Novel Combination Advances in CLL - Episode 2

Available Therapies and Use in CLL

Sameer Parikh, MBBS:Ibrutinib is now approved for the frontline therapy of chronic lymphocytic leukemia [CLL], regardless of the genetic risk factors that the patient’s CLL cells may have. Typically, we considered using ibrutinib for the vast majority of our patients in the frontline setting, except for a small sliver of young patients. By young, I mean patients who are less than 65 years of age, who have standard or low-risk genetic features such as deletion 13q or trisomy 12 by FISH [fluorescence in situ hybridization], and mutatedIGVHgenes, for whom we would consider therapy with fludarabine, cyclophosphamide, and rituximab [FCR].

Several datasets have now suggested that treatment with FCR in this small group of patients can lead to prolonged remissions, which can last for 10 to 15 years and potentially lead to a functional cure. In the remainder of the patients, ibrutinib-based therapy has now been shown to be better than traditional chemoimmunotherapy in 2 major trials that were reported at ASH [American Society of Hematology] last year—the first was the ECOG [Eastern Cooperative Oncology Group] study that randomized patients to FCR versus ibrutinib and rituximab; and the other study was the Alliance [for Clinical Trials in Oncology] study that randomized patients to ibrutinib alone versus ibrutinib and rituximab, versus bendamustine and rituximab.

In both of these studies, the ibrutinib-based regimen demonstrated an improvement in progression-free survival compared with traditional chemotherapy. So I believe that based on these 2 studies, treatment with an ibrutinib-based regimen has generally become the standard of care for the vast majority of patients who need treatment for CLL.

Having heard the results from the Alliance study and the ECOG study at the ASH meeting, ibrutinib was shown to have a better progression-free survival compared with both FCR and BR [bendamustine/rituximab]. However, one of the problems with ibrutinib therapy is the indefinite nature of this treatment. We’ve also found that patients who remain on long-term ibrutinib therapy can develop significant cardiovascular complications, such as hypertension and atrial fibrillation, among others.

This is the reason why venetoclax-based therapy was presented by [Kirsten] Fischer, MD, at ASCO [American Society of Clinical Oncology] in 2019. The CLL14 study compared a fixed duration of venetoclax and obinutuzumab to chlorambucil and obinutuzumab, and we saw really interesting data. Here, the treatment cycles consisted of 1 year of the fixed duration of venetoclax and obinutuzumab. This led to unprecedented rates of complete remission and minimal residual disease [MRD]-negative complete remission at the end of 1 year of therapy.

This now allows us to consider a fixed duration of novel-agent therapy that is not chemotherapy based, which is certainly a big improvement in the right direction compared with continuous ibrutinib-based therapy.

I do believe that there is a role for chemotherapy in the frontline setting for CLL. Again, I think it depends on a number of things. The patient population where I would consider chemotherapy, and I’m specifically referring to fludarabine, cyclophosphamide, and rituximab, would be for a young patient, generally less than 65 years of age, who had mutated IGVH genes, a low-risk FISH profile, and an absence of TP53 mutation on next-generation sequencing.

We’ve typically now considered using only 3 cycles of FCR, based on data from our colleagues at [The University of Texas] MD Anderson Cancer Center. If patients are MRD-negative in the bone marrow after 3 cycles, we do not expose these patients to further cytotoxic chemotherapy, because the outcomes and the long-term progression-free survival of these patients seems to be really good.

The data for lenalidomide maintenance in chronic lymphocytic leukemia come from studies that were done in the era of chemoimmunotherapy. These patients were all given lenalidomide maintenance after they completed their initial chemoimmunotherapy regimens. These patients typically had high-risk features such as unmutatedIGVHgenes or a high-risk FISH panel profile.

Typically, in 2019 and going forward, we would not use chemoimmunotherapy for this group of patients. While the data for lenalidomide maintenance therapy may seem exciting, in routine practice I do not prescribe lenalidomide maintenance for any of my patients because these patients all get on novel agent therapies to begin with.

Transcript edited for clarity.