Leading-edge Clinical Advances in CLL 

1. FLAIR Trial (UK, Frontline, Chemotherapy-Free)

  • In a landmark UK-wide trial (the FLAIR trial) involving 786 previously untreated CLL patients:
    • 94% were alive without disease progression at 5 years when treated with ibrutinib plus venetoclax.
    • That compares to 79% for ibrutinib alone and 58% for standard chemotherapy.
    • Additionally, 66% achieved no detectable bone marrow cancer after 2 years, a much higher rate than other arms.
      The Guardian
  • Results hailed as a milestone in personalized medicine.
    The Guardian

2. CAPTIVATE Trial (Phase 2, Long-Term Follow-Up)

  • Patients (≤ 70 years, both untreated and MRD-guided cohorts):
    • 5.5-year PFS: ~66%, OS: ~97%; fixed-duration cohort: PFS 60%, OS 96%.
    • For del(17p)/TP53-mutated patients: PFS 36%; for others: PFS up to 85%.
    • Most patients (73%) required no further treatment; those retreated had high response rates and excellent survival data.
      Cancer Therapy Advisor

3. Viability of Pirtobrutinib (Jaypirca)

  • FDA-approved in December 2023 for relapsed/refractory CLL/SLL after two prior therapies.
    Wikipedia
  • A recent head-to-head study showed Jaypirca’s higher overall response rate vs. Imbruvica (ibrutinib), meeting non-inferiority goals and trending toward superiority. Further PFS analysis is pending.
    Reuters

4. Zanubrutinib Advances

  • FDA approval of a convenient tablet formulation approved June 2025.
    OncLiveTargeted Oncology
  • SEQUOIA trial: 5-year data demonstrated durable efficacy in CLL/SLL patients with 17p deletions.
    Targeted Oncology
  • Indirect comparison (MAIC) suggests zanubrutinib may offer better PFS than acalabrutinib plus venetoclax.
    OncLive
  • Zanubrutinib + venetoclax shows high response rates in treatment-naïve CLL/SLL.
    OncLive

5. Triplet Regimens

  • A promising triplet of zanubrutinib + venetoclax + obinutuzumab achieved deep remissions and high rates of undetectable minimal residual disease (MRD) in relapsed CLL.
    Targeted Oncology
  • A frontline triplet of Jaypirca + Gazyva + venetoclax achieved nearly 98% MRD negativity in bone marrowand 100% in blood in 41 evaluable patients.
    Reuters

6. Earlier-Phase and Preclinical Developments

  • BTK degraders like BGB-16673, NX-2127, and NX-5948 show early promise in targeting BTK differently—potentially overcoming resistance.
    CLL Society
  • Sonrotoclax (a BCL-2 inhibitor) combined with zanubrutinib produced a remarkable 97% overall response ratein relapsed CLL/SLL.
    CLL Society
  • BGB-16673 alone also showed ~85% overall response rate with favorable safety in relapsed/refractory CLL/SLL.
    OncLive
  • Lisaftoclax (APG-2575) is a climbing BCL-2 inhibitor in multiple Phase 3 trials, including combinations with BTK inhibitors.
    Wikipedia
  • Sonrotoclax continues to be evaluated for resistant CLL.
    Wikipedia
  • Nirogacestat shows preclinical activity in CLL cell lines, particularly with NOTCH1 mutations.
    Wikipedia

Summary Table: 2025 Clinical Data Landscape in CLL

Setting Key Advancement
Frontline (untreated) FLAIR trial: 94% progression-free at 5 years with ibrutinib + venetoclax (no chemo).
MRD-guided fixed therapy CAPTIVATE: durable 5.5-year PFS/OS with excellent retreatment outcomes.
New BTK agents Pirtobrutinib superior responses vs. ibrutinib; zanubrutinib shows strong efficacy and convenience.
Triplet regimens High MRD-negativity (up to 100%) with Jaypirca+Gazyva+venetoclax and zanubrutinib-based triplets.
Novel mechanisms BTK degraders (BGB-16673, etc.) and new BCL-2 inhibitors (Lisaftoclax, Sonrotoclax) showing early promise.

Final Take

The most advanced clinical data highlight chemotherapy-free, highly effective regimens, offering long-term durable remissions, especially for previously untreated patients. Strategic therapy design with MRD-guided management promises tailored remission and treatment breaks. Simultaneously, next-gen agents—BTK degraders and new BCL-2 inhibitors—are pushing the frontier for resistant and high-risk disease.