Mutation Clonal Burden and Transplantation Outcomes in Acute Myeloid Leukemia and Myelodysplastic Syndromes

Although studies have established the prognostic significance of specific genetic mutations in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), the role of mutations as prognostic factors of outcomes after hematopoietic cell transplantation (HCT) is still unclear.

A study from Cleveland Clinic investigators aimed to determine the impact of mutations on post-HCT outcomes in patients with AML and MDS as well as the clinical significance of variant allelic frequency (VAF) of the most common gene mutations on patient outcomes.

“Although exploratory, this study is among the first investigations of the clonal burden of common mutations in AML and MDS and their association with post-transplant outcomes,” says Betty K. Hamilton, MD, hematologic oncologist and lead author of the study.

Study findings were published in Bone Marrow Transplantation and shed new light on the prognostic value of common mutations and VAFs in patients with AML and MDS.

Drawing associations between individual mutations, VAFs and transplant outcomes

The study was conducted on two separately analyzed patient cohorts: patients with MDS (N=80) and patients with AML (N=116). Genomic DNA was extracted from bone marrow mononuclear cells obtained before HCT at a time of significant disease activity. The samples were sequenced in order to identify the 64 most common mutations found in MDS and AML. Mutations were analyzed both individually and based on functional categories; VAF was determined for those mutations identified in at least six patients. The frequencies of most common mutations were calculated and associations between four transplant outcomes — nonrelapse mortality (NRM), overall survival (OS), relapse and relapse-free survival (RFS) — and individual mutations and their VAFs were determined.

The most common mutations in patients with AML were TET2 (14.7 percent), FLT3-ITD (12.9 percent), DNMT3A (12.1 percent) and RUNX1 (7.8 percent). In patients with MDS, the most common mutations were ASXL1 (12.5 percent), SRSF2 (12 percent), TET2 (8.8 percent) and TP53 (8.8 percent). Mutation clustering was not observed in either MDS or AML.

The presence of SRSF2 and TET2 mutations was associated with higher risk of NRM in patients with AML, while the presence of mutations in the RNA-splicing pathway was prognostic for OS. Disease status and complex cytogenetics were significantly associated with worse RFS. Except for mutations in the RNA splicing pathway, individual mutations or VAFs had no prognostic value for OS in this group of patients.

“The lack of associations in the AML cohort may be partially explained by heterogeneity of mutations and small sample size,” explains Dr. Hamilton. “Our main findings were in the cohort of patients with MDS.”

Interestingly, in the MDS cohort, the findings were distinct, and several associations between VAF and outcome parameters were identified.

“In general, we found that higher allelic frequencies of certain mutations in this group of patients were associated with worse outcomes,” says Dr. Hamilton. “More specifically, we found that complex cytogenetics and mutations in the U2AF1 gene were associated with worse RFS. Furthermore, we found that high VAF (> 33 percent) of TP53 and EZH2 mutations were also associated with worse OS and RFS.”

In addition, mutations in SF3B1 and the RNA splicing pathway were associated with higher risk of relapse in patients with MDS.

Opening the doors to additional research

The authors note that prior research has pointed to the adverse effects of TP53 mutation in myeloid malignancies, especially when combined with a complex karyotype. The findings from the current study suggest that the degree of clonal burden may be associated with a poorer outcome; however, the authors caution that these findings are exploratory and need to be verified in a larger cohort.

Dr. Hamilton believes that their study begs additional important questions about the effects of mutations on transplant outcomes in patients with myeloid malignancies.

“We still need to clarify what is important to look at when we study mutations and disease outcomes,” she says. “Refining the prognostic value of mutations and understanding how to best utilize this information remains a challenge.”

Study co-author, Aziz Nazha, MD, Department of Hematology and Medical Oncology, is taking things one step further by using machine learning algorithms to investigate the significance of some of these mutations.

“This is an exciting new approach to evaluate large amounts of complex data, and we will have to see how this can be used clinically,” says Dr. Hamilton.

Image: Confocal image showing the accumulation of myeloid hematopoietic cells throughout the mesenteric adipose tissue. Credit: National Institute of Allergy and Infectious Diseases, National Institutes of Health. Licensed. No changes were made.