Elevated IL-1Ra Levels in the Stem Cell Product Is Associated with the Development of Engraftment Syndrome Following Autologous Stem Cell Transplantation for the Treatment of Multiple Myeloma and Lymphoma
Authors: Fanning Stacey L. , Goldgirsh Kira , Descalzi-Montoya Dante B. , Feinman Rena , Siegel David S , Biran Noa , Vesole David H. , Goy Andre , Feldman Tatyana A. , Leslie Lori A. , Rowley Scott D. , Skarbnik Alan P , McKiernan Phyllis , Baker Melissa , Donato Michele L. , Korngold Robert 
Published: October 2019

Abstract
Engraftment syndrome (ES) is a frequently occurring complication in patients receiving autologous stem cell transplantation (ASCT) for the treatment of multiple myeloma and various types of non-Hodgkin lymphomas. This clinical entity presents as skin rashes, diarrhea, non-infectious fevers and capillary leak syndrome in the peri-engraftment period coinciding with neutrophil recovery. The etiology and risk factors contributing to the development of ES remain unclear. The goal of the present study was to analyze the cytokine composition of the grafted mobilized peripheral blood stem cell product as well as serum cytokine levels in patients undergoing ASCT for the treatment of multiple myeloma and lymphoma. Cytokines were analyzed in the apheresis stem cell product, as well as patient plasma 1-2 days pre-transplant, 12 days post-transplant, and 2-4 months post-transplant using the Luminex xMAP multiplex cytokine platform. The concentrations of 29 cytokines from 38 patients were analyzed. Seventeen of these patients were diagnosed with engraftment syndrome using the Spitzer criteria. Patients who developed ES were shown to have significantly elevated levels of IL-1 receptor antagonist (IL-1Ra) in the apheresis product as compared to patients that did not develop ES (31,033 vs. 6015 pg/ml; p=0.028). IL-1Ra levels were not significantly different at other time points. IL-1Ra competes with IL-1α and IL-1β for binding to the IL-1 receptor thus acting as an antagonist to this proinflammatory cytokine. The gene encoding IL-1Ra has a tandem repeat sequence resulting in polymorphic alleles in the population with varying number of repeats. The allele containing 2 repeats, IL1RN*2, has been associated with various inflammatory diseases including Sjogren's syndrome, ulcerative colitis, Crohn disease, psoriasis, multiple sclerosis, and SLE. We performed PCR on the DNA isolated from the PBMCs of these patients to determine if patients with elevated IL-1Ra possessed the IL1RN*2 allele. Results did not find any correlation between IL-1RN*2 allele and elevated IL-1Ra levels in the apheresis samples. In addition, levels of the chemokine IFN-gamma-induced protein 10 (IP-10/CXCL10) were found to be significantly higher in patients diagnosed with ES at both the day 12 post-transplant (1089 vs. 689 pg/ml; p=0.022) and 2-4 month post-transplant time points (1768 vs. 922 pg/ml; p<0.01), and trending higher in the apheresis product (6132 vs. 2655 pg/ml; p=0.126). IP-10, which plays a role in leukocyte homing to inflamed tissues, has been identified as a major biological marker of disease severity in several inflammatory conditions. The only other cytokine that exhibited a significant difference at any time point was the increased level of IL-12p40 in the apheresis product of those developing ES (412 vs. 74 pg/ml; p=0.026). Characterizing these and other differences in graft product composition and changes that occur during hematopoietic reconstitution may aid in prediction or early identification of ES and may lead to early intervention treatment for this common and potentially serious complication of ASCT.

Disclosures
Siegel: Takeda: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Merck: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; Karyopharm: Consultancy, Honoraria. Biran:Takeda: Consultancy, Speakers Bureau; Merck: Research Funding; Amgen: Consultancy, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; BMS: Research Funding. Vesole:Amgen: Speakers Bureau; Takeda: Speakers Bureau. Feldman:Janssen: Speakers Bureau; Pharmacyclics: Speakers Bureau; Celgene: Speakers Bureau; Johnson and Johnson: Speakers Bureau; Seattle Genetics: Research Funding, Speakers Bureau; KITE: Speakers Bureau; Portola: Research Funding. Skarbnik:Novartis: Honoraria, Speakers Bureau; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead Sciences: Honoraria, Speakers Bureau; Genentech: Honoraria, Speakers Bureau; Jazz Pharmaceuticals: Honoraria, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.