Why Do Some AML Patients Relapse After Stem Cell Transplant?

Hematopoietic stem cell transplant (HSCT) can be curative for patients with acute myeloid leukemia (AML). New research helps to explain why the disease comes back in some patients who undergo HSCT.

The patients who experience relapse do not do so because of acquisition of new AML-specific mutations; rather, relapse occurs through a dysregulation of pathways associated with adaptive (specific) or innate (nonspecific) immunity, say researchers from the Washington University School of Medicine in St. Louis, Missouri.

The results suggest that AML cells do not go into a "stealth mode" as a result of recurring genetic mutations; rather, they activate a "dimmer switch," which dials down the expression of immune markers, the researchers explained in an institute press release.

It may be possible to reverse this process with interferon-gamma, which could offer a new approach to treatment in AML patients who experience relapse, they add.

The new findings were published online October 31 in the New England Journal of Medicine.

Study Details

For their study, the researchers carried out exome sequencing on paired samples obtained from 15 patients at the time they presented with AML and after they had experienced relapse.

Exome sequencing was conducted on a second set of paired samples from 20 patients who experienced relapse following chemotherapy — one at presentation, and a second at relapse.

A comparison of exome sequencing showed that the spectrum of mutational gains or losses was similar across the two sets of paired samples, which suggests that relapse after transplant was not due to the acquisition of new AML-specific mutations or from structural variations in immune-related genes.

When the researchers carried out an RNA analysis of samples obtained at relapse after transplant, they observed dysregulation of a number of genes associated with pathways linked with adaptive (specific) or innate (nonspecific) immunity.

These included downregulation in genes such as HLA-DPA1, HLA-DPB1, HLA-DQB1, and HLA-DRB1. These genes belong to major histocompatibility complex (MHC) class II and are associated with the immune system's recognition of cancer cells.

At relapse, the levels of these genes were three to 12 times lower than levels seen in the paired samples obtained at presentation. These observations suggest a dysregulation of the pathway associated with stem cell transplant.

The researchers confirmed that this was indeed the case using two independent approaches. In 17 of 34 patients who had experienced relapse at transplant, flow cytometry and immunohistochemistry confirmed decreased expression of MHC class II at relapse.

The institute release explained: "When the cancer came back in these patients, it returned in a kind of stealth mode. These stealth leukemia cells lacked proteins that the donor's T cells use to identify them. When the donor's immune cells can no longer detect the leukemia cells, the T cells fail to destroy them."

"We were surprised by these findings because we and others had previously studied samples of relapsed leukemia in every which way," said senior author John F. DiPersio MD, PhD, the Virginia E. and Sam J. Golman Professor of Medicine in Oncology and director of the Division of Oncology at the Washington University School of Medicine in St. Louis.

"But there's a rational explanation, since the way stem cell transplants attack leukemia — through an immunologic mechanism — is going to favor the survival of cancer cells that become invisible to the immune system," he added.

Reversing the Stealth Phenotype Through Interferon-Gamma

The researchers also provide evidence that interferon-gamma treatment could reverse this phenotype in AML blasts in vitro, suggesting a new therapeutic approach for AML patients who experience relapse.

Interferon-gamma is a physiologic cytokine that is responsible for the upregulation of the immune system's response to infection. It also increases the expression of immune markers that stealth cancer cells have concealed.

"When we treated leukemia cells from patients' relapse with interferon-gamma, it turned back on those immune markers that had become invisible, suggesting that this process is reversible," said Matthew J. Christopher, MD, PhD, an assistant professor of medicine and a co–first author of the article. Christopher also treats patients at the Alvin J. Siteman Cancer Center, St. Louis.

The research team hopes to identify other small molecules that may have an effect similar to that of interferon-gamma. Further studies involving many more patients are needed to determine whether other DNA mutations or alternative dimmer switch mechanisms may be involved in relapsed AML, the researchers point out.

N Engl J Med. Published October 31, 2018. Full text

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