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

Table 1.  Dosing Cohorts (N=35)

Cohort	No. of Patients	Maximum CTL019 Cell Dose	Schedule	Fractionated Dosing, %
High-dose single infusion	6	5 × 108	Single	Day 1: 10
Low dose	9	5 × 107	Single/fractionated	Day 2a: 30
High-dose fractionated	20	5 × 108	Fractionated	Day 3a: 60

^aDay 2 and/or day 3 dosing held for early signs of cytokine release syndrome.

Table 2.  Patient Demographics and Baseline Characteristics

Characteristic	All Patients, No. (%)	Cohort, No. (%)
		HDS	LD	HDF
No. of patients	35	6	9	20
Median age at infusion, years (range)	33.8 (20.6–70.4)	53.6 (25.3–63.6)	28.2 (21.2–66.7)	35.5 (20.6–70.4)
Sex
Female	11 (31)	3 (50)	2 (22)	6 (30)
Male	24 (69)	3 (50)	7 (78)	14 (70)
Prior allogeneic transplantation	13 (37)	3 (50)	5 (56)	5 (25)
Prior blinatumomab	11 (31)	0 (0)	4 (44)	7 (35)
Primary refractory disease	11 (31)	1 (17)	1 (11)	9 (45)
Prior lines of therapy
1–2	12 (34)	2 (33)	2 (22)	8 (40)
3–4	13 (37)	2 (33)	3 (33)	8 (40)
≥ 5	10 (29)	2 (33)	4 (44)	4 (20)
Baseline disease burden
≤ 5	2 (6)	0	0	2 (10)
5–50	9 (26)	1 (17)	4 (44)	4 (20)
≥ 50	18 (51)	4 (67)	5 (56)	9 (45)
Unknown	6 (17)	1 (17)	0	5 (25)
BCR-ABL positivea	3 (9)	1	2	0

Abbreviations: HDF, high-dose fractionated; HDS, high-dose single infusion; LD, low dose.
^a BCR-ABL positivity was defined as detectable transcript from a qualitative or quantitative assay.

Table 3.  Outcomes by Cohort

Outcome	All (N = 35)	Cohort			P a
		HDS (n = 6)	LD (n = 9)	HDF (n = 20)
Day 28 response
CR	24 (69)	3 (50)	3 (33)	18 (90)	.0038
NR	11 (31)	3 (50)	6 (67)	2 (10)
Median survival, months (95% CI)
OS	19.1 (6.2 to NE)	3.4 (0.2 to NE)	5.7 (0.3 to 25.4)	Not reached	.0030
EFS	5.6 (2.2 to 19.4)	2.1 (0.2 to NE)	0.9 (0.3 to 5.4)	19.4 (5.1 to NE)	.0003
Two-year survival rate, % (95% CI)
OS	47 (28 to 63)	17 (0.8 to 52)	22 (3 to 51)	73 (46 to 88)
EFS	31 (15 to 49)	17 (0.8 to 52)	0 (0 to 33)b	49.5 (21 to 73)
CRS grade 4/5	6 (17)	3 (50)	2 (22)	1 (5)	.0170

NOTE. Data presented as No. (%) unless otherwise indicated.
Abbreviations: CR, complete response; CRS, cytokine release syndrome; EFS, event-free survival; HDF, high-dose fractionated; HDS, high-dose single infusion; LD, low dose; NE, not estimable; NR, no response; OS, overall survival.
^aFor the survival end points, the log-rank test statistic compares the OS and EFS across dose groups; for proportions, Fisher's exact test P value is provided.
^bThe rule of three was used to estimate the 95% CI for a 0% success rate.¹⁵

Table A1.  Penn Grading System for CRS

Grade	Description
1	Mild reaction: treated with supportive care, such as antipyretics and antiemetics
2	Moderate: IV therapies required or parenteral nutrition; some signs of organ dysfunction (ie, grade 2 creatinine or grade 3 liver function tests) related to CRS and not attributable to any other condition; hospitalization for management of CRS-related symptoms, including fevers with associated neutropenia
3	More severe reaction: hospitalization required for management of symptoms related to organ dysfunction, including grade 4 liver function tests or grade 3 creatinine related to CRS and not attributable to any other conditions; excludes management of fever or myalgias; includes hypotension treated with IV fluids or low-dose pressors, coagulopathy requiring FFP or cryoprecipitate, and hypoxia requiring supplemental O2 (nasal cannula O2, high-flow O2, CPAP, or BiPAP); patients admitted for management of suspected infection as a result of fevers and/or neutropenia may have grade 2 CRS
4	Life-threatening complications such as hypotension requiring high-dose pressors and hypoxia requiring mechanical ventilation
5	Death

Abbreviations: BiPAP, bilevel positive airway pressure; CPAP, continuous positive airway pressure; CRS, cytokine release syndrome; FFP, fresh frozen plasma; IV, intravenous.

Authors and Disclosures

Noelle V. Frey, MD¹, Pamela A. Shaw, PhD², Elizabeth O. Hexner, MD¹, Edward Pequignot, MS², Saar Gill, MD, PhD¹, Selina M. Luger, MD¹, James K. Mangan, MD, PhD¹, Alison W. Loren, MD¹, Alexander E. Perl, MD¹, Shannon L. Maude, MD, PhD³, Stephan A. Grupp, MD, PhD³, Nirav N. Shah, MD⁴, Joan Gilmore, BS⁵, Simon F. Lacey, PhD⁵, Jos J. Melenhorst, PhD⁵, Bruce L. Levine, PhD⁵, Carl H. June, MD⁵ and David L. Porter, MD<sup>1

1</sup>Division of Hematology Oncology, Abramson Cancer Center, Cell Therapy and Transplant, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA
²Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA
³Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA
⁴Medical College of Wisconsin, Milwaukee, WI
⁵Department of Pathology and Laboratory Medicine, Center for Cellular Immunotherapy, University of Pennsylvania Perlman School of Medicine, Philadelphia, PA

Corresponding Author
Noelle V. Frey, MD, Hospital of the University of Pennsylvania, 2 PCAM South, 3400 Civic Center Blvd, Philadelphia, PA 19104; e-mail: noelle.frey@uphs.upenn.edu.

Authors' Disclosures of Potential Conflicts of Interest and Data Availability Statement
Disclosures provided by the authors and data availability statement (if applicable) are available with this article at DOI https://doi.org/10.1200/JCO.19.01892.

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.

Author Contributions
Conception and design: Noelle V. Frey, Edward Pequignot, Saar Gill, Shannon L. Maude, Stephan A. Grupp, Bruce L. Levine, Carl H. June, David L. Porter
Administrative support: Joan Gilmore
Provision of study material or patients: Saar Gill, Selina M. Luger, Alison W. Loren, Alexander E. Perl, Joan Gilmore, Bruce L. Levine
Collection and assembly of data: Noelle V. Frey, Elizabeth O. Hexner, Edward Pequignot, Selina M. Luger, Alison W. Loren, Alexander E. Perl, Joan Gilmore, Simon F. Lacey, Jos J. Melenhorst, Bruce L. Levine
Data analysis and interpretation: Noelle V. Frey, Pamela A. Shaw, Elizabeth O. Hexner, Edward Pequignot, Saar Gill, James K. Mangan, Alison W. Loren, Alexander E. Perl, Stephan A. Grupp, Nirav N. Shah, Simon F. Lacey, Jos J. Melenhorst, Bruce L. Levine, David L. Porter
Manuscript writing: All authors
Final approval of manuscript: All authors
Accountable for all aspects of the work: All authors