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Combination Therapies Poised to Improve CLL Treatment Landscape

Danielle Bucco
Published: Monday, Jan 08, 2018

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. 

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