Posted on

Case study details leukemia patient who shed infectious SARS-CoV-2 for at least 70 days

Source: Cell Press
Date: 11/5/2020
Link to original
Image of article

The majority of people infected with SARS-CoV-2 appear to actively shed infectious virus for about 8 days, but there is a wide range of variability from person to person. Understanding how long people can remain actively infected is important, because it provides new details about a disease and a virus that are still not well understood and informs public health decisions. Researchers report November 4 in the journal Cell an unusual case of one woman with leukemia and a low antibody count who was infected with the coronavirus for at least 105 days, and infectious for at least 70, while remaining asymptomatic the entire time.

“At the time we started this study, we really didn’t know much about the duration of virus shedding,” says senior author Vincent Munster, a virologist at the National Institute of Allergy and Infectious Diseases. “As this virus continues to spread, more people with a range of immunosuppressing disorders will become infected, and it’s important to understand how SARS-CoV-2 behaves in these populations.”

Munster, an expert in emerging infectious diseases, began publishing research on SARS-CoV-2 in January. He was contacted in April by infectious disease specialist Francis Riedo, a study co-author, about a patient in Kirkland, Washington, who had been infected very early in the COVID-19 pandemic. Riedo’s patient had had numerous positive PCR tests for the virus over a period of weeks, and he wanted to know if she was still shedding virus.

The patient, a 71-year-old woman, was immunocompromised due to chronic lymphocytic leukemia and acquired hypogammaglobulinemia. She never showed any symptoms of COVID-19. She was found to be infected with the virus when she was screened after being admitted to the hospital for severe anemia and her doctors recognized that she had been a resident of a rehabilitation facility experiencing a large outbreak.

Munster’s lab at NIAID’s Rocky Mountain Laboratories in Hamilton, Montana, began studying samples that were regularly collected from the patient’s upper respiratory tract. They found that infectious virus continued to be present for at least 70 days after the first positive test, and the woman didn’t fully clear the virus until after day 105. “This was something that we expected might happen, but it had never been reported before,” Munster says.

The investigators believe the patient remained infectious for so long because her compromised immune system never allowed her to mount a response. Blood tests showed that her body was never able to make antibodies. At one point she was treated with convalescent plasma, but Munster doesn’t think the treatment had an effect because of its low concentration of antibodies. Despite her inability to mount an antibody response, she never went on to develop COVID-19.

The team performed deep sequencing on all the virus samples obtained from the patient to see how the virus might have changed over the course of the patient’s infection. Samples collected at various times displayed different dominant gene variants. However, the investigators don’t think that these mutations played a role in how long the virus persisted, because they saw no evidence of natural selection. Selection would have been implicated if one of the variants had appeared to provide the virus with a survival benefit and had become the dominant variant, but none of them did. They also tested whether or not the mutations affected the ability or speed of the virus to replicate and found no differences.

Munster says that as far as he knows, this is the longest case of anyone being actively infect-ed with SARS-CoV-2 while remaining asymptomatic. “We’ve seen similar cases with influenza and with Middle East respiratory syndrome, which is also caused by a coronavirus,” he notes. “We expect to see more reports like ours coming out in the future.”

Posted on

Brigham Offers Cutting-Edge Trials for Patients With AFib

Source: Brigham and Women's Hospital
Date: 1/11/2023
Link to original
Image of article

For patients with atrial fibrillation (AFib), catheter ablation using cold or heat has been the standard of care for about 20 years. Today, thanks to improvements in mapping and other technologies, this procedure is more effective and safer than ever.

While this technique has benefited many patients, further improvements are still needed. The procedure can take several hours, is associated with about a 2% complication rate, and requires adjunctive medications or a repeat procedure in approximately 15% to 20% of patients.

Clinical investigators at the Brigham and Women’s Hospital Cardiac Arrhythmia Service are participating in several clinical trials seeking to develop new, cutting-edge techniques with the potential to benefit more patients. The service, led by cardiologist and electrophysiologist William Henry Sauer, MD, is known worldwide for its expertise in evaluating and treating a wide range of abnormal heart rhythms affecting various patients, particularly those with complex medical concerns.

Dr. Sauer credits Jorge E. Romero, MD, who was recently recruited as director of Arrhythmia & Electrophysiology Research in the Division of Cardiovascular Medicine, for being instrumental in expanding the AFib research portfolio. Dr. Sauer adds that a team-based approach has meant that every member of the Cardiac Arrhythmia Service has contributed to the success of the research programs.

Using Pulsed Field Ablation for Pulmonary Vein Isolation

Among the trials currently active is the AdmIRE study, which uses pulsed field ablation for pulmonary vein isolation to treat people with symptomatic paroxysmal AFib. This technique incorporates high-voltage electricity to electroporate the cardiac muscle cells without requiring extreme temperatures.

“A lot of the complications associated with current ablation procedures are due to the effects of the heat or cold on adjacent structures,” Dr. Sauer says. “These procedures can sometimes cause injury to the esophagus or the phrenic nerve. But with pulsed field ablation, these structures are protected because they’re more resistant to that electroporation compared to the heart tissue.”

Since performing the first pulsed field ablation procedure at the Brigham in September 2022, the team has treated 20 more patients.

“My early experience with this technology is that the procedure is much faster. Patients feel great afterward, and they go home the same day without any problems,” Dr. Sauer says. “Although we have confirmed the procedure’s safety in the short term, more time is needed before we can determine its efficacy in the long term.”

Clinical Trials Offer New Approaches for Patients

Dr. Sauer and his team plan to participate in several other trials related to AFib. One of these, the ADVANTAGE AF Study, will explore the safety and effectiveness of an alternate pulsed field ablation system in patients with drug-resistant, symptomatic persistent AFib. Dr. Sauer expects that the trial will begin treating patients at the Brigham in December 2022.

Another study, the STAR AF3 trial, seeks to address a problem seen across all ablation techniques: The sites that are the source of AFib may be outside the areas around the pulmonary veins that are usually the target of ablation. This trial will evaluate a mapping technique to identify the appropriate areas to be ablated.

Mapping technology is important because it allows physicians to detect repeating patterns by analyzing electrocardiogram data. “These systems guide us toward those patterns that may be causing atrial fibrillation,” Dr. Sauer says. “What all of this research has in common is that it’s focused on leveraging different types of new technology.”

Cardiac Arrhythmia Service Moves the Field Forward

Collaboration is vital across the Cardiac Arrhythmia Service. The service includes a diverse team of specialists with expertise in all areas of cardiac care, including cardiologists, surgeons, inpatient and outpatient care teams, technicians, and nurses. Patients, including those with underlying medical conditions, can benefit significantly from the range of expertise.

“In addition to receiving treatments that have the potential to improve outcomes and are not yet available elsewhere, patients who participate in clinical research at the Brigham make important contributions to science and move our field forward,” Dr. Sauer says. “We are grateful to them for that.”

Posted on

Blood Test Offers Better Prediction of Preeclampsia Risk

Source: Brigham and Women's Hospital
Date: 5/9/2022
Link to original
Image of article

Improvement in rates of maternal morbidity and mortality has been limited by the inability to assess fetal and maternal tissues before symptoms develop. Thomas McElrath, MD, PhD, an obstetrician in the Division of Maternal-Fetal Medicine at Brigham and Women’s Hospital, Michal A. Elovitz, MD, of the University of Pennsylvania, and colleagues have shown in a publication in Nature that the patterns of cell-free RNA (cfRNA) from maternal plasma progress in a predictable gestational-age dependent fashion. As such, these molecular signatures can be used to survey the gestational age of the pregnancy as well as the overall wellbeing of mother, placenta and baby. The team demonstrated this concept by predicting the risk of preeclampsia, a hypertensive condition unique to pregnancy, on average 14 weeks prior to the development of symptoms.

Methods

The researchers measured cfRNA in 2,539 plasma samples drawn from 1,840 pregnant women of multiple ethnicities, nationalities, geographic locations and socioeconomic circumstances, while covering a range of gestational ages. This was the largest and most diverse dataset of maternal transcriptomes ever analyzed.

Measuring Gestational Age

The researchers first restricted their study to plasma samples from healthy pregnancies, building a machine learning model of normal cfRNA patterns in uncomplicated pregnancies. By design, these models also served to predict gestational age. A cfRNA signature was as accurate as second-trimester ultrasound and superior to third-trimester ultrasound while also providing insights into the biology of pregnancy progression.

Thus, the model could offer alternative dating for women who start prenatal care later in pregnancy. Its predictions were driven almost entirely by information from the cfRNA transcripts, as body mass index, maternal age and race accounted for less than 1% of the variance.

A Window into Maternal–Fetal Development

cfRNA profiles also made it possible to assess the molecular status of the placenta, fetal organs, cervix and uterus. Hundreds of independently identified gene sets in maternal blood mirrored the maternal and fetal physiological changes expected during pregnancy.

A study of three independent cohorts verified that multiple gene sets were uniquely associated with specific tissues of origin. These included the uterus and cervix as well as the placenta. Most intriguingly, however, the team also detected the unique signature of fetal tissues including fetal heart, GI tract and kidneys. Thus, the use of cfRNA signatures could reveal and characterize molecular changes in the maternal–fetal dyad during gestation.

Early Prediction of Preeclampsia

As an example of predicting adverse outcomes, the team evaluated the ability of cfRNA signatures in maternal blood during the second trimester to identify women at risk of preeclampsia. A case–control study included 72 women with preeclampsia and 452 without, selected from two independent cohorts.

Correlation tests identified signatures that separated the cases and controls and identified seven genes consistently associated with preeclampsia. A screening test based on those genes achieved a sensitivity of 75%, with an area under the receiver operating curve of 0.82.

The inclusion of maternal body mass index, age and race had no effect on the new test’s performance.

Women who tested positive delivered significantly earlier during gestation than women who tested negative. In addition, a positive test correctly identified 73% of women who had a medically indicated preterm birth—more than three months ahead of clinical symptoms or delivery.

Hypertension vs. Normotension

In pregnant women who have preexisting hypertension, it can be quite challenging to distinguish superimposed preeclampsia from exacerbation of hypertension. The difference is important because one requires delivery for a cure and the other usually doesn’t.

One of the cohorts used to estimate preeclampsia risk included 50 women with hypertension (chronic hypertension, n=31; gestational, n=19) and 263 normotensive women. Genes identified by comparing the two groups showed no overlap with genes significant for preeclampsia. Also, none of the genes were differentially expressed. Thus, the molecular signal for preeclampsia was specific to hypertension driven by a placental disorder.

Clinical Importance

Considering the large, diverse study population, it’s noteworthy that race had almost no effect on gestational age estimates or preeclampsia risk evaluation. Including race in clinical risk assessment has been shown in several fields to be problematic, have little or no utility, and in fact represent a source of latent bias against members of underrepresented minority communities. In contrast, the cfRNA signature directly exposes the development of preeclampsia.

A better understanding of the maternal–fetal–placental transcriptome should lead to precision therapeutic interventions that can target molecular subtypes of preeclampsia and preterm birth.

Posted on

TRIALS ADDRESS NEW OPTIONS FOR TRICUSPID VALVE DEFECTS

Source: Brigham and Women's Hospital
Date: 8/4/2021
Link to original
Image of article

The tricuspid valve is often referred to as the “forgotten valve.” That’s because when it begins to malfunction, it usually doesn’t result in the same severity of symptoms as when there are problems with the aortic and mitral valves. Additionally, when it does stop working properly, fewer interventions are available for treatment.

Recently, however, that situation has begun to change. Experts from Brigham and Women’s Hospital are now participating in two multicenter clinical trials studying catheter-based treatments that could restore the function of the tricuspid valve. One trial is looking at valve repair, and the other is focused on valve replacement. Both approaches would provide new options for patients who don’t respond to medical treatment, but who are not good candidates for open-heart surgery, either because their disease is not severe enough to warrant the risks or due to comorbid conditions.

“We’ve seen tremendous success in the aortic space, to the point that now the majority of aortic valve replacements in the United States are done through a catheter-based treatment rather than by surgery,” said Pinak Bipin Shah, MD, director of the Interventional Cardiovascular Disease Training Program and director of the Cardiac Catheterization Laboratory at the Brigham. “There’s also one approved transcatheter device for the treatment of mitral valve regurgitation. Given what we’ve seen in these other areas, there’s now a lot of interest in looking at whether we can treat the tricuspid valves with catheter-based approaches.”

A Focus on Valve Repair and Replacement

One study being offered at the Brigham is the TRILUMINATE Pivotal Trial, which is a prospective, randomized trial that is evaluating an investigational clip device in patients who are experiencing symptoms from severe tricuspid regurgitation. The other study, the TRISCEND II Pivotal Trial, is looking at Evoque, a tricuspid valve replacement system that doesn’t require open-heart surgery. The control in both trials is medical therapy.

“There’s still much to be learned about the optimal time of treatment for these patients, but we probably ought to be intervening on these patients sooner rather than later,” said Tsuyoshi Kaneko, MD, a cardiac surgeon who specializes in endovascular approaches. “At the same time, the invasiveness of open-heart surgery is often more than we feel comfortable offering to patients who may otherwise feel well. Having transcatheter options for the management of these patients will be an important new option.”

“With tricuspid regurgitation, the patient typically doesn’t notice anything unusual. It’s often picked up on an echocardiogram looking for some other process,” Dr. Shah added. “But although it doesn’t cause symptoms right away, we are learning that this can be a very difficult illness to deal with if left untreated. It can result in dysfunction of the right side of the heart and lead to problems including severe fluid retention, shortness of breath and fatigue.”

Evaluating Less-Invasive Treatments for Tricuspid Valve Defects

Like other transcatheter procedures, tricuspid valve repairs and replacements are done under general anesthesia with echo guidance using a transesophageal echocardiogram. The procedures last no more than two hours, and the team thinks they will need even less time as they gain more experience. Patients who have these procedures require only an overnight stay and usually can go back to normal activities within a week.

For patients who have significant tricuspid regurgitation, especially those who are symptomatic, the comprehensive, multidisciplinary Cardiac Valve Center at the Brigham provides evaluations to determine the best course of action for managing disease. Having additional options for those with tricuspid valve defects adds to the scope of what can be offered to patients.

“This treatment is going to be really revolutionary because it is so much less invasive than open-heart surgery,” Dr. Kaneko said. “We will be able to offer treatment earlier in the disease process, allowing for a much more rapid recovery while preventing later complications.”

Posted on

Single-Cell Study Sheds Light on Leukemia’s Family Tree

Source: Memorial Sloan Kettering - On Cancer
Date: 10/28/2020
Link to original

When Memorial Sloan Kettering postdoctoral fellows Linde Miles and Robert “Bobby” Bowman began working on a new research project in May 2019, they didn’t know how massive a task it would be.

Now, their undertaking — the biggest study ever to examine the genetic causes of leukemia at the level of individual cells — is being published October 28, 2020, in Nature. The findings reveal how a series of mutations in normal blood cells can lead to them eventually becoming cancerous. The study also shows how these mutations accumulate as the disease progresses.

“This single-cell approach gave us new insights into the journey that blood cells take on their path to becoming leukemia,” says physician-scientist Ross Levine, senior author of the paper and a member of the Human Oncology and Pathogenesis Program. “Our hope is that this glimpse into how and why leukemia develops will open up new areas of research in early diagnosis and treatment.”

Learning about Cancer, Cell by Cell

Traditional genomic analysis of cancers — including MSK-IMPACTTM, a test that looks for mutations in 468 genes in patients’ tumors — uses what is called bulk sequencing. That means that it surveys the mutations that are present across all the cells in a tumor sample.

By contrast, the approach used in this study deciphered the mutations found in every single cell. The samples were obtained from 146 people who were treated at MSK for acute myeloid leukemia (AML), as well as those with two blood conditions that can lead to AML: clonal hematopoiesis and a blood cancer called myeloproliferative neoplasms. The analysis yielded data on nearly 750,000 unique blood cells.

“Instead of just broadly profiling all leukemias, we wanted to be able to ask pointed biological questions,” Dr. Bowman explains. “Understanding how these mutations work together will give us insight into their biological function.”

One aspect the study focused on is what’s called the clonal architecture of the cancer. This is the order in which the mutations occur. Dr. Levine compares it to a family tree, with each branch taking the cells in a different direction — some remain healthy and others become aggressive cancer.

“Trying to figure out the clonal architecture is like looking at a maze,” says Dr. Miles, a biochemist who was recently awarded a Marie-Josée Kravis Women in Science Endeavor (WiSE) fellowship. “It required a lot of work to begin to make sense of what we found and begin to detect patterns.”

A United Effort

Dr. Miles spent the summer and fall of 2019 sequencing patient samples. She was able to complete five or six samples a day. When she finished, the amount of data that had been generated was overwhelming.

As a computational biologist, Dr. Bowman’s role was to figure out which mutations occurred together in the same cells and determine the order in which they appeared. At one point, he decided to consult his younger brother, Michael Bowman, a PhD student in mechanical engineering at the Colorado School of Mines.

Michael helped the MSK team develop the right mathematical formulas with an approach he normally uses to study robot behavior. Eventually he came to visit New York City, and spent much of the time that was supposed to be a vacation pouring over data with his brother, Dr. Miles, and Dr. Levine. Michael Bowman is a co-author on the paper.

“This was very much a team effort, and Ross was involved at every step, too,” Dr. Miles says. “It’s probably the most collaborative project I’ve ever worked on.”

Building a New Playbook for Cancer Research

Dr. Levine says the goal of this work is to take the new information about the clonal architecture back to the lab and use it to create more accurate disease models that can then be deployed to develop new diagnostic methods and potentially test new drugs.

“The analogy I like to use is that cancer is like the Death Star in Star Wars,” he says. “You can’t take it apart until you know where the critical nodes are — where the cells are most vulnerable to attack.”

He also explains that, historically, leukemia research has led to methods that can be used to study many other cancers. “Because we can get leukemia samples with a simple blood draw, they’ve always been more accessible,” he says. “Our hope is that similar single-cell studies in solid tumors and other blood cancers will follow and that our work will provide a playbook on how to approach these studies with other kinds of cancer.”

Posted on

Taking on New Challenges: 8 Questions with Gilles Salles

Source: Memorial Sloan Kettering - On Cancer
Date: 12/23/2020
Link to original

Gilles Salles recently joined Memorial Sloan Kettering as Chief of the Lymphoma Service within the Division of Hematologic Malignancies. Dr. Salles came to MSK after a long career at Claude Bernard University in Lyon, France.

In an interview conducted in early December just before the annual American Society of Hematology (ASH) meeting, where he presented updates from several studies he’s conducted, Dr. Salles spoke about his decision to join MSK, his research, and his plans for the Lymphoma Service.

Why did you decide to come to MSK?

MSK is a fantastic place in terms of clinical care, clinical research, and basic research. There are not many places in the world that have strengths in all three of these areas. There are so many opportunities here to bring talented scientists together with clinicians who can help them deliver their discoveries to patients.

I’ve been successful in my career, and I’ve been able to bring many improvements in lymphoma care to patients. I asked myself, “Should I just continue here in France and then retire in six or eight years, or should I take on a new challenge?” I decided that this kind of opportunity, to be able to interact more with basic scientists and to build upon translational research projects, doesn’t happen very often. That’s why I took the leap.

What was your relationship with MSK before you came here?

I already knew many members of the Lymphoma Service as well as people in other groups at MSK. I’ve been involved in collaborations with them over the years and have met them at conferences. They are a large part of the reason I decided to join MSK — it’s exciting to work with such talented people.

What was it like moving to a new continent in the middle of a pandemic?

It was strange. I moved to New York over the summer and started working at MSK in mid-August. I haven’t been in the same room with most of my new colleagues yet. We’ve all been meeting on Zoom.

I studied in the United States for my postdoc about 30 years ago in Boston. And I’ve been to New York and other parts of the United States many times since then, both for work and for vacations with my family. This is not the New York I was wishing to rediscover, but I’m hopeful that the pandemic will end soon.

What’s different about MSK’s Lymphoma Service?

We have the SPORE in Lymphoma [Specialized Programs of Research Excellence, a project funded by the National Cancer Institute to help move basic science findings into the clinic]. That was started by my predecessor, Anas Younes, and is now being led by Andrew Zelenetz, a leading physician in the field of B cell malignancies.  

MSK’s Lymphoma Service is quite large, with more than 20 faculty. Because there are so many of us, we can specialize not just in lymphoma but in particular types of lymphoma.

What types of lymphoma do you specialize in treating?

I was very fortunate 20 years ago to be part of the early development of the first monoclonal antibody drug for diffuse large B cell lymphoma (DLBCL), called rituximab. I’m continuing to work on developing new antibody drugs for DLBCL.

I also treat follicular lymphoma. This disease is unusual because some patients who are diagnosed with it don’t require treatment right away, only active surveillance. But it also doesn’t have a cure. Thanks to new treatments, we’ve been able to extend survival for this disease considerably, from an average of eight to ten years to an average of 15 to 20 years. But I think that with the addition of new treatments, especially different kinds of immunotherapy, we will soon be able to offer a cure for some patients.

What are some of the research collaborations you’re planning?

There are many projects I plan to pursue with people here at MSK.

I’m very excited to work with physician-scientist Santosh Vardhana, who recently started his own lab in the Human Oncology and Pathogenesis Program. He has so much knowledge about T cell biology, and we want to apply this to some of the clinical trials we are developing.

I’ve already had the opportunity to work on projects with hematopathologist Ahmet Dogan. To understand lymphoma, we have to really know what’s happening in the tumor, and pathology is the cornerstone of that.

Before I came here, I had met Sloan Kettering Institute cancer biologist Hans-Guido Wendel a few times, and I knew his work. I’ve joined his very innovative project looking at abnormal RNA translation in lymphoma to help bring his findings to the clinic.

In the past, I’ve participated in studies that looked at the ways a person’s genes influence how they respond to treatments for lymphoma. Through this work, I’ve been involved in some consortia with geneticist Vijai Joseph, who studies hereditary cancer. Now that we’re in the same place, we can find time to work more on this project.

What made you interested in pursuing science and medicine as a career — particularly cancer?

I got interested in medicine because I wanted to help people. Medicine is a profession where you bring something to others — health, one of the most precious things we have. I’m also a curious person, so that made science a natural fit.

When I finished medical school, and I had to choose where to focus, the field of oncology was attractive, in part because it was challenging. At that time, there weren’t many options for people with cancer, other than chemotherapy. We in the field were starting to learn more about the biology and immunology of the disease, and it felt like there were many opportunities to improve treatment for cancer patients.

What are you most looking forward to doing in New York once the pandemic is over?

My wife and I are both excited about getting into the jazz music scene. We sometimes hear musicians when we’re walking through Central Park, and it’s so good to hear live music.

Posted on

MSK Opens New Clinic to Monitor People with a Genetic Risk for Developing Blood Cancer

Source: Memorial Sloan Kettering - On Cancer
Date: 01/23/18
Link to original
Image of article

Most cancers arise by chance and, therefore, are hard to predict. But scientists and doctors are learning more about the genetic changes that cause cancer as well as those that signal a higher risk for it. Thanks to MSK-IMPACT™, Memorial Sloan Kettering’s diagnostic test that looks for genes associated with cancer, more people who carry cancer-related genes are being identified.

To take advantage of these new opportunities, MSK has launched the Precision Interception and Prevention Initiative. This program is focused not only on catching cancer very early but also on eventually preventing it from forming in the first place. One of the program’s components is a clinic for people with an age-related condition called clonal hematopoiesis (CH). MSK’s clinic, the first of its kind, is beginning to see people with CH this month.

“This initiative unites high-impact science and clinical medicine to actively identify and help a population of people who are either at a high risk of developing cancer or who already have cancer but don’t know it,” says Luis Diaz, head of MSK’s Division of Solid Tumor Oncology, who is leading this effort.

A person with clonal hematopoiesis has an increased number of blood cells that carry some of the same mutations that are found in blood cancers. CH occurs when hematopoietic stem cells (which give rise to all types of blood cells) form cells that are genetically distinct from the rest of the blood stem cells. Sometimes these distinct cells carry cancer-associated mutations.

“This is an exciting and quickly growing field, and it’s vital for us to learn as much about it as possible,” says physician-scientist Ross Levine, who will be heading the new clinic. “By launching this effort to monitor and care for people with CH, we will be able to advance our understanding about this important area of science.”

Clonal Hematopoiesis: A Common Phenomenon Linked to Aging

Dr. Levine was part of the research team that was the first to identify the genetic basis of CH and its connection to blood cancer. They first reported that relationship in 2012. Since then, many investigators have begun to study the condition and have shown that CH is very common. Researchers have found that it is linked to an increased risk of certain blood cancers, especially myelodysplastic syndrome and acute myeloid leukemia, as well as cardiovascular disease, heart attacks, and strokes.

The most common cause of CH is aging. Studies have suggested that between 10 and 20% of people over age 70 have signs of it in their blood. Smoking also increases the risk. “CH is very common. Millions of people have it,” Dr. Levine says. “But most people don’t know they have it, and doctors don’t know what to do with it. We thought it was important to do more research on this phenomenon so that we can start figuring out who may need intensive follow-up and treatment right away and who can be observed.”

“Right now we don’t have good ways to predict who is most likely to develop a blood cancer, so any new findings that come out of this clinic have the potential to make a big difference,” says Marcel van den Brink, Head of MSK’s Division of Hematologic Oncology.

In addition, certain types of chemotherapy and radiation therapy can increase the incidence of CH. This explains why cancer survivors carry a risk for secondary leukemia. The still-rare condition is happening more often because more people with cancer are surviving longer or are cured of their disease.

A study last year from Dr. Levine, MSK researcher Michael Berger, and their colleagues found that 25% of people with any type of cancer had CH, a higher number than had previously been observed. Of that group, 4.5% had specific mutations that are known to drive the formation of leukemia.

Treating Blood Cancer Earlier

Most people with CH will never develop blood cancer, but doctors are starting to understand which individuals with CH are at the highest risk. “This is one of the reasons this clinic is so important,” says MSK hematology fellow Kelly Bolton, who will be helping to run the new program. “We hope about 100 patients with high-risk forms of CH will participate in our first year.”

The MSK investigators who designed MSK-IMPACT, including molecular pathologist Marc Ladanyi and Dr. Berger, believed it was important to look for cancer-related genes in people’s normal tissue as well as in their tumors. This would help them determine whether a person’s cancer occurred completely by chance or whether inherited factors played a role. The easiest normal tissue to obtain is blood, and the gene mutations linked to CH started to show up as part of MSK-IMPACT testing.

As MSK launches its CH clinic, people who have undergone MSK-IMPACT testing for other cancers and have been found to have high-risk forms of CH in their blood will be contacted by their surgical or medical oncologist and invited to enroll in the program. MSK patients who are treated for low blood counts and found to have CH as part of their blood work will also be seen.

“In the past, CH has been just an incidental finding. When we were worried someone had an undiagnosed blood cancer, we would refer him or her to the Leukemia Service,” Dr. Bolton explains. “Now when we discover patients with high-risk forms of CH, we will have a clinic with experts in CH to manage and coordinate their care.”

For now, those who enroll in the clinic will have the opportunity to have their blood tested on a regular basis. People who are found to have a blood cancer will be able to start treatment immediately, when the disease is much easier to control.

Looking toward Future Treatments

In the future, MSK investigators hope to launch clinical trials of treatments that could block the progression from CH to active cancer. In addition, treatment for solid tumors may be tailored to protect people who already have an increased risk of developing a second cancer. But doctors don’t yet know enough about what drives the formation of CH to make any changes to treatment now.

Recent studies suggest that people with CH are at risk for cardiovascular diseases. However, testing for CH is not currently part of screening for them. “It’s important for people with CH to follow up with their primary-care doctors and make sure they have had the appropriate screenings for cardiovascular diseases,” Dr. Bolton says. “We will encourage everyone participating in our CH clinic to do this.”

Posted on

Gene Mutations in the Blood Can Complicate Findings from Tumor Sequencing

Source: Memorial Sloan Kettering - On Cancer
Date: 06/05/2018
Link to original
Image of article

MSK-IMPACTTM is a diagnostic test that looks for mutations in more than 450 cancer-causing genes in people’s tumors. It has led to major advances in precision medicine. Based on the mutations that are found, people with cancer may receive treatment with an approved targeted therapy or immunotherapy that’s matched to their cancer. Some people may enroll in a clinical trial based on the results.

When Memorial Sloan Kettering experts — including pathologist Marc Ladanyi and geneticist Michael Berger — built the test, they also included the analysis of an individual’s blood sample in addition to the tumor sample. This component is not part of most other tumor-sequencing tests. That’s what makes it possible to determine which mutations are part of a tumor and likely to be driving the cancer and which may be present in other parts of the body.

Today at the American Society of Clinical Oncology (ASCO) annual meeting, a new study illustrates a major benefit of that approach. The findings show if data about the blood are not part of test results, mutations specific to the blood may be misread as mutations in the tumor. This can potentially affect the therapy that someone gets.

“These findings add another layer of complexity to precision medicine,” says MSK bioinformatician Ahmet Zehir, who presented the study at the ASCO meeting. “They show us that there’s lots to consider when matching patients to the right treatment.”

The Consequences of a Blood Condition

Cancer mutations may be present in a person’s blood, even if they don’t have blood cancer, due to a condition called clonal hematopoiesis (CH). Hematopoietic stem cells give rise to all types of blood cells. In CH, those stem cells form a group of cells that is genetically distinct from the rest of the blood stem cells. MSK physician-scientist Ross Levine was part of the research team that first identified the genetic basis of CH and its connection to blood cancer.

CH is most commonly found in older people, especially those who have a history of smoking. Having CH doesn’t mean that someone has or will get blood cancer. In fact, most people with CH will not: Experts estimate that between 0.1% and 4% of people with CH will develop cancer within ten years of diagnosis, depending on their medical history. MSK recently opened a clinic for people with CH, to study the condition and monitor them for the development of blood cancer as well as heart disease, which is also linked to CH.

The reason CH-related mutations show up in tumor analysis is simple. Tumors have a blood supply, so some DNA from the blood is mixed with the tumor DNA.

A Potential to Influence Treatment Decisions

“We already have some examples of how this situation could directly affect patient care,” Dr. Zehir says. In one case, a person was found to have a mutation in BRCA2, suggesting that he could benefit from a class of drugs called poly (ADP-ribose) polymerase (PARP) inhibitors. But that BRCA2 mutation was due to CH, not genetic changes that were driving tumor growth, so a PARP inhibitor would not have been effective.

This study, which is being published today in JAMA Oncology, outlines this case and others. “The findings show that you also need to analyze a blood sample if you want to be 100% confident in choosing the right therapy,” Dr. Zehir says. He adds that misinterpreted sequencing results could alter the outcomes of clinical trials for new drugs if patients are assigned to a trial for a drug targeting a mutation their tumor doesn’t have. The study’s first author was MSK bioinformatician Ryan Ptashkin.

“Our findings show that this phenomenon could affect up to 5% of people with advanced cancer,” Dr. Zehir concludes. “That may not sound like a high percentage, but it’s still a large number of people. I hope that after doctors at other hospitals learn about our findings, they will be more aware of this issue when they’re interpreting tumor-only sequencing results and deciding which treatments to give patients.”

Posted on

Meet Chronic Lymphocytic Leukemia Expert Anthony Mato

Source: Memorial Sloan Kettering - On Cancer
Date: 06/12/2018
Link to original
Image of article

Hematologic oncologist Anthony Mato recently joined Memorial Sloan Kettering from the University of Pennsylvania. At MSK, he directs the chronic lymphocytic leukemia (CLL) program. He sees patients in Manhattan and at MSK Basking Ridge, in New Jersey.

We recently spoke with Dr. Mato, an internationally recognized leader in CLL, about the disease and MSK’s expertise in treating it.

What is CLL and how is it different from other types of leukemia?

CLL is the most common type of leukemia. About 20,000 people in the United States are diagnosed every year, almost all of them older adults. CLL occurs when the body begins to make too many B cells, a type of white blood cell. The cancer can spread throughout the blood and bone marrow. It can also affect certain organs, most commonly the lymph nodes and spleen.

Many people don’t have symptoms and have no idea that anything is wrong at the time they’re diagnosed. The disease is usually detected when someone gets a blood test as part of a regular checkup and they are found to have an elevated white blood cell count. CLL is most common in the elderly, but younger people can be diagnosed with it too.

Some leukemias, such as acute lymphocytic leukemia and acute myeloid leukemia, need to be treated urgently, but CLL is treated only after it causes symptoms. About a third of people who are diagnosed will never have symptoms and therefore won’t ever need treatment. But the rest ultimately will. CLL is not a curable disease. As its name suggests, it is a chronic disease. But experts in the field have a number of different ways to keep it under control.

What are the symptoms of CLL?

The symptoms of CLL include persistent fevers, fatigue, night sweats, abdominal fullness, and weight loss. As the disease advances, people may be more prone to infections and bleeding because their bone marrow isn’t working properly.

Rarely, CLL can turn into a more aggressive type of lymphoma. This is called Richter’s transformation. It’s usually a life-threatening condition that requires urgent treatment.

What would you tell someone who’s just been diagnosed with CLL and doesn’t have any symptoms?

Even if you are asymptomatic and your doctor says you don’t need treatment, it’s important to see an expert in CLL soon after you are diagnosed. MSK offers state-of-the-art diagnostic and prognostic testing. This enables doctors here to devise a strategy for each patient from the very beginning. Our patients are updated on the standard of care, as well as on what new therapies are on the horizon and any clinical trials that may impact them.

MSK has a great deal of experience in determining how closely someone needs to be monitored if they don’t have symptoms. Being monitored doesn’t necessarily mean that no action is needed. For example, people with CLL still need to receive comprehensive care, like vaccinations to prevent infections and screenings for other health conditions.

People aren’t expected to give up longstanding relationships with their regular doctors when they come to MSK for CLL care. We partner with doctors in the community to make sure that people with CLL get excellent care in all areas related to their health.

For those who develop symptoms, what are the treatments for CLL?

We try to prescribe chemotherapy only when absolutely necessary. Targeted chemotherapy-free approaches are available as an alternative to traditional chemotherapy. Three targeted therapies have already been approved for CLL: ibrutinib  (Imbruvica®), venetoclax (Venclexta®), and idelalisib (Zydelig®). Several more drugs are on the way. All of these drugs are taken as pills and target molecular changes that are specific to CLL.

MSK is also a leader in chimeric antigen receptor (CAR) T therapy for CLL. This is when someone’s immune cells are engineered to recognize and attack cancer. Other types of immunotherapy may be effective as well, and that’s something we plan to study.

Why did you decide to come to MSK?

The Leukemia Service and the whole Division of Hematologic Oncology have an incredible commitment to both research and patient care, and that was really a driving force for me. I’m excited to have the opportunity to do the kind of research that I’ve always wanted to do.

MSK’s team approach to care is fundamental to the way we treat CLL. We’ve formed a CLL working group that meets monthly to coordinate all of our efforts. The program has skilled nurses, pathologists, and pharmacists who are involved in patient care every step of the way.

The incredible collection of scientists, clinicians, and research staff, not only at MSK but also at nearby Weill Cornell Medicine and The Rockefeller University, makes this the perfect place to address important questions in the area of CLL.

Now that you’re here and getting settled in, what are your plans?

My colleagues and I plan to start a number of trials to look for better treatments. These trials will incorporate novel drugs and other therapies, as well as studies on how people who have been treated with the standard of care fare in the long term. Because younger people do have the disease, it’s important for us to develop different strategies. Our hope is to produce extended remissions, so that people can live a long time without treatment and with an excellent quality of life.

I’m also really happy that I’m able to see patients at MSK Basking Ridge. The care offered there allows people with CLL to participate in the most cutting-edge clinical trials without ever having to come into the city, and they can receive the best follow-up care as well.

Posted on

FDA Approves Ivosidenib (Tibsovo®), a Targeted Drug, for Acute Myeloid Leukemia

Source: Memorial Sloan Kettering - On Cancer
Date: 07/26/2018
Link to original
Image of article

The US Food and Drug Administration has approved the drug ivosidenib (Tibsovo®) for the treatment of certain people with acute myeloid leukemia (AML) that has stopped responding to other therapies. Memorial Sloan Kettering hematologist-oncologist Eytan Stein was a co-leader of the study that led to the drug’s approval. The results of the trial were published last month in the New England Journal of Medicine (NEJM), and the drug was approved on July 20, 2018.

Ivosidenib is the first drug in a class called IDH1 inhibitors to receive FDA approval. It works in a similar way as enasidenib (Idhifa®), a drug approved in 2017 to treat AML that’s driven by a mutation in a related gene, IDH2. Both drugs represent a “new approach to treating cancer,” says Dr. Stein.

“Instead of killing cancer cells, like other leukemia drugs, it reprograms them and transforms them into normal, healthy, functioning cells,” he says.

About 10% of people with AML have mutations in the IDH1 gene, and another 15% have IDH2 mutations. These mutations are also found in other types of leukemia as well as myelodysplastic syndromes, glioblastoma, and bile duct cancer. Targeting these mutations is a growing area of cancer drug development.

MSK President and CEO Craig Thompson led the basic science research that explains how IDH1 mutations drive AML, in collaboration with MSK physician-scientists Ross Levine and Omar Abdel-Wahab. The Peter and Susan Solomon Family Foundation supported that research, which was first reported in 2010. The investigators found that the mutations produce a cancer-causing enzyme called hydroxyglutarate (2HG). This enzyme stops the development of the blood cells called myeloid cells when they are in an immature form, which leads to leukemia.

Ivosidenib brings down the level of 2HG, so the blood cells can begin to develop normally again.

The NEJM study was a multicenter phase I trial that reported data on 125 people whose cancer had stopped responding to other treatments. The researchers found that of those treated with ivosidenib, almost 42% responded. Nearly 22% had a complete remission, meaning that their cancer was no longer detectable. The overall survival was longer than what would be expected for people with this stage of AML, and severe side effects were rare.

MSK Leukemia Service Chief Martin Tallman also participated in the study.

Ivosidenib and enasidenib are both made by Agios Pharmaceuticals.