Frontline CLL Therapy: Considerations for Selecting Targeted Therapies


In a session at the American Society of Hematology Annual Meeting and Exposition, held December 7-10 in Orlando, Florida, experts presented on the evolution of CLL therapy, how to make treatment decisions, and what’s to come in the future based on ongoing studies.

With the availability of targeted agents, the treatment of chronic lymphocytic leukemia (CLL) has drastically changed. However, with several options to choose from, providers must be able to weigh the pros and cons of each therapy based on several factors.

In a session at the American Society of Hematology Annual Meeting and Exposition, held December 7-10 in Orlando, Florida, experts presented on the evolution of CLL therapy, how to make treatment decisions, and what’s to come in the future based on ongoing studies.

In her portion of the talk, Jennifer Woyach, MD, associate professor at The Ohio State University, discussed how therapeutic options have evolved and what has led to the current standard of care.

“The difference is we have many, many frontline therapy options at this time,” Woyach said.

This includes Bruton’s tyrosine kinase (BTK) inhibitors, such as ibrutinib and acalabrutinib. These are either given in combination with an anti-CD20 antibody or as a monotherapy. The other option for targeted therapy in the frontline setting is venetoclax, which is a B-cell lymphoma 2 inhibitor, in combination with obinutuzumab. In addition, there are also chemoimmunotherapy options, such as fludarabine, cyclophosphamide, and rituximab (FCR).

With all of these potential options, what is the best way to determine the most appropriate regimen for a patient? With many open questions remaining in the field, Woyach offered a breakdown to considering selection of therapy.

“The first consideration, I think, is that of chemoimmunotherapy versus targeted therapy,” Woyach said.

BTK inhibitors versus chemoimmunotherapy

Woyach pointed to a number of phase 3 clinical trials that have shaped BTK inhibitors’ use in CLL management. The RESONATE 2 trial, in particular, was the first phase 3 study to compare a targeted agent with chemoimmunotherapy in the treatment naïve study.

“While this trial, the RESONATE 2 study, led to the approval of ibrutinib in frontline CLL, one problem with it is the chlorambucil in the comparator arm because even at that time of study, we really weren’t using chlorambucil as frontline treatment,” Woyach said.

The E1912 study and ALLIANCE A041202 trial, on the other hand, were designed to evaluate the spectrum of age in the CLL patient population and then compare ibrutinib-based regimens with standard chemoimmunotherapy. Other studies included the iLLUMINATE and the ELEVATE TN trial, for which follow-up data was also presented at the meeting.

According to Woyach, these trials confirmed that treatment with a BTK inhibitor, with or without an anti-CD20 antibody, is more effective than chemoimmunotherapy. However, for a subset of immunoglobulin heavy chain variable region gene (IgHV)-mutated patients, this may not be true, especially with FCR. Additionally, the studies suggest that anti-CD20 antibodies may be better combined with acalabrutinib than ibrutinib, she noted.

Venetoclax versus chemoimmunotherapy

In considering venetoclax versus chemoimmunotherapy, Woyach discussed the CLL14 study which treated patients who had a high comorbidity index or reduced renal function. In this study, venetoclax plus obinutuzumab was compared with obintuzumab plus chlorambucil for the duration of 1 year.

Overall, the study showed that venetoclax plus obinutuzumab is more effective than chlorambucil plus obinutuzumab. However, this may not be true for a subset of IgHV-mutated patients, Woyach said. At 2 years, progression-free survival for venetoclax plus obinutuzumab is similar to what is reported for ibrutinib.

“I think long-term follow ups are really going to be critical in determining the place for this regimen in clinical practice, in which patients should receive what therapy,” Woyach explained.

Safety considerations

Because there are not enough data to point to exactly which targeted therapy is the most effective to use, Woyach explained that selecting an appropriate treatment must be based on a combination of efficacy, safety, and patient-specific factors.

In the clip below, Woyach addresses the unique adverse effect profiles of each targeted therapy and how these safety profiles fit into treatment decisions.

Looking ahead, more studies are needed to further nail down which targeted therapy option is the most effective. Overall, Woyach concluded that the choice of which targeted therapy to use will involve a discussion of data and considerations of the pros and cons of each option. Based on current data, all targeted therapies appear to be relatively equivalent, therefore choice may come down to patient preference and safety considerations.

The future for frontline CLL therapy seems bright, Woyach said. Studies are currently aimed at evaluating the most effective combination therapies to allow BTK inhibitor discontinuation, as well as looking at different novel therapeutic approaches as well.

Woyach mentioned the upcoming CLL17 trial, which will be run by the German CLL Study Group and initiated next year. The study will include both fit and unfit patients with CLL of all ages and will evaluate ibrutinib monotherapy versus obintuzumab plus venetoclax versus ibrutinib plus venetoclax. According to Woyach, the results of this study will likely answer many important questions in the space.

“Ongoing and future studies will help continue to move the field forward,” Woyach concluded


  • Woyach J, Eichhorst B, Wu C. Response Comes of Age in Chronic Lymphocytic Leukemia. Presented at ASH Annual Meeting and Exposition. December 7-10, 2019. Orlando, Florida.

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