The use of novel-novel combinations in the treatment of CLL was an important topic at ASH 2021, as evidenced by an entire session dedicated to the subject. The novel-novel combination with the most data is ibrutinib plus venetoclax. This combination has been studied previously in the front line, using a fixed-duration regimen and examining minimal residual disease (MRD). For instance, ibrutinib plus venetoclax was compared with chlorambucil plus obinutuzumab for treatment-naive CLL in the GLOW study. Additionally, ibrutinib plus venetoclax was evaluated in patients with relapsed or refractory CLL in the phase 2 CLARITY study, which had a primary end point of eradication of MRD after 12 months of combined therapy.

At ASH 2021, we were presented with some interesting follow-up data from the GLOW study (abstract 70) and other frontline studies, such as CAPTIVATE (abstract 68). My impression of the ibrutinib-plus-venetoclax combination is that this fixed-duration, all-oral regimen is active and induces deep remissions. However, we need to be mindful of the different populations in the respective clinical trials. While the CAPTIVATE study found the combination to be well tolerated, its patient population was younger (median age, 58 years) than the general CLL patient population. The GLOW trial, on the other hand, had an older patient population, and, while we saw low rates of residual disease and progression-free survival rates that looked good with ibrutinib plus venetoclax, in my view, the results were not markedly different from what we would observe with the CLL14-type venetoclax-plus-obinutuzumab regimen. 

It would be interesting to see data on ibrutinib plus venetoclax in older patients with 17p deletion, as well as data on retreatment strategies and resistance. And something that I would like to see more of in all clinical trial designs is the use of clinically relevant, modern controls. We also need data to guide treatment sequencing.

I would say that the results of these studies will leave the door open for the use of ibrutinib plus venetoclax in the clinic; however, at this time, I do not think that the standard of care will shift markedly based on these data or the data that were presented earlier this year during the spring meetings. 

The GAIA (CLL13) study is another trial that incorporated a novel-novel combination in 1 of its arms (abstract 71). The trial explored the following 3 different venetoclax-based combinations in the frontline setting: venetoclax plus rituximab, venetoclax plus obinutuzumab, and venetoclax plus obinutuzumab and ibrutinib. The 3 regimens were compared with chemoimmunotherapy (either bendamustine plus rituximab or fludarabine, cyclophosphamide, and rituximab [FCR regimen]). This was a younger, fit population (median age, 61 years) without TP53 aberrations. And the results that were presented at ASH 2021 were preliminary, with a median observation time of 27.9 months.

Based on these early MRD data from abstract 71, 2 of the regimens (ie, the venetoclax-plus-obinutuzumab arm and the venetoclax-plus-obinutuzumab-and-ibrutinib arm) induced deeper remissions than chemoimmunotherapy, while the third arm (ie, venetoclax plus rituximab) did not. However, at this point, these findings do not necessarily mean that the 2 winning arms will produce more durable remissions than venetoclax plus rituximab. My impression is that these data suggest that venetoclax plus obinutuzumab might be preferable to venetoclax plus rituximab in this setting, but we need to see how this evolves, including with regard to progression-free survival data.

A newly initiated trial that I am involved with called the MAJIC trial is comparing the clinically relevant doublet regimens acalabrutinib plus venetoclax vs venetoclax plus obinutuzumab in an MRD-driven approach (abstract 1553); there is no chlorambucil-based control arm. I think that MAJIC is promising because we will look at whether MRD-guided finite therapy with acalabrutinib plus venetoclax produces noninferior efficacy compared with MRD-guided finite obinutuzumab and venetoclax. This is a new strategy using MRD, as measured via the clonoSEQ assay (Adaptive Biotechnologies), to help make decisions about the duration of treatment exposure.