BMT CTN 1803: Haploidentical Natural Killer Cells (K-NK002) to Prevent Post-Transplant Relapse in AML and MDS (NK-REALM)

Background and Rationale:

Relapse remains the leading cause of treatment failure for patients with high-risk acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) undergoing allogeneic bone marrow transplantation (BMT). Although the risk depends on parameters such as age and conditioning intensity, relapse is experienced by 30–50% of patients after conventional BMT in high-risk AML/MDS.

Initial safety and post-BMT relapse risk reduction results were reported from a phase I study of haploidentical (haplo) donor-derived natural killer (NK) cells expanded ex vivo on feeder cells expressing IL-21 and 4-1BBL (FC21-NK) in conjunction with haploBMT. Of 13 patients with high-risk myeloid malignancies treated with FC21-NK cells, no infusion reactions or dose-limiting toxicities occurred and only 1 patient, treated at the lowest dose of 1×10⁵ cells/kg, relapsed (Ciurea, Blood, 2017). This experience supports investigation of K-NK002, a product derived from haploidentical donor NK cells and expanded ex vivo in a feeder cell-free system using plasma membrane (PM21) particles bearing membrane-bound IL-21 and 4-1BBL. We used contemporary data from the Center for International Blood and Marrow Transplant Research registry to determine baseline relapse rates that informed the statistical design. K-NK002 will be given in the peri-transplant period to test the hypothesis that haploidentical NK cells can mediate an effective anti-leukemia response.

Trial Design and Methods:

BMT CTN 1803 is a phase II, single-arm, open-label, multicenter trial designed to investigate the safety and efficacy of K-NK002 for the treatment of patients with high-risk AML or MDS undergoing haploBMT (NCT04395092). An initial 6 patient safety run-in phase will precede enrollment into the full study of approximately 60 patients. Major inclusion criteria of patients and donors are listed in Table 1.

Production of the haploidentical donor NK-cells is completed prior to the planned haploBMT. BMT conditioning will consist of 140 mg/m² (100 mg/m² for patients ≥60 years old) melphalan on Day -7; 40 mg/m² fludarabine on Days -7, -6, -5, and -4; and 2 Gy of total body irradiation on Day -3. Donor bone marrow will be harvested and given on Day 0. Three doses of K-NK002 (1×10⁸ NK cells/kg) will be administered IV on Days -2, +7, and +28, relative to the haploBMT. Graft-versus-host disease (GVHD) prophylaxis consists of post-transplantation cyclophosphamide with tacrolimus and mycophenolate mofetil.

The primary endpoint is cumulative incidence of relapse at 1 year post haploBMT in patients receiving at least 1 infusion of K-NK002. Secondary endpoints are safety and tolerability of K-NK002; overall survival; non-relapse mortality; relapse-free survival; GVHD-free survival; cumulative incidence of acute GVHD and chronic GVHD; hematologic recovery; donor-cell engraftment; primary and secondary graft failure; overall incidence of toxicity; and cumulative incidence of infections including cytomegalovirus re-activation and symptomatic BK virus hemorrhagic cystitis. Exploratory endpoints are systemic immunosuppression-free survival; immune reconstitution at Days 28, 100, and 365 post haploBMT; proportion of patients with detectable minimal residual disease at Days 28 and 100 post haploBMT; feasibility of administering the planned K-NK002 doses; and impact of NK-cell alloreactivity on relapse and survival.