Optimizing Chimeric Antigen Receptor T-Cell Therapy for Adults With Acute Lymphoblastic Leukemia
Noelle V Frey, Pamela A Shaw, Elizabeth O Hexner, Edward Pequignot, Saar Gill, Selina M Luger, James K Mangan, Alison W Loren, Alexander E Perl, Shannon L Maude, Stephan A Grupp, Nirav N Shah, Joan Gilmore, Simon F Lacey, Jos J Melenhorst, Bruce L Levine, Carl H June, David L Porter, Noelle V Frey, Pamela A Shaw, Elizabeth O Hexner, Edward Pequignot, Saar Gill, Selina M Luger, James K Mangan, Alison W Loren, Alexander E Perl, Shannon L Maude, Stephan A Grupp, Nirav N Shah, Joan Gilmore, Simon F Lacey, Jos J Melenhorst, Bruce L Levine, Carl H June, David L Porter
Abstract
Purpose: The anti-CD19 chimeric antigen receptor T-cell therapy tisagenlecleucel (CTL019) has an 81% response rate in children with relapsed or chemotherapy refractory (r/r) B-cell acute lymphoblastic leukemia (ALL). Cytokine release syndrome (CRS) is a life-threatening treatment-related toxicity that limits the full therapeutic potential in adults. We report outcomes for adults with r/r ALL treated with an optimized CTL019 dosing and CRS management strategy.
Methods: Adults with r/r B-cell ALL received CTL019 in 1 of 2 trials. Patients received lymphodepletion followed by CTL019 as either a one-time infusion or fractionated infusions split over 3 days (day 1, 10%; day 2, 30%; day 3, 60%), which allowed for day 2 and day 3 doses to be held for early CRS. Total planned CTL019 dose varied with adaptive protocol modifications in response to efficacy and CRS toxicity.
Results: Thirty-five adults with r/r ALL received CTL019 in 1 of 3 dosing cohorts. The low-dose cohort (n = 9) received single or fractionated dosing and had manageable toxicity with a 33% complete remission (CR) rate. In the high-dose single infusion cohort, 3 of 6 patients with refractory CRS concurrent with culture-positive sepsis died, and 3 achieved CR. The 20 patients in the high-dose fractionated (HDF) cohort had a 90% CR rate and manageable CRS. The HDF cohort had the highest survival, with a 2-year overall survival of 73% (95% CI, 46% to 88%) and event-free survival of 49.5% (95% CI, 21% to 73%).
Conclusion: Fractionated dosing of CTL019 with intrapatient dose modification optimizes safety without compromising efficacy in adults with r/r ALL.
Trial registration: ClinicalTrials.gov NCT02030847 NCT01029366.
Conflict of interest statement
Optimizing Chimeric Antigen Receptor T-Cell Therapy for Adults With Acute Lymphoblastic LeukemiaThe following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/journal/jco/site/ifc.
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Noelle V. FreyConsulting or Advisory Role: Novartis, Kite Pharma, Gilead
Research Funding: Novartis
Pamela A. ShawPatents, Royalties, Other Intellectual Property: Patent owned by the University of Pennsylvania currently licensed to Novartis for an algorithm that predicts severe cytokine release syndrome for chimeric antigen receptor T-cell 19 therapy; receive 10% of the licensing fees
Elizabeth O. HexnerResearch Funding: Blueprint Medicines (Inst), Tmunity Therapeutics (Inst)
Edward PequignotPatents, Royalties, Other Intellectual Property: As part of the University of Pennsylvania’s role in the US Food and Drug Administration approval of chimeric antigen receptor T-cell (CAR-T) therapy and for my part as an employee of the University of Pennsylvania involved in its research in CAR-T; have received royalties of approximately $300 over the past 2 years
Saar GillStock and Other Ownership Interests: Carisma Therapeutics
Honoraria: Fate Therapeutics, Sensei Biotherapeutics, Aro Biotherapeutics
Research Funding: Novartis (Inst)
Patents, Royalties, Other Intellectual Property: Patents for chimeric antigen receptor T cells for acute myeloid leukemia
Selina M. LugerHonoraria: Pfizer, Daiichi Sankyo, Agios
Research Funding: Cyclacel (Inst), ARIAD (Inst), Onconova Therapeutics (Inst), Biosight (Inst), Roche (Inst), Genentech (Inst), Kura (Inst), Celgene (Inst)
Travel, Accommodations, Expenses: Hemedicus, PER
James K. ManganConsulting or Advisory Role: Agios
Alexander E. PerlHonoraria: Agios, Actinium Pharmaceuticals, Astellas Pharma, Daiichi Sankyo, Jazz Pharmaceuticals, Novartis, Newlink Genetics, Takeda Pharmaceuticals, AbbVie
Consulting or Advisory Role: Arog, Astellas Pharma, Actinium Pharmaceuticals, Daiichi Sankyo, AbbVie
Research Funding: Actinium Pharmaceuticals (Inst), Astellas Pharma (Inst), Bayer AG (Inst), BioMed Valley Discoveries (Inst), Daiichi Sankyo (Inst), Fujifilm (Inst), Novartis (Inst)
Travel, Accommodations, Expenses: Agios, AbbVie, Astellas Pharma, Daiichi Sankyo, Jazz Pharmaceuticals, Novartis, Newlink Genetics, Takeda Pharmaceuticals, Arog
Shannon L. MaudeConsulting or Advisory Role: Novartis, Kite Pharma
Travel, Accommodations, Expenses: Novartis, Kite Pharma
Stephan A. GruppConsulting or Advisory Role: Novartis, Jazz Pharmaceuticals, Janssen Pharmaceuticals, Cellular Biomedicine Group, TCR2 Therapeutics, Humanigen, Roche, Vertex, Adaptimmune
Research Funding: Novartis, Kite Pharma, Gilead, SERVIER
Nirav N. ShahStock and Other Ownership Interests: Exelixis, Oncosec, Geron, Cidara Therapeutics, Cell Vault
Consulting or Advisory Role: Jazz Pharmaceuticals, Kite Pharma, Incyte, Juno Therapeutics, Celgene
Research Funding: Miltenyi Biotec
Travel, Accommodations, Expenses: Miltenyi Biotec
Simon F. LaceyResearch Funding: Novartis (Inst), Tmunity (Inst)
Patents, Royalties, Other Intellectual Property: Patents and intellectual property related to chimeric antigen receptor T-cell technology licensed to Novartis (Inst)
Jos J. MelenhorstConsulting or Advisory Role: Shanghai Unicar Therapy, Simcere of America, IASO Biotherapeutics
Research Funding: Novartis (Inst), Incyte (Inst)
Patents, Royalties, Other Intellectual Property: Dr. Melenhorst is a patent inventor for CTL019
Bruce L. LevineStock and Other Ownership Interests: Tmunity Therapeutics
Honoraria: Novartis, Terumo, Sysmex, Draper, AstraZeneca
Consulting or Advisory Role: Brammer Bio, Avectas, CRC Oncology, Cure Genetics, Ori Biotech, Vycellix
Research Funding: Novartis, Tmunity Therapeutics
Patents, Royalties, Other Intellectual Property: Intellectual property and patents in the field of cell and gene therapy
Travel, Accommodations, Expenses: GE Healthcare, BrammerBio, Avectas, CRC Oncology
Carl H. JuneStock and Other Ownership Interests: Celldex, Tmunity Therapeutics, Cabaletta, Carisma Therapeutics, Cytosen
Honoraria: Novartis, Pfizer, Johnson & Johnson
Consulting or Advisory Role: Celldex, Viracta Therapeutics, Cabaletta, Carisma Therapeutics, Kiadis Pharma, WIRB-Copernicus Group, Janssen Oncology
Research Funding: Novartis, Tmunity Therapeutics
Patents, Royalties, Other Intellectual Property: Intellectual property licensed to Novartis, royalties paid to the University of Pennsylvania; Office of Naval Research, intellectual property and patent royalties; intellectual property licensed to Tmunity Therapeutics (Inst)
David L. PorterEmployment: Genentech (I), Roche (I)
Stock and Other Ownership Interests: Genentech (I), Roche (I)
Consulting or Advisory Role: Novartis, Kite Pharma, Incyte, Gerson Lehrman Group, Bellicum Pharmaceuticals, Glenmark
Research Funding: Novartis
Patents, Royalties, Other Intellectual Property: Dr. Porter is a patent inventor for CTL019
Travel, Accommodations, Expenses: Kite Pharma, Novartis
Other Relationship: National Marrow Donor Program, American Board of Internal Medicine
No other potential conflicts of interest were reported.
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Source: PubMed