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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.

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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 IDH2. Ivosidenib (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.

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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.

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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.”

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Some People Who Need a Bone Marrow Transplant Will Never Find a Donor — and What Can Be Done about It

Source: Memorial Sloan Kettering - On Cancer
Date: 03/27/2019
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For many people who have leukemia, lymphoma, or certain other blood disorders, stem cell or bone marrow transplantation (BMT) offers the best chance of a cure. But only about 25% of people who need an allogeneic transplant — the type of transplant in which donor cells are used — have a sibling who is a suitable genetic match. The remaining 75% usually look to registries of unrelated adult volunteers to find a compatible donor.

A study from investigators at Memorial Sloan Kettering reports that for people of certain racial and ethnic backgrounds, finding an unrelated donor match can be difficult if not impossible. This is despite huge growth in the pool of volunteer donors who have joined these donor registries, to tens of millions in recent years.

“Our research demonstrates that many people will never find a matched volunteer donor from any registry because of their racial and ethnic background,” says lead author Juliet Barker, a hematologic oncologist who specializes in BMT. “For this increasingly large group of the US population, funding for research into alternative donor options such as cord blood transplantation is important. These other options can greatly expand access to transplantation for patients without a matched adult donor.”

Cord blood is collected from the umbilical cord and placenta of healthy newborns and donated by the baby’s parents at birth.

Finding a Matched Donor

The study, published in Blood Advances, followed 1,312 people treated at MSK between 2005 and 2017 who needed a BMT but did not have a suitably matched brother or sister. The patients were categorized by their racial and ethnic backgrounds based on how they identified themselves and their family history. Thirty-four percent had non-European backgrounds. This included patients of Asian, white Hispanic, African, Middle Eastern, and other mixed non-European descents.

“MSK is an ideal center to do this kind of study because our patient population is so diverse,” Dr. Barker says. “And this study is important as the US population is increasingly becoming more diverse: The problem of finding matched donors will impact more and more transplant centers all over the country.”

The researchers also reported that despite the notion that people of European descent can more easily find donors, many patients of southern European ancestry had diverse markers and therefore were not able to find a match. This includes people from places such as southern Italy and Greece.

The Science of HLA Matching

Stem cell donors and bone marrow transplant recipients must be matched for their tissue type. Specifically, the matching process looks at markers, or proteins, known as human leukocyte antigens (HLAs). HLA markers are inherited and allow the immune system to recognize which cells belong and which are foreign. Over hundreds of generations, humans in different parts of the world have acquired many different HLA genes. Some people, such as those from Africa, have very diverse HLA types.

A close HLA match is critical when transplanting blood and bone marrow–forming stem cells from an adult donor to a patient. This makes it difficult for people of certain races or mixed ancestry to find a match.

By contrast, cord blood transplants do not require a strict HLA match. Another important finding from the study was that cord blood was able to extend transplant access to people from a wide variety of racial and ethnic backgrounds.

Benefits of Cord Blood Transplants

Cord blood is a rich source of blood-forming stem cells. Like stem cells from adult donors, cord blood is obtained through donor registries. Dr. Barker is an expert in this type of transplant and leads MSK’s Cord Blood Transplantation Program.

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 cells and the cells of the person receiving them is less strict.

Dr. Barker explains that for patients in need of a donor transplant who don’t have a matched sibling, MSK doctors can determine very quickly, based on the patients’ HLA markers, whether they are likely to find a match in unrelated volunteer donor registries.

She says this allows doctors to move very efficiently to alternative donor options for the transplant. “Timing is especially important,” she says. “Many patients will be too sick to have any kind of transplant if they wait too long.”

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Research Points to a Potential New Approach for Treating Anemia

Source: Memorial Sloan Kettering - On Cancer
Date: 10/04/2019
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Anemia, a condition in which there are not enough red blood cells to transport oxygen throughout the body, affects millions in the United States every year. It can lead to fatigue, dizziness, and shortness of breath, among other symptoms. It’s a common side effect of certain cancer treatments, especially chemotherapy. Anemia occurs frequently in people with a type of blood cancer called myelodysplastic syndrome (MDS). And it’s widespread among people over age 65.

Therapies for anemia exist. They include the drug epoetin alfa (Procrit®, Epogen®), regular blood transfusions, and iron supplements. But researchers continue to be on the lookout for additional and better ways to boost the production of red blood cells. MSK physician-scientist Omar Abdel-Wahab, an expert in MDS, recently published a study in Science Translational Medicine that reported a new approach for treating anemia with medication.

“Anemia is a major medical problem,” says Dr. Abdel-Wahab, whose lab is part of MSK’s Human Oncology and Pathogenesis Program. “This study suggests a new type of drug that we could use to treat it. While the current standard therapies for anemia are very helpful, many people eventually fail to respond to these treatments. Additionally, routine use of blood transfusions has a major negative impact on quality of life and comes with potential side effects. Thus, developing entirely new ways to treat anemia is incredibly important.”

A Different Role for a Known Pathway

The new method was identified through a collaboration between Dr. Abdel-Wahab and Lingbo Zhang, a researcher at Cold Spring Harbor Laboratory and co-senior author of the paper.

The researchers performed a high-throughput screen, in which hundreds or thousands of compounds are tested at the same time. They were hoping to find drugs that could boost the production of red blood cells. They tested the compounds in cell cultures of red blood cell precursors (a type of blood stem cell that has the ability to develop into red blood cells).

They discovered that compounds that block a pathway called CHRM4 increased the production of red blood cells. This pathway is also known to have a regulatory effect on neurotransmitters, such as serotonin and dopamine. Its role in the production of red blood cells had not previously been identified.Anemia is a major medical problem.

After identifying the role of the CHRM4 pathway by studying blood cells in a test tube, the investigators analyzed the effects of giving the compounds to mice with MDS and in bone marrow samples from people with MDS. They also tried them in elderly mice that had reduced red blood cell production because of their age. (In mice, elderly means about 2 years old.) In each case, the drugs boosted the numbers of red blood cells that were made.

Identifying a Novel Therapeutic Approach

Drugs that block the CHRM4 pathway have already been approved by the US Food and Drug Administration to treat certain neurological disorders. The researchers are hoping to use these drugs as a starting point to make new medications that are more effective at treating anemia.

“These drugs don’t seem to have many side effects,” Dr. Abdel-Wahab says. “We think this is a good path to pursue.”

He adds that targeting CHRM4 could also be a good approach for treating hemolysis. This condition occurs when red blood cells break open and release hemoglobin into the blood. Hemolysis can happen in response to infections or drug reactions, among other situations, and can lead to anemia.

This research was funded by the Cold Spring Harbor Laboratory (CSHL) President’s Council; National Institutes of Health grants (CA045508, U01 HL127522, 1K08CA230319-01, and R01 HL128239); a CSHL–Northwell Cancer Translational Research Award; the Edward P. Evans Foundation; the Leukemia and Lymphoma Society; the Henry and Marilyn Taub Foundation; a Department of Defense Bone Marrow Failure Research Program grant (W81XWH-12-1-0041); and the Pershing Square Sohn Cancer Research Alliance.

Dr. Abdel-Wahab has served as a consultant for H3 Biomedicine, Foundation Medicine, Merck, and Janssen, and has received personal speaking fees from Daiichi Sankyo.

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Study in Mice Suggests Lactose in the Diet Feeds Dangerous Gut Bacteria When the Immune System Is Compromised

Source: Memorial Sloan Kettering - On Cancer
Date: 11/29/2019
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Infections with the Enterococcus bacterium are a major threat in healthcare settings. They can lead to inflammation of the colon and serious illnesses such as bacteremia and sepsis, as well as other complications.

Enterococcus infections are particularly risky for people having stem cell and bone marrow transplants (BMTs) to treat blood cancer. Studies have suggested that high levels of Enterococcus increase the incidence of graft-versus-host disease (GVHD), a potentially fatal condition in which immune cells from the donor’s stem cells attack the recipient’s organs.

Now, an international team led by scientists from Memorial Sloan Kettering has shown for the first time that foods containing lactose, a sugar that’s naturally found in milk and dairy products, help Enterococcus thrive in the gut, at least in mice. They also studied changes in the bodies of people having BMTs. The study was published November 29 in Science.

“These findings hint at a possible new way to reduce the risk of GVHD as well as dangerous infections,” says MSK physician-scientist and GVHD expert Jonathan Peled. “But they are still preliminary, and it’s too early to suggest cutting out lactose in the diets of people undergoing BMTs or other hospitalized patients who are at risk from Enterococcus.”

Focusing on the Microbiota

For several years, Dr. Peled and Marcel van den Brink, head of MSK’s Division of Hematologic Malignancies, have been studying the relationship between GVHD and microbiota — the community of microorganisms that inhabit the body. The two of them are co-senior authors of the new study.

Their previous research has shown that when harmless strains of microbes are wiped out, often due to treatment with antibiotics, Enterococcus and other harmful types of bacteria can take over due to lack of competition. As part of the new study, which included analysis of microbiota samples from more than 1,300 adults having BMTs, the team confirmed the link between Enterococcus and GVHD.

The investigators conducted further Enterococcus research in cell cultures and in mice. “Mouse models are very helpful for understanding the mechanisms in the gut that lead to GVHD,” says Dr. van den Brink, who is also Co-Director of the Parker Institute for Cancer Immunotherapy at MSK and leads a lab in the Sloan Kettering Institute’s Immunology Program. “We studied mice that had been given BMTs and found that the cells lining their intestines, called enterocytes, were no longer able to make lactase, the enzyme that breaks down lactose. The high levels of undigested lactose in turn led to a total domination of Enterococcus. It was shocking to see how one type of bacteria completely takes over.”

Dr. van den Brink adds that on top of the defective enterocytes, the loss of competing healthy strains of bacteria caused by antibiotic treatment makes problems in the gut even worse. “It’s a double whammy,” he says.

A Trip to the Pharmacy Leads to a Surprising Discovery

To study whether higher lactose levels were boosting the growth of Enterococcus, or whether the connection was only a coincidence, visiting researcher and first author Christoph Stein-Thoeringer went to the pharmacy to buy Lactaid®. These lactase-containing pills break down lactose, helping people who are lactose intolerant to eat dairy products without side effects.

The researchers discovered that when lactase was added to lab cultures of Enterococcus, the bacterial growth was blocked. So, they began to feed lactose-free chow to lab mice that had been given BMTs and found that mice on the special diet were protected against Enterococcus domination.

“We’re not suggesting this is a cure for GVHD,” Dr. van den Brink says. “But it appears to be an important modulator.”

The investigators have not yet tested the new findings in humans, but existing data suggests that the same connection between lactose and Enterococcus seen in the mice may be at play in people who have had BMTs. “We know which gene variants are associated with being lactose intolerant,” Dr. Peled notes. “We looked at our records and found that people who had these gene variants tended to have a harder time clearing Enterococcus from their guts than others did.”

He adds that many BMT recipients become temporarily lactose intolerant, likely due to the loss of enterocytes caused by chemotherapy. “We are considering doing a trial in which people eat a lactose-free diet or take Lactaid during their cancer treatment to see if the growth of Enterococcus is blocked,” Dr. Peled says.

A Global Effort

Another important aspect of the new study is that it didn’t just look at people treated at MSK. It also included patient samples from Duke University School of Medicine in Durham, North Carolina; Hokkaido University in Sapporo, Japan; and University Hospital Regensburg in Germany. Researchers from those three institutions also contributed to the Science paper.

“Researchers who study the microbiome know that the environment in which a person lives is a major factor,” Dr. van den Brink says. “We’ve made a major effort to collect samples from all over the world, so we know that when we find common features, they are likely to hold up worldwide.”

This work was supported by the German Research Foundation, a Young Investigator-Award from the American Society of Bone Marrow Transplantation, the Lymphoma Foundation, the Susan and Peter Solomon Divisional Genomics Program, the Parker Institute for Cancer Immunotherapy at MSK, the Sawiris Foundation, the Society of MSK, an MSK Cancer Systems Immunology Pilot Grant, the Empire Clinical Research Investigator Program, Seres Therapeutics, the Japan Society for the Promotion of Science, the Center of Innovation Program from Japan Science and Technology, a Conquer Cancer Foundation Young Investigator Award/Gilead Sciences, and more than a dozen National Institutes of Health grants (R01-CA228358, R01-CA228308, P30 CA008748, P01-CA023766, R01-HL125571, R01-HL123340, P01-AG052359, U01 AI124275, R01 AI032135, AI095706, U01 AI124275, KL2 TR001115-03, 2P30AG028716-11, R01CA203950-01, 1R01HL124112-01A, R01 CA203950-01).

Dr. Peled reports research funding, intellectual property fees, and travel reimbursement from Seres Therapeutics and consulting fees from DaVolterra. Dr. van den Brink has received research support from Seres Therapeutics; has consulted, received honorarium from, or participated in advisory boards for Seres Therapeutics, Flagship Ventures, Novartis, Evelo, Jazz Pharmaceuticals, Therakos, Amgen, Magenta Therapeutics, WindMIL Therapeutics, Merck & Co. Inc., Acute Leukemia Forum (ALF), and DKMS Medical Council (Board). He also has IP licensing with Seres Therapeutics and Juno Therapeutics and stock options from Smart Immune.

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Largest Study of Its Kind Reveals New Targetable Genetic Causes of the Rare Blood Disorder Histiocytosis

Source: Memorial Sloan Kettering - On Cancer
Date: 12/04/2019
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Histiocytoses are a group of blood diseases that are diagnosed in only a few hundred people in the United States every year. Despite that rarity, researchers at Memorial Sloan Kettering have extensive experience with histiocytosis. MSK doctors care for more adults with histiocytosis than doctors at any other hospital in the country.

In recent years, MSK investigators have led a number of studies on the specific gene mutations that cause different types of histiocytoses (also called histiocytic neoplasms). On November 25, in Nature Medicine, an international team led by MSK reported findings from the largest study of its kind. They identified mutations for nearly all of the 270 people included in the study.

“We’ve known for some time that most cases of this disease are driven by a single mutation,” says MSK neurologist and histiocytosis expert Eli Diamond, one of the paper’s two senior authors. “In the past, we’ve been able to define those mutations for about 70% of patients.”

“Through the more extensive sequencing that we’ve done in this study, we can now define the mutations driving the disease in close to 100% of patients,” adds MSK physician-scientist Omar Abdel-Wahab, the paper’s other senior author. “For most of these mutations, we already have drugs to target them.”

Previous Success with Targeted Therapies

Histiocytosis occurs when the body makes an unusually large amount of abnormal white blood cells, referred to as histiocytes. These cells can build up and form tumors, which can grow in any part of the body. The bones and skin are most commonly affected.

The most common types of histiocytoses are Erdheim-Chester disease, which occurs mostly in adults; Langerhans cell histiocytosis and Rosai-Dorfman disease, which can affect both children and adults; and juvenile xanthogranuloma, which is found almost exclusively in children. All of these types were included in the study, as well as some other, rarer forms of the disease.

Thanks to earlier research done at MSK and elsewhere, experts already knew about the mutations driving many of these subtypes. That understanding has led to targeted therapies that are effective in treating them.

In 2017, vemurafenib (Zelboraf®) was the first drug approved for people with Erdheim-Chester disease. Vemurafenib targets mutations in a gene called BRAF. In October 2019, the US Food and Drug Administration announced that it had granted a Breakthrough Therapy Designation for the drug cobimetinib (Cotellic®) to treat histiocytosis with mutations in the genes MEK1 and MEK2. This designation indicates that the agency believes the drug is particularly promising. The clinical trials for both of these drugs were led by investigators at MSK.

“Another thing that’s important to note is that unlike treatment with most targeted therapies, where the tumors eventually become resistant to the drugs, when histiocytosis is treated with these therapies, patients’ responses tend to be long-lasting,” Dr. Diamond says. “Many people have remained on these drugs for years with durable benefits and few side effects.”

The new study opens up opportunities for even more people to be treated with targeted therapies. The researchers uncovered mutations in the RET, ALK, and NTRK genes. All of these mutations can be targeted with drugs that are already approved or are in clinical trials for other types of cancer with these mutations.

The study also reported for the first time that the gene CSF1R is implicated in certain cases of histiocytosis. CSF1R was already known to be important in the formation of a type of white blood cell called a macrophage.

“One of the strengths of this study is that it included all subtypes of histiocytosis. We have enough data to make these correlations between specific gene mutations and specific forms of histiocytosis,” says Dr. Abdel-Wahab, who leads a lab in MSK’s Human Oncology and Pathogenesis Program.

New Details about the Causes of Histiocytosis

The study revealed valuable information about the underlying origins of these diseases as well.

For example, doctors observed twins with histiocytosis. The investigators found that the common mutation driving the disease came not from the twins’ parents but from a mutation in the very early embryo that affected how their blood cells developed. These findings have implications for understanding how histiocytosis forms in many people.

Many of the patients whose data were included in the study were treated at MSK, but people treated at hospitals in Europe and other parts of the United States were included, too. Investigators from several other institutions were co-authors on the paper.

One way that the team was able to collect so many samples is through Make-an-IMPACT. This MSK initiative provides individuals with rare cancers the opportunity to receive genomic testing of their tumors at no cost. Histiocytosis is one of the cancer types included in this program.

“It’s very important that everyone who has histiocytosis gets their tumor sequenced,” Dr. Abdel-Wahab says. “It not only can help them but can also make important contributions to research.”

This work was supported by grants from the Histiocytosis Association, the Erdheim-Chester Disease Global Alliance, the American Society of Hematology, the Leukemia and Lymphoma Society, the Pershing Square Sohn Cancer Research Alliance, the Functional Genomics Initiative at MSK, The Society of Memorial Sloan Kettering, a Translational and Integrative Medicine Award from Memorial Sloan Kettering, the Geoffrey Beene Cancer Research Center at MSK, the Frame Family Fund, the Joy Family West Foundation, the Nonna’s Garden foundation, the Flanders Institute for Biotechnology in Belgium, and the National Institutes of Health (K08CA218901, UL1TR001857, P30CA008748, and 1R01CA201247).

This work was also supported by Cycle for Survival, MSK’s rare cancer fundraising program. Make-an-IMPACT is also funded by Cycle for Survival.

Dr. Abdel-Wahab has received grants from H3 Biomedicine and personal fees from H3 Biomedicine, Foundation Medicine, Merck, and Jansen unrelated to this manuscript.

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MSK Experts Report New Findings about Multiple Myeloma at the 2019 ASH Meeting

Source: Memorial Sloan Kettering - On Cancer
Date: 12/09/2019
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Multiple myeloma is a cancer that arises from the type of white blood cells called plasma cells. When normal plasma cells in the bone marrow develop certain genetic mutations, they may turn into myeloma cells.

At the annual meeting of the American Society of Hematology (ASH), held December 7 through 10 in Orlando, Florida, Memorial Sloan Kettering researchers reported on some of the latest advances in detecting and treating multiple myeloma.

A New Combination Therapy

One of those studies, led by MSK hematologic oncologist Ola Landgren, Chair of the Myeloma Service, is a phase II clinical trial looking at a new combination of drugs for those recently diagnosed with multiple myeloma.

In this trial, the participants had a targeted antibody drug called daratumumab (Darzalex®) added to a standard chemotherapy combination, called KRD, which is comprised of three drugs: carfilzomib (Kyprolis®), lenalidomide (Revlimid®), and dexamethasone (Ozurdex®).

“After someone completes treatment for multiple myeloma, the measure of how effective that treatment was is called minimal residual disease, or MRD,” Dr. Landgren explains. “MSK uses two very sensitive tests that can detect a single cancer cell in 100,000 or more plasma cells. If we can’t find any cancer, we feel quite confident the treatment has been successful.”

Among the 30 people who got the KRD-daratumumab combination, 77% of them were MRD negative after eight cycles of treatment. Based on cross-study comparison, the average level of MRD negativity seen with other therapies is 54% for those who get KRD alone, 58% for those who get KRD followed by an autologous stem cell transplant, and 59% for those who get a different chemotherapy combination called VRD-daratumumab followed by a transplant.

Daratumumab is currently approved by the US Food and Drug Administration for use in people who are unable to have transplants because of age or other health problems. Dr. Landgren says that based on these findings and other emerging studies, he thinks daratumumab could be used more widely.

Along with the biotech company Amgen, Dr. Landgren is working with the FDA to develop a large, randomized, multicenter clinical trial designed to evaluate KRD-daratumumab in comparison to the drug combinations that are currently considered the standard of care. He says that if the new combination is shown to be effective in a head-to-head comparison with current standard treatments, it could lead to wider approval of the drug.

“It’s too early to say that the addition of daratumumab to KRD, as a consequence of the high rate of MRD negativity, will result in an increasing proportion of newly diagnosed multiple myeloma patients opting for delaying their transplants, but it’s possible that may be the case,” he says. “Transplants are effective, but they are also associated with significant short-term as well as long-term toxicities, whereas side effects from daratumumab are quite minimal. The current phase II study is limited by small numbers and short follow-up, but the early results showing 77% of patients with no MRD are very exciting.”If we can

Learning How Multiple Myeloma Develops

Another important study looked at the early development of multiple myeloma. The disease is diagnosed in about 32,000 people in the United States every year, but experts estimate that by age 60 many more people — from 3% to 5% of the population — will have cells detectable in their blood that show signs of pre-myeloma.

These myeloma precursors can develop years or even decades before symptoms of the disease begin to develop. The symptoms include bone pain and frequent infections. Since the discovery of these early changes was made about ten years ago, the challenge has been determining who is most likely to develop the disease — and therefore should consider closer observation or possibly treatment — and those who don’t need to worry.

In the new research, an international group of investigators led by MSK hematologic oncologist Francesco Maura, a member of Dr. Landgren’s lab, developed a computational algorithm to understand when the first genetic driver of these pre-myeloma cells is acquired. Using genetic information from samples collected through two large, public databases, the researchers were able to reconstruct the life history of these blood cells long before the myeloma developed.

“We were quite surprised to find that many of the key changes associated with myeloma are acquired when people are in their 20s and 30s, even though the average age of disease onset is 63,” Dr. Maura says. “In this study, we developed a way to find the tumor cells’ mutation rate by looking at when the key drivers are accumulated and the degree to which they contribute to the formation of cancer.”

One of the main goals of this research is to understand who has a high risk of ultimately developing cancer so that it can be treated before symptoms start. “We also know that as it progresses, multiple myeloma develops additional mutations that make it more aggressive and harder to treat,” Dr. Maura says. “Ideally, we would want to eradicate the cancer when it is less complex.”

Dr. Landgren has received funding from the Leukemia and Lymphoma Society, the Rising Tide Foundation, the National Institutes of Health, the US Food and Drug Administration, the Multiple Myeloma Research Foundation, the International Myeloma Foundation, the Perelman Family Foundation, Amgen, Celgene, Janssen, Takeda, Glenmark, Seattle Genetics, and Karyopharm. He has received honoraria from and/or served on the advisory boards of Adaptive, Amgen, Binding Site, Bristol-Myers Squibb, Celgene, Cellectis, Glenmark, Janssen, Juno, and Pfizer.

In addition to the funding he receives as a member of Dr. Landgren’s lab, Dr. Maura also has received funding support from The Society of Memorial Sloan Kettering.