CLL Pts Research Articles

Real-World Outcomes of Zanubrutinib Monotherapy in Chronic Lymphocytic Leukemia: A Multicenter Retrospective Study

Background The second-generation Bruton's Tyrosine Kinase inhibitor (BTKi) zanubrutinib had better BTK specificity and less off-target inhibition than first-generation BTKi ibrutinib. SEQUOIA study demonstrated superior efficacy of frontline zanubrutinib than bendamustine-rituximab combination, and ALPINE study showed improved overall response rate (ORR) and progression free survival (PFS) of zanubrutinib than ibrutinib in relapsed/refractory chronic lymphocytic leukemia (R/R CLL). Meanwhile, adverse event (AE) remained one of the main reasons of zanubrutinib dose reduction and discontinuation. We previously reported the first real-world data of zanubrutinib monotherapy in Chinese CLL patients in our single center, demonstrating zanubrutinib discontinuation significantly deteriorated PFS and overall survival (OS). Herein, we reported the updated results to a multicenter scale, with a special focus on the impact of zanubrutinib dose reduction. Methods From Aug. 2020 to Mar. 2023, CLL pts received zanubrutinib monotherapy for at least 3 months in 7 medical centers in Shanghai were enrolled. Data cut-off time was Jul. 2023. AEs were evaluated and graded according to CTCAE 5.0 and IWCLL criteria. ORR included partial response with lymphocytosis or above. Results In total, 124 pts were enrolled and analyzed. 83 (66.9%) were treatment-naïve (TN) pts and 41 (33.1%) were R/R pts. Zanubrutinib was given 160mg, twice a day. The median age of zanubrutinib initiation was 68 years old (range, 37-87) with a M/F ratio of 2.1:1. Among evaluable pts, 25.0% had TP53 aberration (deletion and/or mutation) and 45.2% had unmutated IGHV. With a median follow-up time of 21.8 months, ORR of the entire cohort, TN and R/R pts were 93.5%, 96.4% and 87.8%, respectively. The estimated PFS and OS rates at 24 months in the entire cohort were 79.6% (95%CI 75.0-84.2%) and 94.2% (95%CI 91.9-96.5%). When stratified by line of therapy, the estimated 24-month PFS rates of TN and R/R pts were 82.7% (95%CI 77.5-87.9%) and 71.8% (95%CI 62.1-81.5%), and 24-month OS rates were 96.1% (95%CI 93.9-98.3%) and 89.1% (95%CI 83.1-95.1%), respectively. Pts with TP53 aberration had a trend of inferior PFS ( P=0.102), and pts received 1 st or 2 nd line zanubrutinib monotherapy had significantly longer PFS compared with 3 rd line or above ( P<0.001) (Fig.1A). No significant impact of gender, age, Binet or Rai stages, 11q deletion or IGHV mutation status on PFS or OS was observed. One hundred and two (82.3%) pts experienced AEs of any grade, and 30 (24.2%) pts experienced AEs of grade 3 or above. The most common grade 3 or above AEs were neutropenia (10.5%) and pneumonia (8.1%). Two pts (1.6%) experienced grade 2 atrial fibrillation. AEs of interest (AEI) are shown in Table 1. Overall, 21 (16.9%) pts had zanubrutinib dose reduction, and the most common reason was AE (61.9%). Zanubrutinib reduction was associated with both inferior PFS (Fig.1B) and OS. Nineteen (15.3%) pts had zanubrutinib discontinuation, and the most common reason was progressive disease (57.9%). Conclusion In our real-world study, the efficacy of zanubrutinib monotherapy in both TN and R/R Chinese CLL pts were slightly inferior to that of clinical trials. Pts receiving ≤ 2 nd line zanubrutinib monotherapy had significantly improved PFS. The toxicity spectrum was similar to data previously reported. Despite an improved safety profile, AE remained the main reason of zanubrutinib dose reduction, and dose reduction significantly associated with shorter PFS and OS. Therefore, better treatment strategies such as combined targeted therapy are required to improve the outcomes of these pts.

Initial Results of a Phase 2 Study of Venetoclax Added to Ibrutinib to Eliminate Ibrutinib Resistance Mutations in CLL

CONCLUSION BTK inhibitors (BTKi) are an important treatment for CLL. As BTKi are given until intolerance or disease progression, resistance is a major challenge. Progressive disease (PD) during BTKi treatment is associated with mutations BTK itself, or the immediate downstream protein, PLCG2. These can be detected 9-12 months prior to PD allowing for intervention. Venetoclax (VEN) is effective after IBR treatment, decreases BTK C481S mutation VAF, and can be combined with IBR. Based on these data, this phase 2 study adding VEN to IBR in patients (pts) with resistance mutations (RMUT) was conducted to test the hypothesis that adding VEN could eliminate molecular resistance. CLL pts taking IBR and with a detectable RMUT with or without PD were eligible. Included RMUT were in BTK at C481 and T474 or in PLCG2 at L845, D334, D1140, R665, and S707. Eligible pts continued IBR and added VEN. VEN was given in cycles (C) of 28 days with standard 5-week dose ramp-up to 400mg daily. Response was assessed after C12 and C24 by iwCLL 2008 criteria. Pts achieving a complete remission (CR) or CR with incomplete marrow recovery (CRi) and undetectable minimal residual disease (uMRD) to a level of 10-4 in both blood and marrow discontinued treatment. Those without a uMRD CR/CRi continued through C24 then discontinued if in uMRD CR/CRi. If this response was still not achieved after C24, they stopped IBR and continued VEN alone. Sequencing for RMUT was performed using an assay with a sensitivity of ≥0.5% VAF on sorted CD19+ B-cells. The primary endpoint is the rate of undetectable RMUT after C12 of IBR and VEN. Secondary endpoints are rate of uMRD CR/CRi after C12, progression-free (PFS), and overall survival (OS). C12 assessments missed due to the COVID-19 pandemic were considered non-assessable (NA). A second analysis included delayed C12 assessments. Adverse events (AEs) were graded according to the CTCAE v5 except hematologic AEs which used iwCLL criteria. Kaplan Meier methods were used to assess PFS and OS. All statistical analyses were performed using SAS version 9.4 (SAS Institute, Inc., Cary, NC). Data cut was 7/13/2023. A total of 28 pts were enrolled between 3/2019 and 2/2022 with baseline characteristics in the Table. The median follow up was 31.7 months (range 2.8-47.0) and 8 (29%) pts remain on treatment, 9 (32%) in follow up off treatment, 10 (40%) off study, and 1 (4%) died. BTK C481S testing was available after baseline at time of analysis. After C12, 13/27 (48%) pts who had a BTK C481S mutation at baseline had undetectable BTK C481S (uBTK C481S). This increased to 16/27 (59%) with C12 delayed assessments. 19/27 (70%) pts had uBTK C481S at anytime on study with a median time to uBTK C481S of 6 months (range 2.0-19.8). Of these 6/19 (32%) regained detectable BTK C481S with a median duration of uBTK C481S of 13.8 months (range 5.3-28.8) and 3/6 had PD. After C12 the overall response rate (ORR) was 71% (4 CR, 4 CRi, 12 partial remissions [PR], 4 stable disease [SD], 1 PD, 3 NA). Including delayed assessments (at C16, C19, and C19), the ORR was 79% (NA->PR n=2, PR->CR n=1). uMRD CR/CRi was attained in 5/28 (18%) and 6/28 (21%) pts after C12 and including delayed assessments, respectively. 12/28 (43%) pts discontinued treatment due to response: 9/28 (32%) in uMRD CR/CRi (C12 n=4, C19 n=1, C25 n=4), 3/28 (11%) electively in CR with detectable MRD (n=1, C12) or PR with uMRD (n=2, C25). Eight (36%) pts had PD with 1 Richter Transformation. The median PFS and OS were 40.7 months (95% CI: 35.9-not reached) and not reached, respectively (Figure). Hematologic AEs were frequent with lymphopenia (75%, 46% grade [gr] 3+), thrombocytopenia 68%, 7% gr 3+), neutropenia (61%, 14% gr 3+), and anemia (43%, 0% gr 3+). AEs experienced by >40% of pts were hypocalcemia (75%), diarrhea (75%), weight loss (57%), hypertension (57%), increased lactate dehydrogenase (54%), nausea (54%), dizziness (50%), vomiting (50%), flu like symptoms (43%), and neoplasms (43%). Gr 3 non-hematologic AEs occurring in >10% of pts were hypertension (21%) and diarrhea (14%). Seven (25%) patients had COVID-19 (all gr 2). There were no episodes of tumor lysis syndrome. In this phase 2 study, the addition of VEN to IBR decreased the BTK C481S mutation below the detection limit in 59% of pts after 12 cycles of treatment. This combination allowed 32% of pts to discontinue treatment in deep remission. The median PFS (40.7 months) supports further investigation of this approach.

Molecular Analysis at Relapse of Patients Treated on the Ibrutinib and Rituximab Arm of the National Multi-Centre Phase III FLAIR Study in Previously Untreated CLL Patients

Background The NCRI FLAIR trial confirmed ibrutinib + rituximab (IR) improved progression free survival (PFS) over FCR in untreated CLL. Durable responses are achieved on continuous Bruton's tyrosine kinase inhibitor (BTKi) therapy, but acquired resistance mutations in BTK, and PLCG2 are reported in up to 80% of relapsed/refractory patients (pts) failing BTKi often detected at low variant allele frequencies (VAF) several months before relapse. Their frequency, evolutionary dynamics, and relevance to progression in the upfront-treatment setting are poorly characterised. We present the observed clonal evolution in standard risk pts with disease progression (DP) on IR, integrating next generation sequencing (NGS) with serial measurable disease monitoring by flow cytometry, and tracking individual BTK mutations ( BTKmt) by digital droplet PCR (ddPCR) from initial detection to DP. Methods 771 randomised pts to FCR (n=385) or IR (n=386). Pts treated with IR received rituximab at 375 mg/m 2 on D1/C1 and 500 mg/m 2 on D1/C 2-6 of every 28-days. I was given orally at 420 mg/day for up to 72 mo. All 61 DP pts on IR were included in the analysis. DNA from baseline and progression peripheral blood (PB) samples were processed for sequencing of 33 genes recurrently mutated in lymphoid malignancies including BTK (exon 15) and PLCG2 (exons 19-20) with an Illumina MiSeq. Variants were reported down to minimum VAF of 3-5% and coverage of 100X. Low VAF (3-6%) BTKmt were validated by ddPCR using the QX200 ddPCR protocol (sensitivity 1-0.1%). ddPCR was used for the individual serial analysis at baseline and 6 monthly in pts with confirmed BTKhot spot mutations (p.C481S (c.1441T>A, c.1442G>C)), p.C481R (c.1441T>C), p.T474I (c.1421C>T) and presented with concurrent PB MRD monitoring using highly sensitive flow cytometry with a detection limit of one CLL cell in 100,000leukocytes (0·001%). Results 61/386 pts progressed after a median follow up of 44 mo. on I with 50/61 pts progressing after >24 mo. No deaths were recorded before DP. 47/61 IR DP samples were sequenced by MiSeq, 10 further samples with low disease burden were only analysed by ddPCR for hotspot BTKmt. 7/47 sequenced at baseline and DP, developed new isolated mutations in ATM, SF3B1, NOTCH1, BIRC3, BRAF, KLF2, CDKNB1 or TRAF2. The most frequently mutated gene at DP was BTK. From 57/61 sequenced samples at DP, 7 were found to have hotspot BTKmt most with multiple mutations (Fig/Table). No BTKmt detected at DP were detected at baseline by NGS or ddPCR. One pt had a PLCG2 mutation at DP (VAF 33.3%). The 8 BTKmt/ PLCG2 mt IR progressions were mostly in late DP pts (median 60.3 mo.) compared to a median time to DP of 54.3 mo in BTKwt/ PLCG2wt pts. The majority of BTKmt IR DP (5/7) were reported after stopping therapy at 72 mo. 6 monthly samples during I were studied for BTKmt. Evolution of BTKmt in the context of increasing disease burden on I, shows a steady rise in the VAF preceding frank DP (Fig). 148/386 (38.3%) IR pts were 100% homologous to germline IGHV unmutated and 31/148 (20.9%) progressed. 12/15 pts, who acquired additional mutations at DP were IGHV unmutated and 9/12 were 100% homologous to germline including 6/8 with acquired BTK/PLCG2 mutations. Conclusion In upfront IR treated standard risk CLL pts 15.8% progressed (61/386), the majority late. Only 13% of the IR DP cohort (8/61) had a BTK/PLCG2 mutation, suggesting other non- BTK/PLCG2 mutations or disease related factors as contributors to DP after initial response in the upfront setting. Interestingly, the background mutation profile did not change from baseline in those who acquired BTK/PLCG2 mutations at DP, but 7/15 acquired non- BTK/ PLCG2mutations at DP. The majority of IR DP with BTK/PLCG2 mutations (6/8), were 100% homologous to germline IGHV unmutated, suggesting an inherent higher risk disease profile as a risk factor for acquiring BTKmt with prolonged BTKi therapy. BTK/PLCG2 mutations were enriched amongst very late progressors with 6/8 pts progressing shortly after stopping therapy at 72 mo., which is later than previously reported for relapsed/refractory CLL pts.

Phase 1b/2 Study of Cirmtuzumab and Ibrutinib in Mantle Cell Lymphoma (MCL) or Chronic Lymphocytic Leukemia (CLL)

Phase 1b/2 Study of Cirmtuzumab and Ibrutinib in Mantle Cell Lymphoma (MCL) or Chronic Lymphocytic Leukemia (CLL)

A Randomized Phase III Study of Venetoclax-Based Time-Limited Combination Treatments (RVe, GVe, GIVe) Vs Standard Chemoimmunotherapy (CIT: FCR/BR) in Frontline Chronic Lymphocytic Leukemia (CLL) of Fit Patients: First Co-Primary Endpoint Analysis of the International Intergroup GAIA (CLL13) Trial

A Randomized Phase III Study of Venetoclax-Based Time-Limited Combination Treatments (RVe, GVe, GIVe) Vs Standard Chemoimmunotherapy (CIT: FCR/BR) in Frontline Chronic Lymphocytic Leukemia (CLL) of Fit Patients: First Co-Primary Endpoint Analysis of the International Intergroup GAIA (CLL13) Trial

A Quality-Adjusted Survival (Q-TWiST) Analysis to Assess Benefit-Risk of Acalabrutinib Versus Idelalisib/Bendamustine Plus Rituximab or Ibrutinib Among Relapsed/Refractory (R/R) Chronic Lymphocytic Leukemia (CLL) Patients

A Quality-Adjusted Survival (Q-TWiST) Analysis to Assess Benefit-Risk of Acalabrutinib Versus Idelalisib/Bendamustine Plus Rituximab or Ibrutinib Among Relapsed/Refractory (R/R) Chronic Lymphocytic Leukemia (CLL) Patients

Phase 1 Study of TAK-659, an Investigational Reversible Dual SYK/FLT-3 Inhibitor, in Patients (Pts) with Lymphoma: Updated Results from Dose-Escalation and Expansion Cohorts

Phase 1 Study of TAK-659, an Investigational Reversible Dual SYK/FLT-3 Inhibitor, in Patients (Pts) with Lymphoma: Updated Results from Dose-Escalation and Expansion Cohorts

A Multicenter, Phase II Study of Ibrutinib Plus FCR (iFCR) As Frontline Therapy for Younger CLL Patients

A Multicenter, Phase II Study of Ibrutinib Plus FCR (iFCR) As Frontline Therapy for Younger CLL Patients

Dynamic of Telomeric Parameters in Relapsing or Refractory (R/R) Chronic Lymphocytic Leukemia (CLL), an Analysis of the Filo ICLL001 Bomp Trial

Dynamic of Telomeric Parameters in Relapsing or Refractory (R/R) Chronic Lymphocytic Leukemia (CLL), an Analysis of the Filo ICLL001 Bomp Trial

Daratumumab Mitigates B-Cell Receptor Signaling and Enhances Antitumor Activity of Ibrutinib in Chronic Lymphocytic Leukemia (CLL) Cells

Introduction: B-cell receptor (BCR) signaling is a central driver of proliferation in chronic lymphocytic (CLL) cells. BCR engagement leads to recruitment of several intracellular kinases such Lyn, Syk and BTK, that activate ERK, NFkB and induce CLL cell proliferation. While this pathway is effectively targeted with the BTK inhibitor, ibrutinib, various combination treatment strategies that result in greater tumor cell killing are under investigation. On B-cells, the BCR interacts with the CD19 and CD38 cell surface antigens; where the later amplifies intracellular pro-survival signal transmission through the BCR. CD38 is a multifunctional protein, which possess both enzymatic and receptor functions. As such, we hypothesized that concurrent targeting of CD38 and BTK would lead to enhanced mitigation of BCR signaling as well as direct cell death than use of either agent alone.Materials: CD19+ cells were isolated from CLL patients (n=30, collected under an IRB-approved protocol) by magnetic bead sorting. JVM13 (CD38+) and MEC1 (CD38-) cell lines were also used. CD38 expression was measured by flow cytometry with quantification of MFI and surface antibody binding (sAbc). Drug-induced antibody-dependent cellular cytotoxicity (ADCC) in target Calcein AM labeled CLL cells was assessed by co-culturing them with healthy donor PBMCs as effectors (effector: target [E:T] ratio, 50:1) and complement dependent cytotoxicity (CDC) was measured using complement-containing serum from a healthy donor. Antibody dependent cellular phagocytosis (ADCP) was measured by co-culturing calcein AM labeled CLL cells with healthy human macrophages at a 2:1 ratio. Apoptosis by annexin-V/PI dual staining along with mitochondrial outer membrane potential (MOMP) using MitoProbeTMDilC1(5) were assessed by flow cytometric analysis. Immunoblotting was performed using antibodies against Lyn, Syk, BTK, PLCγ2, ERK1/2, AKT, Ikβα, NFAT2 and their phosphorylated isoforms along with GAPDH followed by densitometry analysis.Results: Using a cutoff of 30% (gated CD38 expressing cells), we observed 26.6% (n=8) of CLL pts. to be CD38+ and 73.3% of pts. to be CD38- (n=22). As some pts. deemed CD38- had high CD38 MFI or sAbc, we applied an interquartile range (IQR with 95% confidence interval) for CD38 MFI; re-classifying pts. as CD38lo (56.75 - 199) vs. CD38hi (199 - 355). Using this system, specific-lysis of CLL cells from Dara-mediated ADCC was 23.74±2.55% vs. 14.17±1.27, CDC: 15.93±1.68% vs. 12.29±0.88, ADCP: 8.630.96% vs. 9.50±0.97% and apoptosis: 32.42±3.42 vs. 23.65±1.82 in CD38hi vs. CD38lo pts., respectively. Apoptosis was accompanied by a significant shift in MOMP [21.65±7.90% (CD38hi) vs. 32.52±7.42% (CD38lo), p<0.05]. In CLL cells treated with the combination of Ibr + Dara (ID), ADCC increased to 54.21±4.09% vs. 37.66±2.16; CDC: 34.35±2.47% vs. 28.88±1.51%, ADCP 25.56±2.30% vs. 16.69±1.97%, apoptosis: 61.63±3.14% vs 62.06±3.41% and MOMP: 66.22±3.68% vs 71.13±3.31%: in CD38hi vs. CD38lo pts., respectively. Next we examined the effect of Dara +/- Ibr on BCR signaling in CD38hi and CD38lo CLL cells. In CD38hi cells, single agent Dara significantly decreased phosphorylation Lyn, Syk, BTK and PLCγ2 as well as ERK1/2, AKT, Ikβα and NFAT; the ID combination decreasing these further (except Ikβα and NFAT2) (p<0.01). In CD38lo cells, Dara significantly downregulated phosphorylation of Lyn and PLCγ2, however, insignificant changes were noted in all other proteins. In ID combination treated CD38lo cells, Lyn, Syk, BTK, PLCγ2 and AKT were further decreased.Conclusions: Herein, we provide first evidence on the ability of Dara to modulate BCR signaling and associated proteins in primary CLL cells and that this can be further augmented with Ibr. Dara-induced protein changes were more prominent in CD38hi cells; accompanied by higher % apoptosis vs. that observed in CD38lo cells, yet the ID combination significantly enhanced mitochondrial-mediated apoptosis in both CD38hi and CD38lo cells. This indicates that the combination can potentially overcome lower induction of apoptosis and ADCC in CD38lo cells treated with single agent Dara or Ibr. Studies on how Dara and the ID combination induce direct programmed cell death (independent of modulating BCR signaling) are underway. Overall, our investigations provide rationale for clinical testing of Ibr combined with Dara in CLL. DisclosuresParikh:Pharmacyclics: Research Funding; Pharmacyclics: Honoraria; AstraZeneca: Honoraria. Ding:Merck: Research Funding. Sher:LAM Therapeutics, Inc: Research Funding. Malavasi:Jaansen Pharmaceuticals: Research Funding. Ailawadhi:Novartis: Consultancy, Honoraria; Pharmacyclics: Research Funding; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria.

A Phase I/II Study of Reduced Dose FCR (FCR-lite) in Combination with Lenalidomide Followed By Lenalidomide Maintenance (FCR2) for Initial Therapy of CLL: Final Results and Long-Term Follow-up

A Phase I/II Study of Reduced Dose FCR (FCR-lite) in Combination with Lenalidomide Followed By Lenalidomide Maintenance (FCR2) for Initial Therapy of CLL: Final Results and Long-Term Follow-up

Phase I/II Study of Pembrolizumab in Combination with Ublituximab (TG-1101) and Umbralisib (TGR-1202) in Patients with Relapsed/Refractory CLL

Phase I/II Study of Pembrolizumab in Combination with Ublituximab (TG-1101) and Umbralisib (TGR-1202) in Patients with Relapsed/Refractory CLL

Real-World Evidence for Durable Treatment Responses after Toxicity Related Discontinuation of Idelalisib

Introduction: Idelalisib is a PI3K delta inhibitor (KI) approved in combination with rituximab for treating relapsed CLL. Associated toxicities such as transaminitis, diarrhea/colitis, pneumonitis, and infection limit utilization of idelalisib. Notably, these toxicities often lead to permanent drug discontinuation with uncertain outcomes following drug interruption and/or termination. Information on depth and duration of response following idelalisib discontinuation is essential when considering time-limited approaches in study design. To address this gap, 10 large US cancer centers collaborated to capture the experience of 61 CLL pts treated with idelalisib-based therapy.Patients and Methods: We conducted a multicenter retrospective cohort study of CLL patients treated with idelalisib as first KI. The primary study endpoint was progression free survival (PFS) after idelalisib discontinuation. PFS was defined as time from post-idelalisib treatment to progression or last follow up. We analyzed patient characteristics and outcomes, focusing on: demographics, number of prior therapies, time on therapy, toxicity associated with discontinuation, time to next treatment, and response. Kaplan-Meier method was used to estimate survival outcomes. Log rank test was used to compare survival outcomes. This study is unfunded.Results: A total of 61 CLL patients were identified. Median follow up for the cohort was 10.5 months (range .5-42). Median age was 65 years (35-80). Of these, 31% were del(17p) positive, 24% del(11q) positive, and 24% had a complex karyotype (≥ 3 abnormalities). Median number of prior therapies was 2 (ranging 0-7); median time from diagnosis to idelalisib initiation was 80 months (ranging 1-144). 23% of patients required dose modifications and 50% held the drug prior to discontinuation. The overall idelalisib discontinuation rate was 95% (n=58), toxicity was the most common reason for discontinuation (45%) followed by progression of CLL (26%). The three most common toxicities leading to discontinuation were pneumonitis (37%), colitis (32%), and rash (27%). Median time to discontinuation was 5 months (range .5-22) in the setting of toxicity and 12.5 months (range 3-42) in the setting of CLL progression. The best idelalisib responses recorded prior to discontinuation due to toxicity were 84.5% ORR (CR, PR, PL-L) and 3.8% CR. Median PFS was 12 months for the entire cohort. When stratified by discontinuation reason: median PFS was 10 months and OS not reached (idelalisib toxicity group) and median PFS was 13 months and OS was 48 months (CLL progression group). PFS was not statistically significantly different between groups when stratified by reason for discontinuation (p=.24, LR test). Following idelalisib discontinuation, 65% of patients whose course was limited by toxicity have gone on to be treated with a subsequent line of therapy.Conclusions: Toxicity remains the most common reason for idelalisib discontinuation followed by CLL progression. Our data suggests toxicity may be minimized when treatment duration was limited to less than 6 months since many treatment-limiting toxicities occurred beyond that time point. Most patients (> 80%) discontinued in the setting of PR, had durable responses and were able to undergo subsequent treatment regimens. Responses appear to be nearly as durable in the setting of limited treatment exposure (toxicity cohort, median exposure = 5 months, PFS 10 months) as opposed to a treat-to-progression approach (median exposure = 12.5 months, PFS 13 months). Consideration of intermittent / time-limited dosing with idelalisib may be a viable strategy. [Display omitted] DisclosuresBrander:Teva Pharmaceuticals, Genentech, AbbVie, Pharmacyclics: Consultancy; Genentech: Consultancy; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Lamanna:Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding. Ujjani:Gilead: Consultancy; Abbvie: Research Funding, Speakers Bureau; Genentech: Consultancy; Pharmacyclics: Consultancy, Research Funding. Skarbnik:Abbvie: Other: Ad board, Speakers Bureau; Seattle Genetics: Speakers Bureau; Novartis: Speakers Bureau; Genentech: Speakers Bureau; Gilead: Speakers Bureau. Cheson:AbbVie, Roche-Genentech, Pharmacyclics, Acerta: Consultancy; Acerta, Pharmacyclics, Epizyme, Gilead, Roche, AbbVi: Other: Institution receives research support . Dwivedy Nasta:Takeda: Research Funding; Immunogen: Research Funding; Incyte: Research Funding. Svoboda:Seattle Genetics: Consultancy, Research Funding; Kite: Consultancy; Pharmacyclics: Research Funding; Celgene: Research Funding; BMS: Consultancy, Research Funding; Merck: Research Funding. Landsburg:Takeda: Research Funding; Curis: Consultancy, Research Funding. Schuster:Celgene: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Janssen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Nordic Nanovector: Consultancy; Merck: Research Funding; Seattle Genetics: Consultancy. Barr:Seattle Genetics: Consultancy; Novartis: Consultancy; Gilead: Consultancy; Infinity: Consultancy; Celgene: Consultancy; AbbVie: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding. Mato:TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy; Janssen: Consultancy; AbbVie: Consultancy, Research Funding; DTRM: Research Funding; Acerta: Research Funding; Portola: Research Funding; Gilead Sciences, Inc.: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Research Funding; Regeneron: Research Funding; Kite: Consultancy.

Cardiac risk factors and adverse events among patients receiving first-line CLL treatment in a real-world community practice setting.

e24044 Background: First-line (1L) ibrutinib monotherapy (IM) is commonly prescribed for CLL but is associated with cardiovascular adverse events (CVAEs) that may lead to discontinuation. Existing data are largely from clinical trials (both 1L and relapsed/refractory), and real-world evidence is limited. The aim of this study was to compare baseline cardiac risk factors and CVAEs in patients (pts) receiving 1L IM vs intensive therapy (IT; aggressive, less tolerable, majority were bendamustine plus anti-CD20 antibody) or non-intensive therapy (NIT; less aggressive, more tolerable, majority were anti-CD20 antibody alone). Methods: We compared 3 treatment groups (IM, IT, and NIT) in terms of clinical characteristics, baseline CV risk factors, and subsequent CVAEs. Pts were selected from the Flatiron Health database based on the following criteria: aged ≥18 years, CLL/SLL diagnosis, had ≥2 clinic encounters, and initiated 1L treatment between 1/1/2016 and 12/31/2019. Baseline characteristics and subsequent CVAEs were descriptively compared between IM and IT/NIT groups; significance was assumed if p &lt; 0.05. Results: Data on 515 pts were included (IM, 191; IT, 195; NIT, 129). Age at baseline differed significantly between the IM group (mean 71.2 years) and the other 2 groups (IT, 66.2 years; NIT, 74.5 years). The proportion of del(17p) was significantly higher in the IM group vs IT/NIT groups (IM, 26.7%; IT, 3.6%; NIT, 3.1%). Significant differences between IM and IT groups were seen in baseline ECOG (ECOG 0: IM, 28.8%; IT, 43.1%), diabetes mellitus (IM, 56.0%; IT, 44.1%), and hypercholesterolemia (IM, 68.6%; IT, 58.0%). Significant differences between IM and NIT groups were seen in baseline angina/coronary revascularization (2.6% vs 8.5%), atrial fibrillation/atrial flutter (AF; 14.1% vs 26.4%), and cerebrovascular disease (8.9% vs 20.2%). The rate of any CVAE was significantly higher in IM (35.6%) vs IT and NIT groups (IT, 20.0%; NIT, 24.8%) (Table). For IM vs IT treated pts, significant differences were observed in new or worsening (N/W) AF (11.5% vs 5.1%), other arrhythmias (9.4% vs 3.1), and hypertension (HTN; 20.4% vs 8.2%). Conclusions: This is one of the first real-world studies focused specifically on 1L CLL to describe baseline CV risk factors and compare CVAE events in CLL pts treated with IM as compared to IT or NIT. Results show higher CVAE rates of AF, other arrhythmias, and HTN for IM vs IT. [Table: see text]

Updated Results from a Phase I/II Study of Duvelisib and Venetoclax in Patients with Relapsed or Refractory CLL/SLL or Richter's Syndrome

Updated Results from a Phase I/II Study of Duvelisib and Venetoclax in Patients with Relapsed or Refractory CLL/SLL or Richter's Syndrome

Severe Infections in Patients with Chronic Lymphocytic Leukemia Treated with (Immuno-)Chemotherapy: A Pooled Analysis of Gcllsg Trials

Severe Infections in Patients with Chronic Lymphocytic Leukemia Treated with (Immuno-)Chemotherapy: A Pooled Analysis of Gcllsg Trials

Venetoclax Effectiveness, Safety, and Treatment Patterns in Chronic Lymphocytic Leukemia Patients: Results from the CLL Collaborative Study of Real-World Evidence (CORE)

Venetoclax Effectiveness, Safety, and Treatment Patterns in Chronic Lymphocytic Leukemia Patients: Results from the CLL Collaborative Study of Real-World Evidence (CORE)

Clinical Characteristics and Outcomes of Newly Diagnosed Patients with Chronic Lymphocytic Leukemia Who Are 80 Years of Age or Older

Clinical Characteristics and Outcomes of Newly Diagnosed Patients with Chronic Lymphocytic Leukemia Who Are 80 Years of Age or Older

Worldwide Examination of Patients with CLL Hospitalized for COVID-19

Worldwide Examination of Patients with CLL Hospitalized for COVID-19

A Phase 1/2 Study of Umbralisib, Ublituximab, and Venetoclax (U2-Ven) in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL)

A Phase 1/2 Study of Umbralisib, Ublituximab, and Venetoclax (U2-Ven) in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL)