Impact of Molecular Genetics on Disease-Free Survival in Myelofibrosis Patients Following Allogeneic Stem Cell Transplantation

Introduction

Primary or post-ET/post-PV myelofibrosis is one of the Philadelphia chromosome-negative chronic myeloproliferative neoplasia characterized by significantly reduced overall survival. More recently several mutated genes have been detected, which allow, in addition to clinical factors, to identify patients with a significantly shorter overall survival and a higher risk of transformation into acute leukemia.

Allogeneic stem cell transplantation is still the only curative treatment option for patients with myelofibrosis, and due to the inherent risk of the treatment procedure careful selection of the patients is required. Molecular genetics may help to select patients for allogeneic stem cell transplantation.

Patients and methods

To determine the impact of mutated genes in patients with myelofibrosis who underwent allogeneic stem cell transplantation we analyzed samples from 169 patients with a median age of 58 years (r: 18 – 75) who received allogeneic stem cell transplantation either from related (n = 36) or unrelated (n = 133) donor. Stem cell source were more often peripheral blood stem cells (n = 165) than bone marrow (n = 4). The intensity of conditioning was mainly reduced intensity (n = 166), rather than myeloablative conditioning (n = 3). Patients suffered from primary myelofibrosis (n = 110), post-ET/PV myelofibrosis (n = 46), while 13 patients were in acceleration or had transformed into acute myeloid leukemia. According to dynamic IPSS (DIPSS) (n = 165) the patients were either low (n = 7), intermediate-1 (n = 35), intermediat-2 (n = 91), or high risk (n = 32). Regarding molecular genetics we found JAK2V617F mutations in 62%, calreticulin (CALR) mutations in 20%, MPL mutations in 4%, U2AF1 in 7%, SRSF2 in 10%, SF3B1 in 4%, ASXL1 in 29%, IDH1 in 2%, IDH2 in 3%, CBL in 1%, DNMT3A in 4%, TET2 in 10%, EZH2 in 4%, while none of the patients showed mutations in ETV6 and PTPN11. Overall, only in 11 patients no mutation could be detected.  One mutation could be detected in 41%, 2 mutations in 30%, 3 mutations in 11%, 4 mutations in 5%.

Results

During follow-up 39 patients experienced relapse and 46 patients experienced non-relapse mortality.

From the non-molecular factors regarding disease-free survival in univariate analysis age < 58 (p < 0.01), intermediate-1 and low risk according to DIPPS (p = 0.002), HLA-matched vs. mismatched (p = 0.04) were significant factors for improved disease-free survival. Regarding molecular markers improved disease-free survival was seen for patients with mutations in CALR (p = 0.005), while negative impact on disease-free survival was seen for mutations in U2AF1 (p = 0.035), ASXL1 (p = 0.05), IDH2 (p = 0.006), DNMT3A (p = 0.029). No significant difference could be seen for patients with EZH2, IDH1, SRSF2, and SF3B1 mutations. There was no difference in disease-free survival for patients without any mutation vs. 1, and more than 1 mutation (p = 0.12). Regarding the previously described unfavorable mutations ASXL1, SRSF2, EZH2, IDH1, and IDH2, we found 40 patients who had at least 1 of these unfavorable mutations, 11 had 2 of these mutation, and 1 had 3 of these unfavorable mutations. However, the estimated 5-year disease-free survival did not differ significantly between patients without any of these unfavorable mutations, with 1 or with 2 of them (47 vs. 40 vs. 41%, p = 0.5).

Conclusions

These results suggest that some molecular marker such as ASXL1, U2AF1, IDH2 and DNMT3A negatively influence DFS in myelofibrosis after allogeneic stem cell transplantation in a univariate analysis. In contrast, the poor prognosis of the recently described unfavorable mutated genes SRSF2, EZH2, and IDH1 was not observed and may therefore be overcome by allogeneic stem cell transplantation.