We examined the prognostic value of routine NGS data in newly diagnosed acute myeloid leukemia (AML) treated with intensive (7 + 3 backbone) induction, specified by AML subtype. A contemporary (2015-2025) series of 545 Mayo Clinic patients (median age 56 years, females 44%) was considered. Median follow-up was 49 months with 341 (63%) allogeneic hematopoietic stem cell transplantations (AHSCT) recorded. AML subtypes included core-binding factor (CBF; N = 72; 13%), primary non-CBF (N = 403; 74%), post-myelodysplastic syndromes (MDS) or post-myelodysplastic/myeloproliferative neoplasms (post-MDS-MDS/MPN; N = 28; 5%), post-MPN (N = 15; 3%), and therapy-related (t-AML; N = 27; 5%). Corresponding complete remission rates, with/without count recovery (CR/CRi), were 89%, 76%, 64%, 27%, and 78% (p < 0.01) and 5-year transplant-censored survival rates 68%, 57%, 21%, 0%, and 55% (p < 0.01). In multivariable analyses, the prognostic value of specific mutations was mostly limited to primary non-CBF AML where adverse karyotype (OR 1.9; p = 0.04) predicted inferior and FLT3-ITD (OR 0.4; p < 0.01) or NPM1 MUT/FLT3 WT (OR 0.1; p < 0.01) superior CR/CRi while KRAS MUT (HR 8.8; p < 0.01), TP53 MUT (HR 5.4; p < 0.01), and TET2 MUT (HR 2.3; p = 0.01) predicted inferior and NPM1 MUT/FLT3 WT (HR 0.3; p = 0.01) superior survival. Prognostication in intensively-treated AML should start with subtype specification and recognition of the limited value of NGS in non-primary AML. Post-MPN AML is particularly associated with dismal outcomes and should be prognostically distinguished from post-MDS-MDS/MPN AML. In primary non-CBF AML, in addition to previously established risk factors, the favorable impact of FLT3-ITD on achieving CR/CRi and the unfavorable impact of KRAS MUT and TET2 MUT on transplant-censored survival were noted and require confirmation from additional studies.

Bone marrow failure syndromes (BMFS) are rare disorders characterized by impaired hematopoiesis, and distinguishing inherited bone marrow failure syndromes (IBMFS) from acquired aplastic anemia (AA) is essential for management. We retrospectively analyzed clinical, pathological, and genetic data from 159 BMFS patients after central review, assessing the diagnostic and prognostic utility of fetal hemoglobin (HbF) relative to minor paroxysmal nocturnal hemoglobinuria (PNH) clones and telomere length. Elevated HbF (>1%) was frequently observed in both IBMFS and AA but lacked diagnostic specificity (P=0.2). In contrast, rapid onset cytopenias (<3 months before diagnosis, P<0.0001), minor PNH clones (>0.1% in at least two cell types, P<0.0001), and age-adjusted lymphocyte telomere length at or above the 1st centile were characteristic of AA, with the latter two variables holding independent statistical significance in a multivariable analysis to differentiate among BMFS subtypes. The prognostic value of elevated HbF was also limited except at extremely elevated levels (HbF>10%) where it was associated with adverse transplant-censored overall survival (median 6 years versus not reached, P<0.001). In summary, HbF is elevated in both inherited and acquired BMFS and, unlike minor PNH clones and telomere length, lacks diagnostic specificity; its prognostic value is limited except at extremely elevated levels (>10%).

Introduction The phase II CAST trial published by Alhomsi et al studied the use of PTCY in combination with Abatacept, and short course of tacrolimus(TAC) as GVHD prophylaxis in haploidentical transplant (HID). Results were promising for low incidence of GVHD and superior relapse free survival (RFS) compared to a CIBMTR matched cohort (TCT 2024). Objectives Since Nov 2023, we used the CAST regimen at Mayo Clinic Rochester for patients undergoing matched, mismatched unrelated donor and HID. Here we report our single institution experience of the CAST regimen as GVHD prophylaxis. Methods Patients with insurance approval for Abatacept who received GVHD prophylaxis according to the CAST study were included. Abatacept was dosed on days +5, 14, 28, and 56 post alloHCT. Tacrolimus (TAC) was started on day +5, and tapering was initiated on day 60, while it was discontinued by day 90 in the absence of GVHD. Results A total of 73 patients received the CAST regimen. Median age at transplant was 61-years (IQR 50-68) and 39 (53.4%) were males. Out of the 73 patients, 56 (76.7%) had matched unrelated donor (MUD), 10 (13.7%) had mismatched unrelated donor (MMUD), and 7 (9.6%) had HID. A total of 28 (38.4%) patients received myeloablative conditioning. Graft was 100% T-cell replete PBSC. The most common indications for alloHCT were AML [28 (38.4%) patients], MDS [21 (28.8%) patients], and myelofibrosis [7 (9.6%) patients].Disease risk index (DRI) was high/very high in twelve (16.4%) patients, whereas 49 (67.1%) had intermediate and 5 (6.8%) patients had low DRI. DRI was not available for 7 (9.6%) patients. Among AML patients, 9 (32.1%) were MRD-positive pre-transplant.Median time to ANC engraftment was 15 days (IQR 14-17 days), and median time to platelet engraftment was 20 days (IQR 15-27 days), while one (1.4%) patient developed graft failure.After a median follow-up of 11.9 months (95% CI 10.6 – 13 months), 3 (4.1%) patients developed grade 3-4 acute GVHD, while 8 (10.9%) patients developed chronic GVHD requiring systemic therapy. Of the 3 patients with grade 3-4 acute GVHD, 2 patients had stage 4 GI GVHD and 1 had stage 3 liver GVHD.Median OS and RFS were not reached; 1-year OS was 82.4% (95% CI 73.3 - 92.7%) and 1-year RFS was 69.6% (95% CI 59.5 - 81.5%). A total of 15 (20.5%) patients relapsed, 14 (93.3%) were among MUD group, while only 1 (6.7%) patient relapsed in the MMUD/HID group. The 1-yr GRFS rate was 61.1% (95% CI 50.5 – 73.9%). The 1-yr non-relapse mortality (NRM) for the entire cohort was 8.9% and 1-year cumulative incidence of relapse was 21.5%. Conclusion Here we report the first real world experience of CAST across multiple different donor platforms in a predominantly enriched MUD cohort. Shorter time to engraftment was notable with CAST. CAST was associated with a very low incidence of severe acute and chronic GVHD, which translated into a favorable 1-yr NRM. Longer follow up is required to evaluate long term outcomes.

1503 Background: CAR T-cell therapy has revolutionized treatment outcomes in hematological malignancies, but has traditionally required inpatient post-infusion monitoring, which is associated with significant cost and time toxicity. Outpatient CAR T infusion and monitoring has been the standard approach at Mayo Clinic site in Rochester, MN, with demonstrated feasibility and safety (Bansal et al., ASCO 2023). We present data comparing healthcare utilization between CAR T recipients who underwent outpatient remote monitoring and those with traditional inpatient monitoring. Methods: Electronic medical records were retrospectively analyzed for 293 patients who received CAR T-cell therapy for a hematological malignancy at any of the 3 Mayo Clinic sites (MN, AZ, FL) between 2020 and 2024 . Healthcare utilization was compared between patients who received outpatient CAR T with remote patient monitoring in Rochester, MN (N = 125) and those who received inpatient CAR T in the Arizona (n = 90) and Florida (n = 78) sites. Per protocol, patients in the inpatient group underwent mandatory inpatient monitoring for 7 days, with extension per provider discretion. Data was analyzed through Chi-Square and Wilcoxon tests. P values < 0.05 were considered statistically significant. Results: There was no significant difference in baseline sex, age, ethnicity, LDH, platelets, or neutrophils among the 293 patients. Diagnoses included lymphoma (n = 175), multiple myeloma (n = 106), and B-ALL (n = 12). The most common CAR T-cell products used were axicabtagene ciloleucel (n = 138) idecabtagene vicleucel (n = 56), and ciltacabtagene autoleucel (n = 50). Median hospital days were lower in the outpatient group vs the inpatient group at 30 days (4.4 vs 13.3, P < 0.001) and 90 days (4.6 vs 13.6, P < 0.001). ICU admission occurred in 1 outpatient patient ( < 1%) vs 18 inpatient patients (11%) in the first 30 days (P < 0.001). In the first 30 days, 22% of patients in the outpatient group did not require hospitalization, while 56%, 15%, and 6% required 1, 2, and 3 hospitalizations, respectively. Similarly, only 11 (8.8%) patients in the outpatient group had ≥1 ED visit in the first 30 days compared with 32 (20%) pts in the inpatient group (P = 0.009). At 30 days, there was no difference in patient portal use, with 58% of patients using the portal at least once and a median of 1 message in both groups. Within the first 30 days, 53% and 2% of patients in the outpatient group required 1 and 2 outpatient visits, respectively, vs 29% and 2% in the inpatient group (P < 0.001). There was no difference in 30-day mortality (1.6% outpatient vs 2.4% in inpatient) between the 2 groups (P = 1.00) Conclusions: Outpatient CAR T-cell therapy monitoring was associated with significantly fewer hospital days without increased ED visits, ICU stays, portal use, or 30-day mortality. This demonstrates lower healthcare utilization for outpatient CAR-T therapy.

Post-transplant cyclophosphamide (PTCy) has emerged as the standard graft-versus-host disease (GVHD) prophylaxis after allogeneic hematopoietic stem cell transplantation (alloHCT). The Endothelial Activation and Stress Index (EASIX) has been shown to be a key determinant of post-transplant outcomes, yet the dynamic trends of post-transplant EASIX scores across GVHD prophylaxis platforms and its prognostic utility remain incompletely defined. We evaluated longitudinal post-transplant EASIX score trajectories in patients receiving PTCy versus calcineurin inhibitor/methotrexate (CNI/MTX)-based prophylaxis and developed an individualized dynamic risk model for post-transplant survival. Log2-EASIX scores from day +20 to day +120 were evaluated using dynamic landmark analysis and combined with the pre-transplant disease risk index (DRI) to develop a dynamic-EASIX DRI risk prediction model which could predict post-transplant mortality. Patients were randomly segregated in a 2:1 ratio into training and validation cohorts to develop and validate the model, respectively. A total of 534 alloHCT recipients were evaluated, of whom 150 (28.1%) received PTCy. In the training cohort, an increasing log2-EASIX score (HR 1.44, P = 0.001) and an increasing log2-EASIX trend/slope (HR 2.81, P = 0.002), both were associated with an inferior 1-year overall survival (OS). The dynamic-EASIX DRI model had a C-index of 0.82 for 1-year and 0.84 for 2-year survival. In the validation cohort, the area under curve for the dynamic-EASIX DRI model was 70.2% and 75.4% for 1 and 2-yr OS, respectively. The dynamic-EASIX DRI model is a novel tool that can be used to risk stratify patients in the post-transplant follow-up period and can be applied irrespective of GVHD prophylaxis.

Hypomethylating agents (HMA) and allogeneic hematopoietic stem cell transplantation (alloHSCT) have both demonstrated remissions in VEXAS; however, comparative data is lacking. We conducted a multicenter, retrospective analysis of 66 patients diagnosed with VEXAS syndrome treated with HMA (n = 35) or alloHSCT (n = 31). Baseline characteristics such as genetics, co-morbidities, and performance status were balanced between the groups, except older age in the HMA group. Median follow-up from therapy initiation was 18 months (95% CI: 11-26), and 14 (21%) deaths were reported (alloHSCT n = 3; HMA n = 11). Among all evaluable patients within the alloHSCT cohort, all patients achieved molecular remission, and a substantial proportion of patients discontinued glucocorticoids (58%). In contrast, HMA therapy was associated with lower but meaningful rates of molecular remission (22%) and glucocorticoid discontinuation (6%). In a real-world setting, HMA therapy was associated with a high discontinuation rate related to toxicity or lack of response. On multivariable analysis adjusted for age and Charlson Comorbidity Index, alloHSCT was associated with improved overall survival (HR = 0.20, 95% CI: 0.05-0.81; p = 0.024). This association remained consistent across multiple ancillary sensitivity analyses, including restriction to transplant-eligible patients, patients aged ≤ 75 years, 1:1 matching, and propensity score-based weighted analyses. Although limited by retrospective design, these findings suggest that alloHSCT remains an attractive and potentially curative strategy in selected patients with VEXAS. Prospective validation of these findings is warranted.

Toxicities from CAR-T cell therapy are complex, severe, and often require multidisciplinary management. To standardize care, our institution established a Serious Adverse Event Oversight Committee (SAEOC), comprising specialists from hematology, neurology, nephrology, infectious diseases, intensive care, cardiology, and pharmacy. Once activated, the committee convenes virtually twice daily until SAE resolution or deactivation. We retrospectively examined outcomes in patients with macrophage activation syndrome/ hemophagocytic lymphohistiocytosis (MAS/HLH) treated before and after SAEOC implementation in December 2022. Provider perceptions were evaluated through a survey.The SAEOC was activated for 19 patients, most frequently for MAS-like syndromes (n=7), MAS/HLH (n=4), and high-grade ICANS (n=14). Additional triggers included CD8+ T-cell lymphoproliferative disorder, delayed IEC neurotoxicity and enterocolitis, massive pulmonary embolism, and diffuse alveolar hemorrhage.To assess outcomes, we focused on a more homogeneous subgroup of patients with MAS/HLH, comparing all patients treated prior to SAEOC implementation (n=8; 3 axi-cel, 1 tisa-cel, 1 ide-cel, 1 cilta-cel, 2 investigational CAR-Ts) with those treated after (n=6; 3 axi-cel, 1 brexu-cel, 2 cilta-cel). In the post-SAEOC cohort, 30- and 100-day treatment-related mortality were numerically lower, compared with the pre-SAEOC cohort (Table 1). Although these differences did not reach statistical significance, the findings may suggest a potential benefit of structured multidisciplinary oversight, acknowledging the limitations of small sample size and treatment-era differences.A total of 21 providers completed surveys (Figure 1), with ≥80% reporting perceived improvements in timeliness of interventions, consistency and comprehensiveness of management, interdisciplinary communication, and confidence in SAE management (Figure 2). Respondents valued SAEOC contributions to management of complex cases such as IEC-parkinsonism, MAS/HLH, CNS infection, and multiorgan involvement. SAEOC implementation also contributed to refinement of institutional standard operating practices. Reported challenges included workload and meeting frequency. One respondent provided uniformly negative Likert ratings but described the intervention as highly beneficial in free text; this discordant response was kept but interpreted cautiously. Suggested improvements included streamlining activation, reducing meeting frequency when appropriate, formal recognition of provider effort, and greater incorporation of evidence-based frameworks.The SAEOC represents a model for early multidisciplinary engagement and provides a practical framework for harmonizing CAR-T toxicity management, particularly for complex cases.

Introduction Reporting patient outcomes by CAR-T treatment centers is part of the accreditation requirement under the FACT IEC Program standard. CIBMTR audits IEC programs annually and requires the reported data to be >97% accurate. Currently, this is a time-consuming and manual process, making it difficult to sustain with the growing CAR-T indications and patient volume. Objective The objective of this study is to develop a Large Language Model (LLM) to automate the abstraction from the medical record and apply guidelines to define and grade toxicities after CAR-T therapy. Methods Clinical data from patients treated with CAR-T between January 2018 and June 2025, across all three Mayo Clinic sites, Minnesota (MCR), Florida (MCF) and Arizona (MCA) were used. Using LLM (Gemini 2.5 pro), we created a prompt by embedding both the clinical data and the ASTCT guideline for CRS and ICANS grading to generate output for whether or not CRS or ICANS event occurred, and if occurred, dates of occurrence, grade and medications used for management, as well as contextual justification for the output. The CRS and ICANS outcome reports generated by the LLM were then compared to the historical database. Any discrepancies identified were then reviewed manually. Results LLM was optimized using MCR data, showing 100% accuracy and F1 score, and 96% accuracy and 82% F1 score, for identifying CRS and ICANS events respectively, compared to the database. The match rates for CRS and ICANS grades were 83% and 89% respectively (Figure 1). MCA and MCF use different processes for clinical notes and toxicities flowsheet documentation. Applying the same LLM to those two sites yielded a lower rate of accuracy and F1 score for CRS and ICANS (Figure 1). In general, confusion matrix scores are higher for CRS events than for ICANS.Review of the discrepancies between LLM and database identified three main causes for discrepancies between LLM and database: A) Missed information by manual review for the historical database that was correctly identified and categorized by the LLM; B) correct categorization of event by LLM using objective data that was incorrectly graded by clinical team or attributed by the clinical team to other etiologies; C) LLM incorrect (Figure 2). For the first discrepancy, LLM use can improve the accuracy of the data capture for the compliance team. For the second, LLM will be updated with output to alert compliance team of discrepancy between objective data and clinical notes for manual review and final adjudication. For the third, additional review with clinical teams will be done to determine the best action to improve accuracy that may include updates to LLM prompts and clinical documentation process. Conclusion Our study demonstrates that LLMs can significantly reduce manual work to abstract and categorize CAR-T toxicities, while identifying opportunities for process improvement and quality review for the compliance team.

6525 Background: Venetoclax plus hypomethylating agent (Ven-HMA) is the standard treatment for unfit patients with newly diagnosed acute myeloid leukemia (ND-AML), with Ven typically administered for 28 days (d) per cycle (DiNardo NEJM 2020) . However, the optimal duration of Ven across risk groups remains unclear. We examined survival outcomes with Ven 7, 14, 21, and 28d in ND-AML, in the context of European LeukemiaNet (ELN) and Mayo Genetic risk models. Methods: ND-AML patients receiving Ven-HMA at the Mayo Clinic were retrospectively studied. Patients were stratified by ELN 2024 (Döhner Blood 2024) and Mayo Genetic risk (Gangat Am J Hematol 2025) , and analyzed using standard statistical methods. Results: 540 patients (median age 75 years, 52% de novo) received HMA with Ven for 7d ( n =33), 14d ( n =117), 21d ( n =96), or 28d ( n =294). ELN and Mayo risk distributions were 22%/35% high, 18%/56% intermediate, 60%/9% low risk, respectively. Baseline characteristics were comparable. CR/CRi rates were comparable across Ven durations, with the exception of lower CR/CRi with 7d vs 21d (p=0.04). Risk-stratified CR/CRi showed variations across Mayo and ELN groups but without significant differences based on Ven duration (Table). Allogeneic transplant rates were 15%, 18%, 18%, 20% for 7, 14, 21, 28d (p=0.86). At a median followup of 37.7 months, median overall survival (OS) differed by ELN risk (6.6, 11.9, 20 months) and Mayo genetic risk (7.8, 17.4 months, not reached (NR)), for high, intermediate, low risk (p<0.01), respectively. Median OS was comparable across Ven 7, 14, 21, 28 d (13, 13, 17, 14 months; p=0.84), with corresponding 1/3/5-year survival rates (Table). 30/60d mortality differed by Ven duration; 7d 10%/20%, 14d 7%/15%, 21d 4%/13%, 28d 4%/6%. Compared with 28d, 30d mortality was higher with 7d and 14d (p=0.07/0.03), and 60d mortality was higher with 7d, 14d, and 21d (p=0.02/0.01/0.05). OS was comparable across Ven durations within ELN intermediate/low risk and all Mayo risk groups, except among ELN high risk, patients receiving 14d Ven had inferior OS compared with 21d and 28d (p<0.01). Cumulative incidence of relapse at 1 year was similar among patients receiving 14, 21, 28d Ven (16%, 18%, 18%;p >0.1). Conclusions: Survival outcomes were comparable across Ven 7, 14, 21, 28 d in ND-AML, with outcomes driven by Mayo Genetic and ELN risk. Despite differences by Ven duration in high-risk groups, higher early mortality with 7d and 14d likely reflects treatment selection. Prospective trials are needed to establish risk adapted Ven dosing strategies. 7 (N=33) 14 (N=117) 21 (N=96) 28 (N=294) P-value CR/CRi (%) 52 63 72 65 0.19 7≠21 Mayo Risk High 33 49 58 55 0.53 - Intermediate 55 69 80 69 0.17 7≠21 Low 100 85 80 84 0.84 - ELN Risk High 33 30 57 53 0.21 - Intermediate 33 59 64 56 0.63 - Low 62 74 80 73 0.46 - Median OS (months) 13 13 17 14 0.84 - 1/3/5-year survival (%) 53/NR/NR 51/25/22 56/23/20 55/27/20 >0.1 -

e18524 Background: Venetoclax (Ven) in combination with hypomethylating agents (HMA) is FDA-approved front-line therapy for elderly or unfit patients with newly-diagnosed acute myeloid leukemia (ND-AML); however, majority relapse or are refractory ( Pratz AJH 2024 ). We examined survival outcomes in the setting of frontline Ven-HMA failure. Methods: ND-AML patients with failure to achieve complete remission (CR/CRi) or loss of CR/CRi after front-line Ven+HMA, excluding post-transplant relapse were retrospectively studied. Response was evaluated per European Leukemia Net 2022 criteria ( Dohner Blood 2022 ). Results: 356 patients with ND-AML (median age 75 years; 65% males; 55% secondary) receiving frontline Ven+HMA (median; 3 cycles (1-26), had refractory [n=219 (62%)], or relapsed disease [137 (38%)]. At diagnosis, karyotype was complex in 142/347 (41%). Mutations involved TP53 (29)%, ASXL1 (19%), RUNX1 (17%), SRSF2 (15%), KRAS/NRAS (13%), IDH2 (7%), FLT3-ITD (7%), NPM1 (6%) and IDH1 (5%). At treatment failure, complex karyotype was present in 72/180 (40%), including 55 from baseline. In 137 patients with paired NGS, mutations persisted in TP53 (88%), IDH1 (86%), IDH2 (78%), NPM1 (75%), K/NRAS (73%), RUNX1 (70%), FLT3-ITD (65%) mutations. Mutations were acquired in a minority [ IDH1 / IDH2 (2% each) TP53 (3%), NPM1 (4%), FLT3-ITD (5%) K/NRAS (6%)]. Clearance of mutations were infrequent for TP53 (12%) and IDH1 (14%). At median follow-up of 4 months (mo) (0-80) from the time of relapse/refractory disease, 320 (90%) patients have died, with median survival of 4 mo (1-2-3 yr survival 19%/8%/5%). On multivariate analysis, peripheral blasts >20%, complex karyotype, and wild-type IDH1 were independent predictors of inferior survival, while allogeneic stem cell transplant (ASCT) was associated with improved survival. A 3-point prediction model based on peripheral blasts ≥20%, complex karyotype, and wild-type IDH1 stratified patients into low-, intermediate-, and high-risk groups, with median survival of 7, 3, 2 months, respectively (p<0.01). 13 patients underwent ASCT (median survival; 22.5 mo; 3-yr survival 33%), from low (n=10) or intermediate-risk groups (n=3). Salvage therapy (n=170, 48%) yielded CR/CRi of 31% for Ven+HMA (n=36), 54% intensive chemotherapy (n=26), 50% FLT3 inhibitors (i) (n=22), 37% IDH1/2i (n=19), 25% other regimens (n=69). Median survival was similar: Ven+HMA 8 mo, intensive chemotherapy 10 mo, FLT3i 6.5 mo, IDH1/2i 14 mo, other regimens 6 mo, but inferior with supportive care (2 mo; p<0.01). Conclusions: The current study identifies peripheral blasts ≥20%, complex karyotype, and wild-type IDH1 as predictors of inferior survival in ND-AML relapsed/refractory to front-line Ven+HMA and underlines that while no specific salvage therapy conferred superior outcomes, ASCT was indispensable for long-term survival.

The comparative value of liposomal cytarabine/daunorubicin (CPX-351) versus venetoclax plus a hypomethylating agent (Ven-HMA) in the frontline treatment of older adults with primary (de novo) or secondary acute myeloid leukemia (AML) remains uncertain. In the current study, we retrospectively examined outcomes of 600 patients with newly diagnosed AML treated with CPX-351 (N = 112) or Ven-HMA (N = 488). AML subtypes included de novo (N = 277, 46%), post-myelodysplastic syndrome (post-MDS, N = 114,19%), post-myeloproliferative neoplasm (post-MPN, N = 70, 12%), post-MDS/MPN (N = 36, 6%), and t-AML (N = 103, 17%). Patients receiving CPX-351 were younger (median 65 vs. 73 years; p < 0.01), predominantly female (50% vs. 38%; p = 0.02), more likely to have secondary AML (68% vs. 51%; p < 0.01), and less likely to harbor NPM1MUT (5% vs. 12%; p = 0.02). Rates of complete response with or without count recovery (CR/CRi) were comparable between CPX-351 and Ven-HMA (55% vs. 60%; p = 0.30), including AML with myelodysplasia-related gene mutations or cytogenetic abnormalities (AML-MR 60% vs. 63%; p = 0.70). Ven-HMA use was associated with fewer infectious complications (62% vs. 83%; p < 0.01) and yielded higher CR/CRi rates in males (60% vs. 45%; p = 0.04), de novo AML (68% vs. 50%; p = 0.03), and in the presence of STAG2MUT (86% vs. 44%; p = 0.02), or CEBPAMUT (88% vs. 50%; p = 0.03). Overall survival censored for transplant, was similar (median 10 vs. 13 months; p = 0.90), with Ven-HMA being superior in post-MDS AML (median 12 vs. 7 months; p = 0.02) and CPX-351 in the presence of SF3B1MUT (median not reached vs. 14 months; p < 0.01). Our findings suggest that Ven-HMA is as effective and less toxic than CPX-351 in newly diagnosed AML, including AML-MR, despite selection of younger, fitter patients for CPX-351.

INTRODUCTION:The efficacy of donor lymphocyte infusions (DLIs) among various myeloid malignancies (particularly genetic subtypes) and the optimal timing of DLI initiation remains unclear. METHODS:This was a retrospective study of 62 patients with myeloid malignancies treated with alloHSCT and DLI from years 2001 to 2022. DLI indications were therapeutic 55 (89%), preemptive 6 (10%), and prophylactic in 1 (2%) patients with complete remission (CR/CRi) in 20 patients; diagnoses included 9 (45%) acute myeloid leukemia, 6 (30%) myelodysplastic syndromes, and 3 (15%) chronic myelomonocytic leukemia among others. RESULTS:Among patients who received therapeutic DLI (n = 55), the best response was CR/CRi in 16 (29%) patients. At a median follow-up from the date of DLI of 75 (95% CI 35-121) months, there were 49 (79%) deaths with a median OS of 6 (95% CI 4-14) months, higher in patients in CR/CRi versus no CR/CRi (median 51 versus 4 months, p = 0.008). Presence of cytogenetic abnormalities such as complex karyotype, deletions in chromosome 5, 7, and 17p, and mutations in TP53, KRAS, NRAS, RUNX1, or JAK2 were associated with adverse outcomes. CONCLUSION:DLI is an effective treatment strategy for post-transplant relapse across myeloid malignancies, with specific genetic subtypes showing poorer outcomes and survival.

The recently published BLAST clinical risk model for chronic myelomonocytic leukemia (CMML) and its molecular version (BLAST-Mol) differentiate low, intermediate, and high-risk groups. The objective of the current retrospective study was to examine the survival impact of allogeneic stem cell transplant (ASCT) in a consecutive series of Mayo Clinic patients (n = 775; 68% males, median age 71 years) with CMML, overall and adjusted for baseline BLAST/BLAST-Mol risk categories. At a median follow-up of 77 months, 151 (20%) patients underwent ASCT. Overall survival (OS) was longer in the ASCT compared to the non-ASCT cohorts (median 77 vs. 28 months; p < 0.01). The significant difference in OS between the ASCT and non-ASCT cohorts was retained after adjusting for BLAST clinical risk groups: high-risk (median 50 vs. 14 months; p < 0.01), intermediate-risk (81 vs. 28 months; p < 0.01), and low-risk (111 vs. 65 months; p = 0.04), respectively. The same was mostly the case when OS comparison was adjusted for BLAST-Mol with respective p values of < 0.01, < 0.01, and 0.08, respectively. Time-dependent cox models confirmed the favorable survival impact of ASCT in the BLAST/BLAST-Mol high- and intermediate-risk groups. The current study highlights the benefit of ASCT for BLAST/BLAST-Mol high- and intermediate-risk groups in CMML and its potential to overcome the adverse impact of some high risk cytogenetic or molecular abnormalities. These observations support the early use of ASCT in CMML, ideally before BT and regardless of genetic characteristics.

Real-world experience using momelotinib as first-line JAK2 inhibitor therapy in myelofibrosis. Anemia response was moderate (23%) while treatment-emergent adverse events included nephropathy (29%) and peripheral neuropathy (20%).

Hemophagocytic lymphohistiocytosis (HLH) is a rare but fatal complication of acute myeloid leukemia (AML), and contemporary data on its clinical and genomic correlates remain sparse. We retrospectively identified 19 adults with AML who developed HLH across 3 Mayo Clinic sites (2020-2024) and compared them with 73 patients with AML without HLH. HLH occurred at a median of 34 days from AML diagnosis (range, 0-472) and was associated with fever, multiorgan dysfunction, and rapidly rising biomarkers. Morphologic hemophagocytosis was observed in only 18% of cases, underscoring its poor sensitivity. HLH was associated with markedly inferior overall survival (median, 5.7 vs 14.8 months, P = .005), including within adverse risk and TP53-mutated AML subsets. When modeled as a time-dependent covariate, HLH remained strongly associated with inferior survival (hazard ratio [HR], 3.9; P < .001). Genomic profiling demonstrated enrichment of TP53 (58%), NF1 (16%), and RAD21 (11%) mutations, with tumor suppressor and/or DNA damage repair pathway alterations in 68% vs 34% of controls (P = .009). On multivariable analysis, HLH (HR, 3.1; P = .003) and adverse-risk cytogenetics (HR, 2.2; P = .040) independently predicted worse survival. Age of ≥65 years was associated with accelerated HLH onset (14 vs 84 days, P = .032) and higher mortality (HR, 13.4; P = .005). All patients received high-dose corticosteroids; some received tocilizumab or ruxolitinib, and none received etoposide. Despite diverse leukemia-directed therapies, only 3 patients achieved long-term survival. Collectively, these findings indicate that AML-associated HLH arises predominantly in older patients with genomically unstable leukemias, portends poor prognosis, and warrants biomarker-guided surveillance and improved targeted immunomodulatory strategies with antileukemic therapy.

Venetoclax (Ven) plus hypomethylating agents (HMA) is standard frontline therapy for newly diagnosed AML (ND-AML) patients unfit for intensive chemotherapy and is also considered in younger, fit patients. However, consolidation with allogeneic stem cell transplant (ASCT) is often required to secure durable remission. The current study examines posttransplant outcomes in patients with ND-AML treated with frontline Ven-HMA who subsequently underwent ASCT. A total of 111 ND-AML patients (58% male, 60% secondary/therapy-related, median age 70 years [range, 37-80]) received a median of 3 cycles of Ven-HMA. Mutations at the time of diagnosis included RUNX1 (18%), SRSF2 (17%), TP53 (16%), ASXL1, IDH2, K/NRAS, TET2 (14% each), STAG2 (11%), DNMT3A (8%). All patients were in CR/CRi at the time of transplant including 88% after Ven-HMA. Measurable residual disease (MRD) by flow cytometry was detectable in 18/76 (24%) patients. Donors were mostly HLA-matched unrelated (75%); 51% receiving fludarabine/melphalan conditioning and 67% posttransplant cyclophosphamide. At a median follow-up of 15 months, 42 (38%) of patients have died and 18 (16%) experienced posttransplant relapse. Median posttransplant survival was not reached (NR), with 1-, 2-, 3-year survival rates of 69%/60%/57%, respectively. On multivariate analysis, age ≥ 65 years, STAG2 mutation (STAG2MUT), and DNMT3AMUT were associated with superior posttransplant survival. Patients were stratified into low- (0-1 point), intermediate- (2 points), and high-risk (3 points); age < 65 years, STAG2 wild type, and DNMT3A wild type, with 3-year survival rates of 89%, 59%, and 19%, respectively (p < 0.01). Taken together, age, STAG2MUT and DNMT3AMUT stratified posttransplant survival in Ven-HMA treated patients with ND-AML.