Stephan Stilgenbauer, MD: When we focus on the treatment of fit and younger patients with CLL [chronic lymphocytic leukemia] in the frontline setting, there is the ECOG 1912 study, which was particularly designed for young and fit patients with CLL. It excluded patients in the age group of 70 years and older. Here, we have an unusual population of patients who can withstand intense therapy, and for that reason, the standard arm in that trial was the most intense and most efficacious chemoimmunotherapy regimen that we have available: namely the FCR regimen, fludarabine, cyclophosphamide, and rituximab. This had been the standard for younger patients with CLL for a long time because it shows good efficacy, but there is also a considerable toxicity profile.

The remarkable thing about the ECOG 1912 trial is that the randomized comparison between [fludarabine, cyclophosphamide, rituximab] and ibrutinib plus rituximab, the IR regimen, showed with regard to the primary end point of progression-free survival [PFS], a significant superiority of ibrutinib-based therapy compared to [fludarabine, cyclophosphamide, rituximab]. Not only was the primary end point of PFS different, but remarkably, the trial also showed an overall survival difference with superiority of ibrutinib plus rituximab compared to [fludarabine, cyclophosphamide, rituximab]. This is surprising since overall survival differences in CLL trials are hard to find.

In addition to this superiority in efficacy, ibrutinib-based therapy was also better tolerated. In particular, hematologic toxicity, neutropenia, and infections were much more pronounced in the [fludarabine, cyclophosphamide, rituximab] treatment arm. Therefore, the ECOG 1912 study establishes ibrutinib plus rituximab as the preferred treatment option for the vast majority of young and fit patients with CLL in need of frontline treatment.

When searching for improved outcomes for our patients with CLL and leading to results that prolong their lives, the novel trial data using the nonchemotherapeutic agents, the targeted therapies focusing on BTK [Bruton tyrosine kinase], PI3K, and BCL2 are important. The novel agents such as ibrutinib, acalabrutinib, or venetoclax have shown in several randomized comparisons that they are superior with regard to efficacy as measured by progression-free survival, but they are also more well-tolerated compared to the classical chemoimmunotherapy standards that we had available in the past.

For our patients with CLL, these novel treatment options, either when used alone or in the experimental setting in novel combinations, provide tremendous benefits and prolong treatment-free intervals, progression-free survival, and in some instances even overall survival for our patients.

Paolo Ghia, MD, PhD: In the iLLUMINATE study, ibrutinib has been combined with obinutuzumab, a novel anti-CD20 antibody, and compared to chlorambucil plus obinutuzumab in the setting of elderly patients with comorbidities. The combination of ibrutinib plus obinutuzumab is proven to be superior in terms of progression-free survival compared to chlorambucil plus obinutuzumab, and this was regardless of any of the genetic features of the patient.

Unfortunately, in this study we are missing ibrutinib monotherapy, and the impression, though we cannot compare different studies, is that the benefit in terms of PFS is not much different. It is not much improved compared to ibrutinib alone. We know that ibrutinib in combination with rituximab is not improving PFS in patients compared with ibrutinib, and we know this from the Alliance study in which ibrutinib plus or minus rituximab was compared to bendamustine plus rituximab in the setting of the elderly, fit patient. There we did not see any difference; and also the iLLUMINATE study, the results are not as dramatic as from the previous study, so that is casting doubts on the need and benefit of adding a monoclonal antibody, including obinutuzumab, to ibrutinib.

The advantage of the combination of ibrutinib with obinutuzumab is that the patient with obinutuzumab can achieve a complete remission much more frequently, and in particular, much more frequently, undetectable minimal residual disease, in the order of 20% of the patients, which is quite a remarkable number, thinking that with ibrutinib most, if not all, of the patients achieve only partial responses.

I do not think that the addition of monoclonal antibodies, particularly obinutuzumab but also rituximab, can change the attitude of the physician in hematology when treating patients with chronic lymphocytic leukemia. Though the combination is available and accessible in some countries and to some of my colleagues, I hear that the use is particularly for young patients for whom the physician wants to achieve deeper responses to make the patient feel healthier with a much more controlled disease, in particular having a longer life expectancy. Besides that, I do not think at the moment that our evidence is that the addition of monoclonal antibodies to BTK inhibitors is changing the long-term perspective of our patients.

Transcript edited for clarity.