Optimizing Chimeric Antigen Receptor T-Cell Therapy for Adults With Acute Lymphoblastic Leukemia

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 Leukemia

The 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. Frey

Consulting or Advisory Role: Novartis, Kite Pharma, Gilead

Research Funding: Novartis

Pamela A. Shaw

Patents, 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. Hexner

Research Funding: Blueprint Medicines (Inst), Tmunity Therapeutics (Inst)

Edward Pequignot

Patents, 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 Gill

Stock 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. Luger

Honoraria: 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. Mangan

Consulting or Advisory Role: Agios

Alexander E. Perl

Honoraria: 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. Maude

Consulting or Advisory Role: Novartis, Kite Pharma

Travel, Accommodations, Expenses: Novartis, Kite Pharma

Stephan A. Grupp

Consulting 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. Shah

Stock 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. Lacey

Research 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. Melenhorst

Consulting 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. Levine

Stock 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. June

Stock 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. Porter

Employment: 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.

Figures

FIG 1.

Flow diagram for adult patients with acute lymphoblastic leukemia treated with CTL019. CR, complete remission; CRS, cytokine release syndrome; NR, no response; HDF, high-dose fractionated; LD, low dose; HDS, high-dose single infusion.

FIG 2.

Kaplan-Meier graphs of overall survival (OS) and event-free survival (EFS). (A) OS by cohort. (B) EFS by cohort. (C) OS for complete responders. (D) EFS for complete responders. (E) Landmark analysis for OS by subsequent allogeneic hematopoietic stem-cell transplantation (HSCT). (F) Landmark analysis for EFS by subsequent allogeneic HSCT. HDF, high-dose fractionated; HDS, high-dose single infusion; LD, low dose.