title: TGF-α and IL-6 plasma levels selectively identify CML patients who fail to achieve an early molecular response or progress in the first year of therapy.
abstract: Early molecular response (EMR, BCR-ABL1 (IS)⩽10% at 3 months) is a strong predictor of outcome in imatinib-treated chronic phase chronic myeloid leukemia (CP-CML) patients, but for patients who transform early, 3 months may be too late for effective therapeutic intervention. Here, we employed multiplex cytokine profiling of plasma samples to test newly diagnosed CP-CML patients who subsequently received imatinib treatment. A wide range of pro-inflammatory and angiogenesis-promoting cytokines, chemokines and growth factors were elevated in the plasma of CML patients compared with that of healthy donors. Most of these normalized after tyrosine kinase inhibitor treatment while others remained high in remission samples. Importantly, we identified TGF-α and IL-6 as novel biomarkers with high diagnostic plasma levels strongly predictive of subsequent failure to achieve EMR and deep molecular response, as well as transformation to blast crisis and event-free survival. Interestingly, high TGF-α alone can also delineate a poor response group raising the possibility of a pathogenic role. This suggests that the incorporation of these simple measurements to the diagnostic work-up of CP-CML patients may enable therapy intensity to be individualized early according to the cytokine-risk profile of the patient.
authors.affiliation: Cancer Theme, South Australian Health and Medical Research Institute (SAHMRI), Adelaide, SA, Australia.|School of Medicine, University of Adelaide, Adelaide, SA, Australia.
authors.forename: E
authors.initials: E
authors.lastname: Nievergall
authors.affiliation: Biostatistics Platform, Faculty of Medicine, Nursing and Health Sciences, Monash University, The Alfred Centre, Melbourne, VIC, Australia.
authors.forename: J
authors.initials: J
authors.lastname: Reynolds
authors.affiliation: Cancer Theme, South Australian Health and Medical Research Institute (SAHMRI), Adelaide, SA, Australia.|School of Medicine, University of Adelaide, Adelaide, SA, Australia.
authors.forename: C H
authors.initials: CH
authors.lastname: Kok
authors.affiliation: Cancer Theme, South Australian Health and Medical Research Institute (SAHMRI), Adelaide, SA, Australia.|School of Medicine, University of Adelaide, Adelaide, SA, Australia.
authors.forename: D B
authors.initials: DB
authors.lastname: Watkins
authors.affiliation: CSL Limited, Parkville, VIC, Australia.
authors.forename: M
authors.initials: M
authors.lastname: Biondo
authors.affiliation: CSL Limited, Parkville, VIC, Australia.
authors.forename: S J
authors.initials: SJ
authors.lastname: Busfield
authors.affiliation: CSL Limited, Parkville, VIC, Australia.
authors.forename: G
authors.initials: G
authors.lastname: Vairo
authors.affiliation: School of Pathology and Laboratory Medicine, The University of Western Australia, Perth, WA, Australia.
authors.forename: K
authors.initials: K
authors.lastname: Fuller
authors.affiliation: School of Pathology and Laboratory Medicine, The University of Western Australia, Perth, WA, Australia.
authors.forename: W N
authors.initials: WN
authors.lastname: Erber
authors.affiliation: Cancer Theme, South Australian Health and Medical Research Institute (SAHMRI), Adelaide, SA, Australia.|School of Medicine, University of Adelaide, Adelaide, SA, Australia.
authors.forename: T
authors.initials: T
authors.lastname: Sadras
authors.affiliation: Cancer Theme, South Australian Health and Medical Research Institute (SAHMRI), Adelaide, SA, Australia.
authors.forename: R
authors.initials: R
authors.lastname: Grose
authors.affiliation: School of Medicine, University of Adelaide, Adelaide, SA, Australia.|Department of Haematology, SA Pathology, Adelaide, SA, Australia.|Centre for Cancer Biology, SA Pathology and UniSA, Adelaide, SA, Australia.
authors.forename: D T
authors.initials: DT
authors.lastname: Yeung
authors.affiliation: Centre for Cancer Biology, SA Pathology and UniSA, Adelaide, SA, Australia.
authors.forename: A F
authors.initials: AF
authors.lastname: Lopez
authors.affiliation: School of Medicine, University of Adelaide, Adelaide, SA, Australia.|Department of Haematology, SA Pathology, Adelaide, SA, Australia.
authors.forename: D K
authors.initials: DK
authors.lastname: Hiwase
authors.affiliation: Cancer Theme, South Australian Health and Medical Research Institute (SAHMRI), Adelaide, SA, Australia.|School of Medicine, University of Adelaide, Adelaide, SA, Australia.|Department of Haematology, SA Pathology, Adelaide, SA, Australia.|Centre for Cancer Biology, SA Pathology and UniSA, Adelaide, SA, Australia.
authors.forename: T P
authors.initials: TP
authors.lastname: Hughes
authors.affiliation: Cancer Theme, South Australian Health and Medical Research Institute (SAHMRI), Adelaide, SA, Australia.|School of Medicine, University of Adelaide, Adelaide, SA, Australia.|Discipline of Paediatrics, University of Adelaide, Adelaide, SA, Australia.
authors.forename: D L
authors.initials: DL
authors.lastname: White
mesh_terms: D001752:Blast Crisis; D016207:Cytokines / Q000032:analysis / Q000097:blood; D018572:Disease-Free Survival; D006801:Humans; D015850:Interleukin-6 / Q000097:blood*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000097:blood* / Q000175:diagnosis; D008213:Lymphocyte Activation; D057285:Precision Medicine; D011379:Prognosis; D012074:Remission Induction; D013997:Time Factors; D016211:Transforming Growth Factor alpha / Q000097:blood*
chemical_list: D016207:Cytokines; C508600:IL6 protein, human; D015850:Interleukin-6; C587886:TGFA protein, human; D016211:Transforming Growth Factor alpha