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Abstract Introduction: Marrow complete remission (mCR) in 2006 IWG criteria for MDS (Cheson B et al, Blood 2006) reflects achieving bone marrow (BM) blast percentage below 5% but is frequently not associated with meaningful count recovery. While mCR + hematologic improvement (HI) does reflect wide ranges of count improvement or transfusion reductions, HI is difficult to measure accurately in routine clinical practice. The 2023 International Working Group (IWG) response criteria (Zeidan A et al, Blood 2023) eliminated the mCR category without meaningful count recovery and reclassified mCR associated with meaningful count recovery into specific “less-than-CR” categories. Still, many clinical trials continue to use mCR as a secondary efficacy endpoint or as a part of overall response rate (ORR). Within the icMDS VALIDATE database, we assessed the association of mCR with OS in hypomethylating agent (HMA)-treated higher risk (HR)-MDS patients among both (1) transplanted and (2) non-transplanted patients. Methods We included patients with HR-MDS (defined as IPSS ≥1.5 and/or IPSS-R >3.5) who received HMA-based therapies from the international icMDS VALIDATE dataset. We evaluated the best response by IWG 2006 criteria into CR, mCR, or no CR/mCR. We then reclassified patients with mCR per IWG 2023 criteria into either (A) having achieved a composite CR (cCR) defined as CR + CR equivalent (CRequ) + CR with bilineage count recovery (CRbi) + CR with unilineage count recovery (CRuni) + CR with partial hematologic recovery (CRh) or (B) not having achieved cCR (no cCR). OS was calculated from time of HMA initiation to date of death or last follow-up by using 6-month landmark analyses. We used Kaplan-Meier methods to estimate OS, and the Log-rank test to compare OS. VALIDATE is supported by an independent grant from AbbVie. Results A total of1049 patients met eligibility.Median age of patients was 69 (range 21-95), 64% were men. While 61% received azacitidine, 17% received decitabine, and 22% received HMA-based combination therapy. In total, 37% underwent subsequent allogenic stem cell transplantation (allo-HCT). Based on IWG 2006 criteria, 17%, 33%, and 50% achieved CR, mCR, and no CR/mCR as their best response, respectively. Patients achieving CR had superior median OS (25 months, 95% CI: 21-34 months) compared to those with mCR (16 months, 95% CI: 13-18 months; p=0.038) and no CR/mCR (15 months, 95% CI: 12-17 months; p=0.001). In patients who received a subsequent allo-HCT, the median OS for patients with mCR (30 months, 95% CI: 21-54 months; 1 year OS: 71%, 2 year OS: 55%) did not significantly differ compared to patients with CR (59 months, 95% CI: 25 months-not reached, p=0.80; 1 year OS: 73%, 2 year OS 62%) and patients with no CR/mCR (32 months, 95% CI: 21-45 months, p=0.46; 1 year OS: 69%, 2 year OS 54%). In contrast, in patients treated with HMA therapy alone without subsequent allo-HCT, median OS for patients with mCR (11 months, 95% CI: 9-15 months; 1 year OS: 46%, 2 year OS: 23%) did not significantly differ compared to patients with no CR/mCR (11 months, 95% CI: 9-14 months, p=0.85; 1 year OS: 47%, 2 year OS: 22%) but was significantly shorter compared to patients with CR (20 months, 95% CI: 17-28 months, p<0.001; 1 year OS: 69%, 2 year OS: 46%). Patients with mCR by IWG 2006 (N=347) were reclassified per IWG 2023 into having either achieved a cCR (N=219, 63%) or no cCR (N=128, 37%). Specifically, patients with mCR were reclassified per IWG 2023 into CR (4.9%), CRequ (0.6%), CRbi (26.8%), CRuni (29.4%), CRh (1.4%), PR (0%), HI (10%), no response (21.9%) and PD (4.9%). Patients with mCR who were reclassified into cCR had an improved median OS (16 months, 95% CI: 15-26 months; 1 year OS: 62%; 2 year OS: 43%) compared to patients reclassified into no cCR per IWG 2023 (13 months, 95% CI: 11-17 months, p=0.023; 1 year OS: 52%; 2 year OS: 31%). Conclusions Using the large icMDS VALIDATE dataset, we found that achievement of mCR by 2006 IWG criteria was not associated with improved OS compared to patients who did not achieve CR/mCR. Reclassification of mCR using IWG 2023 highlights the heterogeneity within the mCR group and suggests that IWG 2023 criteria stratifies outcomes in patients previously labeled as mCR by IWG 2006. IWG 2023 should be the standard used for ORR assessment in all future clinical trials involving patients with HR-MDS.

Abstract Introduction There is currently no standard-of-care for patients (pts) who cannot tolerate full dose anthracycline regimens in frontline large B-cell lymphoma (LBCL). R-miniCHOP is a commonly used regimen that provides curative intent treatment with manageable toxicity. Despite this, lymphoma and treatment-related mortality are the leading causes of death in these pts. Additionally, many pts may not be eligible to receive R-miniCHOP due to comorbidity or frailty. There are limited clinical trial and real-world data focused on this population. Methods Pts with LBCL age 18 years (yrs) and older were identified from the Lymphoma Epidemiology of Outcomes (LEO) cohort, a prospective study of newly diagnosed pts with non-Hodgkin lymphoma enrolled from 2015-2020 at 8 academic medical centers in the US. Pts with LBCL were included in this analysis if they had received R-miniCHOP or a regimen that did not include an anthracycline (nonAC). NonAC regimens included R-CVP, BR, rituximab, radiation and lenalidomide and rituximab. Pts completed the Vulnerable Elders Survey (VES-13) and were considered vulnerable if they had a score >3. Event-free survival (EFS) was defined as the time from start of treatment until progression/relapse, retreatment, or death due to any cause; EFS at 24 months (EFS24) was a secondary endpoint. Overall survival (OS) was defined as the time from start of treatment until death due to any cause. EFS and OS for R-miniCHOP and non-IC groups, as well as vulnerable and not vulnerable by VES-13 were estimated using Cox models. Results A total of 190 pts received R-miniCHOP (N=139) or nonAC (N=51). R-miniCHOP-treated pts were older (median 82 vs 72 yrs) and more commonly female (55% vs 35%). The majority in both groups (86% vs 78%) received their treatment at a LEO center and did not receive therapy on a clinical trial (89% vs 100%). Most pts receiving R-miniCHOP had high-intermediate (32%) or high (30%) international prognostic index (IPI) score, while both high-intermediate (22%) and high (20%) IPI were lower in the nonAC-treated pts. Cell of origin was determined by immunohistochemistry as available clinically, with GCB 42% vs 31%, non-GCB 32% vs 29%, and not done/unknown 26% vs 39% in R-miniCHOP vs nonAC pts. Double-hit status by FISH was known in 115 pts and was positive in 13% of R-miniCHOP pts and 10% of nonAC pts. The diagnosis-to-treatment interval (DTI) was ≤14 days in 30% of R-miniCHOP pts and 24% of nonAC pts. Of pts who had a VES-13 score (N=119), vulnerable status trended higher in the R-miniCHOP (66%) vs the non-IC group (50%; p=0.15). With a median follow-up of 50.5 months, the median EFS was 37.1 months and median OS was 50.0 months. R-miniCHOP, compared with non-IC, was associated with improved EFS (unadjusted HR=0.54, 95% CI 0.36-0.81; p=0.003) and OS (unadjusted HR=0.58, 95% CI 0.38-0.88; p=0.011). When adjusted for age, IPI, LBCL subtype (diffuse large B-cell lymphoma, not otherwise specified vs other), DTI and VES-13, R-miniCHOP was strongly associated with improved EFS (HR=0.26, 95% CI 0.14-0.50; p<0.001) and OS (adjusted HR=0.29, 95% CI 0.15-0.57; p<0.001). EFS24 rate was 56% in all pts and was superior in pts treated with R-miniCHOP vs non-IC (62.7% vs 34.1%; p=0.001). In the R-miniCHOP group, vulnerable status (adjusted for IPI) was associated with inferior OS (HR=2.22, 95% CI 1.09-4.50; p=0.028) and trended towards inferior EFS (HR=1.76, 95% CI 0.93-3.32; p=0.083). In a competing-risk cumulative-incidence analysis, lymphoma was the leading cause of death for pts receiving R-miniCHOP at 2 (0.16, 95% CI 0.11-0.24) and 5 (0.20, 95% CI 0.14-0.28) yrs, as well as for those receiving non-IC at 2 (0.35, 95% CI 0.24-0.53) and 5 (0.38, 95% CI 0.26-0.56) yrs. Treatment-related mortality was similar in both groups. In the R-miniCHOP group, the 2-yr (0.20 vs 0.03) and 5-yr (0.20 vs 0.11) lymphoma-related mortality was higher in pts who were vulnerable vs not by VES-13, while there were no differences for mortality due to therapy or other causes by vulnerable status. Conclusions These data support R-miniCHOP as a curative regimen in older and frail pts with the majority achieving EFS24. R-miniCHOP compared to non-IC use is strongly associated with improved EFS and OS when adjusted for disease and patient related variables. Within the R-miniCHOP group, vulnerable status is associated with inferior OS. Additional research efforts are needed to optimize outcomes for this group of pts.

Abstract Background: Rural/nonmetropolitan (nonmetro) counties face known barriers to comprehensive cancer care compared with metropolitan (metro) counties, which may impact the outcomes for lymphoma patients. We evaluated the impact metro vs nonmetro status on outcomes after a diagnosis of non-Hodgkin lymphoma (NHL) in the context of clinical, demographic, and lifestyle factors. Methods: Of 7724 participants enrolled in the prospective LEO cohort study from 2015-2020, 7610 (98.5%) had their county of residence at diagnosis assigned a RUCC (2013) code. We compared outcomes of participants from metro (defined as RUCC 1-3, which are central counties with ≥1 urban areas of ≥50,000) vs nonmetro counties (RUCC 4-9, which are counties with smaller urban areas as well as completely rural). We estimated hazard ratios (HRs) and 95% confidence intervals (CI) from univariable and multivariable Cox models for associations of metro status with overall survival (OS). Cause of death (lymphoma [including treatment related], non-lymphoma, unknown) was assessed using a competing risk approach. Results: Compared with metro counties (N=6096), LEO participants from nonmetro counties (N=1514) were older (median age 64 vs 62 years; p<0.001), more likely to be non-Hispanic white (94% vs 75%; p<0.001) and married (84% vs 75%; p<0.001), and less likely to have completed graduate or professional school education (16% vs 27%; p<0.001). There were no notable differences (>5%) by metro status for sex, employment status, NHL subtype, stage, performance status, abnormal lactate dehydrogenase (LDH), international prognostic index (IPI), number of comorbidities, time from diagnosis to treatment interval (DTI) or participation in a clinical trial. Compared with LEO participants from metro counties, those from nonmetro counties had inferior OS at 5 years (74.5% vs 78.4%; HR=1.23, CI 1.10-1.37; p<0.001). The OS association only slightly attenuated after adjustment for age, sex, race/ethnicity and NHL subtype (HR=1.20, CI 1.07-1.34; p=0.002), and held in models that adjusted for clinical prognostic factors (stage, NHL subtype, IPI, DTI), socioeconomic status (SES; education, marital status), health status (comorbidity, frailty), or lifestyle factors (smoking, body mass index). Using a competing risk model, the cumulative incidence of death at 5 years due to lymphoma (16.9% vs 14.1%; p=0.002) and non-lymphoma (5.9% vs 3.9%; p=0.002) was higher for participants from nonmetro vs metro counties, respectively. For participants <65 years, nonmetro vs metro status had inferior OS (HR=1.40, CI 1.17-1.67; p<0.001). This association remained after adjustment for age, sex, race/ethnicity and NHL subtype (HR=1.36, CI 1.14-1.63; p<0.001), as well as after adjustment for clinical prognostic, SES, health status, or lifestyle factors. The cumulative incidence of death at 5 years due to lymphoma was higher in participants from nonmetro vs metro counties (15.1% vs 11.5%; p=0.002), while there was no difference by metro status for non-lymphoma related deaths (2.1% vs 1.7%; p=0.47). In contrast, for participants age 65+ years, there was no differences by metro status for OS (HR=1.04, CI 0.91-1.20; p=0.56). After adjustment for age, sex, race/ethnicity and NHL subtype, participants from nonmetro areas had inferior OS (HR=1.12, 0.97-1.29) although this was not statistically significant (p=0.13), and was attenuated in models adjusting for clinical, health status, or lifestyle factors. The cumulative incidence of death at 5 years due to lymphoma was no different in participants from nonmetro vs metro counties (18.9% vs 18.0%; p=0.37), while non-lymphoma related deaths were higher in nonmetro counties (9.9% vs 6.8%; p=0.017). Conclusion: LEO participants from nonmetro vs metro counties had inferior OS overall, although this was predominately observed for younger (<65 years) participants. These associations did not appear to be explained by demographic, NHL subtype, clinical, SES, health status, or lifestyle factors. Of particular note, the risk of death due to lymphoma was higher in nonmetro areas for participants <65 years but not those 65+ years, while the risk of death due to other causes was higher in nonmetro areas for participants 65+ years but not those <65 years. These findings require further study, particularly related to barriers to care, and suggest the potential need for age-specific strategies to optimize outcomes for NHL patients from nonmetro/rural areas.

Abstract Background: Despite the promising efficacy of CAR-T for patients with relapsed or refractory (R/R) large B-cell lymphomas (LBCL), more than 60% of patients will relapse, the majority of which occur in the first 6 months. Approximately 30% of patients with LBCL treated with CAR-T achieve a partial response (PR) on day 30 (D30) PET-CT assessment. Of patients in a D30 PR, 70% will eventually progress, yet the standard of care remains close observation. Early consolidative treatment strategies utilizing therapies with a different mechanism of action may improve outcomes, but there are currently no reliable biomarkers. Epcoritamab (Epco), a bispecific antibody directed against CD20 and CD3, has been approved by the FDA for LBCL patients who relapse after at least 2 lines of therapy. By treating prior to overt relapse, Epco has the potential to salvage inadequate responses post CAR-T. This study is a trial-in-progress that will evaluate the efficacy of epco compared to observation for patients with LBCLs achieving a PR on D30 post CAR-T PET-CT assessment. Methods This is an investigator-initiated, randomized, phase II, multicenter, open-label study (NCT06238648) evaluating epco monotherapy for a fixed duration of 12 cycles compared to observation for LBCL patients with D30 PR after standard of care CAR-T. A maximum of 120 patients will be randomized 1:1 to epco or observation across 10 academic centers. Stratification factors include line of CAR-T (second vs third line) and costimulatory domain (CD28 vs 4-1BB). Key inclusion criteria include PET evidence of a D30 PR. non-bulky disease ( <7.5cm), ANC of >1000, hemoglobin >7 g/dL if asymptomatic or >8 if symptomatic, platelet count >50,000. G-CSF, pRBCs and platelet transfusions are allowed. Key exclusion criteria include ongoing or uncontrolled CRS or ICANS, and active or symptomatic CNS disease. This study is available to all eligible patients, regardless of race, gender, or ethnic origin. To adapt to current practices, prior bispecific antibody exposure is allowed if used as holding or bridging therapy without disease progression. Epco is administered subcutaneously at a dose of 0.16mg on day 1, 0.8mg on day 8, prior to full dose of 48mg on day 15. Epco is administered weekly in 28 day cycles (C) for C1-3, on day 1 and 15 of C4-9 and on day 1 of C10-12. PET-CT response is assessed by the 2014 Lugano criteria after 2 cycles, and then every 3 months during active treatment. The primary objective is efficacy, measured as conversion from D30 PR to CR. The secondary endpoints include frequency and severity of treatment emergent adverse events, ORR, duration of response, duration of complete response, progression free survival, event free survival, and overall survival. Peripheral blood samples will be collected pre-treatment and during treatment to assess for biomarkers of response and resistance and CAR-T persistence. The study was activated in January 2024 and recruitment is ongoing.

Abstract BACKGROUND Hereditary hemorrhagic telangiectasia (HHT) is the second most common inherited bleeding disorder (IBD) worldwide, afflicting 1 in 5,000 people. HHT is likely the most morbid IBD of women. Severe, recurrent epistaxis, gastrointestinal (GI) bleeding, and solid organ arteriovenous malformations (AVMs) cause major clinical and psychosocial morbidity and reduced survival. In recognition of the serious morbidity of HHT as an IBD, in 2022 the U.S. Congress allocated funding to create CHORUS, the Comprehensive HHT Outcomes Registry of the United States (NCT06259292). Herein, we present the initial report from CHORUS. METHODS CHORUS is a prospective, multicenter, U.S. longitudinal registry enrolling unselected patients with HHT, collecting over 2400 data elements. Data were collected by trained research coordinators at enrollment and follow-up visits via the medical record and direct participant interviews. RESULTS Patients. 600 patients with genetically- or Curacao criteria-confirmed HHT were enrolled from November 2023 to April 2025 at 15 U.S. HHT Centers of Excellence. Median (range) age was 53 (0-88) years, and the cohort was 60% female. Despite most patients developing typical HHT disease manifestations by age 13, most HHT diagnoses (63%) were made during mid-to-late adulthood. Mucosal Bleeding. 568 patients (95%) developed recurrent spontaneous epistaxis, with 339 (60%) developing recurrent epistaxis prior to age 13; 43% had at least one nasal surgery/procedure and 22% had at least one medical therapy (e.g., antifibrinolytic or antiangiogenic) for epistaxis. 180 (30%) had a known diagnosis of chronic GI bleeding. Among post-menarche females, 124 (34%) had been diagnosed with heavy menstrual bleeding. 247 (41%) reported other clinically significant mucocutaneous oral or skin bleeding. 454 (76%) had developed moderate-to-severe HHT-associated mucocutaneous bleeding, defined as an Epistaxis Severity Score >4, bleeding requiring targeted pharmaceutical or surgical intervention, IV iron, and/or red cell transfusion. This includes 334 (56%) with moderate-to-severe HHT-associated epistaxis. CNS and Pulmonary Hemorrhage. 16 patients (3%) suffered one or more intracranial hemorrhages (ICH), with 10 (63%) suffering a first ICH by age 25. 13 (2%) suffered one or more pulmonary hemorrhages. Iron Deficiency and Anemia. 408 patients (68%) had been diagnosed with anemia (351, 59%) or iron deficiency (381, 64%). Of those, 247 (61%) and 150 (37%) required IV iron and RBC transfusion, respectively. Solid Organ AVMs. Brain, pulmonary, and liver AVMs were diagnosed in 81 (15%), 268 (45%), and 128 patients (21%), respectively. Just 30 with brain AVMs (37%) had these diagnosed by age 25. 3 patients (2%) had undergone liver transplantation. Thrombosis. Venous and arterial thromboembolism occurred in 44 (7%) and 38 patients (6%), respectively, including 34 (6%) with ischemic stroke (94% of whom had pulmonary AVMs). Other Serious HHT Complications. These included heart failure in 41 patients (7%), pulmonary hypertension in 44 (7%), chronic liver disease in 17 (2.8%), epilepsy in 24 (4%), severe bacterial/deep-seated tissue infection in 35 (6%), and brain abscess in 15 (3%). 205 (34%) developed migraine. Notably, serious CNS manifestations of HHT (brain AVM, ischemic stroke, intracranial hemorrhage, and/or epilepsy) occurred in 128 (21%). 241 (40%) required emergency room visits and/or hospital admissions specifically to manage HHT complications. CONCLUSIONS This first-of-its-kind HHT registry reliably describes for the first time the incidence and severity of numerous HHT complications. Most patients develop moderate-to-severe recurrent epistaxis and/or chronic GI bleeding as well as iron deficiency anemia (usually requiring IV iron and/or RBC transfusion). Heavy menstrual bleeding, thromboembolism, severe cardiopulmonary complications, and serious CNS complications are all substantially more common in HHT than previously thought. Notably, ICH occurred in 3% of patients, which approximates the ICH incidence of hemophilia in the pre-factor prophylaxis era and is ~2-fold and ~9-fold higher than in hemophilia A treated with modern factor prophylaxis (1.6%) and modern non-factor prophylactic agents (0.3%), respectively, per the ATHN registry. This 3% number may be an underestimation given the known high ICH mortality rate, pervasive delay in HHT diagnosis, and the fact that survival post-ICH is necessary to enroll in CHORUS.

Abstract Background: The Multiple Myeloma Research Foundation (MMRF) and its partners launched the MyDRUG platform clinical trial (NCT03732703) to evaluate the safety and efficacy of genomically-guided treatments for functional high-risk relapsed/refractory myeloma patients (fHRMM). fHRMM patients with no discernible activating mutations and who had received 1-3 prior therapies (exposed to at least one proteasome inhibitor and an IMiD) were given a combination of daratumumab (D), ixazomib (I), pomalidomide (P) and dexamethasone (d) (D-IPd) quadruplet therapy. The goal of this study is to evaluate the immunomodulatory effects of daratumumab-(anti-CD38)-based therapy on fHRMM patients enrolled in the MMRF-sponsored MyDRUG umbrella clinical trial over the duration of therapy and to correlate immune changes with patient response immediately following the first two cycles of therapy. Methods Bone marrow (BM) aspirates were collected at baseline (BL) prior to therapy, at the end of 2 cycles (EOC2), 4 cycles (EOC4) of the quadruplet therapy and at the end of treatment (EOT) or progressive disease (PD). CD138-negative bone marrow mononuclear cells were isolated for profiling the immune microenvironment using scRNAseq, scTCRseq and CyTOF. Results Single-cell RNA and TCR profiles were generated from ~90,000 cells across 41 samples from 16 subjects. scRNAseq identified CD3+ T cells, NK cells, classical and non-classical monocytes and B cells. CD8+ T cells were further resolved into their subsets including precursor (TPEX) and terminally exhausted T cells (TEX) within the bone marrow microenvironment. Within the CD8+ T cell compartment, an expansion of the effector memory (TEM) cell population was observed following 2-cycles of therapy (EOC2). However, this TEM expansion was not sustained at timepoint EOC4. Towards the end of therapy, enrichment of precursors to putative exhausted and terminal dysfunctional effector memory cells (TEMRA) was observed. Subjects with partial (PR), very good partial (VGPR) and complete (CR) best overall responses showed an initial increase in TEM cells followed by a slow expansion of TEX and TEMRAcells over time. One patient with progressive disease (PD) maintained the highest LAG3 expression across the cohort among CD8 T cell subsets (TEMRA, EM) and CD4 Tregs at baseline while observing a significant upregulation of PDCD1 in CD4 Tregs and CD8 Naive cells by EOC2. Cell-cell communication network analysis identified secreted ligands between responders (CR/VGPR) and partial responders (PR) at EOC2. Samples with PR exhibited upregulation of signaling of TNF from the CD8 Naïve compartment (p=0.048, Wilcoxon), IFNG from the CD8 EM (p=0.073, Wilcoxon) and TEMRA (p=0.048, Wilcoxon) populations along with IFNG (p=0.073, Wilcoxon) from NK cells. CD14+ and CD14+16+ Monocytes on the other hand showed enrichment of LGALS9 (p=0.03 (CD14+), p=0.048 (CD14+CD16), Wilcoxon) in the PR group at EOC2 relative to responders. Finally, longitudinal tracking of T cell clonality showed preferential progressive expansion of TEMRA cells after the therapy. We mapped hyperexpanded (more than 16 copies) clonotypes, presumed to be tumor-reactive, to various CD8+ T cell subsets. These hyperexpanded clonotypes are mapped to the TEMRA, TEX and TEM CD8+ T cells. Analysis of TCR repertoires clonality and diversity also demonstrated a reduced richness and increased clonality of CD8+ TCRs in responders. Summary/Conclusion These preliminary analyses of D-IPd quadruplet therapy of RRMM indicate that paired single cell RNA and TCR sequencing of BM T cells suggests a selective expansion of clonotypic CD8+ T cells. When considering patient response, the only PD patient profiled in this study maintained an exhaustive signature (LAG3, PDCD1) in multiple T cell compartments at BL. The differential expression of the receptor ligand pairs after treatment between different clinical response groups suggests an altered TME response that may inform future therapeutic stratification. These results support further explorations of rational combinations of targeted and immune therapies for greater efficacy in this disease.

Abstract BACKGROUND Ivosidenib is an oral inhibitor of mutant isocitrate dehydrogenase type I (IDH1) currently approved for the treatment of IDH1 mutated acute myeloid leukemia and myelodysplastic syndrome (MDS). Hematopoietic stem and progenitor cells carrying preleukemic mutations, referred to as clonal hematopoiesis (CH), are the origin of myeloid neoplasms (MN). Individuals who have cytopenias and CH, but do not meet diagnostic criteria for a hematologic malignancy, are classified as having Clonal Cytopenias of Undetermined Significance (CCUS), a condition associated with a high risk of progression to MN. While CCUS patients (pts) can have multiple mutations, they show lower mutational burden on average compared to MN. Thus, we hypothesized that treatment with ivosidenib would improve cytopenias in IDH1-mutant CCUS. METHODS; We performed a decentralized phase II single-arm study to characterize the safety and efficacy of ivosidenib in IDH1-mutant CCUS (NCT0503044). Drug was shipped to pts with local oncologists performing standard-of-care clinical exams supplemented by study team lead interviews for adverse event monitoring. Research labs were drawn by local providers or through Quest. QT corrected interval (QTc) was monitored through a mobile electrocardiogram device (AliveCor). Eligible patients were aged ≥ 18 years and had confirmed IDH1-mutant CCUS with at least 6 months of unexplained cytopenias (hemoglobin<10 g/dL, platelets<100 x109/L or absolute neutrophil count <1.8 x109/L). The primary endpoint was hematologic response of at least 8 weeks in duration based on the IWG 2006 criteria for MDS. RESULTS 20 pts with IDH1-mutant CCUS have been enrolled. Most were male (70%) with a median age of 66 (range 41-79). Overall, 74% had a self-reported race of non-Hispanic white, 11% of Hispanic white, 5% of Asian and 11% of black or African American. Most pts presented with neutropenia (95%) including some with co-occurring thrombocytopenia (21%). One pt presented with anemia and thrombocytopenia without neutropenia. Prior to treatment, the average number of co-mutations beyond IDH1 was 2 (range 0-3), with most pts (74%) harboring a co-occurring spliceosome gene mutation. The IDH1 variant allele fraction (VAF) was lower in the blood (mean=19%, range 3-35%) than in the bone marrow (mean=31%, range 18-43%) in most (93%) patients. Out of the 20 enrolled pts, 17 received at least 8 weeks of therapy at the time of our data cutoff (7/29/2025) and were included in the efficacy analysis. Grade ≥3 adverse events (AEs) occurred in five patients (26%) including two with grade ≥3 treatment-related adverse events (pancytopenia and sepsis in the first pt, rash in the second pt). The most common all-grade treatment-related adverse events were nausea (n=5, 26%), prolonged QTc (n=3, 16%), anemia (n=3, 16%), and diarrhea (n=3, 16%). There were no instances of reported differentiation syndrome. Overall, 82% of pts achieved a hematologic response (14/17) including improvement in neutropenia (88%) and thrombocytopenia (75%). With a median follow-up of 16 months (range 0.6-24 months), the median duration of hematologic response was not reached. Among responders, 86% had a continued response at one year. Two pts progressed to MDS after 4 and 17 months of treatment characterized by recurrence of cytopenias and the emergence of new clones. A surveillance bone marrow biopsy was performed at 18 cycles for the 8 pts who remained on treatment with none showing disease progression. Most pts (90%, N=9/10) treated for at least 12 months had a decrease in IDH1-mutant CH VAF over time and 40% (N=4/10) showed IDH1 mutation clearance (VAF <2%) with a median time to clearance of 9 months. Among those with decreasing IDH1 clonal burden, all had a corresponding decrease in other co-occurring mutations present at baseline with one responder showing emergence of a newly detectable CHEK2 mutation without disease progression. CONCLUSIONS Decentralized trials represent a feasible solution for the conduct of clinical trials in rare hematologic neoplasms and precursor conditions. Ivosidenib was well-tolerated and induced durable hematologic remissions in IDH1-mutant CCUS. Most pts showed a reduction in clonal burden with mutation clearance commonly seen with long-term treatment demonstrating that ivosidenib modifies the natural history of IDH1-mutant CCUS.

Abstract Background Patients with myeloproliferative neoplasms (MPNs) are at risk of splanchnic vein thrombosis (SVT). Prior studies failed to demonstrate a benefit of hydroxyurea in preventing SVT extension/recurrence, but these were limited by small sample sizes and inability to account for starting, stopping, or switching of cytoreductive therapies. We therefore investigated the role of cytoreduction as a time-dependent covariate on thrombosis recurrence in a large, international cohort of MPN-SVT patients. Methods We performed a retrospective cohort study of MPN-SVT patients included in the international GASTRO-MPN consortium. Patients diagnosed with MPN at any time before, concurrently with, or up to 60 days after initial SVT were included. Primary outcome was time from initial SVT to first thrombosis recurrence, defined as the composite of SVT extension/recurrence, transjugular intrahepatic portosystemic shunt (TIPS) thrombosis, or venous/arterial thrombosis outside the splanchnic veins. Secondary outcomes included SVT extension/recurrence, TIPS thrombosis or extra-SVT thrombosis individually, clinically relevant bleeding (composite of major and clinically relevant non-major bleeding), MPN progression to myelofibrosis or blast phase, and death. Cytoreductive therapy was treated as a time-dependent covariate to account for discontinuation and therapy changes. Multivariable Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CI). Results A total of 757 patients were included for this analysis. Median age was 51 years (IQR 38-62), 59% were female. SVT involved the portomesenteric veins in 558 (77%) patients, hepatic veins in 95 (13%), and both in 54 (7.4%). MPN was known prior to initial SVT in 316 patients (42%) and diagnosed concurrently or up to 60 days after SVT in 441 (58%). Polycythemia vera (PV) was the most common MPN subtype (43%), followed by essential thrombocythemia (ET) in 24%, and primary myelofibrosis in 14%. JAK2V617F mutation was present in 86% and CALR in 2.9%. 13% had prior non-SVT thrombosis. 607 patients (83%) were treated with cytoreduction. At time of SVT, 131 patients (17%) were already on cytoreduction; in those who started after SVT, median time to initiation was 54 days after SVT, and median duration of cytoreduction per patient was 63 months. Cytoreductive therapies used at any point in treatment included hydroxyurea in 504 (69%), ruxolitinib in 182 (25%), and interferon-based in 85 (12%) patients. Anticoagulation (AC) was started within 30 days after SVT in 504 (68%) patients. Median duration of any AC per patient was 24.6 months. During a median follow up of 7.4 years, 245 patients (33%) had thrombosis recurrence; 143 (20%) had SVT extension/recurrence/TIPS thrombosis, 129 (18%) extra-SVT thrombosis (of which 74% venous), 237 patients (32%) experienced clinically relevant bleeding, and 163 (22%) died. After adjusting for age, sex, timing of MPN diagnosis relative to SVT diagnosis, AC within 30 days of SVT, PV/ET vs other MPN, JAK2 mutation, previous thrombosis, non-MPN cancer, and cirrhosis, cytoreductive therapy was associated with a significantly decreased risk of recurrent thrombosis (HR 0.67 95%CI 0.50-0.89, p=0.01). Age was associated with an increased risk of recurrent thrombosis (p=0.01). When considering types of recurrent thrombosis, cytoreduction was associated with a decreased risk of SVT extension/recurrence/TIPS thrombosis (HR 0.62 95%CI 0.42-0.90, p=0.01), but not thrombosis outside the splanchnic veins (HR 0.97 95%CI 0.72-1.30, p=0.82). There was no association between cytoreduction and bleeding (HR 1.10 95%CI 0.82-1.47, p=0.52). Similarly, there was no association between cytoreduction and time to MPN progression (p=0.24) or overall survival (p=0.30). In a subgroup of patients without erythrocytosis/thrombocytosis at initial SVT (n=271), cytoreductive therapy was associated with a HR 0.65 (95%CI 0.40-1.10, p=0.09) for recurrent thrombosis. Limited sample size and low event-rate precluded evaluation of the impact of individual cytoreductive therapies. Conclusions In the largest cohort of MPN-SVT patients to date, we show for the first time that cytoreductive therapy is associated with a decreased risk of thrombosis recurrence, driven largely by decreased SVT extension/recurrence/TIPS thrombosis. Collectively, these findings support use of cytoreductive therapy in individuals with MPN-SVT to prevent recurrent thrombosis.

Abstract Introduction Marginal zone lymphoma (MZL) is an indolent and heterogenous disease. Several prognostic models have been proposed to assess outcomes in MZL, including FLIPI, IPI (primarily designed for overall survival [OS]), and MZL-specific scores such as MALT-IPI (event-free survival [EFS]) and MZL-IPI (progression-free survival). FLIPI24 is a recently developed prognostic index for patients with follicular lymphoma (FL) treated with first-line (1L) immunochemotherapy (IC), identifying a high-risk population with inferior survival and increased risk of lymphoma-related death. FLIPI24 has also demonstrated robust performance in the entire FL population, including patients under observation. This study aimed to evaluate the prognostic utility of FLIPI24 in patients with MZL and to compare its performance with other established indices (FLIPI, MZL-IPI, IPI, MALT-IPI). Methods We pooled harmonized data from newly diagnosed MZL patients with complete available FLIPI24 variables (age, white blood cell count [WBC], hemoglobin [HGB], serum lactate dehydrogenase [LDH], and beta-2-microglobulin [B2M] levels) treated with 1L IC. Data were collected from three prospective international cohorts: NiHiL (Czech Republic; n=897; enrolled 2005–2023), LEO (USA; n=62; 2015–2020), and MER (USA; n=32; 2010–2015), forming a pooled cohort of 991 1L IC-treated patients. The analysis was then extended to include all newly diagnosed MZL patients (n=2,116), regardless of treatment. The primary endpoint in the 1L IC-treated cohort was EFS at 24 months (EFS24), and for all MZL patients, it was OS. Secondary endpoints included OS24 for 1L IC treated cohort, lymphoma-related mortality by FLIPI24 risk groups, and comparative prognostic performance of FLIPI, IPI, and MALT-IPI, by C-statistics; performance of MZL-IPI was assessed on a subgroup of NiHiL patients with available data (n=877 all MZL, n=485 1L IC-treated). Results Among the 991 1L IC-treated patients, the median age at diagnosis was 66 years (range 22–94); 47% were male; 11% had ECOG performance status ≥2, 68% clinical stage III–IV, 42% elevated LDH, 40% IPI 3–5, 42% FLIPI 3–5, and 62% MALT-IPI 2–3. The median B2M level was 2.8 mg/L, WBC 7.0 × 10⁹/L, and HGB 13.1 g/dL. MZL subtypes were: 64% extranodal (EMZL), 22% nodal (NMZL), and 14% splenic (SMZL). Most common 1L IC regimens were R-CVP (46%), R-CHOP-like (32%), R-chlorambucil (9%), and B-R (9%). FLIPI24 stratified patients into low- (18%), intermediate- (37%), and high-risk (45%) groups. High-risk patients were older (median 54 vs 65 vs 71 years for low-, intermediate-, and high-risk groups, respectively; P<0.01), had more frequent adverse baseline features, and were more likely to have the SMZL subtype (2% vs 7% vs 25% for low-, intermediate-, and high-risk groups, respectively; P<0.01). After a median follow-up of 7.2 years, EFS24 was 89%, 85%, and 65% (P<0.01) across low-, intermediate-, and high-risk groups; OS at 2 years was 98%, 97%, and 79%; and OS at 5 years was 96%, 91%, and 62%, resp. (P<0.01). The 5-year cumulative incidence of lymphoma-related death was 13% in high-risk vs 6% in low-/intermediate-risk groups. FLIPI24 showed better prognostic accuracy for EFS compared with FLIPI, MZL-IPI, IPI and MALT-IPI (C-index: 0.640 vs 0.630, 0.622, 0.620 and 0.603, resp.), as well as for OS (C-index: 0.710 vs 0.672, 0.641, 0.663, 0.652, resp.). Prognostic performance was consistent across MZL subtypes. In the extended cohort of 2,116 newly diagnosed MZL patients (47% receiving IC, 17% rituximab monotherapy, 11% radiotherapy, 8% surgery, 2% antibiotics; 15% observed), FLIPI24 stratified patients into low- (24%), intermediate- (39%), and high-risk (37%) groups. OS at 2 year was 99%, 97%, and 83%, at 5 years it was 96%, 91%, and 62%, resp. (P<0.01). The 5-year cumulative incidence of lymphoma-related death was 12% in high-risk vs 4% in low-/intermediate-risk patients. FLIPI24 outperformed other indices (OS C-index: 0.754 vs MZL-IPI 0.654, FLIPI 0.700, MALT-IPI 0.694, IPI 0.699). Conclusion FLIPI24 demonstrates strong and consistent prognostic performance across all MZL subtypes, identifying ~40% of patients as high-risk with significantly worse survival and increased lymphoma-related mortality. The FLIPI24 outperforms FLIPI, MZL-IPI, IPI, and MALT-IPI in predicting outcomes and may serve as a practical tool to guide risk-adapted management and selection of patients for novel therapies in MZL. Funding: NU21-03-00411, P50 CA97274, U01 CA195568.

Abstract Introduction Elevated levels of fetal hemoglobin (HbF) ameliorate sickle cell disease (SCD) manifestations. BEAM-101 is an investigational cell therapy comprising ex vivo base-edited autologous CD34+ hematopoietic stem and progenitor cells (HSPCs) that directly target the HBG1/2 promoters to disrupt BCL11A binding, switching production from sickle (HbS) to majority anti-sickling HbF. We present ongoing data from the BEACON study (NCT05456880), a Phase 1/2, single-arm, open-label study evaluating a single dose of BEAM-101 in individuals with SCD and severe vaso-occlusive crises (sVOCs). Methods Eligible patients were aged 12–35 years with SCD and ≥4 sVOCs in the 2-year period prior to informed consent. After mobilization with weight-based or tiered fixed-dose plerixafor, autologous CD34+ HSPCs were collected by leukapheresis and genetically modified with an adenine base editor. Following conditioning with pharmacokinetically adjusted myeloablative busulfan (target cumulative AUC 80 hr*mg/L), patients received a single dose of BEAM-101 (≥3.0×106 viable CD34+ cells/kg). Patients were then monitored for neutrophil and platelet engraftment, adverse events (AEs), total Hb, Hb fractions, % F-cells, hemolysis markers, sVOCs, and additional protocol endpoints for up to 24 months. Results As of June 16, 2025, enrollment has been completed and 46 patients have initiated mobilization. Of the 26 patients who have received BEAM-101, mean duration of follow-up was 6.2 (range 1.0–18.7) months. Baseline demographics were: age 18–34 years, 24 βS/βS genotype, 21 self-reported Black/African American, and 11 female. One patient, who successfully engrafted and obtained stable HbF levels >60%, withdrew consent 5 months post-infusion. For the 26 treated patients, the median number of stem cell collection cycles was 1 (range 1–4); 18 (69.2%) required a single cycle, 4 required 2 cycles, and 4 required >2 cycles. Target cell dose was achieved with a median of 3 (1–12) collection days. Patients received a mean BEAM-101 dose of 8.4 (range 3.2–23.4) ×106 viable CD34+ cells/kg. By the data cut, patients achieved neutrophil (n=26) and platelet (n=24) engraftment at a median of 18 (12–30) days and 19 (11–50) days, respectively, with a median duration of 7 (4–17) days of neutropenia. Of the 24 evaluable patients, 9 (37.5%) achieved platelet engraftment without requiring platelet transfusion through the transplant process. No patients had ≥Grade 3 AEs or serious AEs related to BEAM-101. One patient died due to respiratory failure, assessed as likely related to busulfan conditioning, 4 months post-infusion as previously reported. Mean total Hb increased to 12.1 (range 9.0–14.7) g/dL by Month (M) 1 (n=24), 15.6 (11.9–18.6) g/dL by M6 (n=11), and was sustained through follow-up. Four patients had total Hb levels above the normal range beyond M6 without any associated clinical manifestations or need for therapeutic intervention. Erythropoietin levels trended towards normal in all patients, including those with elevated total Hb. Mean endogenous HbF (HbF/[HbF+HbS]) was >60% and HbS was <40% by M1, which was sustained through last follow-up. At M6, mean % F-cells were 99.2% (97.0–99.9; n=10) and mean HbF/F-cell was 20.8 (18.0–23.9; n=9) pg, exceeding the protective threshold of 10 pg against sickling. Peripheral blood editing was at a mean of 68.5% by M3 (n=16), 69.6% by M6 (n=10), and 72.8% by M12 (n=5). Hemolysis markers and sickling parameters normalized or improved for all patients. No patients experienced any investigator-reported sVOCs post-engraftment. Conclusions The BEAM-101 treatment process is characterized by a low number of mobilization and collection cycles and high editing efficiency, resulting in rapid neutrophil and platelet engraftment and robust pancellular HbF expression, with durability observed up to 18 months. Additionally, there is a corresponding reduction in HbS levels to <40%, and improvements or resolution of hemolysis parameters and anemia, along with resolution of investigator-reported sVOCs post-engraftment. The safety profile of the BEAM-101 treatment regimen is consistent with busulfan conditioning, autologous HSCT, and underlying SCD. These results demonstrate the potential for base editing of the HBG1/2 promoters as a safe and effective therapeutic modality for the treatment of SCD that also has the potential to minimize hospitalization and treatment process burden for patients, families, and sites.