Secondary cancer risk following transplant-related immune suppression

The immune system is not only the watch dog for pathogens, but it can also recognize cancer cells and eliminate them. Despite these strengths of the immune system, recognition and killing of foreign cells can be a challenging response following a bone marrow or stem cell transplantation when it results in graft-versus-host disease (GVHD), a serious condition in which the donor cells attack the “foreign” or “non-self” recipient cells. To circumvent this disease, patients receiving an allogeneic (donor-derived) hematopoietic cell transplantation (allo-HCT) will receive a conditioning treatment with an immunosuppressive drug and a small dose of total body irradiation, aimed at eradicating malignant cells and reducing the risk of graft rejection as well as immunosuppressive drugs for at least 6 months after HCT to both enhance engraftment and control GVHD. These immunosuppressive drugs may be continued for an extended period after the transplant to treat chronic GVHD, which is persistent GVHD often characterized by damage to the skin epithelium and mucous membranes. While this is a necessary treatment for these patients, it may come with the risk of secondary cancer development due to both immune suppression and chronic repair of epithelial surfaces.

Drs. Phuong Vo and Rainer Storb from the Clinical Research Division at Fred Hutchinson Cancer Center investigated whether toxicities related to the conditioning regimen and post-HCT immune suppression of elderly patients receiving allo-HCT resulted in an increased risk of developing secondary cancers. As in previous studies, the researchers uncovered an increase in skin cancers as compared to the general population. However, these occurrences were rare and associated with chronic GVHD, which is treated with immune suppression and unlikely to be a result of interrupted immune surveillance of cancer cells. These findings were published in Bone Marrow Transplantation.

For elderly people with leukemia or other malignant blood diseases and those with poorer health who require an allo-HCT as compared to those in better health, a lower toxicity conditioning regimen can be used—reduced chemotherapy and/or irradiation (nonmyeloablative conditioning)—to prime the body to receive the donor cells. The researchers followed about 1,700 patients who received the reduced chemotherapy/irradiation conditioning with transplantation (nonmyeloablative allo-HCT) over a whopping 25 years! “The significant contribution of this work to the field lies in its long-term, comprehensive evaluation of cancer risk,” emphasized Dr. Vo.  

The researchers found that only 5% of patients developed secondary cancers at a median of 12 years after receiving nonmyeloablative allo-HCT and most of these cancers occurred at similar frequencies as in the general population. However, there were a few exceptions in which patients had higher than expected incidences of cancer development. For example, the development of non-melanoma skin cancer occurred at a higher rate in their cohort of patients than the predicted for the general population. Although rare, the relationship between immune suppression and skin cancer has been observed with other means of immune suppression including organ transplantation, genetic-based deficiencies, HIV infection, and cancer-induced occurrences. However, GVHD affecting the skin is also known to associate with the development of skin tumors, possibly due to continuous, immune-related skin damage and repair related to chronic GVHD. This raised the possibility that chronic GVHD, and not immune suppression, may be responsible for secondary cancer development in these cases. To support the later line of reasoning, the researchers found a statistically significant correlation between a history of GVHD and subsequent development of skin cancer in their cohort. “The work provides important evidence that these regimens do not significantly increase long-term cancer risk, with the exception of certain cancers associated with chronic GVHD,” summarized Dr. Vo.

“The findings of this study raise several important new questions and open multiple avenues for future research, particularly related to long-term survivorship, immune dysfunction, and cancer surveillance strategies after nonmyeloablative allo-HCT,” shared Dr. Vo. These questions include the following, explained Dr. Vo, “What are the mechanisms linking chronic GVHD to [subsequent malignant neoplasms] SMNs? Are these cancers driven by chronic inflammation, immunosuppression, viral reactivation (e.g., HPV), or direct immune dysregulation? How could targeted prevention or earlier detection mitigate this risk?” Understanding these gaps in knowledge can help determine the best way to treat or limit the rare occurrence of secondary cancers following nonmyeloablative conditioning therapy and allo-HCT.

Apart from the GVHD-associated cancers, other cancers observed were rare and occurred at similar rates as found in the general population. “This study not only reassures clinicians about the overall safety of nonmyeloablative HCT in terms of secondary malignancy risk, but it also highlights a need to better understand and address GVHD-associated cancer risks,” shared Dr. Vo. “Future research will likely focus on biological mechanisms, targeted surveillance, risk stratification, and preventive interventions, transforming long-term survivorship care in this growing patient population.” 

The spotlighted research was funded by the National Institutes of Health, the Laura Landro/Richard Salomon Foundations, and Rubin Family.

Fred Hutch/University of Washington/Seattle Children's Cancer Consortium members Drs. Phuong Vo, Brenda Sandmaier, Ted Gooley, and Rainer Storb contributed to this work.

Vo P, Ng K, Schoch G, Cooper J, Vupalanchi A, Flowers M, Sandmaier BM, Gooley T, Storb R. 2025. Subsequent cancers following non-myeloablative conditioning for allogeneic hematopoietic cell transplantation. Bone Marrow Transplant. Online ahead of print.