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Updates presented at the 2026 European Hematology Association (EHA) Congress demonstrated the ongoing advances in chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). During the VJHemOnc Post-EHA CLL Highlights webinar, leading CLL experts presented abstracts selected by webinar chair Alexey Danilov, MD, PhD, City of Hope, Duarte, CA. From the webinar program, we have highlighted five studies we believe are among the most clinically relevant for current and future CLL management.
BRUIN CLL-322: Fixed-duration pirtobrutinib triplet improves PFS in previously treated CLL/SLL
Fixed-duration venetoclax plus rituximab is an established standard-of-care treatment option for patients with relapsed/refractory (R/R) CLL. However, prospective data remain limited for patients previously treated with covalent Bruton tyrosine kinase inhibitors (BTKis), which are now commonly used in the first-line setting.1
During EHA 2026 and the Post-EHA CLL Highlights webinar, Matthew Davids, MD, MMSc, Dana-Farber Cancer Institute, Boston, MA, presented results from the Phase III BRUIN CLL-322 study (NCT04965493) comparing fixed-duration pirtobrutinib plus venetoclax–rituximab (PVR) with venetoclax-rituximab (VR) in patients with previously treated CLL/SLL.
The study randomized 639 patients 1:1 to receive either PVR (n=321) or VR (n=318). Patients had received a median of two prior lines of therapy, and 79.8% had previously received a covalent BTKi; among these patients, 71.0% had discontinued due to progressive disease.1
PVR significantly improved independent review committee-assessed progression-free survival (PFS) compared with VR, meeting the trial’s primary endpoint (HR 0.547; 95% CI: 0.400–0.748; p=0.0001). Estimated 24-month PFS rates were 86.9% with PVR and 71.8% with VR. Benefit was consistent across prespecified subgroups, including patients with prior covalent BTKi exposure, those who discontinued prior covalent BTKi due to progression, and patients with del(17p)/TP53 mutations.1
PVR treatment was also associated with deeper remissions compared with VR. Among patients with evaluable samples at the end of treatment, peripheral blood undetectable measurable residual disease (uMRD) at 10-4 was achieved in 86% of patients receiving PVR compared with 61% receiving VR.1
Safety was broadly similar between the treatment arms. Grade ≥3 adverse events (AEs) occurred in 78.8% and 73.0% of patients receiving PVR and VR, respectively. Grade ≥3 tumor lysis syndrome occurred less frequently with PVR than with VR (0.9% versus 3.9%). Discontinuation due to treatment-related adverse events (TRAEs) was similar (5.4% versus 5.1%).1
These findings suggest that fixed-duration PVR may represent an effective treatment option for patients with previously treated CLL/SLL, particularly following covalent BTKi therapy.
Sonrotoclax plus zanubrutinib: All-oral frontline combination achieves high uMRD rates in frontline CLL/SLL
Fixed-duration combinations of BTKis and BCL-2 inhibitors (BCL-2i) provide an effective, oral treatment option for first-line CLL/SLL. Ongoing studies are now investigating whether next-generation BTKi-BCL-2i combinations can achieve deeper remissions, reflected by higher rates of uMRD, while maintaining the convenience of an all-oral, fixed-duration approach.2
During EHA 2026 and the Post-EHA CLL Highlights webinar, Chan Cheah, MBBS, Sir Charles Gairdner Hospital, Perth, Australia, presented updated results from a Phase I/Ib study (NCT04277637) evaluating zanubrutinib plus sonrotoclax, a next-generation BCL-2i, in treatment-naïve CLL/SLL.2
Patients received zanubrutinib lead-in therapy for 8–12 weeks before sonrotoclax was introduced using a dose-escalation ramp-up to 320 mg once daily. In total, 86 patients were enrolled in this cohort. Among the 84 efficacy-evaluable patients, the overall response rate (ORR) was 100%, with complete response (CR) achieved in 55%. Median time to response was 2.6 months, no patients experienced disease progression, and the estimated 30-month PFS rate was 100%.2
The best peripheral blood uMRD rate at 10-4 by flow cytometry was 99%, including 100% of patients with del(17p)/TP53 mutations. uMRD rates increased over time, from 81% at Week 24, to 91% at Week 48, and 98% by Week 96. No patient who achieved uMRD at 10-4 subsequently reverted to MRD positivity.2
The most common any-grade treatment-emergent adverse events (TEAEs) included neutropenia (38%), contusion (38%), COVID-19 (33%), and upper respiratory tract infection (30%). Grade ≥3 neutropenia occurred in 29% of patients. No tumor lysis syndrome occurred, and no AEs led to death.2
These Phase I/Ib results suggest that sonrotoclax plus zanubrutinib can achieve rapid, deep remissions in treatment-naïve CLL/SLL, supporting ongoing Phase III evaluation of this all-oral regimen.
ERIC: Real-world outcomes with venetoclax after BTKi therapy
Venetoclax-based therapy is commonly used after BTKi treatment in patients with R/R CLL. However, outcomes in this setting, particularly among patients who discontinue BTKis due to disease progression, remain incompletely characterized.3
During the Post-EHA CLL Highlights webinar, Thomas Chatzikonstantinou, MD, The Institute of Applied Biosciences, Thessaloniki, Greece, presented results from an international, retrospective study conducted by the European Research Initiative on CLL (ERIC), evaluating venetoclax-based treatment after prior BTKi exposure.3
The study included 624 patients who received venetoclax-based therapy after prior BTKi treatment. Venetoclax was administered as monotherapy (n=278, 45%), with rituximab (n=230, 37%), with obinutuzumab (n=78, 13%), or as another venetoclax-based regimen (n=38, 6%). BTKis were the first-line treatment for 153 patients (25%). Overall, 330 patients (53%) had discontinued prior BTKi therapy because of CLL progression.3
The median follow-up was 24 months from venetoclax initiation, the median time to next treatment or death (TTNTD) was 33 months (95% CI: 30–36), and the median overall survival (OS) was 46 months (95% CI: 42–54) in the full cohort.3
Outcomes were significantly worse among patients who discontinued prior BTKis due to progression compared with those who stopped for non-progression reasons (TTNTD: 28 months versus 40 months, p<0.0001; OS: 41 months versus 63 months, p<0.0001).3
In addition, among patients who discontinued BTKi therapy because of progression, median TTNTD was 32 months when BTKi therapy had been used first line compared with 25 months when used in later lines, although this difference was not statistically significant (p=0.089).3
In a multivariable analysis, venetoclax-obinutuzumab was associated with longer TTNTD compared with venetoclax monotherapy (HR 0.26; 95% CI: 0.08–0.85; p=0.03).3
These real-world data demonstrate that outcomes with currently available venetoclax-based therapy remain poor for patients with BTKi-resistant disease, supporting continued development of novel therapeutic strategies.
Reflecting on the clinical implications of the findings, Dr Chatzikonstantinou concluded: “Patients with BTK-resistant CLL should be prioritized for novel treatment strategies within clinical trials before they reach the double-refractory state.”
CLL14: Long-term follow-up of fixed-duration confirms durable disease control with venetoclax-obinutuzumab
One-year fixed-duration venetoclax-obinutuzumab is a standard-of-care frontline regimen for patients with previously untreated CLL. Ongoing long-term follow-up studies are now evaluating the durability of remission and disease control with fixed-duration treatment.4
During the Post-EHA CLL Highlights webinar, Othman Al-Sawaf, MD, University Hospital Cologne, Cologne, Germany, presented the final results from the randomized CLL14 study (NCT02242942) comparing venetoclax-obinutuzumab (Ven-Obi) with chlorambucil-obinutuzumab (Clb-Obi).4
The trial enrolled 432 patients with previously untreated CLL and coexisting conditions, randomized 1:1 to receive either Ven-Obi (n=216) or Clb-Obi (n=216). All patients had been off study treatment for at least eight years at the time of final analysis.4
After a median follow-up of 110.1 months, progressive disease occurred in 87 patients in the Ven-Obi group compared with 144 patients in the Clb-Obi group. This resulted in superior PFS with Ven-Obi compared with Clb-Obi, with median PFS of 76.6 months versus 37.9 months (HR 0.50; 95% CI: 0.39–0.63, p<0.001). Time to next treatment (TTNT) was also significantly prolonged in the Ven-Obi group compared with the Clb-Obi group (median 91.9 versus 52.5 months; HR 0.54 [0.43–0.70], p<0.001).4
Subgroup analyses demonstrated that baseline disease biology impacted long-term outcomes. In the Ven-Obi arm, patients with unmutated IGHV and those with TP53 deletion/mutation had significantly shorter PFS and TTNT than patients without these high-risk features. Multivariable analysis identified del(17p) and unmutated IGHV status as independent adverse prognostic factors for PFS in the Ven-Obi group.4
OS was not significantly different between the treatment arms, the median OS was not reached with Ven-Obi and was 112.7 months with Clb-Obi (HR 0.80 [0.59-1.09], p=0.161). Six years after treatment completion, 10.2% of patients in the Ven-Obi arm had uMRD (<10-4 by next-generation sequencing in peripheral blood).4
Second primary malignancies excluding non-melanoma skin cancers were observed more frequently in the Ven-Obi group than in the Clb-Obi group (19.3% versus 11.2%), including fatal cases in 4.7% and 3.7% of patients, respectively. After adjustment for the follow-up duration, the corresponding incidence rates were 2.6 and 1.5 cases per 1,000 patient-months (p=0.047). No new long-term safety signals were observed during the follow-up.4
The final analysis from the CLL14 study demonstrates the long-term benefit of fixed-duration Ven-Obi in previously untreated CLL and highlights the continued prognostic impact of high-risk genetic features such as unmutated IGHV and TP53 aberrations.4
CaDAnCe-101: BTK degrader BGB-16673 demonstrates durable activity in heavily pretreated CLL/SLL
Resistance to, or intolerance of, BTKis remains an ongoing clinical challenge in R/R CLL/SLL. BTK degradation has emerged as a novel therapeutic strategy by promoting proteasomal degradation of the BTK protein.5
During EHA 2026 and the Post-EHA CLL Highlights webinar, Stephan Stilgenbauer, MD, Ulm University, Ulm, Germany, presented updated Phase I data from the CaDAnCe-101 study (NCT05006716) evaluating the oral BTK degrader BGB-16673, now called tacabrutideg, in patients with heavily pretreated CLL/SLL.5
At the data cutoff, 67 patients received BGB-16673 (50 mg, n=1; 100 mg, n=22; 200 mg, n=17; 350 mg, n=15; 500 mg, n=12). The study population was heavily pretreated, with patients having received a median of four prior lines of therapy. Overall, 94.0% had previously received a covalent BTKi, 20.9% a prior non-covalent BTKi, and 82.1% a BCL-2i.5
The ORR, including partial response (PR) with lymphocytosis, was 85.1% across all treated patients, with a PR or better rate of 77.6%. At the 200 mg dose, the ORR was 94.1%. Median time to first response was 2.8 months, median duration of response was 20.7 months, and the 18-month PFS was 65.2% (95% CI: 50.9–76.2%).5
Safety findings were manageable in this heavily pretreated population. Grade ≥3 TEAEs occurred in 61.2% of patients, most commonly (≥5%) infections (34.3%), neutropenia (25.4%), and thrombocytopenia (7.5%). TEAEs leading to treatment discontinuation occurred in 17.9% of patients, 6.0% of which were considered treatment related. Five patients experienced TEAEs leading to death, all due to infection.5
These early data support continued investigation of BGB-16673 as a novel therapeutic approach for patients with heavily pretreated CLL/SLL, including those previously exposed to both BTK and BCL-2 inhibition. Phase II and III studies evaluating the 200 mg dose are ongoing.5
Together, these studies from EHA 2026 illustrate the continued progression of CLL therapy toward more individualized, time-limited, and mechanism-driven treatment strategies. As treatment sequencing becomes more complex, these findings reinforce the importance of integrating prior therapy exposure, resistance patterns, MRD dynamics, and patient-specific risk factors into clinical decision-making.
References
- Davids M, Eyre TA, Woyach J, et al. Fixed-duration pirtobrutinib plus venetoclax–rituximab versus venetoclax–rituximab for patients with previously treated CLL/SLL: A Phase 3, randomized trial (BRUIN CLL-322). Abstract LB5001. Presented at the European Hematology Association (EHA) 2026 Congress; June 11–14 2026; Stockholm, Sweden.
- Cheah C, Opat S, Lasica M, et al. First-line treatment of CLL/SLL with the all-oral combination of sonrotoclax and zanubrutinib achieves undetectable minimal residual disease rates of >90%, including in patients with del(17p)/TP53. Abstract S145. Presented at the European Hematology Association (EHA) 2026 Congress; June 11–14 2026; Stockholm, Sweden.
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Hampel P, Chatzikonstantinou T, Scarfò L, et al. Outcomes of venetoclax-based treatment in patients with Bruton tyrosine kinase inhibitor (BTKI)-treated chronic lymphocytic leukemia (CLL): An international study conducted by ERIC. Abstract S151. Presented at the European Hematology Association (EHA) 2026 Congress; June 11–14 2026; Stockholm, Sweden.
- Fischer K, Al-Sawaf O, Robrecht S, et al. Venetoclax-obinutuzumab for previously untreated chronic lymphocytic leukemia: final results of the randomized CLL14 study. Abstract S146. Presented at the European Hematology Association (EHA) 2026 Congress; June 11–14 2026; Stockholm, Sweden.
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Stilgenbauer S, Parrondo RD, Thompson MC, et al. BGB-16673, a Bruton tyrosine kinase (BTK) degrader, in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL): A Phase 1 CaDAnCe-101 study update. Abstract S152. Presented at the European Hematology Association (EHA) 2026 Congress; June 11–14 2026; Stockholm, Sweden.
