Mutation patterns in blast phase MPN, including paired sample analysis, point to specific mutations with potential pathogenetic relevance.
RUNX1 mutations predict inferior survival in blast phase MPN, independent of specific treatment strategies.

Key Points

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 JAK2 57%, CALR 20%, MPL 9%, and triple-negative 13%. Sixty-four patients (85%) harbored other mutations/variants, including 37% with ≥3 mutations; most frequent were ASXL1 47%, TET2 19%, RUNX1 17%, TP53 16%, EZH2 15%, and SRSF2 13%; relative mutual exclusivity was expressed by TP53, EZH2, LNK, RUNX1, SRSF2, and NRAS/KRAS mutations. Paired chronic-blast phase sample analysis was possible in 19 patients and revealed more frequent blast phase acquisition of ASXL1, EZH2, LNK, TET2, TP53, and PTPN11 mutations/variants. In multivariable analysis, RUNX1 and PTPN11 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 RUNX1 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 RUNX1 mutations.

Abstract

Visual Abstract

Post-PV AML patients (n = 16): post-PV AML without myelofibrosis phase (n = 9); post-PV AML with myelofibrosis phase (n = 7). Post ET-AML patients (n = 20): post-ET AML without myelofibrosis phase (n = 8); post-ET AML with myelofibrosis phase (n = 12). No mutations identified in CSF3R, RUNX2, and DNMT3A. Bold indicates significant values.

AMC, absolute monocyte count; ANC, absolute neutrophil count.

Only mutations with at least 3 incident cases are included in the survival analysis. Bold indicates significant values.

Bold indicates significant values.

Click here for additional data file.^{(134K, pptx)}

Acknowledgments

This work was supported in part by the Mayo Clinic Harvey-Yulman Charitable Foundation for Myelofibrosis Tissue Bank; the Clinical Database of Molecular and Biological Abnormalities; and the Henry J. Predolin Foundation for Research in Leukemia, Mayo Clinic, Rochester, MN.

Acknowledgments

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