AN UPDATED ANALYSIS OF TISAGENLECLEUCEL IN PEDIATRIC/YOUNG ADULT PATIENTS WITH RELAPSED/REFRACTORY (R/R) B-CELL ACUTE LYMPHOBLASTIC LEUKEMIA (B-ALL) IN A US MULTICENTER CLINICAL TRIAL (ENSIGN)
Author(s): ,
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
,
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
,
Rajen Mody
Affiliations:
Pediatric Phase-I and Experimental Therapeutics Program, Michigan Medicine,Ann Arbor,United States
,
Timothy Driscoll
Affiliations:
Division of Pediatric Blood and Marrow Transplant,Children’s Health Center, Duke University Medical Center,Durham,United States
,
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
,
Muna Qayed
Affiliations:
Aflac Cancer and Blood Disorders Center, Emory University,Atlanta,United States
,
Stella Davies
Affiliations:
Cincinnati Children’s Hospital Medical Center,Cincinnati,United States
,
Christine L. Phillips
Affiliations:
Division of Oncology, Department of Pediatrics,Cincinnati Children’s Hospital Medical Center,Cincinnati,United States
,
Gary Douglas Myers
Affiliations:
Children’s Mercy Hospital Kansas City,Kansas City,United States
,
Keith J. August
Affiliations:
Children’s Mercy Hospital Kansas City,Kansas City,United States
,
Michael A. Pulsipher
Affiliations:
Division of Hematology, Oncology, and Blood and Marrow Transplantation,Children’s Hospital Los Angeles, Keck School of Medicine of USC,Los Angeles,United States
,
Michael W. Boyer
Affiliations:
Department of Pediatrics and Internal Medicine,University of Utah,Salt Lake City,United States
,
Michael R. Verneris
Affiliations:
Division of Pediatric Blood and Marrow Transplant,University of Minnesota,Minneapolis,United States
,
Kara L. Davis
Affiliations:
Department of Pediatrics,Stanford University School of Medicine,Stanford,United States
,
Christian M. Capitini
Affiliations:
Department of Pediatrics,University of Wisconsin,Madison,United States
,
Eneida Nemecek
Affiliations:
Oregon Health & Science University,Portland,United States
,
Carl H. June
Affiliations:
Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania,Philadelphia,United States;Department of Pathology and Laboratory Medicine,Perelman School of Medicine, University of Pennsylvania,Philadelphia,United States
,
Lan Yi
Affiliations:
Novartis Pharmaceuticals Corporation,East Hanover,United States
,
Mariana Cota
Affiliations:
Novartis Pharmaceuticals Corporation,East Hanover,United States
,
Mimi Leung
Affiliations:
Novartis Pharmaceuticals Corporation,East Hanover,United States
John E. Levine
Affiliations:
University of Michigan,Ann Arbor,United States;Icahn School of Medicine at Mount Sinai,New York,United States
EHA Library. Maude S. Jun 15, 2018; 214670; PF174
Dr. Shannon Maude
Dr. Shannon Maude
Contributions
Abstract

Abstract: PF174

Type: Poster Presentation

Presentation during EHA23: On Friday, June 15, 2018 from 17:30 - 19:00

Location: Poster area

Background
Tisagenlecleucel, an autologous T-cell product expressing a CD19-specific chimeric antigen receptor (CAR), demonstrated a high rate of durable responses and manageable safety profile in a single-center phase 1/2a trial in pediatric/young adult patients (pts) with r/r B-ALL.

Aims
To establish safety and efficacy of tisagenlecleucel for transfer from an academic to a centralized industry-based manufacturing process, a multicenter phase 2 trial (ENSIGN; NCT02228096) was initiated.

Methods
13 US sites participated. Leukapheresis products were shipped for centralized manufacturing by the University of Pennsylvania for the first 26 pts or Novartis for subsequent pts. Following lymphodepletion with fludarabine and cyclophosphamide, a single dose of tisagenlecleucel cells was administered (dose range: ≤50 kg, 2.0-5.0x106 cells/kg; >50 kg, 1.0-2.5x108 cells). The primary endpoint was overall remission (ORR=complete remission [CR]+ CR with incomplete blood count recovery [CRi] maintained for ≥28 d) ≤6 mo after infusion. Efficacy analyses were performed on pts who completed 6 mo follow-up or discontinued earlier; OS and safety were evaluated for all infused pts.

Results
At data cutoff (6 Oct 2017) 58/73 enrolled pts (79%) were infused with tisagenlecleucel, 42 completed 6 mo follow-up, 11 withdrew prior to infusion (5 product related issues; 6 deaths), 4 were pending infusion. 3 pts did not receive lymphodepleting chemotherapy due to leukopenia. Median time from enrollment to infusion, 41 d. Median time from infusion to data cutoff, 19.6 mo. Median infused dose was 3.55x106 (range, 0.2-5.0x106) CAR+ transduced viable T cells/kg; 49/58 (84%) infused pts were within and 9 below the dose range. 

The ORR was 69% (29/42 evaluable pts; 95% CI 52.9, 82.4). 13 pts did not achieve CR/CRi (6 did not achieve remission, 3 relapsed <28 days after remission onset, 2 were not evaluable [proceeded to SCT shortly after remission onset without subsequent response assessment], 2 died before day 28 [1 ALL; 1 embolic stroke]). Of 29 pts in CR/CRi, 27 (93%) were minimal residual disease-negative (<0.01%) by multiparameter flow cytometry. Relapse-free survival at 6 and 12 mo was 71% (95% CI, 48.5-85.5) and 61% (95% CI, 38-78); median duration of remission was not reached. Overall survival for all infused pts at 6 and 12 mo was 79% (95% CI, 65-88) and 63% (95% CI, 46-76); median, 23.8 mo (95% CI, 9-NE). Tisagenlecleucel was detected in peripheral blood for up to 764 d.

17 infused pts died >30 days after infusion (16 ALL; 1 complication of transplant); no deaths were attributed to tisagenlecleucel. The most common adverse event was cytokine release syndrome (CRS; all grade [G], 81%; G 3 or 4, 33%; graded on the Penn scale). For CRS treatment, 13 pts (22%) had systemic anti-cytokine therapy, 14 (24%) had high dose vasopressors for hypotension, 6 (10%) had intubation, and 4 (7%) had dialysis. No deaths were attributed to CRS. Neurological events occurred in 19 pts (32.8%; 4 G 3; no G 4; all reversible), including seizures in 3 pts; there were no cases of cerebral edema. Efficacy and safety were consistent across manufacturing processes.

Conclusion
In this first multicenter trial, tisagenlecleucel showed a high ORR with durable remissions in pediatric/young adult pts with r/r B-ALL. CRS was effectively managed with a protocol-specific algorithm by appropriately trained site staff. ENSIGN was instrumental in establishing transfer from an academic to a centralized industry-based manufacturing process, and laid the foundation for the larger global ELIANA trial.

Session topic: 2. Acute lymphoblastic leukemia - Clinical

Keyword(s): B cell acute lymphoblastic leukemia, Targeted therapy

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