Brander, Danielle M.

TPS7100 Background: Bruton tyrosine kinase covalent inhibitors (cBTKi) have been transformative in CLL treatment. Despite achieving extended remissions, in most patients disease still relapses despite cBTKi therapy, often associated with BTK C481 mutations. Non-covalent BTKi (ncBTKi), including pirtobrutinib, can overcome this resistance (Sharman et al. ASCO . 2025). Pirtobrutinib received FDA approval in Dec 2025, for R/R CLL/CLL patients pretreated with cBTKi. Rocbrutinib (LP-168) is a highly selective next-generation BTKi that can covalently bind wild-type and gatekeeper mutations (T474X, commonly seen in patients relapsed after pirtobrutinib) and non-covalently target C481-mutated BTK , with preclinical efficacy in treatment-naïve and BTKi-resistant CLL (Gordon et al. IWCLL . 2025). In the rocbrutinib phase 1 trial (NCT04775745), encouraging safety and efficacy have been observed in CLL patients with prior exposure to BTKi and/or BCL2 inhibitor (BCL2i) (Woyach et al. Blood. 2025). Presented here is the design of a phase 3 trial aiming to compare the efficacy of rocbrutinib versus pirtobrutinib in cBTKi-pretreated R/R CLL/SLL patients. Methods: ROCKET-CLL (NCT07342478) is a randomized, open-label, multicenter, phase 3 study comparing rocbrutinib (Arm 1) to pirtobrutinib (Arm 2) in R/R CLL/SLL subjects who previously received treatments including covalent BTKi. Eligible subjects must require treatment per 2018 iwCLL criteria, have measurable lesions by CT, an ECOG performance score of 0-2, and adequate hematologic and other organ functions. About 306 subjects will be randomized 1:1 based on stratification factors such as 17p deletion/ TP53 mutation presence, reasons for discontinuing prior cBTKi, prior BCL2i treatment, and geographic region. Participants assigned to each arm will receive rocbrutinib (200 mg QD) or pirtobrutinib (200 mg QD) tablets continuously until disease progression, unacceptable toxicity, withdrawal, or other study discontinuation criteria are met. The primary endpoint is progression-free survival (PFS), assessed by an independent review committee (IRC) per iwCLL 2018 criteria with CLL (Hallek et al. 2018) and Lugano 2014 criteria with SLL (Cheson et al. 2014). Important secondary endpoints include overall survival (OS), time to next treatment (TTNT), event-free survival (EFS), overall response rate (ORR), duration of response (DOR), PFS assessed by investigator (INV), concordance between IRC and INV PFS, safety and tolerability, and population PK. Exploratory endpoints include health-related quality of life and biomarker assessment. Recruitment is ongoing. Clinical trial information: NCT07342478 .

7037 Background: TRANSCEND CLL 004 (NCT03331198) is a phase 1/2, open-label, nonrandomized, multicohort study in adult patients (pt) with R/R chronic lymphocytic leukemia/small lymphocytic lymphoma with liso-cel mono and liso-cel + ibrutinib combo cohorts. Given the study design, we performed PS matching/weighting to adjust for differences in key covariates between cohorts to compare efficacy and safety. Methods: Here, PS is the probability of receiving combo given the covariates and estimated by logistic regression. Covariates were hemoglobin, LDH, number of prior therapies, platelets, prior BTKi + venetoclax exposure, R/R on prior BTKi, and bulky disease for efficacy; and ALC, bulky disease, CRP, ferritin, and number of prior therapies for safety. PS balancing methods were optimal 1:1 matching, average treatment effect for treated pts (ATT) full matching, and ATT inverse probability of treatment weighting (IPTW). Efficacy endpoints were response (CR rate, ORR) and time to event endpoints (DOR, PFS, OS). Safety endpoints were proportions of pts with any-grade (gr)/gr ≥ 3 cytokine release syndrome (CRS) and investigator-identified neurological events (NE). Results: Fifty-one and 88 efficacy-evaluable pts were treated at dose level 2 (100 × 10 6 CAR + T cells) in the combo and mono cohorts, respectively. Before matching/weighting on PS, odds of achieving CR and overall response were statistically significantly higher for combo (Table). DOR did not differ between cohorts. For PFS and OS, HRs were lower with combo vs mono (not statistically significant [NS]). Odds of gr ≥ 3 CRS/NE were lower with combo vs mono (NS). After matching/weighting, odds of CR (except IPTW ATT) and overall response remained statistically significantly higher in combo. HRs for PFS and OS and ORs for gr ≥ 3 CRS/NE were numerically lower with combo vs mono (NS, except IPTW ATT for PFS). HRs for DOR were less but close to HR of 1. Conclusions: The liso-cel + ibrutinib combo demonstrated a trend for better efficacy and safety vs liso-cel mono, with statistically significant differences for CR rate and ORR. Clinical trial information: NCT03331198 . Efficacy and safety outcomes: combo vs mono. No adjustment ATT optimal 1:1 IPTW - ATT CR rate, OR (95% CI) 2.07* (1.01–4.28) 2.40* (1.05–5.66) 2.00(0.89–4.61) ORR, OR (95% CI) 3.96* (1.68–10.51) 3.43* (1.33–9.71) 4.18* (1.63–11.78) DOR, HR (95% CI) 0.98(0.51–1.87) 0.88(0.43–1.78) 0.96(0.50–1.85) PFS, HR (95% CI) 0.62(0.37–1.02) 0.61(0.35–1.05) 0.59* (0.35–0.98) OS, HR (95% CI) 0.70(0.38–1.28) 0.73(0.37–1.43) 0.66(0.36–1.22) CRS, OR (95% CI) 0.63(0.26–1.56) 0.67(0.24–1.84) 0.69(0.24–1.88) Gr ≥ 3 CRS, OR (95% CI) 0.23(0.01–1.35) 0.49(0.02–5.28) 0.26(0.01–1.94) NE, OR (95% CI) 0.84(0.41–1.68) 0.92(0.40–2.08) 1.10(0.48–2.52) Gr ≥ 3 NE, OR (95% CI) 0.56(0.19–1.45) 0.58(0.16–1.89) 0.68(0.19–2.30) *Statistically significant difference at 5% level.

Abstract The antiapoptotic protein, myeloid cell leukemia-1 (Mcl-1), contributes to the pathophysiology of acute myeloid leukemia (AML) and certain B-cell malignancies. Tumor dependence on Mcl-1 is associated with resistance to venetoclax. Voruciclib, an oral cyclin-dependent kinase (CDK) inhibitor targeting CDK9, indirectly decreases Mcl-1 protein expression and synergizes with venetoclax in preclinical models. This dose escalation study evaluated voruciclib in patients with previously treated hematologic malignancies. Initially, voruciclib was administered daily, continuously, on a 28-day cycle (group 1). After 2 patients with prior allogeneic stem cell transplantation had a dose-limiting toxicity (DLT) of interstitial pneumonitis at 100 mg, voruciclib administration was changed to days 1 to 14 of a 28-day cycle (group 2). Forty patients, 21 with AML and 19 with B-cell malignancies, were enrolled. Patients had a median of 3 prior lines of therapy (range, 1-8). Dose escalation in group 2 was stopped at 200 mg, a dose that achieved plasma concentrations sufficient for target inhibition, without DLTs observed. The most common adverse events were diarrhea (30%), nausea (25%), anemia (22%), fatigue (22%), constipation (17%), dizziness (15%), and dyspnea (15%). In AML, 1 patient achieved a morphologic leukemia-free state, and 2 had stable disease. Voruciclib treatment led to a decrease in MCL1 messenger RNA expression, downregulation of myelocytomatosis (MYC) and NF-κB transcriptional gene sets, and reduced phosphorylation of RNA polymerase 2. Voruciclib on intermittent dosing was well tolerated, with no DLTs, paving the way for evaluation of the combination of voruciclib with venetoclax for patients with previously treated AML. This trial was registered at www.clinicaltrials.gov as #NCT03547115.

Introduction: Complex karyotype (CK, ≥3 chromosome (chr) abnormalities (abn)) is an important adverse prognostic indicator in chronic lymphocytic leukemia (CLL). CK at diagnosis (dx) of CLL, particularly with major structural chr abn (i.e. unbalanced translocation, add, marker, ring chr), called type-2 CK (CK2), has been associated with an increased risk of Richter transformation (RT) (Visentin Haematologica 2022). RT is defined as development of aggressive lymphoma, most often large B-cell lymphoma, in the setting of CLL. In patients (pts) with relapsed/refractory CLL treated with ibrutinib, CK as a continuous variable and the presence of polyploidy were independent predictors for RT. CK is a common finding at the time of RT, and high-CK (≥5) has been associated with short survival in RT, although previous studies predominantly included pts with prior chemoimmunotherapy (CIT) administration for their CLL. The prognostic significance of CK in pts with RT whose prior CLL-directed therapies include only non-CIT, as is the current standard of care for CLL, has not been evaluated. Methods: We conducted a multicenter, retrospective analysis of pts from 14 academic centers. Pts with RT diagnosed between 6/2011 to 6/2023, who had CLL-directed treatment that did not include prior CIT, with stimulated karyotype data available, were included. Pts who did not receive treatment for their CLL prior to developing RT were not included. Baseline pt, disease, and cytogenetics data were collected via chart review at time of CLL diagnosis and at the development of RT. Karyotype abn up to 20 were counted on both CLL tissue (peripheral blood or bone marrow) and RT tissue using IWGMC guidelines (Chun Leuk Res 2010). CK was categorized as CK1 (balanced abn, deletion, aneusomies) or CK2. Polyploidy was defined as ≥58 chrs. Karyotype was considered evolved if one or more chr abn were seen in a follow-up sample of CLL tissue that were not seen at CLL dx.TP53 disruption was defined as presence of del(17p) or TP53 mutation. Overall survival (OS) was measured from RT dx and estimated using the Kaplan-Meier method. Cox regression model was used to identify prognostic factors associated with OS. Results: A total of 64 eligible pts were identified. Median age at RT dx was 65 years (range 40-89) and 71.9% of pts were male. Of those evaluated (n=49), 79.6% had unmutated IGVH. Median number of therapies for CLL prior to RT was 1 (range 1-5) and included BTK inhibitor (n=37), BCL2 inhibitor (n=3), both (n=18), or other non-CIT treatment (n=6). At CLL diagnosis, 54.7% of pts had a CK, and the median number of chr abn was 3 (range 0-20). Of those with CK, 96.9% had a CK2, and 6.3% had a polyploid subclone. TP53 disruption was found in 46% of pts. At time of RT, chr analysis of CLL tissue was available for 38 pts and showed 78.9% had a CK, and the median number of chr abn was 8 (range 0-20). Polyploidy was found in 29.6%. TP53 disruption (46 pts evaluated) was found in 52.2%. Karyotype evolution from dx (35 pts evaluated) occurred in 74.3% of pts. In RT tissue, of those evaluated (n=29), 96.6% were clonally related to the preceding CLL. MYC translocation (45 pts evaluated) occurred in 17.8%. CK (20 pts evaluated) was found in 70%, with a median number of chr abn of 8 (range 0-20). Of those with CK, 33.3% had a polyploid subclone. With a median follow-up of 17.8 months (range 2.1-83.0) there were 42 deaths, with a median OS of 14.3 months (range 6.9-29.1). For this subset of patients with karyotype data available who would go on to develop RT, an exploratory univariable analysis for OS from RT found that increasing number of chr abn as a continuous variable at CLL dx was associated with worse OS (HR 1.10, 95% CI 1.02-1.19, p=0.01). Similarly, at RT, increasing number of chr abn in CLL tissue (HR 1.09, 95% CI 1.02-1.16, p=0.01) and in RT tissue (HR 1.09, 95% CI 1.01-1.18, p=0.03) was also prognostic of survival. Karyotype evolution in CLL tissue at RT (HR 3.02, 95% CI 1.02-8.94, p=0.05) was borderline significant for worse OS. Conclusions: Our multi-center study identified increasing number of chr abn at CLL diagnosis and at time of RT, and clonal evolution in the CLL tissue, are associated with worse OS in pts with RT whose CLL was treated without CIT. Limitations include incomplete cytogenetics data across the cohort and potential variability across institutions in cytogenetics laboratory practices. This provides further evidence for the clinical utility of chr analysis in the modern era of CLL therapy.

Introduction: Richter transformation is the development of an aggressive lymphoma, most commonly diffuse large B-cell lymphoma, in patients (pts) with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Transformation into Hodgkin lymphoma (HT) is a rare event and outcomes in pts with this complication in the current CLL/SLL therapeutic era of small molecule inhibitors (SMI; e.g., Bruton tyrosine kinase inhibitors [BTKi] and BCL2 inhibitors [BCL2i]) are unknown. Methods: We conducted a retrospective study of pts from 12 academic centers. Pts with HT who had not previously received chemotherapy for CLL/SLL-directed treatment (tx) were included. Pt, disease, and tx characteristics were collected. HT was categorized into 3 groups: “Concurrent HT,” defined as HT and CLL/SLL diagnosed simultaneously (within 3 months); “HT without prior CLL/SLL tx,” defined as HT and CLL/SLL diagnosed >3 months apart with the CLL/SLL never treated; and “HT with prior non-chemotherapy tx for CLL/SLL” defined as having received non-chemotherapy CLL/SLL-directed tx prior to the diagnosis (dx) of HT. Overall survival (OS) was measured from HT dx and estimated using the Kaplan-Meier method. Cox regression model was used to identify prognostic factors associated with OS. Results: Within a total cohort of 402 pts with Richter transformation (all histologies) without prior chemotherapy, 41 pts with HT (10%) were identified: 12 with concurrent HT, 10 with HT without prior CLL/SLL tx, and 19 with HT with prior non-chemotherapy tx for CLL/SLL. The median age at CLL/SLL dx was 62 years (range 31-96 years) and 73% were male. At CLL/SLL dx, 67% (14/21 evaluated) had unmutated IGHV, and 24% (8/34 evaluated) had TP53 disruption (del(17p) and/or TP53 mutation). The median age at HT dx was 65 years (range 31-96 years) among all pts. At HT dx, there was no significant difference in highest SUV on PET (median 12.3, range 3-31.1), lactate dehydrogenase (LDH) level (median 242 U/L, range 112-859 U/L), or lymph node longest diameter (median 4.6 cm, range 1.6-25 cm) among the 3 subgroups. The median time from CLL/SLL dx to HT dx was 5.4 years (range 0.3-16.5 years) in pts with HT without prior CLL/SLL tx and 4.2 years (range 0.5-17.3 years) in pts with HT with prior non-chemotherapy tx for CLL/SLL. The median number of prior non-chemotherapy CLL/SLL-directed tx was 1 (range 1-6) and included BTKi only (n=17) and BTKi and BCL2i sequentially (n=2); no patient had received only prior BCL2i. Among the 19 pts with HT with prior non-chemotherapy tx for CLL/SLL, 18 pts were on active tx at time of dx (17 BTKi, 1 BCL2i). Initial HT management included: doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD; n=16), brentuximab vedotin (BV)-AVD (n=10), radiation only (n=2), other systemic tx (n=11), and supportive cares / hospice (n=2). All but 1 of the 11 other systemic tx were various HL tx regimens. Across all pts with available data (n=32), the overall response rate to 1st line HT tx was 78% (69% complete response rate); 13% had progressive disease and 9% (n=3; all with concurrent HT) died within 6 months without formal response assessment. A total of 11 pts received at least 1 additional line of therapy for HT, which included BV (n=4), an immune checkpoint inhibitor (n=1), or both (n=6) at any point beyond 1st line HT tx. Median follow-up from HT dx was 32.8 months (range 2.4-253.8 months). The 36-month OS for the entire cohort was 75% (95% CI: 55-87%). The 36-month OS estimates by subgroups were: 62% (95% CI: 26-84%) in pts with concurrent HT, 100% in pts with HT without prior CLL/SLL tx (no events by 36 months), and 67% (95% CI: 33-87%) in pts with HT with prior non-chemotherapy tx for CLL/SLL. Exploratory univariable analysis identified TP53 disruption at CLL dx (HR 12.36; 95% CI: 2.55-59.84) and lymph node longest diameter (HR 1.32 per 1 cm increase; 95% CI: 1.12-1.55) and LDH 2-fold increase (HR 3.97; 95% CI 1.24-12.68) at HT dx as prognostic for worse OS. HT subgroup was not prognostic. Conclusions: This is the largest report of outcomes in pts with CLL/SLL who develop HT following SMI tx without any prior chemotherapy, representing a contemporary cohort. Prior CLL/SLL tx status was not associated with OS; however, cautious interpretation is required given the sample size. Our findings support the use of appropriate HL-directed treatment in the setting of HT; however, OS estimates remain worse than would be expected in an older adult de novo HL cohort (Cheng Blood Adv 2022).

Background: The primary analysis of the phase 1/2, single-arm, multicenter TRANSCEND CLL 004 (NCT03331198) study with a median follow-up of 21.1 mo showed that a single administration of liso-cel achieved rapid, deep, and durable responses and a manageable safety profile in pts with heavily pretreated, high-risk R/R CLL/SLL, including those with progression on a previous Bruton tyrosine kinase inhibitor (BTKi) and venetoclax failure (primary efficacy analysis set [PEAS]; Siddiqi T, et al. Lancet 2023). With 5 mo of additional follow-up (median of 23.5 mo), liso-cel continued to demonstrate durable CR/CR with incomplete marrow recovery (CRi) and high undetectable MRD (uMRD; 10−4 by next-generation sequencing) rates with no new safety signals. Median duration of response (DOR) was 35.3 mo (95% CI, 12.4-not reached [NR]), and median OS was 30.3 mo (95% CI, 15.0-NR) (Siddiqi T, et al. Blood 2023). Here, we report updated results from TRANSCEND CLL 004 with 16 mo of additional follow-up since primary analysis and a median on-study follow-up of 23.8 mo (range, 0.4-59.6). Methods: Pts must have received ≥ 2 prior lines of therapy (LOTs), including a BTKi (full population). Eligible pts received liso-cel at a target dose of either 50 × 106 (dose level [DL] 1) or 100 × 106 (DL2) CAR+ T cells after lymphodepleting chemotherapy. The primary endpoint was CR/CRi per independent review committee in the PEAS at DL2. Key secondary endpoints were ORR and blood uMRD rate. All pts who received liso-cel and completed or discontinued early from the study were asked to enroll in a separate long-term follow-up (LTFU) study (NCT03435796) assessing safety and OS for up to 15 y after liso-cel. Results: As of the data cutoff (01/12/2024), 118 of 137 leukapheresed pts received liso-cel (safety set), 97 (DL1, n = 9; DL2, n = 88) were efficacy evaluable, and 54 (DL1, n = 4; DL2, n = 50) were in the PEAS. A total of 22 pts were ongoing in TRANSCEND CLL 004, and 19 of 60 eligible pts enrolled to the LTFU study. In the safety set, pts had a median age of 65 y (range, 49-82), and 83% had high-risk cytogenetic markers (del[17p], 42%; TP53 mutation, 47%; unmutated immunoglobulin heavy-chain variable gene, 47%). Median prior LOTs was 5 (range, 2-14); 86% of pts had prior chemoimmunotherapy. In the PEAS at DL2, CR/CRi rate remained at 20%, ORR at 44%, blood uMRD rate at 64%, and marrow uMRD rate at 60%. Median DOR was NR (95% CI, 12.4-NR), with a median follow-up of 31.7 mo (95% CI, 21.3-35.5). Estimated 36-mo DOR rate was 61% (95% CI, 30-81). Median (95% CI) DOR was NR in pts with CR/CRi. Median (95% CI) PFS was 11.9 mo (5.7-26.2) overall, 26.2 mo (11.9-NR) in pts with blood uMRD, and 2.8 mo (0.8-3.2) in pts with detectable blood MRD. Median OS, including 19 pts in the LTFU, was 43.2 mo (95% CI, 14.5-NR). Efficacy outcomes were similar in the full population at DL2. A subgroup of 23 pts who had only prior BTKi exposure and were venetoclax naïve was less heavily pretreated, with a median of 3 prior LOTs (range, 2-11); all pts had prior chemoimmunotherapy. In the efficacy-evaluable pts of this subgroup at DL2 (n = 18), the CR/CRi rate was 22%; ORR was 61%; and median (95% CI) DOR was NR (17.1-NR), PFS was NR (18.0-NR), and OS was 52.2 mo (26.9-NR). In the safety set, rates of any-grade/grade ≥ 3 cytokine release syndrome (85%/8%), any-grade/grade ≥ 3 neurological events (45%/19%), prolonged cytopenia (grade ≥ 3 at Day 30 after liso-cel infusion [54%]), grade ≥ 3 infections (18%), and second primary malignancy (9%) remained the same as previously reported (Siddiqi T, et al. Blood 2023); most pts with prolonged cytopenia had resolution to grade ≤ 2 by Month 3. Forty-six (34%) of 137 leukapheresed pts died after CAR T cell infusion, including 1 additional pt since the previous report with an unknown cause of death at ~14.5 mo after infusion. Persistence of the liso-cel transgene was detected up to 48 months after liso-cel infusion (2/5 evaluable pts at DL2 at Month 48). Conclusions: In this updated follow-up, liso-cel continued to demonstrate durable responses with an extended median OS of 43.2 mo in pts with R/R CLL/SLL. The safety results were similar to those previously reported with no new safety signals. These data confirm the sustained clinical benefit and favorable benefit-to-risk profile of a single treatment of liso-cel in pts with R/R CLL/SLL.

Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are essentially different manifestations of the same disease that are similarly managed. A number of molecular and cytogenetic variables with prognostic implications have been identified. Undetectable minimal residual disease at the end of treatment with chemoimmunotherapy or venetoclax-based combination regimens is an independent predictor of improved survival among patients with previously untreated or relapsed/refractory CLL/SLL. The selection of treatment is based on the disease stage, presence or absence of del(17p) or TP53 mutation, immunoglobulin heavy chain variable region mutation status, patient age, performance status, comorbid conditions, and the agent’s toxicity profile. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of patients with CLL/SLL.

Abstract High-count monoclonal B-cell lymphocytosis (HCMBL) is a precursor condition to chronic lymphocytic leukemia (CLL). We have shown that among individuals with HCMBL, the CLL-International Prognostic Index (CLL-IPI) is prognostic for time-to-first therapy (TTFT). Little is known about the prognostic impact of somatically mutated genes among individuals with HCMBL. We sequenced DNA from 371 individuals with HCMBL using a targeted sequencing panel of 59 recurrently mutated genes in CLL to identify high-impact mutations. We compared the sequencing results with that of our treatment-naïve CLL cohort (N = 855) and used Cox regression to estimate hazard ratios and 95% confidence intervals (CIs) for associations with TTFT. The frequencies of any mutated genes were lower in HCMBL (52%) than CLL (70%). At 10 years, 37% of individuals with HCMBL with any mutated gene had progressed requiring treatment compared with 10% among individuals with HCMBL with no mutations; this led to 5.4-fold shorter TTFT (95% CI, 2.6-11.0) among HCMBL with any mutated gene vs none, independent of CLL-IPI. When considering individuals with low risk of progression according to CLL-IPI, those with HCMBL with any mutations had 4.3-fold shorter TTFT (95% CI, 1.6-11.8) vs those with none. Finally, when considering both CLL-IPI and any mutated gene status, we observed individuals with HCMBL who were high risk for both prognostic factors had worse prognosis than patients with low-risk CLL (ie, 5-year progression rate of 32% vs 21%, respectively). Among HCMBL, the frequency of somatically mutated genes at diagnosis is lower than that of CLL. Accounting for both the number of mutated genes and CLL-IPI can identify individuals with HCMBL with more aggressive clinical course.

Abstract A041202 (NCT01886872) is a phase 3 study comparing bendamustine plus rituximab (BR) with ibrutinib and the combination of ibrutinib plus rituximab (IR) in previously untreated older patients with chronic lymphocytic leukemia (CLL). The initial results showed that ibrutinib-containing regimens had superior progression-free survival (PFS) and rituximab did not add additional benefits. Here we present an updated analysis. With a median follow-up of 55 months, the median PFS was 44 months (95% confidence interval [CI], 38-54) for BR and not yet reached in either ibrutinib-containing arm. The 48-month PFS estimates were 47%, 76%, and 76% for BR, ibrutinib, and IR, respectively. The benefit of ibrutinib regimens over chemoimmunotherapy was consistent across subgroups of patients defined by TP53 abnormalities, del(11q), complex karyotype, and immunoglobulin heavy chain variable region (IGHV). No significant interaction effects were observed between the treatment arm and del(11q), the complex karyotype, or IGHV. However, a greater difference in PFS was observed among the patients with TP53 abnormalities. There was no difference in the overall survival. Notable adverse events with ibrutinib included atrial fibrillation (afib) and hypertension. Afib was observed in 11 patients (pts) on BR (3%) and 67 pts on ibrutinib (18%). All-grade hypertension was observed in 95 pts on BR (27%) and 263 pts on ibrutinib (55%). These data show that ibrutinib regimens prolong PFS compared with BR for older patients with treatment-naïve CLL. These benefits were observed across subgroups, including high-risk groups. Strikingly, within the ibrutinib arms, there was no inferior PFS for patients with abnormalities in TP53, the highest risk feature observed in CLL. These data continue to demonstrate the efficacy of ibrutinib in treatment-naïve CLL.