As we bid farewell to the past year and step into a new chapter, the field of chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) has seen remarkable progress. Targeted therapies, particularly Bruton's tyrosine kinase (BTK) inhibitors, have not only significantly improved patient survival outcomes but have also driven a paradigm shift away from traditional immunochemotherapy towards a "chemo-free" treatment model.

To mark the beginning of the new year, Hematology Frontier invited Dr. Jianyong Li from the Lymphoma Center at The First Affiliated Hospital with Nanjing Medical University (Jiangsu Province Hospital) to review the key advances in CLL/SLL treatment in 2024. This discussion highlights the evolving role of BTK inhibitors in clinical practice and their future development prospects.

BTK Inhibitors Leading the Way: Ibrutinib Establishing the Foundation of CLL/SLL Therapy

Ibrutinib, the first-generation BTK inhibitor, ushered in the era of targeted therapy for CLL. At the 2024 EHA Annual Meeting, a real-world study led by Professor Shenmiao Yang from Peking University People’s Hospital demonstrated that ibrutinib provided substantial long-term survival benefits and favorable tolerability in both treatment-naïve (TN) and relapsed/refractory (RR) CLL patients. These findings further reinforced the role of ibrutinib as a cornerstone treatment in CLL.

A pivotal study published in Blood, the E1912 trial, compared ibrutinib plus rituximab (IR) to the conventional fludarabine, cyclophosphamide, and rituximab (FCR) regimen as first-line treatment for CLL. With a median follow-up of 5.8 years, results demonstrated a significant progression-free survival (PFS) advantage for the IR regimen over FCR, underscoring the superiority of targeted therapy in the frontline setting.

For intermediate-risk CLL/SLL patients, particularly those with unmutated IGHV, del(11q), or a complex karyotype without TP53 mutations, the final results of the Eradic study, presented at the 2024 ASH Annual Meeting, showed promising potential for ibrutinib plus the BCL-2 inhibitor venetoclax (IV) compared to standard FCR treatment. This combination was particularly effective in achieving higher peripheral blood minimal residual disease (MRD) negativity rates and improved PFS in fit CLL/SLL patients.

Given its well-documented efficacy and safety across multiple clinical trials and real-world studies, ibrutinib remains a preferred treatment option for CLL, as recommended by major clinical guidelines, including those from the National Comprehensive Cancer Network (NCCN) and the Chinese Society of Clinical Oncology (CSCO).

Advancing Efficacy and Safety: Zanubrutinib Strengthens the Treatment Landscape

The next-generation BTK inhibitor zanubrutinib has been structurally optimized to improve selectivity while reducing off-target effects, thereby enhancing efficacy and minimizing adverse events. This has made zanubrutinib a promising therapeutic option for CLL/SLL patients.

At the 2024 ASH Annual Meeting, Professors Shenmiao Yang from Peking University People’s Hospital and Huayuan Zhu from The First Affiliated Hospital with Nanjing Medical University presented a retrospective observational study evaluating the real-world effectiveness of zanubrutinib monotherapy in Chinese CLL/SLL patients. Conducted across 14 medical centers, including Nanjing Medical University and Peking University People’s Hospital, the study reaffirmed the significant clinical benefits of zanubrutinib in CLL/SLL treatment.

In another real-world study led by Professor Jianqing Mi from Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, and published in the American Journal of Hematology, 138 CLL patients who had been treated with zanubrutinib for over three months were analyzed. Among them, 90 were treatment-naïve, and 48 had relapsed/refractory disease. The study assessed long-term survival benefits with a median follow-up of 36.8 months. Additionally, 28 patients received a reduced dose of 80 mg twice daily, allowing for a comparison between standard dosing (160 mg twice daily) and dose-reduced BTK inhibitor therapy.

Findings from this study showed that treatment-naïve patients had a significantly higher three-year PFS rate compared to relapsed/refractory patients (84.3% vs. 64.8%, P = 0.004). Moreover, patients receiving reduced-dose zanubrutinib had significantly lower three-year PFS (82% vs. 57%, P = 0.005) and overall survival (92% vs. 78%, P = 0.031) compared to those receiving full-dose therapy. These results suggest that early zanubrutinib use yields better long-term outcomes, while dose reduction may compromise treatment efficacy.

At the 2024 ASH Annual Meeting, a Phase I/Ib study revealed promising results for the combination of zanubrutinib and the BCL-2 inhibitor sonrotoclax in first-line treatment for CLL/SLL patients. This study demonstrated both strong efficacy and a favorable safety profile, opening new avenues for combination strategies in CLL treatment.

Additionally, the SEQUOIA study, previously published in Lancet Oncology, provided further evidence of zanubrutinib’s superiority over the traditional bendamustine plus rituximab (BR) regimen. A recent update in Journal of Clinical Oncology (JCO) presented the five-year median follow-up data, directly comparing the efficacy and safety of zanubrutinib versus BR in treatment-naïve CLL/SLL patients.

The results showed a significant progression-free survival (PFS) advantage for the zanubrutinib group. At 54 months, the estimated PFS rates were 83.2% for zanubrutinib and 45.2% for BR, while at 60 months, the rates were 78.7% for zanubrutinib and 40.6% for BR. The complete response (CR) and CR with incomplete hematologic recovery (CR/CRi) rates were 20.7% for zanubrutinib and 23.5% for BR, with an overall response rate (ORR) of 97.5% in the zanubrutinib group versus 88.7% in the BR group.

Long-term survival trends also favored zanubrutinib. The estimated overall survival (OS) rate at 54 months was 91.3% in the zanubrutinib group and 87.8% in the BR group, while at 60 months, the OS rates were 89.4% and 86.8%, respectively.

Beyond efficacy, zanubrutinib demonstrated a strong safety and tolerability profile, maintaining disease control while reducing toxicity risks. The SEQUOIA study further confirmed zanubrutinib as a favorable first-line treatment option for treatment-naïve CLL/SLL patients, reinforcing its role as a preferred choice in clinical practice. These findings provide robust evidence supporting zanubrutinib’s widespread adoption in frontline CLL/SLL management.

Beyond the advancements in monotherapy and combination regimens involving ibrutinib and zanubrutinib, the AMPLIFY study, featured in the Best of ASH 2024, further reinforced the potential of fixed-duration chemo-free therapy in CLL. This study evaluated the efficacy and safety of acalabrutinib plus venetoclax (AV) ± obinutuzumab as a first-line treatment compared to conventional chemoimmunotherapy regimens such as FCR (fludarabine, cyclophosphamide, rituximab) or BR (bendamustine, rituximab).

Results demonstrated a significant PFS advantage for the AV regimen over FCR/BR, confirming the effectiveness of targeted therapy combinations in achieving deep and durable responses. Similarly, the AVO regimen (acalabrutinib + venetoclax + obinutuzumab) also showed superior efficacy compared to traditional chemoimmunotherapy, maintaining a high remission rate while offering a manageable safety profile. These findings underscore the increasing clinical value of chemo-free treatment strategies, providing greater flexibility and improved patient outcomes in frontline CLL therapy.

Conclusion: A Transformative Year for CLL/SLL Treatment in 2024

The treatment landscape for CLL/SLL has undergone significant transformation in 2024, marked by multiple groundbreaking advancements. BTK inhibitors, particularly ibrutinib and zanubrutinib, have revolutionized treatment strategies, extending patient survival and improving quality of life. The shift from the era of chemoimmunotherapy to the targeted therapy era represents an unprecedented evolution in CLL/SLL management.

The widespread adoption of BTK inhibitors has played a pivotal role in driving the chemo-free treatment paradigm, offering more effective and safer options for patients. As research continues to refine combination regimens and personalized treatment approaches, the future of CLL/SLL therapy will be increasingly tailored to individual patient profiles.

Looking ahead, continued innovation and the emergence of novel agents will further enhance treatment strategies, bringing brighter prospects for CLL/SLL patients worldwide.