3 Things You Should Know About Advances in CLL Management

The experts

RELEASE DATE: May 1, 2025
EXPIRATION DATE: May 1, 2026

LEARNING OBJECTIVES

Upon successful completion of this activity, you should be better prepared to:

• Assess the role of risk stratification, MRD assessment, and resistance mechanisms in treatment selection and personalization for patients with CLL across multiple therapy lines.
• Analyze trial results from studies that evaluated BCL2 inhibitor– based strategies in patients with CLL across all therapy lines.
• Devise effective strategies to monitor and mitigate treatment-related toxicities in patients with CLL.

Accreditation/Credit Designation

Physicians’ Education Resource^®, LLC, is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

Physicians’ Education Resource^®, LLC, designates this enduring material for a maximum of 0.25 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Acknowledgment of commercial support

This activity is supported by an educational grant from AbbVie Inc.

Off-label disclosure/disclaimer

This activity may or may not discuss investigational, unapproved, or off-label use of drugs. Learners are advised to consult prescribing information for any products discussed. The information provided in this activity is for accredited continuing education purposes only and is not meant to substitute for the independent clinical judgment of a health care professional relative to diagnostic, treatment, or management options for a specific patient’s medical condition. The opinions expressed in the content are solely those of the individual faculty members, and do not reflect those of PER or any company that provided commercial support for this activity.

Instructions for participation/how to receive credit

1. Read this activity in its entirety.
2. Go to https://www.gotoper.com/cll25management-postref to access and complete the posttest.
3. Answer the evaluation questions.
4. Request credit using the drop-down menu.

YOU MAY IMMEDIATELY DOWNLOAD YOUR CERTIFICATE.

Management of patients with chronic lymphocytic leukemia (CLL) has been transformed in recent years by novel targeted therapies that disrupt B-cell receptor signaling. Continuous treatment with the first-generation Bruton tyrosine kinase (BTK) inhibitor ibrutinib, once the paradigm, has been replaced by second-generation BTK inhibitors acalabrutinib and zanubrutinib, and the BCL2 inhibitor venetoclax, with the anti-CD20 monoclonal antibody obinutuzumab as preferred first-line therapy (Table 1).¹ Although BTK inhibitors are generally given continuously, venetoclax with obinutuzumab is a time-limited regimen.^2,3 Care for patients continues to evolve. Here are 3 things you should know when treating patients with CLL.

Table 1. NCCN Guideline–Preferred First-Line Treatment Recommendations¹

1. Time-limited doublet and triplet therapy are being evaluated.

Currently, there is no single standard frontline treatment for patients with CLL. Ultimately, therapy selection is based on factors including genetic risk markers, patient comorbidities, comedications, preference, and logistics.⁴ Doublet therapy, which combines a BTK or BCL2 inhibitor with an anti-CD20 monoclonal antibody or a BTK inhibitor with a BCL2 inhibitor, has been evaluated with promising results.⁵ Notably, the BCL2/BTK inhibitor combination has resulted in deep and durable remissions in a time-limited approach.^6,7

Novel triplet combinations for CLL include a BTK inhibitor, BCL2 inhibitor, and anti-CD20 monoclonal antibody.⁵ Results from the phase 3 AMPLIFY study (NCT03836261) were recently reported. In AMPLIFY, patients with CLL who did not have a deletion of chromosome 17p (del[17p]) or TP53 mutation were randomly assigned to the combination of time-limited venetoclax/acalabrutinib/obinutuzumab, acalabrutinib/venetoclax, or chemoimmunotherapy (investigator’s choice of fludarabine/cyclophosphamide/rituximab or bendamustine/rituximab). Rates of undetectable measurable residual disease (MRD) in the intent-to-treat were highest in patients treated with the triplet regimen (Figure).⁸ With a median follow-up of 40.8 months, the 3-year progression-free survival rate was 76.5% with the doublet, 83.1% with the triplet, and 66.5% with chemoimmunotherapy. The estimated 3-year overall survival rate was 94.1% with the doublet, 87.7% with the triplet, and 85.9% with chemoimmunotherapy (Table 2).⁸ The most common grade 3 or higher adverse event was neutropenia, which occurred in 32.3% of patients receiving the doublet, 46.1% of patients receiving the triplet, and 43.2% receiving chemotherapy.

Updated NCCN Guidelines now list venetoclax plus acalabrutinib with or without obinutuzumab as category 1 preferred regimens for first-line therapy in patients without del(17p) or TP53 mutation.¹

Figure. uMRD* Rates at Key Secondary End Point, EOT, and 3 Months After EOT⁸

Table 2. Results From the Phase 3 AMPLIFY Trial⁸

2. The role of MRD in decision-making is being assessed.

MRD assessment has become a valuable prognostic tool in CLL, but it is not yet approved to guide altering therapy outside of clinical trials. Achieving undetectable MRD at the end of treatment correlates with longer progression-free survival (PFS). Moreover,undetectable MRD4 (MRD levels <10^–4)at the end of treatment with chemoimmunotherapy or time-limited treatment with a BCL2 inhibitor–containing regimen improves survival.¹

Trials such as CAPTIVATE (phase 2; NCT02910583) have explored MRD-guided continuation of treatment, but with current standard practice MRD does not yet guide treatment.^9,10

3. Adverse events still shape outcomes.

Ultimately, keeping patients with CLL on these new lifesaving treatments requires vigilance in managing and mitigating toxicities. It is important to recognize risks of adverse events and provide appropriate mitigation. For example, venetoclax requires step-up dosing to prevent tumor lysis syndrome. Some key adverse events are included in Table 3.¹¹ The incidence of adverse events may increase when agents are combined. Notably, rates of cytopenias, especially neutropenia, are substantially increased in combination treatment with a BTK inhibitor, BCL2 inhibitor, and anti-CD20 monoclonal antibody.⁵ Recognition and appropriate mitigation andmanagement of adverse events are crucial and can lead to improved quality and quantity of life.

Table 3. Select AEs With BTK Inhibitors, BCL2 Inhibitors, and Anti-CD20 mAbs¹¹

Key References

1. NCCN. Clinical Practice Guidelines in Oncology. Chronic lymphocytic leukemia/small lymphocytic lymphoma, version 3.2025. Accessed April 11, 2025. https://www.nccn.org/professionals/physician_gls/pdf/cll.pdf

4. Tausch E, Schneider C, Stilgenbauer S. Risk-stratification in frontline CLL therapy: standard of care.Hematology Am Soc Hematol Educ Program. 2024;2024(1):457-466. doi:10.1182/hematology.2024000656

12. Brown JR, Seymour JF, Jurczak W, et al; AMPLIFY Investigators. Fixed-duration acalabrutinib combinations in untreated chronic lymphocytic leukemia. N Engl J Med. 2025;392(8):748-762. doi:10.1056/NEJMoa2409804

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CME Posttest Questions

1. A 48-year-old man with treatment-naive CLL without del(17p) or TP53 mutation undergoes time-limited therapy with venetoclax and obinutuzumab. At the end of treatment, he remains positive for measurable residual disease (MRD) by 6-color flow cytometry at a sensitivity of 10⁻⁵. Which of the following statements is most accurate regarding the clinical implications of his MRD status?

1. These results should not be used because MRD assessment using flow cytometry is not valid in CLL.

2. His MRD positivity at the 10⁻⁵ threshold is associated with an increased risk of disease progression, but it does not mandate immediate re-treatment.

3. Because he lacks high-risk genetic features, MRD positivity after time-limited treatment does not impact long-term prognosis.

4. Given these results, he should immediately begin treatment with a BTK inhibitor.

2. Which of the following statements is correct regarding results from the AMPLIFY study, which compared acalabrutinib plus venetoclax (AV) with or without obinutuzumab (O) to chemoimmunotherapy in treatment-naive CLL?

1. The undetectable MRD rate at the end of therapy was significantly higher with AV compared with chemoimmunotherapy.

2. There was no difference in the rates of undetectable MRD.

3. Independent Review Committee (IRC)–assessed PFS was significantly higher with AV or AVO compared with chemoimmunotherapy.

4. There was no difference in IRC-assessed PFS between AV or AVO and chemoimmunotherapy.

3. In studies of triplet therapy treatment (BTK inhibitor, venetoclax, and obinutuzumab) in CLL, which of the following treatment-related adverse events was most common?

1. Grade 3 or higher atrial fibrillation

2. Grade 3 or higher infection

3. Grade 3 or higher neutropenia

4. Grade 3 or higher thrombocytopenia

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