Genomic profiling of a randomized trial of interferon-a vs hydroxyurea in MPN reveals mutation-specific responses

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  • Trine Alma Knudsen
  • Vibe Skov
  • Kristen Stevenson
  • Lillian Werner
  • William Duke
  • Charles Laurore
  • Christopher J. Gibson
  • Anwesha Nag
  • Aaron R. Thorner
  • Bruce Wollison
  • Dennis Lund Hansen
  • Karin de Stricker
  • Lukas Frans Ocias
  • Mette Brabrand
  • Ole Weis Bjerrum
  • Ulrik Malthe Overgaard
  • Mikael Frederiksen
  • Thomas Kielsgaard Kristensen
  • Torben A. Kruse
  • Mads Thomassen
  • Torben Mourits-Andersen
  • Marianne Tang Severinsen
  • Jesper Stentoft
  • Joern Starklint
  • Donna S. Neuberg
  • Lasse Kjaer
  • Thomas Stauffer Larsen
  • R. Coleman Lindsley
  • Ann Mullally

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

TidsskriftBlood advances
Udgave nummer7
Sider (fra-til)2107-2119
Antal sider13
StatusUdgivet - 2022

Bibliografisk note

Funding Information:
Conflict-of-interest disclosure: D.L.H. received research funding from Alexion. D.S.N. received research funding from Celgene and Pharmacyclics; and has equity ownership in Madrigal Pharmaceuticals. H.C.H. has received research funding from Novartis; and is on the data monitoring board for AOP Orphan. R.C.L. has received research funding from Jazz Pharmaceuticals and MedImmune; and consultancy for Takeda Pharmaceuticals and Bluebird Bio. A.M. reports research funding and consulting for Janssen; research funding from Actuate Therapeutics; advisory board membership for Constellation; steering committee membership for PharmaEssentia; and consulting for Relay Therapeutics.

Funding Information:
This research was supported by grants from OUH Frie For-skningsmidler, OUH-Region Sjaelland Faelles Forskningspulje, Fonden til Lægevidenskabens Fremme, Ellen og Aage Fausboells Helsefond af 1975, Swedish Orphan, Region Sjaellands

Publisher Copyright:
ß 2022 by The American Society of Hematology

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