Consoli, Ugo

Abstract Introduction FD Ibr+Ven is approved as first-line (1L) treatment (tx) for CLL/SLL in 78 countries across Asia, Europe, the Middle East, and South America, plus Australia, Canada, and New Zealand. Clinical trials with up to 5.5 years (yrs) of follow-up have demonstrated progression-free and overall survival benefits of 1L FD Ibr+Ven in pts with CLL/SLL (Wierda WG, ASH 2024; Jacobs R, EHA 2024). Despite established clinical benefits, there is a lack of RW evidence on the effectiveness and tolerability of FD Ibr+Ven outside of clinical trial settings. Here we present pooled data from REALITY-WW and REALITY-2 to understand the usage, factors for therapy decision, clinical response, and safety of FD Ibr+Ven in routine clinical practice. Methods REALITY-WW and REALITY-2 are prospective observational cohort studies. REALITY-WW is an international study; REALITY-2 is conducted in Germany. Both included previously untreated pts with CLL/SLL from hospitals and medical institutions where Ibr+Ven was routinely used. The decision to start FD Ibr+Ven was made prior to and independent of pt enrollment. Pts aged ≥18 yrs with a confirmed diagnosis of CLL/SLL requiring 1L tx per iwCLL 2018 criteria received 3 cycles of Ibr, followed by 12 cycles of FD Ibr+Ven orally (Ibr, 420 mg/d; Ven, 5-week ramp-up to 400 mg/d). Primary end point was overall response rate (ORR) per iwCLL 2018 criteria. Secondary end points and outcomes of interest included tx-emergent adverse events (TEAEs), tumor lysis syndrome (TLS) risk, and factors associated with physician decision to initiate FD Ibr+Ven in routine clinical practice. Results At data cutoff (REALITY-WW: May 2025; REALITY-2: March 2025), 129 pts from both studies received FD Ibr+Ven (REALITY-WW, 81; REALITY-2, 48). The median (range) time on study was 6.4 (0.1-19.0) months (mo). Median (range) age was 65.0 (37.0-87.0) yrs, with 46.5% of pts aged <65 yrs and 53.5% of pts aged ≥65 yrs; 62.8% were male. Median (range) time from diagnosis to FD Ibr+Ven initiation was 38.1 mo (0.1-238.0) and median (range) duration of tx was 6.0 mo (0.1-15.9) for Ibr and 3.2 mo (0.1-8.4) for Ven. A Cumulative Illness Rating Scale score of >6 was observed in 12.6% of pts, with a higher score in pts aged ≥65 vs <65 yrs (18.0% vs 6.9%). TP53 mutations were seen in 7.4% of pts; 52.8% had an unmutated IGHV status. ORR was assessed in the 44 pts with ≥ 1 post-baseline assessment in REALITY-WW. Of these, 39 showed a response by the end of 6 tx cycles (3 cycles of Ibr + 3 cycles of FD Ibr+Ven) and 5 had stable disease. ORR at 6 mo per iwCLL 2018 criteria (partial response [PR] with lymphocytosis [PR-L] or better) was 88.6% (95% CI, 79.3-98.0), including complete responses in 29.5%, PR in 34.1%, and PR-L in 25.0% pts. Among 129 treated pts, TEAEs were reported in 61.2%; diarrhea was the most common TEAE (14.0%). Serious TEAEs and grade 3/4 TEAEs were reported in 12.4% and 8.5% of pts, respectively. The most common grade 3/4 TEAE was myocardial infarction (1.6%). Dose reduction was observed in 13.2% (Ibr) and 2.3% (Ven) of pts, mainly due to tx-associated TEAE/toxicity/TLS. Rates of TEAEs leading to discontinuation, dose reduction, and interruption of ≥1 study tx were 4.7%, 10.9%, and 20.9%, respectively. At baseline (n=129), 18.6%, 45.0%, and 14.7% of pts had high, intermediate, and low TLS risk, respectively, while 20.2% were not assessed and 1.6% had missing data. After the 3-cycle Ibr lead-in, the distribution shifted to 9.3%, 24.8%, and 24.0%, respectively, with 14.7% not assessed and 27.1% missing. There were no TEAEs of TLS and no hospitalizations due to TLS. Seven pts (6 aged ≥65 yrs and 1 <65 yrs) were hospitalized prophylactically for TLS. Prophylactic hospitalization was observed in 8.5% (11/129) of pts with high or medium TLS risk and impaired renal function for whom the Ven ramp-up was initiated; no pts were hospitalized due to laboratory/clinical TLS during the Ven ramp-up period. Physician questionnaire responses (n=126) indicated the most common factors associated with decision to initiate FD Ibr+Ven were administration route advantage (91.3%), overall health status (87.3%), anticipated superior efficacy of tx (84.1%), and general risk factors such as high tumor burden/genetic risk factors (81.0%). Conclusions Overall findings suggest that FD Ibr+Ven is an effective and safe tx for pts with CLL/SLL in a RW population, including those aged ≥65 yrs. Data with longer follow-up will be presented at the meeting.

Abstract Background: Over the last two decades several phenotypic, molecular, and chromosomal markers have been identified that are significantly associated with the prognosis of CLL patients. Therefore, clinicians managing CLL patients would benefit from a simplified prognostic index. Methods: We analyzed prospectively collected data from 337 Binet A CLL patients enrolled in Italian the O-CLL1-GISL protocol with the aim of developing scores capable of predicting treatment free survival (TFS). Factors independently associated with TFS were included in the prognostic indexes. To account for differences in the magnitude of the association between the individual independent factors and TFS, we assigned a weighted risk score to each factor based on ranges of their corresponding hazard ratios (HRs) (i.e., 1 point for HR 1.1-1.9; 2 points for HR 2.0-2.9, etc.). The total risk score was then calculated by the sum of the ratings of each factor on individual basis. Risk groups were identified combining risk categories with a non-statistically different TFS. Results: We developed two scores based on weighted multivariable models: the first included clinical and laboratory parameters [clinical score (c-score)], while the second was based on biological markers [biological score (b-score)] (Table 1). The c-score allowed to predict the TFS of patients through the combination of Rai stage, b2-microglobulin and absolute lymphocyte count (ALC), while the b-score predicted TFS by IGHV mutational status and CD38 expression. The c-score showed a C-statistic of 0.72, while the b-score was 0.67, although cases stratified according to the b-score showed a more specific mRNA/microRNA profile. When the two scores were forced in a multivariate analysis, both showed an independent predictive value on TFS with a similar HR, demonstrating their complementarity. Thus, we attempted to integrate the two scores performing a further multivariate analysis in which all parameters, significantly associated with TFS at univariate analysis, were tested (Table 1). ALC, Rai stage, b2-microglobulin together with IGHV mutational status, resulted independently associated with TFS. We constructed a weighted score [comprehensive score (co-score)], including all the above 4 variables, which allowed the identification of 3 different risk groups with significantly different TFS (Figure 1). The C-statistic of the g-score was 0.75, showing a better concordance than the other two scores. Moreover, its validity was externally validated in a series of 297 newly diagnosed Binet A CLL patients from the Mayo Clinic, USA. Conclusions: Using this multistep process and external validation, we developed a score with high discriminatory power and predictive significance on the individual patient level. Table 1. Univariate and multivariate Cox proportional Hazards Models Variable Univariate analysis Multivariate analysis Clinical model Biological model Comprehensive model HR (95% CI) P HR (95% CI) P score HR (95% CI) P score HR (95% CI) P score Age (years) <60/>60 1.12 (0.73-1.74) 0.59 - - - - - - - - - Sex Male/Female 0.93 (0.6-1.44) 0.93 - - - - - - - - - Rai stage 0/I-II 2.30 (1.47-3.50) <0.0001 2.13 (1.24-3.03) 0.004 0/2 - - - 1.76 (1.11-2.78) 0.015 0/1 ALC (109/L) <10/>10 3.43 (1.99-5.92) <0.0001 2.91 (1.85-5.20) <0.0001 0/2 - - - 2.70 (1.54-4.72) 0.001 0/2 b-2 microglobulin normal/elevated 3.04 (1.96-4.70) <0.0001 2.78 (1.79-4.30) <0.0001 0/2 - - - 2.65 (1.66-4.21) <0.0001 0/2 LDH normal/elevated 1.25 (0.57-2.71) 0.57 - - - - - - - - - CD38 negative/positive 3.22 (2.06-5.02) <0.0001 - - - 2.11 (1.15-3.16) 0.02 0/2 1.40 (0.80-2.42) 0.24 - ZAP-70 negative/positive 2.34 (1.51-3.61) <0.0001 - - - 1.21 (0.70-2.16) 0.485 - 1.0 (0.98-1.01) 0.72 - IGHV mutated/unmutated 3.57 (2.32-5.50) <0.0001 - - - 2.10 (1.12-3.90) 0.019 0/2 2.39 (1.27-4.50) 0.007 0/2 FISH risk low+int/high 2.93 (1.46-5.90) 0.002 - - - 1.65 (0.76-3.34) 0.216 - 1.80 (0.84-3.88) 0.13 - Abbreviations: ALC: absolute lymphocyte count; CI: confidential interval; HR: hazard ratio. Figure 1. TFS according to comprehensive progression risk score. Figure 1. TFS according to comprehensive progression risk score. Disclosures Shanafelt: Cephalon: Research Funding; Glaxo-Smith-Kline: Research Funding; Genentech: Research Funding; Hospira: Research Funding; Celgene: Research Funding; Jannsen: Research Funding; Polyphenon E International: Research Funding; Pharmacyclics: Research Funding. Kay:Genentech: Research Funding; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Hospira: Research Funding; Tolero Pharma: Research Funding; Pharmacyclics: Research Funding.