Abstract
In this phase I/II clinical trial, we investigated the safety and efficacy of high doses of mb-IL21 ex vivo expanded donor-derived NK cells to decrease relapse in 25 patients with myeloid malignancies receiving haploidentical stem-cell transplantation (HSCT). Three doses of donor NK cells (1 × 105–1 × 108 cells/kg/dose) were administered on days −2, +7, and +28. Results were compared with an independent contemporaneously treated case-matched cohort of 160 patients from the CIBMTR database.After a median follow-up of 24 months, the 2-year relapse rate was 4% vs. 38% (p = 0.014), and disease-free survival (DFS) was 66% vs. 44% (p = 0.1) in the cases and controls, respectively. Only one relapse occurred in the study group, in a patient with the high level of donor-specific anti-HLA antibodies (DSA) presented before transplantation. The 2-year relapse and DFS in patients without DSA was 0% vs. 40% and 72% vs. 44%, respectively with HR for DFS in controls of 2.64 (p = 0.029). NK cells in recipient blood were increased at day +30 in a dose-dependent manner compared with historical controls, and had a proliferating, mature, highly cytotoxic, NKG2C+/KIR+ phenotype.Administration of donor-derived expanded NK cells after haploidentical transplantation was safe, associated with NK cell-dominant immune reconstitution early post-transplant, preserved T-cell reconstitution, and improved relapse and DFS. TRIAL REGISTRATION: NCT01904136 (https://clinicaltrials.gov/ct2/show/NCT01904136).
Highlights
Allogeneic hematopoietic stem-cell transplantation (HSCT) is the preferred curative treatment strategy for patients with advanced hematologic malignancies [1, 2]
The benefit of Natural killer (NK) cell administration in reducing relapse and improved survival was more significant when compared with reduced-intensity conditioning (RIC) controls (HR of controls 14.18; 95% CI 1.75–115.0, p = 0.013 for relapse and 2.28; 95% CI 1.08–4.82, p = 0.03 for disease-free survival (DFS)) (Supplementary Information Table S7), whereas there was a trend towards improved relapse (HR of controls 7.24; 95% CI 0.95–55.16, p = 0.06) and DFS (HR of controls 1.55; 95% CI 0.67–3.55, p = 0.30) when compared with MAC controls (Supplementary Information Table S8)
When patients with donor-specific anti-HLA antibodies (DSA) were excluded from analysis, the 2-year cumulative incidence of relapse was 0%, 40%, 29% and 51% for cases, controls, MAC controls and RIC controls, respectively, whereas DFS was 72%, 44%, 50% and 37%, respectively
Summary
Allogeneic hematopoietic stem-cell transplantation (HSCT) is the preferred curative treatment strategy for patients with advanced hematologic malignancies [1, 2]. The relapse rate for patients with high-risk acute myeloid leukemia (AML) in remission can be 50% or more based on disease risk and status at transplant [5, 6]. Multiple studies have administered NK cells for AML immunotherapy [8]; the therapeutic potential has been limited, at least in part because of the relatively low number of NK cells obtained by apheresis [9]. Our group hypothesized that high doses of NK cells obtained by ex vivo expansion could overcome this limitation, and developed an expansion method using K562 feeder cells expressing membrane-bound IL21 and 4-1BBL (FC21) [10]. We report final results of a phase II extension study and longterm follow-up of all patients treated on this clinical trial, as well as results of an independent comparison with contemporaneous. 1234567890();,: 156 case-matched controls performed by the Center for International Blood and Marrow Transplant Research (CIBMTR)
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