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GLOBAL REGISTRATION TRIAL OF EFFICACY AND SAFETY OF CTL019 IN PEDIATRIC AND YOUNG ADULT PATIENTS WITH RELAPSED/REFRACTORY (R/R) ACUTE LYMPHOBLASTIC LEUKEMIA (ALL): UPDATE TO THE INTERIM ANALYSIS
Author(s):
Jochen Buechner
,
Jochen Buechner
Affiliations:
Oslo University Hospital Rikshospitalet,Oslo,Norway
Stephan A. Grupp
,
Stephan A. Grupp
Affiliations:
Department of Pediatrics,Perelman School of Medicine, University of Pennsylvania,Philadelphia,United States;Division of Oncology,Center for Childhood Cancer Research and Cancer Immunotherapy Program, Children's Hospital of Philadelphia,Philadelphia,United States
Shannon L. Maude
,
Shannon L. Maude
Affiliations:
Department of Pediatrics,Perelman School of Medicine, University of Pennsylvania,Philadelphia,United States;Division of Oncology,Center for Childhood Cancer Research and Cancer Immunotherapy Program, Children's Hospital of Philadelphia,Philadelphia,United States
Michael Boyer
,
Michael Boyer
Affiliations:
Department of Pediatrics and Internal Medicine,University of Utah,Salt Lake City,United States
Henrique Bittencourt
,
Henrique Bittencourt
Affiliations:
Department of Pediatrics,Faculty of Medicine, University of Montreal,Montreal,Canada;Hematology Oncology Division,CHU Sainte-Justine,Montreal,Canada;Charles-Bruneau Cancer Center,CHU Sainte-Justine Research Center,Montreal,Canada
Theodore W. Laetsch
,
Theodore W. Laetsch
Affiliations:
Department of Pediatrics,The University of Texas Southwestern Medical Center,Dallas,United States;Pauline Allen Gill Center for Cancer and Blood Disorders,Children's Health,Dallas,United States
Peter Bader
,
Peter Bader
Affiliations:
Division for Stem Cell Transplantation and Immunology,Hospital for Children and Adolescents, University Hospital Frankfurt,Frankfurt,Germany
Michael R. Verneris
,
Michael R. Verneris
Affiliations:
Adult and Pediatric Blood and Marrow Transplant Program,University of Minnesota,Minneapolis,United States
Heather Stefanski
,
Heather Stefanski
Affiliations:
Adult and Pediatric Blood and Marrow Transplant Program,University of Minnesota,Minneapolis,United States
Gary Douglas Myers
,
Gary Douglas Myers
Affiliations:
Children's Mercy Hospital and Clinics,Kansas City,United States
Muna Qayed
,
Muna Qayed
Affiliations:
Aflac Cancer and Blood Disorders Center,Emory University,Atlanta,United States
Michael A. Pulsipher
,
Michael A. Pulsipher
Affiliations:
Division of Hematology Oncology/Blood and Marrow Transplant,Children's Hospital Los Angeles, USC Keck School of Medicine,Los Angeles,United States
Barbara De Moerloose
,
Barbara De Moerloose
Affiliations:
Department of Pediatric Hematology-Oncology and Stem Cell Transplantation,Ghent University Hospital,Ghent,Belgium;Cancer Research Institute Ghent (CRIG),Ghent,Belgium
Hidefumi Hiramatsu
,
Hidefumi Hiramatsu
Affiliations:
Department of Pediatrics,Graduate School of Medicine Kyoto University,Kyoto,Japan
Krysta Schlis
,
Krysta Schlis
Affiliations:
Department of Pediatrics,Stanford University School of Medicine,Stanford,United States
Kara Davis
,
Kara Davis
Affiliations:
Lucile Packard Children's Hospital Stanford,Palo Alto,United States
Paul L. Martin
,
Paul L. Martin
Affiliations:
Division of Pediatric Blood and Marrow Transplant,Duke University Medical Center,Durham,United States
Eneida Nemecek
,
Eneida Nemecek
Affiliations:
Oregon Health & Science University,Portland,United States
Christina Peters
,
Christina Peters
Affiliations:
Stem Cell Transplantation Unit,St. Anna Children's Hospital,Vienna,Austria
Patricia Wood
,
Patricia Wood
Affiliations:
Novartis Pharmaceuticals Corporation,East Hanover,United States
Tetiana Taran
,
Tetiana Taran
Affiliations:
Novartis Pharmaceuticals Corporation,East Hanover,United States
Karen Thudium Mueller
,
Karen Thudium Mueller
Affiliations:
Novartis Pharmaceuticals Corporation,East Hanover,United States
Yiyun Zhang
,
Yiyun Zhang
Affiliations:
Novartis Pharmaceuticals Corporation,East Hanover,United States
Susana Rives
Susana Rives
Affiliations:
Hospital Sant Joan de Déu,Barcelona,Spain
(Abstract release date: 05/18/17) EHA Library. A. Grupp S. 06/24/17; 181763; S476
Stephan A. Grupp
Stephan A. Grupp
Contributions
PDF Abstract
Abstract

Abstract: S476

Type: Oral Presentation

Presentation during EHA22: On Saturday, June 24, 2017 from 16:00 - 16:15

Location: Hall E

Background
The CD19-targeted chimeric antigen receptor (CAR) T-cell therapy CTL019, an investigational therapy that reprograms cytotoxic T cells to eliminate target cells, resulted in high response rates and a manageable safety profile in pediatric/young adult patients (pts) with R/R B-cell ALL in a single-center trial.

Aims
We report an updated interim analysis from the first multicenter global pivotal registration trial of a CAR T-cell therapy (ELIANA; NCT02435849) including data for 68 pts infused with CTL019, 50 of whom were followed for ≥6 mo.

Methods
This is a single-arm, open-label, multicenter, global, phase 2 study of CTL019 in pediatric/young adult pts with CD19+ R/R B-cell ALL with ≥5% bone marrow lymphoblasts by morphology. CTL019 was manufactured from leukapheresed autologous peripheral blood T cells at a centralized manufacturing facility. The primary endpoint was overall remission rate (complete remission [CR] + CR with incomplete blood count recovery [CRi]) within 3 mo. Secondary endpoints included duration of remission (DOR), overall survival, safety, and cellular kinetics.

Results

As of November 2016, 88 pts were enrolled. There were 7 (8%) manufacturing failures, 9 (10%) pts were not infused due to death or adverse events (AEs), and 4 pts (5%) were pending infusion at the time of data cutoff. Following lymphodepleting chemotherapy in most pts (fludarabine/cyclophosphamide [n=64]) or other [n=1]), 68 pts were infused with a single dose of CTL019 (median dose, 3.0×106 [range, 0.2-5.4×106] transduced CTL019 cells/kg), with a median study follow-up of 6.4 mo. Median age was 12 y (range, 3-23 y); 59% of pts had prior allogeneic stem cell transplant (alloSCT). Five infused patients had not reached 3 mo of follow-up; among 63 evaluable pts, 52 (83% [95% CI, 71%-91%]) achieved CR/CRi within 3 mo of CTL019 infusion, all of whom had minimal residual disease–negative marrow. The relapse-free probability at 6 mo after remission onset was 75% (95% CI, 57%-87%; median DOR not reached). The probability of survival was 89% (95% CI, 77%-94%) at 6 mo and 79% (95% CI, 63%-89%) at 12 mo. Seven pts (13% of responders) proceeded to alloSCT within 6 months while in remission. Cytokine release syndrome (CRS) was graded using the UPenn scale and managed using a protocol-specific algorithm; CRS occurred in 78% of pts (21% grade 3; 27% grade 4); no CRS-associated deaths occurred. 38% of pts received tocilizumab for treatment of CRS with or without other anti-cytokine therapy. Most common grade 3/4 nonhematologic AEs (>15%) other than CRS were hypotension (22%), hypoxia (18%), and increased aspartate aminotransferase (16%). The incidence of serious AEs within 8 weeks of infusion was 69%. 15% of pts experienced grade 3 neuropsychiatric AEs, with no grade 4 events and no cerebral edema reported. Grade 3/4 neutropenia with high (>38.3˚C) fever occurred in 60% of pts. 2 pts died within 30 days of infusion (ALL progression, n=1; cerebral hemorrhage, n=1), and 9 pts died >30 days after infusion (ALL relapse/progression, n=6; HHV-6 encephalitis, pneumonia, systemic mycosis, n=1 each). CTL019 expansion in vivo correlated with CRS severity, and persistence of CTL019 along with B-cell aplasia in peripheral blood was observed for ≥1 year in some responders.

Conclusion
The ELIANA study confirmed the efficacy of a single infusion of CTL019, without additional therapy, observed in a previous interim analysis and a prior single-center CTL019 trial. AEs were effectively and reproducibly managed globally by appropriately trained personnel at study sites.

Session topic: 2. Acute lymphoblastic leukemia - Clinical

Keyword(s): Acute lymphoblastic leukemia

Abstract: S476

Type: Oral Presentation

Presentation during EHA22: On Saturday, June 24, 2017 from 16:00 - 16:15

Location: Hall E

Background
The CD19-targeted chimeric antigen receptor (CAR) T-cell therapy CTL019, an investigational therapy that reprograms cytotoxic T cells to eliminate target cells, resulted in high response rates and a manageable safety profile in pediatric/young adult patients (pts) with R/R B-cell ALL in a single-center trial.

Aims
We report an updated interim analysis from the first multicenter global pivotal registration trial of a CAR T-cell therapy (ELIANA; NCT02435849) including data for 68 pts infused with CTL019, 50 of whom were followed for ≥6 mo.

Methods
This is a single-arm, open-label, multicenter, global, phase 2 study of CTL019 in pediatric/young adult pts with CD19+ R/R B-cell ALL with ≥5% bone marrow lymphoblasts by morphology. CTL019 was manufactured from leukapheresed autologous peripheral blood T cells at a centralized manufacturing facility. The primary endpoint was overall remission rate (complete remission [CR] + CR with incomplete blood count recovery [CRi]) within 3 mo. Secondary endpoints included duration of remission (DOR), overall survival, safety, and cellular kinetics.

Results

As of November 2016, 88 pts were enrolled. There were 7 (8%) manufacturing failures, 9 (10%) pts were not infused due to death or adverse events (AEs), and 4 pts (5%) were pending infusion at the time of data cutoff. Following lymphodepleting chemotherapy in most pts (fludarabine/cyclophosphamide [n=64]) or other [n=1]), 68 pts were infused with a single dose of CTL019 (median dose, 3.0×106 [range, 0.2-5.4×106] transduced CTL019 cells/kg), with a median study follow-up of 6.4 mo. Median age was 12 y (range, 3-23 y); 59% of pts had prior allogeneic stem cell transplant (alloSCT). Five infused patients had not reached 3 mo of follow-up; among 63 evaluable pts, 52 (83% [95% CI, 71%-91%]) achieved CR/CRi within 3 mo of CTL019 infusion, all of whom had minimal residual disease–negative marrow. The relapse-free probability at 6 mo after remission onset was 75% (95% CI, 57%-87%; median DOR not reached). The probability of survival was 89% (95% CI, 77%-94%) at 6 mo and 79% (95% CI, 63%-89%) at 12 mo. Seven pts (13% of responders) proceeded to alloSCT within 6 months while in remission. Cytokine release syndrome (CRS) was graded using the UPenn scale and managed using a protocol-specific algorithm; CRS occurred in 78% of pts (21% grade 3; 27% grade 4); no CRS-associated deaths occurred. 38% of pts received tocilizumab for treatment of CRS with or without other anti-cytokine therapy. Most common grade 3/4 nonhematologic AEs (>15%) other than CRS were hypotension (22%), hypoxia (18%), and increased aspartate aminotransferase (16%). The incidence of serious AEs within 8 weeks of infusion was 69%. 15% of pts experienced grade 3 neuropsychiatric AEs, with no grade 4 events and no cerebral edema reported. Grade 3/4 neutropenia with high (>38.3˚C) fever occurred in 60% of pts. 2 pts died within 30 days of infusion (ALL progression, n=1; cerebral hemorrhage, n=1), and 9 pts died >30 days after infusion (ALL relapse/progression, n=6; HHV-6 encephalitis, pneumonia, systemic mycosis, n=1 each). CTL019 expansion in vivo correlated with CRS severity, and persistence of CTL019 along with B-cell aplasia in peripheral blood was observed for ≥1 year in some responders.

Conclusion
The ELIANA study confirmed the efficacy of a single infusion of CTL019, without additional therapy, observed in a previous interim analysis and a prior single-center CTL019 trial. AEs were effectively and reproducibly managed globally by appropriately trained personnel at study sites.

Session topic: 2. Acute lymphoblastic leukemia - Clinical

Keyword(s): Acute lymphoblastic leukemia

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