Abstract CT116: Dynamics of cytotoxic T-cell subsets during immunotherapy predicts outcome in acute myeloid leukemia
Authors: Ewald Sander Frida , Rydström Anna , Bernson Elin , Kiffin Roberta , Riise Rebecca , Aurelius Johan , Brune Mats , Hellstrand Kristoffer , Bergh Thorén Fredrik , Martner Anna 
Published: July 2016

Preventing relapse after the completion of chemotherapy remains a challenge in acute myeloid leukemia (AML), in particular in older subjects. For the present study, we assessed the distribution of CD8+ (cytotoxic) T cell subsets in the peripheral blood of AML patients undergoing immunotherapy with histamine dihydrochloride and low-dose interleukin-2 (HDC/IL-2) for relapse prevention. Eighty-four non-transplanted AML patients (age 18-79) in first complete remission (CR) received HDC/IL-2 in an international phase IV trial (ClinicalTrials.gov; NCT01347996). Mononuclear cells were recovered from blood samples drawn during 3-week cycles of immunotherapy and analyzed for CD8+ T cell phenotypes by flow cytometry. Patients were followed for leukemia-free survival (LFS) and overall survival (OS) for 2 years after the initiation of immunotherapy. A reduction of the frequency of CD8+ T effector memory cells (TEM cells with CD8+45RO+CCR7-phenotype) during the first cycle of HDC/IL-2 prognosticated LFS (HR 0.25, CI 0.12-0.60, P = 0.001) and OS (HR 0.24, CI 0.08-0.69, P = 0.009). Similarly, induction of T effector cells (CD8+45RO-CCR7-) during cycle 1 impacted favorably on outcome (P = 0.048 for OS). Patients with a concomitant reduction of TEM cells and induction of Teff cells (“TEM to Teff transition”) during immunotherapy showed favorable outcome in terms of LFS (HR 0.19, CI 0.07-0.50, P = 0.001) and OS (HR 0.13, CI 0.03-0.59, P = 0.008). The altered distribution of cytotoxic T cells during treatment with HDC/IL-2 significantly prognosticated LFS and OS within the group of older patients (more than 60 years old, table 1). The reported predictors of clinical outcome remained significant when taking potential confounders (age, risk group classification, number of induction courses required to achieve CR and number of consolidation courses) into account in multivariable analysis. Presence of CD8+ T cells with specificity for leukemia-associated antigens identified patients with low relapse risk (P = 0.01 for LFS). Our results point to novel aspects of T cell-mediated immunosurveillance in AML and provide conceivable biomarkers in relapse-preventive immunotherapy. Multivariable analysis of the impact of T cell distribution on outcome in older AML patientsDynamics of CD8+ T cell phenotypes during cycle 1 (n=27)Hazard ratioConfidence intervalP-valueReduction of TEM vs. LFS0.100.03-0.390.001Reduction of TEM vs. OS0.130.03-0.570.006Induction of Teff vs. LFS0.260.08-0.870.03Induction of Teff vs. OS0.100.02-0.510.005Transition of TEM to Teff vs. LFS&lt;0.001n.a.n.a.Transition of TEM to Teff vs. OS&lt;0.001n.a.n.a.

Citation Format: Frida Ewald Sander, Anna Rydström, Elin Bernson, Roberta Kiffin, Rebecca Riise, Johan Aurelius, Mats Brune, Kristoffer Hellstrand, Fredrik Bergh Thorén, Anna Martner. Dynamics of cytotoxic T-cell subsets during immunotherapy predicts outcome in acute myeloid leukemia. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT116.