Beyond progression-free survival (PFS): time to next treatment (TTNT) as a patient-centered metric of clinical benefit in chronic lymphocytic leukemia (CLL)

Outcomes of Patients with Chronic Lymphocytic Leukemia Discontinuing Bruton Tyrosine Kinase Inhibitors Due to Adverse Effects

Continuous treatment with Ibrutinib in 100 untreated patients with TP53 disrupted chronic lymphocytic leukemia: A real-life campus CLL study.

A Multicentre, Retrospective Observational Study to Evaluate the Clinical Outcomes of Patients with Chronic Lymphocytic Leukaemia (CLL) Treated with Idelalisib and Rituximab in the UK (RETRO-idel) - a Cohort of 110 Patients

Comparison of Familial Versus Sporadic Forms of Chronic Lymphocytic Leukemia: An Italian Multicenter Case-Control Study

Real-World Comparison of BCL2 Inhibitor and BTK Inhibitor Therapy in the Front-Line Treatment of CLL Including Patients with Del(17p)/TP53 Mutation

e23263 Background: Newer BTK inhibitors zanubrutinib (ZANU) and acalabrutinib (ACA) are preferred over first-generation ibrutinib for chronic lymphocytic leukemia (CLL) treatment due to better toxicity profiles shown in randomized controlled trials. However, real-world (RW) evidence for treatment outcomes of ZANU and ACA remains limited. Comparing treatment outcomes of ZANU and ACA in diverse RW populations can provide critical insights to inform clinical practice. Methods: This multi-center, RW, retrospective case-controlled study included adult patients receiving ZANU or ACA between 2021 and 2024 within the University of California Health system. RW treatment patterns and outcomes, including time to discontinuation (TTD), time to next treatment (TTNT), and overall survival (OS), were evaluated using a multivariate Cox proportional hazard model with inverse probability of treatment weighting for balancing covariates between groups. Study endpoints included unadjusted and adjusted hazard ratios (HR) for TTD, TTNT, and OS. Results: This study included 505 patients with a mean age of 73 years (SD: 9.6). 300 received ACA, and 205 received ZANU, with a median follow-up time of 26.2 months. Baseline characteristics indicated 63% male, 76% White, 4% Hispanic or Latino, 4% Asian, and 3% African American (AA). Median Area Deprivation Index (ADI) was 3 (interquartile range: 1-5). The 12-month landmark TTD, TTNT, and OS rates were 74% (95% CI: 67-80), 84% (77-89), and 94% (89-96) for ZANU, and 55% (49-60), 79% (74-83), and 94% (90-96) for ACA, respectively. The median TTD was 14.0 (11.3-18.2) months for ACA and 30.1 (26.9-inf) months for ZANU, median TTNT and OS were not reached for both. Adjusted analysis indicated that patients receiving ZANU were associated with a longer TTD compared with ACA (HR [95% CI]: 0.41 [0.34-0.51]). Higher ADI (1.10 [1.01-1.19]), advanced age (1.07 [1.04-1.10]), and a higher Charlson Comorbidity Index score (1.11 [1.05-1.17]) were associated with shorter OS. AA patients were associated with shorter TTNT (HR [95% CI]: 2.55 [1.47-4.42]) and treatment discontinuation (2.64 [1.63-4.27]). Conclusions: In this RW study, ZANU was associated with a lower discontinuation risk than ACA. Poorer survival outcomes were linked to older age, more comorbidities, lower socioeconomic status, and AA patients faced higher risks of treatment discontinuation. These findings emphasize the need for further investigation into underlying causes to guide clinical decisions and optimize CLL treatment strategies in diverse RW settings. ZANU vs ACA Unadjusted Cox HR [95%CI] TTD 0.52 [0.39-0.70] TTNT 0.80 [0.56-1.14] OS 1.07 [0.59-1.94] Adjusted Cox TTD 0.41 [0.34-0.51] TTNT 0.81 [0.63-1.04] OS 1.23 [0.80-1.88] CI, confidence interval; TTD, time to discontinuation; TTNT, time to next treatment; OS, overall survival.

Predictive and Prognostic Molecular Biomarkers in Familial Chronic Lymphocytic Leukemia: A Pilot Monocentric Study

Background: One-year fixed-duration venetoclax-obinutuzumab (Ven-Obi) is a standard-of-care for patients (pts) with previously untreated chronic lymphocytic leukemia (CLL). Due to its ongoing follow-up, the CLL14 study provides unique insights into long-term outcomes of pts after Ven-Obi therapy. Methods: Pts with previously untreated CLL and coexisting conditions were randomized 1:1 to Ven-Obi or chlorambucil-obinutuzumab (Clb-Obi). Primary endpoint was investigator-assessed progression-free survival (PFS). Secondary endpoints included safety, rates of minimal residual disease (MRD), time to next treatment (TTNT) and overall survival (OS). Results: Of 432 enrolled pts, 216 were randomly assigned to Ven-Obi, 216 to Clb-Obi. At a median follow-up of 76.4 months (interquartile range 52.5–80.5), PFS remained superior for Ven-Obi compared to Clb-Obi (median 76.2 vs. 36.4 months; HR 0.40 [95% CI 0.31–0.52], p < 0.0001). Progressive disease (PD) occurred in 67 cases in the Ven-Obi arm with 39 second-line treatments, and in 141 cases in the Clb-Obi arm (with 103 second-line treatments). TTNT was significantly longer after Ven-Obi (6-year TTNT 65.2% vs. 37.1%; HR 0.44, 95% CI 0.33–0.58, p < 0.0001). In both arms, the most frequent second-line treatments were BTK inhibitors (61.5% in the Ven-Obi arm, 55.4% in the Clb-Obi arm). The PFS and TTNT difference between the two arms was maintained across all risk groups, including pts with TP53 mutation/deletion (median PFS 51.9 vs. 20.8 months; median TTNT 57.3 vs. 29.0 months) and unmutated IGHV status (median PFS 64.8 vs. 26.9 months; median TTNT 85.4 vs. 40.6 months). Multivariate analysis identified TP53 deletion/mutation, unmutated IGHV and lymph node size ≥5 cm as independent negative prognostic factors for PFS in pts treated with Ven-Obi. Five years after treatment completion, 17 (7.9% of the intention-to-treat population) pts in the Ven-Obi arm still had uMRD (<10−4 by NGS in peripheral blood), 22 (10.2%) had low (L)-MRD (≥10-4 and <10-2) and 23 (10.6%) high (H)-MRD (≥10-2), compared to 4 (1.9%) uMRD, 9 (4.2%) L-MRD and 18 (8.3%) H-MRD in the Clb-Obi arm. Overall, 48 deaths were reported in the Ven-Obi arm (9 PD related) and 70 in the Clb-Obi arm (26 PD related); 6-year-OS rate was 78.7% in the Ven-Obi and 69.2% in the Clb-Obi arm (HR 0.69 [0.48–1.01], p = 0.052). Second primary malignancies were reported in 30 pts in the Ven-Obi and 18 in the Clb-Obi arm; cumulative incidences 6 years after randomization were 14.2% and 8.5%, respectively (p = 0.071). No new safety signals were observed. Encore Abstract - previously submitted to EHA 2023 The research was funded by: Roche, AbbVie Keywords: chronic lymphocytic leukemia (CLL), combination therapies Conflicts of interests pertinent to the abstract O. Al-Sawaf Consultant or advisory role: AbbVie, Ascentage, AstraZeneca, BeiGene, Eli Lilly, Gilead, Janssen, Roche Honoraria: AbbVie, Adaptive, AstraZeneca, BeiGene, Eli Lilly, Gilead, Janssen, Roche Research funding: AbbVie, BeiGene, Janssen, Roche Educational grants: AbbVie, AstraZeneca, Janssen, Gilead, Roche

ReVenG: A Phase 2 Study of Venetoclax Plus Obinutuzumab Retreatment in Patients with Relapsed Chronic Lymphocytic Leukemia

Real-World Effectiveness and Safety Outcomes of Acalabrutinib Treatment By Line of Therapy in Patients with Chronic Lymphocytic Leukemia and/or Small Lymphocytic Lymphoma

Impact of 1q gain/amplification in multiple myeloma patients treated with daratumumab-based regimens: A retrospective single-center study

Long-Term Evaluation of Efficacy and Safety of Ofatumumab Added to Fludarabine & Cyclophosphamide in Subjects with Relapsed Chronic Lymphocytic Leukemia: Final Analysis of Complement 2 Trial

Real-world comparison of treatment outcomes between BCL2i and 2nd generation BTKi therapy in first-line CLL patients

Real‑world effectiveness and patient-centered outcomes of fixed‑duration vs continuous first‑line therapy in chronic lymphocytic leukemia (CLL)

Background: One-year fixed-duration venetoclax-obinutuzumab (Ven-Obi) has demonstrated significant improvement of progression-free survival (PFS) as compared to chlorambucil-obinutuzumab (Clb-Obi) in patients with previously untreated chronic lymphocytic leukemia (CLL) and coexisting conditions in the CLL14 trial. As high rates of undetectable minimal residual disease (uMRD) suggested deep remissions, long-term efficacy data including patients with high-risk disease is of particular interest. Aims: The aim of this report is to provide updated efficacy and safety data from the ongoing follow-up of the CLL14 study with all patients being off study treatment for ≥ 4 years. Methods: Patients with previously untreated CLL and coexisting conditions were randomized 1:1 to 12 cycles of venetoclax with 6 cycles of obinutuzumab or 12 cycles of chlorambucil with 6 cycles of obinutuzumab. The primary endpoint was investigator-assessed PFS. Secondary endpoints included safety, rates of MRD response (measured every 3-6 months up to 9 years after last patient enrolment), time to next treatment (TTNT) and overall survival. Follow-up is ongoing, all patients are off study treatment. Results: Of the 432 enrolled patients, 216 were randomly assigned to receive Ven-Obi and 216 to receive Clb-Obi. With a current median follow-up of 65.4 months (interquartile range 52.6-69.4), PFS remained significantly superior for Ven-Obi compared to Clb-Obi (median not reached [nr] vs 36.4 months; hazard ratio [HR] 0.35 [95% CI 0.26-0.46], p<0.0001). At 5 years after randomization, the estimated PFS rate was 62.6% after Ven-Obi and 27.0% after Clb-Obi. Overall, 52 cases of progressive disease (PD) with 28 required second-line treatments occurred in the Ven-Obi arm and 132 with 86 second-line treatments in the Clb-Obi arm. TTNT was significantly longer after Ven-Obi (5-year TTNT 72.1% vs 42.8%; HR 0.42, 95% CI 0.31-0.57, p<0.0001). In both arms, the majority of next-line therapies were BTK inhibitors (54.3% in the Ven-Obi arm, 47.1% in the Clb-Obi arm). The PFS and TTNT difference was maintained across all risk groups, including patients with TP53 mutation/deletion (5-year PFS 40.6% vs 15.6%; 5-year TTNT 48.0% vs 20.8%) and unmutated IGHV status (5-year PFS 55.8% vs 12.5%; 5-year TTNT 66.2% vs 25.1%). A multivariable analysis indicated 17p deletion and high disease burden as independent prognostic factors for PFS in patients treated with Ven-Obi. Four years after treatment completion, 39 (18.1% of the intention-to-treat population) patients in the Ven-Obi arm still had uMRD (<10-4 by NGS in peripheral blood), 27 (12.5%) had low (L)-MRD (≥ 10-4 and < 10-2) and 41 (19.0%) high (H)-MRD (≥ 10-2), compared to 4 (1.9%) uMRD, 13 (6.0%) L-MRD and 24 (11.1%) H-MRD in the Clb-Obi arm. Overall, 40 deaths were reported in the Ven-Obi arm (8 PD related) and 57 in the Clb-Obi arm (23 PD related); at 5 years after randomization the estimated OS rate was 81.9% in the Ven-Obi arm and 77.0% in the Clb-Obi arm (HR 0.72 [0.48-1.09], p=0.12). Second primary malignancies were reported in 44 (20.8%) patients in the Ven-Obi arm and 32 (15.0%) in the Clb-Obi arm. No new safety signals were observed. Image:Summary/Conclusion: These data confirm that over 60% of patients who had received 1-year fixed-duration Ven-Obi have remained in remission four years after end of therapy. The majority of patients treated with Ven-Obi still have not required a second line of CLL therapy. Hence, the 1-year Ven-Obi regimen continues to be an effective fixed-duration option for patients with CLL and coexisting conditions, also in the context of high-risk disease.