TY - JOUR
T1 - Targeted next-generation sequencing in blast phase myeloproliferative neoplasms
AU - Lasho, Terra L.
AU - Mudireddy, Mythri
AU - Finke, Christy M.
AU - Hanson, Curtis A.
AU - Ketterling, Rhett P.
AU - Szuber, Natasha
AU - Begna, Kebede H.
AU - Patnaik, Mrinal M.
AU - Gangat, Naseema
AU - Pardanani, Animesh
AU - Tefferi, Ayalew
N1 - Publisher Copyright:
© 2018 by The American Society of Hematology.
PY - 2018/2/27
Y1 - 2018/2/27
N2 - 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%. Sixtyfour 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.
AB - 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%. Sixtyfour 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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U2 - 10.1182/bloodadvances.2018015875
DO - 10.1182/bloodadvances.2018015875
M3 - Article
C2 - 29467191
AN - SCOPUS:85055674558
SN - 2473-9529
VL - 2
SP - 370
EP - 380
JO - Blood Advances
JF - Blood Advances
IS - 4
ER -