Optimal Treatment Combinations in the Management of CLL/SLL

 Key Takeaways

• Obinutuzumab is the preferred anti-CD20 antibody in combination with venetoclax based on evidence of improved efficacy.
• Long-term data suggest improved survival with acalabrutinib + obinutuzumab compared with acalabrutinib alone.
• Venetoclax + ibrutinib is a guideline supported option for some patients.

Overview
Treatment choices in chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) have rapidly expanded in the past decade. There are 3 commonly utilized Bruton’s tyrosine kinase (BTK) inhibitors (ibrutinib, acalabrutinib, zanubrutinib), 2 anti-CD20 antibodies (rituximab and obinutuzumab), a BCL-2 inhibitor (venetoclax), and 2 phosphoinositide 3-kinase (PI3K) inhibitors (idelalisib and duvelisib). Throughout the history of cancer therapy, it has been commonplace to combine therapies to achieve greater efficacy and reduce resistance, raising the question of what the optimal combination strategies with the available CLL/SLL therapies are. 

Optimal Treatment Combinations in the Frontline Management of CLL/SLL
Venetoclax is an appealing agent because it can be administered for a fixed duration, yet patients can achieve clinically durable responses even after treatment discontinuation. It was initially approved in combination with rituximab for patients with relapsed/refractory (R/R) CLL/SLL who have received ≥1 prior therapy based on the randomized MURANO trial results. Later, venetoclax received approval in previously untreated CLL/SLL in combination with obinutuzumab based on the results of the randomized CLL14 trial. In the frontline setting, patients are treated with venetoclax for 1 year or for 2 years in R/R disease. Additional studies, however, have demonstrated that venetoclax in combination with obinutuzumab works better than its combination with rituximab in CLL/SLL.  

An important question is: Which anti-CD20 antibody is the optimal partner for venetoclax? In the randomized phase III CLL11 study, either obinutuzumab or rituximab was combined with chlorambucil compared with chlorambucil alone for patients with previously untreated CLL and coexisting conditions. After a long-term follow-up, the CLL11 study demonstrated an improvement in overall survival (OS) in favor of the obinutuzumab arm vs the rituximab arm (HR: 0.76; P <.0245). The randomized phase III GAIA (CLL13) study compared 3 time-limited venetoclax-containing treatments vs chemoimmunotherapy (CIT) as frontline therapy for fit patients with CLL without TP53 mutations/del(17p). The venetoclax-based arms include: venetoclax plus obinutuzumab, venetoclax plus obinutuzumab and ibrutinib, and venetoclax plus rituximab. In this study, the rate of undetectable minimal residual disease (MRD) (<10^-4) by flow cytometry in the peripheral blood and progression-free survival (PFS) were significantly improved with either the doublet or triplet venetoclax/obinutuzumab containing regimens vs CIT (P <.0001). On the other hand, no benefit in either undetectable MRD or PFS was seen with venetoclax plus rituximab vs CIT. Therefore, I use obinutuzumab as my preferred anti-CD20 antibody when using venetoclax in patients with treatment naive CLL and in select cases with relapsed or refractory disease where I can access obinutuzumab. 

The role for anti-CD20 antibody therapy in combination with a BTK inhibitor is continually evolving. The phase II NCI-2014-00989 study and the large phase III Alliance A041202 trial have both demonstrated that rituximab did not provide additional benefit when used in combination with ibrutinib. While rituximab may still be used with ibrutinib in the context of autoimmune cytopenias, it should not be expected to improve disease control in CLL/SLL. Obinutuzumab was added to either ibrutinib or chlorambucil in the iLLUMINATE study, but the study design did not allow any conclusions to be drawn regarding the benefit of the anti-CD20 antibody therapy. Therefore, for most investigators, the addition of an anti-CD20 antibody to a BTK inhibitor is not commonly used. In contrast, the randomized ELEVATE-TN study investigated acalabrutinib with or without obinutuzumab compared with obinutuzumab plus chlorambucil. As the data have matured, a clinically meaningful improvement in PFS has been demonstrated with the addition of obinutuzumab to acalabrutinib. At 5 years, the PFS rate was 84% with obinutuzumab plus acalabrutinib vs 72% with acalabrutinib alone (HR: 0.51; P <.0001). The 5-year OS rate was 90% and 82%, respectively (HR: 0.56; P = .0556). Obinutuzumab, therefore, provides some benefit to acalabrutinib but the combination requires infusion visits and is associated with additional toxicity of the anti-CD20 antibody. This option may be considered for fit patients who wish to achieve optimal disease control. 

We now have access to several important datasets from studies combining a BTK inhibitor with venetoclax. The GLOW study compared ibrutinib plus venetoclax vs obinutuzumab plus chlorambucil in patients aged ≥65 years with previously untreated CLL without TP53 mutations or del(17p). Not surprisingly, the novel combination of ibrutinib plus venetoclax demonstrated superior PFS and rates of undetectable MRD. In this older patient population, however, toxicity was problematic with significant diarrhea and concerning cardiac signals. In contrast, when the combination of ibrutinib and venetoclax was administered to a younger population of previously untreated patients with CLL/SLL age ≤70 years in the CAPTIVATE study, the regimen demonstrated impressive activity and the associated adverse events were much more tolerable. Ibrutinib plus venetoclax is endorsed by the NCCN guidelines but the combination is yet to be granted FDA approval. We are awaiting results from the ongoing randomized phase III ACE-CL-311 study evaluating the doublet combination of acalabrutinib plus venetoclax vs the triplet combination of acalabrutinib plus venetoclax and obinutuzumab compared with CIT (NCT03836261). 

Is Venetoclax Better With a BTK inhibitor or an Anti-CD20 Antibody in the Frontline Setting?
With the fixed duration of therapy afforded by venetoclax, an important question to ask is whether it is better to use it in combination with a BTK inhibitor or an anti-CD20 antibody. The ongoing phase III MAJIC trial is investigating this question directly. In the MAJIC trial, patients with previously untreated CLL/SLL will be randomly assigned to receive venetoclax in combination with either acalabrutinib or obinutuzumab (NCT05057494). In addition, the phase III CLL17 trial is a 3-arm study looking at ibrutinib alone, or in combination with venetoclax vs obinutuzumab plus venetoclax (NCT04608318). The CLL17 trial study will help to answer the questions regarding the benefits of doublet therapy vs BTK inhibitor monotherapy. 

Efficacy and Safety of PI3K Inhibitors in CLL/SLL
Over the years, PI3K inhibitors have struggled in CLL. Although there is notable activity with these agents, response durations are not as durable compared with the BTK inhibitors or BCL2 inhibitors. Moreso, the adverse events associated with idelalisib or duvelisib can be significant, especially with regard to grade 3 diarrhea or colitis. In the pivotal studies for patients with R/R CLL, idelalisib was combined with rituximab vs rituximab alone; however, duvelisib was studied as monotherapy vs ofatumumab. Idelalisib is FDA approved in combination with rituximab whereas duvelisib is FDA approved as monotherapy, both for patients with R/R CLL/SLL. Generally, in my practice, I consider how much anti-CD20 antibody a patient has previously received and then try to estimate if they are likely to benefit from additional rituximab before deciding on the optimal PI3K inhibitor to administer in the R/R setting. There are currently no approvals of the combination of a PI3K inhibitor with either obinutuzumab, or a BTK or BCL2 inhibitor in CLL/SLL. 

Future Directions and Conclusions
Of note, other agents in the CLL/SLL field include the noncovalent BTK inhibitors such as pirtobrutinib. In the phase I/II BRUIN trial, pirtobrutinib demonstrated an objective response rate of 67% among patients with CLL who have developed resistance to a previously received covalent BTK inhibitor. Based on these results, the ongoing phase III BRUIN CLL-322 trial is investigating fixed-duration pirtobrutinib in combination with venetoclax and rituximab vs venetoclax plus rituximab for previously treated patients with CLL/SLL (NCT04965493). 

In conclusion, we do not yet have extensive data on the relative benefits of monotherapy vs doublet or triplet regimens with these classes of agents. However, venetoclax, when used in combination with obinutuzumab is more efficacious than its use in combination with rituximab. Although there are some benefits with adding obinutuzumab to acalabrutinib, the combination comes with additional toxicity that may not be suitable for all patients. Important emerging studies such as the ongoing ACE-CL-311, MAJIC, CLL17 trials, should soon provide us with more detail on the benefits of combining a BTK inhibitor with venetoclax. At present, however, adding ibrutinib to venetoclax is best done in the younger population where toxicity is reduced. While this combination is not yet FDA approved, it is endorsed by the NCCN guidelines. 

To Learn More, Attend Our Symposia at ASH 2022!
Want to gain more insights from experts on managing patients with CLL and the use of BTK inhibitors for patients with B-cell malignancies? Join Brian Hill, MD, Deborah Stephens, DO, and Jennifer Woyach, MD, in New Orleans (link to live satellite registration page) or online (link to live webcast registration page) for a CME-certified symposium titled "Application of the Latest Data in CLL/SLL: Guidance for Current and Future Treatment Strategies" at the American Society of Hematology Annual Meeting and Exposition.

Also, join me and my colleagues Ian Flinn, MD and Susan M. O'Brien, MD, in New Orleans (link to live satellite registration page) or online (link to live webcast registration page) for another CME-certified symposium titled "Breakthrough Therapeutics for CLL and Other B-Cell Malignancies: Focus on BTK Inhibitors" at the American Society of Hematology Annual Meeting and Exposition. Both programs will be held on Friday, December 9. 

Your Thoughts?
What are the challenges you experience in your practice when it comes to choosing frontline combination treatments for patients with CLL/SLL without TP53 mutations or del(17p)? Answer the polling question and join the conversation in the discussion box below.