Late Addition of Obinutuzumab to Acalabrutinib/Venetoclax Maintains Responses, Boosts Safety in Treatment-Naive CLL

Findings from a phase 2 trial (NCT04169737) showed the addition of obinutuzumab (Gazyva) to acalabrutinib (Calquence) and venetoclax (Venclexta) after 1 year of therapy with the doublet produced deep responses comparable with early integration of obinutuzumab into the combination, and the late addition reduced rates of infection and neutropenia, supporting further evaluation of 1-year treatment programs for triplet regimens in chronic lymphocytic leukemia (CLL), as well as studies incorporating BTK and next-generation BCL-2 inhibitors into frontline strategies.¹

“This trial showed that bringing the third drug on later for patients with a suboptimal response to a doublet not only results in higher rates of undetectable minimal residual disease [MRD], but the rates of infection and grade 3 neutropenia are much lower,” presenting author Mahesh Swaminathan, MB, BS, shared in an interview with OncLive® at the 2025 ASH Annual Meeting and Exposition. "This opens up options for patients who need more effective treatments…without the same level of worry [about toxicity].”

In the interview, Swaminathan explained the rationale for exploring the potential effect of administering obinutuzumab earlier vs later in the treatment course; shared findings from this phase 2 trial highlighting the overall the superior efficacy of triplet vs doublet regimens in treatment-naive CLL; and discussed how the study's findings provide valuable insights into optimizing triplets for a wider patient population.

Swaminathan is an assistant professor in the Department of Leukemia at The University of Texas MD Anderson Cancer Center in Houston.

OncLive: What was the goal of this phase 2 study evaluating the late addition of ovinutuzumab to acalbrutinib plus venetoclax in treatment-naive CLL? How was the study designed?

Swaminathan:Our data came from a phase 2 clinical trial where we tried to understand if adding obinutuzumab early vs later would help patients in terms of tolerance. The primary goal of this trial was to see if giving 3 drugs—acalabrutinib, venetoclax, and obinutuzumab—could achieve deeper responses.

There were 2 cohorts totaling [84] patients. We included patients who were over 65 years [of age], as well as patients younger than 65 if they had high-risk disease characteristics. When we initially designed the [study] protocol, [high-risk] was defined as the presence of a TP53 aberration, deletion 11q, or unmutated IGHV. Deletion 11q is not always considered an adverse factor nowadays, but it was still [considered one at the time of study initiation]. The majority of patients had unmutated IGHV, correlating with what we would typically expect in the real world. These are the patients who likely need treatment sooner rather than later.

One group started with obinutuzumab [plus acalabrutinib and venetoxlax]. The other group started with just acalabrutinib and venetoclax for one year. At the end of that year, obinutuzumab was added if we saw a suboptimal response, which we defined as having a partial response on a CT scan at the end of cycle 14 or having detectable MRD in the bone marrow. A unique aspect of this design was that even patients who received early obinutuzumab could receive additional doses if their response was suboptimal at the end of 1 year.

How did safety and efficacy outcomes differ with the early vs late addition of obinutuzumab to acalabrutinib/venetoclax in a 2-year treatment course?

The goal was to see if we observed deeper responses, which is what typically happens when 3 drugs are given. We checked for undetectable MRD rates in the bone marrow. In this study, [62%] of patients [with unmutated IGHV] who received the 3 drugs for 9 cycles [n = 32] achieved undetectable MRD [status] compared with [18%] for those who received only [acalbrutinib plus venetoclax (n = 34)]. In that way, the study met its primary end point. This is not necessarily novel, as prior studies have shown that triplets lead to deeper responses.

However, we wanted to take [this research] one [step] further, because the major concern with triplets has been safety, specifically higher rates of infections and grade 3 neutropenia. We wanted to understand if [adding the third drug] later could maintain efficacy [while providing] a better safety profile. What we saw was that when obinutuzumab was added around the second year of the 2-year program, patients achieved deeper responses similar to those who had 3 drugs from the start. There was no compromise in efficacy.

Regarding safety, which was the key factor, we found that when the third drug was introduced in the second year, patients tended to tolerate it much better. The infection rates were significantly lower; for example, the grade 3 or higher infection rate in patients who received early obinutuzumab [n = 33] was [33%], whereas in those who received it later [n = 33], it was [3%]. Similarly, [grade 3 or higher[ neutropenia rates were also lower when patients received the drug during the later part of the treatment regimen [at 27% vs 54% for early administration].

How might these findings help facilitate the integration of triplets into clinical practice for treatment-naive CLL?

The point that has always worried treating physicians is the toxicity of adding more agents. Data from the [phase 3] AMPLIFY study [NCT03836261]² and [a phase 2 study (NCT03580928)] led by Matthew Davids, MD, MMSc, [of Dana-Farber Cancer Institute]³ have shown that while triplets are effective, the rates of infection and neutropenia are significant, even after the height of the COVID-19 pandemic. That's why we don't see [triplets] being widely used or considered for some patients [in clinical practice].

Other than [confirming] that [administering] 3 drugs is probably going to [have] much better efficacy [than just 2], this study showed that when we give 3 drugs to patients, it's best to do it [during] the second half of treatment if the treatment [duration is] 2 years.¹ This opens up options for patients who need more effective treatments to reach undetectable MRD without the same level of worry regarding infections and neutropenia.

What next steps are planned for research with triplet regimens in treatment-naive CLL?

Moving forward, we are looking at triplet trials where we bring on the third drug, obinutuzumab, in the later half of the study. For example, in a one-year program, we might bring the third drug [into play] after cycle 9 so patients get it for the last 6 months. That way, we can deepen responses while hopefully [avoiding] much of the toxicity. We are trying to employ that knowledge in clinical trials coming in the near future.

There are very good treatment options already available as part of the standard of care now, and more clinical trials are focusing on trying to bring these newer drugs, especially BTK degraders, into combination [regimens]. If not, maybe one could [explore regimens incorporating] the second generation of BCL-2 inhibitors.

At this point, if we have treatment-naive patients [who are] considerably higher risk because of the presence of a TP53 aberration, we tend to [use] a BTK inhibitor–based combination. With the ongoing trials in the relapsed/refractory space, these agents have already been shown to be safer and also effective. I am hoping that we will be seeing more and more of these agents coming into the first-line space, and we will be seeing these combinations that were already being tested, but in combination with a BTK degrader.

References

1. Swaminathan M, Thompson P, Burger J, et al. Addition of obinutuzumab after one year of combined acalabrutinib and venetoclax is safer and effective than early obinutuzumab in a randomized phase II trial for treatment naïve CLL. Blood. 2025; 146(suppl 1):681. doi:10.1182/blood-2025-681
2. Brown JR, Seymour JF, Jurczak W, et al. Fixed-duration acalabrutinib combinations in untreated chronic lymphocytic leukemia. N Engl J Med. 2025;392(8):748-762. doi:10.1056/NEJMoa2409804
3. Davids MS, Ryan CE, Lampson BL, et al. Phase II study of acalabrutinib, venetoclax, and obinutuzumab in a treatment-naive chronic lymphocytic leukemia population enriched for high-risk disease. J Clin Oncol. 2025;43(7):788-799. doi:10.1200/JCO-24-02503