Genomic profiling of a randomized trial of interferon-a vs hydroxyurea in MPN reveals mutation-specific responses
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Genomic profiling of a randomized trial of interferon-a vs hydroxyurea in MPN reveals mutation-specific responses. / Knudsen, Trine Alma; Skov, Vibe; Stevenson, Kristen; Werner, Lillian; Duke, William; Laurore, Charles; Gibson, Christopher J.; Nag, Anwesha; Thorner, Aaron R.; Wollison, Bruce; Hansen, Dennis Lund; Ellervik, Christina; Fassi, Daniel El; de Stricker, Karin; Ocias, Lukas Frans; Brabrand, Mette; Bjerrum, Ole Weis; Overgaard, Ulrik Malthe; Frederiksen, Mikael; Kristensen, Thomas Kielsgaard; Kruse, Torben A.; Thomassen, Mads; Mourits-Andersen, Torben; Severinsen, Marianne Tang; Stentoft, Jesper; Starklint, Joern; Neuberg, Donna S.; Kjaer, Lasse; Larsen, Thomas Stauffer; Hasselbalch, Hans Carl; Lindsley, R. Coleman; Mullally, Ann.
I: Blood advances, Bind 6, Nr. 7, 2022, s. 2107-2119.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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T1 - Genomic profiling of a randomized trial of interferon-a vs hydroxyurea in MPN reveals mutation-specific responses
AU - Knudsen, Trine Alma
AU - Skov, Vibe
AU - Stevenson, Kristen
AU - Werner, Lillian
AU - Duke, William
AU - Laurore, Charles
AU - Gibson, Christopher J.
AU - Nag, Anwesha
AU - Thorner, Aaron R.
AU - Wollison, Bruce
AU - Hansen, Dennis Lund
AU - Ellervik, Christina
AU - Fassi, Daniel El
AU - de Stricker, Karin
AU - Ocias, Lukas Frans
AU - Brabrand, Mette
AU - Bjerrum, Ole Weis
AU - Overgaard, Ulrik Malthe
AU - Frederiksen, Mikael
AU - Kristensen, Thomas Kielsgaard
AU - Kruse, Torben A.
AU - Thomassen, Mads
AU - Mourits-Andersen, Torben
AU - Severinsen, Marianne Tang
AU - Stentoft, Jesper
AU - Starklint, Joern
AU - Neuberg, Donna S.
AU - Kjaer, Lasse
AU - Larsen, Thomas Stauffer
AU - Hasselbalch, Hans Carl
AU - Lindsley, R. Coleman
AU - Mullally, Ann
N1 - Publisher Copyright: ß 2022 by The American Society of Hematology
PY - 2022
Y1 - 2022
N2 - Although somatic mutations influence the pathogenesis, phenotype, and outcome of myeloproliferative neoplasms (MPNs), little is known about their impact on molecular response to cytoreductive treatment. We performed targeted next-generation sequencing (NGS) on 202 pretreatment samples obtained from patients with MPN enrolled in the DALIAH trial (A Study of Low Dose Interferon Alpha Versus Hydroxyurea in Treatment of Chronic Myeloid Neoplasms; #NCT01387763), a randomized controlled phase 3 clinical trial, and 135 samples obtained after 24 months of therapy with recombinant interferon-alpha (IFNa) or hydroxyurea. The primary aim was to evaluate the association between complete clinicohematologic response (CHR) at 24 months and molecular response through sequential assessment of 120 genes using NGS. Among JAK2-mutated patients treated with IFNa, those with CHR had a greater reduction in the JAK2 variant allele frequency (median, 0.29 to 0.07; P, .0001) compared with those not achieving CHR (median, 0.27 to 0.14; P, .0001). In contrast, the CALR variant allele frequency did not significantly decline in those achieving CHR or in those not achieving CHR. Treatment-emergent mutations in DNMT3A were observed more commonly in patients treated with IFNa compared with hydroxyurea (P 5 .04). Furthermore, treatment-emergent DNMT3A mutations were significantly enriched in IFNa–treated patients not attaining CHR (P 5 .02). A mutation in TET2, DNMT3A, or ASXL1 was significantly associated with prior stroke (age-adjusted odds ratio, 5.29; 95% confidence interval, 1.59-17.54; P 5 .007), as was a mutation in TET2 alone (age-adjusted odds ratio, 3.03; 95% confidence interval, 1.03-9.01; P 5 .044). At 24 months, we found mutation-specific response
AB - Although somatic mutations influence the pathogenesis, phenotype, and outcome of myeloproliferative neoplasms (MPNs), little is known about their impact on molecular response to cytoreductive treatment. We performed targeted next-generation sequencing (NGS) on 202 pretreatment samples obtained from patients with MPN enrolled in the DALIAH trial (A Study of Low Dose Interferon Alpha Versus Hydroxyurea in Treatment of Chronic Myeloid Neoplasms; #NCT01387763), a randomized controlled phase 3 clinical trial, and 135 samples obtained after 24 months of therapy with recombinant interferon-alpha (IFNa) or hydroxyurea. The primary aim was to evaluate the association between complete clinicohematologic response (CHR) at 24 months and molecular response through sequential assessment of 120 genes using NGS. Among JAK2-mutated patients treated with IFNa, those with CHR had a greater reduction in the JAK2 variant allele frequency (median, 0.29 to 0.07; P, .0001) compared with those not achieving CHR (median, 0.27 to 0.14; P, .0001). In contrast, the CALR variant allele frequency did not significantly decline in those achieving CHR or in those not achieving CHR. Treatment-emergent mutations in DNMT3A were observed more commonly in patients treated with IFNa compared with hydroxyurea (P 5 .04). Furthermore, treatment-emergent DNMT3A mutations were significantly enriched in IFNa–treated patients not attaining CHR (P 5 .02). A mutation in TET2, DNMT3A, or ASXL1 was significantly associated with prior stroke (age-adjusted odds ratio, 5.29; 95% confidence interval, 1.59-17.54; P 5 .007), as was a mutation in TET2 alone (age-adjusted odds ratio, 3.03; 95% confidence interval, 1.03-9.01; P 5 .044). At 24 months, we found mutation-specific response
U2 - 10.1182/bloodadvances.2021004856
DO - 10.1182/bloodadvances.2021004856
M3 - Journal article
C2 - 34507355
AN - SCOPUS:85128146525
VL - 6
SP - 2107
EP - 2119
JO - Blood advances
JF - Blood advances
SN - 2473-9529
IS - 7
ER -
ID: 305397918