N-803, an IL-15 Superagonist Complex as Maintenance Therapy After Allogeneic Donor Stem Cell Transplant for Acute Myeloid Leukemia or Myelodysplastic Syndrome; A Phase 2 Trial

Abstract

Maintenance therapy may improve natural killer (NK) cell surveillance after allogeneic donor hematopoietic cell transplant (HCT) for myeloid malignancies and represents a potential approach to improve cure rates. Interleukin-15 (IL-15) enhances lymphocyte proliferation and antitumor activity. In a prior Phase 1 study of an IL-15 superagonist (N-803) in patients with AML who relapsed after HCT, we observed in vivo expansion of NK cells and antitumor responses. The primary objective of this Phase 2 trial was to determine if post-transplant N-803 could reduce relapse. We administered N-803 (n = 20) (dosed 6 mcg/kg subcutaneously [SQ] at day 60 after HCT to patients with myelodysplastic syndrome [MDS] or acute myeloid leukemia [AML] who were in complete remission [CR]). N-803 treatment was planned weekly, biweekly or every 4 weeks in 2 sequential cohorts. The most common adverse events after administration were self-limited injection sites skin rashes (n = 20). One week after an N-803 dose, we observed enhanced NK cell proliferation and improved antitumor cytotoxicity without inducing immune exhaustion. Five patients who developed acute graft versus host disease (aGVHD) after N-803 responded promptly to steroids and 4 patients developed chronic GVHD. Patients receiving >4 doses of N-803 had a 3-fold decrease in relapse at two years (P = .06). These findings support the safety, immune activation, and potential efficacy of N-803 to prevent relapse of AML/MDS after HSCT.

Keywords: AML; Allogeneic stem cell transplant; IL-15; Leukemia; Maintenance therapy; Myelodysplastic syndrome; N-803.

Figure 1.

N-803 administration in the Weekly Dosing Cohort. Eight patients were enrolled in the weekly dosing cohort with some patients getting N-803 weekly, every other week, or a combination thereof. C = cycle, D = day, Sx = symptoms. Pre N803 chimerism is expressed as the percentage of myeloid cells that are donor derived.

Figure 2.

N-803 dosing schema for participants getting 4-week cycles.

Figure 3.

Cumulative incidence of relapse in AML/MDS post allogeneic donor HCT receiving N-803 maintenance therapy.

Figure 4.

Overall survival at two years.

Figure 5.

Injection site rash after N-803 administration.

Figure 6.

Immune parameters after N-803 administration in cycle 1. (A) ALC from day 1 (baseline, prior to N-803 dosing) and day 8 and 15. (B) NK cell counts measured on day 1, 8, and 15. (C) CD8+ T cell counts measured on day 1, 8, and 15. (D) Ki-67 positive NK cells on day 1, 8, and 15. (E) Ki-67 positive CD56bright NK cells on day 1, 8, and 15. (F) Ki-67 positive CD56dim NK cells on day 1, 8, and 15. (G) NKG2A expression on NK cells on day 1, 8, and 15. All measures were performed by flow cytometry. Individual values are shown with a bar marking the median. ALC, absolute lymphocyte count; NK, natural killer cell.

Figure 7.

K562 killing assays after N-803 administration.

Figure 8.

Checkpoint receptor expression on T cells. (A) PD-1 expression on CD8+ T cells. (B) PD-1 expression on CD4+ T cells. (C) LAG-3 expression on CD8+ T cells. (D) LAG-3 expression on CD4+ T cells. Individual values are shown with the bar marking the median.