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895 Updated Analysis of the Efficacy and Safety of Tisagenlecleucel in Pediatric and Young Adult Patients with Relapsed/Refractory (r/r) Acute Lymphoblastic Leukemia

Program: Oral and Poster Abstracts
Type: Oral
Session: 612. Acute Lymphoblastic Leukemia: Clinical Studies: Improving Outcomes with Cellular Therapy
Hematology Disease Topics & Pathways:
Biological, Therapies, CAR-Ts
Monday, December 3, 2018: 4:30 PM
Room 6A (San Diego Convention Center)

Stephan A. Grupp, MD, PhD1,2, Shannon L. Maude, MD, PhD1,2, Susana Rives3*, Andre Baruchel, MD4, Michael W. Boyer, MD5, Henrique Bittencourt, MD, PhD6,7,8*, Peter Bader, MD, PhD9, Jochen Büchner, MD, PhD10*, Theodore W. Laetsch, MD11,12, Heather Stefanski, MD, PhD13, Gary Douglas Myers, MD14*, Muna Qayed, MD, MSc15, Michael A. Pulsipher, MD16, Barbara De Moerloose, MD, PhD17,18*, Gregory A. Yanik, MD19*, Kara L. Davis, DO20, Paul L. Martin, MD, PhD21, Eneida R. Nemecek, MD, MBA, MSc22, Christina Peters, MD23*, Joerg Krueger, MD24*, Adriana Balduzzi, MD25, Nicolas Boissel, Md, PhD26*, Francoise Marie Mechinaud, MD, FRACP27*, Mimi Leung28*, Lamis K. Eldjerou, MD28, Lan Yi, PhD28*, Karen Thudium Mueller, PharmD, MSc29*, Eric Bleickardt, MD28* and Hidefumi Hiramatsu, M.D., Ph.D.30

1Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
2Division of Oncology, Center for Childhood Cancer Research and Cancer Immunotherapy Program, Children's Hospital of Philadelphia, Philadelphia, PA
3Department of Pediatric Hematology and Oncology, Hospital Sant Joan de Déu de Barcelona, Barcelona, ESP
4Pediatric Hematology and Immunology Department, Robert Debre Hospital, APHP, Paris, France
5Department of Pediatrics and Internal Medicine, University of Utah, Salt Lake City, UT
6Hematology Oncology Division, CHU Sainte-Justine, Montreal, Canada
7Charles-Bruneau Cancer Center, CHU Sainte-Justine Research Center, Montreal, Canada
8Department of Pediatrics, Faculty of Medicine, University of Montreal, Montreal, Canada
9Hospital for Children and Adolescents; Division for Stem Cell Transplantation and Immunology, University Hospital Frankfurt, Frankfurt, Germany
10Department of Pediatric Hematology and Oncology, Oslo University Hospital, Oslo, Norway
11Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX
12Pauline Allen Gill Center for Cancer and Blood Disorders, Children’s Health, Dallas, TX
13Department of Pediatric Blood and Marrow Transplant, University of Minnesota, Minneapolis, MN
14Children’s Mercy Hospital, Kansas City, MO
15Emory University, Atlanta, GA
16Division of Hematology, Oncology, and Blood and Marrow Transplantation, Children’s Hospital Los Angeles, University of Southern California Keck School of Medicine, Los Angeles, CA
17Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium
18Cancer Research Institute Ghent (CRIG), Ghent, Belgium
19C.S. Mott Children’s Hospital, Ann Arbor, MI
20Department of Pediatrics, Stanford University School of Medicine, Stanford, CA
21Division of Pediatric Blood and Marrow Transplant, Duke University Medical Center, Durham, NC
22Pediatric Hematology/Oncology & Bone Marrow Transplantation, OHSU Knight Cancer Institute Doernbecher Children's Hospital, Portland, OR
23Stem Cell Transplantation Unit, St. Anna Children's Hospital, Vienna, Austria
24Department of Translational Oncology, Biological Sciences Platform, Sunnybrook Research Institute, Toronto, Canada
25Clinica Pediatrica Università degli Studi di Milano Bicocca, Monza, Italy
26Hopital Saint-Louis-University, Paris, France
27Children's Cancer Centre, The Royal Children's Hospital Melbourne, Melbourne, Australia
28Novartis Pharmaceuticals Corporation, East Hanover, NJ
29Novartis Institutes for BioMedical Research, East Hanover, NJ
30Department of Pediatrics, Graduate School of Medicine Kyoto University, Kyoto, Japan


Tisagenlecleucel is an FDA approved chimeric antigen receptor (CAR)-T cell therapy that reprograms T cells to eliminate CD19+ B cells. ELIANA (NCT02435849) is a phase 2 pivotal study of tisagenlecleucel in pediatric/young adult patients (pts) with CD19+ r/r B-cell acute lymphoblastic leukemia (ALL), the first global trial of a CAR-T cell therapy. The primary objective was met, with an overall remission rate (ORR) of 81% (complete remission [CR] + CR with incomplete blood count recovery [CRi]). Here we present an update of ELIANA, with additional pts and additional 11 mo follow-up from the previous report (Maude et al. N Engl J Med 2018).


Eligible pts were aged ≥3 y at screening and ≤21 y at diagnosis and had ≥5% leukemic blasts in bone marrow. Tisagenlecleucel was centrally manufactured at 2 sites (Morris Plains, NJ, USA and Leipzig, Germany) by lentiviral transduction of autologous T cells with a vector encoding for a second generation 4-1BB anti-CD19 CAR and expanded ex vivo. Tisagenlecleucel was provided to pts at 25 study centers in 11 countries on 4 continents using cryopreserved apheresed mononuclear cells, central production facilities, and a global supply chain. The primary endpoint, ORR within 3 mo and maintained for ≥28 d among infused pts, was assessed by an independent review committee. Secondary endpoints included duration of remission (DOR), overall survival (OS), safety, and cellular kinetics.


As of April 13, 2018, 113 pts were screened and 97 enrolled. There were 8 manufacturing failures (8%) and 10 pts (10%) were not infused due to death or adverse events (AEs). Following lymphodepleting chemotherapy in most pts (76/79; fludarabine/cyclophosphamide [n=75]), 79 pts were infused with a single dose of tisagenlecleucel (median dose, 3.0×106 [range, 0.2-5.4×106] CAR-positive viable T cells/kg), and all had ≥3 mo of follow-up or discontinued earlier (median time from infusion to data cutoff, 24 mo [range, 4.5-35 mo]). Median age was 11 y (range, 3-24 y); 61% of pts had prior hematopoietic stem cell transplant (SCT).

Among the 65 pts with CR/CRi, 64 (98%) were MRD– within 3 mo. Median DOR by K-M analysis was not reached (Figure): responses were ongoing in 29 pts (max DOR, 29 mo and ongoing); 19 pts relapsed before receiving additional anticancer therapy (13 died subsequently); 8 pts underwent SCT while in remission, 8 received additional anticancer therapy (non-SCT) and 1 discontinued while in remission. The probability of relapse-free survival at 18 mo was 66% (95% CI, 52%-77%). Median OS was not reached; OS probability at 18 mo was 70% (95% CI, 58%-79%).

Cytokine release syndrome (CRS) occurred in 77% of pts (grade [G] 3/4; 48%; graded using the Penn scale); 39% of pts received tocilizumab for treatment of CRS with or without other anti-cytokine therapies; 48% of pts required ICU-level care for CRS, with a median ICU stay of 7 d. All cases of CRS were reversible. Most common G 3/4 nonhematologic AEs (>15%) other than CRS were neutropenia with a body temperature >38.3°C (62% within 8 wk of infusion), hypoxia (20%), and hypotension (20%). 13% of pts experienced G 3 neurological events, with no G 4 events or cerebral edema. Based on laboratory results, 43% and 54% of pts had G 3/4 thrombocytopenia and neutropenia not resolved by d 28; the majority of events resolved to G ≤2 by 3 mo. 25 post-infusion deaths were reported: 2 within 30 d (1 disease progression, 1 cerebral hemorrhage); 23 after 30 d of infusion (range, 53-859 d; 18 disease progression, 1 each due to encephalitis, systemic mycosis, VOD [hepatobiliary disorders related to allogeneic-SCT], bacterial lung infection, and an unknown reason after study withdrawal).

Tisagenlecleucel expansion in vivo correlated with CRS severity, and persistence of tisagenlecleucel along with B-cell aplasia in peripheral blood was observed for ≥2.5 y in some responding pts. Analysis of B-cell recovery and correlation with relapse will be presented.


With longer follow-up, the ELIANA study continues to confirm the efficacy of a single infusion of tisagenlecleucel in pediatric and young adults with ALL without additional therapy. AEs were effectively and reproducibly managed globally by appropriately trained personnel at study sites. The achievement of high overall response rates and deep remissions, in combination with the median duration of response and overall survival not being reached, further corroborate previously reported results.

Disclosures: Grupp: Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy; Adaptimmune: Consultancy; University of Pennsylvania: Patents & Royalties. Maude: Novartis Pharmaceuticals Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees. Rives: Novartis Pharmaceuticals Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel and accommodation for medical congresses, Speakers Bureau; Servier: Honoraria, Other: Travel and accommodation for medical congresses, Speakers Bureau; Shire: Honoraria, Other: Travel and accommodation for medical congresses, Speakers Bureau; Jazz Pharma: Honoraria, Other: Travel and accommodation for medical congresses, Speakers Bureau; Baxalta: Honoraria, Other: Travel and accommodation for medical congresses, Speakers Bureau; Amgen: Other: Travel and accommodation for medical congresses, Speakers Bureau; Erytech Pharma: Other: Travel and accommodation for medical congresses, Speakers Bureau. Baruchel: Celgene: Consultancy; Amgen: Consultancy; Roche: Consultancy; Jazz Pharmaceuticals: Consultancy, Honoraria, Other: Travel, accommodations or expenses; Novartis: Membership on an entity's Board of Directors or advisory committees; Shire: Research Funding; Servier: Consultancy. Bittencourt: Novartis Pharmaceuticals Corporation: Consultancy; Jazz Pharmaceuticals: Consultancy, Honoraria. Bader: Riemser: Research Funding; Cellgene: Consultancy; Medac: Patents & Royalties, Research Funding; Neovii: Research Funding; Novartis: Consultancy, Speakers Bureau. Laetsch: Bayer: Consultancy; Pfizer: Equity Ownership; Eli Lilly: Consultancy; Novartis Pharmaceuticals Corporation: Consultancy; Loxo Oncology: Consultancy. Stefanski: Novartis Pharmaceuticals Corporation: Consultancy, Honoraria, Speakers Bureau. Myers: Novartis Pharmaceuticals Corporation: Consultancy, Honoraria, Research Funding, Speakers Bureau. Qayed: Novartis: Consultancy. Pulsipher: CSL Behring: Consultancy; Amgen: Honoraria; Novartis: Consultancy, Honoraria, Speakers Bureau; Adaptive Biotech: Consultancy, Research Funding. Martin: Novartis Pharmaceuticals Corporation: Research Funding; Jazz Pharmaceuticals: Research Funding. Nemecek: Novartis Pharmaceuticals Corporation: Other: advisory boards. Boissel: Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees. Leung: Novartis Pharmaceuticals Corporation: Employment. Eldjerou: Novartis Pharmaceuticals Corporation: Employment. Yi: Novartis Pharmaceuticals Corporation: Employment. Mueller: Novartis Institutes for Biomedical Research: Employment; Novartis Pharmaceuticals Corporation: Equity Ownership, Other: Patent pending. Bleickardt: Novartis Pharmaceuticals Corporation: Employment.

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