A form of transplant rejection called graft-versus-host disease (GVHD) primarily occurs in recipients of bone marrow transplants and peripheral blood stem cells. GHVD presents a unique situation because the transplanted tissue is capable of producing immune cells; APCs in the donated bone marrow may recognize the host cells as non-self, leading to activation of the donor cytotoxic T cells. Once activated, the donor’s T cells attack the recipient cells, causing acute GVHD.

Acute GVHD typically develops within weeks after a bone marrow transplant, causing tissue damage affecting the skin, gastrointestinal tract, liver, and eyes. In addition, acute GVHD may also lead to a cytokine storm, an unregulated secretion of cytokines that may be fatal. In addition to acute GVHD, there is also the risk for chronic GVHD developing months after the bone marrow transplant. The mechanisms responsible for chronic GVHD are not well understood.

To minimize the risk of GVHD, it is critically important to match the HLAs of the host and donor as closely as possible in bone marrow transplants. In addition, the donated bone marrow is processed before grafting to remove as many donor APCs and T cells as possible, leaving mostly hematopoietic stem cells.

August 18, 2021, by Nadia Jaber

People with chronic graft-versus-host disease (GVHD), a common complication of bone marrow and stem cell transplants, now have a new treatment option. On July 16, the Food and Drug Administration (FDA) approved belumosudil (Rezurock) for people 12 years and older who have already tried at least two other therapies for the disease.

The approval is based partially on findings from a phase 2 clinical trial of 65 people with chronic GVHD, who were in remission from cancer after treatment with a bone marrow or stem cell transplant. Three-quarters of those patients responded to belumosudil, meaning their GVHD symptoms improved.

Although the standard treatment for chronic GVHD—high doses of a steroid such as prednisone—works for about half of patients, it causes many toxic side effects that limit its long-term use. And although there are more than 30 other treatment options, only one is FDA approved for chronic GVHD and there’s no way to know which one will work best for an individual.

“Throughout most of transplant history, we have been taking drugs that were developed for other [purposes], putting them into [patients with chronic GVHD], and seeing if they work,” said study investigator Stephanie Lee, M.D., M.P.H., of Fred Hutchinson Cancer Research Center.

“This is the first time in history that [a drug] was developed, from animal experiments to clinical application, as a therapy for chronic GVHD,” added study investigator Steven Pavletic, M.D., of the Immune Deficiency Cellular Therapy Program in NCI’s Center for Cancer Research.

Chronic Graft-Versus-Host Disease

GVHD occurs when transplanted immune cells (the graft) attack the recipient’s body (the host). The disease can affect nearly every organ and can cause many painful and debilitating symptoms.

GVHD is a concern for people with blood cancer because bone marrow and stem cell transplantation are part of the standard treatments for blood cancers.

“As techniques [for stem cell transplants] became safer and patients started living longer, this late effect became a big issue,” Dr. Pavletic explained. “These patients are cured from cancer, and now they are suffering from a new autoimmune disease that affects [them from] head to toe.”

The disease can develop quickly (acute GVHD) or slowly (chronic GVHD). Chronic GVHD usually develops within 12 months after the transplant and can take 3 to 5 years to resolve, if at all. Around 5,000 people in the United States develop chronic GVHD every year.

Common symptoms of chronic GVHD include skin thickening or rashes, dry mouth and mouth sores, dry eyes, joint stiffness, lung disease, and recurrent infections. In some cases, severe chronic GVHD can even cause death.

Clinical Trial of Belumosudil

The clinical trial that led to the FDA approval included 65 participants who took belumosudil as a pill once per day. The drug works by turning down the activity of immune cells and preventing the buildup of scar tissue—another hallmark of GVHD. The study was supported by Kadmon Pharmaceuticals, the company that makes belumosudil.

At the start of the study, 46 participants (71%) had chronic GVHD that was considered severe. Most participants had previously received three or more treatments for the disease.

The research team assessed each patient’s symptoms over time using guidelines established by Dr. Pavletic and others in 2014. Symptoms are evaluated in eight organs that are most commonly affected by chronic GVHD, namely the eyes, mouth, skin, joints, liver, gut, lungs, and connective tissue (fascia).

For 4 people (6%), belumosudil completely resolved disease symptoms in all eight organs. For 45 others (69%), the treatment partially improved symptoms, meaning there was a meaningful improvement in at least one organ and no worsening of symptoms in other organs.

Those improvements lasted for a median of 50 weeks, and fewer than half of those who responded to belumosudil needed additional treatments. In addition, 20% of participants stopped taking steroids for chronic GVHD and 65% were able to take smaller doses.

Across the board, the researchers saw improvements in every organ that they evaluated, including difficult-to-treat organs such as the lungs and skin. The disease can cause irreversible changes in some organs, so it’s challenging to resolve symptoms in those organs, the researchers explained in a study report published July 15 in Blood.

In an earlier study of belumosudil, Dr. Lee and her colleagues also found that half of the study participants experienced an improvement in quality of life. “For a chronic disease like this, [quality of life] is big. Patients [with chronic GVHD] are suffering from [it] every day,” Dr. Lee said.

Another benefit of belumosudil, Dr. Lee said, is that it seems to be safe to take with most other drugs. That’s “helpful because our patients are on a lot of different kinds of medications, and sometimes those [drug] interactions prevent us from using other medicines” to treat chronic GVHD, she said.

The most common side effects seen in the two clinical trials of belumosudil were infections, lack of energy, nausea, and diarrhea. Some participants stopped the treatment, either temporarily (29%) or permanently (18%), due to side effects. One person died from organ failure and infection, but it was unclear whether this was related to treatment.

The Impact of GVHD Consensus Guidelines

Nearly 2 decades ago, “the bone marrow transplant community realized something should be done [to address] this disease, but there were no tools or rules for how to [study] it,” Dr. Pavletic said.

So, in 2003, NIH put together a multidisciplinary team and developed a comprehensive research program focused on chronic GVHD. This team, led by Dr. Pavletic and collaborating with other scientists around the world, created guidelines and tools to diagnose, stage, and study chronic GVHD in preclinical and clinical studies.

For the first time, researchers could measure chronic GVHD symptoms in a patient and tell if they were getting better or worse, Dr. Lee said. “That laid the groundwork so that, as new [drugs] came along, we had a framework and an infrastructure to test them.” All of that work “really [got] us to this point” of the new FDA approval, she added.

While the approval of belumosudil is a major step forward, Dr. Pavletic said, more research is needed because most patients in the trial only experienced a partial improvement. “It tells us how much more work we have to do to [develop] even better drugs, or combine drugs, or give them at an earlier stage,” he said.

The addition of a new treatment option for chronic GVHD also makes the management of patients more complex because there are so many choices, Dr. Lee said. It’s currently difficult for a doctor to know which of the more than 30 available treatments will be best for their patient.

“Trying to match the right treatment to each patient is more complicated [now]. It’s a good problem to have, but we have to understand it better,” she said.

Prevention and Earlier Treatment of Chronic GVHD

In addition to studying treatments for chronic GVHD, Drs. Pavletic and Lee are also searching for ways to prevent the disease from developing or getting too severe. Dr. Pavletic’s group is developing approaches to predict which patients will go on to develop chronic GVHD, so that they have the option to take medicines to help prevent the disease. Because these prevention treatments come with the risk of serious side effects, it would be helpful if they could be given only to patients who really need them, Dr. Pavletic explained.

Dr. Lee’s group, meanwhile, is working to find early signs of GVHD so that patients can receive treatment before the disease worsens. If there are effective drugs that are also non-toxic and easy for patients to take, then “we can prevent people from having permanent disability and damage to their organs,” she said.

July 14, 2023, by Carmen Phillips

Transplants using stem cells from a donor are essential treatments for people with blood cancers like lymphoma and leukemia. But donor transplants—known as allogeneic transplants—also harbor a substantial risk of a serious, and potentially fatal, side effect called graft-versus-host disease (GVHD).

A large clinical trial has identified a more effective way for reducing the risk of this dangerous complication.

In the clinical trial, funded in part by NCI, about 430 people who had an allogeneic transplant were randomly assigned to receive one of two treatments for preventing GVHD: The standard two-drug regimen of tacrolimus and methotrexate, or a more recently developed three-drug regimen anchored by the chemotherapy drug cyclophosphamide. All patients in the trial had transplants from closely matched donors.

One year after receiving the transplant, 53% of people in the three-drug group had not experienced GVHD and their cancer had not relapsed, compared with 35% of those in the two-drug group. The findings were reported June 22 in the New England Journal of Medicine.

“It’s clearly a very wide difference” between the groups, said the trial’s senior investigator, Javier Bolaños-Meade, M.D., of Johns Hopkins Kimmel Comprehensive Cancer Center. “This is the first time since the 1980s it’s been shown that something is clearly superior” to the standard two-drug treatment.

Treatment with the three-drug regimen, which also includes tacrolimus and mycophenolate, did not lead to more serious infections or a higher risk of the cancer coming back, Dr. Bolaños-Meade continued.

Both findings are particularly important, he said, because other treatments have been found to effectively protect against GVHD, but that protection came at the cost of more dangerous infections or the cancer returning.

“If [the patient] doesn’t develop GVHD but they relapse, that can’t be considered a success,” Dr. Bolaños-Meade said.

An effective treatment with a potentially serious drawback

For many people with blood cancers, allogeneic stem cell transplants can cure their disease.

The transplants, however, can extract a hefty physical price in some people. Even with preventive measures, up to half of people who get an allogeneic stem cell transplant develop GVHD. This condition occurs when immune cells that linger among the donated stem cells (the graft) view healthy cells in the patient (the host) as foreign or dangerous and attack them.

GVHD can occur shortly after the transplant, known as acute GVHD, and it can also arise months after the transplant, called chronic GVHD.

Painful skin rashes, severe nausea, and diarrhea are among the most common symptoms of acute GVHD, explained Salyka Sengsayadeth, M.D., who specializes in treating blood cancers at Vanderbilt University Medical Center. And if these symptoms are bad enough, Dr. Sengsayadeth said, they can be fatal.

These same symptoms are also common in chronic GVHD, along with frequent mouth sores, fatigue and weakness, and shortness of breath, among others. Chronic GVHD symptoms “mostly tend to affect [people’s] quality of life,” she noted, although occasionally they can be fatal as well.

The combination of methotrexate and drugs known as calcineurin inhibitors—of which tacrolimus is the most commonly used—has been the standard treatment to protect against GVHD since the 1980s. Dr. Bolaños-Meade is part of a team at Hopkins that led the way in studying the cyclophosphamide-based regimen—and not just in people with cancer, but also in those undergoing stem cell transplants for noncancer health conditions like sickle cell disease.

In this new trial, the research team wanted to confirm findings from a smaller clinical trial they had conducted that strongly suggested the cyclophosphamide-based three-drug regimen could substantially reduce GVHD risk in those receiving closely matched transplants.

Cyclophosphamide-based regimen shows multiple advantages

The trial was conducted at 37 cancer centers in the United States, under the auspices of the Blood and Marrow Clinical Trials Network. About half of the participants had acute myeloid leukemia; the remainder had other forms of leukemia, lymphoma, or a blood cancer called myelodysplastic syndrome.

Prior to their transplant, all patients in the trial received a reduced-intensity conditioning regimen. Conditioning regimens enable the donated stem cells to more readily take up residence in the bone marrow and begin reproducing.

The benefit of the three-drug regimen went beyond the improvement in GVHD-free, relapse-free survival at 1 year. In particular, when people treated with the cyclophosphamide-based regimen did develop acute or chronic GVHD, it tended to be less severe. And people who received the three-drug regimen also were less likely to need treatment to suppress an out-of-control immune response caused by the transplant.

However, it took longer for levels of platelets to return to normal in people in the three-drug group than the standard-treatment group (low platelet levels increase the risk of internal bleeding), and they also had a higher rate of lower-grade infections.

Based on the limited follow-up time (median time of 1 year), there is no difference in how long patients in either group have lived overall. The team will continue to follow participants to track survival and other measures, Dr. Bolaños-Meade said.

Changing treatment with allogeneic transplants

Excitement about the cyclophosphamide-based regimen in people receiving well-matched transplants began when the results from the smaller trial were reported in 2019, said the trial’s lead investigator, Shernan Holtan, M.D., of the University of Minnesota School of Medicine.

Combined with the results of this larger trial, which were presented late last year at the annual meeting of the American Society of Hematology, the impact on patient care is already being seen.

“I am hearing from colleagues around the globe that practice patterns are changing” based on the trial’s findings, Dr. Holtan continued. “This cyclophosphamide-based regimen could indeed become the new standard of care for [allogeneic stem cell transplants], especially considering the reduction in both severe acute and chronic GVHD.”

Another key aspect of the trial is that the median age of its participants was 66, Dr. Bolaños-Meade stressed. Most diagnoses of AML are in people aged 65 and older. And a decade or so ago, most oncologists were not willing to offer patients of that age a stem cell transplant, he noted.

But that has changed with the advent of reduced-intensity conditioning and improvements in the management of complications and side effects of transplantation.

It’s clear now, he stressed, that allogeneic stem cell transplants are “something that we can perform on our patients who are ‘elderly,’” he said. At Hopkins, he continued, “we have no age limit on who can get a transplant.”

At Vanderbilt, there hasn’t been a shift toward the use of the cyclophosphamide-based regimen yet in patients like those in this trial, Dr. Sengsayadeth said. But she expects that to change.

However, that doesn’t mean every patient will get the three-drug regimen. Cyclophosphamide can affect the heart, so the tacrolimus-methotrexate duo may be preferable for people with heart conditions, particularly those who are older, she said.

Moving toward using the three-drug regimen should be “relatively seamless,” Dr. Sengsayadeth continued. That’s because it’s already commonly used in people receiving allogeneic transplants that are only half matches, called haploidentical transplants, which carry a higher risk of GVHD than well-matched transplants.

The cyclophosphamide-based regimen has also proven to be effective in children and adults who have undergone more intensive conditioning prior to an allogeneic transplant, Dr. Holtan explained, and in people receiving what are called mismatched unrelated donor transplants.

Other options for protecting against GVHD are becoming available. One drug, abatacept (Orencia), was approved by the Food and Drug Administration in December 2021 to protect against acute GVHD in people undergoing allogeneic transplants, she said.

How best to use abatacept is still a challenge for those in the transplantation field, she added, and the cyclophosphamide-based regimen has advantages, including its “comparatively lower cost and … effectiveness in preventing chronic GVHD.”

Taking GVHD Prevention Up a Notch

A drug that blocks a protein in immune cells called DLL4 may help prevent acute GVHD in the intestinal tract, according to a study published June 28 in Science Translational Medicine. DLL4 activates a protein called Notch, which in turn controls a communication pathway in immune cells that is directly linked to intestinal GVHD.

“We found that just a single dose of [anti-DLL4] antibodies to block the Notch signaling pathway, given immediately before the transplant, was able to prevent gastrointestinal GVHD, without impairing immune function in the rest of the body,” said the study’s lead investigator, Ivan Maillard, M.D., Ph.D., of the University of Pennsylvania, in a press release.

The study was conducted in nonhuman primates, following earlier studies in mice showing that this treatment approach had promise. The study team is developing a clinical trial to test the experimental drug in people undergoing stem cell transplants.

May 29, 2020, by NCI Staff

Patients with blood cancers who develop graft-versus-host disease (GVHD) within the first few months after receiving a stem cell transplant and don’t respond to steroids are more likely to respond to the drug ruxolitinib (Jakafi) than to other treatments, according to results from a large clinical trial.

The findings are from the first randomized clinical trial of a treatment for GVHD to yield positive results. And the study confirms findings from a smaller trial that, in 2019, led to the approval of ruxolitinib by the Food and Drug Administration (FDA) for some patients with GVHD.

Both trials tested the drug in patients with a form of the disease called steroid-refractory acute GVHD. In these patients, GVHD develops within the first weeks and months after a transplant of stem cells from a healthy donor, also known as an allogeneic stem cell transplant, and the disease does not respond to steroids.

During a transplant, the donor’s healthy stem cells replace the patient’s own cells that have been damaged by radiation therapy or chemotherapy. But in some patients who receive transplants, the donated cells attack the recipient’s cells, causing damage to the recipient’s tissues and organs, which can lead to GVHD. Symptoms of the disease include a widespread rash, diarrhea, and liver damage.

In the new trial, called REACH2, patients received either ruxolitinib or one of nine commonly used treatments for steroid-refractory acute GVHD (control group). After 28 days of treatment, more patients receiving ruxolitinib had a complete or partial response, compared with patients in the control group (62% versus 39%).

This difference in the response rates persisted through 56 days of treatment, and the side effects were similar in the two groups, Robert Zeiser, M.D., of the University Medical Center Freiburg, Germany, and his colleagues reported in the New England Journal of Medicine (NEJM) on April 22.

“This trial demonstrates that ruxolitinib is a new standard treatment for patients with steroid-refractory acute GVHD,” said Steven Pavletic, M.D., of the Immune Deficiency Cellular Therapy Program in NCI’s Center for Cancer Research, who was not involved in the trial.

“The results are very compelling because the drug was tested not against a placebo but against the best available treatments,” he added.

The First Successful Randomized Clinical Trial in GVHD

Between 30% and 50% of patients who have an allogeneic stem cell transplant develop acute GVHD. Steroids are effective for treating GVHD in only about half of all patients, and GVHD can be fatal in patients for whom steroids are not effective or who have a relapse, Dr. Pavletic noted.

Ruxolitinib, a targeted therapy that patients take as a pill, inhibits two proteins, JAK1 and JAK2, that are thought to play a role in GVHD. Blocking these proteins may lead to a reduction in inflammation that is associated with the disease, according to the researchers.

Ruxolitinib “appears to be a relatively specific drug” that may not interact with many molecules other than JAK1 and JAK2, wrote Nelson Chao, M.D., of the Duke University Medical School in a commentary accompanying the study in NEJM. This specificity could contribute to the limited side effects observed in the patients receiving the drug.

Novartis, the maker of ruxolitinib, funded the randomized trial, which was conducted at sites around the world.

The percentage of patients with a complete response (the disappearance of all signs of the disease) was 34% (53 patients) in the ruxolitinib group and 19% (30 patients) in the control group, the researchers reported. The median overall survival (the length of time that half of the patients in a treatment group are still alive) was 11.1 months in the ruxolitinib group and 6.5 months in the control group.

“We need to see if the improved response rate translates into improved overall survival,” said Dr. Zeiser. “Therefore, a long-term follow-up study is needed.”

He added: “It was important to see that there were no unexpected side effects in the group of 150 patients receiving ruxolitinib, and that the drug was well tolerated by patients.”

The most common side effects up to day 28 were thrombocytopenia (in 33% of the ruxolitinib group and 18% in the control group), anemia (30% and 28%, respectively), and cytomegalovirus (CMV) infection (26% and 21%).

Complications from CMV infections “are a major medical problem after allogeneic stem cell transplantation,” said Dr. Zeiser, who noted that if the problem is not treated patients can develop CMV-related pneumonia or eye infections.

Dr. Zeiser had been expecting higher rates of CMV infection in the ruxolitinib group, but the rates were similar in the two groups. “The observation that ruxolitinib did not increase infectious complications is a major plus in terms of the use of the drug,” he said.

In his commentary, Dr. Chao agreed that the CMV results were interesting but cautioned that the follow-up time for patients was short and longer follow up is needed to assess whether the lack of increase in CMV infection remains the case.

Translating Basic Research into New Treatments

Dr. Zeiser and his colleagues designed the trial to compare ruxolitinib with any of nine commonly used treatments for steroid-refractory acute GVHD because, prior to ruxolitinib, there was no standard treatment for this disease.

Now, however, researchers have begun to test many drugs for GVHD that could have similar effects as JAK inhibitors, noted Dr. Pavletic. “This is a very active area of research.”

The groundwork for the current research activity, he explained, was laid during scientific conferences held at the NIH in 2005 and in 2014 that helped to establish criteria for conducting clinical trials in patients with GVHD.

The REACH2 results “show that advances in our understanding of the biology of the disease can be translated into improved therapies for patients,” said Dr. Pavletic.

“But this trial is not the end of the story,” Dr. Pavletic added. “Ruxolitinib is not effective for all patients, and the field desperately needs good biomarkers to know when to intervene.”

Researchers are also testing ruxolitinib in patients with chronic GVHD, which can develop a few months after a stem cell transplant. “We are eager to see those results,” Dr. Pavletic said. (In 2017, ibrutinib (Imbruvica) became the first drug approved by FDA-to treat chronic GVHD.)

Dr. Zeiser expects that future studies will evaluate the potential for using ruxolitinib rather than steroids as the initial treatment for chronic GVHD. In addition, he added, “we’d like to see whether therapies could be used in combination with ruxolitinib to further increase its effectiveness.”

February 17, 2022, by Sharon Reynolds

For some people with aggressive blood cancers, such as certain types of leukemia, a treatment called an allogeneic stem cell transplant can provide the most wished-for outcome in cancer treatment: a cure.

But sometimes, the procedure results in a long-term, debilitating condition known as graft-versus-host disease (GVHD). GVHD occurs when immune cells from the donor that are given along with the stem cells during transplantation attack healthy tissues in the recipient’s body along with the cancer cells.

A new study reports what may be a way to prevent chronic GVHD after a stem cell transplant: by removing immune cells called naive T cells from the donated cells before they are transplanted. The researchers found that this substantially reduced the risk of chronic GVHD among study participants without any apparent increase in their likelihood of relapse.

“It’s a strategy that seems to hit the sweet spot” between preserving the delivery of beneficial immune cells and preventing chronic GVHD, explained Marie Bleakley, M.D., Ph.D., of the Fred Hutchinson Cancer Research Center, who led the study.

In three small clinical trials, only 7% of 138 patients who received a naive T cell–depleted transplant developed chronic GVHD, compared with more than 40% of a group of similar patients who received a standard transplant at the same cancer center in the past. Of the cases of chronic GVHD that did develop in patients who got the experimental transplant, none were severe.

Results from the trials were published together January 10 in the Journal of Clinical Oncology.

The trials were all nonrandomized phase 2 trials, meaning that all participants received the experimental treatment. Dr. Bleakley and her colleagues are currently performing two randomized studies to confirm these early results.

Randomized studies are needed before changes to the standard transplant regimen could be adopted, explained Steven Pavletic, M.D., of NCI’s Center for Cancer Research. “But if we can do allogeneic transplants without patients suffering from [chronic] GVHD, that’s huge,” he said.

Stem cell transplants: The original cancer immunotherapy

Blood cancers arise from stem cells in bone marrow that produce the body’s blood cells, including the white blood cells needed to fight infections. As part of treatment for some aggressive types of blood cancer, people may receive an allogeneic stem cell transplant.

This procedure destroys the bone marrow, where the stem cells reside, with high doses of chemotherapy and sometimes radiation therapy. Then, the patient gets an infusion of healthy stem cells from a donor, often a family member, matched to minimize the risks of transplant rejection and GVHD.

These stem cells travel to the bone marrow and, over time, provide the patient with all-new blood cells. In addition, the immune cells infused along with the stem cells will hopefully recognize and kill any remaining cancer cells in the body, a phenomenon called the graft-versus-leukemia effect.

“Allogeneic stem cell transplant is a form of cancer immunotherapy,” said Dr. Pavletic. “It’s been around for more than 50 years, but it’s really the precursor of [things like] CAR T-cell therapy that we have today.”

T cells are among the many types of immune cells that can attack cancer cells. But there are several subsets of T cells. Naive T cells have never encountered an antigen—a protein or other molecule that can provoke an immune response. For reasons that are not yet fully understood, they are more likely to react to healthy cells in the transplant recipient.

If immune cells attack and damage those healthy tissues, GVHD can result. GVHD can develop within a few months of the transplant, which is called acute GVHD. The most commonly damaged organs in acute GVHD are the skin, liver, and intestines.

For some people, acute GVHD can resolve with the use of immunosuppressive drugs. GVHD that develops later and has certain distinct characteristics—including specific changes to the skin, mouth, eyes, and joints—is considered chronic GVHD, explained Dr. Bleakley.

“Chronic GVHD is often a really serious condition and can last months to years,” said Dr. Bleakley. “It’s the primary cause of disability and chronic disease in [stem cell] transplant recipients,” she added. In some people, the condition can be fatal.

And if someone develops chronic GVHD, they may need to be on drugs that suppress their immune system for many years.

Immune-suppressing drugs can have side effects and increase the person’s risk of infection. They can also cause problems if a cancer recurs, explained Dr. Bleakley. People generally can’t receive immunotherapies like CAR T cells while on these drugs, but they can’t stop taking them without the risk of their GVHD worsening. “Then we’re in a sort of Catch-22 position,” she said.

Targeted T-cell depletion: Getting rid of naive T cells only

Researchers had previously tried removing all T cells from donated cells before transplantation, a strategy called T cell depletion. But not all T cells are created equal. Without memory T cells, for example, which have prior exposure to and can remember specific pathogens, many people developed severe or fatal infections after their transplants.

The idea to remove only naive T cells emerged almost two decades ago, explained Warren Shlomchik, M.D., director of Hematopoietic Stem Cell Transplant and Cell Therapy at the UPMC Hillman Cancer Center in Pittsburgh, the study’s senior investigator.

At the time, while working at Yale University, Dr. Shlomchik and his colleagues looked at the difference between the contribution of naive and memory T cells to GHVD. “When we realized that memory cells caused less GVHD, we saw the opportunity to translate [that finding] from the bench to the bedside,” he said.

To pull specific types of T cells out of donor grafts, they adapted a laboratory technique for separating cells that uses antibodies joined to microscopic iron beads. The antibodies are engineered to bind to proteins found only on specific types of T cells. The donor blood is then passed by a magnet, which latches on to the iron beads, removing only the unwanted T cells from the graft.

His team quickly saw the potential for the technique to be used in the clinic. In 2005, they joined NCI’s Developmental Therapeutics Program Rapid Access to Intervention Development (RAID) program, which was designed to translate ideas from basic research into testable treatments.

They then partnered with Fred Hutchinson, which has one of the largest stem cell transplant programs in the United States, and brought a biotechnology company partner on board to manufacture a product needed for the selective T cell–depletion method.

Over the next decade, the clinical team at Fred Hutchinson tested the strategy in three early-phase trials. They started out using high doses of chemotherapy and radiation therapy before transplantation—known as the conditioning regimen—which limited participation to younger, healthier people.

Over time, the researchers found that less-intensive conditioning regimens could also be used. This allowed the team to increase the upper age limit for participation from 55 to 60 years old for the third trial.

Between 2009 and 2020, 138 people with acute leukemia received the naive T cell–depleted transplants. All participants also received the standard drugs given immediately after transplantation to prevent GVHD. By the time the results were published, surviving study participants had been followed for a median of 4 years.

Going head-to-head against the standard of care

Almost three-quarters of the participants developed mild acute GVHD, mostly affecting the upper gastrointestinal tract. Participants who developed acute GVHD were less likely to have their cancer return or to die, which Dr. Bleakley attributed to the graft-versus-leukemia effect.

Of the 7% of participants who developed chronic GVHD, in nearly all cases the symptoms were mild and none were severe. By comparison, between 42% and 45% of people who previously received standard stem cell transplants at Fred Hutchinson developed chronic GVHD.

Slightly more than 20% of participants who received the naive T cell–depleted transplants had a relapse of their cancer, similar to what has been seen in historical comparison groups. This, and similar odds of survival compared with people who had received standard transplants, suggests that the graft-versus-leukemia effect was not compromised by removal of the naive T cells, Dr. Bleakley explained.

Two small randomized trials—one in adults and one in children—are now directly comparing rates of chronic GVHD in people randomly assigned to receive one of three types of transplants: naive T cell–depleted transplants, standard transplants, or a type of transplant that has come into wider use recently. Patients receiving this last type will get the chemotherapy drug cyclophosphamide immediately after transplantation, which can suppress T cells likely to attack the recipient’s tissues.

In addition to the goal of lowering rates of chronic GVHD with naive T cell–depleted transplants, “we [also] want high survival rates and low relapse rates,” she continued. “Is what we’ve developed really better than the standard of care? We think so, but we can’t know until we actually do the randomized trials.”

The ongoing trials will also determine whether this method for depleting naive T cells can be replicated at other hospitals. The initial experience in the pediatric trial showing feasibility in replication of the technique have been encouraging, Dr. Bleakley explained.

“We’ve trained half a dozen other centers, and they’re getting really nice results for the naive T cell depletion [so far],” she said.

If the results from the ongoing trials turn out as hoped, the new technique will also need to be tested in older adults, said Dr. Pavletic. All participants in the ongoing randomized trials are aged 60 or younger, but “about 80% of [blood] cancers occur in patients older than 60,” he explained. Currently, stem cell transplants are rarely used in people over age 75, he added.

The Fred Hutchinson team had begun testing a combination of the less-intensive conditioning regimens used for older patients and naive T cell depletion as part of the recently published study, Dr. Bleakley said.

When she and her colleagues first began these trials, she explained, they weren’t sure whether intensive conditioning regimens were a prerequisite for transplants to work—that is, take up residence in the bone marrow and begin making healthy blood cells, known as engraftment.

“But in the last trial, we had half the patients receive a less-intensive conditioning regimen and their engraftment was just fine. So we think we can back off [the intensity even further],” she said.