Phase II Study of Combination Obinutuzumab, Ibrutinib, and Venetoclax in Treatment-Naïve and Relapsed or Refractory Chronic Lymphocytic Leukemia

Kerry A. Rogers, MD; Ying Huang, MA, MS; Amy S. Ruppert, PhD; Lynne V. Abruzzo, MD, PhD; Barbara L. Andersen, PhD; Farrukh T. Awan, MBBS, MS; Seema A. Bhat, MD; Allison Dean, CNP; Margaret Lucas, PA; Christin Banks, BS; Cara Grantier, APRN-CNP, MPH; Nyla A. Heerema, PhD; Gerard Lozanski, MD; Kami J. Maddocks, MD; Thomas R. Valentine, PhD; David M. Weiss, PhD; Jeffrey A. Jones, MD, MPH, MBA; Jennifer A. Woyach, MD; John C. Byrd, MD

Disclosures

J Clin Oncol. 2020;38(31):3626-3637.

Abstract and Introduction

Abstract

Purpose: The development of highly effective targeted agents for chronic lymphocytic leukemia offers the potential for fixed-duration combinations that achieve deep remissions without cytotoxic chemotherapy.

Patients and Methods: This phase II study tested a combination regimen of obinutuzumab, ibrutinib, and venetoclax for a total of 14 cycles in both patients with treatment-naïve (n = 25) and relapsed or refractory (n = 25) chronic lymphocytic leukemia to determine the response to therapy and safety.

Results:The primary end point was the rate of complete remission with undetectable minimal residual disease by flow cytometry in both the blood and bone marrow 2 months after completion of treatment, which was 28% in both groups. The overall response rate at that time was 84% in treatment-naïve patients and 88% in relapsed or refractory patients. At that time, 67% of treatment-naïve patients and 50% of relapsed or refractory patients had undetectable minimal residual disease in both the blood and marrow. At a median follow-up of 24.2 months in treatment-naïve patients and 21.5 months in relapsed or refractory patients, the median progression-free and overall survival times were not yet reached, with only 1 patient experiencing progression and 1 death. Neutropenia and thrombocytopenia were the most frequent adverse events, followed by hypertension. Grade 3 or 4 neutropenia was experienced by 66% of patients, with more events in the relapsed or refractory cohort. There was only 1 episode of neutropenic fever. A favorable impact on both perceived and objective cognitive performance during treatment was observed.

Table 1. Baseline Characteristics of Patients
Characteristic	TN Patients (n = 25)	RR Patients (n = 25)	All Patients (N = 50)
Median age, years (range)	59 (24–77)	58 (42–73)	59 (24–77)
Age ≥ 70 years, No. (%)	4 (16)	2 (8)	6 (12)
Women, No. (%)	10 (40)	9 (36)	19 (38)
Median No. of prior therapies (range)	—	1 (1–3)	—
High-risk modified Rai stage, No. (%)	17 (68)	—	—
IGHV unmutated, No. (%)^a	17 (71)	19 (79)	36 (75)
Zap-70 methylated, No. (%)^b	8 (36)	11(50)	19 (43)
Complex CLL karyotype, No. (%)^c	8 (32)	8 (33)	16 (33)
FISH panel, No. (%)^d
del(17p)(p13.1)	3 (12)	1 (4)	4 (8)
del(11q)(q22.3)	5 (20)	9 (36)	14 (28)
Trisomy 12	3 (12)	4 (16)	7 (14)
No abnormalities	9 (36)	5 (20)	14 (28)
del(13q)(q14)	5 (20)	6 (24)	11 (22)
TLS risk at baseline, No. (%)^e
Low	1 (4)	7 (28)	8 (16)
Medium	18 (72)	8 (32)	26 (52)
High	6 (24)	10 (40)	16 (32)
Baseline laboratory values, median (range)
Creatinine, mg/dL	1.1 (0.4–1.6)	1.0 (0.5–1.9)	1.1 (0.4–1.9)
Lactate dehydrogenase, U/L	230 (98–710)	223 (131–725)	226.5 (98–725)
β₂-Microglobulin, mg/L	3.3 (1.8–6.8)	3.6 (1.5–6.9)	3.5 (1.5–6.9)
WBC count, × 10³/μL	115.9 (8.4–434.5)	32.7 (3.3–366.1)	66.2 (3.3–434.5)
Absolute neutrophils, × 10³/μL	4.6 (1.1–26.0)	2.7 (0.7–27.8)	3.4 (0.7–27.8)
Absolute lymphocytes, × 10³/μL	108.7 (3.7–412.8)	28.6 (0.2–347.8)	61.9 (0.2–412.8)
Hemoglobin, g/dL	10.4 (8–13.4)	12.2 (8.7–15.5)	11.5 (8–15.5)
Platelets, × 10³/μL	166 (68–231)	132 (52–255)	135.5 (52–255)

Abbreviations: CLL, chronic lymphocytic leukemia; FISH, fluorescence in situ hybridization; RR, relapsed or refractory; TLS, tumor lysis syndrome; TN, treatment naïve.
^aTwo missing values (1 TN, 1 RR).
^bSix missing values (3 TN, 3 RR).
^cOne missing value in RR.
^dHierarchical according to risk.
^eAssessed according to US prescribing information.

Table 2. Frequent or Serious Treatment-Related Adverse Events
Adverse Event^a	No. of Patients (%)
	TN Patients (n = 25)			RR Patients (n = 25)			All Patients (N = 50)
	Grade 1–2	Grade 3–4	Any Grade	Grade 1–2	Grade 3–4	Any Grade	Grade 1–2	Grade 3–4	Any Grade
Neutrophil count decreased	9 (36)	14 (56)	23 (92)	5 (20)	19 (76)	24 (96)	14 (28)	33 (66)	47 (94)
Platelet count decreased	13 (52)	10 (40)	23 (92)	14 (56)	8 (32)	22 (88)	27 (54)	18 (36)	45 (90)
Hypertension	10 (40)	12 (48)	22 (88)	12 (48)	7 (28)	19 (76)	22 (44)	19 (38)	41 (82)
Hypocalcemia	20 (80)		20 (80)	21 (84)		21 (84)	41 (82)		41 (82)
Fatigue	20 (80)	2 (8)	22 (88)	15 (60)	2 (8)	17 (68)	35 (70)	4 (8)	39 (78)
Bruising	19 (76)		19 (76)	18 (72)		18 (72)	37 (74)		37 (74)
Infusion-related reaction	20 (80)		20 (80)	17 (68)		17 (68)	37 (74)		37 (74)
Myalgia	17 (68)		17 (68)	19 (76)		19 (76)	36 (72)		36 (72)
Hyperglycemia	17 (68)	1 (4)	18 (72)	13 (52)	2 (8)	15 (60)	30 (60)	3 (6)	33 (66)
Diarrhea	15 (60)	1 (4)	16 (64)	14 (56)	2 (8)	16 (64)	29 (58)	3 (6)	32 (64)
Hyperuricemia	13 (52)	1 (4)	14 (56)	16 (64)	2 (8)	18 (72)	29 (58)	3 (6)	32 (64)
Mucositis oral	19 (76)		19 (76)	13 (52)		13 (52)	32 (64)		32 (64)
Nausea	18 (72)		18 (72)	13 (52)		13 (52)	31 (62)		31 (62)
Weight gain	17 (68)		17 (68)	14 (56)		14 (56)	31 (62)		31 (62)
Dyspepsia	17 (68)		17 (68)	12 (48)		12 (48)	29 (58)		29 (58)
Arthralgia	14 (56)	1 (4)	15 (60)	13 (52)		13 (52)	27 (54)	1 (2)	28 (56)
Headache	14 (56)		14 (56)	11 (44)	1 (4)	12 (48)	25 (50)	1 (2)	26 (52)
AST increased	10 (40)	2 (8)	12 (48)	13 (52)		13 (52)	23 (46)	2 (4)	25 (50)
Rash, maculopapular	17 (68)		17 (68)	8 (32)		8 (32)	25 (50)		25 (50)
Constipation	15 (60)		15 (60)	9 (36)		9 (36)	24 (48)		24 (48)
Chills	13 (52)		13 (52)	10 (40)		10 (40)	23 (46)		23 (46)
Cough	12 (48)		12 (48)	11 (44)		11 (44)	23 (46)		23 (46)
Anemia	9 (36)	1 (4)	10 (40)	12 (48)		12 (48)	21 (42)	1 (2)	22 (44)
Hypokalemia	12 (48)		12 (48)	7 (28)	3 (12)	10 (40)	19 (38)	3 (6)	22 (44)
Upper respiratory infection	11 (44)		11 (44)	9 (36)	2 (8)	11 (44)	20 (40)	2 (4)	22 (44)
Hypoalbuminemia	13 (52)		13 (52)	8 (32)		8 (32)	21 (42)		21 (42)
Paresthesia	13 (52)		13 (52)	8 (32)		8 (32)	21 (42)		21 (42)
Sinusitis	7 (28)		7 (28)	13 (52)	1 (4)	14 (56)	20 (40)	1 (2)	21 (42)
Anorexia	13 (52)		13 (52)	7 (28)		7 (28)	20 (40)		20 (40)
Sinus bradycardia	9 (36)		9 (36)	11 (44)		11 (44)	20 (40)		20 (40)
Blood bilirubin increased	11 (44)		11 (44)	8 (32)		8 (32)	19 (38)		19 (38)
Dyspnea	9 (36)		9 (36)	10 (40)		10 (40)	19 (38)		19 (38)
Epistaxis	11 (44)		11 (44)	8 (32)		8 (32)	19 (38)		19 (38)
Sore throat	12 (48)		12 (48)	7 (28)		7 (28)	19 (38)		19 (38)
Back pain	11 (44)		11 (44)	7 (28)		7 (28)	18 (36)		18 (36)
Allergic rhinitis	8 (32)		8 (32)	9 (36)		9 (36)	17 (34)		17 (34)
Creatinine increased	8 (32)		8 (32)	9 (36)		9 (36)	17 (34)		17 (34)
Insomnia	11 (44)		11 (44)	6 (24)		6 (24)	17 (34)		17 (34)
Localized edema	9 (36)		9 (36)	8 (32)		8 (32)	17 (34)		17 (34)
Dizziness	9 (36)		9 (36)	6 (24)	1 (4)	7 (28)	15 (30)	1 (2)	16 (32)
ALT increased	5 (20)	1 (4)	6 (24)	9 (36)		9 (36)	14 (28)	1 (2)	15 (30)
Vomiting	7 (28)		7 (28)	8 (32)		8 (32)	15 (30)		15 (30)
Blurred vision	9 (36)		9 (36)	5 (20)		5 (20)	14 (28)		14 (28)
Dry skin	8 (32)		8 (32)	6 (24)		6 (24)	14 (28)		14 (28)
Fever	6 (24)		6 (24)	8 (32)		8 (32)	14 (28)		14 (28)
Hypoglycemia	6 (24)	1 (4)	7 (28)	7 (28)		7 (28)	13 (26)	1 (2)	14 (28)
Pain	6 (24)		6 (24)	8 (32)		8 (32)	14 (28)		14 (28)
Edema, limbs	6 (24)		6 (24)	7 (28)		7 (28)	13 (26)		13 (26)
Fall	7 (28)		7 (28)	6 (24)		6 (24)	13 (26)		13 (26)
Hypernatremia	5 (20)		5 (20)	8 (32)		8 (32)	13 (26)		13 (26)
Nail loss	6 (24)		6 (24)	7 (28)		7 (28)	13 (26)		13 (26)
Hypophosphatemia	5 (20)	1 (4)	6 (24)	4 (16)	2 (8)	6 (24)	9 (18)	3 (6)	12 (24)
Pain in extremity	4 (16)	1 (4)	5 (20)	6 (24)	1 (4)	7 (28)	10 (20)	2 (4)	12 (24)
Hyponatremia	2 (8)	2 (8)	4 (16)	3 (12)	3 (12)	6 (24)	5 (10)	5 (10)	10 (20)
Skin infection	4 (16)		4 (16)	4 (16)	1 (4)	5 (20)	8 (16)	1 (2)	9 (18)
Bronchial infection	3 (12)		3 (12)	4 (16)	1 (4)	5 (20)	7 (14)	1 (2)	8 (16)
Atrial fibrillation	2 (8)	1 (4)	3 (12)	2 (8)		2 (8)	4 (8)	1 (2)	5 (10)
Lung infection	3 (12)	1 (4)	4 (16)		1 (4)	1 (4)	3 (6)	2 (4)	5 (10)
Chest pain, cardiac	2 (8)		2 (8)	1 (4)	1 (4)	2 (8)	3 (6)	1 (2)	4 (8)
Leukocytosis		3 (12)	3 (12)		1 (4)	1 (4)		4 (8)	4 (8)
Syncope		2 (8)	2 (8)		2 (8)	2 (8)		4 (8)	4 (8)
Pneumonitis	2 (8)	1 (4)	3 (12)				2 (4)	1 (2)	3 (6)
Nervous system disorders, other, reversible cerebral vasoconstriction syndrome	1 (4)		1 (4)		1 (4)	1 (4)	1 (2)	1 (2)	2 (4)
Cataract		1 (4)	1 (4)					1 (2)	1 (2)
Cardiac disorders, other, coronary artery disease		1 (4)	1 (4)		1 (4)	1 (4)		1 (2)	1 (2)
Cardiac disorders, other, sinus node dysfunction					1 (4)	1 (4)		1 (2)	1 (2)
Cholecystitis					1 (4)	1 (4)		1 (2)	1 (2)
Colitis		1 (4)	1 (4)					1 (2)	1 (2)
Dehydration		1 (4)	1 (4)					1 (2)	1 (2)
Febrile neutropenia					1 (4)	1 (4)		1 (2)	1 (2)
Menorrhagia		1 (4)	1 (4)					1 (2)	1 (2)
Pelvic infection		1 (4)	1 (4)					1 (2)	1 (2)
Sepsis		1 (4)	1 (4)					1 (2)	1 (2)
Vasovagal reaction		1 (4)	1 (4)					1 (2)	1 (2)

Abbreviations: RR, relapsed or refractory; TN, treatment naïve.
^aOccurring in at least 25% of patients or in at least 1 patient at a severity of grade ≥ 3.

Authors and Disclosures

Kerry A. Rogers, MD^1,2, Ying Huang, MA, MS¹, Amy S. Ruppert, PhD¹, Lynne V. Abruzzo, MD, PhD³, Barbara L. Andersen, PhD⁴, Farrukh T. Awan, MBBS, MS¹, Seema A. Bhat, MD¹, Allison Dean, CNP², Margaret Lucas, PA², Christin Banks, BS², Cara Grantier, APRN-CNP, MPH², Nyla A. Heerema, PhD³, Gerard Lozanski, MD³, Kami J. Maddocks, MD¹, Thomas R. Valentine, PhD⁴, David M. Weiss, PhD⁴, Jeffrey A. Jones, MD, MPH, MBA¹, Jennifer A. Woyach, MD^1,2 and John C. Byrd, MD^1,2

¹Division of Hematology, The Ohio State University, Columbus, OH
²The Ohio State University Comprehensive Cancer Center, Columbus, OH
³Department of Pathology, The Ohio State University, Columbus, OH
⁴Department of Psychology, The Ohio State University, Columbus, OH

Corresponding Author
Kerry A. Rogers, MD, The Ohio State University, 410 W 12th Ave, Wiseman Hall, CCC Rm 458, Columbus, OH 43210; e-mail: kerry.rogers@osumc.edu.

Author Contributions
Conception and design: Kerry A. Rogers, Ying Huang, Amy S. Ruppert, Barbara L. Andersen, Jeffrey A. Jones, John C. Byrd
Administrative support: Christin Banks
Provision of study materials or patients: Kerry A. Rogers, Barbara L. Andersen, Farrukh T. Awan, Seema A. Bhat, Allison Dean, Margaret Lucas, Cara Grantier, Kami J. Maddocks, Jeffery A. Jones, Jennifer A. Woyach, John C. Byrd
Collection and assembly of data: Kerry A. Rogers, Amy S. Ruppert, Ying Huang, Lynne V. Abruzzo, Farrukh T. Awan, Allison Dean, Margaret Lucas, ChristinBanks, Cara Grantier, Nyla A. Heerema, Gerard Lozanski, Kami J. Maddocks, Thomas R. Valentine, David M. Weiss, Jennifer A. Woyach, John C. Byrd
Data analysis and interpretation: Kerry A. Rogers, Ying Huang, Amy S. Ruppert, Barbara L. Andersen, Thomas R. Valentine, David M. Weiss, Jeffrey A. Jones, Jennifer A. Woyach, John C. Byrd
Manuscript writing: All authors
Final approval of manuscript: All authors
Accountable for all aspects of the work: All authors

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.20.00491.

Phase II Study of Combination Obinutuzumab, Ibrutinib, and Venetoclax in Treatment-Naïve and Relapsed or Refractory Chronic Lymphocytic 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/jco/authors/author-center.
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Kerry A. Rogers
Consulting or Advisory Role: Acerta Pharma, AstraZeneca, Pharmacyclics, AbbVie
Research Funding: Genentech (Inst), AbbVie (Inst), Janssen (Inst)
Travel, Accommodations, Expenses: AstraZeneca

Lynne V. Abruzzo
Patents, Royalties, Other Intellectual Property: Royalties from a licensing agreement for a patent held by the University of Maryland

Farrukh T. Awan
Consulting or Advisory Role: Novartis, Gilead Sciences, AstraZeneca, Janssen Oncology, AbbVie, Genentech, Celgene, Pharmacyclics, Sunesis Pharmaceuticals, Blueprint Medicines, DAVA Pharmaceuticals, Medscape, Clinical Care Options, MEI Pharma, Verastem, Karyopharm Therapeutics
Speakers' Bureau: AstraZeneca, AbbVie
Research Funding: Innate Pharma, Pharmacyclics

Seema A. Bhat
Consulting or Advisory Role: Janssen

Cara Grantier
Consulting or Advisory Role: Pharmacyclics/Janssen

Gerard Lozanski
Research Funding: Genentech (Inst)

Kami J. Maddocks
Honoraria: Pharmacyclics, Bayer, Novartis, Teva, Celgene, Seattle Genetics, Morposys
Research Funding: Pharmacyclics, Merck, Bristol-Myers Squibb

Jeffrey A. Jones
Employment: Celgene, Bristol-Myers Squibb
Stock and Other Ownership Interests: Celgene, Bristol-Myers Squibb

Jennifer A. Woyach
Consulting or Advisory Role: Pharmacyclics, Janssen, AstraZeneca, ArQule
Research Funding: Janssen, Karyopharm Therapeutics, MorphoSys, Verastem, Loxo, AbbVie

John C. Byrd
Honoraria: Pharmacyclics, AstraZeneca, Novartis, Syndex, Trillium Therapeutics
Consulting or Advisory Role: Acerta Pharma, Pharmacyclics, Genentech, Jazz Pharmaceuticals
Research Funding: Acerta Pharma (Inst), Pharmacyclics (Inst)

No other potential conflicts of interest were reported.