Posttransplant AML Relapse Linked to Pathways Influencing Immune Function

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There were no previously unknown AML-specific mutations or structural variations in immune-related genes among patients with AML who had undergone transplant.
There were no previously unknown AML-specific mutations or structural variations in immune-related genes among patients with AML who had undergone transplant.

Patients with acute myeloid leukemia (AML) who underwent hematopoietic stem cell transplantation (HSCT) did not gain any different relapse-specific mutations compared with patients who relapsed after chemotherapy, a new study has found.1

Instead, the study showed that “AML cells that escaped the immune surveillance provided by allogeneic T cells after allogeneic hematopoietic stem-cell transplantation frequently had dysregulation of a number of pathways that regulate immune function.”

“These changes appeared to be epigenetic in nature in at least some cases, which suggests that therapeutic strategies to resensitize AML cells to the graft-versus-leukemia effect may be feasible,” the researchers wrote.

In the study, the researchers thought that the relapse of AML after transplantation might be caused by genetic changes that influence immune function. To test this, the researchers collected samples from 15 patients with AML at presentation and then at relapse after transplant and from 20 patients who had relapse after chemotherapy. Patients in the transplant group had undergone either HLA-matched sibling, HLA-matched unrelated donor, or HLA-mismatched unrelated donor transplant.

Testing showed no acquisition of previously unknown AML-specific mutations or structural variations in immune-related genes among patients with AML who had undergone transplant. Instead, RNA sequencing of samples posttransplant showed dysregulation of pathways involved in adaptive and innate immunity. Among the results was a down-regulation of major histocompatibility complex (MHC) class II genes such as HLA-DPA1, HLA-DPB1, HLA-DQB1, and HLA-DRB1. The levels were 3 to 12 times lower than the levels seen in paired samples obtained at baseline.

The researchers then measured MHC class II expression in a group of additional patients using flow cytometry and immunohistochemistry. They found decreased expression of MHC class II proteins among 17 of 34 patients with posttransplant relapse.

Reference

  1. Christopher MJ, Petti AA, Rettig MP, et al. Immune escape of relapsed AML cells after allogeneic transplantation [published online October 31, 2018}. N Engl J Med. doi: 10.1056/NEJMoa1808777

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