An Ongoing Commitment to Research and Innovation Has Transformed the Lives of Thousands of Patients
February 22, 2023
Stem Cell/Bone Marrow Transplant
By Richard Saltus
Physicians have performed about 1 million bone marrow or stem cell transplants since the procedure was first tried more than 70 years ago, often saving or extending the lives of thousands of patients with blood cancers or non-malignant blood diseases. The procedure, in which a patient is treated with chemotherapy or radiation and then receives an infusion of healthy donor cells (or their own cells), has become an established and increasingly safe treatment even for many patients in their late 70s.
But the path to stem cell transplant success has been far from easy. When they were first attempted in the 1950s, clinicians had not yet discovered that patients and donors needed to be genetically matched. It took years of scientific perseverance and, for a long time, most patients undergoing a transplant died. But as knowledge of the immune system grew, so did the success of the procedure.
Today, about 23,000 transplants are done annually in the United States. Dana-Farber, which has one of the largest and most successful transplant programs in the country, has performed more than 11,800 transplants in its 50-year history. Over that span, one-year survival rates have improved substantially, placing Dana-Farber among the best in the country – despite taking on some of the more challenging cases.
Transplants are used to replace bone marrow cells that have been transformed by cancer or damaged by high doses of chemotherapy or radiation used to treat the patient's cancer. In the early years of transplants, the stem cells were bone marrow cells extracted from inside the donor's bones. Today, many transplants are carried out with stem cells harvested from the donor's circulating blood — a much less arduous process for the donor than having bone marrow extracted. Once retrieved from the donor, the stem cells are infused into the recipient's bloodstream, and travel to niches in the bone marrow where they engraft or "take" and begin to form new, healthy blood cells and restore the immune system. These transplants are now generally referred to as stem cell transplants.
There are two primary types of transplants. In an autologous stem cell transplant, the patient's own stem cells are removed prior to the treatment and afterward returned to the body. These account for about 60% of transplants in the United States.
In the more complex process known as allogeneic transplants, stem cells are provided by another person, a donor whose cells if possible are closely "matched" — that is, they have similar HLA (human leukocyte antigen) biomarkers to those of the recipient.
In the past, a fully precise HLA match between donor and recipient was required to perform an allogeneic transplant. However, advances in treatment now enable patients to receive transplants from "haploidentical" — that is, half-matched — donors, usually family members. In these matches, there is a good likelihood of success even though as few as six of the 12 HLA markers may be identical between patient and donor.
The increase in recent years of haploidentical transplants has greatly benefited members of ethnic and racial populations who often have a difficult time being matched exactly with a donor.
A small number of transplants, in addition, use stem cells taken from the umbilical cord blood of newborn infants.
The Importance of a Match
Marrow transplants were first conceived of in the 1940s as a way of treating patients whose bone marrow had been damaged by blood diseases such as aplastic anemia, or those who might have been exposed to high doses of radiation.
But the early attempts invariably failed, with transplants thwarted by infections, disease relapses, and attacks by the donor graft cells against the recipient's tissues (graft-versus-host disease, or GVHD). By the 1960s, efforts to replace a patient's damaged bone marrow with marrow from a different individual — which had worked in mice but not in humans — had failed so often that most scientists abandoned the work entirely.
However, a small number of undaunted scientists continued to pursue the elusive goal. The immunological barrier that distinguishes "self" from "non-self" was discovered in the late 1950s. It consists of a set of genes that make HLA (human leukocyte antigen) proteins, known as the transplantation antigens. In the late 1960s, testing became available to determine if a patient and a potential donor had closely matched HLA antigens, which indicates the likelihood that transplanted marrow will be accepted by the recipient's immune system.
This recognition of the need to match patients and donors by their HLA biomarkers led to improved outcomes. There had been successful transplants between identical twins and compatible siblings. But the first successful human transplant from an HLA-matched unrelated donor was carried out in 1979 for a patient with acute lymphoblastic leukemia (ALL). Today, a national registry called Be The Match includes more than 11 million U.S. volunteer donors who stand ready to donate their stem cells when the need arises. There also are other registries in other countries.
All early transplantations for acute leukemia were performed in patients who were in refractory relapse. As a result, in addition to fatalities from GVHD, many patients died from post-transplantation relapse. A decision in the mid-1970s to transplant patients earlier in the course of their disease, while the leukemia burden was low, reduced the relapse risk and led to a significant improvement in survival among patients with acute leukemia.
In the 1980s, researchers began working on autologous transplants, in which a patient's own stem cells are harvested and then returned after the patient receives high-dose chemotherapy treatment to eradicate the cancer. Autologous transplants are an option for patients whose cancer is in remission or has stabilized. They avoid the need to find an HLA-matched donor. And these transplants are free of the risk of graft-vs-host disease that often occurs with allogenic transplants, and there is no need for immunosuppressive therapy to prevent GVHD.
However, a graft from a donor — an allogeneic transplant — includes immune cells which may help fight the cancer in the recipient, and there is generally a lower risk for disease recurrence after allogenic transplants compared to autologous transplants. In general, autologous transplants have been used more often in solid tumors, lymphoma, and myeloma, while allogenic transplants have been used predominantly in treating leukemias and myelodysplastic syndromes.
The Early Days: Many Transplants Treated Children
Dana-Farber's Stem Cell Transplant program evolved from a small joint program established in 1972 by Brigham and Women's Hospital (BWH) and Boston Children's Hospital.
"A lot of the early transplants were done in children," notes Robert Soiffer, MD, chief of the Division of Hematologic Malignancies and a past president of the American Society for Blood and Marrow Transplantation. "And then the adult program took off at [BWH]."
The Dana-Farber transplant program began in the early 1980s and initially focused on autologous transplants in patients who did not have HLA-matched sibling donors. This was one of the first autologous transplant programs in the country. However, in patients with acute lymphoblastic leukemia (ALL), autologous bone marrow harvests could contain small numbers of leukemia cells that could lead to relapse of the leukemia when infused back into the patients. The laboratory of Jerome Ritz, MD, had developed monoclonal antibodies that could distinguish ALL cells from normal hematopoietic stem cells. These antibodies were used to purge any residual ALL cells from the patient's own bone marrow in the laboratory that was processing these cells. This allowed the patient to receive intensive chemotherapy and radiation therapy to treat their leukemia, and the patient's harvested and purged bone marrow cells could be infused to allow recovery of normal bone marrow function.
Subsequently, similar approaches were developed for patients with relapsed B cell lymphoma, myeloma, and acute myeloid leukemia (AML) using a variety of different antibodies that had been developed in other research laboratories at Dana-Farber.
In patients undergoing allogeneic stem cell transplants, mature T cells in the donor stem cell product can lead to GVHD, a common and serious complication of the treatment. Having shown that antibodies could be used to purge residual tumor cells from autologous bone marrow, Ritz began to use T12 antibody (now termed CD6) that had been developed by Ellis Reinherz, MD, at Dana-Farber to purge T cells from normal donor marrow to prevent GVHD after transplant. In a series of clinical trials led by Soiffer, T-cell-depleted bone marrow engrafted rapidly and was associated with a very low incidence of acute and chronic GVHD after transplant.
To support Dana-Farber's transplant program, Ritz and colleagues created a unique cell manipulation laboratory capable of the complex processing required for purging residual tumor cells from autologous bone marrow products and T cells from normal allogeneic bone marrow. This laboratory also developed methods for cryopreserving and thawing stem cell products and evaluating the quality and safety of these products. In 1996, a generous gift formally established the Connell and O'Reilly Families Cell Manipulation Core Facility at Dana-Farber. Directed by Ritz, this laboratory supports both adult and pediatric stem cell transplants. In recent years, it has expanded to manufacture other cellular products, such as genetically modified tumor cell vaccines and genetically modified blood stem cells.
In 1996, the BWH and Dana-Farber adult transplant programs merged under the leadership of Joseph Antin, MD, chief of stem cell transplantation emeritus, and Soiffer to create one of the largest programs in the nation. Today, it treats about 500 patients annually for cancers such as leukemia, lymphoma, multiple myeloma, and myeloproliferative diseases. The program carries out more unrelated donor transplants than any other program.
Understanding the Biology of Transplants
Dana-Farber's clinical achievements and basic scientific discoveries have helped advance the transplant field, and owe much to a cadre of physician scientists, many of whom, like Soiffer, Antin, Ritz, and others, have spent decades working to understand the biology underlying transplant success and failure, and harnessing those findings to improve the clinical outcomes of patients.
Ever since the early days of the program, says Arnold Freedman, MD, an Institute physician who specializes in lymphomas, "we had a large number of physician-scientists developing monoclonal antibodies and doing groundbreaking work in human immunology, but they also had a clinical interest. They asked, 'how can we apply what we're doing in the laboratory to human disease, and make a difference by doing that?'"
As a result, by any measure, patients do much better today than in the past.
"It's so much easier on patients and so much better," says Antin. "It was very stressful, very demanding, with long hospital stays. Now, it is easier on the doctors, nurses, dieticians, and most importantly, the patients. We can do an outpatient allogenic transplant now that in 1981 would have required a three-month hospital stay."
Importantly, after many years in which transplants were restricted to recipients age 35 and younger, older patients can now receive transplants. This is due to reduced-intensity chemotherapy regimens that make it possible for patients in their late 70s to receive transplants — a major advance, since many blood cancers and diseases primarily affect older people.
Working to Control Transplant Risks
Despite the many advancements, stem cell transplants still carry significant risks. The two biggest concerns, which researchers are working hard to address, are disease relapse and GVHD.
GVHD, which affects 30 to 50% of patients undergoing an allogenic SCT, can cause damage throughout the body — the skin, mucus membranes, the liver, the gastrointestinal tract — and can trigger painful rashes, diarrhea, nausea, and weight loss. There are two forms of GVHD: acute, occurring within the first 100 days after the transplant, and chronic, which appears later and can reduce long-term survival.
Dana-Farber physician-scientists have been at the center of research aimed at reducing the risk and severity of GVHD. Corey Cutler, MD, MPH, led a clinical trial, the ROCKstar study, that showed that the drug belumosudil had long-lasting effectiveness against chronic GVHD. The drug lowers the activity of immune cells and reverses tissue scarring; it alleviated symptoms in 75% of the 132 patients who received the drug, and the improvements lasted for a median of 50 weeks. The results contributed to the Food and Drug Administration (FDA) approval of the drug for patients with chronic GVHD who have already tried at least two other therapies for the disease.
"The action makes belumosudil the first drug developed specifically for chronic GVHD to be FDA-approved," says Cutler, medical director and director of clinical research for the Adult Stem Cell Transplantation Program at Dana-Farber Brigham Cancer Center. "With it, we now have three drugs approved for the disease. The other two, ibrutinib and ruxolitinib, were borrowed from other fields. Belumosudil is probably the most effective compound we have for chronic GVHD right now."
Stemming from a series of trials led by John Koreth, MBBS, DPhil, Soiffer, and Ritz, one treatment has benefited hundreds of patients with chronic GVHD. The treatment itself seems counterintuitive. It involves the drug interleukin-2 (IL-2), which is best known as an immune system stimulant. Using it to dampen the activity of immune cells responsible for chronic GVHD sounds paradoxical, but IL-2 also stimulates regulatory T cells (Treg) and studies in Ritz's laboratory found that Treg could be stimulated by very low concentrations of IL-2 that would not activate other T cells. This led to a series of clinical trials where Koreth and his associates showed that low doses of IL-2 selectively increased Treg without stimulating other T cells. Over the course of 5 different studies, half of the adult participants and 90% of children with active chronic GVHD benefited from the treatment.
"We're encouraged by the fact that some pharma companies are developing modified versions of IL2, which, if approved as standard therapy by the FDA, would be under patent protection, making them attractive candidates for industry-sponsored trials," Koreth states.
Graft-Versus-Host Can Sometimes Bring Benefits
Importantly, there can be a silver lining to GVHD. Experts previously thought that a transplant's benefit was entirely due to the high doses of chemotherapy or radiation given prior to the transplant, and that all the donor cells did was restore the patient's blood-forming and immune functions. But in fact, it's now known that at least in some cancers, the donor's immune cells — which are the cause of the GVHD — also attack cancer cells in the recipient.
"It was the [donor] cells themselves that were mediating the anti-tumor activity — not only the drugs, not only the chemotherapy, but the donor cells as well," says Soiffer. "I thought that was almost magical." This became known as the graft-vs-leukemia effect, and is now seen as a major component of the overall beneficial effect of allogeneic transplantation. (It does not occur in autologous transplants, where the donor is the patient.)
If donor immune cells in the graft could kill the patient's cancer cells, that suggested that a patient who received a transplant, but had relapsed, could then be given an infusion of immune T cells from the same donor to "top up" the patient's immune system and improve its ability to kill remaining cancer cells. Simply put, the donor's immune system is capable of recognizing the leukemia and killing it. This led to efforts to try to induce GVHD in patients who had relapsed to try to put them back into remission.
This procedure, now known as donor lymphocyte infusion, was one of the first examples of successful immunotherapy, which has become a major part of cancer treatment.
"Donor lymphocyte infusions are now a routine part of transplantation therapy," says Antin. "We were among the first to do that internationally." Antin was the senior author on a 1994 report in the New England Journal of Medicine that showed the benefit of inducing a graft-versus-leukemia reaction with interferon alfa-2b and infusions of donor cells in patients with chronic myeloid leukemia who had relapsed after transplantation. The findings showed that donor lymphocyte infusion is an effective antileukemic therapy that may offer an alternative to a second marrow transplantation.
These trials and outcomes led to the realization that patients undergoing allogenic SCT could receive less-toxic doses of chemotherapy and radiation, and depend more heavily on the capacity of the immune system to eradicate the malignancy. This gave rise to the reduced-intensity conditioning transplant, or RIC, which made transplants safer for patients who otherwise might not be eligible for transplants because of their ability to withstand the treatment.
Long-Term Follow-Up Care
One of the special aspects of transplantation medicine is that transplant patients are generally followed for many years — often by the same physicians — because of the possibility of late long-term effects.
"When patients ask how long they'll be coming here, we tell them we want to keep tabs on them forever, because there are things that can happen down the line," says Soiffer.
Antin agrees. "I had a man come relatively recently who I transplanted a good 25 years ago. I hadn't seen him in over 20 years, and all of sudden, he shows up on my doorstep. I'm thinking, 'oh my God, what happened now?' You think he's in some sort of trouble. I said, 'What's wrong?' He said, 'I haven't seen you in 20 years; I came up from Long Island just to see you and sit down and say thank you.'
"What's better than that?"
Todd Ellison (middle) returned to Dana-Farber to celebrate the 20th anniversary of his stem cell transplant, here joined by his doctors, Joseph Antin, MD (right), and Hanno Hock, MD, PhD (left; now at Massachusetts General Hospital).
Stem cell transplant physicians Robert Soiffer, MD (left), John Koreth, MBBS, DPhil (center), and Jerome Ritz, MD (right), led a series of clinical trials and studies that benefited patients with chronic graft-versus-host disease.