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

Source: Memorial Sloan Kettering - On Cancer
Date: 10/28/2020
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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.”

Taking on New Challenges: 8 Questions with Gilles Salles

Source: Memorial Sloan Kettering - On Cancer
Date: 12/23/2020
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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.

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
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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.

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.”

Gene Mutations in the Blood Can Complicate Findings from Tumor Sequencing

Source: Memorial Sloan Kettering - On Cancer
Date: 06/05/2018
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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.”

Meet Chronic Lymphocytic Leukemia Expert Anthony Mato

Source: Memorial Sloan Kettering - On Cancer
Date: 06/12/2018
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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.

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

Source: Memorial Sloan Kettering - On Cancer
Date: 07/26/2018
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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 syndromesglioblastoma, 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.

Cord Blood Transplants Provide an Opportunity for a Cure from Blood Cancer

Source: Memorial Sloan Kettering - On Cancer
Date: 08/30/2018
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Allogeneic stem cell or bone marrow transplants can be lifesavers for people with a blood cancer such as leukemia or lymphoma. After chemotherapy is used to destroy the cancer, blood-forming stem cells from a donor are infused to repair and restore the bone marrow.

Unfortunately, only about one-quarter of the people who need an allogeneic transplant have a sibling who is a genetic match and able to donate stem cells. The other three-quarters need to find another donor for their transplant.

People can receive bone marrow or stem cells donated by an adult who is not related to them. But many who need a transplant are not able to find a matched donor from any of the volunteer donor registries. These people can benefit from a different procedure called a cord blood transplant, which uses stem cells from the umbilical cord blood of a healthy newborn. Stem cell donations from adult volunteers and cord blood collections are found through Be the Match or another donor registry.

We recently spoke with Juliet Barker, Director of Memorial Sloan Kettering’s Cord Blood Transplant Program. Here, she describes MSK’s expertise with cord blood transplantation.

What is cord blood, and why is it a good option for some people who need a stem cell transplant?

Cord blood is collected from the umbilical cord and placenta of healthy newborns and is a rich source of blood-forming stem cells. Parents have the option of donating it at birth. The cells are stored frozen in public cord blood banks.

A major advantage of cord blood is that the immune system of a newborn baby is not yet fully developed. This means that the match that’s required between the cord blood stem cells and the person receiving them is less strict.

However, even though the cord blood immune system is very malleable, it can still develop into a healthy immune system. Also, cord blood cells are very good at fighting cancer. This ability is called the graft-versus-leukemia effect. It can help prevent a person’s cancer from returning after their transplant.

What does it mean for donor cells to be matched, and why is it often hard for people to find a match?

The test that’s used to identify appropriate donors is called HLA matching. HLA stands for human leukocyte antigen. HLAs are proteins that are present on most cells in your body. Your immune system uses HLAs to recognize which cells belong in your body. When using an adult donor, it’s important that the donor and the person undergoing the transplant have HLAs that match so the donor immune system doesn’t attack the patient’s normal tissues, a complication called graft-versus-host disease.

A person’s HLA type is inherited from their parents, which is why siblings offer the best chance of finding a match. People’s HLA type can be determined with a simple blood test or cheek swab.

People of southern European, Asian, African, Hispanic, and Middle Eastern backgrounds tend to have more diverse HLA types. These types are less commonly found in adult volunteer donor registries. It can also be difficult for someone with a mixed background — for example, part Asian and part Hispanic — to find a donor who is a match. For them, cord blood transplants offer a good opportunity for a cure.

What kind of expertise does MSK have in performing cord blood transplants?

MSK has one of the most active and successful cord blood transplant programs in the world. We have performed more than 350 cord blood transplants in adults and children — more than half of them being of non-European ancestry.

However, these transplants are complex. They offer great benefits, provided the hospital where the transplant is done has the expertise to manage the potential complications. MSK has experts who can tackle transplant complications as a matter of routine.

How did you become an expert in cord blood transplants?

I did my medical training in Australia, where I’m from. In 1996, I came to the United States to the University of Minnesota to train under famous transplant specialists, including John Wagner. Dr. Wagner is a pioneer in cord blood transplantation.

In Minnesota, I was trained in doing stem cell transplants in adults. I was chosen to develop the adult cord blood transplant program there. I was in the right place at the right time. In 2001, our team reported in the New England Journal of Medicine on the then-new technology of combining two different cord blood collections from two different babies, a procedure known as double-unit transplantation. This approach has been very successful and has since been adopted as the standard way of doing cord blood transplants in adults around the world.

Why did you decide to come to MSK?

In 2005, I had the opportunity to come to MSK and create the Cord Blood Transplant Program here. Thanks to the leadership of Richard O’Reilly beginning in the 1970s, MSK has many decades of experience in developing and improving stem cell transplants. MSK’s strong research focus also lends itself very well to the development and adoption of new innovations.

In addition, New York City is much more ethnically diverse than Minnesota. This has meant that there is a much greater number of people who will not find a matched donor. There are so many patients here who can benefit from cord blood transplants. This is one of the reasons why our program has been so successful. And now we are developing a number of new clinical trials to even further improve the results of these transplants.

What do we know about outcomes for people who undergo this type of transplant?

Recently, MSK analyzed the outcomes of double-unit cord blood transplants in adults with cancers of the blood and bone marrow. The investigation showed that our results are some of the best in the world. They are as good as transplants with cells from adult donors. This data will be presented at the annual conference of the American Society of Hematology later this year.

How Acute Myeloid Leukemia Is Treated at MSK: An Interview with Martin Tallman

Source: Memorial Sloan Kettering - On Cancer
Date: 09/11/2018
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Acute myeloid leukemia (AML)
 is one of the most common types of blood cancer. The word “acute” means that the cancer can advance quickly and needs to be treated right away. The word “myeloid” refers to the type of cells that are cancerous.

Myeloid cells are blood cells that develop into many different kinds of immune cells. They also develop into platelets, which are responsible for blood clotting. This explains why excessive bruising and bleeding are symptoms of AML.

We recently spoke with Martin Tallman, Chief of Memorial Sloan Kettering’s Leukemia Service. He reviewed the latest advances in treatment for AML and how people can benefit from receiving their treatment at MSK.

How common is AML?

About 20,000 people in the United States are diagnosed with AML every year. The average age at the time of diagnosis is 72, but it can develop at any age.

We know that AML is becoming more common, but we’re not sure why. For most adults, the cause is not known. But there has been speculation that more people are developing AML because they have been treated with chemotherapy and radiation for other types of cancer. As a result of advances in cancer care, more people are surviving long enough to develop these secondary cancers.

In children and young adults, however, past treatment with chemotherapy and radiation is a common cause of AML.

How is treatment for AML changing?

Until recently, there had been no new continually approved drugs for treating AML since 1973. Then in 2017, four new drugs were approved by the US Food and Drug Administration. One more has been approved so far in 2018, and there are three or four others that are poised to be approved within the next year or so.

One of the new drugs, liposomal daunorubicin-cytarabine (VyxeosTM), is a new formulation of a standard leukemia drug. Another, gemtuzumab ozogamicin (MylotargTM), is made from an antibody linked to a potent toxin. Midostaurin (Rydapt®) is a drug that targets a mutated protein called FLT3.

Enasidenib (Idhifa®) was approved to treat AML that carries a mutation in a gene called IDH2Ivosidenib (Tibsovo®) targets cancers with a mutation in the related gene IDH1. Both enasidenib and ivosidenib work by converting cancer cells back into normal cells rather than killing them. MSK’s Leukemia Service led the trials that resulted in both of these drugs being approved.

In addition to new chemotherapy and targeted drugs currently being studied, there are clinical trials looking at chimeric antigen receptor (CAR) T therapy and other types of immunotherapy for AML. We are also looking at new combinations of drugs.

We’ve been able to develop all these new treatments because — thanks to research in both the lab and the clinic — we now have a much better understanding of what drives this disease. This knowledge leads to more-effective ways to target malignant cells. It’s an amazing, exciting time to be doing leukemia research.

How often are stem cell or bone marrow transplants used to treat AML?

Blood or marrow stem cell transplants are recommended for many, but not all, people with AML. For those who are able to find a donor and are able to safely tolerate the transplant process, this treatment may offer the best chance for a cure.

For people whose disease is considered low risk because of its molecular characteristics, a transplant is usually not recommended. These people usually do well without that procedure.

For others, especially those who have serious, unrelated health problems, a transplant may not be recommended. That’s why it’s so important that we have all these new treatments. They offer a good alternative to transplants.

What does MSK offer people with AML that most other hospitals don’t?

We recently conducted a pilot project in which people were able to receive their consolidation chemotherapy — the second part of their treatment — as outpatients. In consolidation therapy, chemotherapy is given on alternating days throughout the week. This is done every week for a month.

Under our new procedure, the way it works is that patients come in on a Monday and get their first treatment. During that appointment, their chemotherapy for Wednesday and Friday is loaded into an electronic pump. At the end of their treatment on Monday, they can go home. Then on Wednesday and Friday, they use telemedicine to communicate with their nurse, who can then activate the pump remotely for the next two doses.

Historically, induction chemotherapy — the first part of the treatment — has always been done on an inpatient basis. People have to stay in the hospital for at least a month. This is difficult for them and their families. With new developments in technology, a study will soon start for people to receive their induction treatments mostly at home.

The only strict requirement for receiving treatment this way is that patients have to live a reasonable distance from one of our locations, within an hour or two, in case they need to come back in.

What else is special about the way MSK treats AML?

There are 22 doctors on our service who are completely focused on leukemia, myelodysplastic syndrome, and myeloproliferative neoplasms. We also have nurses and nurse practitioners with fantastic expertise in caring for people with acute leukemia. Some of them have many years of experience.

We have a team of clinical pharmacists who are dedicated to working with the Leukemia Service. They are vital for understanding all the new drugs that are being given to patients, whether as part of standard care or a clinical trial. And they’re very good at educating patients about what they need to know when taking these drugs.

We also have wonderful colleagues on the Infectious Disease Service. They focus on the prevention and treatment of the infections that are common in people receiving leukemia therapy. They closely monitor our patients for signs of trouble. They also perform clinical and laboratory-based research that’s leading to better treatment for all people with cancer.

Proof that Fecal Transplants Can Restore a Gut’s Natural Balance of Microbes

Source: Memorial Sloan Kettering - On Cancer
Date: 09/26/2018
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Fecal microbiota transplants (FMTs) are also known as stool transplants. The process involves collecting feces from a healthy donor, processing it, and then delivering it into the colon of the recipient. Just a decade ago, FMTs were unconventional. But they are becoming accepted by the medical establishment. The procedure is primarily used to treat intestinal infections from a bacterium called Clostridium difficile (C. diff), but it’s being studied for other conditions as well. 

FMTs are not formally approved by the US Food and Drug Administration. But in 2013, the FDA said that doctors could use them to treat chronic C. diff infections that have not responded to other treatments, opening the door for more controlled clinical studies.

A clinical trial at Memorial Sloan Kettering is now showing for the first time that FMTs can reestablish the health-promoting bacteria that are often lost in people who have stem cell or bone marrow transplants for blood cancer. The trial involves collecting and storing a person’s own stool prior to the procedure. After the stem cell or bone marrow transplant, the FMT is given to the patient. Because the FMT comes from a person’s own body, it is called an autologous FMT. The results are being published today in Science Translational Medicine.

“When we started this trial three years ago, we knew much less about FMTs than we know today,” says MSK infectious diseases specialist Ying Taur, the study’s first author. “This study is really a milestone. It removes whatever trepidation there may have been about exploring this procedure in people who have recently undergone cancer treatment.” 

Addressing Serious Complications from Bone Marrow Transplant

People who have stem cell or bone marrow transplants to treat blood cancer face a number of challenges. These complications especially affect those whose transplanted blood cells come from a donor, called an allogeneic transplant. In order for the body to accept the donor’s cells, the recipient’s own blood cells are wiped out with high doses of chemotherapy. During the time when the new blood cells are growing, recipients are prone to infections and require high doses of antibiotics. But those antibiotics can, in turn, destroy the healthy microorganisms that live in the body and allow more dangerous microbes to take over.

This is where an FMT comes in: The procedure helps restore a balance of healthy bacteria in the gut.

In earlier work, MSK physician-scientists Eric Pamer and Marcel van den Brink found that out-of-balance intestinal microbes can contribute to serious side effects. This disparity can affect outcomes after stem cell transplants. In particular, when harmful bacteria like C. diff dominate in the intestine, people are more likely to suffer complications from graft-versus-host disease. This potentially fatal side effect occurs when immune cells from the donor attack healthy tissues in the recipient, especially the intestinal lining. Dr. Pamer is one of the senior authors on the new paper; Dr. van den Brink is a coauthor.

Restoring the Balance of Microorganisms after Transplant

In the current study, participants’ own fecal material is collected before beginning the stem cell transplant process. Using their own feces helps ensure that the transplant won’t expose them to any unfamiliar flora. Any new bacteria could cause problems after the FMT. The collected stool is frozen to preserve the healthy microbe balance when the processed fecal material is reintroduced after the stem cell transplant.

The paper reports the results from the first 25 people in the study, 14 of whom received a transplant of their own fecal material and 11 controls, who did not.

The investigators looked at a number of measures. They considered levels of beneficial microbes as well as potentially harmful microbes. The mixture of microorganisms that came from the stored fecal material was able to reestablish itself after transplant. This resulted in more diverse, balanced microbiota.

“The important message here is that we showed we could bring the microbiota back to a level that was much closer to what people came in with before their stem cell transplant,” says Dr. Pamer, who heads a lab in the Sloan Kettering Institute’s Immunology Program.

Wide-Ranging Implications for the Health of People with Cancer

Another study from MSK researchers reported that having higher numbers of certain healthy bacteria in the intestinal tract contributed to fewer viral infections in the lungs after a stem cell transplant. Respiratory infections are another major complication in people who have stem cell transplants. This study points to the importance of maintaining healthy microbiota for overall recovery, not just for the health of the intestinal tract. The results were published online in April in the journal Blood.

Drs. Pamer and Taur say that since assembling the results in the current report, they have brought the total number of people in the FMT trial to 59. The MSK team is continuing to follow them, with the goal of determining whether autologous FMT can affect overall clinical outcomes and improve survival. They expect those results to be available next year.

Investigators plan to study using fecal material from healthy donors rather than a patient’s own stool for the transplant.

Gut Microbes May Protect People Having Bone Marrow Transplants

Source: Memorial Sloan Kettering - On Cancer
Date: 12/02/2018
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One of the most serious complications of blood stem cell or bone marrow transplants (BMTs), which are used to treat many types of blood cancer, is graft-versus-host disease (GVHD). In this condition, a donor’s immune cells attack the vital organs of a transplant recipient. It can cause death in some cases.

In the past few years, researchers from Memorial Sloan Kettering and other institutions have found that a transplant recipient’s microbiota plays an important role in their survival after a BMT. (The microbiota is the community of organisms, or flora, that live in the body, especially in the gut.) Now, for the first time, investigators have found an association between the health of the microbiota before a transplant and a person’s survival afterward. The findings were presented December 2, 2018, at the annual meeting of the American Society of Hematology (ASH).

“Patients who went into the BMT process with a gut flora that was already disrupted had a higher risk of death after the transplant,” says the study’s senior author, Marcel van den Brink, Head of MSK’s Division of Hematologic Malignancies. “The thing that we keep coming back to is that preserving the commensal flora in the microbiome is good for transplant patients.” Commensal flora are microbes that live in the body without causing disease. In some people, they may be beneficial.

The Forgotten Organ

Many of those who study the gut microbiota refer to it as the “forgotten organ.” It can have a huge impact on someone’s health. But scientists are still learning what makes it healthy or damaged, and what can be done to correct that damage.

“There are as many bacterial cells as there are human cells in our bodies,” says first author Jonathan Peled, an MSK medical oncologist who specializes in BMTs. “In addition, these bacteria are really important for the way our bodies function.”

“Before someone has a BMT to treat their cancer, we do a lot of screening tests to make sure they are otherwise healthy. We look at things like their heart, lung, and kidney function,” says Dr. van den Brink, who runs a lab in the Sloan Kettering Institute’s Immunology Program. “This study suggests that we should also screen the microbiota. If we find out that it’s in bad shape, we could do something to repair it.”

Dr. Peled adds, “This study opens the door to repairing the microbiota in the pretransplant period. Because this is a time when we’re usually not in a rush to move forward with treatment, it’s also a good time to look for ways to do this before continuing the transplant.” Interventions that could improve the health of the microbiota include changes to diet, using or avoiding certain antibiotics, and fecal transplants of healthy gut microbes.

MSK doctors are already conducting research on fecal transplants that make use of a patient’s own stool. The stool is preserved before the BMT and given back to the patient after the process. A recent study led by MSK physician-scientists Eric Pamer and Ying Taur found that fecal transplants are effective in restoring the balance of healthy microbes that is lost during a BMT. Researchers also plan to study the safety of providing fecal transplants with material from a healthy donor. Donor stool may ultimately prove to be a better option for people who come to a BMT with a microbiota that’s damaged.

Throwing Off the Healthy Balance of the Gut

In the analysis presented at ASH, the researchers studied 1,922 stool samples from 991 people having allogeneic BMTs. “Allogeneic” means the blood or marrow stem cells come from a donor. (In the other type of transplant, an autologous procedure, a patient’s own blood cells are stored before treatment and later infused back into the body.) The people were treated at MSK and three other hospitals. The samples were evaluated for a range of bacteria types, including commensal strains and those that are known to cause disease.

The investigators found that, on average, the people about to have BMTs had decreased diversity of bacteria in their guts. They also found that different strains were dominant, compared with healthy volunteers. This was a new finding, but it was not surprising. Most people with blood cancer who need transplants have gone through months or years of treatment with chemotherapy drugs and antibiotics that throw off the normal, healthy balance.

Diversity in the microbiota is important because commensal bacteria help keep more dangerous strains in check. Previous studies have also shown that certain commensal strains actually provide specific benefits for people having transplants. Some strains release substances that protect the walls of the intestines, for example.

In the current study, only 10 to 30% of patients had what researchers considered a balanced gut flora before their transplant. The more the ecology of the microbiota was disrupted, the more likely it was that patients had fatal complications from GVHD. However, the researchers emphasize that this study showed only an association, not direct causation.

A Study with a Broad Geographic Scope

Investigators at three other transplant centers also participated in the research and contributed patient samples: Duke University School of Medicine in Durham, North Carolina; Hokkaido University in Sapporo, Japan; and University Hospital Regensburg in Germany. Different locations were included because other research has shown that microbiotas across geographic regions vary widely. Factors like environment and diet are thought to play a role.

All of the samples were analyzed in MSK labs, Dr. Peled says, improving the validity of the results across the sites.

“One of the main findings of this study was that the injury patterns that we saw in people’s microbiotas were comparable across geography,” he concludes. “This suggests that if we find interventions to correct these imbalances at one center, they will also apply to people being treated in other parts of the world.”