New partnership seeks to increase access to lifesaving stem-cell transplants

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Dr. Effie Wang Petersdorf
Dr. Effie Wang Petersdorf Fred Hutch file photo

New partnership seeks to increase access to lifesaving stem-cell transplants

Fred Hutchinson Cancer Research Center has entered into a new partnership with Leidos Biomed for the Frederick National Laboratory for Cancer Research that aims to increase access to lifesaving stem-cell transplants for those without a tissue-matched, related donor. If successful, the collaboration could improve current methods of donor selection and make stem-cell transplants more readily available for those with leukemia, multiple myeloma and other blood disorders.

For such patients, transplantation can be a lifesaving treatment, but it requires the availability of compatible stem-cell donors. Otherwise, serious post-transplant complications can arise, including the potentially deadly graft-vs.-host disease, or GVHD, which occurs when transplanted immune cells attack the recipient’s healthy tissues.

The partnership is co-led by Fred Hutch clinical researcher Dr. Effie Wang Petersdorf and Dr. Mary Carrington, director of the Basic Science Program at Frederick; both specialize in studying the genes that influence tissue matching between donors and transplant recipients. Specifically, they are interested in studying genes that can influence the risk of GVHD.

The current method for determining donor/recipient compatibility relies on human leukocyte antigen, or HLA, matching to tell how closely the tissues of one person match the other. However, matched stem-cell sources are not always available, particularly for unrelated donor-recipient pairs, and there are no criteria for selecting the least-risky mismatched donor.

To help improve the donor-selection process and increase the availability of transplants for more patients, Fred Hutch and Frederick National Laboratory have signed a contractor Cooperative Research and Development Agreement, or cCRADA, to jointly conduct research exploring the role of HLA expression in defining permissible HLA mismatches.

The use of HLA expression is a novel approach for optimizing donor selection, Petersdorf said. “With the availability of laboratory methods that permit long-range definition of sequence variation across an HLA gene, it is now feasible to identify variants in the regulatory regions of HLA genes that influence HLA expression,” she said.

Petersdorf and colleagues at Frederick previously found that diversity within the major histocompatibility complex region is important for patient outcomes for both HLA-matched and HLA-mismatched transplants.

Through their collaboration, Petersdorf, Carrington and colleagues will examine large, ethnically diverse transplant populations to study such genetic factors that affect patient outcomes. They then will rank immunogenetic factors that most strongly predict survival to help guide optimal donor selection.

“We are entering into an exciting phase of immunogenetics research, where information on gene expression may positively impact our approach to the selection of transplant donors,” Petersdorf said. “Not only is it important to know what kinds of HLA proteins the patient and transplant donor have, and how those proteins differ from one another, but we now appreciate that the amount of HLA protein expressed is also clinically relevant.”

Adapted from a Frederick National Laboratory for Cancer Research news release

Dr. George Georges
Paper co-author Dr. George Georges Fred Hutch file photo

Stem cell transplant for severe autoimmune disorder improves survival, quality of life

New clinical trial findings, published Wednesday in The New England Journal of Medicine, show that a therapeutic regimen involving transplantation of a person’s own blood-forming stem cells can improve survival and quality of life for people with severe scleroderma, a life-threatening autoimmune disease.

The transplant regimen includes chemotherapy and total-body radiation to destroy the bone marrow followed by transplantation of the person’s own stem cells to reconstitute the marrow and immune system. The study found this regimen, called myeloablative autologous hematopoietic stem cell transplant, or HSCT, to be superior to treatment with the immune-suppressing drug cyclophosphamide.

The clinical trial, called Scleroderma: Cyclophosphamide or Transplantation, or SCOT, compared the safety and potential benefits of the two treatment regimens among 75 people with diffuse systemic sclerosis who had lung or kidney involvement.

The trial showed that compared with cyclophosphamide, transplantation offered significantly greater long-term benefits but also carried known short-term risks, such as infections and low blood cell counts.

“The SCOT trial definitively shows that autologous hematopoietic stem cell transplantation is the most effective treatment for diffuse systemic sclerosis,” said study co-author Dr. George Georges of Fred Hutchinson Cancer Research Center’s Clinical Research Division. The regimen “effectively ‘resets’ the immune system and eliminates the destructive, autoreactive immune cells,” he said.

“The trial establishes autologous hematopoietic stem cell transplantation as the standard of medical care for a severe, life-threatening autoimmune disease.  We believe that these results will encourage insurance companies to pay for the autologous HSCT for patients with scleroderma and other autoimmune diseases,” he added.

Scleroderma is characterized by hardening of the skin and connective tissues. Diffuse systemic sclerosis is a severe, often fatal form of the disease that also involves the internal organs. Treatment options are limited. People with the disease may take antirheumatic and immune-suppressing drugs like cyclophosphamide to help manage symptoms, but none of these medications has been proven to provide long-term benefit.

Dr. Keith M. Sullivan of Duke University led the SCOT trial, which was conducted at 26 clinical research sites in the United States and Canada. One of these sites was the Fred Hutch/University of Washington Cancer Consortium, which played a lead role in the early clinical development of the transplant regimen for scleroderma.

Participants were randomly assigned to receive either myeloablative autologous HSCT or one year of treatment with monthly doses of intravenous cyclophosphamide. The transplant procedure began with doctors collecting a participant’s blood-forming stem cells, after which the participant received chemotherapy and radiation to eliminate the bone marrow. Finally, doctors infused the participant’s own blood stem cells to rebuild the bone marrow and a normally functioning immune system.

At four and a half years of follow up, participants who received a transplant experienced significantly better outcomes overall than those who received cyclophosphamide. In addition, 44 percent of participants who received cyclophosphamide had begun taking antirheumatic drugs for progression of their scleroderma, compared to only 9 percent of those who received a transplant.

During the study, seven participants in the transplant arm died, compared to 14 in the cyclophosphamide arm. Participants who received transplants were much less likely to die from progression of their scleroderma compared to those who received cyclophosphamide. There was a lower rate of transplant-related death in the transplant arm than previously reported for HSCT. No deaths were attributed to cyclophosphamide.

Participants in both study arms experienced treatment side effects, such as infections. Most serious adverse events among transplant recipients occurred during the first 26 months after transplant. Overall infection rates in the two study arms were similar, although more transplant recipients developed infections with varicella zoster, the virus that causes chickenpox and shingles.

The investigators are continuing to follow many of the SCOT participants to further assess their long-term health outcomes.

— Modified from a National Institutes of Health news release

Dr. Betz Halloran
Dr. Betz Halloran Fred Hutch file photo

Dr. Betz Halloran chair-elect of AAAS Section on Statistics

Fred Hutchinson Cancer Research Center biostatistician Dr. Betz Halloran has been elected chair-elect of the Section on Statistics of the American Association for the Advancement of Science, the world’s largest multidisciplinary scientific society and publisher of the journal Science.  Her three-year term begins Feb. 20, which coincides with the AAAS annual meeting in Austin, Texas. She will serve as section chair in 2019 and as retiring chair in 2020.

The Section on Statistics is one of 24 groups that direct the organization’s activities, including planning symposia, electing fellows, and educating the general public about science. Statistics — or what statisticians describe as “the science of learning from data and of measuring, controlling, and communicating uncertainty” — is becoming ever more critical to navigating an era of big data and data-driven decision-making. “It cuts across all the different fields,” Halloran said.

A member of Fred Hutch’s Vaccine and Infectious Disease and Public Health Sciences divisions, Halloran also is a University of Washington biostatistics professor and director and founder of UW’s Summer Institute in Statistics and Modeling in Infectious Diseases. She heads a Models of Infectious Disease Agent Study Center of Excellence at Fred Hutch, one of three such MIDAS sites around the nation that use computational and mathematical models to advise the U.S. government about the spread of polio, dengue fever, tuberculosis, influenza, Ebola, Zika and other infectious diseases. She also is an adviser to the World Health Organization.

Halloran was named an AAAS fellow in 2009, an honor bestowed by her peers “for her integration of sophisticated mathematical modeling of infectious-disease dynamics with strong foundations in the design and analysis of field studies,” according to the organization’s citation. The winner last year of the Aspen Institute Italia Award for research into the impact of Ebola treatment centers, she is considered among the world’s leaders in using biostatistics to detect patterns of infectious disease spread, monitor the effectiveness of interventions, and evaluate vaccine efficacy.

— Mary Engel / Fred Hutch News Service

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