At the European Hematology Association (EHA) 2026 Congress, several therapies for patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) have shown promise.
BeOne’s oral regime shows promise
BeOne Medicines’ wholly owned, all-oral combination of Beqalzi (sonrotoclax) plus Brukinsa (zanubrutinib) was investigated as a first line treatment in the Phase I/Ib BGB-11417-101 trial.
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Beqalzi is a next-generation B-cell lymphoma 2 (BCL2) inhibitor designed to differentiate from venetoclax through greater BCL2 potency and selectivity and a shorter half-life; Brukinsa is a next-generation Bruton’s tyrosine kinase (BTK) inhibitor.
The trial included patients with del(17p) and/or tumor protein p53 (TP53) mutations.
In BGB-11417-101, treatment-naïve CLL/SLL patients received a Brukinsa lead-in followed by Beqalzi ramp-up, with protocol-defined elective discontinuation after 96 weeks at the target dose. The 320mg Beqalzi cohort enrolled 86 patients and had a median follow-up of 34.1 months.
In 135 efficacy-evaluable patients across cohorts, the overall response rate (ORR) was 100%; in the 320mg cohort, the complete response rate was 59.5%, and no progression events were observed, with 24-month progression-free survival (PFS) of 100%.
Any-grade and grade ≥3 treatment-emergent adverse events (TEAEs) occurred in 98.8% and 60.5% of patients, respectively, with 3.5% discontinuing Beqalzi due to TEAEs. No clinical or laboratory tumor lysis syndrome and no TEAE-related deaths occurred. Undetectable measurable residual disease at 10^-4 (uMRD4) in the 320mg cohort increased from 81.2% at week 24 to 98.2% at week 96, and the best uMRD5 was 87.3%.
Despite the depth of response, the data remains early from a single-arm Phase I/Ib study. The absence of progression events is encouraging but also means PFS remains event-immature, and the commercial relevance of the regimen will depend on randomised Phase III confirmation.
The most relevant competitors for Beqalzi + Brukinsa in first-line CLL/SLL include AbbVie/Roche’s Venclexta (venetoclax) plus Roche’s Gazyva (obinutuzumab), AstraZeneca’s Calquence (acalabrutinib) plus Venclexta, and Johnson & Johnson/AbbVie’s Imbruvica (ibrutinib) plus Venclyxto (venetoclax) in Europe.
Emerging non-covalent BTK inhibitors, including Eli Lilly’s Jaypirca (pirtobrutinib) in BRUIN CLL-313/314 and MSD’s nemtabrutinib in BELLWAVE-011, could add competition to the continuous BTK inhibitor market in first-line CLL/SLL. BeOne is also evaluating Beqalzi plus Brukinsa in Phase III treatment-naïve CLL studies, including CELESTIAL-TNCLL and CELESTIAL-TNCLL-2.
BeOne’s key strategic advantage is that Beqalzi + Brukinsa is a wholly owned, all-oral, fixed-duration regimen that could extend the Brukinsa franchise beyond continuous BTK inhibitor monotherapy. Strategically, BeOne is trying to convert Brukinsa’s strength in continuous BTK inhibitor therapy into a wholly owned fixed-duration franchise, directly challenging venetoclax-based regimens while protecting its long-term share of the BTK inhibitor market. According to GlobalData’s analyst consensus forecast, Beqalzi sales are expected to reach almost $1.3bn by 2032, while Brukinsa global sales are forecast to reach nearly $7bn in the same year.
Lilly’s Jaypirca data
Also at EHA, Eli Lilly presented data from the global, multicenter, open-label, Phase III BRUIN CLL-322 clinical trial.
This trial evaluated the safety and efficacy of Jaypirca, a highly selective, reversible, non-covalent Bruton’s tyrosine kinase (BTK) inhibitor, in combination with Venclexta, a B cell lymphoma 2 (BCL-2) inhibitor, and Roche’s Rituxan (rituximab) as a second-line or later therapy in patients CLL and SLL.
In BRUIN CLL-322, 639 patients with previously treated CLL/SLL were randomized 1:1 to fixed duration Jaypirca plus Venclexta and Rituxan (JVR) or Venclexta plus Rituxan (VR). Around 80% of patients had received prior covalent BTK inhibitor therapy, making the trial highly relevant to current relapse sequencing.
At a median follow-up of 27.3 months, JVR reduced the risk of disease progression or death by 45% versus VR, with a 24-month PFS of 86.9% versus 71.8%. Median PFS was not estimable with the JVR arm versus 39.7 months with the VR control arm.
The JVR arm also showed delayed time to next treatment, achieved a higher complete response rate (at 31.8% versus 23.3% in the VR arm), and higher end of treatment peripheral blood undetectable minimal residual disease at 10^-4 (at 86.3% versus 60.7% in the VR arm).
Overall survival (OS) remained immature, with no statistically significant difference at this interim analysis.
Grade 3 or higher TEAEs were reported in 78.8% in the JVR arm versus 73.0% in the VR arm, with similar treatment-related discontinuations at 5.4% in the JVR arm versus 5.1% in the VR arm. Overall, the data support JVR as a potentially practice-changing fixed-duration option for previously treated CLL/SLL, particularly in patients who were previously exposed to covalent BTK inhibitors.
If approved, JVR could become a strong fixed-duration second-line or later option for patients with CLL/SLL who relapse after covalent BTK inhibitor therapy and remain suitable for Venclexta-based treatment. The regimen would expand Jaypirca beyond its current role as a monotherapy after prior covalent BTK inhibitor exposure, and position it as a potential combination backbone in relapsed CLL/SLL.
Competition remains high, with VR already established as a fixed-duration regimen. Brukinsa and Calquence also remains as strong continuous BTK inhibitor options, and Bristol Myers Squibb’s Breyanzi (lisocabtagene maraleucel) offering a one-time chimeric antigen receptor T-cell therapy option after both BTK and BCL2 inhibitor therapy.
Eli Lilly’s strategy to move Jaypirca across multiple CLL/SLL treatment settings has been strengthened by BRUIN CLL-322, together with positive data from BRUIN CLL-321, BRUIN CLL-313, and BRUIN CLL-314.
CLL and SLL are among the most common haematological malignancies in adults. According to GlobalData’s Chronic Lymphocytic Leukemia: Opportunity Assessment and Forecast – Update report, diagnosed prevalent cases of CLL/SLL in the seven major markets (7MM: the US, France, Germany, Italy, Spain, the UK, and Japan) are expected to increase from 429,348 cases in 2026 to 478,279 cases by 2032. Targeted therapies, including BTK inhibitors and BCL2 inhibitors used alone or in combination, have become standard-of-care options for treatment-naïve CLL/SLL. However, an important unmet need remains for fixed-duration regimens that can deliver deep remissions, durable treatment-free intervals, and manageable toxicity, particularly in high-risk patients.Â
