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Abstract Introduction: Only 30% of patients (pts) presenting with abnormal bleeding symptoms receive a clear diagnosis, with many classified as having bleeding disorder of unknown cause, or BDUC (Baker et al. 2021). Currently, the recommended diagnostic workup for BDUC by the International Society on Thrombosis and Haemostasis (ISTH) includes plasmatic assays for coagulation factors, von Willebrand factor (vWF) antigen/activity, and platelet function testing (PFT), specifically platelet function analyzer-100 (PFA-100) and light transmission aggregometry (LTA). However, PFTs are not widely available and cannot be mailed to reference laboratories. We studied the diagnostic yield of an expanded testing panel which includes quantitative platelet glycoprotein flow cytometry (GpFL) and platelet electron microscopy (PTEM), which we have optimized for specimen mailing. Methods: We conducted a minimal risk, retrospective study by reviewing the electronic health records of pts (18 years and older) who were seen in the Coagulation Clinic of a tertiary academic medical center for evaluation of a bleeding disorder between October 2017 and June 2025. Testing included plasma-based assays including PT, APTT, vWF assay, FVIII, FIX, FXIII screen, and thrombin time (and additional reflex assays as needed). At the discretion of the treating clinician, PFTs (PFA-100 and LTA), GpFL, PTEM, and fibrinolysis assays (plasminogen activator inhibitor-1 antigen [PAI-1 Ag] and alpha-2 plasmin inhibitor) were included. We abstracted clinical data on pt demographics, ISTH bleeding scores, and the results of coagulation testing. Pts with an established diagnosis of a bleeding disorder, underlying malignancy, and those who did not have plasma-based coagulation testing were excluded from this study. Results: 109 pts met study criteria, and 82.6% were females (n = 90) with a median age of 45 years (range = 18-88 years). The median ISTH-BAT score was 7 (range: 2-21). About half of the pts, 49.5% (n = 54), had normal coagulation profiles and PFTs. All 54 had PTEM performed, of which 14.8% (n = 8) were abnormal (alpha and/or dense granule deficiencies). 85.2% (n = 46) had GpFL testing performed, with one showing reduced Gp2b/CD42 and Gp3a/CD61 expression, four showing reduced Gp1a/CD49b expression, and three showing reduced GpVI expression. Half of the pts, 50.5% (n = 55) had an abnormal coagulation profile from plasma and/or PFTs, of which 20% (n = 11) had a clinically significant coagulation factor deficiency (FV, FVII, FX). Roughly 9.1% (n = 5) had type 1 vWD of which 1 also had PAI-1 deficiency. One pt had isolated PAI-1 deficiency. Abnormal coagulation profiles were noted in 53 pts who had PFA-100 and LTA done, and both tests were normal in 22.6% (n = 12). Within the abnormal coagulation profile group, 10.9% (n = 6) had ultrastructural abnormalities on PTEM (dense and alpha granule abnormalities). Majority of the pts (n = 46) had GpFL done, and one had abnormal reductions in Gp1b-aCD42b, three in Gp1aCD49b, and seven in GPVI. Comparison of the ISTH BAT score between the normal and abnormal coagulation profiles/PFTs groups by non-parametric (Mann-Whitney U test) and parametric (Welch's t-test) showed no significant difference (p = 0.56 and p = 0.87) respectively. Conclusion: In this cohort of pts with abnormal bleeding, standard recommended testing resulted in a diagnosis in 66.4% pts. The remainder would have been classified as BDUC. The addition of GpFL and PTEM resulted in establishing a diagnosis that explains the bleeding phenotype in 14.8% of pts with an otherwise normal coagulation profile and PFT. Although abnormal PFTs indicate a platelet function defect, GpFL and PTEM may further define the abnormalities particularly differentiating syndromic from non-syndromic inherited platelet disorders. Additional studies are needed to confirm our findings and explore the possibility of addition of GpFL and PTEM for patients with BDUC.

Abstract Background: Partial tandem duplications of the histone methyltransferase KMT2Agene(KMT2A-PTD) are the most common KMT2A-aberration in adult acute myeloid leukemia (AML). KMT2A-PTD AML represents a high-risk disease subset with a poor prognosis. However, KMT2A-PTD leukemia is under studied, likely due to a lack of experimental models, and therefore the underlying mechanisms of leukemogenesis remain elusive. Since KMT2A-PTD leukemias possess high-level expression of HOXAgenes, similar to KMT2A-rearranged (KMT2A-r) and NPM1c AML, patients with this type of AML are currently enrolled into several phase I/II trials assessing menin inhibitors (MIs). However, mechanistic or clinical evidence for treatment response is lacking. To date, no targeted therapeutic approaches for KMT2A-PTD leukemia are available. Results: To better understand KMT2A-PTD mediated leukemogenesis, we endogenously tagged the KMT2A-PTD or KMT2A-wildtype (WT) allele in EOL-1 cells with a dTAG that can be degraded with PROTACs. Targeted protein degradation showed that the KMT2A-PTD, but not the KMT2A-WT protein, is critical to maintain leukemia cell growth. We identified KMT2A-PTD specific genome-wide chromatin binding sites and direct target genes as assessed by changes in nascent RNA production that started to occur within 30 minutes of KMT2A-PTD degradation. KMT2A-PTD target genes identified in this study included HOXA9, HMX2, HMX3, CDKN2C, MYC and CDK6 among others. Having defined the KMT2A-PTD target gene program, we assessed the effect of MI on KMT2A-PTD function. In KMT2A-PTD cell lines, PDXs and cells from a published murine KMT2A-PTD/FLT3-ITD knockin model, we observed intrinsic resistance to revumenib characterized by retained chromatin binding of KMT2A-PTD, but not KMT2A-WT after MI treatment. We next defined critical domains for KMT2A-PTD function via a KMT2A domain scan. This revealed the CXXC domain and AT hooks as critical dependencies in EOL-1 cells. Overexpression of KMT2A or mutants with duplicated domains in 293T cells showed that a duplication of the CXXC domain or the AT hooks is sufficient to mediate retained KMT2A chromatin binding under MI. Therefore, the resistance to MIs is likely due to the duplicated protein of KMT2A subverting menin function at critical target loci. Given that KMT2A-PTD remains chromatin-bound upon menin inhibition, we focused on ENL as a potential regulator of leukemia gene expression programs. In KMT2A-r and NPM1c leukemia, the ENL protein has been shown to be a critical dependency as it associates with acetyl lysine via its YEATS domain. ENL/AF9 YEATS inhibitors reverse ENL-dependent gene expression including HOXA9 and MYC. Using the small molecules TDI-11055 and TM-7, we show that YEATS inhibition leads to loss of members of the super-elongation complex and DOT1L from KMT2A-PTD driven loci and downregulation of target gene expression. Treatment of KMT2A-PTD PDXs with YEATS inhibitors induced differentiation and significantly reduced leukemia burden in vivo. Interestingly, we show that in contrast to previous findings in KMT2A-r leukemia, loss of ENL alone is insufficient to abrogate leukemic proliferation of EOL-1 cells. Instead, by combining ENL degradation with CRISPR-Cas9 mediated knockdown of AF9, we find that both YEATS proteins, ENL and its paralogue AF9, support aberrant gene expression in KMT2A-PTD leukemia. Finally, we show that the novel combination of MI and YEATS inhibition (revumenib plus TDI-11055) synergistically affects proliferation and induces differentiation in cell line and PDX models of KMT2A-PTD leukemia, which in turn prolongs survival of mice with KMT2A-PTD leukemia. Conclusions: KMT2A-PTD leukemia is dependent on the mutated, but not the WT KMT2A allele. It is characterized by a relative, intrinsic resistance to MI monotherapy, which is mediated by a duplication of the CXXC domain and AT hooks of KMT2A. Targeting both, the ENL and AF9 YEATS domain, is a possible treatment strategy and when combined with revumenib, YEATS inhibition has synergistic effects and overcomes intrinsic MI resistance. However, based on our studies, MI monotherapy may not be effective for most patients with KMT2A-PTD leukemia. Given that numerous compounds targeting the ENL (and AF9) YEATS domain are under study and MIs have recently obtained FDA approval, the combination of MI and YEATS inhibition could be translated into clinical trials for patients with KMT2A-PTD leukemia in the relatively near future.

Abstract Introduction: Leukemogenesis is driven by nucleophosmin 1 mutations(NPM1-m) or lysine methyltransferase 2A rearrangements(KMT2A-r) in ~35–40% of acute myeloid leukemia (AML) cases. Nearly half of AML patients will develop relapsed/refractory (R/R) disease within a year, with <20% expected response rate following venetoclax/azacitidine (Ven/Aza) and progressively poorer outcomes with each subsequent line of therapy. Ziftomenib–a potent, highly selective, oral, investigational menin inhibitor–has demonstrated clinical activity as both monotherapy and in combination for adults with R/R NPM1-m or KMT2A-r AML. KOMET-007 (NCT05735184) is an ongoing, open-label, ph1a/b study of ziftomenib in combination with standard chemotherapies in adults with newly diagnosed and R/R NPM1-m or KMT2A-r AML. Here we present updated safety and clinical activity in patients with R/R AML treated with the recommended ph2 dose (RP2D) of ziftomenib 600 mg in combination with Ven/Aza across ph1a/b. Methods: Adults (≥18y) with R/R NPM1-m or KMT2A-r AML enrolled independently into separate arms; patients in dose escalation (ph1a) and expansion (ph1b) were treated with oral ziftomenib 600 mg once daily (QD; continuously from C1D8 onward) plus standard doses of Ven/Aza. Primary endpoints: AEs, complete remission (CR; ELN 2022), dose limiting toxicities (DLT; ph1a only). Key secondary endpoints: composite CR (CRc; CR with full, partial or incomplete hematologic recovery), overall response, duration of response. Results: As of June 25, 2025, 80 patients (51 NPM1-m, 29 KMT2A-r) with R/R AML were enrolled (20 ph1a; 60 ph1b) and treated with ziftomenib 600 mg QD + Ven/Aza. Median age was 63y (range 19–85), 50% were female, 74% had ECOG PS 0–1; 22 (28%) had FLT3 co-mutations and 7 (9%) had IDH co-mutations. Median number of prior therapies was 1 (range 1–6); 18% (14/80) had prior stem cell transplant; 25 (49%) NPM1-m and 19 (66%) KMT2A-r patients had prior Ven exposure. 71 patients (89%) had Gr ≥3 treatment-emergent AEs, most commonly (≥20% of patients) febrile neutropenia (31%), decreased platelet count (28%), decreased white blood cell count (26%) and decreased neutrophil count (23%). Gr ≥3 ziftomenib-related AEs occurred in 30 patients (38%), most commonly febrile neutropenia (9%) and anemia (8%). 6% of patients discontinued ziftomenib treatment due to AEs. Differentiation syndrome (DS) occurred in 1 (1%) NPM1-m patient (Gr 3), which lasted 1d and successfully resolved with protocol-specified DS mitigation. No ziftomenib-related QTc prolongation was reported with the combination, and no DLTs were observed in ph1a. 70 patients (43 NPM1-m; 27 KMT2A-r) were response-evaluable (≥1 response assessment or death). Median follow-up was 18.0 wks for NPM1-m and 16.4 wks for KMT2A-r. Overall response rates (ORRs) were 65% (28/43) for NPM1-m and 33% (9/27) for KMT2A-r. CRc rates were 49% (21/43) for NPM1-m and 22% (6/27) for KMT2A-r after median time to first CRc of 4.9 wks (range 2.7–15.6) and 5.5 wks (range 2.6–18.9), respectively; measurable residual disease (MRD)-negativity rates (local) among tested CRc responders were 50% (9/18) for NPM1-m and 60% (3/5) for KMT2A-r after median time to first MRD-negativity of 5.9 wks (range 2.9–15.6) and 8.1 wks (range 7.7–18.9), respectively. During continuous ziftomenib administration in patients who achieved CRc, median time to neutrophil recovery (≥1×109/L) was 43d overall (43d for NPM1-m; 71d for KMT2A-r), and median time to platelet recovery (≥100×109/L) was 27d overall (27d for NPM1-m; 23d for KMT2A-r). As of the data cutoff, overall median duration of CRc was not estimable; median overall survival was not estimable for NPM1-m and 21.1 wks for KMT2A-r. In Ven-naive patients, CRc rates were 71% (15/21) for NPM1-m and 33% (3/9) for KMT2A-r; CR rates were 48% (10/21) and 11% (1/9); and ORRs were 81% (17/21) and 56% (5/9), respectively. The study is ongoing with 44% (19/43) of NPM1-m and 11% (3/27) of KMT2A-r patients still on treatment, with responses continuing to evolve.Updated data to be presented.Conclusions: In the ongoing KOMET-007 study, ziftomenib RP2D of 600 mg QD + Ven/Aza was well tolerated with robust clinical activity in patients with R/R NPM1-mor KMT2A-rAML. No ziftomenib-related QTc prolongation was reported. One case of DS (NPM1-m, Gr 3) successfully resolved with protocol-specified mitigation. These data support further investigation of ziftomenib-based combinations in R/R NPM1-mand KMT2A-rAML.

Abstract Introduction: Nucleophosmin 1 mutations (NPM1-m) drive leukemogenesis in approximately 30% of acute myeloid leukemia (AML) cases. Ziftomenib is a potent, highly selective, oral, investigational menin inhibitor that has demonstrated clinical activity as both monotherapy and in combination for adults with NPM1-m or lysine methyltransferase 2A-rearranged (KMT2A-r) AML. KOMET-007 (NCT05735184) is an ongoing, open-label, dose-escalation (phase 1a) and expansion (phase 1b) study of ziftomenib in combination with standard chemotherapies in NPM1-m or KMT2A-r AML. Here we present phase 1b safety and clinical activity in patients with newly diagnosed NPM1-m AML who received the recommended phase 2 dose (RP2D) of ziftomenib 600 mg in combination with venetoclax and azacitidine (Ven/Aza). Methods: Adults (≥18 years) with newly diagnosed NPM1-m AML who were not eligible for intensive chemotherapy were enrolled in phase 1b and received ziftomenib 600 mg once daily plus standard doses of Ven/Aza. Ziftomenib was orally administered once daily continuously from Cycle 1 Day 8 onward. Phase 1b primary endpoints were adverse events (AEs) and complete remission (CR) per ELN 2022. Secondary endpoints included composite CR (CRc; defined as CR with full, partial, or incomplete hematologic recovery), overall response, and duration of response. Local measurable residual disease (MRD) was assessed by next-generation sequencing, RT-qPCR, and multiparameter flow cytometry. Results: As of June 25, 2025, 39 patients with newly diagnosed NPM1-m AML were enrolled and treated with ziftomenib 600 mg once daily plus Ven/Aza in phase 1b. Median age was 75 years (range 53–93), 54% were female, 46% had ECOG PS 0–1; 12 (31%) had FLT3 co-mutations and 9 (23%) had IDH co-mutations. Median duration of follow-up was 16.3 weeks (range 1.6–41.1). Twenty-nine patients (74%) had grade ≥3 treatment-emergent AEs, most commonly (≥20% of patients) decreased neutrophil count (31%) and decreased platelet count (23%). Grade ≥3 ziftomenib-related AEs occurred in 14 patients (36%), most commonly decreased neutrophil count (15%) and decreased platelet count (13%). No ziftomenib treatment discontinuations occurred due to AEs. Differentiation syndrome occurred in 1 (3%) patient (grade 2), which successfully resolved with protocol-specified mitigation. One patient (3%) had investigator-assessed ziftomenib-associated QTc prolongation (grade 3); however, there were concomitant significant electrolyte abnormalities and event resolved with electrolyte repletion. At time of data cutoff, 31 NPM1-m patients were response-evaluable (≥1 response assessment or death). CRc rate was 84% (26/31) after a median time to first CRc of 3.5 weeks (range 2.4–9.4), with local MRD-negativity rates among tested CRc responders of 54% (13/24) after a median time to first MRD-negativity of 8.4 weeks (range 2.9–17.4). CR rate was 58% (18/31) and overall response rate was 94% (29/31), with responses and MRD-negativity rates continuing to evolve. During continuous ziftomenib administration in patients who achieved CRc, median time to neutrophil recovery (≥1×109/L) was 36 days, and median time to platelet recovery (≥100×109/L) was 28 days. The median duration of response and median overall survival were not reached as of the data cutoff, at a median follow-up of 16.3 weeks. The study is ongoing, with 81% (25/31) of NPM1-m patients still on-study and 77% (24/31) still on ziftomenib treatment. Updated safety and clinical activity results will be presented.Conclusions: In the ongoing KOMET-007 study, ziftomenib RP2D of 600 mg once daily combined with Ven/Aza was well tolerated and demonstrated robust clinical activity in patients with newly diagnosed NPM1-m AML, including 84% CRc after a median of 3.5 weeks and 54% CRc MRD-negativity after a median of 8.4 weeks. Low rates of ziftomenib-related cytopenia and no additional myelosuppression were observed with this combination. One case each of differentiation syndrome (grade 2) and investigator-assessed QTc (grade 3) were successfully resolved. Taken together, these data support the RP2D determination and advancement of this ziftomenib-based combination in the KOMET-017 (NCT07007312) randomized phase 3 study in patients with newly diagnosed NPM1-m AML.

Abstract Introduction Nadir bone marrow biopsies (BM Bx) are routinely performed around day 14 to assess early response to AML intensive induction therapy. The presence of residual disease prompts initiation of reinduction therapy, often with another cycle of intensive chemotherapy. Whether there are characteristics of nadir BM Bx that predict for response to intensive reinduction is unknown. To evaluate this, we analyzed data from ECOG-ACRIN clinical trials in AML of intensive induction chemotherapy with nadir biopsy information available to determine predictors of outcomes after reinduction. Methods We included patients from ECOG-ACRIN E1900 (Fernandez NEJM 2009) and arm A of E2906 (Foran ASH 2015) who received induction therapy with daunorubicin and cytarabine (7+3), had residual disease (blasts ≥5% or cellularity ≥20%) at nadir BM Bx and received reinduction chemotherapy. Nadir BM Bx characteristics that were evaluated included blast percentage and cellularity as well as both absolute and relative (percentage change, e.g. 20% to 10% = -50%) differences calculated between diagnosis and nadir for each parameter. Complete remission (CR) after reinduction therapy, disease free survival (DFS) and overall survival (OS) were outcomes for all analyses. Logistic regression models were used to evaluate associations with CR, and Cox proportional hazards models were used for DFS and OS. For models evaluating changes in blast percentage or cellularity as predictors, baseline blast percentage or cellularity was included as a covariate, respectively. Results Of 1013 patients identified, 750 (74%) had a nadir biopsy, 233 (23%) had evidence of residual disease, received reinduction therapy, and were included in the primary analysis. The median age was 58 and 42% were female. Cytogenetic risk category (by ELN2017) was adverse in 31%, intermediate in 66% and favorable in 3%. The median nadir BM Bx blast was 30% (range 0 to +97%) and cellularity was 20% (0 to +100%). The median absolute difference in blast percentage between baseline and nadir BM Bx was -15% (-95% to +66%) with a median relative difference of -36% (-100% to +400%). After reinduction, 118 patients (52%) achieved a CR. Neither absolute difference in blast percentage (OR 0.99, 95%CI 0.98-1.00, p=0.20) nor relative difference (OR 1.00, 95%CI 0.99-1.00, p=0.33) predicted CR. There was similarly no association with DFS (HR = 1.00, 95%CI: 0.99-1.01, p=0.65) or OS (HR = 1.00, 95%CI 0.99-1.01, p=0.76). Blast reduction ≥50% similarly did not predict these outcomes. We also evaluated the impact of any reduction in blast percentage (responders) from baseline to nadir and again found no association with CR (OR 1.65, 95%CI 0.90-3.03, p=0.11). Similarly, there was no association with DFS (HR 0.74, 95%CI 0.51-1.09, p=0.13) or OS (HR 0.81, 95%CI 0.58-1.13, p=0.21) in responders vs nonresponders. No association with CR, DFS or OS were identified when performing the same analysis in intermediate and adverse cytogenetic subgroups. We found no association with CR when nadir cellularity was assessed as a continuous variable (OR 0.99, 95%CI 0.98-1.00, p=0.10) or by relative difference (OR 0.99, 95%CI 0.99-1.00, p=0.10). There was a trend towards association with absolute reduction in cellularity from baseline to nadir and CR (OR 0.99, 95%CI 0.98-1.00, p=0.06). No association was identified between relative difference in cellularity and DFS and OS, nor was there an association among cytogenetic risk subgroups with any outcome. Discussion In intensively treated patients with residual disease at nadir BM Bx (i.e. day 14) who received intensive reinduction, the likelihood of achieving a CR was not influenced by the magnitude of disease reduction nor the extent of disease at the time of nadir biopsy. Similarly, there were no nadir biopsy features that predicted DFS or OS after intensive reinduction therapy. Given alternative reinduction therapies such as hypomethylating agents and venetoclax are available, these results suggest that the decision to attempt a second intensive induction cycle following the unequivocal presence of residual disease should not be influenced by characteristics of the nadir BM Bx. Although patient-specific factors such as patient fitness may favor a switch to less intensive options, these results support consideration of intensive reinduction therapy in patients with residual disease at nadir biopsy, even without changes in blasts or cellularity.

Abstract Background and Significance: Waldenström's Macroglobulinemia (WM) is an indolent B cell disorder characterized by proliferation of clonal lymphoplasmacytic lymphocytes in the bone marrow, lymph nodes, as well as liver and spleen, and secreting a monoclonal IgM Protein. WM is a rare disorder with about 1,700 cases diagnosed in the U.S. each year. There have been significant advances in the management of patients with WM in the last decade, with Bruton's tyrosine kinase (BTK) inhibitors (ibrutinib and zanubrutinib) emerging as a major treatment advancement in this disease. Currently, both BTK inhibitors are approved for the treatment of WM patients with newly diagnosed as well as relapsed/refractory (R/R) disease. BTK inhibitors are effective for the therapy of WM, especially among patients with MYD88 mutation, although the response rates are lower in patients with CXCR4 mutations. In addition, these drugs can cause cardiac side effects such as atrial and ventricular arrhythmias as well as an increased risk of bleeding/bruising. Thus, these drugs can be difficult to use in patients who are older and have cardiac comorbidities. BCL-2 overexpression is well described in a number of B cell malignancies, including WM, leading to inhibition of apoptosis of malignant cells. BCL-2 inhibition with venetoclax has been tested in patients with R/R WM and showed excellent activity with an overall response rate (ORR) of 85% and very good partial response (VGPR) rate of 19%. The therapy was overall well tolerated with no evidence of cardiac toxicity. Given the excellent activity and tolerability of Venetoclax in WM, we are conducting a national cooperative group randomized phase 2 trial comparing ibrutinib+rituximab (IR) vs. venetoclax+rituximab (VR) in patients with newly diagnosed WM. Our hypothesis is that with this trial, we have the potential to develop a more effective therapy targeting BCL-2 for patients with untreated WM, that does not have cardiac or hemostatic toxicity. In addition, we are testing use of a fixed duration therapy with these regimens. Study design and methods: The ongoing clinical trial () is being conducted through the Southwest Oncology Group (SWOG) and is enrolling at multiple SWOG, ECOG, and ALLIANCE centers throughout the US. Major inclusion criteria include 1) newly diagnosed WM confirmed by biopsy and measurable disease (≥0.5 g/dl IgM type paraprotein), 2) meeting WM-related clinical criteria to initiate therapy (cytopenias, B symptoms, bulky lymphadenopathy, neuropathy, hyperviscosity) 3) adequate blood counts (ANC >1000, HGB ≥7.5, PLT ≥50,000), 4) eGFR ≥30 ml/min, 5) adequate liver function tests (total bilirubin ≤1.5 x ULN and AST, ALT and alkaline phosphatase ≤3 x ULN), 6) Zubrod performance status ≤2, 7)prior treatment with single-agent R allowed as long as >6 months prior to registration. Once enrolled the patients will be randomized 1:1 to IR vs. VR. I will be started at 420 mg daily at start of therapy while V will be given at 400mg daily during cycle 1 week 1 and then increased to 800 mg daily from cycle 1 day 8 onwards. R will be given weekly x 4 in cycles 2 and 5. Dose adjustments for both I and V can be done depending on toxicity. Therapy will be given for 2 years and then the patients will be observed off treatment. Patients with disease progression during these 2 years of therapy can cross-over to the other arm. The primary endpoint of the study is rate of VGPR or better. With 41 eligible participants per arm (total N=82), this design has 80% power to reject the null hypothesis of a 25% VGPR rate, given the alternative of a 50% VGPR rate, with a one-sided alpha of 10%. To account for an anticipated 10% ineligibility rate, approximately 46 participants will be accrued per arm (92 total). Current enrollment stands at 15 patients. The secondary end points include ORR, complete response rate, major response rate, progression free and overall survival rates.

Abstract Introduction: NAVD has become a standard-of-care for frontline (1L) treatment (tx) of advanced stage cHL, based on the results of the S1826 study. S1826 demonstrated a 1-year progression free survival (PFS) of 94% for NAVD compared to 86% for brentuximab vedotin-AVD, which remained durable at 2 years (Herrera et al, NEJM 2024). Adverse events (AEs) and efficacy have not been reported in patients (pts) treated with NAVD outside of a clinical trial. Hence, we sought to evaluate safety profile and efficacy outcomes of pts with cHL treated with 1L NAVD in a real-world setting (RWS). Methods: In this multicenter retrospective cohort study, we included pts ≥18 years with cHL treated with 1L standard of care NAVD between 2023 and 2025 at 20 US academic sites. The safety evaluable cohort received at least 1 cycle of NAVD and included pts who have not completed tx. The efficacy evaluable cohort had completed 6 cycles of tx including end of treatment (EOT) PET-CT and included pts who intended to complete tx but died or discontinued due to progressive disease or AEs. The primary endpoint was EOT overall response rate (ORR). Secondary endpoints included EOT complete response rate (CRR), PFS and overall survival (OS). PFS and OS were calculated from the start date of tx and analyzed using the Kaplan Meier method. Results: A total of 311 pts with cHL were treated with NAVD with 26% of pts with tx ongoing (n=83) and 73% with tx completed (n=228). Baseline demographics included 55% male pts, 60% with stage IV disease (stage IIB, n=4) and 84% with nodular sclerosis subtype. Median age was 37 years (range 18-88), 29% had bulky disease (>7.5 cm), 28% were EBV positive (n=74/268), 8% had history of an autoimmune disease, and 31% had an IPS 4-7. G-CSF was given in 64% of pts. All patients were safety evaluable. Tx was interrupted (any length) in 24%, reduced in 12%, and discontinued in 14%. The most common reason for dose reduction was neuropathy in 4%. Nivolumab was discontinued in 10% and all therapy in 3.7% due to toxicity. Any AE and any grade 3 or higher AE (>G3) were observed in 92% and 62%, respectively. Neutropenia of any grade occurred in 68% (48% >G3), infection in 25% (10% >G3), and neuropathy in 30% (2.8% >G3). Hospitalization for an AE occurred in 20% (4.5% febrile neutropenia). Among pts with complete data (n=305), any immune related AE (irAE) occurred in 78 pts (25.6%) with any >G3 irAE in 23 pts (7.5%). The most common irAEs included hypothyroidism (7.9%, all grade 1-2), hepatotoxicity (1.6% G1/G2, 3.3% >G3), inflammatory arthritis (3% G1/G2, 0.6% >G3), rash (2.6%, all grade 1-2), and colitis (1% G1/G2, 1% >G3). Other notable >G3 irAEs included adrenal insufficiency (n=2), AKI/ATN (n=1), myocarditis (n=1), diabetes (n=1) and pancreatitis (n=1). Of 84 irAE events, 47 (56%) have had complete resolution. Among all pts, 14.4% (n=45) required systemic steroids at any time (intravenous in 4.1%), 3.2% (n=10) require ongoing steroids/immunosuppression and 8.3% other therapy for an irAE (n=23 levothyroxine, n=1 hemodialysis, n=1 heart failure tx, n=1 insulin). Among all pts, 265 (85%) had an interim PET-CT after 2-4 cycles. The ORR and CRR at interim PET-CT were 97% and 78%, respectively. In the efficacy evaluable population (n=228), the EOT ORR and CRR were 96% and 90%. The median follow up was 10.2 mo (range 0.27-28.52). The 1-year PFS and OS estimates were 93.8% (95% CI: 90.8-98.4%) and 99.1% (95% CI: 97.9-100%), respectively. In multivariable analysis (MVA), only IPS score (OR 0.6, 95%CI: 0.59-0.60) was associated with lower CRR. In Cox univariable analysis, EBV+ status (HR=14.8, 95% CI: 3.2-69.2), IPS score (HR=1.5, 95% CI: 1.0-2.2), and ESR (HR=1.02, 95% CI: 1.00-1.04) were associated with worse PFS. Among the 11 pts with progression/relapse, 9 were primary refractory. 10 pts were started on second line (2L) therapy, and all pts are alive (1 pt pending 2L tx initiation). There were 2 deaths: one related to infectious complications and other unknown and both occurred after the first cycle of therapy. Conclusions: Pts treated with NAVD in a large RWS showed comparable response rates and 1-year survival outcomes to those in the pivotal S1826 trial. Most AEs were similar and grade 1-2, but close monitoring of irAEs is necessary given the potential long-term toxicity of checkpoint inhibitors and potential for ≥G3 irAEs (7.5%) in this young patient population. Our data supports the use of NAVD for 1L advanced stage cHL.

Abstract Background: Although progression-free survival (PFS) in early-stage (ES) classic Hodgkin Lymphoma (cHL) is high, there remains a subset of patients (pts) at higher risk of worse outcomes, particularly in those with unfavorable risk disease. Leveraging pt-level data from within the HoLISTIC (Hodgkin Lymphoma International STudy for Individual Care) Consortium, the E-HIPI was developed in clinical trial pts and validated in real-world registry pts to predict 2-year (y) PFS (Rodday. NEJM Evidence 2025). Continuous, objective, and readily measurable pre-treatment variables were considered, with sex, maximum tumor diameter, albumin, and hemoglobin included as significant predictors. Using the E-HIPI, interactive calculators for pt risk, comparison, and stratification were created (https://rtools.mayo.edu/holistic_ehipi/). Although the E-HIPI was developed and validated in both unfavorable and favorable ES cHL pts, the clinical predictors are primarily markers of unfavorable disease. In the development and initial validation cohorts, 2y PFS was 93.7% and 90.3%, respectively, the C-statistic was 0.63 in both cohorts, calibration was strong with slight underprediction of events in the validation cohort, and the E-HIPI outperformed the historic binary classification of patients as favorable or unfavorable using EORTC criteria. However, since pts in the original E-HIPI development and validation were primarily treated with ABVD chemotherapy protocols, additional validation is needed, particularly among pts with unfavorable ES cHL who were treated initially with more intensive chemotherapeutic platforms (e.g., BEACOPP-based). Thus, we conducted an external validation of the E-HIPI in pts treated on recent unfavorable ES cHL GHSG trials. Methods: The validation cohort included 2367 adults (ages 18 to 60y) with newly-diagnosed unfavorable cHL from randomized phase 3 trials conducted by the GHSG (HD14 von Tresckow. JCO 2012; and HD17 Borchmann. Lancet 2021). We calculated the predicted probability of 2y PFS events based on the E-HIPI model equation (scale 1-100%). Model performance was assessed using discrimination and calibration. Discrimination, which is the model's ability to separate high and low risk pts, was assessed using Harrell's C-statistic. Calibration, which is the model's ability to accurately predict absolute risk, was assessed by comparing observed and predicted probabilities of 2y PFS events within quintiles of predicted probabilities and estimating calibration-in-the-large (predicted minus observed event rate) and the calibration slope. Results: For pts treated on unfavorable GHSG trials, mean age was 33y, 95% had stage II disease, mean baseline E-HIPI score (i.e., predicted 2y PFS event rate) was 6.0% (SD=2.3%), and the observed 2y PFS rate was 96.2% (95%CI: 95.4-97.0%). The C-statistic was 0.65 (95% CI: 0.59-0.70), calibration-in-the-large was 0.02, and the calibration slope was 1.08 (95% CI: 0.52, 1.64). Within the lowest risk E-HIPI quintile, the observed 2y PFS event rate was 1.6%, compared with 6.1% in the highest risk quintile. Conclusions: In external validation of the recently published E-HIPI in pts with cHL treated on unfavorable GHSG trials using more intensive BEACOPP-based protocols, discrimination was similar to the original development and validation cohorts. Collectively, the E-HIPI is a treatment-agnostic prediction tool across varied treatment regimens for unfavorable ES cHL pts. Better 2y PFS in the GHSG trials than in the E-HIPI development and initial validation cohorts may have contributed to mild misclassification, likely reflecting differences in treatment regimens. This may be resolved with recalibration or incorporating granular treatment variables into future models. Additional research is needed to understand E-HIPI performance in pts with favorable disease who have even lower event rates as well as to more fully predict individualized pt outcomes across varied chemotherapy platforms and radiation received for all ES cHL pts.

Abstract Introduction: While the incidence of multiple myeloma (MM) is 2-3 fold higher in Black compared to white individuals, the impact of racial differences on treatment outcomes remains unclear due to the confounding effect of socioeconomic barriers and disparities in access to effective therapies and clinical trials. In this study, we explored the relationship between race, social deprivation, and outcomes in newly diagnosed MM (NDMM) patients (pts) receiving modern therapies with triplet or quadruplet regimens. Methods: Pts with NDMM diagnosis, who received first line treatment between 2015-2025, and had data available on response and survival outcomes were identified through the ASH Research Collaborative MM Data Hub (a real-world database with pts across 11 U.S. institutions). Data on patient demographics (age, race, ethnicity, sex), disease risk status (ISS/R-ISS stage, FISH cytogenetics), treatment regimens (triplet vs quadruplet, anti CD38 monoclonal antibody-based vs not), and disparity measures were abstracted from electronic medical records. Race and ethnicity were self-reported by pts. Social Deprivation Index (SDI) score was calculated based on ZIP code, where higher scores reflect greater deprivation. Progression free survival (PFS) was defined as time from start of treatment until progression or death. Overall survival (OS) was defined as time from start of treatment until death from any cause. Kaplan-Meier methods were used to compare PFS and OS between groups, and cox regression models with log-rank tests were used to evaluate the influence of various factors on outcomes. Results: A total of 1,743 patients were identified; 1,116 (63.8%) identified as non-Hispanic White (NHW) and 402 (23.3%) as non-Hispanic Black (NHB) [note: 85 pts (4.9%) were Hispanic but not included due to limited numbers]. The median age (years) at the start of treatment (61.8 vs. 65.6) was lower for NHB compared to NHW pts (p<0.001). The proportion of females was greater in NHBthan NHW pts(53.5% vs. 41.1%, p=0.0016). Median SDI scores were significantly higher for NHBcompared to NHW pts (68.4 vs. 39.4; respectively; p<0.001), reflecting significantly higher rates of social deprivation. While NHB ptshad higher rates of advanced stage disease (ISS III 26.9% vs. 20.9%, p=0.009), lower rates of autologous stem cell transplant (ASCT) (56.7% vs. 63.6%, p=0.014), and longer median time from treatment initiation to ASCT (6.5 vs. 5.9 months, p=0.043), the rates of standard risk cytogenetics on FISH (72.3% vs. 77.6%), and utilization of CD38 monoclonal antibody-based regimen (29.9% vs. 27.7%) were similar between the two groups. Best response after treatment initiation was similar between the NHB and NHW pts (p=0.12) with complete response 45.7% vs. 52.6% and very good partial response 37.3% vs 34.7%; respectively. However, time to best response (months) was longer in NHB pts (7.2 vs. 6.5, p=0.005). Median follow-up for OS was 4.2 years (95% CI 3.9-4.4; 182 OS events) and for PFS was 1.3 years (95% CI: 1.1-1.6; 302 PFS events) across the two groups. Unadjusted PFS was similar for NHB vs NHW pts (HR=1.05, 95% CI: 0.81- 1.36; median: 5.0 vs 4.9 years; 3-year PFS: 66% vs. 71%). Similarly, unadjusted OS was not significantly different in NHB vs NHW pts (HR=1.12, 95% CI: 0.79-1.59; 5-year OS: 86.4% vs 85.6%). Higher SDI scores were significantly associated with worse OS (HR=1.07, 95% CI: 1.02-1.12; p=0.0065) but not PFS (HR=0.99, 95% CI: 0.95-1.02; p=0.46). Though not statistically significant, univariate analyses indicated a greater impact of high SDI scores (≥70, 75th percentile across all pts) in NHW (HR=1.45, p=0.068) than in NHB pts (HR=0.78, p=0.35) for OS. Adjusting for age, sex, ISS stage, and SDI, NHB did not appear to have worse OS (HR=0.75, 95% CI: 0.35-1.60; p=0.46) or PFS (HR=1.23, 95% CI: 0.78-1.96; p=0.37) compared to NHW pts. Conclusions: Our study represents a diverse population enriched for pts who received modern day standard of care frontline therapies including triplet and quadruplet regimens with or without ASCT. Based on SDI scores, higher social deprivation levels were seen in NHB compared to NHW pts without a difference in outcomes between the two races. Our analysis supports that higher social deprivation among different races rather than race and ethnicity alone may drive differential outcomes and adjustment for factors like SDI is critical to interpretation of survival outcomes by race.

Abstract Introduction LINVO, a human B-cell maturation antigen (BCMA)xCD3 bispecific antibody, was recently approved for triple-class exposed (TCE) RRMM after ≥3 prior therapies (EU) or ≥4 prior lines of therapy (US), demonstrating high efficacy and a generally manageable safety profile. Combining LINVO with an anti-CD38 mAb, such as DARA or ISA, may provide additional benefit to pts with RRMM. Here we report pooled safety and efficacy results from the LINVO + DARA and LINVO + ISA cohorts during the dose-finding portion of the Phase 1b LINKER-MM2 trial (NCT05137054). Methods Eligible pts were aged ≥18 years with RRMM that progressed after ≥3 lines of therapy (LoTs), or ≥2 LoTs if TCE or double-class refractory (immunomodulatory drug [IMiD] + proteasome inhibitor [PI]). Prior treatment (tx) with DARA or ISA was allowed if previously tolerated and ≥6 months (mos) or ≥3 mos washout, respectively, had elapsed since last exposure. Tx began with LINVO monotherapy (Cycle [C]0; 28-day cycle) consisting of 2 step-up doses (5 mg, 25 mg) and 2 full doses (dose level [DL]1 100 mg; DL1b 150 mg; DL2 200 mg) before standard dosing of DARA or ISA was added at C1. LINVO was given once weekly in C1–3 and once every 2 weeks in C4+. At the end of 2024, dosing once every 4 weeks was implemented after C6 if a very good partial response or better (≥VGPR) was achieved. Dexamethasone premedication was required during the first 2 cycles and then given per label for DARA or ISA. Primary endpoints: dose-limiting toxicities (DLTs) and tx-emergent adverse events (TEAEs). Key secondary endpoints: overall response rate (ORR), duration of response (DOR), progression-free survival (PFS), and rate of minimal residual disease (MRD) negativity. The analyses reported here combine the LINVO + DARA and LINVO + ISA cohorts. Results As of May 7, 2025, 42 pts were enrolled. All pts were included in the safety analysis set: DL1 (DARA, n=12; ISA, n=6), DL1b (n=6; n=10), or DL2 (n=8; n=0); 37 were included in the efficacy analysis set: DL1 (DARA, n=11; ISA, n=5), DL1b (n=5; n=9), or DL2 (n=7; n=0). At baseline, all pts had received ≥1 PI (refractory to ≥1 PI: 76%) or ≥1 IMiD (refractory to ≥1 IMiD: 86%), and 21 pts (50%) had received prior DARA or ISA (refractory to DARA or ISA: 33% [DARA, n=4; ISA, n=10]). Median number of prior LoTs was 3 (range 2–8), including 50% of pts with TCE and 21% with triple-class refractory disease. Median age was 68 years (range 42–86); male, 57%; ISS stage III at study entry, 12%; high-risk cytogenetics, 31%; bone marrow plasma cells ≥50%, 31%; and soft tissue plasmacytomas, 33% (extramedullary, 12%). Median follow-up duration was 14.8 mos for DL1 (DARA 21.3; ISA 11.3), 7.6 mos for DL1b (DARA 13.5; ISA 5.2), and 5.9 mos for DL2 (all DARA), with 44%, 50%, and 63% of pts still receiving tx, respectively. The most common TEAEs were anemia (any grade [Gr] 48%; Gr 3/4 26%), neutropenia (41%; 41%), diarrhea (38%; 2%), and thrombocytopenia (38%; 17%). Cytokine release syndrome was reported in 33% of pts (all Gr 1/2 events except 1 Gr 3 event during the step-up period that fully resolved). No pts experienced immune effector cell-associated neurotoxicity syndrome (ICANS). Infections were reported in 32 pts (any Gr 76%; Gr ≥3 40%), and 3 resulted in death (1 tx related: cytomegalovirus [CMV] pneumonia; 2 tx unrelated: C. diff colitis and lower respiratory infection). One DLT was observed at DL1b in the ISA cohort (Gr 3 Epstein–Barr virus pharyngitis) and 1 was observed at DL2 in the DARA cohort (Gr 5 CMV pneumonia). Among efficacy evaluable pts, ORR was 75% at DL1 (12/16; ≥VGPR rate 75%), 93% at DL1b (13/14; ≥VGPR rate 57%), and 86% at DL2 (6/7; ≥VGPR rate 86%). Of 10 MRD-evaluable pts, all were MRD negative (<10−5by clonoSEQ or EuroFlow). The 12-mo DOR rate was 79% (95% confidence interval [CI] 52–92; median DOR not reached) and 12-mo PFS rate was 73% (95% CI 53–86; median PFS not reached). Pharmacokinetic analyses showed LINVO concentrations were not affected by the addition of DARA or ISA. ConclusionsIn pts with heavily pretreated RRMM, half of whom had prior anti-CD38 mAb exposure, the combination of LINVO and DARA or ISA was feasible, inducing a high rate of deep and durable responses, and exhibiting a safety profile similar to that reported for each individual drug. These preliminary data support continued development of LINVO plus an anti-CD38 mAb for the tx of pts with MM.