Barrientos, Jacqueline C.

Abstract Hairy cell leukemia (HCL) and HCL variant (HCLv) are distinct, rare, and chronic splenic B-cell lymphomas/leukemias that partially overlap in clinicopathologic presentation but differ in genetic basis, prognosis, and management. HCL is caused by the BRAF-V600E kinase–activating mutation in >95% of the patients, usually has excellent responses to chemotherapy with purine analogues, and is also amenable to BRAF inhibitor–based targeted treatments. In contrast, HCLv lacks BRAFV600E mutation, requires combined therapy with purine analogues in addition to rituximab, and generally shows less durable responses. Here, an international team of hematologists, experts on these rare diseases, was convened by the Hairy Cell Leukemia Foundation to update the previous guidelines (published in 2017) by providing a summary of current methods to diagnose and manage patients with HCL and HCLv as well as a prospective on newer targeted therapies to further improve outcomes.

Abstract The Bridging the Gaps (BTG) in Leukemia, Lymphoma and Multiple Myeloma Consensus Conference 2025 brought together a multidisciplinary group of oncology experts to address the complexities of lymphoma management, focusing on mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL), and diffuse large B‐cell lymphoma (DLBCL). This article presents consensus recommendations developed through a modified Delphi process, which emphasize the need for tailored therapeutic strategies in light of recent advancements in treatment options. Key recommendations include the screening for high‐risk features in MCL, use of the BOVen regimen (zanubrutinib, obinutuzumab, and venetoclax) for TP53 ‐aberrant cases, and integration of chimeric antigen receptor T‐cell therapy for patients with mantle cell lymphoma that is refractory to covalent Bruton tyrosine kinase inhibitors. For CLL, recommendations include consideration of time‐limited therapies for younger patients and a “watch and wait” strategy for asymptomatic patients despite the improved activity and safety of current treatment regimens. For DLBCL, this article highlights the challenges in treatment sequencing and the role of circulating tumor DNA and minimal residual disease testing in monitoring disease progression. Overall, the conference describes the importance of ongoing research to refine management strategies and improve patient outcomes in lymphoma care, addressing the gaps in clinical practice where high‐level evidence is lacking.

Abstract Background The treatment (tx) landscape for chronic lymphocytic leukemia (CLL) has evolved, with National Comprehensive Cancer Network (NCCN) guideline-preferred novel therapies (NTs), such as acalabrutinib, zanubrutinib, and venetoclax-based regimens, now preferred over ibrutinib and chemoimmunotherapy (CIT) in front-line (1L) settings. We previously showed that patients (pts) from different racial/ethnic groups may not have equitable access to NTs. Here, we examined racial/ethnic inequities in 1L NT utilization among US pts with CLL and potential social determinants of health (SDOH) drivers of these inequities. Methods This retrospective cohort study utilized the US-based, electronic health record-derived de-identified Flatiron Health Research Database, linked to neighborhood (US Census track or block group) data from American Community Survey and Agency for Healthcare Research and Quality datasets. Eligible pts included adults with CLL who started 1L tx 01/01/2019-07/31/2024. The primary outcome was receipt of 1L therapy (CIT vs preferred NTs, ibrutinib vs preferred NTs), with NCCN guideline-preferred NTs (v2.2023-v3.2025) as a reference. Associations between race/ethnicity (White, Black, Hispanic) and 1L tx types were assessed using logistic regressions, adjusting for age, sex, year of 1L start, immunoglobulin heavy chain variable region status, and del17p/TP53 status. To better understand which SDOH factors contribute to racial and ethnic inequities in tx utilization, we performed mediation analysis using Multiple Mediation Analysis implemented through nonlinear multiple additive regression tree models. Individual-level (Eastern Cooperative Oncology Group status, practice type, insurance) and 20 area-level SDOH factors measuring social deprivation (defined as limited access to economic, social, neighborhood, physical, or healthcare resources) were assessed as potential mediators. Results Of the 4452 pts included in the study, 3717 were White (83%), 371 were Black (8%), 209 were Hispanic (5%), and 155 were Other race (4%). Black and Hispanic pts were more likely to live in neighborhoods with higher social deprivation, such as residential segregation (predominant race/ethnicity in the area: White, Black, Hispanic, Diverse), with no internet access, no vehicle ownership, and no health insurance coverage. Overall, 37% of pts received a preferred NT, highest among White (38%) pts, followed by Black (35%) and Hispanic (26%) pts. Compared with White pts, Hispanic pts were more likely to receive CIT than preferred NTs (adjusted odds ratio [aOR] 2.12; 95% confidence interval [CI] 1.46-3.09); Black (aOR 1.44; 95% CI 1.05-1.97) and Hispanic pts (aOR 1.83; 95% CI 1.17-2.85) were more likely to receive ibrutinib than preferred NTs. Pts living in areas with the highest social deprivation were less likely than their counterparts in lowest social deprivation neighborhoods to receive preferred NTs. Specifically, residence in predominantly Black or Hispanic neighborhoods (26% or 27% vs 39% predominantly White), areas with lowest socioeconomic status (32% vs 40%), and neighborhoods with the lowest levels of internet access (32% vs 39%), vehicle ownership (32% vs 39%), and health insurance coverage (34% vs 41%) was associated with lowest receipt of preferred NTs. In the mediation analysis, individual- and area-level SDOH factors explained 94.4% (95% CI 2.9-185.9) of the observed Black-White inequity in receipt of ibrutinib versus preferred NTs; residential segregation appeared to be the most important mediator (59.7%; 95% CI −3.5 to 123.0). Similarly, the Hispanic-White inequity in receipt of preferred NTs was driven by the combined effect of area-level SDOH and individual-level variables (88.5%; 95% CI 45.6-131.3), with residential segregation as the main driver (48.3%; 95% CI 10.7-85.9), followed by practice setting (9.8%; 95% CI −3.5 to 23.1). In contrast, measured SDOH factors did not explain the inequity in receipt of CIT versus preferred NTs between Hispanic and White pts (21.5%; 95% CI −8.3 to 51.4), suggesting that other factors may contribute to the observed inequities. Conclusion Black and Hispanic pts with CLL were less likely than White pts to receive preferred NTs. A significant proportion of these disparities was explained by area-level SDOH, particularly residential segregation. These findings underscore the need to address structural barriers to ensure equitable access to emerging, guideline-recommended treatments.

e13741 Background: The NCCN guidelines for first-line (1L) regimens in CLL have evolved over the past decade, shifting from ibrutinib (ibr) and chemoimmunotherapy (CIT) to second-generation BTK inhibitor and venetoclax combinations. We evaluated real-world use of preferred 1L treatment (tx) since 2016 in CLL patients (pts) in routine care to identify differences in prescribing based on race/ethnicity and practice type. Methods: This retrospective observational study utilized the US nationwide Flatiron Health electronic health record-derived de-identified database. Eligible pts had confirmed CLL and initiated 1L tx between 01/01/16-07/31/24. Primary outcome was receipt of preferred 1L tx defined by NCCN guidelines in four time periods by race/ethnicity (Hispanic, White, Black, Asian/Other). Odds ratios (ORs) were estimated using logistic regression, additionally adjusting for age, sex, ECOG performance status, IGHV, del17p/ TP53 mutation status, time period, and practice type. Results: A total of 7528 pts were included. Compared with White pts (n = 5472), Black pts (n = 640) were younger (median age at 1L: 68 vs 71). More Black and Hispanic (n = 290) pts were treated at community practices (86% vs 80% White). Of those pts tested, more Black pts had unmutated IGHV than White (77% vs 56%). Presence of del17p/ TP53 mutation was similar across races/ethnicities. The proportion of pts receiving preferred 1L tx based on the NCCN Guidelines significantly differed by race/ethnicity (Table) ( P = 0.0021). The proportion of Hispanic pts treated with preferred 1L tx was significantly lower than White (OR = 0.61; 95% CI: 0.47-0.79), but Black was similar to White (OR = 1.07; 95% CI: 0.89-1.30). Updates to NCCN guidelines were significantly associated with pts receiving preferred 1L tx by practice type ( P = 0.0005). In 2016-2018, 44% of community practices and 55% of academic centers adopted targeted therapies (TTs); in 2019, ibr use increased in both practices (77% vs 68%, respectively). Adherence to preferred tx improved across practices in 2020 but decreased with the prioritization of second-generation therapies. After the approval of zanu, use of TTs was 71% in community practices and 74% in academic centers. Conclusions: Inequities in pts with CLL receiving preferred 1L tx suggests disproportionate use of CIT and ibr by race/ethnicity. Use of preferred TTs also differed by practice type and time period, with increased adoption after pivotal trials. Time period % Pts receiving preferred tx by race a White Black Hispanic Asian/Other 2016-2018:Preferred tx ibr 46% 50% 43% 45% 2019(v2.2019: Jan 2019)Preferred tx ibr 76% 76% 67% 79% 2020-Jun 2022(v4.2020: Feb 2020)Preferred tx acala, VO, ibr 84% 84% 69% 83% Jul 2022-Jul 2024(v2.2023: Aug 2022)Preferred tx acala, VO, zanu 72% 66% 56% 73% VO, venetoclax + obinutuzumab. a By listing of NCCN preference (preferred vs other) among non-del17p and age >65.

Introduction: Ibrutinib, a Bruton tyrosine kinase inhibitor (BTKi), changed the treatment landscape by demonstrating improved overall survival (OS) compared with chemotherapy/chemoimmunotherapy across multiple phase 3 trials in patients (pts) with CLL, including those with high-risk genomic features. Recently, data were reported for pts treated with ibrutinib in the phase 3 RESONATE-2 trial with up to 10 years of follow-up, representing the longest follow-up of any BTKi used in first-line treatment of CLL. With the most robust long-term follow-up data among BTKis, ibrutinib therapy trials are uniquely positioned to assess the long-term OS benefit of first-line BTKi treatment in pts with CLL across pt subgroups. We previously demonstrated that first-line ibrutinib is associated with OS rates that are similar to those in the age-matched general population, with a median follow-up of 5.9 years since initial diagnosis (Ghia P et al. HemaSphere 2024), but it remains unclear whether this holds true for pts with high-risk genomic features. This updated analysis evaluated long-term OS outcomes with a median follow-up of 8 years since randomization and 10 years since initial diagnosis in a pooled population of pts with previously untreated CLL, including those with high-risk features, who received first-line ibrutinib treatment in 2 phase 3 trials with comparison of survival estimates to the US age-matched general population. Methods: Data were pooled for pts who received first-line treatment with single-agent ibrutinib or ibrutinib + rituximab in the RESONATE-2 (NCT01722487) and ECOG-ACRIN E1912 (NCT02048813) trials, respectively. OS probabilities from the time of randomization and from the time of initial diagnosis for ibrutinib-treated pts were compared with an age-matched general population using 2021 life tables for the total US population published by the Centers for Disease Control and Prevention using the Kaplan-Meier method. Subgroup analyses were performed for high-risk pts, defined as those with del(11q), del(17p), mutated TP53, and/or unmutated IGHV (uIGHV). Results: A total of490 pts were pooled across the 2 studies: 352 pts (71.8%) were treated with ibrutinib + rituximab, and 135 pts (27.6%) were treated with single-agent ibrutinib; 3 pts did not receive study treatment. The median age at time of randomization was 61 years; 36.5% (179/490) were aged ≥65 years, 21.8% had del(11q), 7.8% had del(17p) and/or mutated TP53, and 54.7% had uIGHV. The median time from initial CLL diagnosis to randomization was 20.9 months (range, 0.0-341.8); the median follow-up was 123.5 months (10.3 years) from initial diagnosis and 99.2 months (8.3 years) from the time of randomization. From the time of randomization, estimated 9-year OS rates were 81.2% (95% CI, 76.8-84.9) in all ibrutinib-treated pts versus 82.0% (95% CI, 78.3-85.2) in the age-matched population (hazard ratio [HR] 1.17; 95% CI, 0.86-1.58). In high-risk pts, estimated 9-year OS rates were 79.5% (95% CI, 73.5-84.3) for ibrutinib-treated pts versus 83.2% (95% CI, 78.5-86.9) in the age-matched general population (HR 1.24; 95% CI, 0.84-1.84). In pts aged ≥65 years, estimated 9-year OS rates were 68.7% (95% CI, 60.5-75.6) for ibrutinib-treated pts and 68.7% (95% CI, 61.4-75.0) in the age-matched general population (HR 1.12; 95% CI, 0.77-1.63). In pts aged <65 years, estimated 9-year OS rates were 89.3% (95% CI, 84.6-92.7) for ibrutinib-treated pts and 90.0% (95% CI, 86.1-92.9) in the age-matched general population (HR 1.15; 95% CI, 0.68-1.94). From the time of initial diagnosis, estimated 15-year OS rates were 78.4% (95% CI, 72.8-83.0) in all ibrutinib-treated pts versus 72.0% (95% CI, 67.8-75.7) in the age-matched general population (HR 0.83; 95% CI, 0.62-1.11). Study treatment had been discontinued in 59.8% (293/490) of pooled ibrutinib-treated pts; the most frequent reasons for discontinuation were adverse events (43.0%; 126/293) and progressive disease (20.5%; 60/293). Study treatment was ongoing in 31.8% of pooled pts (156/490). Conclusions: With the longest follow-up time for any commercially available targeted therapy, this pooled analysis demonstrates that, regardless of evaluation from randomization or initial diagnosis, and irrespective of age or high-risk features, first-line treatment with ibrutinib provides long-term OS benefit with survival estimates that appear similar to those of a US age-matched cohort.

Background: Menin, a protein involved in transcriptional regulation, plays a role in the genesis of multiple cancers. Preclinical data from BMF-219, an investigational, highly selective, oral small-molecule inhibitor of menin, show sustained potent abrogation of menin-dependent oncogenic signaling. BMF-219 is the first and only covalent menin inhibitor in clinical development and is being evaluated in multiple hematologic malignancies, solid tumors, and diabetes mellitus. COVALENT-101 (NCT05153330) is a Phase I dose-escalation and -expansion study of BMF-219 in R/R AL (Cohort 1), DLBCL (Cohort 2), MM (Cohort 3), and CLL (Cohort 4). Here we report preliminary safety, PK and anticancer activity data from Cohort 1 (AL). Methods: Doses of BMF-219 are escalated independently for each indication, initially in single-subject cohorts followed by a “3 + 3” design. Eligible patients (pts) include adults with R/R AL ineligible for standard therapy. Initially pts were enrolled agnostic to molecular status. A subsequent amendment introduced quotas for KMT2Ar (MLL1r), NPM1 and other known menin-dependent mutations: CEBP/A, MLL1-PTD, MN1, NUP98, NUP214, PICALM-AF10, SETBP1. Prior exposure to reversible menin inhibitor therapy is permitted. Subjects receive BMF-219 daily for continuous 28-day cycles until progression/intolerability. There are 2 parallel dose-escalation arms: pts not taking (Arm A) or taking (Arm B) moderate or strong CYP3A4 inhibitors. The study is ongoing and accruing in the escalation. Expansion cohorts will enroll pts to obtain further safety and efficacy data at the OBD/RP2D. Results: As of data cutoff of 7/24/2023, 26 pts with R/R AL (24 AML; 2 ALL) are enrolled; 7 remain on study treatment. Baseline characteristics include 17(65%) males and 9(35%) females with a median age of 57.5 years (range 33-84). There is a median of 4 (range 1-8) prior lines of therapy and 11 (42%) with prior HSCT(s). Six pts (23%) had KMT2Ar, 3 (12%) KMT2A-PTD, 4 (15%) NPM1, and 13 (50%) WT for KMT2A and NPM1. Dosing began with single-patient cohorts at 100 mg QD (Arm A) and 25 mg QD (Arm B) and has been escalated through 4 dose levels. Thus far, pts have been dosed up to 500 mg QD (Arm A) and 125 mg QD (Arm B). BMF-219 exposures were comparable between arms, with ~2-4-fold higher exposures observed with co-administration of a moderate or strong CYP3A4 inhibitor. At the highest dose (DL4) in which PK was evaluated, Arm A (500 mg QD) and Arm B (125 mg QD), pts on average achieved ~50% of target exposure (2000 ng*hr/mL) with some pts surpassing it. Higher QD dosing or corresponding BID dosing is expected to achieve desired exposure. BMF-219 has generally been well tolerated with no DLTs observed and no discontinuations due to treatment-related toxicities. No related QTc prolongation was observed. At the time of data cutoff, 23 of 26 pts were included in the safety population. Common TRAEs (≥10%) include vomiting 13% (3) and Differentiation Syndrome (DS) 13% (3). No Grade 5 TRAEs were reported. The only common Grade ≥3 TRAE (≥5%) was DS 13% (3). The efficacy evaluable population includes AML pts who meet the following criteria: dosed at or near predicted efficacious dose (500 mg or above [Arm A]; 125 mg or above [Arm B]), had known menin-dependent mutations, and completed at least one scheduled response assessment (or had a minimum of 7 doses if discontinued prematurely). Thus far, 2 of 5 efficacy evaluable patients achieved a complete remission (1 CR; 1 CRi) and both continue BMF-219 treatment. Patient A: 39/M, NUP98-NSD1, ECOG=0, 500 mg QD, Arm A, 4 prior lines of treatment including intensive chemotherapy and allo-HSCT. At C1D27, marrow blasts were reduced to 6% from 13% at study entry. The patient achieved CR at C2D28 with 0% blasts.Patient B: 70/F, NPM1m, ECOG=1, 125 mg QD, Arm B, 1 prior line of treatment with decitabine and an investigational agent. At C1D28, marrow blasts were reduced to 34% from 52% at study entry. The patient achieved CRi with 3% blasts at C2D28. Conclusion: BMF-219 is generally well tolerated with no DLT observed (and able to be taken with and without CYP3A4 inhibitors) with no pts discontinuing therapy due to toxicity. BMF-219 dose escalation is ongoing and approaching target exposure. BMF-219 demonstrates early signs of clinical activity in different genomic subgroups. The trial is ongoing and includes enrollment for pts diagnosed with AL, DLBCL, MM and CLL.