Combinations Continue to Push CLL Field Forward

Jacqueline C. Barrientos, MD, discusses recent combination trials in CLL, and emerging agents in the pipeline.

Jacqueline Claudia Barrientos, MD

Chronic lymphocytic leukemia (CLL) is entering a new age of combination therapy, according to Jacqueline C. Barrientos, MD.

Ibrutinib (Imbruvica) has proven itself to be a mainstay in the CLL paradigm, with recent trials such as TAP CLARITY demonstrating the agent’s combinatorial potential. Results from the TAP CLARITY study presented at the 2017 ASH Annual Meeting showed that the combination of ibrutinib and venetoclax (Venclexta) elicited a complete response (CR) or CR with incomplete hematologic recovery rate of 47% for patients with relapsed/refractory CLL.1 All 38 patients evaluable for efficacy experienced at least a partial response to the regimen, and 37% were negative for minimal residual disease (MRD) in the peripheral blood at 8 months.

Findings from the phase III MURANO trial, also presented at ASH, showed that the combination of venetoclax and rituximab (Rituxan) was superior to bendamustine (Treanda) plus rituximab in patients with relapsed/refractory CLL. Venetoclax/rituximab reduced the risk of disease progression or death by 83% versus bendamustine/rituximab (HR, 0.17; 95% CI, 0.11-0.25; P <.0001).2

With multiple combinations on the horizon, Barrientos said that subpopulations of patients with CLL who have not benefitted from current regimens will now have a greater opportunity to achieve response. These regimens, she adds, have the potential to change practice.

“The sky is the limit as of now,” said Barrientos. “Combinations can offer us the opportunity to treat certain patients who would not be optimally treated with the currently available regimens.”

OncLive: Can you discuss the impact of recent combination trials in CLL?

In an interview with OncLive, Barrientos, an associate professor at the Feinstein Institute for Medical Research at Northwell Health, discussed these combinations trials, as well as emerging agents in the CLL pipeline.Barrientos: We are trying to get deeper responses than what we have seen with regular use of a B-cell receptor signaling agent. Moving forward, data such as from the TAP CLARITY trial presented by the UK group during the 2017 ASH Annual Meeting, is going to be very important. This trial evaluated ibrutinib in combination with venetoclax in patients with relapsed/refractory CLL. There was no increase in toxicity with the combination, while achieving deep responses. The MRD negativity in the patients who had more than 6 cycles was unbelievable, and many of the patients showed no evidence of disease in the peripheral blood or in the bone marrow. Additionally, many of them achieved complete remission, which is unheard of in patients taking ibrutinib as monotherapy.

Based on these data, we are currently testing this combination in the frontline setting. This combination may be a way we treat the disease in the future.

Other combination studies include the BTK inhibitor ibrutinib with a monoclonal antibody, such as obinutuzumab (Gazyva). Ibrutinib has also been working fine in this combination. We have determined that B-cell receptor signaling agents in combination with a monoclonal antibody is safe and will move into the frontline treatment of our patients.

What population of patients are best suited to receive ibrutinib as a single agent as opposed to in combination?

People older than 65 don’t traditionally do well with a chemotherapy regimen like fludarabine, cyclophosphamide, and rituximab (FCR), and now have the opportunity to benefit from combination therapy. Even patients in their 80s can receive these regimens. It is clearly changing the natural evolution of the disease. We can now treat our patients with high-risk disease that otherwise would not respond very well to chemotherapy. There is a possibility of a future full of chemotherapy-free regimens for our patients, and it will provide the opportunity for our patients to achieve deeper responses, so they do not have to be on a drug indefinitely. I believe that the perfect candidate for ibrutinib monotherapy is a patient who is over 65. Ibrutinib is a drug that must be taken continuously, so if it is given in the frontline or relapsed/refractory setting to a younger patient, it might expose that patient to long-term toxicities, such as hypertension, arthritis, bleeding events, and arrhythmias.

In high-risk disease, different clinical trials are showing that patients with 17p deletion are the ones who will relapse the earliest, even though they initially respond beautifully. Combination strategies would be best for these patients. There are many clinical trials currently evaluating the role of combinations in this high-risk patient group.

Patients who may not be good candidates for ibrutinib monotherapy or in combination are those who have history of bleeding, such as a hemorrhage from a recent surgery, or an intracranial bleed. I would consider the use of a drug such as venetoclax in these patients. Venetoclax is approved in the United States for the treatment of patients with CLL who have relapsed/refractory disease and 17p deletion, but some of us in the field are using it off label.

Now that we have the MURANO trial data from the 2017 ASH Annual Meeting, we know that the outcomes of venetoclax in combination with rituximab are very good when compared with bendamustine and rituximab in patients with relapsed/refractory disease. It’s a drug that works as a single agent and in combination, making it is another option of care.

Until then, what role do you see acalabrutinib playing in the landscape of CLL?

There are ongoing trials comparing ibrutinib with the second-generation BTK inhibitor acalabrutinib (Calquence) in high-risk patients who have 11q deletion or 17p deletion. As of right now, both drugs are doing so well that we do not have the outcomes yet. We are all eagerly awaiting the results of this trial. Due to the success of both drugs, it will take some time for patients to relapse. Only then will we figure out once and for all which drug is better as a single agent for these high-risk patients. There was an abstract presented at the 2016 ASH Annual Meeting that showed that some patients who were responding to ibrutinib, but had to stop due to an intolerable side effect, could be salvaged with acalabrutinib and continue to have a response. Very few of them had a significant toxicity that led to a discontinuation of the drug. As of right now, acalabrutinib is only approved in the United States for relapsed/refractory mantle cell lymphoma, but it is moving toward an approval in patients with CLL. If approved, it would then be an alternative for patients who cannot tolerate venetoclax.

If a patient has severe kidney disease that is high risk for tumor lysis syndrome, perhaps acalabrutinib could be a better choice than venetoclax. We do not have that data, that is just from clinical experience. If the patient has a severe intracranial bleed that leads to debilitation, I would not choose a drug like acalabrutinib as that bleeding event may come back because the anatomy of the brain vessels is different. Therefore, perhaps not for that case specifically, but I would consider acalabrutinib for patients who have issues with arrhythmias that are causing them to discontinue ibrutinib. Or, I would suggest acalabrutinib if they have arthritis—it’s worth a shot. We have some preliminary data for the use of acalabrutinib in those situations.


  1. 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 2017 ASH Annual Meeting and Exposition; December 9-12, 2017; Atlanta, Georgia. Abstract 428.
  2. 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.