Combination Therapies Poised to Improve CLL Treatment Landscape

Danielle Bucco

Aaron Logan, MD, PhD
Aaron Logan, MD, PhD
Combination regimens are generating excitement in the field of chronic lymphocytic leukemia (CLL), according to Aaron Logan, MD, PhD.

The combination of the BTK inhibitor ibrutinib (Imbruvica), and the BCL-2 inhibitor venetoclax (Venclexta), for example, achieved a complete response (CR) or a CR with incomplete hematologic recovery (CRi) in 47% of patients with CLL in the TAP CLARITY study. That trial investigated 38 efficacy-evaluable patients who experienced at least a partial response to ibrutinib plus venetoclax. Of these patients, 37% achieved minimal residual disease (MRD) negativity in the peripheral blood at 8 months.

“We are going to have to wait 1 or 2 years to accrue more patients to see whether these early results are going to be sustainable,” Logan said. “We will need to see what happens in the patients who do stop therapy. Do they maintain their remission and do they have MRD negativity? Do they become MRD-positive again?” 

In an interview during the 2017 OncLive® State of the Science SummitTM on Hematologic Malignancies, Logan, an assistant professor of clinical medicine, Division of Hematology/Oncology, University of California, San Francisco Helen Diller Family Comprehensive Cancer Center, discussed the most promising combinations and available treatments for patients with CLL.

OncLive®: What is the current state of CLL?

Logan: CLL remains to be the most common leukemia in adults, representing about 25% of leukemia diagnoses. Due to its prevalence, there has been a lot of innovation in therapy for CLL, initially with combination monoclonal antibodies and cytotoxic agents called (chemoimmunotherapy). Those regimens have been standards of therapy for many years. We recognize that there are patients who have certain cytogenetic abnormalities, such as 17p deletion or abnormalities in p53, who did not benefit from those chemoimmunotherapy approaches. 

Fortunately, we have many targeted agents that hit various Achilles’ heels of the CLL cells, including BTK inhibitors such as ibrutinib and BCL-2 inhibitors like venetoclax. These are even in patients who carry some of these high-risk features, such as 17p deletions and immunoglobulin heavy-chain unmutated tumors, which represent a higher-risk subgroup of patients. 

Now, we have a number of studies that have demonstrated activity of these agents in the frontline setting. Ibrutinib is approved for patients with 17p deletion or not in the frontline setting and beyond. Venetoclax is approved for patients who have 17p deletions after at least 1 therapy, but there are ongoing studies to bring [it] to the frontline setting. Some of the studies that were reported at the 2017 ASH Annual Meeting are looking at direct comparisons between novel agents such as ibrutinib versus chemoimmunotherapy approaches.

One of the most difficult choices when we see a patient with CLL is determining whether we should give them a novel agent or chemoimmunotherapy. Right now, we are making those decisions outside the context of a strong evidence base, but those studies are going to lead us in that direction. 

Some of the more interesting studies that were reported at the meeting included the MURANO study, which reported great outcomes for relapsed patients receiving venetoclax plus rituximab (Rituxan) in comparison with bendamustine and rituximab. That study, in addition to other studies that have looked at ibrutinib in comparison to chemoimmunotherapy, demonstrated no role for chemoimmunotherapy in relapsed disease. These patients should be getting a novel agent with or without a monoclonal antibody.

There were a couple of great studies looking at combinations of the novel agents, particularly ibrutinib and venetoclax. In a UK study, it was demonstrated that this combination is very potent in the relapsed/refractory setting. Many patients achieved a CR even if they had high-risk features, such as prior early failure of fludarabine, cyclophosphamide, and rituximab (FCR), bendamustine-based chemotherapy, or patients who had prior idelalisib (Zydelig). 

At the meeting, there was a presentation discussing a similar approach combining ibrutinib and venetoclax. They had the relapsed/refractory cohort, which is similar to the UK study, with patients achieving MRD negativity after 1 year of combination targeted therapy. Importantly, they had a treatment-naïve group, basically moving the combination to the frontline setting in high-risk patients. Although the numbers are small, it looks like there are great responses with all patients eventually developing MRD negativity with the combination of BTK inhibition and BCL-2 inhibition. 

Fortunately, both of those studies have incorporated the achievement of MRD negativity as an endpoint. There will be a scheduled cessation of therapy so that we can see if it is possible with the combination therapies to achieve MRD negativity and then stop treatment. This is very important clinically, so that we can eliminate any of the toxicities that patients experience, but also financially, as there is a lot of financial toxicity involved in continuing novel agent therapy. It is important for these studies to determine whether it is possible to stop therapy at a specific time so we can minimize the cost of therapy in this era of novel agents. 

Will the combination of ibrutinib and venetoclax likely get approved? If so, how will this impact the treatment landscape, particularly for patients receiving single-agent ibrutinib?

These studies are still very early and the numbers are small. We are going to have to wait 1 or 2 years to accrue more patients to see whether these early results are going to be sustainable. We will need to see what happens in the patients who do stop therapy. Do they maintain their remission and do they have MRD negativity? Do they become MRD-positive again? 

I am not quite sure whether this combination will achieve immediate approval because it is not yet clear that the FDA is quite ready to use MRD as an endpoint for clinical trials. It is moving in that direction, particularly in indolent diseases like CLL, where it is hard to do a study looking at progression-free survival or overall survival as an endpoint because those studies just take too long. It remains to be seen whether the FDA is ready to approve drugs based on MRD as a primary endpoint. I am not quite sure about that. 

The field will move beyond where the studies go and beyond where the FDA label goes. Many practitioners may try to do combinations if the studies look favorable, even if they do not have an FDA approval for combination therapy. There will be some restrictions based on the pair and whether that will be financially supported, but there is going to be some clinical use.

Choosing between monotherapy versus combination therapy will be a difficult decision to make until there are comparison studies. That will be a long time from now. We are doubling the cost of therapy if you use both agents at the same time. However, if you do achieve MRD negativity and can stop therapy after 1 year, then the overall cost to the patient and the healthcare economy will be lower than putting a patient on ibrutinib and continuing for years until progression.

That is going to be a hard assessment to make because those cost-efficacy studies will take years; treatment to progression is going to take years to determine what the associated costs are. I am not sure how long that will take for us to be able to answer that question. In the field, we are going to move forward with whatever therapy is best for individual patients. We are going to individualize it based on the context of their mutational profiles beyond using fluorescence in situ hybridization, cytogenetics, patient life circumstances, comorbidities, and financial implications.

What are your thoughts on acalabrutinib (Calquence)? 

The development of more specific agents is a general theme that has emerged in targeted therapy. We realize that, in many cases, there are off-target toxicities. With ibrutinib, the principal off-target toxicity is the development of cardiac arrhythmia experienced in a number of patients. There is also some off-target inhibition of the platelet-derived growth factor alpha receptor pathways creating bleeding events.

A more targeted BTK inhibitor in principal might have some advantages. Acalabrutinib looks like it might have more a favorable side effect profile but, in the early studies that have been reported, it is not yet clear that it is superior to ibrutinib in terms of efficacy. It will remain to be seen with additional studies where acalabrutinib or other second-generation BTK inhibitors are going to fall into place in comparison with ibrutinib. 

What I suspect is that we will probably start with ibrutinib and if patients tolerate it and have a great response, they will stay on ibrutinib. However, if they do not tolerate it or have specific contraindications, such as an existing arrhythmia, that might be where we initially want to consider one of the second-generation BTK inhibitors, such as acalabrutinib. 
Hillmen P, Munir T, Rawstron A, et al. Initial results of ibrutinib plus venetoclax in relapsed, refractory CLL (Bloodwise TAP CLARITY study): high rates of overall response, complete remission and MRD eradication after 6 months of combination therapy. In: Proceedings from the 59th ASH Annual Meeting and Exposition; Dec. 9-12, 2017; Atlanta, Georgia. Abstract 428.
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