Shah, Meera

PURPOSE Ziftomenib—a potent, highly selective, oral menin inhibitor—was well tolerated and demonstrated encouraging clinical activity as monotherapy for relapsed/refractory NPM1 -mutated ( NPM1 -m) and KMT2A -rearranged AML in the KOMET-001 phase I trial. METHODS In the registration-enabling phase II part of KOMET-001, patients with relapsed/refractory NPM1 -m AML received ziftomenib 600 mg once daily. The primary end point was the rate of complete remission with full hematologic recovery (CR)/CR with partial hematologic recovery (CRh). RESULTS From January 26, 2023, to May 13, 2024, 92 patients (median age, 69 years [range, 33-84]) were treated. The primary end point was met, with a CR/CRh rate of 22% (95% CI, 14 to 32; P = .0058); 61% were negative for measurable residual disease. Overall response rate was 33% (95% CI, 23 to 43), with a median duration of 4.6 months (95% CI, 2.8 to 7.4). Prespecified subgroup analyses showed comparable CR/CRh regardless of previous therapy, including venetoclax, or type of comutations. Median overall survival was 6.6 months (95% CI, 3.6 to 8.6). Common grade ≥3 treatment-emergent adverse events were febrile neutropenia (26%), anemia (20%), and thrombocytopenia (20%). Differentiation syndrome occurred in 25% of patients (15% grade 3; no grade 4-5) and was manageable with protocol-defined mitigation. Three patients (3%) discontinued treatment because of ziftomenib-related adverse events. CONCLUSION Ziftomenib demonstrated significant clinical benefit and deep responses in patients with heavily pretreated, relapsed/refractory NPM1 -m AML. Ziftomenib was well tolerated with a safety profile consistent with previous studies, including manageable differentiation syndrome, lack of clinically significant QTc prolongation, and low rates of myelosuppression.

Abstract Erdheim-Chester disease (ECD) is a rare systemic histiocytic neoplasm, with cardiac morbidities, including cardiovascular (CV) risk factors and cardiac conditions, playing a significant yet poorly understood role in the disease burden. This study evaluated the prevalence, characteristics, and prognosis of ECD in patients with (ECD-C) and without cardiac involvement (ECD-noC) and compared the burden of cardiac morbidities with matched controls. Patients diagnosed with ECD between 1990 and 2021 at a tertiary center were included, with cardiac involvement centrally assessed using radiographic studies. Cardiac morbidities were compared with a control group without ECD, matched for age, sex, body mass index, and smoking history. Among 104 patients with ECD, 39 (37%) had cardiac involvement. Patients with ECD-C had higher rates of hypertension (67% vs 46%), hyperlipidemia (67% vs 40%), heart failure (36% vs 8%), and pericardial effusion (28% vs 2%) than those with ECD-noC. Compared with the matched non-ECD cohort, patients with ECD had higher prevalence of coronary artery disease (20% vs 7%), heart failure (18% vs 4%), and antihypertensive drug use (55% vs 40%). Notably, patients with ECD-C had inferior progression-free survival (PFS) from frontline therapy compared with patients with ECD-noC (5-year PFS, 28.3% vs 70.5%). These findings highlight the burden of CV risk factors and cardiac conditions in ECD, even without a clinical diagnosis of ECD-C. Importantly, this cardiac morbidity burden is substantial for patients with ECD-C compared with ECD-noC. Our findings highlight the need for comprehensive cardiac risk assessment and management strategies to improve patient outcomes.

Abstract Allogeneic stem cell transplant (ASCT) remains the only curative option in chronic myelomonocytic leukemia (CMML). We retrospectively analyzed 138 CMML patients who underwent ASCT at the Mayo Clinic. Patients who transitioned to ASCT while in chronic phase (Group A) displayed superior post-transplant survival (PTS), compared to those in whom ASCT was performed after blast transformation (BT; Group B) (median 95 vs. 16 months; p=0.01). In Group A, PTS was superior in patients with <5% bone marrow (BM) blasts at time of ASCT (median 164 vs. 13.5 months; p=0.01). Other predictors of superior PTS included day-100 BM blast <5% or normal cytogenetics (median 164 vs 18 months; p=0.01) or presence of chronic graft-versus-host-disease (GVHD; median 164 vs. 26 months; p=0.01). Pre-ASCT hypomethylating agent exposure (HR=2.03; p=0.03), and receiving more than one line of pre-ASCT chemotherapy (p=0.01) predicted inferior PTS. In multivariable analysis, predictors of superior GVHD-free and relapse-free survival (GRFS) included the use myeloablative conditioning and the absence of morphologically or cytogenetically apparent disease at day-100. The use of post-transplant cyclophosphamide (PTCy) was associated with higher cumulative incidence of relapse (p=0.02) and numerically inferior PTS (p=0.1). Group B patients also appeared to benefit from achieving BM blast <5% at time of ASCT (p=0.4) as well as at day-100 (p=0.01), in terms of PTS, while full chimerism and normal cytogenetics at day-100 were associated with superior GRFS. These observations support the value of ASCT in CMML, especially if performed prior to BT and in the presence of <5% BM blasts at time of ASCT. Additionally, the observed detrimental impact of PTCy requires additional studies to confirm and investigate the underlying mechanisms.

e18523 Background: Allogeneic hematopoietic stem cell transplant (AHCT) remains the only curative option for genetically high-risk acute myeloid leukemia (AML). Venetoclax plus hypomethylating agents (Ven+HMA) is approved as frontline treatment in elderly patients with AML ( NEJM 2020; 383); however, less is known on the post-transplant outcomes following such therapy. Methods: Newly diagnosed (ND) AML patients who received Ven+HMA and underwent AHCT at Mayo Clinic from 2019 to 2024 were retrospectively recruited. Patients who required salvage therapy following Ven+HMA were excluded. Post-transplant survival (PTS) and relapse incidence were computed. Results: 55 ND-AML patients (60% male, 49% de novo , median age 69 [38-77]) received Ven+HMA (median cycles 3 [2-11]). ELN 2022 cytogenetic risk at time of diagnosis was non-adverse in 67% of patients, while 33% had adverse karyotype. Common mutations at diagnosis included: K/NRAS (88%), TP53 (26%), RUNX1 (23%), ASXL1 (16%), and IDH1/2 (17%). At the time of AHCT, 98% ( n=54 ) were in CR/CRi or MLFS; ELN cytogenetic risk was non-adverse in 91%, and adverse in 5 (9%) patients. Common mutations included: TP53 (16%), TET2 (18%), SRSF2 (15%), ASXL1 (13%), RUNX1 (18%), and DNMT3A (9%). Donor types included HLA-matched unrelated (75%), haplo-identical (11%), matched related (7%), mismatched unrelated (7%). 58% received fludarabine/melphalan conditioning and 54% GVHD prophylaxis with cyclophosphamide. At a median follow up of 25 months (0.7-68 mo), 20 patients (36%) have died, due to relapse in 10 (18%) cases. 3-year cumulative incidence of non-relapse mortality (NRM) was 17%. Median PTS was not reached (1/2/3-year survival 74%/66%/62%). Univariate analysis identified Karnofsky Performance Score <70% (3 vs. 21 months, p<0.01 ), TP53 (14 vs. 21 months p=0.02 ) and TET2 mutation at time of transplant (11 vs. 21 months , p=0.02 ) as risk factors. Multivariable analysis confirmed the prognostic impact of TP53 (HR 2.8) and TET2 mutations (HR 2.9). Age, adverse karyotype at transplant, and donor type did not impact PTS (p>0.1). 13 patients (24%) experienced post-transplant relapse; 1/2/3-year cumulative incidence of relapse was 10%, 21% and 25%, respectively. ELN-defined adverse karyotype at transplant increased risk of relapse (3 year cumulative incidence 80% vs. 17% for non-adverse , p<0.01 ). Overall, 51% of patients developed GVHD; 54%, 39% and 7% were acute, chronic GVHD and both, respectively. GVHD was protective against relapse (3 year incidence 15% vs. 36% in absence of GVHD [p=0.04]). Conclusions: Ven+HMA frontline treatment is associated with favorable post-transplant outcome in elderly ND-AML (3 year PTS 62%/cumulative incidence of relapse 25%/NRM 17%). TP53 mutation and ELN 2022-defined adverse karyotype at the time of transplant independently predicted PTS and relapse incidence, respectively.

e18508 Background: BPDCN is a rare and aggressive hematologic malignancy. Despite the advent of targeted therapies, median overall survival (mOS) remains <1 year (y) in the absence of stem cell transplant (SCT). This study evaluates clinical and molecular predictors of outcomes in a large cohort of BPDCN patients at a tertiary center. Methods: BPDCN patients seen at Mayo Clinic (AZ, FL, MN) between 2000-2024 were identified retrospectively. Analyses considered parameters at diagnosis. Next generation sequencing (NGS) was performed using a 47-gene assay. Standard statistical methods were used; calculations used R. Results: Among 69 patients, the median age was 70y (range 19-94) with male predominance (83%). At presentation, skin (80%), bone marrow (73%), lymph nodes (52%), spleen (27%), and CNS (12%) were involved; 26% had a concurrent hematologic malignancy. Among 20 cases with NGS, the median number of mutations was 3 (range 0-5), most frequently TET2 (n=16), ASXL1 (n=13), SRSF2 (n=7), and NRAS (n=5). Frontline therapy (Table) yielded a complete response (CR) rate of 63% and overall response rate of 76%. CR rates were similar among regimens, but patients who received an ALL (hyper-CVAD based) regimen (8/13) or tagraxofusp (6/9) were more likely to be bridged to SCT (6/29, p<0.01). After median follow up of 38 months (mo), mOS for all was 15 (95% CI 12-21) mo; 44 (64%) were deceased at last follow up. Among 62 evaluable patients, 20 (32%, median age 60 vs 74y, p<0.01) underwent SCT which improved survival (mOS 51 vs 10 mo, 3y OS 52% vs 5%, p<0.01); mOS was not different between allogeneic (n=17) and autologous (n=3) SCT (54 vs 38 mo, p=0.45). When censored for SCT, the 1y OS for patients receiving an ALL regimen, tagraxofusp, or other regimen was 82%, 67%, and 47%, respectively (p=0.15). In univariate analysis, age ≥50y, lymph node involvement, bone marrow involvement, hemoglobin <10 g/dL, leukocytes (WBC) >11 x10 9 /L, abnormal karyotype, and HCT were significantly associated with OS. In multivariate analysis, WBC >11 x10 9 /L (HR 3.7, p<0.03), abnormal karyotype (HR 5.4, p<0.01), and SCT (HR 0.23, p<0.01) remained significant. Separately, SRSF2 mutation was associated with inferior OS (15 vs 51 mo, p=0.02), but significance was lost when adjusted for age, abnormal karyotype, and SCT. Conclusions: Newly-diagnosed BPDCN patients treated with an ALL regimen or tagraxofusp followed by SCT had longer OS compared to those treated with all other regimens. WBC >11 x10 9 /L and abnormal karyotype were independent predictors of inferior survival whereas SCT was beneficial. Regimen N Age (y) ANNOVA CR Chi Sq HCT Chi Sq 1y OS mOS (mo) Log-rank Tagraxofusp 9 68 (40-70) <0.001 7 (78%) 0.548 6 (67%) 0.018 88% 20.8 0.121 ALL 13 43 (20-72) 8 (67%) 8 (62%) 74% 50.7 Hyper-CVAD 11 43 (20-72) 6 (60%) 6 (60%) 67% 35.8 AML 18 70 (48-80) 13 (76%) 5 (28%) 58% 14.2 Intensive 8 66 (48-77) 7 (88%) 3 (38%) 57% 12.4 HMA+Venetoclax 8 69 (65-80) 6 (75%) 2 (25%) 50% 14.0 Lymphoma 8 74 (49-85) 3 (43%) 1 (13%) 50% 14.0 CHOP 6 74 (49-85) 3 (50%) 1 (17%) 50% 17.7 Other 3 66 (63-73) 1 (33%) 0 (0%) 33% 12.0