title: Phase II Study of Haploidentical Natural Killer Cell Infusion for Treatment of Relapsed or Persistent Myeloid Malignancies Following Allogeneic Hematopoietic Cell Transplantation.
abstract: We conducted a phase 2 study to determine the efficacy of HLA-haploidentical related donor natural killer (NK) cells after cyclophosphamide-based lymphodepletion in patients with relapsed or progressive acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS) following allogeneic hematopoietic cell transplantation (HCT). Eight patients (2 with MDS and 6 with AML) were treated with cyclophosphamide 50 mg/kg on day -3 and day -2 before infusion of NK cells isolated from a haploidentical related donor. One patient also received fludarabine 25 mg/m2/day for 4 days. Six doses of 1 million units of interleukin-2 (IL-2) were administered on alternating days beginning on day -1. The median number of NK cells infused was 10.6 × 10(6)/kg (range, 4.3 to 22.4 × 10(6)/kg), and the median number of CD3 cells infused was 2.1 × 10(3)/kg (range, 1.9 to 40 × 10(3)/kg). NK infusions were well tolerated, with a median time to neutrophil recovery of 19 days (range, 7 days to not achieved) and no incidence of graft-versus-host disease after NK infusion. One patient with AML and 1 patient with MDS achieved a complete response, but relapsed at 1.7 and 1.8 months, respectively. One patient with MDS experienced resolution of dysplastic features but persistence of clonal karyotype abnormalities; this patient was stable at 65 months after NK cell therapy. The median duration of survival was 12.9 months (range, 0.8 to 65.3 months). Chimerism analysis of CD3(-)/CD56(+) peripheral blood cells did not detect any circulating haploidentical NK cells after infusion. NK phenotyping was performed in 7 patients during and after IL-2 infusion. We found a slight trend toward greater expression of KIR2DL2/2DL3/2DS2 (5% versus 28%; P = .03) at 14 days in patients who survived longer than 6 months from NK cell infusion (n = 4) compared with those who died within 6 months of NK cell therapy (n = 3). In summary, our data support the safety of haploidentical NK cell infusion after allogeneic HCT.
authors.affiliation: Adult Bone Marrow Transplant Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York; Weill Cornell Medical College, New York, New York.
authors.forename: Brian C
authors.initials: BC
authors.lastname: Shaffer
authors.affiliation: Immunology Program, Sloan Kettering Institute for Cancer Research, New York, New York.
authors.forename: Jean-Benoit
authors.initials: JB
authors.lastname: Le Luduec
authors.affiliation: Weill Cornell Medical College, New York, New York; Bone Marrow Transplant Service, Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Christopher
authors.initials: C
authors.lastname: Forlenza
authors.affiliation: Adult Bone Marrow Transplant Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York; Weill Cornell Medical College, New York, New York.
authors.forename: Ann A
authors.initials: AA
authors.lastname: Jakubowski
authors.affiliation: Adult Bone Marrow Transplant Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York; Weill Cornell Medical College, New York, New York.
authors.forename: Miguel-Angel
authors.initials: MA
authors.lastname: Perales
authors.affiliation: Adult Bone Marrow Transplant Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York; Weill Cornell Medical College, New York, New York; Immunology Program, Sloan Kettering Institute for Cancer Research, New York, New York.
authors.forename: James W
authors.initials: JW
authors.lastname: Young
authors.affiliation: Adult Bone Marrow Transplant Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York; Weill Cornell Medical College, New York, New York; Immunology Program, Sloan Kettering Institute for Cancer Research, New York, New York. Electronic address: hsuk@mskcc.org.
authors.forename: Katharine C
authors.initials: KC
authors.lastname: Hsu
mesh_terms: D000328:Adult; D002066:Busulfan / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D003520:Cyclophosphamide / Q000627:therapeutic use; D005260:Female; D015870:Gene Expression; D006086:Graft vs Host Disease / Q000276:immunology / Q000401:mortality / Q000473:pathology / Q000517:prevention & control; D006239:Haplotypes; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007223:Infant; D007376:Interleukin-2 / Q000627:therapeutic use; D007694:Killer Cells, Natural / Q000276:immunology / Q000637:transplantation*; D015470:Leukemia, Myeloid, Acute / Q000276:immunology / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D019653:Myeloablative Agonists / Q000627:therapeutic use; D009190:Myelodysplastic Syndromes / Q000276:immunology / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D055607:Receptors, Natural Killer Cell / Q000235:genetics / Q000276:immunology; D012008:Recurrence; D063268:Sialic Acid Binding Ig-like Lectin 3 / Q000235:genetics / Q000276:immunology; D035781:Siblings; D016019:Survival Analysis; D019172:Transplantation Conditioning / Q000379:methods*; D014184:Transplantation, Homologous
chemical_list: C571163:CD33 protein, human; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D019653:Myeloablative Agonists; D055607:Receptors, Natural Killer Cell; D063268:Sialic Acid Binding Ig-like Lectin 3; D003520:Cyclophosphamide; D002066:Busulfan
keywords: AML; Allogeneic transplantation; MDS; Natural killer cell