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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 Introduction : Current standard of care for smoldering multiple myeloma (SMM), an asymptomatic precursor of multiple myeloma (MM), is observation until progression to active MM. Increasing evidence suggests that patients (pts) with SMM at high risk for progression to active MM may benefit from early treatment (tx). In AQUILA, a phase 3 study in pts with high-risk SMM (NCT03301220), daratumumab (Dara) monotherapy significantly reduced risk of progression to active MM or death with a trend of extending overall survival (OS) vs active monitoring (ActMon), with no new safety concerns. Given the evolution in SMM risk stratification, a post hoc analysis was performed to assess outcomes using the IMWG 2020 and IMWG 2020 plus cytogenetic risk models to assess which AQUILA pts benefited most from Dara monotherapy. Safety and efficacy analysis by age and stem cell collection outcomes were also assessed. Methods: Eligible pts with a confirmed diagnosis (≤5 y) of high-risk SMM per IMWG 2014 criteria, defined as clonal bone marrow plasma cells (BMPC) ≥10% and ≥1 risk factor (IgA SMM, serum protein ≥30 g/dL, serum involved:uninvolved free light chain [I/U FLC] ratio ≥8 and <100, immunoparesis with reduction of 2 uninvolved Ig isotypes, and/or clonal BMPC >50% to <60%) at study entry, were randomized 1:1 to receive subcutaneous Dara or ActMon for 39 cycles, 36 months, or until confirmed disease progression (PD), whichever came first. Primary endpoint was progression-free survival (PFS) assessed by independent review committee, defined as progression to active MM (based on IMWG SLiM-CRAB diagnostic criteria) or death. Secondary endpoints included time to first-line (1L) MM tx and OS. For this post hoc analysis, we assessed outcomes by age, IMWG 2020 high-risk SMM criteria (BMPC >20%, monoclonal spike >2 g/dL, serum FLC ratio >20; ≥2 factors=high risk; also known as the Mayo 2018 or the 20-2-20 criteria), and the IMWG 2020 plus cytogenetic criteria (IMWG 2020 criteria + presence of ≥1 high-risk cytogenetic abnormalities [t(4;14), t(14;16), +1q and/or del13q]; ≥3 factors=high risk). Results : Dara tx showed a PFS benefit across all IMWG 2020 risk subgroups (low: hazard ratio [HR], 0.59; intermediate: HR, 0.70), with the largest benefit in the high-risk subgroup, where the PD/death rate in the ActMon arm was ~1.6-fold that in the Dara arm (62.8% vs 37.5%; HR, 0.36). This benefit of Dara vs ActMon was preserved over time, with 5-year PFS rates of 78.2% vs 71.6%, 56.2% vs 42.9%, and 60.4% vs 23.6% in IMWG 2020 low-, intermediate-, and high-risk groups, respectively. There was a positive trend favoring Dara for time to 1L MM treatment across all IMWG 2020 risk groups (low-risk HR, 0.63; 95% CI, 0.22–1.80; intermediate-risk HR, 0.57; 95% CI, 0.35–0.92; high-risk HR, 0.39; 95% CI, 0.25–0.62). IMWG 2020 plus cytogenetic risk classification results will be available at the time of presentation. When comparing the younger (<65y HR, 0.51; 95% CI, 0.32–0.79) vs the older (≥65y, HR, 0.50; 95% CI, 0.32–0.77) pt population, a PFS benefit was observed regardless of age. Similarity was also observed in TEAE incidence rate when looking into <65, 65 to <75, and ≥75 y subgroups (82.7%, 81.1%, and 87.5% with ActMon; 96.2%, 98.5%, and 95.2% with Dara); however, serious TEAEs were more frequently observed in older ActMon pts (12.2%, 18.9%, and 50.0% with ActMon; 24.8%, 35.8%, and 28.6% with Dara). Across all pts treated/monitored in AQUILA, 23 (11.9%) and 41 (20.9%) pts in the Dara and ActMon arms, respectively, received autologous stem cell transplant as part of their first tx after progressing to active MM, with very limited plerixafor use (Dara, 3 [1.6%] vs ActMon, 9 [4.6%]). Median (range) CD34+ cell yield was 5.0 (2–20)×106 cells/kg body weight among 22 pts in the Dara arm and 5.1 (2–21)×106 cells/kg body weight among 39 pts in the ActMon arm. Conclusions : In this analysis, pts with high-risk SMM from the phase 3 AQUILA study treated with Dara monotherapy experienced long-term PFS benefit across IMWG 2020 subgroups, with the most pronounced benefit in the high-risk subgroup. No notable differences in PFS or safety were observed across age subgroups. Early Dara tx for high-risk SMM did not have a detrimental impact on stem cell yield. Although mature OS analyses are forthcoming, overall, these results further support early intervention with Dara monotherapy vs ActMon among pts with high-risk SMM, regardless of risk stratification criteria used.

Abstract Background: The t(11;14) translocation occurs in 50-60% patients with systemic AL amyloidosis. Venetoclax, an oral BCL2 inhibitor, has shown promising efficacy across t(11;14)-positive plasma cell disorders. However, till date, there are no prospective data in patients with previously treated AL amyloidosis, including those with prior exposure to anti-CD38 monoclonal antibodies (mAbs). Methods: We conducted an investigator-initiated phase 1/2 multicenter open-label trial of venetoclax (± dexamethasone) in patients with relapsed/refractory AL amyloidosis. Key inclusion criteria were central-laboratory confirmed t(11;14) by FISH analysis in ≥5% of CD-138-selected cells on bone marrow aspirate, measurable hematologic disease (dFLC≥2 mg/dL and/or M-spike ≥0.5 g/dL), prior exposure to anti-CD38 mAb, and ≥1 prior line of therapy. Key exclusion criteria were NT-proBNP>8500 pg/mL, NYHA class IIIb/IV, and ECOG>2. Phase 1 dose escalation utilized Bayesian Optimal Interval Network (BOIN) design to determine maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) across four levels: DL1 (venetoclax 200mg), DL2 (400mg), DL3 (400mg + dexamethasone 10mg weekly), and DL4 (400mg + dexamethasone 20mg weekly). A maximum of 6 cycles of therapy on the protocol were planned, with dose limiting toxicities (DLTs) being evaluated in cycle 1. The design accommodated 12-15 patients with ~67% probability of selecting the dose closest to the 25% target toxicity rate. Here, we present the results of the Phase 1 portion of the study, which has completed enrollment. Accrual in Phase 2 portion is currently ongoing. Results: Of 16 patients screened, 12 were enrolled and evaluable for safety and efficacy. Screen failures were attributed to second malignancy (n=2), t(11;14) positivity in <5% CD-138-selected cells (n=1), and t(11;14) negativity (n=1). Enrolled patients had a median age of 64 years, with 25% female, and 17% Black representation. At screening, the median percentage of CD-138-selected cells with t(11;14)-positivity on FISH was 65%. All patients had prior anti-CD38 mAb-exposure by protocol design, with 11/12 patients also exposed to bortezomib. The median number of prior lines of therapy was 1 (range, 1-5). Disease markers at treatment initiation included median dFLC of 14.35 mg/dL (range, 2.13-186.28), median NT-proBNP of 712.5 pg/mL (range, 54-8831), and the median serum creatinine of 0.99 mg/dL (range, 0.69-3.01). Regarding safety, there were no DLTs encountered during the specified timeframe. One patient each received DLs 1, 2, and 3, with all remaining patients receiving DL 4 (400mg + dexamethasone 20mg weekly), which is the RP2D in this trial. There was only one patient that developed grade 3 infection (lung infection; COVID-19). No tumor-lysis syndrome, grade 3 or higher cytopenia, or treatment-emergent deaths occurred. Hematologic overall response (PR or better) was achieved in 11/12 patients (91.7%), with 9/12 (75%) attaining ≥VGPR [4/12 (33.3%) heme-CR, with the remaining being VGPR]. The median time from treatment initiation to best response was 29 days. Among 7 patients that were evaluable for cardiac response, one underwent heart transplant after 3 cycles of study treatment (while in heme-CR), hence was no longer evaluable for cardiac organ response. Of the remaining 6 patients, 2 have achieved cardiac response till date. Renal organ response was observed in 4/7 evaluable patients. At a median follow-up of 8.8 months, 4 out of 12 patients have completed 6 treatment cycles, with 2 receiving ongoing therapy. Six patients discontinued treatment early due to hematologic progression (n=1), suboptimal hematologic response (n=2), patient preference (n=2), and heart transplant (n=1). Patient-reported outcomes (assessed by PROMIS-29) showed no significant changes in Physical Functioning and Fatigue domains among 5 patients with paired baseline and end-of-treatment assessments. Updated follow-up data will be presented at the meeting. Conclusions: To our knowledge, this represents the first prospective evaluation of venetoclax-dexamethasone in relapsed/refractory t(11;14) AL amyloidosis. The combination demonstrated substantial hematologic efficacy (75% ≥VGPR rate) and a favorable safety profile without dose-limiting toxicities. Our results support investigation of venetoclax-based combinations in the frontline treatment of newly diagnosed t(11;14) AL amyloidosis.

Abstract BackgroundWarm autoimmune hemolytic anemia (wAIHA) is clinically characterized by autoantibody-mediated (typically IgG) erythrocyte destruction at body temperature. While oral corticosteroids remain first-line therapy, rituximab is frequently used as a second-line agent, mostly supported with concomitant background medications, yet real-world evidence is limited and utilization is driven by published retrospective data and expert opinion. Real-world evidence characterizing its utilization patterns and outcomes is needed to inform clinical practice. AimsThis study aimed to: 1) describe treatment patterns among patients with newly diagnosed wAIHA, 2) evaluate rescue therapy use and healthcare resource utilization (HCRU) with current standard of care (SOC), 3) characterize patterns of rituximab use during the first year. MethodsNewly diagnosed wAIHA patients were identified from multiple US databases (MarketScan® Databases, IQVIA PharMetrics, Optum Clinformatics®, and Optum PanTher EHR). Patients with ≥1 wAIHA diagnosis code in any position (ICD-10-CM D59.11) from October 2020 to December 2023 and 12-month post-index follow-up were pooled together. Secondary wAIHA was defined with evidence of hematologic malignancy, solid tumors, immunodeficiencies, or autoimmune diseases in the 6 months prior to diagnosis. Patients on treatment were defined by use of oral corticosteroids (OCS), immunosuppressants (IST) (including azathioprine, mycophenolate mofetil, cyclosporine, cyclophosphamide, or tacrolimus) or rituximab. Initial therapy was defined as the first treatment occurring ≥ 30 days prior to diagnosis. Therapies were identified as combination when initialized within 21 days of each other. The regimen is considered active until all therapies are discontinued or a new agent is initiated. Rituximab regimens were classified as standard (4 weekly doses), alternative (2 doses given 2 weeks apart), single infusion, or extended (>4 infusions). Results Among 2,028 wAIHA patients (median age 62.0 years, 59% female), 55% had secondary wAIHA. Among patients on treatment (n=1,439), 64% received OCS monotherapy; rituximab and IST, alone or in combination with OCS were received by an additional 28% and 5% of patients, respectively. Overall, 80% of treated patients received OCS in some combination during initial therapy. Within 12 months following diagnosis, 1 in 4 patients required ≥ 1 blood transfusion, 1 in 8 required either erythropoiesis-stimulating agents (ESA) or intravenous immunoglobulin (IVIG). Within 12 months of diagnosis, 35% of patients required ≥ 1 hospitalization, average length of stay 3.8 days; AIHA was the principal diagnosis for 65% cases. Greater than 1/3 of patients (38%) had ≥ 1 emergency department visit. Almost all wAIHA patients (98%) had an all-cause outpatient visit with a median of 31 visits per patient. Among patients receiving rituximab in any line (n=613), median time from diagnosis to first administration was 59.0 days (interquartile range: 42.0-171.0). For the first course of rituximab, 62.2% of patients received a complete course (standard, alternative, or extended courses). Among patients with a completed course, 39.8% had >4 infusions without a 90-day gap between administrations with a median of 8 administrations within 12 months. Of the nearly 38% of patients that did not receive a complete course of rituximab, 33% received a single infusion. The use of rescue medications in the period prior to rituximab treatment was compared to the period after treatment (defined as 60 days to 12-months post final rituximab infusion). Use of blood transfusions was observed to increase from 9.0% to 32.8%, while the use of ESA and IVIG were stable at approximately 2% and 4%, respectively.Conclusion With current wAIHA SOC, US HCRU remains high, posing a financial burden in terms of the rate of outpatient and emergency department visits, and inpatient stays. Rituximab is an early line therapy post-diagnosis, typically in combination with OCS. No changes in rescue treatments, and an increase in blood transfusions after rituximab infusion suggest treatment gaps remain. Analysis reveals heterogeneity in rituximab dosing patterns including high deviation from standard dosing practices; this variance from published expert opinion along with common use of rescue therapies suggests continued need for standardized guidelines and development of targeted therapies in wAIHA.

Abstract Allogeneic hematopoietic cell transplantation (HCT) using an HLA mismatched unrelated donor (MMUD) with calcineurin inhibitor-based graft versus host disease (GVHD) prophylaxis results in increased incidence of non-relapse mortality (NRM) and lower survival compared to matched donor HCT. The NMDP sponsored 15-MMUD study demonstrated that post-transplant cyclophosphamide (PTCy)-based prophylaxis following bone marrow derived MMUD HCT resulted in reduced incidence of GVHD and favorable survival. Because marrow grafts can be difficult to procure and vary in quality, we conducted a phase II, prospective, multicenter study to evaluate PTCy-based GVHD prophylaxis in adult recipients of MMUD using peripheral blood stem cell (PBSC) allografts. The primary study aim was to estimate the probability of one-year overall survival (OS) post HCT. Secondary aims were to assess other key clinical endpoints and determine the rate of severe infections. Initial results of the first 70 recipients who received reduced intensity conditioning (RIC) were previously reported by Al Malki et al (JCO 2025) demonstrating a 1-year OS of 78.6% (95% CI, 67% to 86.5%). Here, we report results from a planned expansion of the study that included 123 additional RIC recipients, with updated results from the initial cohort of 70 patients (total N = 193 subjects) treated at 33 centers. Study participants received cyclophosphamide 50 mg/kg (ideal body weight) administered on days 3 and 4 post HCT with tacrolimus and mycophenolate mofetil as previously described (Al Malki, JCO, 2025). The median study participant age was 65.0 (range: 22.9-78.9); 92 (47.7%) of participants were male, and 84 (43.5%) identified as having other than non-Hispanic white ancestry. The HCT comorbidity index was high-risk (>3) in 65 (33.7%). Underlying histologic diagnosis was AML in 96 (49.7%) participants, MDS in 43 (22.3%), ALL in 20 (10.4%), lymphoma or CLL in 24 (12.4%), and CML/other leukemias in 10 (5.2%). Conditioning regimens used were fludarabine and melphalan (100 or 140 mg/m2) (N=120; 62.2%), 2-day busulfan and fludarabine (N=38; 19.7%), and fludarabine, cyclophosphamide and total body irradiation (200 cGy) (N=32; 16.6%). Donor HLA matching (considering HLA-A, -B, -C, and -DRB1) was 7/8 in 131 (67.9%) of participants, 6/8-matched in 51 (26.4%), and 4-5/8-matched in 11 (5.7%) participants. Median donor age was 25.5 years (range: 18.7-35.7). The one-year overall OS estimate was 79.6% (95% confidence interval [CI]: 73.2-84.7). Survival was similar among HLA 7/8-matched donor recipients (77.8%, 69.7-84%) and <7/8 matched donor recipients (83.7%, 71.8-90.9%). The one-year GVHD-free, relapse-free survival (GRFS) was 49.9% (42.6-56.9%) and the one-year progression-free survival was 70.2% (63.2-76.2%). The one-year cumulative incidence (CI) rates of NRM and relapse were 12.5% (8.3-17.6%) and 17.3%(12.3-23%), respectively. The 6-month CI of grade II-IV and grade III-IV acute GVHD were 40.0% (33.0-46.8%) and 7.8% (4.6-12.1%), respectively. The one-year incidence of all chronic GVHD and severe chronic GVHD were 15.6% (10.7-21.2%) and 3.7% (1.6-7%), respectively, by NIH consensus criteria. The CI of grade 1-4 cytokine release syndrome (CRS) by day 7 post HCT was 28.0% (21.8-34.9%), and grade 3-4 CRS was 0.5% (0-2.9%). Primary engraftment failure occurred in 9 (4.7%) participants. Among 145 evaluated participants, 85.5% were >95% donor in blood chimerism at day 100 post HCT. Within the first 100 days after HCT, CTCAE grade 2-5 infections occurred in 113 (58.5%) of participants and grade 3-5 infections occurred in 59 (30.6%) of participants. The most common etiologies of grade 2-5 infections were bacterial (N=78), followed by viral (N=48). The most common grade 3-5 non-infectious toxicities were cardiac disorders, which occurred in 4 (2.1%) of participants. In conclusion, the results including this expansion cohort demonstrate encouraging 1-year OS, NRM and relapse rates in RIC recipients of PTCy-based GVHD prophylaxis and PBSC allografts from MMUDs. This larger cohort of 193 recipients re-affirm the results from the initial cohort with greater robustness.Measures to mitigate infection risk are likely to further improve outcomes. Reducing the dose of PTCy is a candidate approach currently being tested in the ongoing OPTIMIZE trial (NCT 06001385).These results support the extension of PBSC MMUD using PTCy to individuals who lack an HLA-matched donor and require RIC HCT.

Abstract INTRODUCTION Allogeneic hematopoietic cell transplantation (alloHCT) is indicated in patients (pts) with FLT3-ITD mutated AML. The randomized BMT CTN 1506 trial (Levis et al. JCO) demonstrated that maintenance with FLT3 inhibitor gilteritinib (gilt) significantly improved relapse-free survival (RFS) among pts with detectable peri-alloHCT minimal residual disease (MRD) but was also associated with a greater degree of myelosuppression and infections. In older pts, aged >60 years, increasing post-HCT toxicity may adversely impact outcomes. On this basis, we performed a post-hoc analysis of pts aged > 60 years enrolled onto BMT CTN 1506 to examine the impact of gilteritinib maintenance in older pts. METHODS Pts ≥60 years randomized on BMT CTN 1506 (gilt=47, placebo=57; N=104) were included. The primary endpoint of this post-hoc analysis was RFS. We additionally assessed overall survival (OS), incidence of relapse, non-relapse mortality (NRM) in all pts and in pts with detectable MRD. RESULTS Baseline characteristics were balanced. Age was similar (65.2 vs 64.7 years; p = 0.12), as was prior TKI exposure, and NPM1 mutation status. Myeloablative conditioning (MAC) was used in 8 (17%) pts randomized to gilt and 18 (32%) pts randomized to placebo (p=0.08). Median f/u of survivors was 43.8 months (range:1-61 mo.). Estimated RFS and OS at 48 months were not different between groups (RFS: gilt: 57.0%, 95%CI 44.1-73.7%, placebo: 57.1%, 95%CI 45.4-71.8%; OS: gilt: 56.9%, 95%CI 42.9-46.7%, placebo: 58.4%, 95%CI 46.7-73.1%). While gilt assignment did not affect survival, several predictors of poorer survival were identified including use of reduced intensity conditioning (RIC) (HR = 3.46; p = 0.014), use of calcineurin inhibitor/MTX for graft-vs-host disease (GVHD) prophylaxis (HR = 2.29; p = 0.041), high-risk cytogenetics (HR = 2.64; p = 0.021), and MRD (+) pre-HCT (HR = 2.29; p = 0.018). Finally, relative to gilt assignment, opposing rates of relapse and NRM were observed. The incidence of relapse was lower with gilt (16%, 95%CI 6.8-28% vs 32%, 95%CI 20-45%, p=0.046) but NRM was higher (27%, 95%CI 15-41% vs 11%, 95% CI 4.3-21%, p=0.033). We next analyzed the 49 pts (gilt=22, placebo=27) with detectable peri-HCT MRD. RFS and OS again were not different (RFS: gilt: 44.4%, 95%CI 27.1-72.7%, placebo: 43.8%, 95%CI 28.4-67.5%, OS: gilt: 49.2%,95%CI, 31.3-77.4%, placebo: 55.6%, 95%CI 39.4-77.8%). The incidence of relapse trended lower in gilt pts (25%, 95%CI, 5.3-44.7% vs 45% (95%CI, 25-63%), p=0.2) while NRM trended higher (31%, 95%CI 12-52% vs 11%, 95%CI, 2.7-26%, p=0.12). Seventeen (36%) patients completed planned 2 year maintenance with gilt compared to 29 (51%) completing therapy with placebo. Median time on gilt was 13.2 months. The most common reason for discontinuation was adverse events (n=19, 40%), of which cytopenias (n=8) and infections (n=4) were most frequent. Non-relapse causes of death among gilt treated pts included infections (n=8), intracranial hemorrhage related to thrombocytopenia (n=1), second cancer (n=1), and Guillain-Barre syndrome (n=1). Most infections (n=5) were attributed to GVHD as an underlying cause. CONCLUSION Among pts aged ≥60 years, gilt maintenance did not improve RFS or OS. Gilt use was associated with reduced relapse regardless of peri-HCT MRD status demonstrating disease effect; however, higher NRM limited overall benefit. In older FLT3 mutated pts, employing strategies to mitigate HCT related toxicity, e.g. alternative GVHD prophylaxis strategies, may better accommodate use of maintenance therapy including gilt. Lower doses of gilt (particularly with azole co-use) may be worth exploring to mitigate drug AEs, improve compliance, thus further improving benefit.

Abstract Background: The addition of the CD19/CD3 bispecific T-cell engager, blinatumomab, to standard consolidation chemotherapy in adults with ALL who achieved a measurable residual disease negative (MRDneg) remission (CR), demonstrated an improvement in 3-year overall survival (OS, 85% vs 68%, HR 0.41, P=0.002) and 3-year relapse-free survival (RFS, 80% vs 64%, HR 0.53) compared to conventional chemotherapy in the ECOG-ACRIN E1910 study (Litzow et al, NEJM 2024). Given the complex therapy in this study, treatment delays and modifications are expected. We herein explored the impact of such delays on patient outcomes. Methods: In the phase 3 ECOG-ACRIN E1910 trial (NCT02003222), adults aged 30-70 years with newly diagnosedALL who had achieved MRDneg CR following induction and intensification were randomized to consolidation chemotherapy with blinatumomab (blina arm) or chemotherapy alone (chemo arm). We examined the association between the timing of the initiation of maintenance therapy and OS and RFS. The expected duration of consolidation was 252 days vs 126 days for patients on the blina and chemo arms, respectively. For this analysis, participants were classified into two groups (no/short delay or long delay) depending on whether they started on time/before or after the median time between the beginning of consolidation and start of maintenance therapy for their treatment group (medians: 335 days, range, 181-457 days vs 176 days, range, 139-265 days for blina and chemo arms, respectively). Multivariate analyses of OS and RFS were performed to examine the effect of no/short delay vs. long delay in starting maintenance. Patients were stratified according to their assigned consolidation treatment arm, and the models were further adjusted for age, sex, white blood cell count, platelets, hemoglobin, peripheral blood blasts, bone marrow blasts, performance status and genetic-genomic risk at diagnosis. Results: Of the 488 patients enrolled, 224 MRDneg patients were randomized to consolidation chemotherapy with or without blinatumomab and 135 of the 224 went on to maintenance therapy on study (N= 66 on blina arm and 69 on chemo arm, respectively). The median follow-up from the time of maintenance registration was 43.4 months. There were no significant differences in baseline characteristics between patients in either arm who experienced no/short delay or long delay. In the blina group, 60 of 66 patients (90.9%) received all 8 cycles of consolidation therapy of which 31 (45.6%) had long delays. Sixty-eight of 69 patients on the chemo arm (98.5%) received all cycles of consolidation therapy, of which 34 (50%) had a long delay. Strikingly, patients who had a long delay before initiation of maintenance had a significant improvement in OS in multivariate analysis compared to patients who had no/short delay (HR 0.31, 95% CI: 0.11-0.91; P =0.03). However, within each treatment group, OS benefit did not reach statistical significance (blina arm: HR 0.04, 95% CI: 0.001-1.64; P =0.09; chemo arm: HR 0.32, 95% CI: 0.08-1.38; P =0.13). Similar results were observed for RFS in multivariate analysis (HR 0.40, 95% CI: 0.16-1.01; P =0.05), though this impact on improved RFS was noted in the chemo arm but not in blinatumomab treated patients (blina arm: HR 0.56, 95% CI: 0.10-3.24; P =0.52; chemo arm: HR 0.19, 95% CI: 0.04-0.83; P=0.03). Additionally, patients who had no/short delay before starting maintenance experienced a longer median duration of maintenance treatment (blina arm, 548 days; chemo arm, 708 days) compared to patients who had a long delay (blina arm 488 days; chemo arm 598 days) before initiation of maintenance (P=0.0008). Conclusion: In the phase 3 randomized ECOG-ACRIN E1910 clinical trial, long delays between initiation of consolidation therapy and start of maintenance therapy were associated with improved OS compared to no/short delays. However, within each treatment group (blina or chemo), no significant difference of OS was observed. We postulate that these longer delays allowed more patients to receive all of the recommended protocol-assigned therapy thereby resulting in improved survival. Furthermore, patients who had no/short delays had a significantly longer duration of maintenance therapy. These data indicate that treatment delays during consolidation do not worsen survival. Further studies are being done to better understand why patients with long delays had better overall survival.

Abstract Introduction: Multiple Myeloma (MM) is a complex hematologic malignancy, where patients often display one or more potentially high risk cytogenetic alterations associated with poor outcomes. Traditional high risk cytogenetics events in myeloma, such as NSD2 t(4;14) translocations, gain of 1q21, or deletion of 17p13, have often been studied in isolation, but emerging evidence suggests the combination of these high risk alterations has a greater negative prognostic impact than any on their own. This has been recently reflected in risk stratification guidelines from IMS and IMWG, which consider certain events, such as t(4;14), as high risk only in combination with gain of 1q21 or deletion of 1p32. Still, the mechanisms through which multi-hit high risk events disrupt the microenvironment and promote poor outcomes remains unclear. We hypothesize that myelomas with multiple high risk alterations remodel the immune environment to promote tumor progression and immune escape. Methods: To study the role of multi-hit high risk cytogenetics on the immune microenvironment, we analyzed CD138-bone marrow aspirate single-cell RNA sequencing (scRNAseq) data from 337 newly diagnosed MM patients from the MMRF CoMMpass study, generated as part of the Immune Atlas initiative. Cytogenetic alterations for these patients were derived from whole-genome and whole-exome sequencing of CD138+ bone marrow aspirates from the MMRF CoMMpass cohort. Patients were classified as multi-hit high-risk MM if they exhibited either (i) two high-risk cytogenetic events, including NSD2 t(4;14), MAF t(14;16), del(17p13), or (ii) one high-risk event with gain of 1q21. Results: Based on cytogenetic information, 33 patients in the Immune Atlas cohort were classified as 'multi-hit’ high-risk, while 34 patients had only a single high-risk alteration. These multi-hit high risk patents displayed significantly worse progression free survival compared to standard risk patients, adjusting for age, therapy, and ASCT (HR=2.34, p<7.2e-5), while single-hit patients showed a non-significant trend towards worse outcomes (HR=1.51, p=0.071). The most frequent multi-hit risk event in the cohort was NSD2 t(4;14) in combination with 1q21, observed in 23 patients. Compositional analysis of the immune populations in the scRNAseq data revealed that relative to both standard and single-hit high risk patients, multi-hit high risk patients displayed significant reductions in IFN-I stimulated CD4+ and CD8+ T cell populations, marked by decreased expression for antiviral response markers such as ISG15, XAF1, and IFI44L. Enrichment of inflammatory CD16+ non-classical monocytes was also observed. Further analysis of the most frequent multi-hit risk event, NSD2 with 1q21, revealed distinct enrichment of late-activated cytotoxic HLA+ CD8+T cells and cytotoxic CD4+.T cells. Neither alteration was observed in patients with single-hit NSD2 or 1q21. Further analysis on the interactions between high risk events revealed distinct transcriptomic profiles dependent on the high risk events involved, particularly in multi-hit events involving mutations or deletions of TP53 or gain of 1q21. Reduction in IFN-I signaling across various immune populations was primarily restricted to multi-hit risk events involving gain of 1q21. Conversely, patients with biallelic loss of TP53 displayed significant enrichment of these same IFN-I populations. Given this contrast in IFN-I signaling spanning multiple immune subtypes, we hypothesized that the malignant myeloma cells might similarly display altered IFN-I activity. Utilizing CD138+ myeloma bulk RNA sequencing data from CoMMpass, we found that IFN-I response scores strongly correlated between paired scRNA immune and bulk RNAseq tumor datasets (R2: 0.75, p=1.63e-32). Across 660 patients with bulk RNAseq and cytogenetic data, we confirmed significant reductions in IFN-I response scores in tumor cells in multi-hit high risk involving 1q21, and significant enrichment in those with complete loss of TP53 relative to standard-risk MM. Conclusions: Overall, we do observe that MM patients with multiple high risk cytogenetic alterations display distinct immunologic traits relative to standard risk or single-hit high risk patients in addition to significantly worse outcomes. Furthermore, we find variability in the immune alterations observed based on the cytogenetic events involved, further illustrating the heterogeneity in how MM shapes the immune microenvironment.

Abstract Introduction: HMA monotherapy (HMAm) continues to be the standard of care for HR-MDS. While the addition of VEN to azacitidine (AZA) improved overall survival (OS) and complete remission (CR) rates among older pts with acute myeloid leukemia (AML) over AZA monotherapy, the recently completed phase III VERONA trial of AZA+/-VEN in HR-MDS failed to show an OS benefit for AZA/VEN over AZA monotherapy. Using the icMDS VALIDATE database, we compared outcomes of pts with HR-MDS treated with HMA or HMA/VEN as frontline therapy. Methods: The icMDS VALIDATE database includes over 4000 adult MDS pts who received HMA-based therapy from 32 international centers in 9 countries. For this analysis, we included pts with HR-MDS defined by International Prognostic Scoring System [IPSS] ≥1.5 or IPSS-revised [IPSS-R] ≥4 (at diagnosis or HMA initiation) and treated with HMAm or HMA/VEN as frontline therapy for HR-MDS. We assessed responses based on IWG 2023 criteria (Zeidan A et al, Blood 2023). Composite complete remission (cCR) was defined as CR+CRbi+CRuni+CRh+CRequivalent. We calculated OS from time of HMA initiation to date of death from any cause. Pts lost to follow-up were censored at the date they were last known to be alive. We used Kaplan-Meier methods to calculate OS and compared OS between different groups using the log-rank test. We used Cox and logistic regression models to adjust for baseline prognostic variables as appropriate. The study was funded by an independent grant from Abbvie. Results: A total of 1907 pts met eligibility and were included (1552 AZA, 221 decitabine, 134 HMA+VEN). 479 pts subsequently underwent allogeneic stem cell transplant (allo-SCT; 430 after HMAm [32.6%]; 49 after HMA/VEN [37.1%]). Our cohort was enriched for pts with adverse disease characteristics including complex karyotype (33.6%) and TP53 mutations (28.7%). Compared to pts treated with HMA/VEN, pts treated with HMAm were more likely to be male (p=0.012), have lower baseline platelet counts (p=0.037), peripheral blood (PB) blasts (p=0.004), or bone marrow blasts (p<0.001), and were less likely to have very high risk IPSS-M (p<0.001), TP53 mutations (p<0.001), or complex karyotype (p=0.020). In unadjusted analyses, the rate of cCR was significantly lower in HMAm treated pts compared to HMA/VEN treated pts (27.7% vs. 48.8%, p<0.001). However, CR rate was not significantly different (11.7% vs. 17.1% for HMAm and HMA/VEN, respectively, p=0.22). After adjusting for age, sex, and IPSS-M, pts treated with HMA/VEN were more likely to achieve cCR compared to HMAm with an odds ratio (OR) of 2.49 (95% CI: 1.56-3.96, p<0.001). When separated by TP53 mutation status, the OR for cCR for HMA/VEN vs HMAm was 4.17 (95%CI: 2.14-8.31; p<0.001) and 1.27 (95%CI: 0.54-2.86; p=0.57) for TP53 wild-type and TP53-mutant pts, respectively. In unadjusted analyses, median OS was 17.4 months for HMAm and 19.6 months for HMA+VEN, and OS did not differ significantly by treatment type (p=0.33). For HMAm treated pts, the OS rates at year 1, 2, 3 were 0.65 (95%CI: 0.63-0.67), 0.38 (95%CI: 0.36-0.40), and 0.27 (95%CI: 0.25-0.29), respectively. For HMA/VEN treated pts, the OS rates at year 1, 2, 3 were 0.64 (95%CI: 0.56-0.73), 0.45 (95%CI: 0.36-0.56), and 0.37 (95%CI: 0.27-0.51), respectively. In a multivariate analysis adjusting for age, sex, PB blast, IPSS-M and allo-SCT as a time-varying covariate, treatment with HMA/VEN vs HMAm did not significantly influence OS (hazard ratio (HR) of OS for HMA/VEN vs HMAm: 0.89, 95%CI: 0.69-1.13, p=0.33). When stratified by TP53 mutation status, HR of HMA/VEN vs. HMAm was favorable for TP53 wild-type (HR: 0.47; 95%CI: 0.29-0.74) but not TP53-mutant pts (HR=0.96; 95%CI: 0.66-1.41). Adjusting for other variables in the model, HR for pts who underwent vs. those who did not undergo allo-SCT were 0.65 (95% CI: 0.49-0.85) and 0.36 (95%CI: 0.24-0.53) in TP53 wild-type and mutant patients, respectively. Conclusion: In this large, international retrospective analysis from the icMDS VALIDATE database, HMA/VEN was associated with higher cCR rates—but not CR rates—compared to HMAm among pts with HR-MDS, though we observed no significant differences in OS. In our analysis, clinical benefit from the addition of VEN was most clear in TP53 wild-type pts, and allo-SCT was associated with improved OS regardless of baseline TP53 status. Our analysis was limited by the relatively small number of HMA/VEN-treated pts and heterogeneous real-world treatment patterns.

Abstract Introduction Diffuse large B-cell lymphoma (DLBCL) is a heterogenous disease with varied expressions of CD30. Brentuximab vedotin (BV) is a CD30-directed antibody-drug conjugate approved for treatment of patients with relapsed or refractory DLBCL in combination with lenalidomide (Len) and rituximab (R). In the phase 3 ECHELON-3 study (NCT04404283), BV + Len + R showed significant overall survival (OS) benefit compared with placebo + Len + R in patients with relapsed or refractory DLBCL. Subgroup analysis from this study showed that BV + Len + R provided clinical benefit regardless of CD30 expression level. We hypothesized that even sub-threshold levels of CD30 expression, below the detection limits of immunohistochemistry (IHC), may be sufficient to elicit the antitumor activity of BV. Here, we further investigated whether trace amounts of CD30 staining are required for patients to benefit from BV + Len + R. Methods In the ECHELON-3 study, patients with relapsed or refractory DLBCL were randomized 1:1 to receive BV + Len + R or placebo + Len + R. The primary endpoint was OS, with progression-free survival (PFS) and objective response rate (ORR), per Lugano 2014, as key secondary endpoints. CD30 expression was assessed by IHC by central and/or local testing. CD30 positivity was scored as the percentage of CD30 positive cells out of neoplastic cells or out of total lymphocytes, when neoplastic cells could not be distinguished. In this updated analysis, patients with CD30 <1% staining by central laboratory IHC were further grouped into CD30 <1% with trace staining and CD30 <1% with no staining. Results Overall, 60 patients in the BV + Len + R group had CD30 <1% expression; of these, 34 had CD30 <1% with trace staining and 26 had CD30 <1% with no staining. In the placebo + Len + R group, 63 patients had CD30 <1% expression; of these, 36 had CD30 <1% with trace staining and 27 had CD30 <1% with no staining. In the overall CD30 <1% groups, numerically greater OS and PFS benefits were observed with BV + Len + R vs placebo + Len + R (HR for OS, 0.57; 95% CI, 0.36-0.89 and HR for PFS, 0.53; 95% CI, 0.34-0.82). In patients with CD30 <1% with trace staining, BV + Len + R showed a numerically higher OS compared with placebo + Len + R, with HR of 0.48 (95% CI, 0.26-0.90); median OS was 15.6 vs 5.2 months. In patients with CD30 <1% with no staining, there was a trend toward higher OS with BV + Len + R vs placebo + Len + R, with HR of 0.66 (95% CI, 0.34-1.28); median OS was 14.8 vs 11.8 months. Similarly, in patients with CD30 <1% with trace staining, BV + Len + R showed a trend toward longer PFS compared with placebo + Len + R, with HR of 0.60 (95% CI, 0.33-1.11); median PFS was 2.8 vs 1.5 months. In patients with CD30 <1% with no staining, a numerically longer PFS benefit was observed with BV + Len + R vs placebo + Len + R, with HR of 0.41 (95% CI, 0.21-0.79); median PFS was 4.2 vs 2.7 months. In the overall groups, ORR was 60.0% with BV + Len + R and 34.9% with placebo + Len + R. Higher ORR was observed with BV + Len + R compared with placebo + Len + R in both CD30 <1% with trace staining (55.9% vs 25.0%) and CD30 <1% with no staining (65.4% vs 48.1%) groups. Conclusions Results from this updated analysis indicate that visible CD30 detection by IHC is not required for response to BV + Len + R in patients with relapsed or refractory DLBCL. Treatment with BV + Len + R showed efficacy benefit compared with placebo + Len + R regardless of CD30 expression level, including in patients with no visible CD30 IHC staining. These results are consistent with those from the overall ECHELON-3 study population, in which significant improvement in OS was demonstrated with BV + Len + R compared with placebo + Len + R.