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Abstract Introduction: Marrow complete remission (mCR) in 2006 IWG criteria for MDS (Cheson B et al, Blood 2006) reflects achieving bone marrow (BM) blast percentage below 5% but is frequently not associated with meaningful count recovery. While mCR + hematologic improvement (HI) does reflect wide ranges of count improvement or transfusion reductions, HI is difficult to measure accurately in routine clinical practice. The 2023 International Working Group (IWG) response criteria (Zeidan A et al, Blood 2023) eliminated the mCR category without meaningful count recovery and reclassified mCR associated with meaningful count recovery into specific “less-than-CR” categories. Still, many clinical trials continue to use mCR as a secondary efficacy endpoint or as a part of overall response rate (ORR). Within the icMDS VALIDATE database, we assessed the association of mCR with OS in hypomethylating agent (HMA)-treated higher risk (HR)-MDS patients among both (1) transplanted and (2) non-transplanted patients. Methods We included patients with HR-MDS (defined as IPSS ≥1.5 and/or IPSS-R >3.5) who received HMA-based therapies from the international icMDS VALIDATE dataset. We evaluated the best response by IWG 2006 criteria into CR, mCR, or no CR/mCR. We then reclassified patients with mCR per IWG 2023 criteria into either (A) having achieved a composite CR (cCR) defined as CR + CR equivalent (CRequ) + CR with bilineage count recovery (CRbi) + CR with unilineage count recovery (CRuni) + CR with partial hematologic recovery (CRh) or (B) not having achieved cCR (no cCR). OS was calculated from time of HMA initiation to date of death or last follow-up by using 6-month landmark analyses. We used Kaplan-Meier methods to estimate OS, and the Log-rank test to compare OS. VALIDATE is supported by an independent grant from AbbVie. Results A total of1049 patients met eligibility.Median age of patients was 69 (range 21-95), 64% were men. While 61% received azacitidine, 17% received decitabine, and 22% received HMA-based combination therapy. In total, 37% underwent subsequent allogenic stem cell transplantation (allo-HCT). Based on IWG 2006 criteria, 17%, 33%, and 50% achieved CR, mCR, and no CR/mCR as their best response, respectively. Patients achieving CR had superior median OS (25 months, 95% CI: 21-34 months) compared to those with mCR (16 months, 95% CI: 13-18 months; p=0.038) and no CR/mCR (15 months, 95% CI: 12-17 months; p=0.001). In patients who received a subsequent allo-HCT, the median OS for patients with mCR (30 months, 95% CI: 21-54 months; 1 year OS: 71%, 2 year OS: 55%) did not significantly differ compared to patients with CR (59 months, 95% CI: 25 months-not reached, p=0.80; 1 year OS: 73%, 2 year OS 62%) and patients with no CR/mCR (32 months, 95% CI: 21-45 months, p=0.46; 1 year OS: 69%, 2 year OS 54%). In contrast, in patients treated with HMA therapy alone without subsequent allo-HCT, median OS for patients with mCR (11 months, 95% CI: 9-15 months; 1 year OS: 46%, 2 year OS: 23%) did not significantly differ compared to patients with no CR/mCR (11 months, 95% CI: 9-14 months, p=0.85; 1 year OS: 47%, 2 year OS: 22%) but was significantly shorter compared to patients with CR (20 months, 95% CI: 17-28 months, p<0.001; 1 year OS: 69%, 2 year OS: 46%). Patients with mCR by IWG 2006 (N=347) were reclassified per IWG 2023 into having either achieved a cCR (N=219, 63%) or no cCR (N=128, 37%). Specifically, patients with mCR were reclassified per IWG 2023 into CR (4.9%), CRequ (0.6%), CRbi (26.8%), CRuni (29.4%), CRh (1.4%), PR (0%), HI (10%), no response (21.9%) and PD (4.9%). Patients with mCR who were reclassified into cCR had an improved median OS (16 months, 95% CI: 15-26 months; 1 year OS: 62%; 2 year OS: 43%) compared to patients reclassified into no cCR per IWG 2023 (13 months, 95% CI: 11-17 months, p=0.023; 1 year OS: 52%; 2 year OS: 31%). Conclusions Using the large icMDS VALIDATE dataset, we found that achievement of mCR by 2006 IWG criteria was not associated with improved OS compared to patients who did not achieve CR/mCR. Reclassification of mCR using IWG 2023 highlights the heterogeneity within the mCR group and suggests that IWG 2023 criteria stratifies outcomes in patients previously labeled as mCR by IWG 2006. IWG 2023 should be the standard used for ORR assessment in all future clinical trials involving patients with HR-MDS.

Abstract 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.

Abstract Introduction: Nucleophosmin 1 mutations (NPM1-m) drive leukemogenesis in approximately 30% of acute myeloid leukemia (AML) cases. Ziftomenib is a potent, highly selective, oral, investigational menin inhibitor that has demonstrated clinical activity as both monotherapy and in combination for adults with NPM1-m or lysine methyltransferase 2A-rearranged (KMT2A-r) AML. KOMET-007 (NCT05735184) is an ongoing, open-label, dose-escalation (phase 1a) and expansion (phase 1b) study of ziftomenib in combination with standard chemotherapies in NPM1-m or KMT2A-r AML. Here we present phase 1b safety and clinical activity in patients with newly diagnosed NPM1-m AML who received the recommended phase 2 dose (RP2D) of ziftomenib 600 mg in combination with venetoclax and azacitidine (Ven/Aza). Methods: Adults (≥18 years) with newly diagnosed NPM1-m AML who were not eligible for intensive chemotherapy were enrolled in phase 1b and received ziftomenib 600 mg once daily plus standard doses of Ven/Aza. Ziftomenib was orally administered once daily continuously from Cycle 1 Day 8 onward. Phase 1b primary endpoints were adverse events (AEs) and complete remission (CR) per ELN 2022. Secondary endpoints included composite CR (CRc; defined as CR with full, partial, or incomplete hematologic recovery), overall response, and duration of response. Local measurable residual disease (MRD) was assessed by next-generation sequencing, RT-qPCR, and multiparameter flow cytometry. Results: As of June 25, 2025, 39 patients with newly diagnosed NPM1-m AML were enrolled and treated with ziftomenib 600 mg once daily plus Ven/Aza in phase 1b. Median age was 75 years (range 53–93), 54% were female, 46% had ECOG PS 0–1; 12 (31%) had FLT3 co-mutations and 9 (23%) had IDH co-mutations. Median duration of follow-up was 16.3 weeks (range 1.6–41.1). Twenty-nine patients (74%) had grade ≥3 treatment-emergent AEs, most commonly (≥20% of patients) decreased neutrophil count (31%) and decreased platelet count (23%). Grade ≥3 ziftomenib-related AEs occurred in 14 patients (36%), most commonly decreased neutrophil count (15%) and decreased platelet count (13%). No ziftomenib treatment discontinuations occurred due to AEs. Differentiation syndrome occurred in 1 (3%) patient (grade 2), which successfully resolved with protocol-specified mitigation. One patient (3%) had investigator-assessed ziftomenib-associated QTc prolongation (grade 3); however, there were concomitant significant electrolyte abnormalities and event resolved with electrolyte repletion. At time of data cutoff, 31 NPM1-m patients were response-evaluable (≥1 response assessment or death). CRc rate was 84% (26/31) after a median time to first CRc of 3.5 weeks (range 2.4–9.4), with local MRD-negativity rates among tested CRc responders of 54% (13/24) after a median time to first MRD-negativity of 8.4 weeks (range 2.9–17.4). CR rate was 58% (18/31) and overall response rate was 94% (29/31), with responses and MRD-negativity rates continuing to evolve. During continuous ziftomenib administration in patients who achieved CRc, median time to neutrophil recovery (≥1×109/L) was 36 days, and median time to platelet recovery (≥100×109/L) was 28 days. The median duration of response and median overall survival were not reached as of the data cutoff, at a median follow-up of 16.3 weeks. The study is ongoing, with 81% (25/31) of NPM1-m patients still on-study and 77% (24/31) still on ziftomenib treatment. Updated safety and clinical activity results will be presented.Conclusions: In the ongoing KOMET-007 study, ziftomenib RP2D of 600 mg once daily combined with Ven/Aza was well tolerated and demonstrated robust clinical activity in patients with newly diagnosed NPM1-m AML, including 84% CRc after a median of 3.5 weeks and 54% CRc MRD-negativity after a median of 8.4 weeks. Low rates of ziftomenib-related cytopenia and no additional myelosuppression were observed with this combination. One case each of differentiation syndrome (grade 2) and investigator-assessed QTc (grade 3) were successfully resolved. Taken together, these data support the RP2D determination and advancement of this ziftomenib-based combination in the KOMET-017 (NCT07007312) randomized phase 3 study in patients with newly diagnosed NPM1-m AML.

Background/Objectives: Muscle aging is a complex, dynamic process that impairs overall metabolism and physiological function. The molecular mechanisms underlying declines in muscle performance and metabolic efficiency remain poorly understood, largely due to the time and resource demands of traditional model organisms. The hawk moth Manduca sexta offers a promising alternative, with a short adult lifespan (~10 days) and notable similarities to vertebrate muscle systems, making it well-suited for time-course molecular dissection of muscle aging. Methods: In this study, we performed high-resolution temporal analysis of muscle tissues from aging M. sexta, spanning the physiomuscular aging process from middle age to advanced age. Results: We observed decreased expression of genes involved in fatty acid β-oxidation, ATP synthase subunits, superoxide dismutase, glutathione S-transferases, and heat shock proteins. In contrast, genes associated with proteolysis, catabolic processes, insulin signaling, akirin, titin, high-affinity choline transporters, and vesicular acetylcholine transporters were increased in expression. Conclusions: These changes suggest a shift toward increased proteolysis and protein catabolism with age. Our findings support the use of M. sexta as a complementary model for muscle aging research. However, it remains unclear whether the observed gene expression changes are driven by intrinsic, sex-specific age-related muscle aging or confounded by potential starvation effects in older males.

Objective Individuals with serum elevations of anti–cyclic citrullinated peptide (anti‐CCP) antibodies are at increased risk for future rheumatoid arthritis (RA). No pharmacologic interventions have been approved for the prevention of RA in such at‐risk individuals. However, hydroxychloroquine (HCQ) is used without supporting clinical trial evidence. Methods In this phase 2 randomized trial, individuals at risk for RA with anti‐CCP3 ≥2 times the upper limit of normal (ULN) were assigned to receive HCQ or placebo for 12 months, with up to 24 months of postdrug follow‐up. The primary outcome was the development of clinical RA, as defined in the protocol, at 36 months. Secondary outcomes included safety, development of inflammatory arthritis (IA), and participant‐reported joint symptoms. Results Of 144 randomized participants, 71 were assigned to HCQ and 73 to placebo. In the modified intent‐to‐treat population, clinical RA occurred in 21 of 69 (30.4%) participants in the HCQ group and 24 of 73 (32.9%) in the placebo group. The risk of clinical RA at 36 months was 0.336 with HCQ and 0.394 with placebo (difference −0.058; 95% confidence interval −0.336 to 0.220; P = 0.52). Results for IA were similar. The occurrence and severity of joint symptoms were not observed to differ between groups. Adverse event incidence was similar between groups. Conclusion In this trial involving individuals with anti‐CCP3 levels ≥2 times the ULN, 12 months of HCQ did not prevent the development of clinical RA at 36 months. image

Objective: The objective of this study was to systematically review the literature-reported outcomes of CRYO compared to standard of care without CRYO (non-CRYO) after PEx repair. Summary Background Data: Surgical repair of pectus excavatum (PEx) via the Nuss or Ravitch procedures is associated with substantial postoperative pain. Intercostal nerve cryoablation (CRYO) performed during the primary surgical repair has been adopted as a non-opioid modality for pain management. Methods: A literature search was conducted in PubMed, Embase, and using additional online approaches to identify comparative studies of patients undergoing the Nuss or Ravitch procedure for PEx repair with CRYO versus non-CRYO between years 2014-24. Meta-analysis was performed to quantitatively evaluate primary outcomes of hospital length of stay (LOS) and opioid consumption. Secondary outcomes were hospital costs and complications, summarized qualitatively. Results: Of 178 studies, 32 comparative studies encompassing 13,103 patients were included; 28% (n=3,620) received CRYO. Random effects meta-analyses demonstrated a significantly shortened LOS by 1.8 days (95% confidence interval [CI]: -2.12, -1.42) and a significant reduction in inpatient and outpatient opioid consumption with CRYO by 186 morphine mg equivalents (MME) (95% CI: -262.26, -109.08) and 147 MME (95% CI: -255.72, -38.26), respectively. Complications with CRYO were either decreased or similar between groups and resolved over time. Hospital costs were similar. Conclusions: This systematic review suggests CRYO during PEx repair is associated with a significantly shorter hospital LOS, as well as decreased opioid consumption both in the hospital and after discharge. Complications were infrequent and time-limited.

ABSTRACT Bipolar disorder’s (BD) clinical heterogeneity has an unresolved genetic basis. We meta-analyzed genome-wide association studies (GWAS) of 16 BD subphenotypes in 226,032 individuals from 57 cohorts (38,022 cases); 10 advanced to multivariate and multi-trait analyses. Four factors (compulsive, psychotic, dysregulated, internalizing) explained 82.8% of shared genetic variance. BD1 and BD2 loaded on distinct factors despite a high genetic correlation; 87.0% of common-factor loci were significant in neither subtype. Unipolar mania aligned with psychosis over internalizing, and was distinguishable from BD1, and rapid cycling showed heritable cross-domain liability. We identified 356 risk loci, 158 novel, including the first univariate-GWAS associations for psychosis, unipolar mania, rapid cycling and schizoaffective disorder—and 249 credible genes (89 high-confidence), 12 with approved-drug or clinical-phase annotations. Cell-type association showed a midbrain dopaminergic–GABAergic gradient along the psychotic factor. BD’s genetic architecture appears hierarchical—a general liability resolving into dimensions of course and comorbidity beyond diagnostic subtypes.

Abstract Objective The objective of this study was to examine the clinical outcomes during the implementation of a self-administered patient decision-aid (PtDA) for lupus. Methods We provided an effective computerized lupus PtDA in 15 rheumatology outpatient clinics 2019–2024 (including the COVID pandemic). We undertook Organizational Readiness to Implement Change Surveys (ORICs) and Team Learning and Psychological Safety Surveys (TLPSSs) at baseline. The primary study outcome objective measure, percent penetration/reach, was defined as the number of patients who viewed the lupus PtDA at the end of the study, divided by the total number of eligible patients (times 100). We used validated clinical personnel surveys to examine the perceived lupus PtDA appropriateness, acceptability, feasibility, success, and permanence, at 4 months, 12 months and 24 months post-PtDA implementation. Results Among the sites, the clinical personnels’ (n = 184) baseline ORIC commitment and efficacy scores (a 0–5 scale, higher = better) ranged from 3.5 to 4.2, and 3.4 to 4.4, respectively; the TLPSS scores (a 0–7 scale, higher = better) were 3.9–5.5 for internal learning, 3.7–5.6 for external learning, and 4.3–5.5 for psychological safety. The penetration (primary outcome) among 15 geographically diverse US rheumatology clinics ranged from 3% to 44%. We found that the total number of providers in the clinic was positively associated with higher penetration. Clinical personnel–perceived lupus PtDA outcomes were optimal at 4 months (all scale scores ranged from 1 to 5, higher = better): (i) appropriateness, 3.43 (s.d. 0.86); (ii) acceptability, 3.53 (s.d. 0.83); (iii) feasibility, 3.44 (s.d. 0.71); (iv) success, 3.41 (s.d. 0.73); and (v) permanence, 3.22 (s.d. 0.74). Conclusion We implemented a lupus PtDA with varied success rates during the COVID pandemic; more providers were associated with higher clinic penetration. Clinical personnel perceived high lupus PtDA appropriateness, acceptability, feasibility, success, and permanence that persisted up to 24 months. Trial Registration ClinicalTrials.gov, http://clinicaltrials.gov, NCT03735238.

The interplay between intracellular and intravascular lipolysis is crucial for maintaining circulating lipid levels and systemic energy homeostasis. Adipose triglyceride lipase (ATGL) and lipoprotein lipase (LPL), the primary triglyceride (TG) lipases responsible for these two spatially separate processes, are highly expressed in adipose tissue. Yet the mechanisms underlying their coordinated regulation remain undetermined. Here, we demonstrate that genetic ablation of G0S2, a specific inhibitory protein of ATGL, completely abolished diet-induced hypertriglyceridemia and significantly attenuated atherogenesis in mice. These effects were attributable to enhanced whole-body TG clearance, not altered hepatic TG secretion. Specifically, G0S2 deletion increased circulating LPL concentration and activity, predominantly through LPL production from white adipose tissue (WAT). Strikingly, transplantation of G0S2-deficient WAT normalized plasma TG levels in mice with hypertriglyceridemia. In conjunction with improved insulin sensitivity and decreased ANGPTL4 expression, the absence of G0S2 enhanced the stability of LPL protein in adipocytes, a phenomenon that could be reversed upon ATGL inhibition. Collectively, these findings highlight the pivotal role of adipocyte G0S2 in regulating both intracellular and intravascular lipolysis, and the possibility of targeting G0S2 as a viable pharmacological approach to reducing levels of circulating TGs.

The NCCN Guidelines for Myelodysplastic Syndromes (MDS) provide recommendations for the evaluation, diagnosis, and comprehensive care of patients with MDS based on a review of recent clinical evidence that has led to important advances in treatment or has yielded new information on biologic factors that may have prognostic significance in MDS. The multidisciplinary panel of MDS experts is convened at least on an annual basis. During the annual meeting, the panel evaluates new and emerging data to inform their recommendations. These NCCN Guidelines Insights review the recent updates, including treatment recommendations both for lower-risk and higher-risk MDS, preference stratification of therapeutic agents, and emerging data on novel therapeutics.