Targeted next-generation sequencing in blast phase myeloproliferative neoplasms

Terra L. Lasho, Mythri Mudireddy, Christy M. Finke, Curtis A. Hanson, Rhett P. Ketterling, Natasha Szuber, Kebede Begna, Mrinal M Patnaik, Naseema Gangat, Animesh D Pardanani, Ayalew Tefferi

Research output: Contribution to journalArticle

12 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)370-380
Number of pages11
JournalBlood advances
Volume2
Issue number4
DOIs
StatePublished - Feb 27 2018
Externally publishedYes

Fingerprint

Blast Crisis
Mutation
Neoplasms
Confidence Intervals
Essential Thrombocythemia
Polycythemia Vera
Primary Myelofibrosis
Survival
Lymphocyte Activation
Transplants

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Lasho, T. L., Mudireddy, M., Finke, C. M., Hanson, C. A., Ketterling, R. P., Szuber, N., ... Tefferi, A. (2018). Targeted next-generation sequencing in blast phase myeloproliferative neoplasms. Blood advances, 2(4), 370-380. https://doi.org/10.1182/bloodadvances.2018015875

Targeted next-generation sequencing in blast phase myeloproliferative neoplasms. / Lasho, Terra L.; Mudireddy, Mythri; Finke, Christy M.; Hanson, Curtis A.; Ketterling, Rhett P.; Szuber, Natasha; Begna, Kebede; Patnaik, Mrinal M; Gangat, Naseema; Pardanani, Animesh D; Tefferi, Ayalew.

In: Blood advances, Vol. 2, No. 4, 27.02.2018, p. 370-380.

Research output: Contribution to journalArticle

Lasho TL, Mudireddy M, Finke CM, Hanson CA, Ketterling RP, Szuber N et al. Targeted next-generation sequencing in blast phase myeloproliferative neoplasms. Blood advances. 2018 Feb 27;2(4):370-380. https://doi.org/10.1182/bloodadvances.2018015875
Lasho, Terra L. ; Mudireddy, Mythri ; Finke, Christy M. ; Hanson, Curtis A. ; Ketterling, Rhett P. ; Szuber, Natasha ; Begna, Kebede ; Patnaik, Mrinal M ; Gangat, Naseema ; Pardanani, Animesh D ; Tefferi, Ayalew. / Targeted next-generation sequencing in blast phase myeloproliferative neoplasms. In: Blood advances. 2018 ; Vol. 2, No. 4. pp. 370-380.
@article{037a7f80eab843e186a00581de298d01,
title = "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 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.",
author = "Lasho, {Terra L.} and Mythri Mudireddy and Finke, {Christy M.} and Hanson, {Curtis A.} and Ketterling, {Rhett P.} and Natasha Szuber and Kebede Begna and Patnaik, {Mrinal M} and Naseema Gangat and Pardanani, {Animesh D} and Ayalew Tefferi",
year = "2018",
month = "2",
day = "27",
doi = "10.1182/bloodadvances.2018015875",
language = "English (US)",
volume = "2",
pages = "370--380",
journal = "Blood advances",
issn = "2473-9529",
publisher = "American Society of Hematology",
number = "4",

}

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

AU - Patnaik, Mrinal M

AU - Gangat, Naseema

AU - Pardanani, Animesh D

AU - Tefferi, Ayalew

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%. 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.

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%. 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.

UR - http://www.scopus.com/inward/record.url?scp=85055674558&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85055674558&partnerID=8YFLogxK

U2 - 10.1182/bloodadvances.2018015875

DO - 10.1182/bloodadvances.2018015875

M3 - Article

VL - 2

SP - 370

EP - 380

JO - Blood advances

JF - Blood advances

SN - 2473-9529

IS - 4

ER -