Ziftomenib - a potent, selective, oral menin inhibitor - is approved as monotherapy for adults with relapsed/refractory (R/R) NPM1-mutated acute myeloid leukemia (NPM1-m AML). The KOMET-007 phase 1 trial investigated clinical activity and tolerability of ziftomenib in combination with standard therapies for R/R and newly diagnosed AML. Here, we report outcomes of adults with R/R NPM1-m AML treated with ziftomenib plus venetoclax/azacitidine. In phase 1a, patients received ziftomenib 200, 400, or 600 mg once daily with standard doses of venetoclax/azacitidine. In phase 1b, ziftomenib 600 mg was selected for expansion. Sixty-seven patients were treated (27 phase 1a; 40 phase 1b). Median age was 66 years, and 55% were men. Median number of prior therapies was 1 (range 1-8); 55% received prior venetoclax and 22% had prior transplantation. Most common (≥20%) grade ≥3 treatment-emergent adverse events were leukopenia (34%), thrombocytopenia (28%), febrile neutropenia and neutropenia (25% each). Six patients developed QTc prolongation (1 ziftomenib-related; grade 1), and 2 experienced differentiation syndrome (grade 3); all events were successfully managed. In patients receiving ziftomenib 600 mg, composite complete remission (CRc) rate was 46% (22/48), with 67% (12/18) achieving central measurable residual disease (MRD) negativity (<0.01% threshold). In venetoclax-naïve and -exposed patients, CRc rates were 70% (16/23) and 24% (6/25), with MRD-negativity rates of 75% (9/12) and 50% (3/6), respectively. Median duration of response was 8.6 months, and median overall survival was not reached. The combination of ziftomenib 600 mg with venetoclax/azacitidine was well tolerated with deep and durable clinical activity in R/R NPM1-m AML. This trial was registered at www.ClinicalTrials.gov as #NCT05735184.

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

To examine activity of ibrutinib in steroid-refractory chronic GVHD (SR-cGVHD) after FDA approval, we conducted a multicenter retrospective study. Data were standardly collected (N=270 from 19 centers). Involved organs included skin (75%), eye (61%), mouth (54%), joint/fascia (47%), GI (26%), lung (27%), liver (19%), genital (7%), other (4.4%). NIH severity was mild in 5.7%, moderate 42%, severe 53%. 39% had overlap subtype. KPS was ≥ 80% in 72%. Median prednisone (mg/kg) was 0.21 (0-2.27). Ibrutinib was started at median of 18.2 months after cGVHD onset and in earlier lines of therapy (2nd line: 26%, 3rd: 30%, 4th: 21%, 5th: 9.6%, 6th: 10%, 7th or higher: 1.2%)). Among evaluable subjects, the 6 month NIH overall response rate (CR/PR) was 45% (PR 42%, CR 3%). Median duration of response was 15 months (range 1-46). Liver involvement had association with 6 month ORR (multivariate (MVA) OR 5.49 (95% CI 2.3-14.2, p <0.001). Best overall response was 56%, with most (86%) achieving by 1-3 months. With median follow up for survivors of 30.5 months, FFS was 59% (53-65%) at 6 months and 41% (36-48%) at 12 months. On MVA, increased age (HR 1.01, 95% CI 1.0-1.02, p=0.033), higher baseline prednisone (HR 1.92, 1.09-3.38, p=0.032), and lung involvement (HR 1.58, 1.1-2.28, p=0.016) had worse FFS. Ibrutinib discontinuation was most commonly due to progressive cGVHD (44%) or toxicity (42%). These data support that ibrutinib has activity in SR-cGVHD, provide new insight into factors associated with response and FFS, and demonstrate the toxicity profile associated with discontinuation.

Background: PIM1 is overexpressed in hematologic malignancies, including myelofibrosis (MF), contributing to disease progression by modulating cytokine-driven pathways such as PI3K/AKT and JAK/STAT. Elevated pro-inflammatory cytokines are a hallmark of MF and are closely linked to symptom burden and poor prognosis. Preclinically, PIM1 knockout was shown to prevent MF progression without affecting the platelet (PLT) counts, whereas pan-PIM knockout caused thrombocytopenia (TCP). Nuvisertib (TP-3654), an oral, investigational, highly selective PIM1 kinase inhibitor, alone or in combination with JAK inhibitor ruxolitinib has demonstrated reduction in spleen size, bone marrow (BM) fibrosis, and expression of cytokine response genes in JAK2V617F and MPLW515L MF mouse models. Methods: The ongoing global phase 1/2 study evaluates the safety and efficacy of nuvisertib monotherapy in patients (pts) with MF (NCT04176198, Arm 1). Study population includes primary or secondary MF, previously treated with or ineligible for JAK inhibitor, DIPSS intermediate or high-risk MF, PLT ≥25 x 109/L, splenomegaly (≥450 cm3 by imaging), and ≥2 measurable symptoms per MFSAF v4. The study aims to identify the RP2D of nuvisertib monotherapy and assess the safety, clinical activity (spleen volume reduction [SVR], total symptom score [TSS] improvement), and PK and PD markers (cytokine, BM fibrosis etc.). Results: As of 29 May 2025, total 77 pts enrolled in 5 dose levels of nuvisertib from 480 mg QD to 720 mg BID. At baseline, median age 71 years (49, 85); spleen volume 1988 cm3 (270, 7718); TSS 23 (4, 62); hemoglobin (Hgb) 9.7 g/dL (5.6, 17.2; 52% pts were <10 g/dL; 39% pts required transfusion); PLT 96 x 109/L (24, 816; 51% pts were <100 x 109/L). 75% pts were DIPSS Int-2 or high risk; 41% pts had high molecular risk mutation; and 30% pts received ≥2 prior JAK inhibitors. Median nuvisertib treatment duration was 22 weeks (2, 197), and 16 (21%) pts on active treatment. No DLT occurred. Treatment-related adverse events (TRAEs) occurring in ≥20% of pts were primarily grade 1/2 diarrhea, nausea, and vomiting. Grade ≥3 TRAE occurring in ≥3 pts included TCP (n=8, 7 of 8 pts had baseline TCP). Mean Hgb and PLT remained stable throughout the 24-week treatment. In pts treated with 720 mg BID dose for ≥12 weeks, ≥25% SVR was observed in 4 of 20 pts (20% SVR25 response) and ≥50% reduction in TSS in 9 of 20 pts (44% TSS50 response) at any time. Absolute improvement in symptoms was seen across all 7 parameters. A strong correlation (p<0.001) between cytokine modulation (e.g. ↓ENRAGE, ↓MIP1β, ↓PAI-1, ↓IL-1Ra, and ↑adiponectin) and SVR25, TSS50, and individual symptom improvement were observed. In pts with baseline Hgb <10 g/dL, 6 of 26 (23%) pts showed Hgb response [mean ≥1.0 g/dL Hgb increase for ≥12 weeks without transfusion, including 3 pts with ≥1.5 g/dL Hgb increase]. Hgb responses were also observed in pts with baseline Hgb >10 g/dL. In pts with baseline PLT <100 × 109/L, 8 of 30 (26.7%) pts showed PLT response [≥30×109/L increase maintained ≥4 weeks], and PLT recovered to ≥100 × 109/L in all responders. Modulation of circulating biomarkers was observed in PLT responder pts including increased TN-C, a protein reported to be involved with PLT recovery, and decreased VCAM-1, a marker involved in PLT endothelial cell adhesion and chronic inflammation. 13 of 34 (38.2%) evaluable pts (assessments at baseline and every 24 weeks) showed ≥1 grade reduction in BM fibrosis which correlated with cytokine reduction (e.g. ↓MIP1β, ↓TNFR1); and 11 of 13 pts also showed at least one of SVR25, TSS50, Hgb or PLT responses (5 pts showed dual Hgb and PLT responses). The 1-year overall survival rate following nuvisertib treatment in this heavily pretreated pts with relapsed/refractory (R/R) MF was 81% which also correlated with cytokine modulation (e.g. ↓MIP1β, ↓TNFR1, and ↑FVII). Conclusions: Nuvisertib monotherapy appeared well tolerated with no DLTs. Preliminary data in pts with R/R MF showed that nuvisertib treatment leads to significant modulation of cytokine profiles, demonstrating a strong correlation with clinical responses, including SVR25 and TSS50 responses, and improvements in Hgb, PLT and BM fibrosis, suggesting that selective PIM1 inhibition may offer disease-modification with limited hematologic toxicity. Emerging data supports ongoing clinical development of nuvisertib in combination with ruxolitinib and momelotinib (NCT04176198, Arms 2 and 3, respectively).

Background: FLT3 mutations occur in 25-35% of patients with AML and are associated with poor prognosis. FLT3 mutations are most frequently the result of an internal tandem duplication (ITD) of amino acids in the juxtamembrane region of FLT3 or point mutations in the tyrosine kinase domain (TKD). FLT3-ITD mutations are associated with increased incidence of relapse, shorter duration of remission, and decreased disease-free and overall survival. BMF-500 is a novel orally bioavailable, highly potent and selective covalent inhibitor of FLT3 including wildtype (WT), ITD, TKD, as well as a variety of additional resistance-conferring mutations such as the gatekeeper F691. BMF-500 has demonstrated high affinity for FLT3, lack of cKIT inhibition, and sustained cell-killing capacity despite drug washout (Law et al., ASH 2022 Abstract 2756). BMF-500 has shown sustained tumor regression and improved survival in both subcutaneous and disseminated xenograft models of mutant FLT3-driven AML. Study Design: COVALENT-103 (NCT05918692) is an open-label, non-randomized, multicenter, first-in-human Phase I study evaluating the safety, tolerability, and clinical activity of escalating doses of twice daily oral BMF-500 in patients with relapsed or refractory (R/R) AL, including AML, ALL, or MPAL, with or without FLT3 mutations. The trial has 2 arms that will undergo dose escalation in parallel: Arm A (without) and Arm B (with) concomitant use of a moderate or strong CYP3A4 inhibitor. Utilizing an accelerated titration design (ATD), doses of BMF-500 will be escalated in single-subject cohorts until 1 subject experiences either a Grade 2 or higher related-adverse event or dose-limiting toxicity (DLT). At that point, the cohort will switch to a classical “3 +3” design. Patients with WT FLT3 AL may be enrolled, up to a limit of 33% per arm. Treatment will continue in 28-day cycles until progression or intolerability. Expansion cohorts will enroll additional patients to obtain further safety and efficacy data. Patients must be refractory, relapsed or must have progressed on or following discontinuation of the most recent anti-cancer therapy or be ineligible for any approved standard of care therapies, including HSCT. Participants with FLT3-mutant AML must have received treatment with a FLT3 inhibitor approved for treatment of relapsed or refractory FLT3-mutant AML. Key inclusion criteria include ECOG PS ≤ 2, adequate organ function, and documented FLT3 mutation status. Key exclusion criteria include known CNS disease involvement, clinically significant cardiovascular disease, and WBC count >50,000/µL (uncontrollable with cytoreductive therapy). Objectives: The primary objective of the study is to evaluate safety and tolerability and to determine the optimal biological dose (OBD)/ recommended Phase 2 dose (RP2D) of BMF-500 oral monotherapy based on evaluation of available PK/ PD, safety and efficacy data. Secondary objectives include characterization of the pharmacodynamics and pharmacokinetics of BMF-500, and assessment of its antitumor activity per modified Cheson (2003) criteria or the NCCN Clinical Practice Guidelines (ALL Version 1.2022) as determined by the investigator. Endpoints include best overall response rate (ORR), complete remission (CRc), duration of response (DOR), relapse-free survival (RFS) and overall survival (OS). The study was initiated in July 2023 and will enroll ~110 participants at approximately 30 sites.

Background: Nucleophosmin 1 (NPM1) mutations and lysine methyltransferase 2A (KMT2A) rearrangements drive leukemogenesis in approximately 35-40% of acute myeloid leukemias (AML). Ziftomenib, a potent selective menin inhibitor, has shown clinical activity as monotherapy in adults with relapsed/refractory (R/R) NPM1-mutated (NPM1-m) or KMT2A-rearranged (KMT2A-r) AML. KOMET-007 is an ongoing, open-label, dose-escalation (phase 1a) and expansion (phase 1b) study of ziftomenib in combination with standard chemotherapies in newly diagnosed (ND) and R/R NPM1-m or KMT2A-r AML (NCT05735184). Here we report interim results from phase 1a in patients (pts) with ND AML. Methods: Adults (age ≥18 years) with ND, high-risk NPM1-m or KMT2A-r AML were enrolled into separate dose-escalation cohorts for each genotype. High-risk disease was defined as adverse-risk cytogenetics per ELN criteria, age ≥60 years, or treatment-related AML regardless of age. Following a rule-based approach, at least six dose-limiting toxicity (DLT) evaluable pts were assigned to each cohort where ziftomenib (200, 400, or 600 mg once daily) was escalated with standard doses of cytarabine and daunorubicin (7+3). Ziftomenib was administered orally from Cycle 1 Day 8 and continuously thereafter (through induction, consolidation and continued therapy including post-transplant). Primary endpoints in phase 1a were DLTs and adverse events (AEs); key secondary endpoints included composite complete remission (CRc; defined as complete remission [CR] or CR with partial or incomplete hematological recovery) and minimal residual disease (MRD). Here we present results for the first 34 pts with ND AML (ziftomenib 200 mg, n=18; 400 mg, n=16). Enrollment in the 600 mg cohort is ongoing. Results: As of the June 21, 2024 data cutoff, median age was 58 (range 28-74) years and 62% were female; 44% (15/34) had NPM1-m (high-risk only) and 56% (19/34) had KMT2A-r. At 200 mg and 400 mg, respectively, median follow-up was 33 and 18 weeks for ND pts with NPM1-m, and 22 and 12 weeks for those with KMT2A-r. The most common (≥20% of pts) grade ≥3 treatment-emergent AEs (TEAEs) were febrile neutropenia (56%), decreased platelet count (47%), decreased neutrophil count (38%), anemia (32%) and decreased white blood cell count (29%). Nine pts (26%) had grade ≥3 ziftomenib- or backbone-related AEs, including decreased platelet count (18%), decreased neutrophil count (15%) and anemia (9%). During continuous ziftomenib administration, in NPM1-m pts without persistent AML at end of Cycle 1, median time to neutrophil recovery (ANC ≥1K) was 33 and 28 days at 200 mg and 400 mg, respectively, and 33 and 26 days to platelet recovery (≥100K); in KMT2A-r pts, median time to neutrophil recovery was 31 and 24 days, and 28.5 and 28.5 days to platelet recovery. There were no cases of differentiation syndrome (DS), ziftomenib-associated QTc prolongation or DLTs with the 200 mg or 400 mg dose levels. Thirty-three pts (15 with NPM1-m; 18 with KMT2A-r) had ≥1 response assessment as of the data cutoff. For NPM1-m pts, CRc rates were 100% (8/8) at 200 mg and 86% (6/7) at 400 mg, with MRD negativity among tested responders of 100% (8/8) and 80% (4/5), respectively. For KMT2A-r pts, CRc rates were 90% (9/10) at 200 mg and 63% (5/8) at 400 mg, with MRD negativity among tested responders of 83% (5/6) and 100% (3/3), respectively. The study is ongoing, with 100% (15/15) of ND NPM1-m pts (200 mg, n=8; 400 mg, n=7) and 84% (16/19) of ND KMT2A-r pts (200 mg, n=7; 400 mg, n=9) remaining on study. Conclusion: In the ongoing KOMET-007 study, ziftomenib combined with 7+3 was well tolerated, with a consistent safety profile across dose levels, and continued to demonstrate evidence of robust clinical activity in ND pts. No DLTs or events of ziftomenib-induced QTc prolongation were reported, and rates of ziftomenib-related cytopenias were low, with no additional myelosuppression observed with the combination. Additionally, no DS events were reported at 200 mg or 400 mg, including among KMT2A-r pts, suggesting that ziftomenib can be safely combined with induction chemotherapy. In response-evaluable ND pts, CRc rate at both dose levels was 93% (14/15) for NPM1-m and 78% (14/18) for KMT2A-r. Taken together, these data support the advancement of ziftomenib in combination with intensive chemotherapy. Updated results will be presented, as data from the 400 mg cohorts continue to mature and 600 mg cohorts are enrolling.

The treatment setting influences acute myeloid leukemia (AML) outcomes. Most cancer patients receive care in the community, yet few studies have evaluated the effectiveness of clinical programs outside of academic or National Cancer Institute (NCI)-designated cancer centers. This was a multi-level, case-controlled study of real-world outcomes for initial AML treatment in a community-based network for 1,391 patients with AML between 2011 and 2018. We benchmarked survival within our network against the Surveillance, Epidemiology, and End Results (SEER) database. Coarsened exact matching was performed against 17,186 chemotherapy-treated patients in the SEER database. Cox proportional and accelerated failure time multivariable modeling were performed to identify patient, disease, therapy and center characteristics associated with the risk of AML mortality. Within the network, 799 patients were treated at six specialized blood cancer centers and 592 at 63 other hospitals. Patients receiving high-intensity induction at specialized centers had improved median survivals of 31 months versus 18 months [P<0.001] at non-specialized centers. Median survivals were 13 for non-specialized centers versus 10 months for SEER [P<0.001], and 18 for the entire network versus 10 months for SEER [P<0.001]. Multivariable modeling showed significant impacts from age (HR = 1.025), high-intensity induction therapy (HR= .695), diagnosis year (HR= .937), neighborhood income (HR = .997; P<0.01), higher acuity (HR = 1.002) and Charlson comorbidity score (HR = 1.117). AML treatment may be effectively delivered in the community hospital setting, with specialized centers producing better outcomes for higher intensity treatments.

Introduction PF-08046040 (SEA-CD70) is a humanized, nonfucosylated, CD70-directed IgG1 monoclonal antibody (Ab) with enhanced effector functions under development for treatment of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). CD70 is expressed on myeloid blasts in myeloid malignancies and is a potential target. SEA-CD70's proposed mechanisms of action include eliminating CD70+ cells via enhanced Ab-dependent cellular cytotoxicity, Ab-dependent cellular phagocytosis, and mediation of complement-dependent cytotoxicity. It also blocks interaction of CD70 with CD27, whose signal promotes stemness and proliferation of leukemic blasts. Preclinical studies showed additive activity of SEA-CD70 in combination with azacitidine (AZA), which is known to increase CD70 expression. The study's aim is to evaluate the safety, tolerability, pharmacokinetics, and antitumor activity of SEA-CD70 monotherapy and SEA-CD70 + AZA in patients (pts) with MDS. Methods This is a 6-part, Phase 1, open-label, multicenter, dose-finding and dose expansion study (NCT04227847). Here, we report findings in pts with previously untreated higher-risk (HR) MDS in Part D (dose optimization for combination of SEA-CD70 + AZA). Eligible pts were aged ≥18 years with treatment-naïve HR-MDS (Intermediate-2 or High risk per International Prognostic Scoring System [IPSS]), increased blasts (5-19%), and Eastern Cooperative Oncology Group performance status (ECOG PS) of ≤2. Pts were also categorized by revised IPSS (IPSS-R; Moderate High, High, or Very High). Pts received intravenous (IV) SEA-CD70 at 10 mg/kg or 20 mg/kg on D1 and D15 and subcutaneous/IV AZA 75 mg/m2 on D1-D7 of 28-day cycles. Results At data cutoff, June 9, 2024, 35 pts were enrolled, and 32 received ≥1 dose of SEA-CD70 (10 mg/kg, n = 14; 20 mg/kg, n = 18) + AZA. Median age was 72 y (range, 60-82). At baseline, most pts had an ECOG PS of 0-1 (84%) and High or Very High IPSS-R category (78%). Total median duration of SEA-CD70 + AZA treatment was 9.6 wks (range, 2-80); 44% of pts were receiving treatment at data cut-off. Most common (≥25%) treatment-emergent adverse events (TEAEs) were constipation (50%), diarrhea (31%), fatigue (25%), and thrombocytopenia (25%); infusion related reactions occurred in 16% of pts. Most common Grade ≥3 TEAEs were anemia, neutropenia, and thrombocytopenia (19% each). Most common reasons for permanent treatment discontinuation were progressive disease (20%), patient decision (14%), and AE (11%). For pharmacokinetics, SEA-CD70 plasma concentrations increased dose proportionally from 10 mg/kg to 20 mg/kg. There were 25 efficacy evaluable pts (10 mg/kg, n = 12; 20 mg/kg, n = 13). Objective response rate, defined by a modified 2006 International Working Group response criteria as the proportion of pts who achieved a best response of complete remission (CR), CR with partial hematologic recovery (CRh), or partial remission, was 42% (95% CI 15.2-72.3) for 10 mg/kg, 46% (95% CI 19.2-74.9) for 20 mg/kg, and 44% (95% CI, 24.4-65.1) overall. Blast clearance rate, defined as the proportion of pts who achieved a best response of CR, CRh or marrow CR, was 58% (95% CI 27.7-84.8) for 10 mg/kg, 54% (95% CI 25.1-80.8) for 20 mg/kg and 56% (95% CI, 34.9-75.6) overall. For the responders, median time to response (TTR) was 3.7 mo (range 1.6-3.8) for 10 mg/kg, 1.6 mo (range 0.7-1.7) for 20 mg/kg and 1.6 mo (range, 0.7-3.8) overall. Across both dose cohorts, median duration of response (DOR) was 13.6 mo (95% CI, 3.7-NE), median event-free survival (EFS) was 8.1 mo (95% CI, 2.1-NE), and median overall survival (OS) was 19.6 mo (95% CI, 8.1-NE). Of note, at data cut-off, OS/EFS/DOR data are not mature. The rate of conversion to transfusion independence was 36% (95% CI, 18.0-57.5), and the rate of transfusion independence maintenance was 28% (95% CI, 12.1-49.4). Following treatment, 5 (16%) pts received stem cell transplant; 3 immediately after and 2 pts received intervening anticancer therapy. Conclusion s SEA-CD70 appears to be well tolerated at 10 mg/kg and 20 mg/kg in combination with AZA. Overall, AEs were manageable, and there were no treatment-related or treatment-emergent dose reductions. Preliminary efficacy was observed for pts with HR-MDS, with 16% of pts subsequently receiving transplant for both 10 mg/kg and 20 mg/kg dose cohorts. Results support the continued development of SEA-CD70 + AZA for pts with myeloid malignancies.

Ibrutinib has been studied in steroid-refractory chronic graft vs. host disease (SR-cGVHD), yet the phase II trial that led to FDA approval contained 42 subjects, had restricted organ involvement, and median 2 prior lines of therapy. To expand on this evidence base, we conducted a multi-center real-world study.Eligible subjects had SR-cGVHD, did not have relapsed malignancy post-transplant, and were treated with ibrutinib after the FDA approval date (8/2017 onward). No other restrictions were placed for cGVHD organ sites/features, or prior lines of cGVHD therapy. The NIH 2014 Consensus Response Measures were used to compute responses using serial cGVHD organ scores. Time-to-event outcomes were assessed from ibrutinib start date. Failure-free survival (FFS) was a composite outcome including death, relapse, or new line of cGVHD therapy.270 subjects from 19 centers were studied. Median age was 57 (range 4-77). The majority had previously received PBSC grafts with non-PTCY GVHD prophylaxis. Involved organs at ibrutinib start included skin (59%), eye (50%), mouth (45%), joint/fascia (40%), GI (24%), lung (22%), liver (15%), genital (6.3%), other (4.4%). Overall NIH severity was mild in 5.7%, moderate 42%, severe 53%. 61% had overlap subtype. KPS was ≥ 80% in 79% of subjects. Median prednisone (mg/kg) was 0.21 (0-2.27). Ibrutinib was started at median of 18.2 months after cGVHD onset most commonly at 420mg dose (66% of subjects; reductions in others for drug interaction or clinician discretion) and largely in earlier lines of therapy (2nd line: 26%, 3rd: 30%, 4th: 21%, 5th: 9.6%, 6th/beyond: remainder).Among evaluable subjects, the 6 month overall response rate (CR/PR) was 45% (PR 42%, CR 3%), with others having lack of response (unchanged/mixed/progression). Median duration of response was 13 months (range 1-46). Most cGVHD features (overlap status, PLT, KPS, prednisone dose, NIH overall severity, time from cGVHD, prior lines of therapy) did not have significant association with 6 month CR/PR, except liver involvement (multivariate (MVA) OR 5.49 (95% CI 2.3-14.2, p <0.001) had greater response. The best overall response (CR/PR) was 56%, with the majority (86%) achieving best response by 1-3 months after start. With median follow up time for survivors of 30.5 months, FFS was 59% (53-65%) at 6 months and 41% (36-48%) at 12 months (Fig 1). On final MVA, increased age (HR 1.01, 95% CI 1.0-1.02, p=0.033), higher baseline prednisone dose (HR 1.92, 1.09-3.38, p=0.032), and lung involvement (HR 1.58, 1.1-2.28, p=0.016) were associated with worse FFS. OS at 6 and 12 months was 93% (90-97%) and 87% (83-91%), respectively. Toxicities (hold/stop ibrutinib) are in Fig 2-3).These multicenter real-world data support that ibrutinib has activity in SR-cGVHD, provide new insight into factors associated with response and FFS, and demonstrate the toxicity profile associated with dose reduction or discontinuation.

Background: In approximately 35-40% of acute myeloid leukemia (AML) cases, leukemogenesis is driven by nucleophosmin 1 (NPM1) mutations or rearrangements in lysine methyltransferase 2A (KMT2A). Ziftomenib, a potent selective menin inhibitor, has shown clinical activity as monotherapy in adult relapsed/refractory (R/R) NPM1-mutated (NPM1-m) or KMT2A-rearranged (KMT2A-r) AML. KOMET-007, an ongoing, open-label, dose escalation (phase 1a) and expansion (phase 1b) study, aims to evaluate ziftomenib in combination with standard chemotherapies in adults with newly diagnosed and R/R NPM1-m or KMT2A-r AML (NCT05735184). Here we report interim results from phase 1a in patients with R/R AML. Methods: Adults (age ≥18 years) with R/R NPM1-m or KMT2A-r AML were enrolled into separate dose escalation cohorts for each genotype. Following a rule-based approach, at least six dose-limiting toxicity (DLT)-evaluable patients were assigned to each cohort where ziftomenib (200, 400, or 600 mg, once daily) was escalated with standard doses of venetoclax and azacitidine (Ven/Aza). Ziftomenib was administered orally from Cycle 1 Day 8 and continuously thereafter. Primary endpoints in phase 1a were DLTs and adverse events (AEs); key secondary endpoints included composite complete remission rates (CRc; defined as complete remission [CR] or CR with partial or incomplete hematological recovery). Here we present data for the first 34 patients (pts) treated in the R/R cohorts (ziftomenib 200 mg, n=18; 400 mg, n=16). Enrollment in the 600 mg cohort is ongoing. Results: As of the June 21, 2024 data cutoff, median age was 56 (range 23-86) years, and 50% were female; 41% (14/34) had NPM1-m and 59% (20/34) had KMT2A-r. Median follow-up was 35 and 14 weeks at 200 mg and 400 mg, respectively, for R/R pts with NPM1-m; and 15 and 14 weeks for those with KMT2A-r. Median number of prior therapies was 2 (range 1-8); 32% (11/34) had prior transplant; and 74% (25/34) were menin inhibitor-naive, including 68% (17/25) who had prior Ven exposure. No DLTs or ziftomenib-induced QTc prolongation were reported. The most common (≥20% of patients) grade (Gr) ≥3 treatment-emergent AEs (TEAEs) were febrile neutropenia (35%), decreased platelet count (35%), anemia (26%), decreased neutrophil count (24%), and pneumonia (24%). Gr≥3 ziftomenib- and/or backbone-related AEs occurred in 44% of patients, including decreased platelet count (18%), decreased neutrophil count (15%), and anemia (12%). On-target differentiation syndrome (DS) occurred in 12% (4/34) of R/R patients (1 NPM1-m [400 mg, Gr3] and 3 KMT2A-r [200 mg, 1-Gr3; 400 mg, 1-Gr2 and 1-Gr3]), and all cases were manageable per the DS guidance. Twenty-four menin inhibitor-naive patients (NPM1-m, n=11; KMT2A-r, n=13) had ≥1 response assessment as of the data cutoff. Among R/R NPM1-m patients, the overall response rate (ORR) was 100% (5/5) at 200 mg and 67% (4/6) at 400 mg; CRc rates were 80% (4/5) at 200 mg and 50% (3/6) at 400 mg. In NPM1-m patients who received prior Ven, ORR was 100% (3/3) at 200 mg and 50% (2/4) at 400 mg. For R/R KMT2A-r patients, ORR was 43% (3/7) at 200 mg and 33% (2/6) at 400 mg; CRc rates were 29% (2/7) at 200 mg and 17% (1/6) at 400 mg. In KMT2A-r patients who received prior Ven, ORR was 40% (2/5) at 200 mg and 25% (1/4) at 400 mg. The study is ongoing, with 50% (7/14) of R/R NPM1-m patients (200 mg, n=4; 400 mg, n=3) and 30% (6/20) of R/R KMT2A-r patients (200 mg, n=3; 400 mg, n=3) remaining on study. Conclusion: In the ongoing KOMET-007 study, ziftomenib combined with Ven/Aza was well tolerated at the dose levels tested to date and continued to demonstrate promising clinical activity in R/R pts. No DLTs or ziftomenib-induced QTc prolongation were reported. On-target DS occurred in 12%, including in 3 of 20 KMT2A-r patients, and all patients had resolution of DS with appropriate management. In response-evaluable, menin inhibitor-naive R/R patients, CRc rates were 80% at 200 mg and 50% at 400 mg for NPM1-m AML; and 29% and 17% for KMT2A-r AML, respectively. Clinical activity was also demonstrated in previously Ven-exposed NPM1-m and KMT2A-r patients. Based on these encouraging initial results, a dose expansion phase evaluating this triplet combination in newly diagnosed and R/R NPM1-m and KMT2A-r AML patients is underway. Updated results will be presented, as data from the 400 mg cohorts continue to mature and 600 mg cohorts are enrolling.

Introduction Relapsed or refractory (r/r) acute myeloid leukemia (AML) has a dismal prognosis. Treatment options are limited and include fludarabine (Flu) and cytarabine (Ara-C), +/- anthracyclines (e.g., FLAG-Ida). Recent progress has been limited to targeted therapies, which benefit only a subset of the population; efforts to develop cellular therapies have not been met with success. NKX101 is an NK cell therapy derived from healthy donors and engineered to express an NKG2D ligand-directed chimeric antigen receptor (CAR) to enhance killing of malignant cells, as well as a membrane bound form of interleukin (IL)-15 to promote persistence and activity. Because Ara-C is known to upregulate NKG2D ligand expression, use of Flu/Ara-C as an alternative to standard Flu/cyclophosphamide (Flu/Cy) for lymphodepletion (LD) was tested for NKX101. Methods Six patients with r/r AML were enrolled in this cohort of NKX101-101, a Phase 1 safety study. All patients had received at least one prior line of therapy, as well as approved targeted therapies for those with underlying genetic mutations. Patients received NKX101 at a dose of 1.5 billion (B) viable CAR+ cells/dose on Days 0, 7, and 14 after LD comprising Flu (30 mg/m2) and Ara-C (2 g/m2) each once daily for five days and 2 days of rest. Efficacy assessments were performed on Day 27 and included bone marrow aspiration and biopsy. Additional treatment cycles of LD and NKX101 were given to some patients to deepen or consolidate responses. Pharmacokinetic (PK) and cytokine sampling were performed throughout the treatment cycle(s). Results At baseline, five out of six patients had poor-risk genetic features, including TP53 mutation; the median bone marrow blast count was 35% (range: 20 - 86%). Patients had received a median of two prior lines of therapy, with all patients having previous venetoclax exposure (Table 1). All patients received at least three doses of NKX101 at 1.5 B cells/dose. There were no cases of cytokine release syndrome (CRS), immune cell associated neurotoxicity syndrome (ICANS), or graft-versus-host disease of any grade in any patients (Table 2). Myelosuppression and infection were the most common higher-grade toxicities. Four out of six patients had CR/CRi, with three out of six achieving CR. Three of these patients had no detectable MRD by flow, and one had 0.18% RUNX1-RUNX1T1 translocation via polymerase chain reaction testing on bone marrow. One subject was taken to consolidative hematopoietic cell transplant (HCT) and remains in CR. Another subject received a consolidative cycle of therapy and remains in CR. A third subject had three cycles of treatment with successive decrease in disease burden and remains in CRi. The fourth subject had CR after one cycle of treatment. PK profiling showed that NKX101 was consistently detected and correlated with infusion days (Figure 1). Cytokine data showed minimal post-infusion elevations above baseline; no association was observed between clinical response and elevation of serum cytokines (including IL-15, IL-6, IFNγ, IL-10, and IL-8). Data on the expression of NKG2D ligands (MICA, MICB, ULBP1, and ULBP3) in subject bone marrow samples were obtained via multiplex immunohistochemistry. This was evaluated as a composite H-score. Responders were split between those with relatively low ligand expression and those with higher ligand expression, suggesting that further factors may contribute to NK cell resistance. Conclusions Alternative LD with Flu/Ara-C followed by NKX101 shows promising early responses including MRD negativity in r/r AML. The toxicity profile of this regimen is manageable and was consistent with underlying AML and exposure to LD, without any events of CRS or ICANS. Expansion of enrollment and longer follow-up are needed. Despite being an allogeneic, non-HLA-matched cell product, NKX101 persisted for up to three weeks in PK testing. Directly comparing the data from patients treated with Flu/Cy with NKX101 versus Flu/Ara-C with NKX101 suggests that Flu/Ara-C can replace the Flu/Cy regimen common to CAR T cell therapy as LD without compromising overall NKX101 exposure.

TPS7074 Background: Patients with relapse/refractory (r/r) AML have poor outcomes. Allogeneic stem cell transplantation (allo-SCT) can potentially cure some patients with r/r AML who achieve second CR (CR2). However, barriers to transplantation such as advanced age, poor functional status/comorbidities or lack of donor exist and not all patients are able to proceed to allo-SCT. Therefore, novel strategies to decrease relapse risk in these patients are urgently needed. A National Cancer Institute consensus study on prioritization of cancer antigens ranked the Wilms tumor 1 (WT1) protein as the top immunotherapy target in cancer. WT1 has emerged as an encouraging vaccine target in AML due to its overexpression in leukemic blasts. Maintenance therapy with Galinpepimut-S (GPS), a multivalent heteroclitic WT1 peptide vaccine, has shown promising activity in patients with AML by inducing a strong innate immune response (CD4+/CD8+) against the WT1 antigen and across a broad range of HLA types. Methods: This is an open-label, multicenter, randomized, phase III study of GPS vs. BAT in patients with AML in CR2/CRp2 (CR2 with incomplete platelet recovery). BAT may include observation, low dose cytarabine and hypomethylating agents +/- venetoclax. The primary endpoint of the study is overall survival (OS). Secondary endpoints include safety and tolerability of GPS and leukemia-free survival. Exploratory endpoints include WT1-specific immune response dynamics in blood and bone marrow. Approximately 125 - 140 patients will enroll, in a 1:1 ratio, to provide at least 90% power under an assumed hazard ratio of 0.52, based on median OS of 8.0 m (BAT) and 15.4m (GPS). Randomization will be stratified by duration of CR1 ( < 12m vs. ≥12m), Cytogenetics (poor-risk vs. all other), CR2 vs. CRp2 and measurable residual disease (MRD) after CR2 (MRD- vs. MRD+). Inclusion criteria consists of willing subjects ≥18y with AML within 6m of achieving CR2/CRp2, ineligible for allo-SCT due to any reason, with ≥300 lymphocytes/ul and with adequate renal and hepatic function. Subjects with central nervous involvement, having received a live vaccine 30d prior to first dose of study drug, having a diagnosis of immunodeficiency, receiving ≥10mg daily of prednisone equivalent (or any other systemic immunosuppressant) for any indication 7d prior to first dose of study drug, hypersensitivity to study agent and with a history of solid organ transplant would be excluded. The clinical trial is actively enrolling, and the registry number is NCT04229979 . Clinical trial information: NCT04229979 .

e19047 Background: Human Leukocyte Antigen (HLA) typing is a necessary but expensive process to identify suitable donors for allogeneic hematopoietic cell transplantation (HCT) for the treatment of bone marrow disorders and hematologic malignancies. The likelihood of a patient and sibling being fully HLA matched is 25%. An HLA-identical related donor remains the preferred source among HCT recipients due to superior outcomes when compared to unrelated, mismatched, haploidentical, or cord blood. Because of the high probability of finding an HLA matched donor among siblings, and the benefit of quick access to these donors, it had been standard procedure at our institute to test all siblings to identify potential matches. The estimated costs of HLA typing alone is approximately $300-$1000 and is contingent upon the lab utilized and resolution of typing. The costs of HLA typing, additional testing, and screening are significant to patients and health care systems. Methods: Our institution initiated a protocol to assess potential sibling donors prior to HLA typing as per the donor eligibility guidelines of the National Marrow Donor Program (NMDP). From 2018-2020 each sibling was given a questionnaire prior to HLA typing and screened for suitability. If a sibling was determined to be ineligible for donation based on the NMDP guidelines, HLA typing and work up for that sibling was not pursued. Results: Between 2018 and 2020 we identified 789 potential donors for HCT. All potential donors were sent eligibility questionnaires. Based on this screening, 568 potential donors were found to be eligible for donation whereas 221 were ineligible. HLA typing was pursued in all eligible donors. This resulted in and estimated cost savings of $66,000-$221,000 in HLA typing alone. This translated into a substantial health care cost savings for our institution as compared to our prior policy of typing all siblings. Conclusions: Identification and work up for potential HLA matched siblings is critical for identifying optimal donors for HCT. Our previous policy of universal sibling screening was found to be costly due to typing individuals who later were found to be ineligible to donate. We found that the initiation of a simple donor screening protocol that excluded ineligible sibling donors resulted in significant cost savings compared to our prior policy of HLA typing all potential sibling donors. Cost savings are a relevant consideration in all aspects of healthcare and this screening tool could be a practical component of the best practice guidelines for HLA matching and HCT.

Chronic graft-versus-host disease (cGVHD) is a major cause of morbidity and late mortality after allogeneic hematopoietic stem cell transplantation. Cutler and colleagues report on a randomized phase 2 clinical trial of belumosudil, an oral ROCK2 inhibitor, in 132 patients with cGVHD requiring third- or later-line therapy. They found that treatment with 200 mg of belumosudil daily induces responses in 74% of patients, including those with cGVHD refractory to steroids, ruxolitinib, and ibrutinib. These data form the basis for this agent’s recent approval by the US Food and Drug Administration.

Chronic graft-versus-host disease (cGVHD) is a complication of hematopoietic cell transplantation (HCT). Although the clinical outcomes of cGVHD are well documented, few studies have assessed treatment practices outside of clinical trials. The present study aimed to quantify the prevalence of cGVHD, examine provider prescribing patterns, and evaluate the healthcare cost and resource utilization (HCRU) in a US cGVHD population. We analyzed anonymized claims from the Medicare Fee-for-Service (FFS) 5% sample for beneficiaries enrolled between 2013 and 2016 and PharMetrics commercial 2013 to 2018 databases to identify cGVHD in allogeneic HCT recipients. cGVHD was identified based on International Classification of Diseases Ninth/Tenth Revision diagnosis codes for cGVHD or unspecified GVHD with a first diagnosis >180 days post-HCT or a maintained unspecified GVHD diagnosis for >12 months postindex of unspecified GVHD diagnosis. Longitudinal and line of therapy (LOT) analyses were based on the PharMetrics dataset for 2013 to 2018. Healthcare costs were calculated by adding the inpatient, outpatient, and pharmacy insurer and beneficiary paid amounts for the commercially insured population. Total HCRU was assessed using the number of inpatient and outpatient visits following the initial cGVHD diagnosis. In 2016, the projected prevalence of cGVHD in the United States based on the Medicare FFS and PharMetrics commercial databases was 14,017 individual patients. Within 3 years after undergoing allogeneic HCT, 42% of patients developed cGVHD; 66% of the cGVHD patients had a prior diagnosis of acute GVHD. The majority of cGVHD patients received at least one systemic therapy; 71% and 47% of cGVHD patients progressed to a second and third LOT, respectively. A total of 24 unique therapeutic agents and more than 150 combinations were used in the second and third LOTs. Corticosteroids and corticosteroid combination therapy were the most common forms of treatment across all examined LOTs. Furthermore, the most commonly used agents in the first LOT, second LOT, and third LOT were corticosteroids only, calcineurin inhibitors only, and corticosteroids only, respectively. In the 12 months postdiagnosis, cGVHD patients had an average of 21.0 cGVHD-related inpatient and outpatient visits (2.8 inpatient and 18.2 outpatient visits). A significant proportion of allogeneic HCT recipients continue to develop cGVHD, and despite advances in the understanding of cGVHD, corticosteroids remain the mainstay of therapy. Patients often progress beyond the first LOT, at which time the utilization of systemic therapies is highly variable, demonstrating the need for evidence-based treatment approaches.