GENEVA, SWITZERLAND – [Date of Publication] – The European Hematology Association (EHA) 2026 Congress has become a focal point for groundbreaking advancements in the treatment of chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL), two common forms of non-Hodgkin lymphoma. Presentations at the congress highlighted promising therapeutic strategies, offering renewed hope for patients and underscoring the rapid evolution of care in hematological malignancies. Among the most significant developments were an all-oral, fixed-duration regimen combining novel agents for frontline therapy and a potent combination therapy demonstrating improved outcomes in relapsed or refractory settings.
BeOne’s All-Oral Regimen Shows Remarkable Promise in First-Line CLL/SLL
One of the most anticipated presentations focused on BeOne’s wholly owned, all-oral combination of Beqalzi (sonrotoclax) and Brukinsa (zanubrutinib), investigated as a first-line treatment in the Phase I/Ib BGB-11417-101 trial. This innovative approach targets the distinct pathways crucial in CLL/SLL pathogenesis, offering a potentially streamlined and highly effective treatment option for newly diagnosed patients.
The Science Behind the Combination:
Beqalzi, a next-generation B-cell lymphoma 2 (BCL2) inhibitor, is engineered to surpass existing therapies like venetoclax. Its design boasts greater potency and selectivity for BCL2, a protein that promotes cancer cell survival, coupled with a shorter half-life. This profile aims to enhance efficacy while potentially mitigating certain side effects. Brukinsa, a next-generation Bruton’s tyrosine kinase (BTK) inhibitor, targets another critical signaling pathway in B-cell malignancies. By inhibiting BTK, Brukinsa disrupts the signals that drive the proliferation and survival of malignant B-cells. The combination of a potent BCL2 inhibitor and a next-generation BTK inhibitor represents a synergistic approach designed to induce deep and durable responses.
Trial Design and Patient Population:
The BGB-11417-101 trial enrolled treatment-naïve CLL/SLL patients, including those with high-risk genetic mutations such as del(17p) and/or tumor protein p53 (TP53) mutations. These mutations are often associated with more aggressive disease and poorer prognoses, making this patient population a critical focus for novel therapies. The trial employed a novel treatment strategy: a Brukinsa lead-in period followed by a Beqalzi ramp-up, with a protocol-defined elective discontinuation after 96 weeks at the target dose. This fixed-duration approach is a key differentiator, aiming to provide a finite treatment course with the potential for long-term remissions.
The 320mg Beqalzi cohort, which is the focus of the presented data, enrolled 86 patients. These patients have been followed for a median of 34.1 months, providing substantial insight into the regimen’s efficacy and safety.
Compelling Efficacy Data:
The results presented were striking, showcasing unprecedented response rates. Across 135 efficacy-evaluable patients in various cohorts, the overall response rate (ORR) reached an impressive 100%. Within the 320mg Beqalzi cohort specifically, the complete response (CR) rate was a remarkable 59.5%. Crucially, no progression events were observed in this cohort, leading to a 24-month progression-free survival (PFS) of 100%. This level of sustained disease control in treatment-naïve patients, particularly those with high-risk features, is highly encouraging.
Furthermore, the depth of response was underscored by measurable residual disease (MRD) assessments. Undetectable MRD at a sensitivity of 10^-4 (uMRD4) in the 320mg cohort saw a significant increase, rising from 81.2% at week 24 to an exceptional 98.2% at week 96. The best observed uMRD5 reached 87.3%, indicating a profound elimination of leukemia cells. Deep MRD negativity is a strong predictor of long-term PFS and treatment-free intervals in CLL/SLL.
Safety Profile and Tolerability:
The safety profile of the Beqalzi plus Brukinsa combination was generally manageable. Any-grade and grade ≥3 treatment-emergent adverse events (TEAEs) occurred in 98.8% and 60.5% of patients, respectively. Discontinuation of Beqalzi due to TEAEs was low, at 3.5%. Importantly, no clinical or laboratory tumor lysis syndrome (TLS) events, a potential concern with BCL2 inhibitors, were observed. Additionally, no TEAE-related deaths occurred. This favorable safety profile, especially the absence of TLS, is a critical factor for patient tolerability and long-term adherence.
Implications and Future Directions:
While the data from this single-arm Phase I/Ib study is early and requires further validation, the results are undeniably promising. The 100% PFS in the 320mg cohort, while event-immature, suggests a highly effective regimen. The commercial relevance will ultimately hinge on confirmation in randomized Phase III trials, which are already underway. BeOne is actively evaluating Beqalzi plus Brukinsa in pivotal Phase III treatment-naïve CLL studies, including CELESTIAL-TNCLL and CELESTIAL-TNCLL-2.
The strategic advantage for BeOne lies in this combination being a wholly owned, all-oral, fixed-duration regimen. This has the potential to significantly expand the Brukinsa franchise beyond its current role as a continuous BTK inhibitor monotherapy. By offering a fixed-duration option, BeOne aims to directly challenge the dominance of venetoclax-based regimens while simultaneously protecting its long-term share of the BTK inhibitor market. Analyst consensus forecasts project substantial sales for both Beqalzi and Brukinsa, highlighting the market’s anticipation for these innovative therapies. Beqalzi sales are expected to approach $1.3 billion by 2032, with Brukinsa global sales forecasted to reach nearly $7 billion in the same year.
Competitive Landscape:
The first-line CLL/SLL market is highly competitive. Key competitors for the Beqalzi + Brukinsa regimen include established combinations such as Venclexta (venetoclax) plus Gazyva (obinutuzumab) from AbbVie/Roche, Calquence (acalabrutinib) plus Venclexta from AstraZeneca, and Imbruvica (ibrutinib) plus Venclyxto (venetoclax) in Europe. Emerging non-covalent BTK inhibitors, such as Eli Lilly’s Jaypirca (pirtobrutinib) and MSD’s nemtabrutinib, are also poised to add further competition to the BTK inhibitor market.
Lilly’s Jaypirca Demonstrates Significant Benefit in Relapsed/Refractory CLL/SLL
In parallel, Eli Lilly presented compelling data from the global, multicenter, open-label, Phase III BRUIN CLL-322 clinical trial, showcasing the efficacy of Jaypirca (pirtobrutinib) in combination with Venclexta and Rituxan (rituximab) as a second-line or later therapy. This trial addresses a critical unmet need for patients who have relapsed after initial treatments.
Jaypirca: A Next-Generation BTK Inhibitor:
Jaypirca is a highly selective, reversible, non-covalent Bruton’s tyrosine kinase (BTK) inhibitor. Its non-covalent binding mechanism offers a distinct advantage over earlier covalent BTK inhibitors, particularly in patients who may have developed resistance or intolerance to those agents. Combined with Venclexta, a BCL-2 inhibitor, and Rituxan, a monoclonal antibody targeting CD20 on B-cells, this regimen, termed JVR, aims to provide a potent and potentially curative approach in the relapsed setting.
Trial Design and Patient Population:
The BRUIN CLL-322 trial randomized 639 patients with previously treated CLL/SLL to either the JVR arm (Jaypirca + Venclexta + Rituxan) or the VR arm (Venclexta + Rituxan). A significant proportion of patients, approximately 80%, had prior covalent BTK inhibitor therapy, making this trial highly relevant to current clinical practice and the sequencing of treatments in relapsed disease.
Key Efficacy Outcomes:
At a median follow-up of 27.3 months, the JVR regimen demonstrated a significant improvement in PFS. It reduced the risk of disease progression or death by 45% compared to the VR control arm. The 24-month PFS rate was 86.9% for JVR versus 71.8% for VR. While the median PFS was not estimable in the JVR arm, it was 39.7 months in the VR arm, indicating a substantial and clinically meaningful benefit with the addition of Jaypirca.
Beyond PFS, the JVR arm also showed a delayed time to next treatment, a higher complete response rate (31.8% vs. 23.3% in the VR arm), and a significantly higher rate of undetectable MRD (uMRD) at the end of treatment (86.3% vs. 60.7% in the VR arm). These findings suggest that the JVR regimen not only controls disease for longer but also achieves deeper remissions, potentially leading to longer treatment-free intervals.
Overall survival (OS) data remains immature at this interim analysis, with no statistically significant difference observed. However, the substantial PFS benefit and improvements in MRD negativity are strong indicators of long-term efficacy.
Safety and Tolerability:
The safety profile of the JVR arm was comparable to the VR arm. Grade 3 or higher TEAEs were reported in 78.8% of patients in the JVR arm versus 73.0% in the VR arm. Treatment-related discontinuations were also similar, at 5.4% for JVR versus 5.1% for VR. This suggests that the addition of Jaypirca does not significantly increase the toxicity burden of the Venclexta and Rituxan combination.
Clinical Significance and Future Potential:
The data from BRUIN CLL-322 strongly supports Jaypirca plus Venclexta and Rituxan as a potentially practice-changing fixed-duration option for previously treated CLL/SLL patients, especially those who have relapsed after covalent BTK inhibitor therapy. If approved, this regimen could become a cornerstone of second-line or later treatment, offering a finite therapeutic course with deep remissions.
This would expand Jaypirca’s utility beyond its current role as monotherapy after prior covalent BTK inhibitor exposure, positioning it as a vital component in combination strategies for relapsed CLL/SLL.
Competitive Landscape in Relapsed Disease:
The relapsed/refractory CLL/SLL landscape is also highly competitive. The VR regimen is already an established fixed-duration option. Continuous BTK inhibitors like Brukinsa and Calquence remain strong contenders. Furthermore, the emergence of CAR T-cell therapies, such as Bristol Myers Squibb’s Breyanzi, offers a one-time treatment option after both BTK and BCL2 inhibitor therapy, representing another significant advancement in managing relapsed disease.
Eli Lilly’s Strategic Vision:
Eli Lilly’s strategic approach to position Jaypirca across multiple CLL/SLL treatment settings has been significantly bolstered by the BRUIN CLL-322 results, complementing positive data from other trials like BRUIN CLL-321, BRUIN CLL-313, and BRUIN CLL-314. This comprehensive development program underscores Lilly’s commitment to establishing Jaypirca as a versatile and impactful agent in the management of CLL/SLL.
Broader Context: The Evolving Landscape of CLL/SLL Treatment
Chronic lymphocytic leukemia and small lymphocytic lymphoma are among the most prevalent hematological malignancies in adults. GlobalData forecasts indicate a steady increase in diagnosed prevalent cases in the seven major markets, highlighting the persistent and growing need for effective therapeutic interventions.
Targeted therapies, including BTK inhibitors and BCL2 inhibitors, used as monotherapy or in combination, have become the standard of care for treatment-naïve CLL/SLL. However, an important unmet need remains for fixed-duration regimens that can achieve deep remissions, lead to durable treatment-free intervals, and offer manageable toxicity, particularly for patients with high-risk disease.
The advancements presented at EHA 2026, from BeOne’s promising all-oral fixed-duration combination for frontline therapy to Eli Lilly’s compelling data on Jaypirca in the relapsed setting, represent significant steps forward. These developments underscore the dynamism of research in hematology and offer a brighter outlook for patients navigating the complexities of CLL and SLL. The focus on fixed-duration regimens, deep remissions, and manageable toxicity reflects a maturing understanding of how best to treat these diseases, aiming not just for disease control but for long-term quality of life and potential cure. The coming years will be critical in translating these promising trial results into approved therapies that can profoundly impact patient outcomes.
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