63rd ASH Annual Meeting and Exposition
December 11-14, 2021
  • COVID-19 Takes a Toll on People with Blood Cancers and Disorders
  • Studies Highlight Novel Approaches to Screening for and Treating Blood Disorders

Studies aim to evaluate impact of COVID-19-related infection, treatments, and vaccination across this uniquely vulnerable population


As the COVID-19 pandemic continues to evolve, five studies being presented during the 63rd American Society of Hematology (ASH) Annual Meeting and Exposition shed light on the persisting burden that COVID-19 has had on people with underlying blood disorders.

“We take care of the patients at the highest risk for COVID-19 illness and those who are among the least likely to respond to the vaccine; these and other studies underscore the dual vulnerability facing many of our patients,” said press briefing moderator, Laura Michaelis, MD, of the Medical College of Wisconsin. “Hematologists have continued to play a unique role in contributing to the emerging science of COVID-19, especially given our expertise in clotting, and ASH has continued to provide leadership in an uncertain time with vetted resources and timely guidance for how best to manage our patients amid the pandemic.”

Two studies analyze data from the ASH Research Collaborative (ASH RC) COVID-19 Registry for Hematology, which started in the early days of the pandemic to provide real-time observational data summaries to clinicians on the front lines of the fight against COVID-19, as well as researchers and providers around the world. In September 2021, the Centers for Disease Control and Prevention (CDC) awarded the ASH RC funding to identify the overall burden of COVID-19, the effects of health disparities and outcomes, and the areas where future resources should be focused for treatment for people living with hematologic malignancies. Specifically, CDC funding, in part, supports additional data submissions to the ASH RC COVID-19 Registry, real-time public data summaries, and research activities. As the Registry dataset has grown, researchers have identified potential drivers of severe illness, hospitalization, and mortality. The data also suggest that aggressive supportive treatment of COVID-19 can improve outcomes for many patients and should be offered.

A third study conducted among individuals living with sickle cell disease (SCD), suggests COVID-19 infection can cause occlusive events, resulting in pain episodes, but these patients seem to respond to COVID-19 treatments and also were quick to adopt precautions and shift to virtual appointments as needed.

The final two studies look at antibody response following vaccination among people with various hematologic malignancies, helping give clues into which groups of patients may still be at high risk of COVID-19 after getting the vaccines.

“A number of studies have shown that people with blood cancers have less than optimal responses to vaccination, and there is a need to continue to push for mitigation strategies,” said Dr. Michaelis.

This press briefing will take place on Saturday, December 11, at 12:30 p.m. Eastern time in press briefing room A315.


3040: Risks for Hospitalization and Death Among Patients with Blood Disorders from the ASH RC COVID-19 Registry for Hematology

Patients with blood cancers, particularly those with more advanced disease, are especially vulnerable to serious COVID-19 outcomes, including an elevated chance of severe illness and death from COVID-19, according to an analysis of more than 1,000 patients in the ASH RC COVID-19 Registry for Hematology. Based on the report, 17% of patients with blood cancers who developed COVID-19 died from COVID-related illness, a strikingly higher mortality rate than what was seen in the general population, according to researchers. Older age, male sex, poor cancer prognosis, and electing to defer intensive care when it was recommended were all independently associated with a heightened chance of dying.

“In our analysis, having a poor prognosis for underlying disease prior to COVID-19 and deciding to forgo ICU-level care for that disease were the most powerful predictors of mortality among patients with blood cancer and COVID-19–and the two may very well be related,” said Lisa K. Hicks, MD, MSc, of St. Michael’s Hospital in Toronto, Canada. “If someone is sick enough to require ICU-level care and their preference is not to receive this type of care, we would expect that decision to have a major impact on their survival.”

According to the data, patients whose physician had estimated that they had less than six months to live due to their cancer before getting COVID-19 had six-fold higher odds of dying and these odds nearly doubled among people who decided to forgo more intensive care due to COVID-19. However, these groups represented a small proportion of the overall sample with only 7% estimated to have a pre-COVID-19 prognosis of under six months, and 9% deferring ICU care.

Of particular interest to the field was whether blood cancer treatment would affect COVID-19 mortality. Most patients included in the dataset (71%) received cancer treatment during the previous year; others were either in remission or had not yet needed treatment. In addition, receiving cancer treatment in the year prior to COVID-19 infection did not significantly increase the risk of death as some had feared; however, it was linked to an increased risk of hospitalization if infected by COVID-19. Older age, being male, having active cancer, and having other health conditions were also associated with an increased risk of hospitalization from COVID-19 among patients with blood cancers.

“In the early days of the pandemic, there was a lot of uncertainty about whether we should withhold or modify blood cancer treatments in regions with high levels of COVID-19,” said Dr. Hicks. “The data are somewhat reassuring in that, while recent cancer treatment was linked to a higher risk of hospitalization among those with blood cancer and COVID-19, it wasn’t independently associated with a statistically greater likelihood of dying. The type of blood cancer was also not associated with a higher risk of COVID-19 mortality. These findings suggest that patients who need treatment for their hematologic malignancy should likely proceed with that treatment.”

Data were collected between April 1, 2020, and July 2, 2021, as part of the ASH RC’s COVID-19 Registry for Hematology, which is a public-facing, volunteer registry reporting outcomes of COVID-19 infection in patients with underlying blood disorders. A total of 1,029 patients from around the globe were included in this analysis. Of these, 41% were female. The median age was 50-59 years of age, and patients ranged from five to more than 90 years of age; 27% had at least one co-existing condition such as heart disease, hypertension, respiratory disease, or diabetes. Researchers sought to identify factors associated with a higher likelihood of hospitalization and death from COVID-19.

Of people included in the analysis, 354 (34%) had acute leukemia or myelodysplastic syndromes (MDS), 255 (25%) had lymphoma, 206 (20%) had plasma cell dyscrasia (myeloma/amyloid/POEMS), 116 (11%) had chronic lymphocytic leukemia (CLL), and 98 (10%) had myeloproliferative neoplasm (MPN). Patients with MPN and plasma cell dyscrasia had less severe COVID-19 illness overall compared to patients with CLL, leukemia, MDS, or lymphoma, which Dr. Hicks said is not surprising as patients with MPN typically live with their disease for many years, are generally in better health, and may not require immunosuppressive treatment.

“The data from the ASH RC COVID-19 Registry has limitations and findings should generally be regarded as hypothesis generating,” Dr. Hicks said. “Nonetheless, the data do suggest that patients with blood cancers are at substantial risk from COVID-19; this finding has implications for our patients, how we manage our clinics amid COVID-19 and the changing variants, and how vaccines, boosters, and antibody treatments are distributed.”

In this analysis, 17% of those with blood cancers died of COVID-19; the mortality rate among those infected with SARS-CoV-2 in the general U.S. population has been reported to be between 1.6 and 6.2% at various times during the pandemic, Dr. Hicks added.

The ASH RC Registry is a public voluntary registry that continues to accrue cases and provide the information on a public dashboard to help keep the hematology community apprised on changing trends. Dr. Hicks said the team will also be looking at how the risks of hospitalization and death changed as vaccines and COVID-19 treatments became more widely available.

Lisa Hicks, MD, MSc, will present this study during a poster presentation on Saturday, December 11, at 5:30 p.m. Eastern time in Hall B5.


280: Clinical Predictors of Outcome in Adult Patients with Acute Leukemias and Myelodysplastic Syndrome and COVID-19 Infection: Report from the American Society of Hematology Research Collaborative (ASH RC) Data Hub

In separate analyses of 257 patients with acute leukemia or MDS who developed COVID-19 and are part of the ASH RC COVID-19 Registry for Hematology, both neutropenia (a type of low white blood cell count) and having active MDS or leukemia (versus being in remission) were found to strongly and independently predict severe COVID-19 illness. Once hospitalized, active disease by itself – whether someone was newly diagnosed or had relapsed – was not tied to a greater odds of dying from COVID-19, nor was receiving ongoing cancer treatment.

For this retrospective analysis, which included data from 135 patients with acute myeloid leukemia (AML), 82 with acute lymphocytic leukemia (ALL) and 40 with MDS who were diagnosed with COVID-19 from 2019 to present, researchers sought to identify characteristics that put patients at higher risk of severe illness or death from COVID-19. At the time of COVID-19 diagnosis, 46% were in remission and 44% had active disease. COVID-19 severity was defined as mild (no hospitalization required), moderate (hospitalization required), or severe (ICU admission required). After adjusting for several risk factors, active disease and neutropenia at the time of COVID-19 diagnosis were also associated with severe COVID-19 illness that necessitated ICU-level care.

Overall, one out of five (21%) patients died from COVID-19, which was higher than the mortality rate reported for the registry as a whole (17%) or what was seen in the general public during the same period of time, researchers reported. Mortality among hospitalized patients with COVID-related illness was 34%, and mortality among patients once admitted in the ICU was 68%. The two factors most strongly associated with a higher likelihood of dying among these patients were: 1) how long someone was perceived to live from the underlying MDS or leukemia before getting COVID-19, as defined as a physician’s estimated prognosis of less than six months survival, and 2) whether or not they decided to go to the ICU if it was recommended. Older age, male sex, and neutropenia at diagnosis were also associated with COVID-19 mortality though less strongly.

“This is a particularly vulnerable population and we suspected they may do worse because they are immunocompromised and, as it is, the average survival for acute blood cancers if untreated is three to six months, so if COVID-19 comes together with that diagnosis, it’s very concerning,” said Pinkal Desai, MD, MPH, of Weill Cornell Medical College, New York. “Our data suggest these patients can survive COVID-19 and their underlying disease itself was not associated with worse mortality, which means that if these patients are given appropriate and aggressive treatment, we can help them recover. But if there are decisions that are made after they get to the hospital (for example, whether to go to the ICU) that clearly plays a role.”

In fact, patients for whom ICU-level care was recommended and declined had five times higher odds of dying compared with patients who opted to go to the ICU.

“Patients who went to the ICU did better regardless of disease status,” said Dr. Desai. “Just having acute leukemia or MDS puts these patients at high risk of severe COVID-19, and they need to be hospitalized and receive treatments, but decisions about the ICU should be individualized, a patient’s prognosis should be discussed, and if a patient wants aggressive care for COVID-19 that should be offered.”

Patients were more likely to forgo ICU care if they were older, male, smokers, or if they had active disease or an estimated pre-COVID-19 survival of less than six months. Forgoing ICU care was associated with a higher COVID-19 mortality in all patients.

“Our data show that these patients do survive COVID-19 after receiving care in the ICU and underscore that cancer treatments should not be withheld as inferior treatment would quickly put many of these patients into the category of a prognosis of less than six months,” said Dr. Desai. “COVID-19 vaccination is also critically important.”

The data are limited in that they were collected before COVID-19 vaccines were widely available; future data should inform about mortality rates among vaccinated patients.

Pinkal Desai, MD, MPH, will present this study during an oral presentation on Saturday, December 11 at 2:00 p.m. Eastern time in B312-B314.


3105: COVID-19 Infection and Outcomes at a Comprehensive Sickle Cell Center

The Georgia Comprehensive Sickle Cell Center at Grady Hospital in Atlanta – the nation’s largest treatment center for adults living with sickle cell disease (SCD) – quickly switched to offering virtual visits for routine follow-up care of its more than 1,300 patients as the COVID-19 pandemic emerged. People living with SCD, an inherited disorder characterized by crescent- or sickle-shaped red blood cells, are immunocompromised and thus at high risk for COVID-19. The center established a database to track all COVID-19 cases among its patients.

The first report from that database – the largest single-center study to date on COVID-19 in people with SCD – now shows that between March 2020 and March 2021, just 55 (4%) of the center’s 1,343 patients contracted COVID-19, of whom 16 (29%) were hospitalized and two ultimately died from complications of infection with the virus. Eleven patients (20%) required neither hospitalization nor emergency-room treatment for complications of either COVID-19 or SCD during the one-year follow-up period.

“Our findings show that when supported by virtual visits, most of our patients successfully reduced their exposure to and complications from COVID-19,” said study author Fuad El Rassi, MD, of Emory University and director of research at the Grady Comprehensive Sickle Cell Center. “They understood the risks and followed recommendations to stay at home and avoid interacting with other people.”

The 55 patients who contracted COVID-19 were aged 28 on average and 51% were female. Of those who visited an emergency room or were hospitalized during the year of follow-up, 27 (49%) sought care for a painful episode of SCD and 15 (27%) for complications of COVID-19. Among those who sought care for COVID-19 symptoms, 32 (58%) had pain as their primary symptom, followed by cough and fever (40%) and shortness of breath (31%); 25% had chest x-ray evidence of pneumonia. Sixteen patients received treatment, with nine receiving the antibody treatment remdesivir, eight receiving the steroid drug dexamethasone, and seven receiving red-blood-cell products to treat pain.

Twenty cases of COVID-19 were diagnosed between March and September of 2020. The two patient deaths from COVID-19 occurred in June and July of 2020. Among the 35 cases diagnosed between October 2020 and March 2021, no patients died and the number of hospitalizations decreased as better treatments for COVID-19 became available.

One of the patient deaths was due to a blood clot in the lungs, Dr. El Rassi said. “This unfortunately occurred before it became the standard of care to treat hospitalized COVID-19 patients with blood thinners,” he said.

“Despite the second peak in COVID-19 cases in the winter of 2021, there were no reported deaths among our patients who developed the disease,” Dr. El Rassi added. “This suggests that the patients’ vigilance in staying home may have been crucial to reducing illness and death, and having the option for virtual visits was also key.” Patients who needed blood tests or to obtain medication refills were sent to satellite centers.

Patient adherence to COVID-19 precautions was measured based on their responses to physician questions at intake and during virtual follow-up visits.

Dr. El Rassi and his colleagues plan to conduct further studies to evaluate the impact of the delta variant on diagnosis, illness, and death from COVID-19 among the sickle cell center’s patients.

Fuad El Rassi, MD, will present this study in an oral presentation on Monday, December 13, at 6:00 p.m. Eastern time in Hall B5.


218: Antibody Response to Vaccination with BNT162b2, mRNA-1273, and ChADOx1 in Patients with Myeloid and Lymphoid Neoplasms 

According to a new study, about 15% of people with blood cancers and other blood disorders had no vaccination-related antibodies after receiving a COVID-19 vaccine. While researchers say it is encouraging that 85% of study participants did show an antibody response, the findings suggest that additional precautions may be warranted to prevent COVID-19 infection among people with blood disorders.

The study examined antibody levels after COVID-19 vaccination in people with blood cancers such as lymphoid and myeloid neoplasms, autoimmune disorders, and non-cancerous disorders of blood or immune cells. The results suggest that patients with lymphoma and those currently receiving treatment are the least likely to build antibodies in response to a COVID-19 vaccine.

“Some patients with hematologic diseases do not have an adequate antibody response and might, therefore, not have sufficient protection from vaccination,” said Susanne Saussele, MD, of III. Medizinische Klinik, Medizinische Fakultät Mannheim, Universität Heidelberg, Germany. “This study can help guide vaccination strategies for these patients. In addition, our study suggests that when it is possible to delay beginning treatment for their underlying disorder, it may be best to wait so that a patient can receive a vaccine or booster first.”

People with blood disorders face a high risk of hospitalization and death if they become infected with COVID-19, especially if they are older or have received therapies that reduce B-cells, a type of immune cell. Since the majority of participants in the study did respond to COVID-19 vaccines, the results underscore the role of vaccination as an important strategy for preventing severe disease, researchers said. However, the findings also suggest vaccination should be complemented with other precautions. “We should recommend ongoing protective measures such as masks, social distancing, and screenings, as well as prioritizing vaccination for family members and caregivers to protect the patients,” Dr. Saussele said.

For the study, the researchers recruited 373 patients treated for blood disorders at University hospital Mannheim in Germany and measured vaccine-related antibodies in their blood a median of 12 weeks after final vaccination. More than 90% of participants had blood cancer, while 9% had either autoimmune disease or a non-malignant blood disorder. Most patients had received the Pfizer/BioNTech vaccine; 10% received the Moderna vaccine, 7% received the AstraZeneca vaccine, and 6% received one dose from each of the two vaccine types.

Overall, 85% of participants tested positive for vaccine-related antibodies and 15% tested negative. The rate of negative antibody results was highest among those with lymphoid neoplasms, a group of diseases that include lymphoma, myeloma, and lymphoid leukemia. Among these patients, 36% tested negative for vaccine-related antibodies. Patients with indolent non-Hodgkin lymphoma, a slow-growing type of lymphoma, had the weakest response to vaccination overall.

Being on active therapy was associated with a reduced antibody response. Overall, 61% of study participants were on active therapy. Of those who tested negative for vaccine-related antibodies, most (71%) were on active therapy. Therapies correlated with a negative response were rituximab, ibrutinib/acalabrutinib, and ruxolitinib.

“Our study suggests that most people with blood malignancies – not only those who are currently under treatment – should monitor their antibody levels and work closely with their care team to determine how to continue to protect themselves from COVID-19,” Dr. Saussele said. “Antibody measurements offer a hint of who has responded to the vaccine and can perhaps ease up on precautions a bit.”

Dr. Saussele noted that the results are limited in that the study did not examine participants’ T-cell response to vaccination, meaning that some patients’ level of protection may have been underestimated. The researchers plan to continue to measure antibody levels for at least a year and to assess participants’ rates of breakthrough infections and response to vaccine boosters.

Jil Rotterdam, MD, Medizinische Klinik, Medizinische Fakultät Mannheim, Universität Heidelberg, will present this study in an oral presentation on Saturday, December 11, at 2:00 p.m. Eastern time in Hall B308-B309.


217: Responses to SARS-Cov-2 Vaccines in Patients with Myelodysplastic Syndrome and Acute Myeloid Leukemia

In one of the largest studies to date of the antibody response to vaccination against COVID-19 in people who had been treated for acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), patients responded well to two doses of the Moderna mRNA vaccine and saw a particularly dramatic increase in levels of antibodies against the virus after receiving their second vaccine dose.

“We observed a strong antibody response to the vaccine in a group of patients at high risk for severe COVID-19, including among patients who were on active treatment for AML or MDS,” said Jeffrey Lancet, MD, of the H. Lee Moffitt Cancer Center and Research Institute in Florida. “The fact that antibody levels increased so dramatically after the second vaccine dose suggests potential utility in additional dosing, even for patients who initially respond poorly to the vaccine.”

Previous studies had shown that patients with other types of blood cancer – specifically, B-cell lymphomas or chronic lymphocytic leukemia – often have a poor antibody response to vaccination with one of the COVID-19 mRNA vaccines. Treatment of these cancers suppresses the ability of the immune system to produce white blood cells such as B cells and T cells to fight off infection.

“The treatment of myeloid cancers such as AML and MDS, including allogeneic transplantation, also suppresses white blood cells and leaves patients vulnerable to infection,” said Dr. Lancet. “We conducted this study to find out whether patients with these cancers would also have a suppressed or absent immune response to COVID-19 vaccination.”

The study involved 46 patients who either had previously or were currently undergoing treatment for AML or MDS. The patients’ median age was 68 years; 59% were male and 96% were white. On average, they were about two years out from the diagnosis of their cancer. Fifteen patients (33%) were receiving treatment for their cancer at the time they were vaccinated. Thirty-two patients (70%) had undergone a transplant of blood-forming stem cells from a healthy donor as part of their cancer treatment. Forty patients (87%) were in remission when they were vaccinated. (Note that some patients are counted twice – e.g., if they had undergone a stem cell transplant and were in remission, they would be counted in both categories. For this reason, the percentages add up to more than 100%.)

All patients received a first dose of the Moderna mRNA vaccine (this vaccine type was being given at the clinic) in late January 2021 and a second dose four weeks later. The investigators collected blood specimens from each patient before each vaccine dose was administered and again at four weeks after the second dose. The primary aims of the study were to describe the immune response and assess the safety profile of the vaccine in a cohort of patients with AML or MDS.

Blood test results at 29 days after the first vaccine dose showed that 70% of patients had an antibody response; at 57 days – following the second dose – 97% had an antibody response. Antibody levels were significantly higher after the second dose compared with after the first dose. Patients’ antibody response was not significantly affected by age, gender, race, disease status (i.e., active or in remission), time from disease diagnosis to vaccination, number of treatments patients had undergone for their cancer, whether patients had received a stem cell transplant, or whether they were on active treatment at the time of vaccination.

The most common adverse events following vaccination were the typical ones reported after vaccination with a COVID-19 mRNA vaccine, such as fatigue, headache, arm swelling, and mild pain at the injection site.

“The study results should be confirmed in a larger group of patients,” Dr. Lancet said. “However, based on these data, we feel comfortable advising patients with AML or MDS that they should get vaccinated against COVID-19. Due to their vulnerability to COVID-19, they stand to benefit from the vaccine more than most.”

This is an observational study without an identified control, or comparator, group, Dr. Lancet cautioned. Another limitation is that because the participants were overwhelmingly white, it is not known whether patients of other races or ethnicities would show a similar antibody response. In addition, the actual protective effect of the vaccine and the T-cell responses to it in this patient population are not yet known; the researchers are currently gathering these data.

The investigators are now following the same cohort of patients to determine whether a third dose of the vaccine can achieve even higher antibody levels than were seen after the second dose.

Akriti Jain, MD, Moffitt Cancer Center, will present this study in an oral presentation on Saturday, December 11, at 2:00 p.m. Eastern time in Hall B308-B309.

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


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.


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.


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.


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.


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