In:
Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 1912-1912
Abstract:
Introduction:Indoleamine 2,3 dioxygenase (IDO1) is the rate-limiting enzyme during metabolism of the essential amino acid tryptophan (TRP). IDO1 is up-regulated mainly by interferons during infection and inflammation and depletes tryptophan, which results in reduced T cell activation and proliferation as well as expansion of immunosuppressive regulatory T cells. Deregulation of IDO1 activity has been implicated in cancer immune evasion, but its role in chronic phase (CP) CML remains elusive so far. Methods:A large panel of circulating pro-inflammatory cytokines and components of the IDO-pathway (soluble IDO1=sIDO1 and kynurenine/tryptophan ratio=KYN/TRP as a product of IDO1 activity) as well as plasmacytoid dendritic cells (pDC) were analyzed alongside the prospective pan-european ENEST1st clinical study (NCT01061177). This substudy included 52 nilotinib-naïve chronic phase (CP)-CML patients that were subsequently treated with 300 mg BID nilotinib and analyzed at months 6 and 12. Molecular responses were quantified in central EUTOS reference laboratories. Results: Soluble IDO (sIDO1) levels and KYN/TRP ratio are significantly up-regulated in newly diagnosed CP-CML and significantly drop during nilotinib therapy. sIDO1 levels significantly correlate with increased KYN/TRP, suggesting increased IDO1 activity at diagnosis. Increased sIDO is linked to a pro-inflammatory status in CML patients, as it positively correlates to increased serum neopterin levels as well as to various other pro-inflammatory markers, such as IFN-g, IL-8, IL-10, IL-17A, sVEGF-A, sVCAM-1 and sTNFR-1. Interestingly, albeit being an IFN-regulated gene, IDO1 activity (KYN/TRP) negatively correlated with the proportion of pDC, the main producers of IFN-a. Interestingly, a higher KYN/TRP is linked to superior molecular response, as demonstrated by a significant correlation of the KYN/TRP ratio to BCR-ABL transcript levels. Patients having a high KYN/TRP ratio ( 〉 mean +2SD of post therapy levels) reach deep molecular response rates (i.e. MR4.5) significantly earlier and at higher rates. Conclusions: CML diagnosis in CP is linked to an inceased inflammatory status, as shown by increased levels of sIDO and its metabolites kynurenine leading to an increased KYN/TRP ratio. In solid cancer increased IDO expression/activity is linked to inferior outcome by favoring immune evasion. In contrast, in CML an increased KYN/TRP ratio is associated with improved molecular outcome during nilotinib 1st-line therapy. One reason could be that IDO activity may reflect endogenous IFN-α production, a known factor favoring immune-mediated CML-control. Disclosures Sopper: Novartis: Other: Travel costs reimbursement. Mustjoki:BMS, Novartis, Pfizer: Consultancy, Honoraria, Research Funding. Gastl:Novartis: Consultancy, Research Funding. Giles:Novartis: Consultancy, Honoraria, Research Funding. Hochhaus:BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; ARIAD: Honoraria, Research Funding. Janssen:BMS: Honoraria; Pfizer: Honoraria; ARIAD: Consultancy; Novartis: Research Funding.
Type of Medium:
Online Resource
ISSN:
0006-4971
,
1528-0020
DOI:
10.1182/blood.V128.22.1912.1912
Language:
English
Publisher:
American Society of Hematology
Publication Date:
2016
detail.hit.zdb_id:
1468538-3
detail.hit.zdb_id:
80069-7
