Considerations for Selecting Small Molecule Inhibitors for Patients With CLL

Clement Chung, PharmD, MS, BCOP, BCPS, senior clinical pharmacy specialist, hematology and oncology, Houston Methodist West Hospital, reviews the landscape of small molecule inhibitors for chronic lymphocytic leukemia, including important clinical considerations to guide therapy selection.

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Welcome back to PopHealth Perspectives, a conversation with the Population Health Learning Network where we combine expert commentary and exclusive insight into key issues in population health management and more.

My name is Clement Chung. I currently work as a senior clinical pharmacy specialist in hematology/oncology at Houston Methodist West Hospital, in Houston, Texas. I've been working in this role for the past 20 years. I moved here from Seattle, Washington, where I was leader of hematology oncology clinical improvement programs. 

My current role is in the community hospital setting, where I engage with both physicians and nurses to develop an interdisciplinary, treatment-related toxicity and reduction symptom management program. I also help patients triage and manage their treatment-related toxicities, and create, manage and revise the treatment plans for patients with cancer receiving different types of therapies. PSET pharmacy residents and students engage in quality initiatives system-wide, and within the facility. 

Thank you, Dr Chung. What inspired your research into small molecule inhibitors for CLL?

Well, the background has to do with my first publication, back in 2014, for the emergence of small molecule inhibitors, indicated for CLL. Because over the last 10 to 15 years, the treatment paradigm for CLL has changed from traditional chemoimmunotherapy—ie, anti-CD20 monoclonal antibody in combinations with cytotoxic chemo agents, for both fit and unfit patients—to the current small molecule inhibitors. 

The treatment paradigm has changed entirely, because of the durable clinical response rate associated with those small molecule inhibitors. Studies actually confirm less toxicities with small molecule inhibitors compared to traditional chemoimmunotherapy. 

That was my background back in 2014 for that paper in Pharmacotherapy, because I was interested in the Bruton's tyrosine kinase 7 (BTK) pathway. My current publication in the European Journal of Hematology is an update on the current treatments for small molecule inhibitors in the CLL space.

What are the most important considerations when choosing a therapy for CLL, and how do those considerations differ between monotherapy or combo therapy?

When choosing a therapy for patients with CLL, there are a lot of considerations. The first thing that comes in my mind is the patient fitness issue; like their age, their comorbidities, and their functional status. A lot of older patients and those who have major comorbidities cannot tolerate even the small molecule inhibitors very well, on a continuous administrative basis. The traditional, first-generation and even second-generation BTK inhibitors had to be offered continuously until disease progression or intolerable toxicities, vs the BCL2 inhibitor, like venetoclax, which can be given in a fixed or timed duration. All those things need to be considered very carefully when you plan out a first-line treatment option.

The second thing to consider is certain data regarding the supportive clinical advantages vs toxicities. Based on current trials, say, when you compare ibrutinib with acalabrutinib in the ELEVATE-TN trial, you can see ibrutinib has a lot more toxicities like atrial fibrillation, bleeding, hypertension issues, vs acalabrutinib in the first-line setting. Then there is the new approval for zanubrutinib. Zanubrutinib has a much better, improved toxicity profile compared to ibrutinib in the first-line setting as well. You have to consider all those toxicities.

And then, you have to look at the duration of benefits, how long patients can likely maintain their response rate. What's the current data, if available, for the progression-free survival vs the overall survival? But because of the durable response for all those small molecule inhibitors, the endpoints for overall survival probably have not been reached. So we have to compare not just the progression-free survival data for patients on those agents. You have to look at the so-called negativity of the minimal residual disease status, see which agents or what combination can give you the best response rate, and also a minimum residual disease level.

And then, of course, lastly will be patient convenience. Do they want to stay close to a hospital? Or can they come less often to the hospital? They don't need to come to the acute care facility to have a frequent bed check. This is oftentimes needed if they are on the oral pills, venetoclax, in the very first few weeks of treatments to monitor their tumor lysis syndrome risk.

And then you'll also consider the patient preference. Do they want to have a fixed duration like venetoclax combination therapy? They can have 6 months of therapy vs a continuous, indefinite therapy for BTK inhibitors. Many of those chemical factors and specific patient issues also need to be weighed in before you finalize a treatment plan during the first-line decision-making process.

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This transcript has been edited for clarity.