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. 2018 Feb 27;2(4):370-380.
doi: 10.1182/bloodadvances.2018015875.

Targeted next-generation sequencing in blast phase myeloproliferative neoplasms

Terra L Lasho  1 , Mythri Mudireddy  1 , Christy M Finke  1 , Curtis A Hanson  2 , Rhett P Ketterling  3 , Natasha Szuber  1 , Kebede H Begna  1 , Mrinal M Patnaik  1 , Naseema Gangat  1 , Animesh Pardanani  1 , Ayalew Tefferi  1
Affiliations

Targeted next-generation sequencing in blast phase myeloproliferative neoplasms

Terra L Lasho et al. Blood Adv. .

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.

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Conflict of interest statement

Conflict-of-interest disclosure: The authors declare no competing financial interests.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
Molecular signature in 75 patients with blast phase MPN. (A) stratification headed by driver mutations followed by most frequent mutations. (B) Stratification headed by mutations that are overrepresented compared with historical data on chronic phase disease.
Figure 2.
Figure 2.
Molecular signature in paired samples from chronic phase (CP) and blast phase (BP) disease in 19 patients with MPNs.
Figure 3.
Figure 3.
Survival data in 75 patients with blast phase MPN stratified by RUNX1 mutation and treatment strategy.
See this image and copyright information in PMC

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