron overload following chelation therapy, and that iron control was maintained after chelation was discontinued.

Eight patients experienced serious adverse events while in the long-term follow-up study. No adverse events related to the genetic modification of the patients’ stem cells were reported beyond two years after treatment.

A transplant of healthy stem cells from a matched sibling donor remains the standard of care for beta thal major, Dr. Thompson said. Gene therapy, however, offers a new treatment option for patients who do not have a matched sibling donor.

Alexis A. Thompson, Ann & Robert Lurie Children’s Hospital of Chicago, will present this study during an oral presentation on Monday, December 13, at 10:30 a.m. Eastern time in C202-C204.

Press Briefing Highlights
AM Highlights Image: Blood Disorders

Additional press briefings will take place throughout the meeting on immunotherapy, diversifying care in acute leukemia, COVID-19, and selected late-breaking abstracts. For the complete annual meeting program and abstracts, visit www.hematology.org/annual-meeting. Follow ASH and #ASH21 on Twitter, Instagram, LinkedIn, and Facebook for the most up-to-date information about the 2021 ASH Annual Meeting.

The American Society of Hematology (ASH) (www.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. For more than 60 years, the Society has led the development of hematology as a discipline by promoting research, patient care, education, training, and advocacy in hematology. ASH publishes Blood (www.bloodjournal.org), the most cited peer-reviewed publication in the field, and Blood Advances (www.bloodadvances.org), an online, peer-reviewed open-access journal.

Leah Enser, American Society of Hematology
[email protected], 202-552-4927