Frontline Ibrutinib/Venetoclax Elicits Durable Responses in CLL With Undetectable MRD

Fixed-duration ibrutinib (Imbruvica) plus venetoclax (Venclexta) produced superior progression-free survival (PFS) when compared with chlorambucil plus obinutuzumab (Gazyva) in the frontline treatment of patients with chronic lymphocytic leukemia (CLL), with durable responses observed in those who achieved undetectable minimal residual disease (MRD) negativity, according to Paolo Ghia, MD, PhD.

Results from the phase 3 GLOW trial (NCT03462719) showed that at a median follow-up of 28 months, ibrutinib/venetoclax was found to reduce the risk of progression or death by 78% vs chlorambucil/obinutuzumab (HR, 0.216; 95% CI, 0.131-0.357). The investigative doublet also resulted in significantly higher MRD rates vs the control regimen in the bone marrow, at 51.9% vs 17.1%, respectively (P <.0001); the rates in the peripheral blood were 54.7% and 39.0%, respectively (P = .0259).

“What is interesting is the durability of responses [observed] in those patients who achieved undetectable MRD,” Ghia said. “At 12 months after the end of the treatment, approximately 85% of those patients maintained undetectable MRD status.”

In an interview with OncLive®, Ghia, a professor of Medical Oncology and the director of the Strategic Research Program on CLL and the B Cell Neoplasia Unit at Università Vita-Salute San Raffaele University, discussed results from the GLOW trial examining frontline ibrutinib/venetoclax in patients with CLL and next steps for research with the regimen.

OncLive®: Could you provide the rationale and design of the phase 3 GLOW study?

Ghia: GLOW is a phase 3 international study where treatment-naïve patients with CLL were randomized to [receive] either the combination of ibrutinib plus venetoclax, or standard-of-care treatment with chlorambucil plus obinutuzumab. The population was made up of elderly patients, older than 65 years of age, or younger patients with comorbidities.

The rationale is [supported by] the fact that we want to move away from [single-agent] chemotherapy in elderly patients with CLL, who represent the vast majority of those affected by the disease. [Additionally], we want to preserve the benefit of a fixed-duration treatment. The experimental arm, which is evaluating the combination of the BTK inhibitor ibrutinib and the BCL-2 inhibitor venetoclax, [is given] for 12 cycles, or approximately 12 months. The combination is preceded by 3 months of ibrutinib alone to debulk the patient and decrease the risk of tumor lysis syndrome when adding venetoclax.

What were the main takeaways from this study?

The combination of ibrutinib plus venetoclax in elderly patients with CLL [was found to be] very effective. We were able to achieve undetectable MRD in the peripheral blood in more than 80% of patients at any time during the treatment. [The rate of MRD negativity proved to be very similar] in the bone marrow, at approximately 70%. As such, this is suggestive of deep responses.

What did the safety look like with the combination in this population?

Aside from the high efficacy [observed with] the treatment, we found that the [regimen] was [also] well tolerated. Only a low number of patients had to discontinue the drug, and the adverse effects [AEs] were as expected. In particular, the level of toxicity was rather similar to what we have seen with younger patient treated with the same regimen in other studies.

What are some of the next steps for this research?

Future research [efforts will focus on how to] build upon this fixed-duration treatment and to understand how long [patients with undetectable MRD] maintain their responses. Inevitably, some patients will progress, and those are the patients who we must pay more attention to and focus our studies on [so that we can] understand whether we can predict up front who will [not derive benefit from] this fixed-duration treatment so that we can deliver a continuous treatment [approach] instead; we know [the latter] is effective in the vast majority of patients.

How do you foresee this regimen ultimately being utilized the treatment paradigm?

Although this is a very effective treatment, we cannot forget that we are using 2 drugs that we have available. We need to have patients come [into the clinic] more frequently to do the ramp up with the BCL-2 inhibitor. In that sense, I do not believe that this will be one-size-fits-all treatment. We will be using [this regimen] in a great portion of patients [for whom] we want to [provide] a fixed-duration treatment—especially in younger patients [for whom we] want to obtain deep responses and then stop treatment. Some elderly patients, especially the fit ones, will probably also benefit from this treatment [approach]. However, there will always be some patients, particularly the very old patients or those with many comorbidities, [for whom] we will just want to give monotherapy with ibrutinib; [this is] a continuous treatment that can last for up to 7 years in more than 61% of patients.

Reference

1. Kater A, Owen C, Moreno C, et al. Fixed duration ibrutinib and venetoclax (I+V) versus chlorambucil plus obinutuzumab (CLB+O) for first-line (1L) chronic lymphocytic leukemia (CLL): primary analysis of the phase 3 GLOW study. Presented at: European Hematology Association 2021 Virtual Congress; June 9-1