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

Autor:	Knudsen TA; Department of Hematology, Zealand University Hospital, Roskilde, Denmark., Skov V; Department of Hematology, Zealand University Hospital, Roskilde, Denmark., Stevenson K; Department of Data Science, Dana-Farber Cancer Institute, Boston, MA., Werner L; Department of Data Science, Dana-Farber Cancer Institute, Boston, MA., Duke W; Division of Hematology, Brigham and Women's Hospital, Boston, MA., Laurore C; Division of Hematology, Brigham and Women's Hospital, Boston, MA., Gibson CJ; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA., Nag A; Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, MA., Thorner AR; Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, MA., Wollison B; Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, MA., Hansen DL; Department of Hematology, Odense University Hospital, Odense, Denmark., Ellervik C; Department of Data and Innovation Support, Region Zealand, Soroe, Denmark.; Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.; Department of Laboratory Medicine, Boston Children's Hospital, Boston, MA.; Department of Pathology, Harvard Medical School, Boston, MA., El Fassi D; Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.; Department of Hematology, Herlev and Gentofte Hospital, Herlev, Denmark.; Department of Hematology, Copenhagen University Hospital, Copenhagen, Denmark., de Stricker K; Department of Pathology, Odense University Hospital, Odense, Denmark., Ocias LF; Statens Serum Institut, Copenhagen, Denmark., Brabrand M; Department of Hematology, Odense University Hospital, Odense, Denmark., Bjerrum OW; Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.; Department of Hematology, Copenhagen University Hospital, Copenhagen, Denmark., Overgaard UM; Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.; Department of Hematology, Copenhagen University Hospital, Copenhagen, Denmark., Frederiksen M; Department of Hematology, Hospital of Southern Jutland, Haderslev, Denmark., Kristensen TK; Department of Pathology, Odense University Hospital, Odense, Denmark., Kruse TA; Department of Clinical Genetics, Odense University Hospital, Odense, Denmark., Thomassen M; Department of Clinical Genetics, Odense University Hospital, Odense, Denmark., Mourits-Andersen T; Department of Hematology, Hospital of South West Jutland, Esbjerg, Denmark., Severinsen MT; Department of Hematology, Clinical Cancer Research Center, Aalborg University Hospital, Aalborg, Denmark.; Department of Clinical Medicine, Aalborg University, Aalborg, Denmark., Stentoft J; Department of Hematology, Aarhus University Hospital, Aarhus, Denmark., Starklint J; Department of Hematology, Holstebro Hospital, Holstebro, Denmark; and., Neuberg DS; Department of Data Science, Dana-Farber Cancer Institute, Boston, MA., Kjaer L; Department of Hematology, Zealand University Hospital, Roskilde, Denmark., Larsen TS; Department of Hematology, Odense University Hospital, Odense, Denmark., Hasselbalch HC; Department of Hematology, Zealand University Hospital, Roskilde, Denmark.; Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark., Lindsley RC; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA., Mullally A; Division of Hematology, Brigham and Women's Hospital, Boston, MA.; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.; Broad Institute, Cambridge, MA.
Jazyk:	angličtina
Zdroj:	Blood advances [Blood Adv] 2022 Apr 12; Vol. 6 (7), pp. 2107-2119.
DOI:	10.1182/bloodadvances.2021004856
Abstrakt:	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 (IFNα) 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 IFNα, 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 IFNα compared with hydroxyurea (P = .04). Furthermore, treatment-emergent DNMT3A mutations were significantly enriched in IFNα-treated patients not attaining CHR (P = .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 = .007), as was a mutation in TET2 alone (age-adjusted odds ratio, 3.03; 95% confidence interval, 1.03-9.01; P = .044). At 24 months, we found mutation-specific response patterns to IFNα: (1) JAK2- and CALR-mutated MPN exhibited distinct molecular responses; and (2) DNMT3A-mutated clones/subclones emerged on treatment. (© 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.)
Databáze:	MEDLINE
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