Autologous Stem Cell Transplant May Age Immune Cells as Much as 30 Years
University of North Carolina (UNC) Lineberger Comprehensive Cancer Center researchers, by tracking p16INK4a, a molecular marker that has been shown to increase in white blood cells as people age, have uncovered clues suggesting that stem cell transplant is linked to a marked increase in the “molecular age” of these immune cells in a group of patients with hematologic malignancies. Wood et al reported these findings in EBioMedicine.
Patients treated with an autologous stem cell transplant had elevated levels of expression of messenger RNA (mRNA) for this age-related marker. They found expression levels increased to a degree comparable to an additional 30 years of chronologic age.
Predicting Risk
Despite the risk for significant short- and long-term side effects, the researchers say stem cell transplant is an extremely important treatment option. They believe their findings could lay the foundation for future studies into using this age marker to enable physicians to better quantify a patient's potential risk and benefit associated with stem cell transplant.
“We know that transplant is life-prolonging, and in many cases, it's life-saving, for many patients with blood cancers and other disorders,” said the study's lead author William Wood, MD, Associate Professor in the UNC School of Medicine Division of Hematology and Oncology. “At the same time, we're increasingly recognizing that survivors of transplant are at risk for long-term health problems, and so there is interest in determining what markers may exist to help predict risk for long-term health problems, or even in helping choose which patients are the best candidates for transplantation.”
Dr. Wood continued: “It's a well-known concept in geriatric oncology that different people age biologically at different rates, and that their overall health status may or may not correspond with chronologic age. On the one hand, we would not want to use chronologic age itself to exclude patients from transplant, since there are now patients up to the age of 80 who would benefit from transplant if they are otherwise appropriate candidates. A measure of biologic age could help us to identify appropriate older candidates who might have previously been excluded from transplant. On the other hand, there are other, potentially younger patients who may be less physiologically fit because of prior treatment or comorbid illness, for whom transplant carries increased risks.”
Autologous vs Allogeneic Stem-Cell Transplant
The UNC Lineberger researchers studied the impact of two different transplant types—autologous stem cell transplant and allogeneic stem cell transplant—on 63 patients treated at UNC Hospitals for myeloma, lymphoma, or leukemia. The researchers reported higher expression of mRNA coding for the protein p16 in the T cells of patients who received either allogeneic or autologous transplant, but patients receiving autologous transplant had a larger increase—three times their pretransplant levels.
They also noted that autologous stem cell transplant, as measured by p16 mRNA expression, had the strongest impact on molecular aging of T cells—even greater than cytotoxic chemotherapy. A previous study had found that cytotoxic chemotherapy in breast cancer led to an approximately twofold increase in p16 mRNA expression, equivalent to about 10 years of chronologic aging.
To try to explain why autologous stem cell transplant might age T cells faster, they speculated that the forced regeneration of bone marrow that accompanies reengraftment may contribute to stem cell aging. Chemotherapy prior to transplant may also contribute to increased p16 mRNA expression—so recipients of autologous transplant are in effect aged twice.
While the researchers did not have data showing a clear connection between changes in p16 mRNA expression levels and the actual function of the T cells, they did argue that expression of this marker is “arguably one of the best in vivo marker of cellular senescence and is directly associated with age-related deterioration.”
Study Implications
“Many oncologists would not be surprised by the finding that stem cell transplant accelerates aspects of aging,” said the study's senior author Norman Sharpless, MD, Director of UNC Lineberger and the Wellcome Distinguished Professor in Cancer Research. “We know that years after a curative transplant, stem cell transplant survivors are at increased risk for blood problems that can occur with aging, such as reduced immunity, increased risk for bone marrow failure, and increased risk of blood cancers. What is important about this work, however, is that it allows us to quantify the effect of stem cell transplant on molecular age.”
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
