Targeted next-generation sequencing in blast phase myeloproliferative neoplasms

Abstract

Among 248 consecutive patients with blast phase myeloproliferative neoplasm (MPN-BP), DNA collected at the time of blast transformation was available in 75 patients (median age, 66 years; 64% men). MPN-BP followed primary myelofibrosis in 39 patients, essential thrombocythemia in 20 patients, and polycythemia vera in 16 patients. A myeloid neoplasm-relevant 33-gene panel was used for next-generation sequencing. Driver mutation distribution was <i>JAK2</i> 57%, <i>CALR</i> 20%, <i>MPL</i> 9%, and triple-negative 13%. Sixty-four patients (85%) harbored other mutations/variants, including 37% with ≥3 mutations; most frequent were <i>ASXL1</i> 47%, <i>TET2</i> 19%, <i>RUNX1</i> 17%, <i>TP53</i> 16%, <i>EZH2</i> 15%, and <i>SRSF2</i> 13%; relative mutual exclusivity was expressed by <i>TP53</i>, <i>EZH2</i>, <i>LNK</i>, <i>RUNX1</i>, <i>SRSF2</i>, and <i>NRAS/KRAS</i> mutations. Paired chronic-blast phase sample analysis was possible in 19 patients and revealed more frequent blast phase acquisition of <i>ASXL1</i>, <i>EZH2</i>, <i>LNK</i>, <i>TET2</i>, <i>TP53</i>, and <i>PTPN11</i> mutations/variants. In multivariable analysis, <i>RUNX1</i> and <i>PTPN11</i> mutations/variants were associated with shorter survival duration; respective hazard ratios (HRs) (95% confidence interval [CI]) were 2.1 (95% CI, 1.1-3.8) and 3.0 (95% CI, 1.1-6.6). An all-inclusive multivariable analysis confirmed the prognostic relevance of <i>RUNX1</i> mutations (HR, 1.9; 95% CI, 1.5-5.5) and also showed additional contribution from a treatment strategy that includes transplant or induction of complete or near-complete remission (HR, 0.3; 95% CI, 0.2-0.5). The current study points to specific mutations that might bear pathogenetic relevance for leukemic transformation in MPN and also suggest an adverse survival effect of <i>RUNX1</i> mutations.