Yi, Cecilia Ysabel Arana

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.

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 -

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

e18596 Background: The International Consensus (ICC), but not the 5 th edition of the WHO classification (WHO5), distinguishes mature from immature mast cell leukemia (MCL) and systemic mastocytosis (SM) associated with myeloid neoplasm (SM-AMN) from SM associated with myeloid or lymphoid neoplasm (SM-AHN). The objectives of the current study were i) to assess prognostic input from disease classification by ICC vs. WHO5, and ii) to compare the predictive performance of the Mayo Alliance Prognostic scoring (MAPS) with other prognostic models and its prognostic interaction with the ICC-based morphologic classification. Methods: Study patients met diagnostic criteria per ICC/WHO5. MAPS risk variables included i) age >60 years, ii) hemoglobin below sex-adjusted lower limit of normal, iii) platelets <150 × 10⁹/L, iv) alkaline phosphatase above upper limit of normal, and v) advanced, including MCL, SM-AMN, and aggressive (ASM) vs. indolent/smoldering (ISM/SSM) SM. ICC-defined MCL includes only MCL-immature whereas WHO-defined MCL includes both MCL-immature and MCL-mature. WHO-defined SM-AHN includes SM-AMN and SM associated with lymphoid neoplasm (SM-ALN). Results: 910 Mayo Clinic patients with SM were diagnosed between 1968 and 2024 (median age 56 years). ICC categories were ISM/SSM (N=552), ASM (N=115), SM-AMN (N=235), and MCL (N=8). At median follow-up of 4 years, 345 (38%) deaths and 35 (3.8%) leukemic transformations were documented. Overall survival (OS) predictive performance at 5 years was superior with ICC (AUC 0.85), compared to WHO5 (AUC 0.83); median survival was 24.3 years in ISM/SSM, 5.8 years for ASM, 2.0 years for SM-AMN, 2.3 years for SM-AHN, 1.8 years for MCL-mature and 0.08 years for MCL-immature; the difference in OS was significant between MCL-immature and SM-AMN (p<0.01) but not between MCL-mature and SM-AHN (p=0.3). Similarly, OS was similar between MCL-mature and ASM (p=0.8) and between SM-ALN and ASM (p=0.08) but different between MCL-immature and ASM (p<0.01), SM-AMN and ASM (p<0.01), and MCL-mature and MCL-immature (p<0.01). Predictive performance at 5 years was superior with MAPS (AUC 0.91) and MAPS-molecular (AUC 0.91), compared to the mutation-adjusted risk score (MARS; AUC 0.82). Median OS estimates were not reached, 24.2, 11.7, 5.7, 2.6, and 0.7 years, in the presence of 0, 1, 2, 3, 4, or 5 of the forementioned MAPS risk factors. Among informative cases, ASXL1 mutation was the only genetic risk factor with MAPS-independent prognostic relevance. Prognostic inter-independence between ICC and MAPS was confirmed by multivariable analysis. Conclusions: The current study confirms the superior performance of MAPS, in regard to survival prediction, with little additional contribution from mutations. SM sub-classification by the ICC is prognostically independent of MAPS and more valuable than classification by WHO5.

e19078 Background: MECOM (EVI1) rearrangements in MDS/AML are rare and carry an unfavorable prognosis. Although allogeneic stem cell transplantation (allo-HSCT) may prolong survival, factors impacting outcomes are not known. We conducted a retrospective analysis of patients with MECOM (EVI1) to associate clinicopathologic variables with prognosis. Methods: This study was approved by the Mayo Clinic IRB. Patients >18 years of age with MDS or AML and MECOM EVI1 at Mayo Clinic between 01/2012 and 12/2022 were included. Response was defined by ELN criteria. Intensive chemotherapy was defined as 7+3 or high dose cytarabine. Non-intensive chemotherapy included hypomethylating agents with or without venetoclax. Median overall survival (OS) and median leukemia free survival (LFS) were estimated using the Kaplan-Meier method. Outcome differences between sub-groups and univariate analyses were assessed with Cox regression. Results: Sixty patients met criteria for inclusion. Sixty-three percent (n = 38) were male and the median age at diagnosis was 67.8 yrs (range, 56 – 75). Eighty percent had AML (n = 48) and 18% had MDS (n = 11). Sixty-seven percent of patients had secondary AML/MDS (n = 40). Inv(3)/t(3;3) was present in 65% (n = 39) and t(3;21) was present in 12% (n = 7). Thirty-eight percent (n = 23) of patients had cooccurring monosomy 7 or 7q deletion and 5% had complex karyotype (n = 3). SF3B1 was the most common cooccurring mutation in 31% (n = 10), followed by KRAS in 19% (n = 6). Thirty-eight percent of patients (n = 23) received intensive chemotherapy. Complete response (CR) rates were 36% with intensive treatment (n = 8) and 4% with non-intensive treatment (n = 1; p = 0.007). Thirty percent (n = 18) underwent SCT (78% in CR1 and 22% in CR2) and of those, myeloablative conditioning (MAC) was used in 38% while 61% received reduced intensity conditioning (RIC). The mOS in the entire cohort was 11 months (95% CI 6.2, 17). Patients who received a SCT had longer mOS compared to patients who did not (19 vs 6.2 months, HR = 0.31, 95% CI 0.16,0.64; p = 0.001). AML-MRC was a poor prognostic factor in the HCST group for OS (HR = 4.23, 95% CI 1.02, 17.5, p = 0.047). Intensive vs. non-intensive chemotherapy, response prior to transplant (CR vs. no CR), or having 2 or more mutations on NGS did not significantly impact OS or LFS. Conclusions: In line with previous reports, allo-HSCT was associated with improved survival outcomes. Our results showed a high frequency of secondary AML/MDS, but only AML-MRC was associated with decreased survival outcomes. Regardless of therapy type, outcomes were poor. Novel therapies are urgently needed for these patients.

e19014 Background: Stromal Antigen 2 ( STAG2), located on Xq25, is the most mutated (m) cohesin-complex gene in myeloid neoplasm (MN) patients (pts). mSTAG2 is present in around 5% of MN and has been linked to secondary AML and potential poor impact on outcome. Methods: We retrospectively screened MN pts who had next-generation sequencing (NGS) (OncoHeme) performed at Mayo Clinic between 2018-2021. m STAG2 pts were included at the date of NGS. Charts were reviewed for clinical information after obtaining IRB approval. BlueSky Software V7.40 was used for statistical analysis. Results: Characteristics: 70 pts with mSTAG2 MN were identified, their median age was 72 years (range 25-91); with 55 pts (79%) being males. Complete blood counts showed median white blood cell count of 2.8 x109/L, hemoglobin of 8.9 gm/dL and platelets of 89 x109/L. The diagnosis was MDS in 38 pts (54%), AML in 20 (29%), MDS/MPN in 9 (13%), MPN in 2 (3%), and CCUS in 1 (1%). 11 cases (16%) were defined as therapy-related MN (tMN). Cytogenetics were normal in 45 pts (64%) and abnormal in 22 (31%). 10/50 non-AML pts progressed to AML (after median time of 9.8 months). Hematopoietic cell transplantation (HCT) was done in 20 pts (29%). mSTAG2: median VAF (mVAF) was 50% (range, 5%-100%). Males had higher mVAF compared to females (64% vs. 27%, p= .001), and tMN pts had higher mVAF compared to de novo (dn) MN pts (66% vs. 43%, p= .03). mVAF had no correlation with disease classification (50% in AML, 52% in MDS, 41% in MDS/MPN, 36% in MPN and 5% in CCUS, p= .5). STAG2 mutations were nonsense, frameshift, and splice site in 50%, 37%, and 13%, respectively. Co-mutations : median number of co-mutations was 3 (range, 0-6). Most common co-mutations were ASXL1 (66%), SRSF2 (37%), TET2 (36%), RUNX1 (29%), IDH2 (21%), BCOR (20%) and U2AF1 (16%) while least common were TP53, SETBP and ZRSR2 (1% each). Neither number (p= .08) nor type of co-mutation correlated with MN classification. There was no difference in the co-mutational pattern between tMN and dnMN pts. Survival : median overall survival (mOS) was 16.3 months with a median follow up time of 24.5 months. Pts who received HCT had better OS compared to non-HCT pts (mOS not reached vs. 14.9 months, p= .003). Pts with an isolated m STAG2 had better OS than co-mutated pts (p= .04), while the type of STAG2 mutation did not affect OS (p= .3). Pts with tMN had worse OS than dnMN pts (9.9 vs. 20.4 months, p= .02). VAF ≥75% had a negative impact on OS (20.5 vs 8.1 months, p= .008). mOS did not differ based on MN diagnosis. On multivariate analysis, only HCT (HR 0.3, p= .01) and VAF ≥75% (HR 2.3, p= .02) had impact on OS. Conclusions: mSTAG2 was more common in elderly males and MDS diagnosis. mSTAG2 was uncommon as an isolated mutation, indicating a possible role in disease progression with preferred certain co-mutations ( ASXL1/SRSF2/RUNX1/IDH2). mOS was poor regardless of MN diagnosis indicating a molecularly driven significance of an aggressive disease. The study needs to be validated by larger studies.

e19010 Background: Mutated DEAD-box helicase 41 (m DDX41), and mutated GATA2 are germline mutations associated with familial predisposition syndromes. In this study, we compare the clinical characteristics and survival outcomes (OS) of m DDX41 and m GATA2 MN patients (pts). Methods: We retrospectively screened pts who had next-generation sequencing (NGS) (OncoHeme panel) performed at Mayo Clinic. 4,524 consecutive pts (2018-2021) were screened for DDX41 mutations and 3,872 for GATA2 mutations (2015-2020) and included 36 MN pts with m DDX41 genetic alterations, and 55 m GATA2 MN pts. m GATA2 cases were included at NGS date while m DDX41 were included at diagnosis date. Germline workup was not done in all cases. JMP 16.2.0 Software was used for statistical analysis. Results: Patient characteristics: The most common diagnosis was MDS (N = 22, 61% in m DDX41 N = 17, 31% in m GATA2 group; p = .0044). MDS/MPN overlap was seen in m GATA2 group only; (29% vs. 0%; p = .0004). Majority of pts were males with median age of 68 and 67 years for m DDX41 and m GATA2 pts; respectively (p = .7). m DDX41 pts had higher hemoglobin, platelets, and MCV (< .0001, 0.005, < .0001; respectively) and significantly lower white blood cells (WBC) count compared to m GATA2 pts (< .0001). All m DDX41-AML pts were (ELN) intermediate-risk, and 64% of m DDX41 MDS were intermediate risk (IPSS-R). In contrast, of m GATA2 pts 62% of AML were adverse risk and 44% of MDS very high risk. Majority of m DDX41 pts had normal karyotype (N = 32; 91% vs. N = 19, 37%; p < .0001), had isolated mutations (N = 23; 64%) and the most common co-mutations were DNMT3A (38%), ASXL1 (30%), JAK2 (23%). The majority of m GATA2 pts were co-mutated (96%) with a different co-mutation pattern ASXL1 (60%), SRSF2 (34%), RUNX1 (19%). Germline data: One m GATA2 pts had proven germline mutation, and 10/11 (91%) m DDX41 pts were confirmed Survival and progression in MDS/AML: After median follow-up of 30 months in MDS/AML, 7 (21%) m DDX41 and 23 (77%) m GATA2 pts died with superior OS in m DDX41 compared to m GATA2 pts with median OS of (136.7 vs. 6.8 months, p < .0001). Seven (31%) of 22 m DDX41 and 6 (35%) m GATA2 MDS pts progressed into AML with a median time to progression of (11.2 vs. 5.2 months, p = .045). The leukemia free survival (LFS) for m DDX41 MDS pts was significantly longer than LFS of m GATA2 MDS pts (24.4 vs. 6 months, p < .0001). Conclusions: We compare the outcomes of two unique mutations associated with germline predisposition. We found m DDX41 pts had fewer cytogenetic aberrations, no MDS/MPN overlap, and lower WBC count. Majority of m DDX41 MDS/AML pts were intermediate risk category, compared to predominance of adverse risk disease in m GATA2 pts, translating into better OS and LFS. This study is limited by the small size, lack of germline workup in all cases, and retrospective nature. However, it supports the favorable prognosis and indolent course of m DDX41 pts recently described.

TPS7080 Background: Myelodysplastic syndrome/myeloproliferative neoplasms (MDS/MPN) are classified as a distinct category under the World Health Organization (WHO) classification of myeloid neoplasms. MDS/MPN with RS and thrombocytosis (MDS/MPN-RS-T) and MDS/MPN, unclassifiable with > 15% bone marrow ring sideroblasts (MDS/MPN-U-RS) have similar clinical and pathological characteristics with symptomatic or transfusion-dependent anemia as the predominant morbidity. Luspatercept has been approved in myelodysplastic syndromes with ring sideroblasts (MDS-RS) and MDS/MPN overlap syndromes, based on the phase 3 MEDALIST clinical trial which primarily included MDS-RS patients with an objective erythroid response rate of approximately 40 per cent. In this trial, some MDS-RS patients also experienced an increase in neutrophil and platelet counts. This raises a safety concern for MDS/MPN patients with elevated platelet or WBC counts such as MDS/MPN-RS-T and MDS/MPN-U-RS. Previous studies have shown clinical and biological differences between MDS-RS and MDS/MPN-RS-T, with the latter group at a significantly elevated risk for thrombotic events. Additionally, several MDS/MPN-RS-T patients are on hydroxyurea which may blunt the erythroid response of luspatercept. Therefore, it is imperative to establish the safety and efficacy of luspatercept in this patient group. Methods: This is an investigator-initiated, prospective, phase II study of luspatercept in MDS/MPN overlap neoplasms with ring sideroblasts and thrombocytosis or unclassifiable with ring sideroblasts with 2 arms; hydroxyurea-independent (cohort A) and hydroxyurea-dependent (cohort B). Hydroxyurea and/or aspirin use is allowed as per investigator discretion. The primary goal is to study the efficacy and safety of luspatercept in MDS/MPN-RS-T or MDS/MPN-U-RS with symptomatic anemia. The primary endpoint is to assess erythroid response rate as per the 2015 International Working Group MDS/MPN response criteria. Secondary endpoints include response duration, time to acute myeloid leukemia (AML) transformation, thrombosis rate, AML-free and overall survival. Inclusion criteria include newly diagnosed or relapsed/refractory adult patients with WHO-defined diagnosis of MDS/MPN-RS-T or MDS/MPN-U-RS with symptomatic or transfusion-dependent anemia and unlikely to respond (EPO level > 200 IU/L) or intolerant to erythropoiesis stimulating agent (ESA) therapy. Prior therapy with lenalidomide, hypomethylating agents or immunosuppressive therapy is allowed. The overall plan is to enroll 54 patients across the three Mayo Clinic sites, Minnesota, Arizona and Florida. Enrollment to the trial began in January 2022 with 1 patient enrolled at the time of abstract submission. Clinical trial information: NCT05005182.

TPS7070 Background: Outcomes of adults with relapsed/refractory T-cell acute lymphoblastic leukemia (T-ALL) and acute myeloid leukemia (AML) have remained poor. CD38 is a transmembrane glycoprotein with several important functions including its role in immune escape of tumor cells [Chillemi A et al. Front Immunol 2017, Furano A et al. J Immunol 1990]. Several studies have demonstrated that CD38 is expressed in T-ALL and AML and is targetable with CD38 blocking agents [Naik J et al. Haematologica 2019, Bride KL et al. Blood 2018, Tembhare et al. J Immunother Cancer 2020]. XmAb18968 is a novel CD38-CD3 bi-specific T-cell engager with Fc domain modified to minimize Fcγ receptor binding and non-selective T-cell activation resulting in reduced cytokine release without compromising target cell killing. We hypothesize that targeting CD38 in relapsed/refractory T-ALL and AML would be safe and feasible using XmAb18968. Methods: This is an investigator-sponsored multi-institutional phase I study evaluating the safety and tolerability of XmAb18968. Patients aged 18 years or above with relapsed/refractory T-ALL or AML (including measurable residual disease relapse), CD38 expression ≥ 20% by flow cytometry, and adequate organ function will be eligible. Major exclusion criteria are hematopoietic cell transplantation within 6 months of enrollment, active acute graft-versus-host disease, and acute promyelocytic leukemia. The primary objective is to determine the recommended phase 2 dose (RP2D) and toxicity profile of XmAb18968. The secondary objectives include determination of response rates, duration of response, survival and pharmacokinetics. Exploratory objectives include correlation of responses with genomic profile, characterizing changes in serum cytokines and phenotypic expression of activated T-cells and leukemic cells, correlation of the phenotypic expression with changes in the transcriptome at the single-cell level, proteomics evaluation of cytokine secretion at the single-cell level and correlation of response with N-glycan profiling, quantitative site-occupancy and direct glycopeptide analysis. The study will follow 3+3 design. Dose escalation will proceed in two separate groups: Group A for subjects with T-ALL and Group B for subjects with AML. Patients will be entered sequentially to each dose level [0.8mg cohort, 1mg cohort, 1.3mg cohort, 1.5mg cohort). The observation period for dose-escalation will be 28-days. RP2D will be defined as the highest dose level at which none of the 3 treated subjects, or no more than 1 of the 6 treated subjects’ experiences a dose limiting toxicity. A minimum of 24 and a maximum of 60 patients will be enrolled. The study is being conducted at 6 sites in United States and is currently open for enrollment. Clinical trial information: NCT05038644.