Chronic Lymphocytic Leukemia Treatment Trends in Community Oncology Settings

In this interview with the Journal of Clinical Pathways, Danielle Brander, MD, associate professor of medicine and director at the Duke Cancer Institute, highlights current trends in the community oncology setting for treating chronic lymphocytic leukemia (CLL) and how clinical pathways can assist oncologists with decision making for frontline therapy in CLL.

Please introduce yourself by stating your name, title, organization, and relevant professional experience.

Hi, my name is Danielle Brander. I'm associate professor of medicine and director of the CLL and Lymphoma Clinical Research Program at the Duke Cancer Institute and Duke Health System in Durham, North Carolina.

What trends do you see in the community oncology setting for treating CLL?

In the community oncology setting for treating CLL, some of the similar principles in selecting the right or preferred frontline therapy for an individual patient still apply while considering the patient-specific factors such as comorbidities and aspects of their disease that might be unique in addition to markers. For example, if they have bulky lymph nodes as the reason to treatment or cytopenia, but also how the regimens are administered in particularly an oral therapy vs requiring infusions. Over the last few years we have seen an uptick and shift based on frontline trials showing superiority of the targeted agents moving away from chemotherapy to the targeted agents. Logistically there are still differences in whether patients receive BTK inhibitors—maybe vs fixed duration of venetoclax therapy. But again, these two classes of drugs were approved at different points in time. And so, we may see that changing as time goes on as well.

But there are a number of patients I want to highlight that are still receiving chemotherapy. And importantly, we also see across the US a large portion of patients that aren't having markers tested at all before they start frontline therapy. That is, including patients receiving chemo where we know there are markedly inferior responses. If there are high risk changes, many patients are not having fluorescence in situ hybridization (FISH) testing, immunoglobulin heavy-chain variable region gene (IGHV) mutation testing, or TP53 mutation testing before first treatment. And again, as chemoimmunotherapy is still being used, many of those patients—though not known—are likely receiving much inferior treatment. Over the coming years we'll see if the uptick for novel therapies in the community setting remains to be BTK inhibitors vs if patients will either be treated with a combination or with a venetoclax-based therapy.

How can clinical pathways help oncologists with decision making when treating patients with CLL?

Both prior to the start of treatment, but especially at the frontline time of therapy, given the lack of head-to-head data, it's important to consider not just the options for frontline therapy, but in pathways we want to highlight what the preferred ones are because of demonstrating superior progression-free survival. In the [A041202] trial, for younger patients that was an intensive chemo of FCR (fludarabine, cyclophosphamide, and rituximab) vs ibrutinib and there was a survival difference as well. So, the hope is that pathways in the frontline setting—especially with continued emerging data—will highlight not only the options but the preferred therapy based on evidence-based clinical trials.

In a relapsed refractory setting, the questions continue to change because now what patients are receiving as first treatment is no longer chemotherapy, such that when they relapse there are all these novel agent approaches. Rather, as more patients are receiving targeted novel agents in the frontline setting, in the relapsed or refractory setting pathways that outline what the options for treatment become more important. For example, if patients received a frontline BTK inhibitor ibrutinib, which is the first generation, but have to stop due to intolerance, then in the relapsed refractory setting pathways can highlight options to switch to other second generation covalent BTKs, such as zanubrutinib or acalabrutinib vs venetoclax-based therapy. But there are other emerging questions that hopefully data will answer and can be reflected in the pathway. For example, patients who receive fixed duration venetoclax in the frontline setting and then go to a BTK inhibitor and neither for intolerance or resistance stop. Outside of clinical trials, considering possibly some of those patients who may benefit from venetoclax re-treatment. Ongoing data is being collecting on this and understanding how we can use it in a re-treatment setting.

Mostly pathways still reflect that there are many questions yet answered, and we still support consideration either in the frontline or relapsed refractory setting. Patients that are eligible and interested in clinical trials should be considered for such approaches. And then lastly, in a great area of unmet need that hopefully pathways can help us navigate is patients who transform from CLL to aggressive pathology lymphoma (Richter's transformation). And in these cases, unfortunately despite other areas of CLL market improvement with novel agents, for Richter's transformations patient survival is markedly reduced an average of 8 months or potentially less if they've received a novel targeted agent. We need to reflect any evidence as well as treatment options for these patients.