Abstract 2545: Histamine dihydrochloride and interleukin-2 for relapse prevention in AML: Initial results of the Re:MISSION phase IV trial

Abstract

Abstract BACKGROUND AND METHODS. Immunotherapy with histamine dihydrochloride and low-dose interleukin-2 (HDC/IL-2) has been approved within the EU for relapse prevention in the post-consolidation phase of acute myeloid leukemia (AML) (Blood 108:88). We have performed a phase IV trial (Re:MISSION) to assess the immunomodulatory properties of this regimen and to correlate potential biomarkers of immunity with outcome. Eighty-nine patients (age 19-80) with AML in first complete remission received HDC (0.5 mg sc bid) and human recombinant IL-2 (1MIU sc bid) in ten repeated three-week cycles for 18 months or until relapse. Mononuclear cells were analyzed for NK and T cell phenotypes by flow cytometry at onset and during cycles 1 and 3. INDUCTION OF NK CELLS AND NCR EXPRESSION DURING THERAPY. Treatment with HDC/IL-2 resulted in a 3-fold expansion of both CD56bright (CD56/CD16-) and CD16+ (CD56+/CD16+) NK cells during cycle 1 (CD56+, P= 10-6, n=47; paired samples t-test). During cycle 1, the median expression intensity of the natural cytotoxicity receptors (NCRs) NKp46 and NKp30 on CD16+ NK cells increased by 50% and 30%, respectively (P=6 x10-8 for NKp46; P=2 x10-7 for NKp30, n=56). For CD56bright cells, the results were discordant for the NCRs with pronounced induction of NKp30 (P=4 x10-13) during cycle 1 but no induction of NKp46 (P=0.51, n=56). ROLE OF NCR EXPRESSION FOR MAINTENANCE OF REMISSION. An interim analysis of immune markers vs. relapse-free survival (RFS) revealed a strong impact of NK cell NKp46 expression. Patients with NKp46 expression above the median after one 21-day cycle of HDC/IL-2 thus showed significantly higher RFS than those with lower expression (CD16+, P=0.003, HR=3.0, CI 1.4-6.4; CD56bright, P=0.002, HR=3.3, CI: 1.5-7.0; logrank test). High NK cell expression of NKp46 after a treatment cycle also identified a population of elderly patients (>60 years old) with favorable outcome (CD16+, P=0.002, HR=4.1, CI: 1.6-10.2; logrank test). We observed a pronounced expansion of CD4+/CD25+/Foxp3+ regulatory T cells during cycles that did not impact on relapse risk. CONCLUSION. These results highlight the role of NK cells and NCR expression for relapse-free survival in AML. Citation Format: Anna Martner, Anna Rydström, Rebecca Riise, Johan Aurelius, Mats Brune, Kristoffer Hellstrand, Fredrik Bergh Thorén. Histamine dihydrochloride and interleukin-2 for relapse prevention in AML: Initial results of the Re:MISSION phase IV trial. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2545. doi:10.1158/1538-7445.AM2014-2545