TY - JOUR
T1 - Genomic Profiling of a Randomized Trial of Interferon-α versus Hydroxyurea in MPN Reveals Mutation-Specific Responses
AU - Knudsen, Trine Alma
AU - Skov, Vibe
AU - Stevenson, Kristen E.
AU - Werner, Lillian
AU - Duke, William
AU - Laurore, Charles
AU - Gibson, Christopher James
AU - Nag, Anwesha
AU - Thorner, Aaron R.
AU - Wollison, Bruce
AU - Hansen, Dennis Lund
AU - Ellervik, Christina
AU - El Fassi, Daniel
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 - © 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.
PY - 2022/4/12
Y1 - 2022/4/12
N2 - Background Although somatic mutations influence the pathogenesis, phenotype, and outcome of myeloproliferative neoplasms (MPN), little is known about their impact on molecular response to cytoreductive treatment. Methods We performed targeted next-generation sequencing (NGS) on 202 pre-treatment samples obtained from patients with MPN enrolled in the DALIAH trial (randomized controlled phase III clinical trial, NCT01387763) and 135 samples obtained after 24 months of therapy with recombinant interferon-alpha (IFNα) or hydroxyurea (HU). 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. Results Among JAK2-mutated patients treated with IFNα, those with CHR had a greater reduction in the JAK2 variant allele frequency (VAF) (median 0.29 to 0.07; p<0.0001) compared with those not achieving CHR (median 0.27 to 0.14; p<0.0001). In contrast, the CALR VAF did not significantly decline in neither those achieving CHR nor those not achieving CHR. Treatment-emergent mutations in DNMT3A were observed more commonly in patients treated with IFNα compared with HU, p=0.04. Furthermore, treatment-emergent DNMT3A-mutations were significantly enriched in IFNα treated patients not attaining CHR, p=0.02. A mutation in TET2, DNMT3A, or ASXL1 was significantly associated with prior stroke (age-adjusted OR=5.29 [95% CI, 1.59-17.54]; p=0.007) as was a mutation in TET2 alone (age-adjusted OR=3.03 [95% CI, 1.03-9.01]; p=0.044). Conclusion At 24 months, we found mutation-specific response patterns to IFNα: (1) JAK2- and CALR-mutated MPN demonstrated distinct molecular responses and (2) DNMT3A-mutated clones/subclones emerged on treatment.
AB - Background Although somatic mutations influence the pathogenesis, phenotype, and outcome of myeloproliferative neoplasms (MPN), little is known about their impact on molecular response to cytoreductive treatment. Methods We performed targeted next-generation sequencing (NGS) on 202 pre-treatment samples obtained from patients with MPN enrolled in the DALIAH trial (randomized controlled phase III clinical trial, NCT01387763) and 135 samples obtained after 24 months of therapy with recombinant interferon-alpha (IFNα) or hydroxyurea (HU). 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. Results Among JAK2-mutated patients treated with IFNα, those with CHR had a greater reduction in the JAK2 variant allele frequency (VAF) (median 0.29 to 0.07; p<0.0001) compared with those not achieving CHR (median 0.27 to 0.14; p<0.0001). In contrast, the CALR VAF did not significantly decline in neither those achieving CHR nor those not achieving CHR. Treatment-emergent mutations in DNMT3A were observed more commonly in patients treated with IFNα compared with HU, p=0.04. Furthermore, treatment-emergent DNMT3A-mutations were significantly enriched in IFNα treated patients not attaining CHR, p=0.02. A mutation in TET2, DNMT3A, or ASXL1 was significantly associated with prior stroke (age-adjusted OR=5.29 [95% CI, 1.59-17.54]; p=0.007) as was a mutation in TET2 alone (age-adjusted OR=3.03 [95% CI, 1.03-9.01]; p=0.044). Conclusion At 24 months, we found mutation-specific response patterns to IFNα: (1) JAK2- and CALR-mutated MPN demonstrated distinct molecular responses and (2) DNMT3A-mutated clones/subclones emerged on treatment.
KW - Genomics
KW - Humans
KW - Hydroxyurea/therapeutic use
KW - Interferon-alpha/therapeutic use
KW - Mutation
KW - Myeloproliferative Disorders/drug therapy
UR - http://www.scopus.com/inward/record.url?scp=85128146525&partnerID=8YFLogxK
U2 - 10.1182/bloodadvances.2021004856
DO - 10.1182/bloodadvances.2021004856
M3 - Journal article
C2 - 34507355
SN - 2473-9529
VL - 6
SP - 2107
EP - 2119
JO - Blood advances
JF - Blood advances
IS - 7
ER -