ABSTRACT:Briquilimab is a monoclonal antibody inhibiting stem cell factor (SCF) binding to CD117 (c-Kit). Based on preclinical data demonstrating the antibody clears hematopoietic stem and progenitor cells (HSPC) and myeloid malignant cells, we conducted a phase 1 trial examining briquilimab plus nonmyeloablative fludarabine (Flu) and total body irradiation (TBI) as conditioning for older adults with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) undergoing matched donor allogeneic hematopoietic cell transplantation (HCT). Briquilimab was infused 10 to 14 days before transplant day (TD) 0; Flu 30 mg/m2 and TBI 2 to 3 Gy were administered on TD -4 to -2 and TD0, respectively. Graft-versus-host disease prophylaxis consisted of tacrolimus, sirolimus, and mycophenolate mofetil. Thirty-two patients enrolled (n = 13 AML in complete remission [CR]; n = 3 AML in relapse; n = 16 MDS). Median age was 70 years, and most had detectable measurable residual disease (MRD) at screening. There were no briquilimab infusion reactions, dose-limiting toxicities, or primary graft failure events; briquilimab clearance was predictable across patients. Among the AML in CR cohort, 1-year event-free survival (EFS) was 69.2%; 1-year overall survival (OS) was 75%. Among the MDS cohort, 1-year EFS was 53.8%; 1-year OS was 76.4%. One of 3 patients with AML in relapse experienced a transient response. Marrow samples obtained before and after briquilimab and before Flu/TBI demonstrated AML/MDS HSPC depletion (mean, 62.4% ± 22.7%) with resultant threefold increase in serum SCF. In summary, we demonstrate the feasibility, safety, and proof of concept of CD117 targeting with briquilimab as HCT conditioning for AML/MDS. The trial was registered at www.clinicaltrials.gov as NCT04429191.

Even with new drugs available, how best to treat unfit adults with acute myeloid leukemia (AML) remains uncertain. In a previous trial in such patients, we found high-dose cytarabine-based therapy with CLAG-M yielded higher response rates but no more toxicity than lower-intensity therapy with dose-attenuated CLAG-M. Here, we conducted a single-institution phase 2 trial (NCT04195945) randomizing 60 adults with untreated AML and medical unfitness with Treatment-Related Mortality (TRM) score of ≥13.1 (68% with ECOG performance status 3-4) 1:1 to standard-dose CPX-351 or CLAG-M. Primary endpoint was 3-month overall survival (OS); key secondary endpoints included overall response rate, rate of measurable residual disease (MRD) negativity, toxicity/mortality rates, and survival estimates. Only CLAG-M met the primary endpoint of ≥63% 3-month OS (70% vs. 60%; P = 0.41), and CLAG-M therapy was associated with a non-significantly higher complete remission (CR) plus CR with incomplete hematologic recovery rate (73% vs. 47%, P = 0.064). Nonetheless, there was no statistically significant difference in relapse-free survival following CLAG-M vs. CPX-351 (median 37.6 vs. 19.9 months; P = 0.80) or OS (median 10.5 vs. 5.8 months; P = 0.76). In patients with proliferative disease, however, OS following CLAG-M was longer (median 18.5 vs. 3.9 months; P = 0.02) suggesting a role for intensive therapy in this patient subset.

TPS6604 Background: In preclinical evaluations, sequential treatment (tx) with RUX, a Janus kinase inhibitor (JAKi), and IME, a telomerase inhibitor, selectively reduced MF hematopoietic stem cells (HSC) and progenitor cells. In the Phase 2 IMbark trial (NCT02426086), IME monotherapy showed clinical activity and disease-modifying potential in pts with INT-2 or HR MF relapsed/refractory to JAKi. These findings, and the nonoverlapping mechanisms of action, supported the evaluation of IME+RUX in frontline MF. IMproveMF (NCT05371964) is an open-label study of IME+RUX in pts with INT-1/INT-2/HR MF. In Phase 1 (dose finding), IME+RUX was generally well tolerated, with no dose-limiting toxicities at any dose, and a safety profile consistent with reports from other IME trials. Notably, a dose-dependent signal of clinical activity was observed. The pharmacokinetics for the combination were similar to those of previous monotherapy studies. Thus, the recommended Phase 1b dose of 8.9 mg/kg IME active dose (equivalent to 9.4 mg/kg IME sodium) was chosen. Methods: Phase 1b (dose confirmation and expansion) will enroll adult pts with INT-1/INT-2/HR MF with an Eastern Cooperative Oncology Group performance status ≤2 and peripheral blood and bone marrow blasts <10%, ≥2 active symptoms with a score of ≥3, or a total score of ≥10 on the MF Symptom Assessment Form v4.0, an absolute neutrophil count of ≥1.5×10 9 /L independent of growth factor support and platelets of ≥75×10 9 /L (updated criterion), no active systemic hepatitis infection, acute or chronic liver disease unrelated to underlying MF, and no prior history of HSC transplantation. The study was planned to evaluate 2 cohorts. In cohort A (JAKi-naive pts), upon enrollment, pts will start RUX for ≥12 weeks (24 weeks max); once the RUX dose is stable for 4 weeks, 8.9 mg/kg IME intravenously (IV) every 4 weeks will be added. Per the updated protocol (November 2025), the study will no longer recruit pts into cohort A. Existing enrollees will continue in the study per schedule. In cohort B, ~15 pts will be enrolled who are currently on first-line RUX per standard of care for ≥12 weeks, with ≥4 weeks at a stable dose, and will begin 8.9 mg/kg IME IV every 4 weeks after enrollment. Tx will continue until toxicity, disease progression, or withdrawal. The primary endpoint includes safety and symptom response rate at week 24 (proportion of pts with ≥50% reduction in total symptom score [TSS] at week 24 from start of IME+RUX tx). Secondary endpoints include absolute change in TSS at week 24, average absolute change in TSS over 24 weeks, spleen response (≥35% spleen volume reduction) at week 24, and progression-free survival. The primary analysis is planned ~6 months after the last pt’s first dose of IME+RUX; the final analysis will occur after the study ends. Cohort B is actively enrolling. Clinical trial information: NCT05371964 .

6535 Background: For adults with ND Ph- B-ALL, frontline regimens now often include the CD19/CD3 bispecific blinatumomab (blin). However, blin administration is challenging, particularly for less-experienced centers. DA-EPOCH ± R is safe and active in these patients (pts; Cassaday, et al, Leuk Lymphoma , 2023) and easier to deliver. Tafa is a CD19 monoclonal antibody active in B-cell lymphomas. We hypothesized that the addition of tafa to DA-EPOCH ± R will yield higher rates of measurable residual disease negativity (MRD-) without increasing toxicity or administration complexity. Methods: This is a phase II investigator-initiated study (NCT05453500) in adults (>18 years) with ND CD19+ Ph- B-ALL not eligible for a pediatric regimen. DA-EPOCH ± R was given as cited above; tafa 12 mg/kg was given IV on day (d) 1, 8, and 15 of each cycle (C). After blin consolidation was FDA approved, pts could receive this off-study. The primary endpoint was MRD- by multiparameter flow cytometry (MFC) per EuroFlow (~<10 -4 ) after C1 (~d 20); secondary endpoints included MRD- by MFC after C4 (~d 80); non-hematologic adverse events (AEs, CTCAE v5); and relapse-free (RFS) and overall survival (OS). Exploratory endpoints included high-throughput sequencing (HTS; <10 -6 ) by clonoSEQ in marrow and cerebrospinal fluid (CSF). If ³13 of 30 evaluable pts (³43%) are MRD- after C1, the primary endpoint is met (vs 28% with DA-EPOCH ± R alone; 80% power and one-sided α = 0.05). Results: From 3/2023 to 12/2025, 30 pts enrolled: 2 pts did not finish C1 due to grade (G) 4 AST elevation (related) and G5 C. perfringens sepsis (unrelated); 27 were evaluable for response and are the focus here. Median age was 67 (44-84), 70% male, 56% poor risk cytogenetics by NCCN, and 9 received R. Complete response (CR) rate was 85% (23/27); MRD- by MFC after C1 was 44% (12/27) and 80% (20/25) by C4 in pts with sufficient follow-up (f/u). In pts MRD- by MFC, 53% (8/15) were MRD- by HTS. Other G3+ AEs seen in >2 pts: infection (9); febrile neutropenia (8); low fibrinogen (6); hypotension (5); and syncope (4). Initial CSF MFC was positive in 3 pts; HTS was positive in these plus 4 more (7 total). With a median f/u among survivors of 10 mo (1-37), there were 3 relapses: 1 post-HCT and 1 after only 2 treatment cycles; all were CD19+, and 0 involved CNS. Only 2 pts got blin consolidation. 6 pts died: 4 non-relapse causes (3 post-HCT) and 2 from refractory ALL. No deaths were due to study treatment. 1-year RFS and OS were estimated to be 67% and 76%, respectively. Conclusions: DA-EPOCH ± R + tafa yields high rates of MRD-. Follow-up is immature, but early survival rates are comparable to more complex strategies. This study is on pace to reach its primary endpoint, with enrollment ending before the conference. HTS on CSF can identify CNS disease more frequently. Clinical trial information: NCT05453500 .

ABSTRACT:Myelodysplastic syndromes/neoplasms (MDSs) are heterogeneous stem cell malignancies characterized by poor prognosis and no curative therapies outside of allogeneic hematopoietic stem cell transplantation. Despite some recent approvals by the US Food and Drug Administration, (eg, luspatercept, ivosidenib, decitabine/cedazuridine, and imetelstat), there has been little progress in the development of truly transformative therapies for the treatment of patients with MDS. Challenges to advancing drug development in MDS are multifold but may be grouped into specific categories, including criteria for risk stratification and eligibility, response definitions, time-to-event end points, transfusion end points, functional assessments, and biomarker development. Strategies to address these challenges and optimize future clinical trial design for patients with MDS are presented here.

Ruxolitinib (Rux), the first FDA-approved JAK inhibitor for the treatment of myelofibrosis (MF), was initially studied in patients who were ineligible for hematopoietic cell transplantation (HCT). However, the resultant decrease in splenomegaly and improvement in symptoms allowed some of the study patients to become HCT-eligible. We aimed to determine whether giving Rux to HCT-eligible MF patients would yield favorable HCT outcomes in relation to a historical cohort at our center. We conducted this single-arm Phase II prospective single-center study of Rux followed by HCT in adult patients with primary and secondary MF between 2014 and 2020. Patients were not required to have symptoms or splenomegaly. Patients took Rux for at least 8 weeks (no maximum) prior to the start of conditioning and tapered off by day -4 of HCT conditioning. A total of 101 patients were enrolled in the study (median age, 57 years; range, 34 to 71 years), of whom 61 (60%) proceeded to HCT (59% primary MF, 70% DIPSS [dynamic international prognostic scoring system] intermediate-2 or high-risk) after a median of 7 months (range, 2 to 89 months) on Rux. Patients engrafted at a median of 20 days; there was 1 primary graft failure. Nonrelapse mortality (NRM) was 13% at 1 year, compared to 26% in our historical cohort. With a median follow-up of 5.6 years among survivors, overall survival was 79% (95% confidence interval [CI], 69% to 90%) at 2 years, compared to 67% in our historical cohort, and 5-year survival was 74% (95% CI, 64% to 86%). The hazard ratio of death for those who had a Rux response relative to those who did not was 0.57 (95% CI, 0.20 to 1.61; P = .29). In this prospective Phase II study, patients receiving pre-HCT Rux had encouraging NRM and survival rates relative to historical patients at our center who proceeded to HCT without prior Rux.

6515 Background: IME, a first-in-class, direct, and competitive inhibitor of telomerase activity, showed potential survival improvements and disease-modifying activity in the phase 2 IMbark MF trial (NCT02426086). Preclinical evidence demonstrated IME+RUX reduced disease burden better than either agent alone. IMproveMF (NCT05371964) aims to evaluate IME+RUX in pts with INT-1/INT-2/HR MF. Methods: IMproveMF is an open-label, single-arm, phase 1/1b trial (part 1: dose escalation; part 2: dose confirmation and expansion) of IME+RUX in adults with DIPSS INT-1, INT-2, or HR MF. In part 1 (up to 21 pts), RUX was required for ≥12 wk with a stable dose for ≥4 wk immediately before adding IME; pts received IME via intravenous infusion at each dose level cohort (4.7, 6.0, 7.5, and 9.4 mg/kg IME sodium; equivalent to 4.4, 5.6, 7.1, and 8.9 mg/kg active dose, respectively) every 28 d based on Bayesian Optimal Interval design to identify the recommended part 2 dose (RP2D). Pts in part 1 were dose adjusted to the RP2D as needed in part 2, with 2 dose reductions allowed. Part 2 of the trial will enroll pts who are RUX naive. Primary endpoints are adverse events (AE), including dose-limiting toxicity (DLT), in part 1 and AEs and 24-wk response rate (≥50% reduction in MF total symptom score [TSS]) in part 2. Secondary endpoints include pharmacokinetics (PK) and clinical activity. Total planned enrollment is ≈41 pts. Results: As of 11/04/2024, 17 pts were enrolled in part 1 with a median age of 67 y (71% aged ≥65 y); 7 had INT-1, 9 INT-2, and 1 HR MF. Respective to the dose levels in the Methods, 3, 3, 4, and 7 pts received the corresponding IME dose level. No DLTs were reported for IME; 2 pts had dose reductions due to neutropenia. Five pts discontinued IME (none due to AEs). Four pts had RUX dose reductions (due to AEs and other, n=2 each). AEs were experienced by 15 pts; 8 experienced grade 3 events of anemia (n=4), neutropenia (n=3), leukopenia (n=2), abdominal pain, fatigue, epistaxis, and pneumonia (n=1 each; the latter 2 and 1 anemia event were considered serious AEs). There were no grade 4/5 AEs. There was an overall reduction in TSS from baseline (median, −5 points in maximum absolute reduction up to wk 24) with IME regardless of dosing, and a trend of dose-dependent spleen volume decrease. A reduction in variant allele frequency of several driver mutations was also observed. Hematologic, PK, and additional mutational data will be included in the presentation, as available. Conclusions: In part 1 of IMproveMF, no DLTs were observed and the RP2D dose of 9.4 mg/kg IME was determined. AEs were consistent with those observed in other IME clinical trials, and preliminary efficacy was positive, demonstrating the potential of IME+RUX in this pt population with high unmet needs. Part 2 of this trial is ongoing across the US at 6 sites. Clinical trial information: NCT05371964 .

Introduction/ Background: Hypomethylating agents (HMAs) such as azacitidine (AZA) and decitabine (DEC) are FDA-approved for patients with MDS/CMML and acute myeloid leukemia (AML). Treatment is generally administered parenterally as a daily injection or infusion over 5-7 days per four-week cycle. The oral fixed-dose combination of decitabine with cedazuridine, ASTX727, was approved by regulators in the USA and Canada for patients with MDS and CMML based upon the demonstration of biologically equivalent pharmacokinetics (PK) area under the curve (AUC) vs IV decitabine. ASTX030 is a combination of AZA and cedazuridine (CED), a cytidine deaminase inhibitor (CDAi), which enables oral AZA to achieve systemic AUC similar to that of parenteral (subcutaneous) AZA. Development and approval of an oral AZA providing equivalent PK exposure to the parenteral therapy has the potential to markedly reduce the treatment burden associated with parenteral treatment. This Phase I trial is designed to determine the dose combination for oral AZA plus CED to replicate SC AZA AUC exposures in subjects with MDS and MDS/MPN, including CMML. Methods: Adult patients with confirmed MDS, CMML, and other MDS/MPN or AML who are candidates to receive benefit from single agent AZA were enrolled in this open label Phase 1 trial. In addition to assessing safety and efficacy of each combination, the primary PK endpoint was to achieve oral AZA PK AUC 0-24 equivalence versus subcutaneous AZA (at the approved dose of 75 mg/m 2 over the span of 7 days). In the first cycle, patients received oral AZA alone on Day -3, followed by SC AZA at 75 mg/m 2 on Day 1. Subsequently, oral ASTX030 (combination of AZA with CED) was given at varying dose combinations of AZA and CED for each cohort. After cycle 1, patients received oral ASTX030 on Days 1-7 for each 28-day cycle. Dose levels for cohorts in escalation were determined by the data safety and review committee based on safety and PK results. Pharmacodynamic (PD) impact was assessed by changes in LINE-1 DNA methylation in peripheral blood cells. Clinical response assessments were based upon International Working Group (IWG) 2006 criteria for MDS patients and IWG 2015 criteria for MDS/MPN and CMML patients. Results: As of 05 JUL 2023, 65 patients were treated across 8 different dose combinations, with ≥6 patients per cohort. The median age was 72 years old (range 26-87), 36.9% (n=24) were female, 6.2% (n=4), had previously received HMA treatment (unlimited). Of the enrolled patients, 69% (n=45) had MDS, 25%(n=16) had CMML, and 6% (n=4) had MDS/MPN (other). Evaluated dose levels for AZA ranged from 60-136mg and CED dose ranged from 20-100 mg. In cohorts 1-2, tablet formulation was tested first (AZA ranging 80-100mg with CED ranging 80-100mg). Starting with cohort 3, capsule formulation was introduced for AZA to optimize the interaction effect of CDA inhibition by CED. In both tablet and capsule formulation, grade ≥3 AE's (regardless of causality) were observed in 75.9% of patients. The most common Grade ≥3 AE's regardless of relation to drug were leukopenia (25%), thrombocytopenia (20%), and anemia (20%). Gastrointestinal toxicity were similar (for example, nausea 70% ASTX030 vs 71% SC AZA) to those reported for SC AZA (VIDAZA USPI)). No dose limiting toxicity was observed in any of the cohorts. The CED dose of 20 mg resulted in ~100% bioavailability for AZA, suggesting inhibition in a linear range. LINE-1 demethylation results were similar to those reported historically with SC AZA. Although a clinical response comparable to SC AZA was observed, the immature nature of the data requires continued analysis to yield results on treatment efficacy. Conclusion: ASTX030 successfully achieved the primary endpoint of PK equivalence versus SC AZA based on total cycle AUC. The dose combinations evaluated were well tolerated, and the safety profile similar to that of SC AZA, with no unique AE's. LINE-1 demethylation and clinical response confirm the clinical activity of ASTX030. Phase 1B dose expansion for the ASTX030 study at the recommended dose combination of 144mg AZA with 20mg CED will begin soon to confirm PK equivalence for this dose level. An orally bioequivalent AZA based HMA offers significant opportunity for novel combinations and improved convenience for patients with high grade myeloid malignancy.

Introduction: MF is a progressive myeloproliferative neoplasm commonly associated with driver mutations in JAK2, CALR, or MPL genes. Janus kinase inhibitors (JAKi; eg, ruxolitinib [RUX]) can reduce MF spleen size and symptom burden but do not have disease-modifying activity. Imetelstat (IME), a first-in-class direct and competitive inhibitor of telomerase enzymatic activity approved in the United States (US) to treat patients (pts) with transfusion-dependent low- to intermediate (INT)-1-risk myelodysplastic syndromes, demonstrated potential survival improvements and disease-modifying activity in the phase 2 IMbark trial (NCT02426086) in pts with MF relapsed or refractory to JAKis. Preclinical evidence demonstrated that the combination of IME+RUX reduced disease burden better than either agent alone. IMproveMF (NCT05371964) aims to evaluate safety, pharmacokinetics (PK), and clinical activity of IME+RUX in pts with INT-1/INT-2/high-risk (HR) MF. Methods: IMproveMF is an ongoing, open-label, single-arm, multicenter, phase 1/1b trial (part 1: dose escalation; part 2: dose confirmation and expansion) of IME+RUX in adults with Dynamic International Prognostic Scoring System INT-1, INT-2, or HR MF with an Eastern Cooperative Oncology Group performance status of ≤2 and peripheral blood and bone marrow blasts <10%. In part 1 (up to 21 pts), RUX treatment is required for ≥12 weeks with a stable dose for ≥4 weeks immediately before adding IME; IME is administered intravenously at each dose level in cohorts of 3 pts each (4.7, 6.0, 7.5, and 9.4 mg/kg imetelstat sodium, equivalent to 4.4, 5.6, 7.1, or 8.9 mg/kg active dose, respectively) every 28 days based on Bayesian Optimal Interval Design to identify the recommended part 2 dose (RP2D). Once established, enrollment in part 2 of the trial may begin and pts in part 1 may be dose-adjusted to the RP2D as needed, with 2 dose reductions allowed. Part 2 of the trial will enroll pts who are JAKi-naive. Pts will start RUX for ≥12 weeks (24 weeks maximum) and once the dose is stable, the pt will start the IME RP2D dose. Treatment continues until toxicity, disease progression, or withdrawal. Primary endpoints include the following: part 1, adverse events (AE), including dose-limiting toxicity (DLT); part 2, AEs and 24-week response rate (≥50% reduction in total symptom score [TSS] measured by Myelofibrosis Symptom Assessment Form v4.0). Secondary endpoints include PK (assessed with blood samples taken on cycle 1, day 1 and day 1 of each cycle thereafter) and clinical activity. Total planned enrollment is ≈41 pts. Results: As of 07/10/2024, 13 pts were enrolled in part 1 (9 males/4 females) with a median age of 70 years (77% aged ≥65 years); 5 had INT-1, 7 INT-2, and 1 HR MF. Three pts received each IME dose level (except n=4 at 7.5 mg/kg). There were no DLTs reported for IME. One pt had an IME dose reduction from 7.5 to 6.0 mg/kg at cycle 4 due to grade 3 neutropenia. RUX dose range was 10-20 mg twice daily, with 3 pts who experienced dose reductions from 10 to 5 mg in later cycles. Four pts discontinued IME treatment (2 withdrew, 1 per physician decision, and 1 to enroll in another clinical trial). AEs were experienced by 9 pts. Six pts experienced grade 3 events of neutropenia (n=3), leukopenia (n=2), abdominal pain (n=1), anemia (n=1), fatigue (n=1), and pneumonia (n=1). The grade 3 pneumonia was a serious AE but considered to be related to underlying disease and resolved without dose modification. For IME, maximum plasma concentration (Cmax) was reached at 2 hours (end of infusion) and a more than dose-proportional increase for exposure at the dose range tested was observed, consistent with the IME PK profile from other studies. Cmax was reached at 1-2 hours after receiving RUX, with a trend suggestive of linear PK. Symptom response, hematologic, and biopsy results will be included in the presentation, as available. Conclusions: In part 1 of the IMproveMF phase 1/1b trial of IME+RUX in pts with INT-1, INT-2, or HR MF, no DLTs were observed, and AEs were consistent with those observed in other clinical trials of IME. IME and RUX PK profiles in the combination study were similar to previous monotherapy studies. This trial is ongoing across the US at 6 sites and will continue to enroll at the 9.4 mg/kg imetelstat sodium dose level to confirm the RP2D before starting part 2. These early results demonstrate promise for the tolerability of the combination of IME+RUX in this pt population with high unmet needs.

7068 Background: In patients with myelofibrosis (MF), JAK inhibitor therapy can improve both splenomegaly and disease symptoms. Unfortunately, dosing – and thus efficacy – of available current JAK1/2 inhibitors is frequently limited in patients with cytopenic MF due to drug-induced exacerbation of cytopenias. Pacritinib is a novel JAK1-sparing inhibitor of JAK2/IRAK1/ACVR1 that has been studied at full dose in patients with MF regardless of cytopenias. Here, we present data on spleen and symptom benefit in pacritinib-treated patients across the cytopenic spectrum, stratified by both baseline platelet (PLT) count and hemoglobin (HB) level. Methods: Evaluable patients treated with pacritinib in the PERSIST-1 and PERSIST-2 studies were analyzed, stratified by baseline PLT (<100, ≥100x10 9 /L) and HB (<8, 8 to <10, ≥10 g/dL). Groups were analyzed for depth of spleen volume response (SVR), modified total symptom score (TSS) response, patient global impression of change (PGIC), and dose intensity. Results: Of 276 patients evaluable for spleen response, median age was 67 years, 51.5% had grade 3 fibrosis, 70% had primary MF, and 16% had prior JAK2 inhibitor exposure. Median dose intensity was >99.7% for the duration of the study across PLT and HB subgroups. Overall, 80% of patients had ≥10% SVR (SVR-10), 75.5% had TSS-10, and 78% reported that their symptoms were improved at week 24. Week 24 spleen reduction occurred consistently across PLT and HB strata, with 84-93% and 86-90% of patients respectively (Table). SVR-35 occurred in 23-25% of patients across PLT strata and in 21-28% of patients across HB strata. Symptom response was also consistent across strata, though TSS-50 occurred at highest rates (62.5%) in patients with HB <8 g/dL. There was no diminution in symptom burden reduction in patients with thrombocytopenia (Table). Across all subgroups, at least three-quarters of patients reported symptoms were “improved” at week 24. Conclusions: Pacritinib demonstrates consistent efficacy for spleen and symptom response in patients with MF regardless of blood counts. This consistent effect may be related to pacritinib’s unique kinome profile and its ability to be delivered at full dose in patients regardless of cytopenias. Clinical trial information: NCT01773187 , NCT02055781 . [Table: see text]

Background: Azacitidine (AZA) and decitabine (DEC) are parenteral DNA methyltransferase inhibitors (DNMTis) approved for the treatment of patients with MDS and acute myeloid leukemia. Oral DNMTi options have been limited due to their rapid clearance by cytidine deaminase (CDA). Combining DNMTis with the CDA inhibitor cedazuridine (CED) has demonstrated oral availability and led to the approval of oral DEC-C based on pharmacokinetic (PK) area under the curve (AUC) exposure equivalence versus intravenous DEC. ASTX030-01 (NCT04256317) is a phase 1-3 trial of ASTX030 (oral AZA + CED) versus subcutaneous (SC) AZA in patients with MDS and MDS/MPN (including chronic myelomonocytic leukemia; CMML). The aim of the phase 1 trial was to determine the optimal dose and formulation to achieve oral AZA PK AUC comparable to SC AZA. Methods: This open-label phase 1 trial enrolled adult patients with confirmed MDS and MDS/MPN overlap syndromes who may benefit from single-agent AZA. Both immediate-release (IR) and delayed-release (DR) AZA formulations at several dose combinations were explored. There were six or more patients per dose cohort. The primary objective was to determine the ASTX030 recommended phase 2 dose (RP2D). Secondary objectives were safety, tolerability, PK, DNA methylation, and preliminary efficacy. Results: Overall, 88 patients received a median of 6.0 (range, 1-32) ASTX030 treatment cycles (data cutoff: May 24, 2024). Median age was 72 years (range, 26-87), 35% (n=31) of patients were female, prior treatments included DNMTis (9% [n=8]), luspatercept (3% [n=3]), lenalidomide (3% [n=3]), and erythropoiesis-stimulating agents (3% [n=2]). Of the enrolled patients, 72% (n=63) had MDS, 22% (n=19) had CMML, and 7% (n=6) had non-CMML MDS/MPN overlap syndromes. In the dose-escalation part, sensitivity of AZA to CDA inhibition was confirmed with the IR formulation. To optimize the ASTX030 dose, six dose combinations of DR AZA (60-144 mg) and CED (20-100 mg) were evaluated. Two ASTX030 doses (136/20 mg and 144/20 mg AZA/CED) were investigated in the dose-expansion part. Adverse events (AEs) were reported in 100% (n=88) of patients; 84% (n=74) of patients experienced a Grade ≥3 AE; 5% (n=4) of patients discontinued ASTX030 due to an AE. The most common Grade ≥3 AEs (any cause) were related to myelosuppression: leukopenia, 27%; neutropenia, 26%; thrombocytopenia, 23%. Gastrointestinal toxicities were similar for ASTX030 and SC AZA (VIDAZA USPI). One patient receiving 136/20 mg AZA/CED had a dose-limiting toxicity (DLT) of prolonged Grade 4 neutropenia, possibly related to study drug; no other DLTs were observed. Safety and tolerability up to 144 mg DR AZA was confirmed. PK data indicated that 20 mg CED resulted in sufficient inhibition of CDA to increase absolute bioavailability of oral AZA to ~100% versus SC AZA. In the dose-expansion part, 144/20 mg AZA/CED slightly exceeded the 90-110% range of oral/SC ratio based on calculated total cycle AUC exposures and 136/20 mg AZA/CED achieved PK AUC in the lower end of the 90-110% range. Based on these data, 140/20 mg AZA/CED was selected as the RP2D. LINE-1 demethylation data were comparable to those reported for SC AZA (for cohorts with similar PK AUC exposures to SC AZA). Preliminary clinical efficacy assessments for patients with sufficient follow-up (36.2 months; n=33) from cohorts with comparable AUC exposures versus SC AZA had overall survival of 29.5 months, with 24% complete response, 24% marrow complete response, 33% stable disease, and 18% efficacy status unknown. Conclusion: All ASTX030 dose combinations evaluated were well tolerated and the safety profile was similar to SC AZA, with emerging clinical efficacy also consistent with parenteral AZA. Based on the results of the phase 1 trial, 140/20 mg AZA/CED was selected as the RP2D. Enrollment for the phase 2 randomized, crossover (oral vs SC) trial is ongoing and combination dosing is in preparation.

We aim to evaluate impact of donor types on outcomes of hematopoietic cell transplantation (HCT) in myelofibrosis, using CIBMTR registry data for HCTs done between 2013 and 2019. In all 1597 undergoing HCT for myelofibrosis, the use of haploidentical donors increased from 3% in 2013 to 19% in 2019. In study eligible, 1032 patients who received peripheral blood grafts for chronic phase myelofibrosis, 38% recipients of haploidentical-HCT were of non-White/Caucasian ethnicity. Matched sibling donor (MSD)-HCTs were independently associated with superior overall survival (OS) in the first 3 months [reference MSD, haploidentical HR 5.80 (95% CI 2.52-13.35), matched unrelated HR 4.50 (95% CI 2.24-9.03), and mismatched unrelated HR 5.13 (95% CI 1.44-18.31), P<0.001]. This difference in OS aligns with lower graft failure with MSD [haploidentical HR 6.11 (95%CI 2.98-12.54), matched unrelated HR 2.33 (95%CI 1.20-4.51), mismatched unrelated HR 1.82 (95%CI 0.58-5.72). There was no significant difference in OS among haploidentical, matched unrelated, and mismatched unrelated donor HCTs in the first 3 months. Donor type was not associated with differences in OS beyond 3 months post-HCT, relapse, disease-free survival or OS among patients who underwent HCT within 24 months of diagnosis. Patients who experienced graft failure had more advanced disease and commonly used nonmyeloablative conditioning. While MSDs remain a superior donor option due to improved engraftment, there is no significant difference in HCT outcomes from haploidentical and matched unrelated donors. These results establish haploidentical-HCT with posttransplantation cyclophosphamide as a viable option in myelofibrosis, especially for ethnic minorities underrepresented in the donor registries.