1University Hospital Frankfurt, Department for Children and Adolescents, Frankfurt, Germany, 2Geneva University Hospital, Children and Adolescents, Geneva, Switzerland, 3Universitsklinik Hamburg Eppendorf, Stem Cell Transplantation, Hamburg, Germany, 4University Hospital Essen, Hematology- Oncology, Essen, Germany, 5University Medical Center Schleswig-Holstein, Paediatrics, Kiel, Germany, 6University Medical Center Düsseldorf, Hematology-Oncology, Düsseldorf, Germany, 7LMU, von Hauner Kinderspital, Hematology-Oncology, Munich, Germany, 8University Hospital Munich, Munich, Germany, 9German Red Cross Blood Center Frankfurt and Institute of Transfusion Medicine and Immunohematology, Frankfurt, Germany, 10Univeristy Hospital Frankfurt, Department for Children and Adolescents, Frankfurt, Germany
Background: Children, adolescents and young adult patients with ALL with second relapse, relapse after allogeneic SCT or patients with primary refractory disease have a poor prognosis with conventional treatment concepts. In this patient group several studies using second generation CD19 chimeric antigen receptor T- cells (CAR-T cells) demonstrated high efficacy with two year survival rates of up to 65%. Recently, two different CAR-T cell products were approved by the FDA and in 2018 also by the EMA in Europe: Tisagenlecleucel (Kymriah®) for the treatment of patients with B-precursor ALL who are i) refractory, ii) in second relapse or iii) who relapsed after allogeneic SCT (relapsed/refractory ALL; r/r ALL) as well as for diffuse large cell lymphoma (DLBCL) and Axicabtagen Ciloleucel (Yescarta®) for the treatment of B-cell lymphoma. Here we report our first results using commercially available CAR-T-cell product Tisagenlecleucel (Kymriah®) in patients with ALL which were treated by the University Hospital for Children and Adolescents Frankfurt am Main (n=9), the Department of Medicine III, University Hospital LMU Munich (n=1), and the von Hauner Kinderspital, LMU Munich, Germany (n=1).
Methods: Between October and December 2018 eleven patients received apheresis for CAR-T cell generation. Nine patients suffered from r/r c-ALL, and two from r/r B-precursor ALL. Eight patients had relapsed after allogeneic HSCT, one patient each suffered from first r/relapse , second r/relapse or from primary r/ALL. In 9/11 (82%) patients CAR-T cell production was successful after one and in 2 patients (18%) after a second apheresis.
Median patients' age was 16.7 years (1.1-25.4). Between apheresis and start of lymphodepleting chemotherapy (LDC), 10/11 patients received low dose chemotherapy according to the FRAPOSTALL protocol (Willasch et al. 2016) and one patient was treated with inotuzumab. Production slots were immediately available, resulting in turn-around-time from apheresis to product delivery of 3-4 weeks. Disease status at start of LDC was CR w/o MRD (n=4), CR MRD pos. (n=2), CRi (n=1), persistence of blasts (n=2), and disease progression (80-100% blasts, n=2). LDC consisting of FLU-CYC was given to 9/10 patients, one patient did not receive LDC.
Results: CAR-T cells could be transfused to 10/11 patients at a median dose of 1.5 Mio/kgBW (0.145 Mio 8.5). In one patient, in whom a second viral transduction procedure was necessary; neither LDC nor CAR-T cell transfusion could be given because of diseases progression and deterioration of the patient's general condition. Cytokine release syndrome (CRS) grade I was observed in one patient; 8/10 patients did not develop CRS. Cytokine related encephalopathy syndrome (CRES) grade II was observed in 1/10 patients. At day +28 8/10 patients (80%) achieved MRD negative CR. The two patients with progressive disease at time of LDC did not respond although CAR-T cells could be seen morphologically under the microscope. This might be explained by multidrug related phenomenon protecting refractory leukemia from CAR-T cell attack.
Conclusions: Commercial available CAR-T cell product Tisagenlecleucel (Kymriah®) showed high efficacy in r/r-ALL patients to re-induce CR.
Clinical Trial Registry: Commercial available CAR-T cell product Tisagenlecleucel (Kymriah®) showed high efficacy in r/r-ALL patients to re-induce CR.
Disclosure: PB: Novartis (consultancy: included expert testimony, speaker bureau, Honoraria); Medac (Research Funding, Patents and Royalties); Riemser (Research Funding); Neovii (Research Funding); Amgen (Honoraria). AJ: Novartis and Bluebird: (Consultancy). All other author declare no COI.