Daurismo (glasdegib) / Pfizer - LARVOL DELTA

Daunorubicin and cytarabine liposomal (CPX-351) plus glasdegib for newly diagnosed secondary Acute Myeloid Leukemia: Results of University of California hematologic malignancies consortium trial 1913 (ASH 2025) - P2 | "Thus clearance, not just morphologic remission,may be a critical endpoint in sAML.Conclusion Despite encouraging safety/activity, the study did not meet the primary endpoint of EFS. TheCPX-351/glasdegib combination may offer benefit in sAML, particularly as a bridge to alloHCT.Encouraging responses with MRDneg rates were observed in TP53mut pts."

Acute Myelogenous Leukemia • Febrile Neutropenia • Gastroenterology • Gastrointestinal Disorder • Immunology • Infectious Disease • Neutropenia • Oncology • Respiratory Diseases • Septic Shock • TP53

Targeting hedgehog signaling/KL4-dependent M2 macrophage polarization for treatment of chronic graft-versus-host diseases and tissue fibrosis (ASH 2025) - "Tissue immune microenvironment analysis by multiplex IF revealed the enrichment of M2 MФand Smo+ MФ and their association with tissue fibrosis of the lung and skin, as well as skin damageseverity scores (Lee SJ, Blood, 2017) in cGVHD pts cohorts.Moreover, cGVHD mice were treated with vehicle control, Smo inhibitor (Smoi, Glasdegib), KLF4 inhibitor(KLF4i, Kenpaullone), and their combination for 28 days, starting on day 12 or 28 post-HCT forpreventative or curative therapy... Our study using mouse models and patient cohorts underscored the relevance of theHh/KLF4-dependent M2 polarization in cGVHD progression and tissue fibrosis, demonstrating thatgenetic and therapeutic targeting of Smo/KLF4-mediated M2 MФ polarization blocked the progression ofcGVHD and tissue fibrosis. Our results identified a novel mechanism of cGVHD, providing importantinsights and clinical relevance for precisely targeting M2 macrophage polarization as a new therapeuticapproach for treating cGVHD and..."

Bone Marrow Transplantation • Chronic Graft versus Host Disease • Dermatology • Fibrosis • Graft versus Host Disease • Immunology • Pulmonary Disease • Respiratory Diseases • ITGAM • KLF4 • MRC1 • TGFB1

MULTISARC: Molecular Profiling of Advanced Soft-tissue Sarcomas (clinicaltrials.gov) - P3 | N=603 | Active, not recruiting | Sponsor: Institut National de la Santé Et de la Recherche Médicale, France | Trial completion date: Oct 2025 ➔ Jan 2026

IO biomarker • Trial completion date • Oncology • Sarcoma • Soft Tissue Sarcoma • Solid Tumor

Acute myeloid leukemia drug resistance: targetable nodes and the clinical trajectory of small-molecule inhibitors. (PubMed, Front Pharmacol) - "Over the past decade, six targeted or pathway-directed small molecules-midostaurin, gilteritinib, quizartinib, ivosidenib, enasidenib, venetoclax and glasdegib-have changed frontline and relapsed/refractory (R/R) practice in genomically defined subgroups or in patients unfit for intensive chemotherapy. Here we integrate mechanistic insights with clinical evidence to: (i) map resistance biology onto targetable nodes (apoptosis control; signalling kinases; chromatin/lineage programmes; RNA splicing; DNA-damage response; nuclear export; niche adhesion and innate immune evasion); (ii) summarise the clinical trajectory and current limits of approved and emerging small molecules (including menin and LSD1 inhibitors); (iii) propose rules for rational doublets and triplets that are biologically orthogonal yet clinically tolerable; (iv) outline a regulatory timeline for key AML small molecules; and (v) prioritise where drug development should go next, including next-generation..."

Journal • Review • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

A Phase 1b Multi-Center Study of the FLT3 Inhibitor Gilteritinib in Combination with the IDH1 Inhibitor Ivosidenib or the IDH2 Inhibitor Enasidenib for Patients with Relapsed or Refractory Acute Myeloid Leukemia Who Have Co-Occurring FLT3/IDH1 or FLT3/IDH2 Mutations (ASH 2023) - P1 | "This study is partially supported by Astellas Pharma Global Development, Inc. The study population will include patients with AML with dual FLT3 and IDH1/IDH2 mutations R/R to initial intensive induction therapy, or for patients treated with low intensity therapy, the patient must be refractory to treatment with a single agent hypomethylating agent (HMA) or low dose cytarabine (LDAC) (at least two cycles) or an HMA/LDAC in combination with venetoclax (at least one cycle) or another standard of care therapy (e. g. gemtuzumab ozogamicin, glasdegib/LDAC). Patients with a history of autologous or allogeneic stem cell transplant for AML are permitted to participate in the study."

Clinical • Combination therapy • P1 data • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • FLT3 • IDH1 • IDH2

Representation of Older Adults in FDA and EMA Registrational Trials for Acute Myeloid Leukemia (AML) (ASH 2024) - "Four drugs were approved in 2017 : midostaurin (ND FLT3-ITD/-TKD+ AML), enasidenib (R/R IDH2-mutated AML), CPX-351 (ND secondary-AML), and gemtuzumab ozogamicin (ND or R/R CD33+ AML)...Venetoclax combinations with decitabine/azacitidine/LDAC (newly diagnosed AML ≥75 years or unfit for IC) were approved between 2018-2020...Five trials (ivosidinib in ND, ivosidinib with azacitidine, glasdegib+LDAC, and venetoclax combined with azacitidine or LDAC) had a median age of >75 years and these trials were designed as specific to patients ≥75 years or those ineligible for IC...Trials assessing FLT3 inhibitors had a lower median age than other therapies with median ages of 48 (midostaurin), 56 (quizartinib), and 62 (gilteritinib) years on these trials...In the future, reporting of trials should include and distinguish patients both older than 65 and older than 75 for subgroup analyses. Standardization of age subgroup reporting with subpopulation analysis will better enable..."

Clinical • Acute Myelogenous Leukemia • Geriatric Disorders • Hematological Malignancies • Leukemia • Oncology • CD33 • FLT3 • IDH1 • IDH2

Glasdegib in combination with temozolomide and radiotherapy in adult patients with newly diagnosed glioblastoma: the phase Ib/II GEINO 1602 trial. (PubMed, Nat Commun) - P1/2 | "Despite not surpassing the futility threshold, 30% lived at the data cutoff. Translational research will help define the molecular traits of long-term survivors."

Journal • P1/2 data • Brain Cancer • Glioblastoma • Oncology • Solid Tumor

Predictors of Relapse and Post-Relapse Outcomes in Patients with Newly-Diagnosed Acute Myeloid Leukemia Treated with Venetoclax + Hypomethylating Agent (ASH 2024) - "50 of 99 (65%) patients received salvage therapy which included cladribine-cytarabine-Ven (n=19), intensive induction chemotherapy (n=9), FLT3 inhibitors (n=5), Ven-HMA-FLT3 inhibitor (n=1), IDH1/2 inhibitors (n=5), glasdegib-cytarabine (n=4), gemtuzumab (n=3), lenalidomide (n=1), or investigational therapies (n=3); in addition, Ven-HMA was resumed in 14 patients in whom treatment had been discontinued for a median of 5 months (2-12). Conclusions The current study identifies male gender, TP53 mutations, and MRD status as powerful predictors of relapse and proposes a relapse prediction model for ND-AML patients receiving Ven-HMA therapy. Furthermore, relapse following Ven-HMA was associated with uniformly poor outcomes, regardless of salvage treatment strategy."

Clinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • ASXL1 • DDX41 • DNMT3A • FLT3 • IDH1 • IDH2 • NPM1 • NRAS • RUNX1 • SRSF2 • TET2 • TP53

Racial Disparities in Acute Myeloid Leukemia and Myelodysplastic Syndrome US FDA Drug Approval Trials (ASH 2023) - "(Table 1) Olutasidenib, glasdegib plus low dose cytarabine, gemtuzumab-ozogamicin, liposome-encapsulated combination of daunorubicin and cytarabine, ivosidenib, and midostaurin were approved for AML. An oral combination of decitabine and cedazuridine was approved for MDS... Despite being affected adversely to a significant degree by AML, black patients are underrepresented in drug trials. More efforts should be made to include them in trials so that better treatment plans can be formulated for this underrepresented group of patients."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology

Prospective Real-World Outcomes of Acute Myeloid Leukemia (ASH 2023) - "7%) backbone and Azacitidine alone (13... Progression free survival obtained after induction therapy and overall survival were relatively shorter than the ones which were presented by other real-world registries. Lack of early access to the targeted and novel agents, like Flt3 inhibitors, Venetoclax, IDH1 and 2 inhibitors, CPX351 and Glasdegib should be a potential explanation to this relatively short PFS and OS. We have also been aware of un-ideal access to well established and nation wide cytogenetic laboratory service to induce early integration of targeted agents to the treatment and better risk stratification to determine the patients who should obtain the best prolonged survival via allo-HCT."

Clinical • Real-world • Real-world evidence • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • IDH1

Association of Glasdegib + Low-Dose Cytarabine (AraC)) in the Real-Life Treatment of Very Frail Elderly Acute Myeloid Leukemias (AML) Patients (ASH 2024) - "Twenty-three out of 29 pts (79.3%) had a previous myelodysplastic neoplasia (MDS) and 19 of them have been treated with azacytidine (AZA) during the MDS phase. Pts with any type of response had a significantly longer OS compared to pts with progressive/stable disease [median not reached after 12.5 months versus 2.5 (95%CI 1.1-3.9) months, respectively (p=0.026)].Conclusions : Our real-life data suggest that glasdegib + AraC combination could be useful only in a small fraction of very frail/elderly AML pts, with an ORR of about 20% in subjects otherwise unfit for any available curative approach : despite the poor outcomes, the potential OS benefit observed in pts who achieved any type of response points to a better selection of pts candidates to this association. Moreover, the addition of other targeted therapies driven by NGS should be explored in the next future in this subset."

Clinical • Acute Myelogenous Leukemia • Geriatric Disorders • Hematological Disorders • Hematological Malignancies • Infectious Disease • Leukemia • Myelodysplastic Syndrome • Neutropenia • Oncology • Respiratory Diseases

Indirect Treatment Comparison of Ivosidenib and Other Therapies in Patients with Newly Diagnosed Acute Myeloid Leukemia (ASH 2024) - P3 | "Introduction : The combination of ivosidenib (IVO) (an inhibitor of mutant isocitrate dehydrogenase 1 [IDH1]) and azacitidine (AZA) has recently shown significant clinical benefit, compared with placebo and AZA, in a Phase III trial in patients with newly diagnosed IDH1-mutated (IDH1m) acute myeloid leukemia (AML) who were ineligible for intensive induction chemotherapy (iCI) (AGILE; ClinicalTrials.gov number, NCT03173248)...Results : Following the SLR and feasibility assessment, six studies were considered eligible for inclusion in the NMA, which reported outcomes for the treatments IVO + AZA, AZA, low-dose cytarabine (LDAC), decitabine, venetoclax + AZA, venetoclax + LDAC and glasdegib + LDAC...Results from the anchored MAIC demonstrated consistent survival benefit with the NMA, for the comparison of IVO + AZA compared to venetoclax + AZA (HR 0.71; 95% CI 0.43-1.19). Conclusions : ITCs using both NMA and MAIC methods generated consistent results, demonstrating a..."

Clinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • IDH1

Deciphering the Role of RAS Pathway Mutations in the Biology of Human Acute Myeloid Leukemia Using In Vivo Models (ASH 2023) - "Some SMO inhibitors have been tested in clinical trial and Glasdegib is FDA approved in combination with low dose cytarabine in elderly patients. Given the success of generating these two point mutations, we are currently generating more RAS pathway mutations, including other KRAS mutations, PNTP11 and NF1 mutations. Conclusion These experiments showed: 1) It is possible to induce 2 oncogenic hits in human primary cells and get leukemia in vivo; 2) the KRAS G13D and NRAS G12D mutations shorten the latency of the disease and 3) increase the LSC frequency in secondary mice; 4) a possible involvement of the Hh pathway on stemness/LSC in RAS mutated cells; 5) our experimental approach is robust and very promising to decipher the RAS pathway in human MLL leukemias."

Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • CD34 • KRAS • NF1 • NRAS • PTCH1

The Challenge of Treating Relapsed Myeloid Leukemia in Children with Down Syndrome - a Targeted Analysis Using Patient-Derived Xenograft Models (ASH 2023) - "We used patient-derived xenografts (PDX) of human ML-DS and relapsed ML-DS blasts in immunodeficient mice (NSG and NSG-W41) to determine in vivo responses to standard chemotherapeutic agents (cytarabine, vincristine) and novel approaches such as demethylating agents (azacytidine), inhibition of histone deacetylation (panobinostat), mTOR (rapamycin), PARP (olaparib), and sonic hedgehog signaling (glasdegib) alone or in combination (glasdegib + cytarabine; panobinostast + azacytidine). Patient-specific molecular mechanisms underlying relapsed ML-DS are likely to have an impact on drug sensitivity. They should be determined for all patients with relapsed ML-DS to assist identification of targets and selection of drugs in order to establish urgently needed but currently still lacking efficacious treatment for relapsed ML-DS."

Preclinical • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Bone Marrow Transplantation • Developmental Disorders • Genetic Disorders • Hematological Disorders • Hematological Malignancies • Immunology • Leukemia • Oncology • T Acute Lymphoblastic Leukemia • Transplantation • GATA1

DECITABINE/CEDAZURIDINE THERAPY FOR VERY ELDERLY PATIENTS WITH ACUTE MYELOID LEUKEMIA: SINGLE-CENTER EXPERIENCE IN 5 CASES (SIE 2025) - "The combination of a HMAs with venetoclax has shown good efficacy and tolerability in this setting...In these cases, the preferred therapeutic options are usually monotherapy with a HMAs or the combination of Glasdegib and low dose cytarabine...Table 1. Clinical features of AML patients treated with Decitabine/cedazuridine."

Clinical • Acute Myelogenous Leukemia • Anemia • Hematological Disorders • Hematological Malignancies • Infectious Disease • Leukemia • Neutropenia • Pneumonia • Thrombocytopenia • FLT3 • NPM1

ASSOCIATION OF GLASDEGIB + LOW-DOSE CYTARABINE IN THE REAL-LIFE TREATMENT OF VERY FRAIL ELDERLY PATIENTS WITH ACUTE MYELOID LEUKEMIA (SIE 2025) - "In addition, the potential OS advantage observed in responding pts highlights the need for a better selection of pts candidates to this association. Moreover, the addition of NGS- driven targeted therapies should also be explored in the near future in this subset."

Clinical • Acute Myelogenous Leukemia • Geriatric Disorders • Hematological Disorders • Hematological Malignancies • Infectious Disease • Leukemia • Neutropenia • Respiratory Diseases • ASXL1 • IDH1 • RUNX1 • SRSF2

Dual Targeting of Smoothened, a Key Regulator in the Hedgehog Pathway, and BCR-ABL1 Effectively Eradicates Drug-Insensitive Stem/Progenitor Cells in Chronic Myeloid Leukemia. (PubMed, Cells) - "Inhibition of SMO through genetic knockdown or with a potent, selective SMO inhibitor, Glasdegib, reduces the survival of cells from nonresponder patients. Notably, SMO inhibition also sensitizes TKI-nonresponder stem/progenitor cells to Bostutinib, a second-generation TKI, both in vitro and in a patient-derived xenotransplantation (PDX) model. These findings present a promising therapeutic target and a model for curative combination therapies in stem-cell-driven cancers."

Journal • Chronic Myeloid Leukemia • Hematological Malignancies • Leukemia • Oncology • Transplantation • ABL1 • BCR • CD34 • GLI2

Gastrointestinal adverse events associated with Hedgehog pathway inhibitors: a disproportionality analysis. (PubMed, Int J Pharm Pract) - "HPIs had triggered various types of GIAEs. Liver injuries were a safety concern for the HPI-treated patient, which was not listed by the USFDA. Further researches are needed to confirm these findings."

Adverse events • Journal • Basal Cell Carcinoma • Liver Failure • Non-melanoma Skin Cancer • Oncology

A Novel Three Small Molecule Inhibitor Combination Therapy For Prostate Cancer. (PubMed, Anticancer Res) - "The combined treatment proposed in this study is novel and promising in overcoming drug resistance and side-effects of single agents and may herald a new era in the treatment paradigm for prostate cancer."

Journal • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

pf04: Acute myeloid leukemia - Clinical (EHA 2025) - No abstract available

Clinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

DETERMINING THE INVOLVEMENT OF THE HEDGEHOG SIGNALING PATHWAY IN THE DEVELOPMENT OF RESISTANCE AGAINST VENETOCLAX IN ACUTE MYELOID LEUKEMIA (EHA 2025) - "While the BCL2 inhibitor Venetoclax combined with either Azacitidine or low-dose Cytarabine showed promising initial responses, 25-56% of patients relapsed within 3.9-11.7 months in two studies. The Hh signaling is dysregulated upon development of Venetoclax resistance in MOLM-13 cells. The addition of Glasdegib to Venetoclax overcomes this resistance in VE-RE MOLM-13 induced by the intermittent Venetoclax dosing. This finding provides a rationale for clinical trials incorporating both intermittent Venetoclax and Glasdegib for AML treatment."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • ANXA5 • BCL2L1 • CCND1 • MCL1 • MDM4 • PTCH1

Indirect treatment comparison of ivosidenib and other therapies in patients with newly diagnosed acute myeloid leukemia. (PubMed, Future Oncol) - "To assess the relative efficacy of ivosidenib + azacitidine versus other therapies (venetoclax, glasdegib, azacitidine, decitabine and low-dose cytarabine [LDAC]) for the treatment of patients with newly diagnosed IDH1-mutated (mIDH1) acute myeloid leukemia (AML) ineligible for intensive induction chemotherapy. The MAIC showed that ivosidenib + azacitidine was associated with numerically favorable OS compared to venetoclax + azacitidine. Both NMA and MAIC methods generated consistent results, demonstrating a benefit of ivosidenib + azacitidine versus other therapies for the treatment of newly diagnosed IDH1m AML."

Journal • Review • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • IDH1

Smoothened Inhibitor, PF-04449913 Inhibits the Development of Myelofibrosis in a JAK2V617F Transgenic Mouse Model by Reducing TGF-β and MAPK Signaling Pathways. (PubMed, Res Sq) - "Treatment of JAK2V617F driven myeloproliferative neoplasms (MPNs) with Ruxolitinib (JAK inhibitor, JAKi) has shown limited disease-modifying benefits and has led to the search for other pathways as potential therapeutic targets for this disease. Finally, we found that SMO inhibitor blocks bone marrow fibrosis by reducing TGF-β signaling. In conclusion, this report provides critical insight into the mechanism of action of SMO inhibitors in JAK2V617F associated MPN."

Journal • Preclinical • Bone Marrow Transplantation • Fibrosis • Immunology • Myelofibrosis • Myeloproliferative Neoplasm • Oncology • Transplantation • TGFB1

Budget Impact Analysis of Venetoclax Combination Therapies for the Treatment of Newly Diagnosed Acute Myeloid Leukemia Patients Who Are Aged 75 Years or Older, or Who Have Comorbidities That Preclude Use of Intensive Induction Chemotherapy (ISPOR 2025) - "The most up-to-date market share, reflecting the current treatment landscape projected venetoclax + azacitidine or decitabine to capture 53% and 15% market share, respectively, from existing treatments (azacitidine, low-dose cytarabine [LDAC], decitabine, ivosidenib, gemtuzumab ozogamicin, glasdegib + LDAC, and ivosidenib + azacitidine). Use of venetoclax combinations for the treatment of FDA-approved indication of ND AML reduced the budget impact and provides potential financial benefit for US payers."

Clinical • Combination therapy • HEOR • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

Glasdegib combined with chemotherapy in the treatment of patients with acute myeloid leukemia: a comprehensive meta-analysis. (PubMed, Invest New Drugs) - "Glasdegib combined with chemotherapy demonstrates promising efficacy in improving survival outcomes for AML patients, particularly in combination with Cytarabine and Daunorubicin. While adverse events were common, they were generally manageable, supporting Glasdegib as a viable therapeutic option. Further research is warranted to optimize treatment regimens and evaluate long-term safety and quality-of-life outcomes."

Journal • Retrospective data • Review • Acute Myelogenous Leukemia • Febrile Neutropenia • Hematological Disorders • Hematological Malignancies • Leukemia • Neutropenia • Oncology