Top Takeaways from ASH: Mutations in MDS, AML impact prognosis, spur development of novel agents

Findings presented at the ASH Annual Meeting and Exposition contribute to the growing body of literature that demonstrates a correlation between specific gene mutations and prognosis among patients with acute myeloid leukemia and myelodysplastic syndrome. Opinions are mixed in regard to how the evidence could impact scoring systems used to classify patients, which currently do not consider these mutations, but experts agree that the evidence promotes the development of new therapeutic agents.

“There is a wealth of emerging information that demonstrates that specific mutations in MDS are associated with prognosis, inside and outside the context of allogeneic hematopoietic stem cell transplantation,” William A. Wood, MD, of the Leukemia, Lymphoma and Myeloma Program and the Bone Marrow and Stem Cell Transplantation Program at the University of North Carolina School of Medicine, told Healio.com. “Further, the presence of these mutations may contribute independent prognostic information in addition to what is already known through the most commonly used prognostic scoring systems in this disease.”

William A. Wood

In particular, mutations in the ASXL1, IDH2, NRAS and TP53 genes were associated with a worse prognosis in more than one study. Research presented by Betty K. Hamilton, MD, of the Taussig Cancer Institute at the Cleveland Clinic, and Tetsuichi Yoshizato, MD, of the Graduate School of Medicine at Kyoto University in Japan, found correlations between the presence of specific mutations and poor relapse-free survival after HSCT. In addition, findings from Michael Heuser, MD, of Hannover Medical School in Germany, and Rafael Bejar, MD, PhD, of the University of California, San Diego, demonstrated that patients with MDS and some genetic mutations experienced reduced OS.

Wood and Edward Copelan, MD, of the Levine Cancer Institute at Carolinas Health Care System, discussed the impact of these findings with Healio.com.

Data leads to debate about scoring system for MDS, AML
In addition to ASXL1, IDH2, NRAS and TP53, mutations in RUNX1 and TET2 are also associated with prognosis in patients with AML and MDS.

“All of these studies indicate that the specific mutations themselves – and their evolution with time and with treatment – are important in regard to prognosis,” Copelan said.

Edward Copelan

The increased understanding of the role these mutations may play biologically and prognostically has led some to call for changes to the Revised International Prognostic Scoring System, or R-IPSS, the most common of several systems used to classify patients with MDS.

“There is increasing evidence, especially with the findings from ASH, that mutations affect prognosis independently of the factors used in these scoring systems, including the R-IPSS, and that they may affect transplant outcomes,” Copelan said. “In order to improve accuracy, the mutations will need to be incorporated into scoring systems. In addition, we’re going to have to look more carefully at patients with the specific mutations to see how any individual treatment – be it a hypomethylating agent, or the addition of a second agent, or transplant – works in patients with that mutation.”

Wood provided additional perspective about the evidence that will be needed to incorporate these findings into practice.

“While it is clear that some mutations unfavorably alter risk and increase the chances of post-transplant relapse, it is more difficult to show that the presence of certain mutations should warrant earlier referral to HSCT than is done in current practice,” Wood said. “It is also challenging to demonstrate that certain mutations confer such an adverse prognosis that HSCT would be considered ineffective, or that they confer a sufficiently favorable prognosis that transplant could be delayed despite other adverse risk factors on the R-IPSS.”

Mutations represent new therapeutic targets for AML, MDS

The results of another study presented at ASH, which demonstrated that the FLT3 inhibitor midostaurin improved EFS and OS for patients with newly diagnosed AML and FLT3 mutations, is an example of the impact these mutations may have in developing novel agents.

“By identifying the driver mutations that are actually causing the disease, that informs us as to how we might logically approach therapy,” Copelan said. “There are several agents in phase 1 and phase 2 clinical trials that target specific mutations.”

Wood concurred.

“Further work will be needed to integrate emerging molecular prognostic information in MDS into rational clinical decision-making strategies that differ from current practice,” he said. “But the pace of progress in this area suggests that translation of improved molecular risk stratification into improvements in clinical care may not be far in the future.” – by Julia Ernst, MS

References:

Bejar R, et al. Abstract 907.

Hamilton BK, et al. Abstract 740.

Heuser M, et al. Abstract 912.

Yoshizato T, et al. Abstract 711.

Presented at: ASH Annual Meeting and Exposition; Dec. 5-8, 2015; Orlando, Fla.

Disclosure: Copelan and Wood report no relevant financial disclosures.