Naqvi, Kiran

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.

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.

PURPOSE The FMS-related tyrosine kinase 3 (FLT3) inhibitor gilteritinib is standard therapy for relapsed/refractory FLT3-mutated ( FLT3 mut ) acute myeloid leukemia (AML) but seldom reduces FLT3 mut burden or induces sustained efficacy. Gilteritinib combines synergistically with the BCL-2 inhibitor venetoclax in preclinical models of FLT3 mut AML. METHODS This phase Ib open-label, dose-escalation/dose-expansion study (ClinicalTrials.gov identifier: NCT03625505 ) enrolled patients with FLT3 wild-type and FLT3 mut (escalation) or FLT3 mut (expansion) relapsed/refractory AML. Patients received 400 mg oral venetoclax once daily and 80 mg or 120 mg oral gilteritinib once daily. The primary objectives were safety, identification of the recommended phase II dose, and the modified composite complete response (mCRc) rate (complete response [CR] + CR with incomplete blood count recovery + CR with incomplete platelet recovery + morphologic leukemia-free state) using ADMIRAL phase III–defined response criteria. RESULTS Sixty-one patients were enrolled (n = 56 FLT3 mut ); 64% (n = 36 of 56) of FLT3 mut patients had received prior FLT3 inhibitor therapy. The recommended phase II dose was 400 mg venetoclax once daily and 120 mg gilteritinib once daily. The most common grade 3/4 adverse events were cytopenias (n = 49; 80%). Adverse events prompted venetoclax and gilteritinib dose interruptions in 51% and 48%, respectively. The mCRc rate for FLT3 mut patients was 75% (CR, 18%; CR with incomplete blood count recovery, 4%; CR with incomplete platelet recovery, 18%; and morphologic leukemia-free state, 36%) and was similar among patients with or without prior FLT3 inhibitor therapy (80% v 67%, respectively). The median follow-up was 17.5 months. The median time to response was 0.9 months, and the median remission duration was 4.9 months (95% CI, 3.4 to 6.6). FLT3 molecular response (< 10 −2 ) was achieved in 60% of evaluable mCRc patients (n = 15 of 25). The median overall survival for FLT3 mut patients was 10.0 months. CONCLUSION The combination of venetoclax and gilteritinib was associated with high mCRc and FLT3 molecular response rates regardless of prior FLT3 inhibitor exposure. Dose interruptions were needed to mitigate myelosuppression.

Abstract Background: Delirium is a highly prevalent and morbid syndrome in mechanically ventilated intensive care unit (ICU) patients. Music is a promising non-pharmacological intervention with beneficial effects on anxiety and stress, while its effects on delirium duration and severity are not well understood.Methods/design: Our study is a two-arm, randomized parallel-group, clinical trial to evaluate the efficacy of music intervention compared to a silence-track attention control on delirium/coma duration in mechanically ventilated critically ill older adults. One-hundred-sixty mechanically ventilated adults 50 years of age or older will be randomized to one of two arms within 72 hours of ICU admission: (1) one-hour music listening sessions twice daily through noise-cancelling headphones, or (2) one-hour sessions of a silence track twice daily through noise-cancelling headphones. Our primary aim is to compare delirium/coma free days after randomization during the 7-day study intervention phase using the Confusion Assessment Method for the ICU (CAM ICU) and the Richmond Agitation Sedation Scale (RASS) for delirium and coma. Secondary outcomes include pain and anxiety evaluated twice daily during the intervention phase and throughout the duration of ICU stay using the Critical Care Pain Observation Tool (CPOT) and Visual Analogue Scale-Anxiety (VAS-A). Enrolled participants will be followed after hospital discharge to further measure cognition as well as screening for depression and anxiety using the following telephone-based instruments: Indiana University Telephone-Based Assessment of Neuropsychological Status (IU TBANS), Patient Health Questionnaire-9 (PHQ-9), and Generalized Anxiety Disorder-7 (GAD-7).Discussion: This randomized clinical trial will measure the efficacy of a music listening intervention for delirium and coma duration early in the intensive care unit among older adults.Trial Registration: https://clinicaltrials.gov/ct2/show/NCT04182334

Abstract Gilteritinib (Gilt), a FLT3 tyrosine kinase inhibitor (TKI), is approved for the treatment of relapsed/refractory (R/R) FLT3-mutated (FLT3 +)acute myeloid leukemia (AML). However, long-term survival is limited by the development of drug resistance mutations in persistent FLT3 + clones. Combination regimens may deepen response and improve outcomes. Venetoclax (Ven), a BCL-2 inhibitor, is approved in combination with hypomethylating agents for newly diagnosed AML not suitable for standard induction therapy. FLT3 + AMLhas been associated with clinical resistance to Ven. Still, FLT3 TKIs + Ven have demonstrated synthetic lethality in preclinical models, prompting this multicenter, open-label, phase 1b trial (NCT03625505) to evaluate Ven + Gilt for R/R AML. Here, we report final response and survival endpoints, and molecular clearance among patients (pts) treated at the recommended phase two dose (RP2D). The study design has been previously described (Daver, et al. ASH 2020, Abstract 333). Pts in the dose expansion cohort received Ven 400 mg + Gilt 120 mg (RP2D) daily in 28-day cycles, following Ven ramp-up. The primary endpoint was mCRc (complete response [CR] + CR with incomplete platelet recovery [CRp] + CR with incomplete blood count recovery [CRi] + morphologic leukemia-free state) to align with the ADMIRAL phase III trial (Perl, et al. NEJM 2019). Baseline co-mutations and serial FLT3 internal tandem duplications (ITD) allelic burden were assessed using the MyAML panel (Invivoscribe, San Diego, CA) and FLT3-ITD MRD assay with sensitivities of 5% and 0.001%, respectively. As of the data cut off of January 31, 2021, 54 pts were treated at the RP2D. Fifty-two pts (as assessed locally) had FLT3 +AML; 41 had FLT3-ITD only, 8 had tyrosine kinase domain only, 3 had both mutations, and 2 were FLT3 wild type (wt). Additional baseline characteristics are in Table 1. Grade 3 or 4 AEs occurred in 51 (94.4%) pts, and 39 (72.2%) pts had serious AEs. Grade 3 or 4 cytopenias occurred in 43 (79.6%) pts. AEs of special interest included tumor lysis syndrome (2 [3.7%]) and QT prolongation (1 [1.9%]). AEs leading to dosing interruptions (Ven, 27 [50%]; Gilt, 26 [48.1%]), reductions (Ven, 3 [5.6%]; Gilt, 4 [7.4%]), and discontinuation (Ven, 7 [13%]; Gilt, 7 [13%]) were reported for both study drugs. There was 1 treatment-emergent death of typhlitis. Among FLT3 + pts with post-baseline assessments (51/52), mCRc was achieved by 38 pts (74.5%; CR/CRp/CRi, 19 [37.3%] pts), with a median follow-up time of 12 mo (range: 0.8 - 20.1). The mCRc in pts with prior TKI (32) or prior Ven (10) use were 78.1% and 60%, respectively. The mOS among all FLT3 +pts was 10 mo (95%CI: 6.6, NE), with a median DoR (mDoR) of 5.4 mo (95% CI: 3.3, 6.6). Pts with FLT3-ITD had a mOS of 10.5 mo (95%CI: 6.8, NE), and a mDoR of 5.6 mo (95% CI: 3.3, 8.3). For the 14 pts who had a transplant, the mOS was not reached (95%CI: 10.0, NE) vs 6.89 mo (95%CI: 3.0, 10.5) for those who did not have a transplant (37). The mOS for pts with prior TKI or Ven was 9.6 (95% CI: 4.3, NE) and 10.5 mo (95% CI: 2.0, NE), respectively, with a mDoR of 9.6 (95% CI: 4.3, NE) and 6.2 mo (95% CI: 2.6, NE), respectively. The 60-day mortality rate was 11.8% (95% CI: 4.4, 23.9). The mCRc for NPM1 + and NPM1wt were 92.3% and 61.1%, respectively. mCRc for DNMT3A + and DMNT3A wt pts were 82.4% and 64.3%, respectively. WT1 + and WT1 wt mCRc were 66.7% and 77.3%, respectively. The mCRc for NPM1 + and DNMT3A + co-mutated pts was 100%. In a post hoc analysis of the 30 analyzable mCRc pts with at least one follow-up MRD assessment, 17 (56.7%) achieved molecular clearance defined as FLT3 allelic burden &lt; 10 -2. The mOS of pts achieving mCRc with FLT3 allelic burden of &lt; 10 -2 vs mCRc with FLT3 allelic burden ≥ 10 -2 (Figure 1) was not reached (95% CI: 9.76, NE) vs 6.83 mo (4.21, NE). Ven + Gilt achieved high mCRc in patients with R/R FLT3 + AML, with or without prior TKI exposure, and an encouraging mOS. FLT3 mutation clearance was seen in a majority of patients and associated with longer OS. Encouraging remission rates were observed across many genotypes and were particularly high among pts with NPM1 + +/- DNMT3A co-mutation. Cytopenias were common but manageable with appropriate Ven or Gilt dosing modifications. Serial NGS molecular data, as well as updated survival data will be presented at the meeting. Figure 1 Figure 1. Disclosures Daver: Hanmi: Research Funding; Abbvie: Consultancy, Research Funding; Trillium: Consultancy, Research Funding; Trovagene: Consultancy, Research Funding; Novimmune: Research Funding; FATE Therapeutics: Research Funding; Glycomimetics: Research Funding; Amgen: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Gilead Sciences, Inc.: Consultancy, Research Funding; Sevier: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; Novartis: Consultancy; Jazz Pharmaceuticals: Consultancy, Other: Data Monitoring Committee member; Dava Oncology (Arog): Consultancy; Celgene: Consultancy; Syndax: Consultancy; Shattuck Labs: Consultancy; Agios: Consultancy; Kite Pharmaceuticals: Consultancy; SOBI: Consultancy; STAR Therapeutics: Consultancy; Karyopharm: Research Funding; Newave: Research Funding. Perl: Actinium: Consultancy; Genentech: Consultancy; Roche: Consultancy; Astellas: Consultancy, Research Funding; Forma: Consultancy; Syndax: Consultancy; Loxo: Consultancy; Fujifilm: Research Funding; Arog: Research Funding; BMS/Celgene: Consultancy; AbbVie: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Onconova: Consultancy; Sumitomo Dainippon: Consultancy. Levis: Amgen, Astellas Pharma, Daiichi-Sankyo, FujiFilm, and Menarini: Honoraria; Astellas and FujiFilm: Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; Jazz: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Ritchie: Astellas: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria; Celgene/BMS: Consultancy, Other: travel support, Speakers Bureau; Bristol Myers Squibb: Consultancy, Research Funding; NS Pharma: Research Funding; Incyte: Consultancy, Honoraria, Speakers Bureau; Abbvie: Consultancy, Honoraria; Jazz: Consultancy, Research Funding; Protaganist: Consultancy, Honoraria; ARIAD Pharmaceuticals: Ended employment in the past 24 months, Speakers Bureau; Pfizer: Consultancy, Research Funding. Litzow: Astellas: Research Funding; Omeros: Other: Advisory Board; Pluristem: Research Funding; AbbVie: Research Funding; Amgen: Research Funding; Actinium: Research Funding; Jazz: Other: Advisory Board; Biosight: Other: Data monitoring committee. McCloskey: Jazz: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Smith: AbbVie: Research Funding; Revolutions Medicine: Research Funding; Daiichi Sankyo: Consultancy; FUJIFILM: Research Funding; Astellas Pharma: Consultancy, Research Funding; Amgen: Honoraria. Schiller: Takeda: Research Funding; Trovagene: Research Funding; Tolero: Research Funding; Ono: Consultancy; Novartis: Consultancy, Research Funding; ASH foundation: Other: Chair-unpaid; Pfizer: Current equity holder in publicly-traded company, Research Funding; Incyte: Consultancy; Sanofi: Honoraria, Research Funding, Speakers Bureau; Ariad: Research Funding; Stemline Therapeutics, Inc.: Honoraria, Research Funding, Speakers Bureau; Ono-UK: Consultancy, Research Funding; Karyopharm: Research Funding; Kite/Gilead: Honoraria, Research Funding, Speakers Bureau; Onconova: Research Funding; Mateon: Research Funding; Sangamo: Research Funding; Samus: Research Funding; Regimmune: Research Funding; PrECOG: Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AstraZeneca: Consultancy; Kaiser Permanente: Consultancy; Cyclacel: Research Funding; MedImmune: Research Funding; Ambit: Research Funding; Agios: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy, Current equity holder in publicly-traded company, Honoraria, Research Funding, Speakers Bureau; Jazz: Consultancy, Honoraria, Research Funding, Speakers Bureau; Elevate: Research Funding; Bio: Research Funding; Pharma: Consultancy; Johnson & Johnson: Current equity holder in publicly-traded company; Biomed Valley Discoveries: Research Funding; Eli Lilly: Research Funding; Sellas: Research Funding; Geron: Research Funding; Genentech-Roche: Research Funding; Gamida Cell Ltd.: Research Funding; FujiFilm: Research Funding; Forma: Research Funding; Delta-Fly: Research Funding; Deciphera: Research Funding; Daiichi-Sankyo: Research Funding; Constellation Pharmaceuticals: Research Funding; Celator: Research Funding; BMS/Celgene: Consultancy, Current equity holder in publicly-traded company, Research Funding, Speakers Bureau; Astellas: Honoraria, Research Funding, Speakers Bureau; Arog: Research Funding; Actuate: Research Funding; Actinium Pharmaceuticals, Inc: Research Funding; Abbvie: Research Funding; Leukemia & Lymphoma Society: Research Funding; Bluebird Bio: Research Funding; Boehringer-Ingleheim: Research Funding; Cellerant: Research Funding; CTI Biopharma: Research Funding; Janssen: Research Funding; Kura Oncology: Research Funding; Pharmacyclics: Honoraria, Speakers Bureau; Millennium: Research Funding; National Marrow Donor Program: Research Funding; NIH: Research Funding; Onyx: Research Funding; Pharmamar: Research Funding; UC Davis: Research Funding; UCSD: Research Funding; Evidera: Consultancy; NCI: Consultancy; Novartis: Speakers Bureau. Bradley: AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Tiu: Astellas Pharma: Current Employment; Eli Lilly and Company: Current equity holder in publicly-traded company, Ended employment in the past 24 months. Naqvi: Genentech/Roche: Current Employment, Current holder of stock options in a privately-held company. Dail: Genentech/Roche: Current Employment, Current equity holder in publicly-traded company. Siddani: AbbVie: Current Employment, Current holder of stock options in a privately-held company. Wang: AbbVie: Current Employment, Current holder of stock options in a privately-held company. Chyla: AbbVie: Current Employment, Current equity holder in publicly-traded company. Lee: AbbVie: Current Employment, Current holder of stock options in a privately-held company. Altman: Astellas: Consultancy, Other: Advisory Board, Research Funding; AbbVie: Consultancy, Other: Advisory Board, Research Funding; Biosight: Consultancy, Other: Travel fees, Research Funding; Daiichi Sankyo: Consultancy; Kura Oncology: Consultancy; Syros: Consultancy; Theradex: Consultancy, Other: Advisory boards; GlycoMimetics: Other: Participation on an advisory board; ALZ Oncology: Research Funding; Amgen: Research Funding; Aprea: Research Funding; BMS: Research Funding; Boehringer Ingelheim: Research Funding; Fujifilm: Research Funding; Immunogen: Research Funding; Kartos: Research Funding; Kura: Research Funding. OffLabel Disclosure: Venetoclax is a B-cell lymphoma 2 inhibitor approved in combination with azacitidine, or decitabine, or low-dose cytarabine for the treatment of newly-diagnosed acute myeloid leukemia (AML) in adults who are age 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy. Gilteritinib is a kinase inhibitor indicated for the treatment of adult patients who have relapsed or refractory acute myeloid leukemia (AML) with an FLT3 mutation as detected by an FDA-approved test.

Chronic myeloid leukemia (CML) is defined by the presence of Philadelphia chromosome (Ph) which results from a reciprocal translocation between chromosomes 9 and 22 [t(9;22] that gives rise to a BCR-ABL1 fusion gene. CML occurs in 3 different phases (chronic, accelerated, and blast phase) and is usually diagnosed in the chronic phase. Tyrosine kinase inhibitor therapy is a highly effective first-line treatment option for all patients with newly diagnosed chronic phase CML. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of patients with chronic phase CML.