Prognostic Effect of ASXL1 Mutations in Patients with MDS and Secondary AML Following MDS After Allogeneic Hematopoietic Stem Cell Transplantation

Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative therapy for patients with myelodysplastic syndromes (MDS), but it is associated with high mortality and morbidity. Predictors for treatment outcome after HSCT are limited. Recently, mutations in ASXL1 have been described as an independent adverse prognostic marker for MDS patients not undergoing HSCT. The aim of this study was to investigate the prognostic impact of ASXL1 in a large cohort of patients with high risk MDS or secondary AML following MDS (sAML) undergoing HSCT.

Patients and Methods: Patients (n=105) with a diagnosis of MDS (34.3%) or sAML (65.7%) who received an allogeneic HSCT at Hannover Medical School between 1996 and 2010 and for whom genomic DNA was available from a time when the disease was active, were evaluated for the presence of ASXL1 mutations by direct sequencing. Patients gave their informed consent in accordance with the Declaration of Helsinki, and the study was approved by the institutional review board of Hannover Medical School. Overall survival (OS) and cumulative incidence of non-relapse mortality endpoints, measured from HSCT, were death (failure) and alive at last follow-up (censored). A Cox proportional hazards model was constructed for multivariate analysis and the two-sided level of significance was set at P <.05.

Median follow up from time of transplantation was 3.67 years. Median patient age at time of HSCT was 58 years (range 22–72) and the median donor age was 39 years (range 0–71). Twenty-seven patients (26.0%) were in complete remission and 78 patients (74%) had active disease before transplantation. In MDS, 9, 21, and 6 patients had intermediate-1, intermediate-2, or high risk IPSS, respectively. Low, intermediate, and high risk cytogenetics according to IPSS were found in 40, 21, and 44 patients, respectively. Related donor HSCT was performed in 24 patients (23%), and unrelated donor HSCT in 81 patients (77%). Six patients received bone marrow (6%), two cord blood (2%), and 97 (92%) received peripheral blood stem cells. Myeloablative preparative regimens were used in 17 patients (16%), and a non-myeloablative regimen was given to 88 patients (84%).

Mutations in ASXL1 were detected in 21 (20%) patients with 17 (16.2%) mutations being frameshift mutations. Previously, we showed that only frameshift mutations are prognostically relevant in MDS patients and therefore considered only those for further analysis. ASXL1 frameshift mutations were not correlated with clinical parameters (age, sex, MDS vs. sAML, cytogenetics, bone marrow blasts, blood group, CMV status of patient, type of previous treatment, and remission status prior to transplantation). ASXL1 frameshift mutated patients had received a graft from a related donor (41 vs. 19%, respectively, P=.05) and from bone marrow (17.6 vs. 3.4%, respectively, P=.03) more often compared to wildtype patients, however, there were no differences regarding other transplant-related characteristics (reduced intensity vs. standard conditioning, GvHD prophylaxis, donor age, donor sex, and CMV compatibility between recipient and donor). The presence of ASXL1 frameshift mutations was associated by trend with a shorter overall survival (5-year OS 31 vs. 47%, HR 1.87; 95%CI 0.96–3.64; p=.06). In multivariate analysis, when considering variables with P<.1 in univariate analysis (karyotype, stage [MDS vs. sAML], CMV serostatus of patient, donor type [related vs. unrelated], donor sex, donor age, and GvHD prophylaxis), ASXL1 frameshift mutations were an independent prognostic marker for OS (HR 2.63; 95%CI 1.29–5.38; P=.008) besides karyotype, stage, donor type, and GvHD prophylaxis. The cumulative incidence of relapse was similar between ASXL1 mutated and wildtype patients (P=.47). However, the cumulative incidence of non-relapse mortality was significantly higher in mutated compared to wildtype patients in univariate (61 vs. 34%, P=.01) and multivariate (P=.03) analysis. Grade III-IV acute GvHD was more frequent in ASXL1 mutated patients (37.5 vs. 7.4%, P=.002), while no extensive chronic GvHD was noted in these patients (0 vs. 20%, P=.14).

ASXL1 frameshift mutations independently predicted worse patient outcome after allogeneic HSCT in MDS and sAML patients in our study. The high rate of non-relapse mortality in ASXL1 mutated patients warrants further investigation.

*equal contribution

No relevant conflicts of interest to declare.