Breakthroughs in hematopoietic cell transplantation to be presented at 53rd ASH meeting

Hematopoietic cell transplantation (HCT), the transplantation of blood-forming stem cells from the bone marrow, peripheral blood, or umbilical cord blood, is the primary option for treatment for many patients who suffer from various hematologic disorders, including blood cancers, sickle cell disease, bone marrow deficiencies, bleeding disorders, and autoimmune disorders. Research investigating breakthroughs in hematopoietic cell transplantation will be presented today at the 53rd Annual Meeting of the American Society of Hematology.

"The studies that will be presented today demonstrate the major advances underway in the field of hematopoietic cell transplantation," said Stephanie J. Lee, MD, MPH, moderator of the press conference and Professor of Medicine at the University of Washington School of Medicine in Seattle. "Although hematopoietic cell transplantation is considered a standard approach for treating blood disorders, there are still many complications involved, underscoring the continual need for novel research that can improve survival rates and quality of life for patients who undergo these procedures."

This press conference will take place on Saturday, December 10, at 11:00 a.m. PST.

Increased Incidence of Chronic Graft-Versus-Host Disease (GVHD) and No Survival Advantage with Filgrastim-Mobilized Peripheral Blood Stem Cells (PBSC) Compared to Bone Marrow (BM) Transplants From Unrelated Donors: Results of Blood and Marrow Transplant Clinical Trials Network (BMT CTN) Protocol 0201, a Phase III, Prospective, Randomized Trial [Abstract 1]

A new study reveals that peripheral blood stem cell (PBSC) transplants from unrelated donors are associated with higher rates of chronic graft-versus-host-disease (GVHD) and have no survival advantage when compared to transplants using stem cells taken from the bone marrow.

PBSCs are stem cells originally found in the bone marrow that have been moved, or mobilized, into the blood stream by a special drug regimen. Unlike bone marrow stem cells, which must be extracted from the bones in an operating room, PBSCs are more easily obtained through apheresis, a process similar to regular blood donation, which collects the PBSCs through a tube inserted in a vein. A critical step before the transplant is to find a donor that is tissue matched to the recipient.

About one-third of patients who need a PBSC or bone marrow transplant for treatment of a blood disease have a matched, related donor. According to the National Marrow Donor Program, of the 70 percent who cannot find a donor within their family, most will be able to find an unrelated donor. Since the majority of transplant patients ultimately receive cells from unrelated donors, there is a need to better understand the risks associated with transplants of unrelated donor cells.

Previous clinical trials on related donor transplants have demonstrated that PBSC transplants in patients with leukemia and other blood diseases result in better engraftment, lower relapse rates, and increased survival compared to transplants with bone marrow stem cells. However, those trials also found that PBSC transplants carry an increased risk of GVHD, a serious and often deadly post-transplant complication that occurs when the newly transplanted donor cells recognize the recipient's own cells as foreign and attack them. Patients who survive early post-transplant may develop chronic GVHD, a disabling condition managed with long-term immunosuppressant therapy.

Many transplant centers are increasingly using PBSCs as a source for adult stem cells because of their superiority in clinical trials that have directly compared outcomes between PBSCs and bone marrow stem cells from related donors. However, to date, there has not been a comparative study of the two transplant sources that has prospectively analyzed patient outcomes in unrelated donor transplants.

To determine whether graft source – PBSCs or bone marrow – affects transplant outcomes in unrelated donor transplants for patients with leukemia or other hematologic malignancies, the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) conducted a clinical trial, BMT CTN Protocol 0201, to compare two-year survival probabilities for patients transplanted with PBSCs or bone marrow stem cells from unrelated donors. Fifty transplant centers in the United States and Canada participated in this large, Phase III, prospective, multicenter study which randomized patients to receive bone marrow>

According to the trial analyses, there were no observed differences in overall survival, relapse, non-relapse mortality, or acute GVHD between the patients receiving PBSCs or bone marrow stem cells from unrelated donors. While engraftment was faster in patients receiving PBSCs, there was a higher incidence of overall chronic GVHD in these patients (53%) than in those transplanted with bone marrow stem cells (40%). Patients receiving transplants of PBSCs from unrelated donors also had a higher incidence of chronic extensive GVHD (46%) than patients who received bone marrow stem cells (31%).

"Although PBSCs from related donors have demonstrated clinical benefits, our trial demonstrates that when these stem cells originate from unrelated donors they are not superior to bone marrow stem cells in terms of patient survival, and they increase the risk for chronic GVHD," said lead author Claudio Anasetti, MD, Chair of the Department of Blood & Marrow Transplant at Moffitt Cancer Center in Tampa, Fla. "More effective strategies to prevent GVHD are needed to improve outcomes for all patients receiving unrelated donor transplants."

This trial was supported by the National Heart, Lung, and Blood Institute (NHLBI) and the National Cancer Institute (NCI) of the National Institutes of Health (NIH).

Dr. Anasetti will present this study during the Plenary Scientific Session on Sunday, December 11, at 2:05 p.m. PST at the San Diego Convention Center in Hall AB.

Burden of Morbidity in 10+ Year Survivors of Hematopoietic Cell Transplantation (HCT): A Report From the Bone Marrow Transplant Survivor Study (BMTSS) [Abstract 841]

New research concludes that long-term (10 or more years) survivors of hematopoietic cell transplant (HCT), when compared to their siblings, have a higher risk of psychological and chronic health conditions, including heart attack, stroke, diabetes, subsequent cancers, and long-term generalized pain or discomfort referred to as somatic distress.

While HCT is a life-saving treatment for patients with blood disorders, it is often accompanied by an increased risk of long-term physical complications such as infections, relapse, and GVHD. High-intensity conditioning regimens and powerful immunosuppressant medications given to recipients to prepare the body to receive donor cells and prevent rejection can have a variety of negative side effects. In addition to these complications, recent research has found that the psychological health of HCT survivors is also affected.

"Although previous research has shown that morbidity increases with length of survival after an HCT, this is the first study to specifically examine the burden of morbidity in those who have survived 10 or more years after a transplant," said lead author Can-Lan Sun, PhD, Associate Research Professor at City of Hope in Duarte, Calif.

To study late medical effects and quality of life in HCT survivors, researchers analyzed patient data from 366 10-or-more-year HCT survivors and their 309 siblings from the Bone Marrow Transplant Survivor Study, the largest of its kind to date. Survivors and their siblings were evaluated for the presence of any chronic conditions, which were given a severity score from 1 (mild) to 5 (death due to condition), as well as any psychological conditions, including somatic distress, anxiety, and depression. The current status of health-care utilization by survivors, an estimated figure accounting for frequency of visits to doctors, hospitalizations, and other factors, was also evaluated.

Results from the analysis revealed that nearly three-fourths (74%) of HCT survivors reported at least one chronic health condition over the 15-year follow-up period, compared with 29 percent of siblings. Additionally, one-fourth of survivors reported severe or life-threatening conditions compared to only 8 percent of siblings. Commonly reported severe or life-threatening chronic health conditions included heart attack, stroke, blindness, diabetes, musculoskeletal problems, and subsequent cancers. The 15-year cumulative incidence of any chronic health conditions in survivors was 71 percent, while the incidence of particularly severe or life-threatening conditions or death was 40 percent. Investigators also found that HCT survivors were nearly six times more likely than their age- and sex-matched siblings to develop a severe or life-threatening condition.

While prevalence of anxiety and depression were comparable between the two groups, HCT survivors were nearly three times more likely than their siblings to report somatic distress. Approximately 90 percent of HCT survivors reported having health insurance; a high proportion needed ongoing specialized medical care. Nearly two-thirds (61%) of survivors reported a cancer- or HCT-related visit to a specialist at an average of 15 years after transplant.

"The long-term physical and psychological burden of HCT on survivors is substantial, resulting in high usage of specialized health care among this population," said senior author Smita Bhatia, MD, MPH, Director of the Center for Cancer Survivorship and BMT Long-Term Follow-up Program and Ruth Ziegler Chair in Population Sciences at City of Hope in Duarte, Calif. "Patients, families, and health-care providers need to be made aware of this high burden so they can plan for post-HCT care, even many years after transplant."

Dr. Sun will present this study in an oral presentation on Monday, December 12, at 4:30 p.m. PST at the Manchester Grand Hyatt in the Elizabeth Ballroom FG.

Over-Expression of TRAIL on Donor T-Cells Enhances GVT and Suppresses GVHD Via Elimination of Alloreactive T-Cells and Host APC [Abstract 817]

Scientists have discovered a method of using genetically engineered T-cells to help the body kill cancer cells more effectively without causing a deadly post-transplant complication.

One of the reasons cancer cells are able to grow, multiply, and spread so quickly is that the body recognizes them as normal, rather than diseased. Patients with blood cancers often receive a transplant of healthy hematopoietic, or blood-forming, stem cells to help attack cancer cells, called hematopoietic cell transplantation (HCT). When these immune system cells found in the bone marrow are transplanted from a healthy donor to a cancer patient, donor cells may recognize the cancer cells in the recipient's body and attack them, a desirable phenomenon known as the graft-versus-tumor (GVT) effect. However, one of the challenges of HCT is the risk for graft-versus-host disease (GVHD), a serious and often deadly post-transplant complication which occurs when the donor cells attack the recipient's healthy cells instead.

To combat GVHD, doctors administer powerful medications to suppress the immune system. While these medications reduce the probability of GVHD, they can also reduce the GVT effect. Recognizing this challenge, researchers sought to create a new method to suppress GVHD without compromising the GVT effect by using genetically engineered donor T-cells that over-express a protein known to induce cell death in an effort to specifically attack cancer cells.

The protein, Tumor Necrosis Factor (TNF)-Related Apoptosis-Inducing Ligand, or TRAIL, is naturally expressed on some immune cells in the body. TRAIL targets tumor cells and keeps them from multiplying and spreading by interacting with death receptor molecules, which are highly expressed on the surface of tumor cells, making them more susceptible to therapeutic targeting using TRAIL.

To evaluate the effect of genetically engineered donor T-cells over-expressing TRAIL (TRAIL+) on GVHD and GVT, investigators from Memorial Sloan-Kettering Cancer Center performed HCT using TRAIL+ donor T-cells versus control donor T-cells in experimental mouse models with cancerous tumors. Mice that received TRAIL+ donor T-cells displayed significantly higher survival rates, indicating greater antitumor activity than in those treated with control donor T-cells. The researchers also used donor TRAIL+ progenitor T-cell with autologous (stem cells from the patient) HCT in tumor-bearing mice and found a significantly higher anti-tumor effect compared with controls. In addition to enhanced GVT effect, the transplant recipients treated with TRAIL+ T-cells experienced significantly less severe GVHD. Researchers further found that the immune cells, which trigger GVHD, also express TRAIL-sensitive death receptors, and TRAIL+ T-cells can suppress GVHD by targeting these cells.

"Our data show that donor T-cells over-expressing TRAIL can suppress GVHD while simultaneously enhancing the GVT effects. We hope this approach will provide fresh insights into separating cancer cell killing from indiscriminate killing of normal tissues," said Arnab Ghosh, MD, PhD, lead author and a Research Scholar in the laboratory of Dr. Marcel van den Brink at Memorial Sloan-Kettering Cancer Center in New York. "Furthermore, the ability to combine genetic engineering with T-cell progenitor cells highlights the possibilities of developing these approaches into an effective, 'off the shelf' cell therapy."

Dr. Ghosh will present this study in an oral presentation on Monday, December 12, at 4:30 p.m. PST at the Manchester Grand Hyatt in Douglas Pavilion A.

Haploidentical Transplantation Using T-Cell Replete Peripheral Blood Stem Cells and Myeloablative Conditioning in Patients with High-Risk Hematologic Malignancies who Lack Conventional Donors is Well Tolerated and Produces Excellent Relapse-Free Survival: Results of a Prospective Phase II Trial [Abstract 889]

Researchers have found that a new preparatory regimen prior to haploidentical hematopoietic stem cell transplantation (HCT) may improve outcomes in patients with high-risk blood cancers who lack a matched donor.

Patients with blood cancers are often treated with HCT, the transplantation of blood-forming bone marrow stem cells, including peripheral blood stem cells (PBSCs), stem cells originally found in the bone marrow that have been moved, or mobilized, into the blood stream. According to experts, the gold standard for HCT is to have a transplant from a matched donor, but for some patients a matched donor is not available. A haploidentical (partial match) HCT is the next best treatment option, but it comes with higher risk of relapse and non-relapse mortality.

For those patients without a matched donor, past approaches including ex vivo T-cell depletion and myeloablative preparative regimens (intense chemotherapy and/or radiation to help prevent the immune system from attacking transplanted cells) have been associated with high rates of graft rejection, infection, and severe GVHD. Some progress has been demonstrated recently by using a less aggressive, non-myeloablative preparative regimen, followed by an infusion of unmanipulated bone marrow and the post-transplant use of a common chemotherapy drug, cyclophosphamide (Cy), but relapse is relatively common, especially in those with high-risk myeloid malignancies. This study sought to determine whether it is possible to decrease the probability of relapse in these high-risk patients by using a myeloablative preparative regimen with PBSCs, instead of bone marrow, as the graft source.

Between January 2009 and March 2011, the investigators initiated a clinical trial enrolling 20 patients with high-risk blood cancers, including leukemia and both Hodgkin and non-Hodgkin lymphoma, undergoing haploidentical HCT. Participants were eligible for the trial if they were perceived to be at a high risk of relapse using a less aggressive preparative regimen following transplantation. Eleven patients (55%) had relapsed or refractory disease, while the remaining nine patients (45%) had standard-risk disease, the majority being leukemia patients in remission but associated with poor-risk features. After the administration of the myeloablative preparative regimen, patients underwent transplantation with PBSCs, followed by an immunosuppressive regimen of Cy (50mg/kg/day) on days three and four post transplant along with other supportive therapies.

After an average follow-up of 14 months, investigators reported an estimated one-year overall survival rate of 74 percent and a disease-free survival (DFS) rate of 51 percent for all patients; for standard risk patients, one year overall survival was 100 percent and DFS was 76 percent. Non-relapse mortality at 100 days and 12 months was 10 percent for all patients and zero for standard risk patients. The cumulative incidence of chronic GVHD at one year was 42 percent.

Non-infectious fever developed in 90 percent of patients within a median of 2.5 days of transplant and was resolved by day six following post-transplant administration of Cy. Viral cystitis (viral infection of the bladder) occurred in 75 percent of patients and was severe in 35 percent of patients. Other severe infections were not seen at increased frequency compared to conventional donor myeloablative transplants conducted at the transplant center.

"The results of our study demonstrate that haploidentical HCT using this unique pre- and post-transplant conditioning regimen is associated with improved rates of engraftment, GVHD, non-relapse mortality, and disease-free survival, making it a potentially important option to help improve outcomes in patients with high-risk malignancies who may not have a matched donor," said senior author Scott R. Solomon, MD, Medical Director of the Stem Cell Processing Laboratory and the Matched Unrelated Donor Program at Northside Hospital in Atlanta. "With the exception of viral cystitis, post-transplant toxicity was manageable and similar to what might be expected with any myeloablative transplant regimen in high-risk patients. Future studies aim to reduce the incidence of viral cystitis, which, although not life-threatening, can be a significant problem for patients."

Dr. Connie A. Sizemore will present this study in an oral presentation on Monday, December 12, at 6:15 p.m. PST at the San Diego Convention Center in Room 31.


American Society of Hematology


The opinions expressed here are the views of the writer and do not necessarily reflect the views and opinions of News Medical.
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