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. 

In This Article

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.

Conclusion: The combination regimen of obinutuzumab, ibrutinib, and venetoclax offers time-limited treatment that results in deep remissions and is now being studied in phase III cooperative group trials.

Introduction

Targeted agents have transformed the way chronic lymphocytic leukemia (CLL) is treated. These agents have superior treatment outcomes with decreased toxicity compared with chemoimmunotherapy and are particularly important for cytogenetically high-risk patients.[1–7] They also hold the potential for combination regimens that result in high rates of deep remission, allowing for time-limited treatment without cytotoxic chemotherapy. To investigate this, we designed and tested a novel fixed-duration triplet combination of obinutuzumab, ibrutinib, and venetoclax and studied it in both patients with treatment-naïve (TN) and relapsed or refractory (RR) CLL.

Ibrutinib is an inhibitor of Bruton's tyrosine kinase (BTK) in the B-cell receptor signaling cascade, and venetoclax inhibits B-cell lymphoma protein 2 (Bcl-2) interaction with select BH3 domain proteins, thereby promoting apoptosis. Both agents have superior progression-free survival (PFS) when compared with chemoimmunotherapy.[1–6] They have complementary mechanisms of action in preclinical testing with overlapping toxicities limited to cytopenias, making them suitable for combination.[1,6,8–11] An anti-CD20 monoclonal antibody was also included because these agents have consistently improved outcomes when combined with chemotherapy.[12,13] Obinutuzumab was chosen because it has superior efficacy and higher rates of achieving undetectable minimal residual disease (MRD) compared with rituximab.[14,15]

Treatment was given for a total of 14 cycles (28 days each) and then stopped. The 3 agents were introduced sequentially, with obinutuzumab in cycle 1, ibrutinib in cycle 2, and venetoclax in cycle 3. This allowed for maximal safety because obinutuzumab and ibrutinib reduced the disease burden and thus tumor lysis syndrome (TLS) risk before venetoclax was started.[9]

A phase IB study with this regimen was completed with 12 patients and was tolerable with preliminary evidence of efficacy. The overall response rate (ORR) was 92%, and 3 of 12 patients achieved complete remission (CR) with undetectable MRD.[16]

We then conducted this phase II study in separate cohorts of TN and RR patients with a primary end point of MRD-undetectable CR. We included measures of cognitive function and health-related quality of life to better understand the impact of this regimen on our patients.[17–19]

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