Turning down the heat

From the Deeg Laboratory, Clinical Research Division

Allogeneic hematopoietic stem cell transplant (HCT) is a standard treatment for many hematologic malignancies and nonmalignant diseases. While HCT can be curative, it also carries some risks. Conditioning for HCT often involves treating patients with high doses of chemotherapy and total body irradiation (TBI). Conditioning allows donor cells to engraft in the patient and eliminates cancerous cells, but also damages healthy cells. These damaged cells might then evolve into cancerous cells unrelated to the original malignancy, known as subsequent malignant neoplasms (SMN). As these SMNs can be devastating, the laboratory of Dr. Joachim Deeg and other researchers at Fred Hutch and University of Washington published a study in the journal Blood analyzing the risk factors for SMN. They followed 4,905 patients who survived free of SMNs for one year after undergoing HCT at Fred Hutch from 1969-2014. The authors found that 499 of these patients developed at least one SMN with a median time of 10.3 years. Among the most common SMNs diagnosed in the studied patients were breast cancer, oral carcinomas, tumors of the central nervous system, and skin cancers.

They next compared risk factors for HCT patients to develop SMNs. The authors found that a single high dose of TBI (>600 cGy) carried the greatest risk, estimated at eight times higher than the U.S. population when matched by age, sex, and calendar year. The authors found that although splitting TBI into smaller doses can lower the risk, the high risk returned when the smaller doses added up to more than 1440 cGy. The risk of developing SMNs in patients receiving low dose TBI (200-450 cGy) was not significantly different than those patients who received only chemotherapy, around twice that of the general population. This increased risk is likely because these therapies damage healthy cells and may change gene expression and cytokines towards a more supportive environment for the development of malignant cells.

Standardized incidence ratios showing the risk of developing malignancies in different sites after HCT.
Standardized incidence ratios showing the risk of developing malignancies in different sites after HCT. Image provided by Dr. Joachim Deeg

Additionally, the authors found that there was a moderate increase in risk of SMNs with white patients, younger patients, patients diagnosed with acute graft-vs.-host disease (GVHD) after HCT, or patients who received cord blood or peripheral blood stem cells (PBSCs) as the source of stem cells. The authors posited that since transplant using PBSCs leads to chronic GVHD more often than transplants done with bone marrow stem cells, this could play a role in the increased risk of SMN development they saw in patients.

Dr. Deeg explained how the study contributes to the understanding of HCT: “The probability of developing a new malignancy with low dose TBI was comparable to the probability seen with chemotherapy conditioning but was clearly lower than with high dose TBI. This suggests that we should avoid high dose TBI whenever possible. It is also important to note that we did not observe a single type of cancer that might be related to the transplant procedure. Rather, the spectrum is very broad, comprising malignancies that also occur in a non-transplanted population.”


Dr. Deeg also discussed how HCT is changing based on studies like this: “The direction is away from high dose radiation. One direction the work is taking is the use of radioimmunotherapy, which allows to ‘target’ the radiation delivered by radioisotopes to the cells of interest (leukemia, lymphoma etc.) with sparing of non-intended targets. This should, in principle, reduce radiation-induced damage in healthy tissues, thereby reducing the likelihood of inducing a new malignancy.”

This work was supported by the National Institutes of Health.

Fred Hutch/UW Cancer Consortium members K. Scott Baker, Ralph Ermoian, Mary Flowers, Rainer Storb, Brenda Sandmaier, and H. Joachim Deeg contributed to this research.

Baker KS, Leisenring WM, Goodman PJ, Ermoian RP, Flowers ME, Shoch G, Storb R, Sandmaier BM, Deeg HJ. Total body irradiation dose and risk of subsequent neoplasms following allogeneic hematopoietic cell transplantation. Blood. 2019 Apr 16;. doi: 10.1182/blood.2018874115. [Epub ahead of print]