Lara Maria Gómez García1, Adela Escudero2, Carmen Mestre3, Jose L Fuster Soler4, Antonia Pascual Martínez5, Jose M Vagace Valero6, María Vela3, Beatriz Ruz2, Alfonso Navarro3, Lucia Fernández7, Adrián Fernández7, Alejandra Leivas7, Joaquin Martínez-López7, Cristina Ferreras3, Raquel De Paz8, Miguel Blanquer4, Victor Galán9, Berta González9, Dolores Corral9, Luisa Sisinni9, Isabel Mirones9, Antonio Balas10, José Luis Vicario10, Paula Valle11, Alberto M Borobia11, Antonio Pérez-Martínez12. 1. Hematology Department, University Clinic Hospital of Valladolid, Valladolid, Spain. 2. Institute of Medical and Molecular Genetics (INGEMM), La Paz University Hospital, Madrid, Spain. 3. Translational Research in Pediatric Oncology, Hematopoietic Transplantation and Cell Therapy, IdiPAZ, Madrid, Spain. 4. Pediatric Hematology-Oncology Unit, University Clinic Hospital Virgen de la Arrixaca, El Palmar, Spain. 5. Pediatric Hematology Unit, Maternal and Children Hospital, Regional University Hospital of Málaga, Málaga, Spain. 6. Pediatric Hematology Department, Maternal Pediatric Hospital, University Hospital Complex of Badajoz, Badajoz, Spain. 7. Hematological Malignancies Clinical Research Unit, National Center for Cancer Research (CNIO), Madrid, Spain. 8. Hematology Department, La Paz University Hospital, Madrid, Spain. 9. Pediatric Onco-Hematology Department, La Paz University Hospital, Madrid, Spain. 10. Histocompatibility and HLA Typing Laboratory, Transfusion Center of the Community of Madrid, Madrid, Spain. 11. Clinical Pharmacology Department, La Paz University Hospital, Madrid, Spain. 12. Institute of Medical and Molecular Genetics (INGEMM), La Paz University Hospital, Madrid, Spain; Translational Research in Pediatric Oncology, Hematopoietic Transplantation and Cell Therapy, IdiPAZ, Madrid, Spain; Pediatric Onco-Hematology Department, La Paz University Hospital, Madrid, Spain; Faculty of Medicine, Autonomous University of Madrid, Madrid, Spain. Electronic address: aperezmartinez@salud.madrid.org.
Abstract
BACKGROUND: Acute myeloid leukemia (AML) accounts for approximately 20% of pediatric leukemia cases; 30% of these patients experience relapse. The antileukemia properties of natural killer (NK) cells and their safety profile have been reported in AML therapy. We proposed a phase 2, open, prospective, multicenter, nonrandomized clinical trial for the adoptive infusion of haploidentical K562-mb15-41BBL-activated and expanded NK (NKAE) cells as a consolidation strategy for children with favorable and intermediate risk AML in first complete remission after chemotherapy (NCT02763475). PATIENTS AND METHODS: Before the NKAE cell infusion, patients underwent a lymphodepleting regimen. After the NKAE cell infusion, patients were administered low doses (1 × 106/IU/m2) of subcutaneous interleukin-2. The primary study endpoint was AML relapse-free survival. We needed to include 35 patients to demonstrate a 50% reduction in relapses. RESULTS: Seven patients (median age, 7.4 years; range, 0.78-15.98 years) were administered 13 infusions of NKAE cells, with a median of 36.44 × 106 cells/kg (range, 6.92 × 106 to 193.2 × 106 cells/kg). We observed chimerism in 4 patients (median chimerism, 0.065%; range, 0.05-0.27%). After a median follow-up of 33 months, the disease of 6 patients (85.7%) remained in complete remission. The 3-year overall survival was 83.3% (95% confidence interval, 68.1-98.5), and the cumulative 3-year relapse rate was 28.6% (95% confidence interval, 11.5-45.7). The study was terminated early because of low patient recruitment. CONCLUSION: This study emphasizes the difficulties in recruiting patients for cell therapy trials, though NKAE cell infusion is safe and feasible. However, we cannot draw any conclusions regarding efficacy because of the small number of included patients and insufficient biological markers.
BACKGROUND: Acute myeloid leukemia (AML) accounts for approximately 20% of pediatric leukemia cases; 30% of these patients experience relapse. The antileukemia properties of natural killer (NK) cells and their safety profile have been reported in AML therapy. We proposed a phase 2, open, prospective, multicenter, nonrandomized clinical trial for the adoptive infusion of haploidentical K562-mb15-41BBL-activated and expanded NK (NKAE) cells as a consolidation strategy for children with favorable and intermediate risk AML in first complete remission after chemotherapy (NCT02763475). PATIENTS AND METHODS: Before the NKAE cell infusion, patients underwent a lymphodepleting regimen. After the NKAE cell infusion, patients were administered low doses (1 × 106/IU/m2) of subcutaneous interleukin-2. The primary study endpoint was AML relapse-free survival. We needed to include 35 patients to demonstrate a 50% reduction in relapses. RESULTS: Seven patients (median age, 7.4 years; range, 0.78-15.98 years) were administered 13 infusions of NKAE cells, with a median of 36.44 × 106 cells/kg (range, 6.92 × 106 to 193.2 × 106 cells/kg). We observed chimerism in 4 patients (median chimerism, 0.065%; range, 0.05-0.27%). After a median follow-up of 33 months, the disease of 6 patients (85.7%) remained in complete remission. The 3-year overall survival was 83.3% (95% confidence interval, 68.1-98.5), and the cumulative 3-year relapse rate was 28.6% (95% confidence interval, 11.5-45.7). The study was terminated early because of low patient recruitment. CONCLUSION: This study emphasizes the difficulties in recruiting patients for cell therapy trials, though NKAE cell infusion is safe and feasible. However, we cannot draw any conclusions regarding efficacy because of the small number of included patients and insufficient biological markers.