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CLL: Personalizing 1L Tx
My Take on Personalizing First-line Treatment for Patients With CLL

Released: October 22, 2020

Expiration: October 21, 2021

William G. Wierda
William G. Wierda, MD, PhD
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The clinical development of targeted agents for chronic lymphocytic leukemia (CLL) has greatly improved patient outcomes, even while standards on when to start treatment have remained the same. In CLL, the first-line setting presents the best opportunity to achieve treatment objectives. Clinicians must consider multiple factors to select the optimal first-line treatment for a particular patient. These considerations include patient age, comorbidities, and performance status; presence of del(17p)/TP53 mutation; and IGHV mutation status. Below, I share how I individualize treatment for my patients based on these different factors.

Patients Who Are Older (Aged ≥ 65 Years) or With Comorbidities, and With No del(17p)/TP53 Mutation
This group comprises approximately 75% of patients with CLL. Because cure is not an option in this population, long-term disease management is an important goal when selecting first-line treatment. Comorbidities, concurrent medications, limitations in provider access, and financial constraints are more common among these patients, along with renal insufficiency and a need for anticoagulation therapy. Other important factors to consider include patient preferences along with the need for social distancing and minimizing potential exposure to COVID-19 by reducing provider visits. 

Phase III studies demonstrated improved outcomes with treatments based on Bruton’s tyrosine kinase (BTK) or BCL-2 inhibition vs chemoimmunotherapy (CIT), which no longer has a therapeutic role for this group. Treatment based on the BTK inhibitors ibrutinib and acalabrutinib is highly effective—indeed, the median PFS has not been reached in phase III trials of these agents and is expected to be similar for those with mutated or unmutated IGHV. However, this approach commits patients to continuous treatment for many years along with potential toxicities. Monitoring at treatment initiation is less intense compared with the BCL-2 inhibitor venetoclax, allowing for fewer provider visits and labs. Given the continuous nature of treatment, financial considerations can be a major issue for patients on a fixed income who do not have supplemental insurance to cover drug cost.

Treatment with venetoclax is also highly effective and differs from BTK inhibitors in that it is given for a fixed duration of 1 year in the first line; during the first 6 months, venetoclax is administered with obinutuzumab (which is given alone for the first cycle). Most patients achieve very deep remission with undetectable measurable residual disease (uMRD), with similar response rates for those with mutated vs unmutated IGHV. There is a trend toward shorter PFS among patients with unmutated IGHV with long-term follow-up after treatment, but preliminary data suggest that retreatment with BCL-2 inhibition is a reasonable option, particularly for those who have a first remission lasting more than 2 years.

In my practice, I prioritize remission and time off treatment, making BCL-2 inhibitor–based therapy my preferred treatment for this group, if the patient has adequate renal function. BTK inhibitors are also reasonable choices, and both acalabrutinib and ibrutinib have received category 1 recommendation in the NCCN guidelines. It is vital to include patients in the treatment decision because there is currently no known survival advantage among these first-line targeted options.

Patients Who Are Younger (Aged < 65 Years) and Fit, and With No del(17p)/TP53 Mutation
Up to 15% of patients with CLL are in this group, for whom IGHV mutation status and depth of remission are important considerations.

Patients with CLL and mutated IGHV can experience very long and durable remission following fixed-duration treatment. Approximately one half of patients achieve a PFS lasting beyond 10 years, and there is the potential for cure with standard fludarabine, cyclophosphamide, and rituximab (FCR) treatment. This potential for cure has not been observed with other CIT regimens, such as bendamustine plus rituximab. Because of the depth of remission achieved with fixed-duration venetoclax plus obinutuzumab, my preference is to use this regimen in patients who do not want FCR.

Patients with CLL and unmutated IGHV can also experience long and durable remissions with fixed-duration treatment but are anticipated to eventually relapse and require retreatment. Treatment recommendations in this setting vary among CLL experts because there are multiple good treatment options. IGHV mutation status does not appear to predict response to BTK or BCL-2 inhibition. With BTK inhibitor–based treatment, PFS appears to be similar between patients with mutated vs unmutated IGHV, whereas fixed-duration BCL-2 inhibitor–based treatment appears to be associated with shorter PFS for those with CLL and unmutated IGHV. Selecting BTK inhibitor–based treatment commits patients to long-term continuous treatment; this approach is preferred for patients with renal insufficiency but presents challenges to those with provider access issues and a desire to limit provider visits. Younger patients generally experience fewer toxicities with BTK inhibition. In my practice, I prefer BCL-2 inhibitor–based, fixed-duration treatment with the expectation of retreatment at a later date. I favor this approach because it limits time on treatment while reducing the risk for toxicities and rapid disease evolution.

Patients With del(17p)/TP53 Mutation
Up to 10% of patients fall into this high-risk group, and a long-term management strategy is critical for this population, particularly for younger individuals. Patients with del(17p)/TP53-mutated CLL should not receive CIT. Although targeted therapy greatly improves PFS in this population, the PFS is still shorter than that observed in patients without del(17p)/TP53 mutation. Comparing across trials, PFS appears to be better with first-line BTK inhibitor–based vs BCL-2 inhibitor–based treatment in this group. Due to the proliferative nature of del(17p)/TP53-mutated CLL, along with its propensity to develop resistance and evolve to more aggressive disease, continuous treatment with BTK inhibitor–based treatment currently is preferred. The combination of a BCL-2 inhibitor plus an anti-CD20 antibody can be used for patients with disease that becomes refractory to BTK inhibition, with the goals of debulking and achieving continued disease control while buying time to review clinical trial options and plan for allogeneic stem cell transplant in younger patients.

Final Thoughts
First-line CLL represents the optimal setting for achieving treatment objectives with all treatment modalities. I remain very optimistic and highly motived to develop clinical trials that work toward developing modalities that achieve a higher rate of uMRD with shorter treatment duration along with the potential for cure.

Your Thoughts
What are your most pressing questions about the care of your patients with CLL? Please let us know in the discussion box below so that we can consider them for our upcoming virtual symposium.

Be sure to join my colleagues Jeremy S. Abramson, MD, MMSc; Brian Hill, MD, PhD; and me for our upcoming virtual satellite symposium at ASH 2020 on Friday, December 4, to learn more about optimizing the care of patients with CLL.

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In your current clinical practice, which of the following therapies are you recommending for most of your patients with previously untreated CLL?
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