378 Plasma IL-7 and IL-15 Levels Vary Greatly after Low-Intensity Conditioning and May be Associated with Clinical Outcome in Recipients of High-Dose Sirolimus Gvhd Prophylaxis

Track: Poster Abstracts
Saturday, February 14, 2015, 6:45 PM-7:45 PM
Grand Hall CD (Manchester Grand Hyatt)
Syed Abbas Ali, MD , Experimental Transplant and Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD
Seth M. Steinberg, PhD , Biostatistics and Data Management Section, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Rockville, MD
Miriam Mossoba, PhD , ETIB, NCI, Bethesda, MD
Joseph Rimando , Medical Research Scholars Program, National Institutes of Health, Bethesda, MD
Scott Rowley, MD , John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ
Michele L. Donato, MD , John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ
Kevin Camphausen, MD , Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD
George Sigal , Meso Scale Diagnostics, Gaithersburg, MD
Fran Hakim, PhD , Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD
Ronald Gress, MD , * Co-Senior Experimental Transplantation and Immunology Branch/NCI/NIH, Bethesda, MD
David Halverson, MD , Experimental Transplantation and Immunology Branch, NCI, Bethesda, MD
Daniel Fowler, MD , Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD
Presentation recording not available for download or distribution as requested by the presenting author.

In previous studies using a preparative regimen of fludarabine (Flu) plus high-dose cyclophosphamide (Cy; total dose, 4800 mg/m2) and GVHD prophylaxis of cyclosporine plus methotrexate, it was determined that transplant recipients had quite variable plasma levels of the T cell homeostatic cytokines IL-7 (Dean et al; JCO, 2008) and IL-15 (Boyiadzis et al; BBMT, 2008); and cytokine levels were associated with acute GVHD (IL-7) or pattern of immune reconstitution (IL-15). However, it is not known whether recipients of lower-intensity conditioning or sirolimus-based GVHD prophylaxis have variable levels of these cytokines or whether such potential cytokine variability is associated with clinical outcome. To begin to address this, we measured multiple cytokine levels (MesoScale multiplex assay; current analysis restricted to IL-7 and IL-15 levels at day 0 of transplant) in recipients of low-intensity conditioning (Flu/Cy; total Cy dose, 1200 mg/m2; see Table 1). Patients received GVHD prophylaxis consisting of cyclosporine plus short-course sirolimus (d-2 through d14 post-SCT) at either standard-dose (n=46; “SD Cohort”) or high-dose (n=20; “HD Cohort”) (target trough level: 5-10 or 20-30 ng/ml, respectively). All patients received pre-emptive DLI consisting of rapamycin-resistant T cells (Fowler et al; Blood, 2013); however, in the current study, T cell manufacturing was reduced from 12-days to 6-days. Clinical outcomes (Table 1) were similar in SD and HD Cohorts, including: donor T cell and myeloid cell chimerism pre-DLI (d14 post-SCT) and post-DLI (d28 post-SCT), and incidence of classical acute GVHD. Remarkably, a wide range of IL-7 and IL-15 values were detected at day 0 of SCT in both SD and HD Cohorts (no difference between cohorts). In the SD Cohort, there was no association of IL-7 or IL-15 values with donor T cell chimerism, myeloid cell chimerism, or acute GVHD. However, in the HD Cohort, IL-7 values were associated with donor T cell chimerism and GVHD; and, IL-15 values were associated with donor T cell chimerism, myeloid cell chimerism, as well as GVHD. In conclusion, these data indicate that: (1) IL-7 and IL-15 values differ widely amongst recipients of low-intensity conditioning; and (2) IL-7 and IL-15 values were potentially associated with allo-engraftment and GVHD in the setting of high-dose sirolimus but not standard-dose sirolimus. This latter result provides a new insight into the pharmacodynamics of mTOR blockade post-transplant, and suggests that a more complete block of cytokine receptor signaling in vivo can unmask relationships between cytokine biology and post-transplant outcome.

Disclosures:
G. Sigal, Meso Scale Diagnostics, Employee: Salary

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