Flinn Highlights Emerging Combinations in CLL

Ian W. Flinn, MD, PhD

Several promising combinations are being investigated for patients with chronic lymphocytic leukemia (CLL), according to Ian W. Flinn, MD, citing a number of ongoing trials presented at the 2017 ASH Annual Meeting.

Findings from the phase III MURANO trial presented at ASH showed that the combination of venetoclax (Venclexta) and rituximab (Rituxan) reduced the risk of disease progression or death by 83% versus bendamustine (Treanda) plus rituximab in patients with relapsed/refractory CLL (investigator-assessed HR, 0.17; 95% CI, 0.11-0.25; P <.0001). The 2-year progression-free survival (PFS) rates were 84.9% versus 36.3%, and the complete response rates were 26.8% versus 8.2%, respectively.

OncLive^®: What recent advances have we seen in CLL?

In an interview during the 2018 OncLive^® State of the Science Summit^TM on Hematologic Malignancies, Flinn, director of the Blood Cancer Research Program at Sarah Cannon Research Institute, discussed ongoing advances with emerging combination regimens in CLL.Flinn: There are changes in the way we are treating patients with CLL. We now have the wonderful advancement of BTK inhibitors, such as ibrutinib (Imbruvica). Patients will stay on these therapies indefinitely, which has changed the natural history of the disease. We are moving the field along and are developing combination regimens.

At the 2017 ASH Annual Meeting, we saw many different studies looking at combination trials with ibrutinib, venetoclax, obinutuzumab (Gazyva), and rituximab. One of the most exciting studies was the MURANO trial, in which Dr John F. Seymour and colleagues presented data where patients were randomized between bendamustine and rituximab versus venetoclax and rituximab. In this trial, there were not only superior response rates, complete remission rates, and dramatically improved PFS, but also an overall survival (OS) advantage in the patients who received the combination of venetoclax and rituximab. Patients received this treatment for a fixed duration of approximately 2 years, which is another exciting advancement for the field.

We saw many other studies that are also exciting. Every imaginable doublet combination is being investigated, such as venetoclax and obinutuzumab. According to the results of that study presented at the 2017 ASH Annual Meeting, 100% of patients responded to this treatment. This was investigated in an untreated patient population. Everyone on the trial became minimum residual disease (MRD)-negative in their peripheral blood and three-quarters of the patients became MRD-negative in their marrow. This MRD negativity held for more than 1 year after therapy.

Please expand on the challenge of selecting the best regimen for each patient.

We are still unsure of what the right regimen is. There are many different doublets and triplets, making it hard to determine which regimen will be most beneficial. The sequencing of these agents is an additional challenge.That is an important question. At this point, we do not know [which combination is optimal for which patient]. We know that combination therapy works broadly in the high-risk patient populations as we are seeing deep remissions, but we are not sure if the patients with low-risk disease need the same combinations. These combinations are expensive and perhaps we can dial it down in some patient populations. However, we are at a starting point where we are getting patients into MRD-negative complete remissions that we have never seen before.

A remaining question is, “Do you need to combine ibrutinib with rituximab?” In the early developmental days of ibrutinib and other B-cell receptor pathway drugs, we saw tremendous lymphocytosis occur, which was frightening to some patients and doctors. The question is whether we should add an anti-CD20 agent with that combination.

Will the field be moving into triplet regimens?

There were data presented at the 2017 ASH Annual Meeting that suggested this might not be helpful. The group at The University of Texas MD Anderson Cancer Center did a randomized trial in the relapsed and frontline setting where patients received ibrutinib alone, whereas the other half received ibrutinib with rituximab. Unfortunately, the rituximab combination did not add anything in this setting. CD20 is important with venetoclax combinations but there are no dramatic differences with ibrutinib combinations. In that study, there was no difference in PFS or OS.Those studies are currently ongoing. We saw data from Dr Kerry Rogers of The Ohio State Comprehensive Cancer Center that was looking at a triplet regimen. These are exciting data, but it is hard to read since these studies investigated small numbers of patients in each of the high-risk subgroups. It is unclear what to do.

Where are we at with chimeric antigen receptor (CAR) T-cell therapy in CLL?

There is the argument that we should save something in case a patient progresses. My tendency is to be more conservative until we know what we should do.CLL was one of the first places that CAR T cells were shown to be active. A few years ago, we saw multiple publications investigating this. The problem has been that there are issues with high toxicities compared with efficacy, especially when we have other medications and drugs that we can use for this patient population.

It seems that the initial enthusiasm has dimmed down in CLL, unlike what we are seeing in lymphoma. However, multiple different groups are reinvigorated and are retesting CAR T-cell therapy in CLL to make it better tolerated. We want to take what we have learned in aggressive lymphomas and apply that to CLL to decrease the morbidity rate. We are going to see more trials coming out.

Seymour JF, Kipps TJ, Eichhorst BF, et al. Venetoclax plus rituximab is superior to bendamustine plus rituximab in patients with relapsed/ refractory chronic lymphocytic leukemia - results from pre-planned interim analysis of the randomized phase 3 MURANO study. In: Proceedings from the 2017 ASH Annual Meeting and Exposition; December 9-12, 2017; Atlanta, Georgia. Abstract LBA-2.