Long-Term Data Showcase the Clinical Utility of Fixed-Duration Venetoclax/Obinutuzumab in Treatment-Naïve CLL

Othman Al-Sawaf, MD

Fixed-duration venetoclax (Venclexta) plus obinutuzumab (Gazyva) demonstrated prolonged remissions compared with chemoimmunotherapy in elderly patients with previously untreated chronic lymphocytic leukemia (CLL) and comorbidities, said Othman Al-Sawaf, MD, who added that the deep remissions and high rates of minimal residual disease (MRD) negativity noted across patient subgroups with the regimen suggests that it could be considered for the frontline treatment of all patients with CLL.

During the EHA 2021 Virtual Congress, long-term findings from the phase 3 CLL14 trial (NCT02242942) were presented, revealing that 74% of patients treated with venetoclax/obinutuzumab were progression free at 3 years following treatment cessation.

No late-onset toxicities were observed in the venetoclax/obinutuzumab–treated arm, and the rate of secondary malignancies was similar with the fixed-duration approach compared with chlorambucil/obinutuzumab.

Notably, the benefit was observed across all evaluated subgroups, including patients with TP53 deletions or mutations and unmutated IGHV. Additionally, undetectable MRD remissions were found to be deeper and more sustained with venetoclax/obinutuzumab vs chlorambucil/obinutuzumab in this patient population.

“The fact that we see such deep remissions and MRD-negativity rates that are higher than 70% in this elderly patient population [with CLL] is highly suggestive of similar efficacy in younger, fitter patients,” said Al-Sawaf. “Therefore, we can recommend—and most of the treatment guidelines that exist at the moment reflect this—this treatment for all patients with previously untreated CLL.”

In an interview with OncLive, Al-Sawaf, a physician at the University Hospital of Cologne in Germany, discussed the long-term follow-up data from the CLL14 trial, the lack of long-term toxicity with the fixed-duration treatment of venetoclax/obinutuzumab, and ongoing research efforts that have the potential to further the clinical utility of this treatment approach in treatment-naïve CLL.

OncLive: What did the initial findings from the CLL14 trial show?

Al-Sawaf: CLL14 was a randomized phase 3 study that was started several years ago. [The investigators] aimed to enroll patients with previously untreated CLL with co-existing conditions. The patients were randomized to receive 12 cycles of chlorambucil [plus] obinutuzumab or 12 cycles of venetoclax [plus] obinutuzumab. The primary end point of the study was progression-free survival [PFS].

The primary read out of the study showed a significant advantage in terms of PFS with the novel BCL-2–targeting treatment of venetoclax plus obinutuzumab. The main aim of these ongoing follow-ups is to better understand what the long-term outcome of this fixed-duration approach is, and how and when disease progression eventually occurs. We don’t expect that this treatment is curative for most patients.

Basically, that is why at this [year’s] EHA meeting [we presented] new data [from CLL14] with longer follow-up. All patients in this study have been off treatment for more than 3 years. This allows us to understand long-term toxicities and efficacy, as well as the durability of the remissions in both arms.

What methods were employed to evaluate this regimen? What patients were eligible for enrollment?

The study population in CLL14 is relatively special in that all patients had co-existing conditions, which was the main inclusion criteria. This was assessed by the Cumulative Illness Rating Scale [CIRS], in which all patients had to have more than 6 points, such as a clinically relevant burden of co-existing conditions. Additionally, [patients had to have] impaired renal function with a creatinine clearance below 70 mL/minute, as this is a good surrogate for patient fitness.

We can see in the baseline characteristics of the patients that the median age was 72 to 73 years, so this was an elderly patient population. Also, the median CIRS was 9 points, suggesting that [this was] a patient population with relevant co-existing conditions. This is important to bear in mind when looking at the long-term data because we can control the disease quite well with our BCL-2–targeted treatments. However, we do have a strong competing risk in all our survival analyses because of the co-existing conditions. Therefore, it is important to [note] that our patient population is quite vulnerable and is at risk of having cardiac events and other sorts of complications from their co-existing conditions.

How did the findings of the long-term analysis advance the initial results from the study?

With this long-term analysis we can see that most patients who received venetoclax plus obinutuzumab remain in remission. Although all patients have not received any sort of treatment for more than 3 years after venetoclax plus obinutuzumab, over 70% of patients remain without disease progression. Only 35 disease progression [events] have been observed in the venetoclax/obinutuzumab arm; of those, only 17 [events] have required the next line of treatment.

The majority of PFS events in the venetoclax[-containing] arm were driven by deaths [related] to the co-existing conditions or the older age of patients rather than the CLL. This suggests that we are now able to control the disease quite well with a fixed-duration approach so that patients do not [have poor] quality of life. The survival of the patients is not dependent on the cancer anymore, but rather the co-existing conditions. That is a huge advancement for our field. We are now able to control the effects of CLL on survival by choosing a limited-duration approach to treatment in the frontline setting.

Were any long-term or late-onset toxicities observed? How did the rates of secondary malignancies compare between the arms?

We showed that a big advantage of the fixed duration is that virtually all toxicity occurs while patients are on treatment. After treatment, no toxicity was observed, so we don’t see any long-term hematologic toxicities or late-onset neutropenia. Those are [toxicities] that we might have seen in the era of more intensive chemoimmunotherapies. We do see that [venetoclax/obinutuzumab] is quite well tolerated in the long term, particularly when patients come off treatment.

Also, in previous follow-ups, we looked at secondary neoplasms. We know that patients with CLL have a higher risk of developing secondary malignancies. We also know that some intensive chemoimmunotherapies increase the risk of specific malignancies, such as secondary acute myeloid leukemia after an FCR [fludarabine, cyclophosphamide, and rituximab (Rituxan)] treatment, so we have a particular focus of looking at secondary malignancies.

In initial follow-ups [of the CLL14 trial], we observed a slight discordance in favor of chlorambucil plus obinutuzumab where there was a numerically lower number of secondary malignancies. Now with longer follow-up, we see that this has pretty much evened out and there is no statistically significant difference between both arms regarding secondary malignancies. This suggests that the previous observation was by chance; this doesn’t substantiate with longer follow-up.

We do see that, overall, the number of secondary malignancies is higher than what we would expect in an aged-matched population that doesn’t have CLL. This confirms our previous observations that we have seen for over a decade that patients with CLL have a higher risk of secondary malignancies. We don’t see that any type of treatment is increasing or decreasing this risk in a meaningful way.

What do these data suggest in terms of the clinical utility of venetoclax/obinutuzumab in this patient population?

The data suggest that a frontline approach with venetoclax and obinutuzumab is very feasible and effective for an elderly patient population [with CLL]. We are in an interesting situation because the treatment in Europe and the United States is approved for all patients with previously untreated CLL, whereas this study was strict and only enrolled elderly and unfit patients [with previously untreated CLL]. There are ongoing studies that also enrolled fit patients that compared this treatment with more intensive chemoimmunotherapies than chlorambucil. We expect the first read outs [of these studies] within this year or early next year.

We also looked at different subgroups and see, overall, that the treatment is better for all biological and clinical subgroups compared with chemoimmunotherapy. Therefore, we can recommend it for all patients with previously untreated CLL irrespective of low- or high-risk disease.

What are the next steps of this research?

We are eagerly awaiting the data from studies that are enrolling fit patients, particularly the CLL13 trial [NCT02950051], which is also conducted by our study group in collaboration with many other European study groups. The trial design will investigate the benefit of venetoclax in younger patients [with CLL], so it will be a very important practice-informing study.

On the other hand, we still need to see a head-to-head comparison between this fixed-duration approach and other existing targeted approaches, particularly the continuous BTK inhibitor approach. We are seeing a lot of activity with the BTK inhibitors now, but we do not know whether the continuous single-agent therapy is superior or noninferior to the fixed-duration approach. This is something that we are addressing with the CLL17 study [NCT04608318] that has recently started enrollment several weeks ago. In this study, we are comparing venetoclax plus a CD20-directed antibody or BTK inhibitor to continuous treatment to compare not just [targeted therapy] with chemoimmunotherapy, but also with other targeted treatments. Hopefully this will further inform our practice and our treatment stratification for patients.

Reference

1. Al-Sawaf O, Zhang C, Robrecht S, et al. Venetoclax-obinutuzumab for previously untreated chronic lymphocytic leukemia: 4-year follow-up analysis of the randomized CLL14 study. Presented at: EHA 2021 Virtual Congress; June 9-17, 2021; Abstract S146.