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Sorting Through the Alphabet Soup of Evolving Treatments in CLL

Christina T. Loguidice
Published: Tuesday, May 15, 2018
Dr. William G. Wierda
William G. Wierda, MD, PhD
The rapid introduction of new therapies for chronic lymphocytic leukemia (CLL) during the past several years has remade the treatment paradigm, presenting clinicians with a challenging array of options at a time when further advancements are in the works.

That was the picture that emerged from a recent OncLive Peer Exchange® program in which experts in CLL offered their perspectives on developments in the field. “The availability of novel therapies for CLL has drastically improved outcomes but has also increased the complexity of treating symptomatic patients,” said William G. Wierda, MD, PhD, who moderated the discussion. “Moreover, there remains a substantial unmet need for many patients who relapse.”

The panelists provided insights on novel combination therapies, discussed several promising agents, including phosphoinositide 3-kinase (PI3K) inhibitors, and reviewed areas of research that might open new treatment avenues in the frontline and relapsed/refractory settings.

“It’s a very exciting time because of all the novel therapies, and I think now our goal is to develop new generations of therapy, trying to minimize the toxicity with the oral agents, and to improve upon what we have available by doing the novel–novel combination or novel– conventional combinations to achieve a really deep response,” said Shuo Ma, MD, PhD. She noted that minimal residual disease (MRD) negativity is now achievable and will hopefully translate to a very long progression- free survival (PFS) for patients.

The CLL Landscape

CLL is the most prevalent adult leukemia in Western countries, predominantly affecting middle-aged and elderly adults (>90% diagnosed at ≥55 years).1 In the United States in 2018, more than 20,000 new CLL cases are expected to be diagnosed, with approximately 4500 people dying from the disease.2

Until 2014, many patients with CLL had few treatment options, particularly because advanced age often limited tolerance to the severe adverse effects (AEs) commonly experienced with standard chemotherapeutic regimens. By 2015, 4 new effective and better tolerated drugs were approved for CLL: the small-molecule inhibitors ibrutinib (Imbruvica) and idelalisib (Zydelig) and the anti-CD20 monoclonal antibodies obinutuzumab (Gazyva) and ofatumumab (Arzerra). These advancements led the American Society of Clinical Oncology to name “transformation of CLL treatment” its cancer Advance of the Year in its Clinical Cancer Advances 2015 report.3 In 2016, the FDA approved another small-molecule inhibitor, venetoclax (Venclexta), for patients with CLL and 17p deletion (del[17p]).

Novel Combinations in CLL

Currently, in the frontline and relapsed/refractory setting, most combinations recommended by the National Comprehensive Cancer Network include rituximab (Rituxan). Ibrutinib plus bendamustine and rituximab, idelalisib plus rituximab, and venetoclax plus rituximab are the preferred regimens in the relapsed/refractory setting, including for high-risk patients.1 Numerous clinical trials are currently underway that are examining a variety of novel–novel combinations.

“It’s a bit of an alphabet soup,” said Matthew S. Davids, MD, MMSc, noting that some key agents being combined include ibrutinib, venetoclax, and obinutuzumab (Table 14-7). “We’re really seeing some dramatic rates of MRD negativity,” he noted. However, these studies are still early, mainly in phase II, and, although the data are promising, these combinations are not yet ready for clinical practice. “It’s challenging because right now in the United States, we don’t have access to combinations of these agents, so we can’t really do this off-label. I don’t think most insurers would pay for both novel agents at the same time. So, I think these data are going to need to mature more before we see them in practice,” he said.

Table 1. Selected Combinations in Clinical Trials in CLL4-7

A major goal with new combinations will be to enable time-limited therapy versus patients having to continue therapy, such as ibrutinib monotherapy, though there is a place for both approaches, noted Davids. “If I have an 82-year-old who wants to have good disease control, I think ibrutinib monotherapy may be a great option. But if I have a 62-year-old who wants to live another 30 years, that might be a patient I want to focus on a timelimited combination approach—get them into an MRD-negative state, and then hopefully give them a long treatment-free interval before they may need treatment again,” he said.


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