Contemporary Management of CLL - Episode 1

Selecting Frontline Therapy to Treat CLL

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Alan P. Skarbnik, MD: Fortunately, we have many options to treat CLL [chronic lymphocytic leukemia] today, still including chemoimmunotherapy for a subset of patients who are highly selected. We have continuous therapy with Bruton tyrosine inhibitors [BTK]—the approved ones are ibrutinib and acalabrutinib—with or without the use of an anti-CD20 antibody.

Certainly, all these therapies have pros and cons. One of the issues we discuss quite a bit is, who would be an ideal candidate for continuous therapy? There are a number of issues associated with continuous therapy. One issue is prolonged exposure to treatment and prolonged exposure to potential adverse effects and risks. Of course, cost associated with the therapy is also an issue, particularly for patients who don’t have commercial insurance coverage.

Based on the data seen in multiple frontline trials, it seems that, for most patients, therapy is appropriate, particularly for those patients with IGHV mutations. Those patients, certainly, can enjoy a long-term progression-free survival and treatment-free survival without the need for continuous therapy.

However, it seems that for patients with high-risk cytogenetics, particularly with a 17p deletion or TP53 mutation, this therapy may not be the best answer. We don’t have a head-to-head comparison trial to evaluate that, but by looking at the curves of trials that include a discontinuation of therapy at a certain period of time, it seems that those patients with high-risk disease started to progress earlier than we would expect, especially compared with their non-high-risk counterparts.

It is my opinion that for the very high-risk patients, continuous therapy would be more appropriate, given the data that we have at the moment. Of course, this may change as we have more data moving forward, but it seems that those patients may enjoy a longer control of disease by having the disease continuously suppressed by a therapy.

Not all patients require treatment upon diagnosis, and some don’t require treatment for many years. Some don’t require treatment at all. But once treatment is indicated, we discuss options. Starting with IGHV mutations, we look at cytogenetic risk, as well as performance status, comorbidities, if the patient is fit, what the patient will be able to tolerate, what are the patient’s goals are, and so on.

But all things being equal, we’ll look at the cytogenetic risk—an IGHV mutation is the first determining factor. Certainly, for patients who have a disease that’s unmutated in the IGHV molecule, which is higher risk—this is about 65% of patients who do require treatment in the first-line setting—chemoimmunotherapy is, truthfully, not indicated for those patients. FCR[fludarabine, cyclophosphamide, rituximab]and BR [bendamustine, rituximab]don’t have that much of a role anymore in this particular population.

Then we discuss novel therapies, which in the frontline setting include venetoclax and obinutuzumab, acalabrutinib, or ibrutinib with or without anti-CD20 therapies. Of course, there are pros and cons to each approach.

The biggest advantage of venetoclax and obinutuzumab is that they are given in a fixed duration. It’s about a year worth of therapy. Logistically, it is a bit more complex than using 1 of the BTK inhibitors. It requires an infusion of an antibody. There are 4 infusions of an antibody in the first month. Once you start the venetoclax-BR [bendamustine, rituximab] therapy, there is a weekly ramp-up over 4 weeks that requires a number of doctor visits and several laboratory check-ups. Sometimes these need to occur 2 days in a row. Some patients require hospitalization, particularly patients who are high-risk for tumor lysis syndrome. This is a very potent medication, in terms of killing the CLL cells.

Using a tyrosine kinase inhibitor does not require such frequent lab check-ups, and certainly, there are fewer doctor visits. This type of treatment does not require hospitalization. It does not require an infusion. You don’t have the ramp-up, so logistically it’s much easier. However, you need to take that continuously until disease progression or intolerability.

We discuss the particular adverse-effect profile of each treatment with the patient. As of right now, we don’t have a head-to-head comparison of those agents to understand which option will be better and which will be worse. It seems like all of them work very well.

After discussing all these factors, including patient-specific characteristics, then we decide the preferred approach for that patient.

Catherine C. Coombs, MD: Shared decision-making is a huge component of care for a patient with CLL. I don’t think there is aright answer to what is the best treatment. We have a lot of treatments that work pretty well; they are just very different. Some are oral only. Some are oral plus IV [intravenous]. They have different adverse-effect profiles. Depending on a patient’s comorbidities and tolerance of certain toxicities, really coming together as a team to make the best decision is the best approach when selecting a frontline therapy.

There are key considerations that I take into account when selecting a therapy for any given patient. In addition to their preference for therapy, there are biological factors that are very important. I consider genetic risk of any given patient, which is determined both by cytogenetic testing via FISH [fluorescence in situ hybridization] and karyotype testing, to look for high-risk genetic abnormalities such as 17p, complex karyotype, 11q deletions, TP mutations, and also the status of the IGHV gene, whether it is mutated or unmutated. Depending on the presence or absence of high-risk markers, that can make us lean in the direction of 1therapy more than another.

In addition to these biological factors, patient preference plays a role as well. Some patients are very open to doing a more intensive treatment, provided that they have the benefit of being able to stop therapy. However, other patients prefer oral-only options. It depends not only on their biological risk factors, but of course what their preferences are.

Lastly, all these therapeutic regimens have different adverse-effect profiles. For example, one therapeutic regimen may be a better fit for a patient who has cardiovascular disease than a patient who has renal disease, to avoid toxicities that may make them have trouble with the therapy going forward.

Transcript Edited for Clarity