Peter Bader¹, Jan Soerensen¹, Eva Rettinger¹, Andre Willasch¹, Anne Sonntagbauer¹, Sümmeyye Elgaz¹, Franziska Kalensee¹, Hermann Kreyenberg¹, Marc Ansari², Christine Wolschke³, Richard Noppeney⁴, Gunnar Cario⁵, Guido Kobbe⁶, Tobias Feuchtinger⁷, Marion Subklewe⁸, Thomas Klingebiel¹, Martin Hutter¹, Evelyn Ullrich¹, Halvard Bönig⁹, Sabine Huenecke¹⁰, Andrea Jarisch^{1 1}University 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.