Mutation status predicts outcomes after HSCT in myelodysplastic syndrome, AML

Somatic mutations in ASXL1, RUNX1 and TP53 appeared independently associated with poor outcomes and shorter OS in patients undergoing allogeneic hematopoietic stem cell transplantation for myelodysplastic syndrome or acute myeloid leukemia, according to study results published in Journal of Clinical Oncology.

“Myelodysplastic syndrome (MDS) are myeloid neoplasms that range from conditions with a near-normal life expectancy to forms that are close to acute myeloid leukemia,” Marco G. Della Porta, MD, of Fondazione IRCCS Policlinico San Matteo in Pavia, Italy, and colleagues wrote. “Their clinical heterogeneity reflects different somatic mutations that cause clonal proliferation and evolution of myelodysplastic cells.”

HSCT serves as the only curative option for patients with MDS; however, the effect of driver somatic mutations on outcomes of patients undergoing HSCT has not been studied.

Della Porta and colleagues identified 401 patients with MDS (n = 274) or AML evolving from MDS (n = 127) who underwent HSCT between 1997 and 2013.

The researchers used parallel sequencing to examine tumor samples collected prior to HSCT for 34 recognized gene mutations in myeloid neoplasms, which they then analyzed for impact on outcomes after HSCT.

Seventy-nine percent (n = 318) of patients had at least one oncogenic point mutation and 37% (n = 149) had cytogenetic abnormalities; combining sequencing and cytogenetics increased the percentage of patients with mutations to 87%.

The most frequently mutated genes included RUNX1 (23%), SRSF2 (17%), ASXL1 (17%), SF3B1 (16%), KRAS/NRAS (16%), DNMT3A (15%), TP53 (13%), and TET2 (10%).

Patients with MDS had a greater prevalence of mutations in splicing factors (P = .021), whereas patients with AML evolving from MDS had more frequent occurrence of DNA methylator mutations (P = .001).

The number of somatic mutations had a significant effect on OS (P = .017) and probability of relapse after HSCT (P < .001).

A univariate analysis showed greater relapse risk and shorter OS in patients with mutations in RUNX1 (relapse, HR = 1.78; OS, HR = 1.69), ASXL1 (relapse, HR = 1.89; OS, HR = 1.73), IDH1/2 (relapse, HR = 1.74; OS, 1.42) and TP53 (relapse, HR = 1.95; OS, HR = 1.92).

Further, RUNX1 mutations appeared associated with multilineage dysplasia (P = .012), excess blasts (P = .018) and decreased platelet levels (P = .031).

IDH1/2 mutations were associated with excess blasts (P = .018) and multilineage dysplasia (P = .009). TP53 mutations were associated with poor or very poor cytogenetic risk (P < .001), transfusion dependency (P = .042) and decreased neutrophil levels (P = .033).

An analysis of patients with MDS showed independent associations with probability of relapse and OS after HSCT in mutations to ASXL1 (relapse, HR = 1.89; OS, HR = 1.72), RUNX1 (relapse, HR = 1.67; OS, HR = 1.59) and TP53 (relapse, HR = 1.9; OS, HR = 1.82).

Similarly, an analysis of patients with AML evolving from MDS showed similar independent prognoses for relapse (ASXL1, HR = 2.41; RUNX1, HR = 2.46; TP53, HR = 3.12) and OS (ASXL1, HR = 2.09; RUNX1, HR = 1.96; TP53, HR = 2.54).

Somatic mutations remained an independent prognostic factor when compared with the revised International Prognostic Scoring System in patients with MDS.

However, the researchers found that introducing mutation status into the prognostic model would change outcome predictions after HSCT for 34% of patients.

The researchers acknowledged the retrospective study design and lack of a matched cohort as potential limitations.

“These results serve as a proof of concept that the integration of somatic mutations significantly increase the ability to capture prognostic information in patients with MDS and AML evolving from MDS who are receiving allogeneic HSCT, and may provide a basis for improving clinical decision making,” Della Porta and colleagues wrote. “Possible interventions in patients with high risk [for] disease relapse after HSCT according to genotype may include the anticipation of the transplant procedure in early disease phase, the use of innovative conditioning regimens to increase the probability of eradicating the MDS close and prophylaxis of disease recurrence after transplantation by donor leukocyte infusions and targeted/novel therapies.” – by Cameron Kelsall

Disclosure: Della Porta reports no relevant financial disclosures. Please see the full study for a list of all other researchers’ relevant financial disclosures.