A phase 1 study of IO-202, an anti-LILRB4 antibody, in chronic myelomonocytic leukemia and acute myeloid leukemia.

IO-202 is a humanized immunoglobulin G1 monoclonal antibody with high affinity and specificity for leukocyte immunoglobulin-like receptor B4 (LILRB4; ILT3), which is predominantly expressed in monocytes and monocytic blasts. IO-202 induces antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis in vitro and in patients with leukemia. Herein, we present the phase 1a dose escalation data of IO-202 as monotherapy and in combination with azacitidine (AZA) in patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) and R/R chronic myelomonocytic leukemia (CMML), and the phase 1b dose expansion data of IO-202 combined with AZA for the treatment of hypomethylating agent (HMA)-naïve CMML.

Apoptosis-targeting BH3 mimetics: transforming treatment for patients with acute myeloid leukaemia.

Acute myeloid leukaemia (AML) remains a challenging haematological malignancy, with most patients developing resistance to standard-of-care (SOC) treatments. This resistance is often attributed to the overexpression of anti-apoptotic BCL-2 family proteins, which regulate the intrinsic apoptotic pathway by inhibiting pro-apoptotic effector proteins such as BAX and BAK. AML cells exploit this imbalance to evade apoptosis and sustain survival, necessitating the development of novel therapeutic strategies.

Preclinical efficacy of tasquinimod-based combinations in advanced myeloproliferative neoplasms (MPN) in blastic phase.

The alarmins, S100A8 (A8) and S100A9 (A9), are low molecular weight proteins belonging to the S100 protein family. A8 and A9 are secreted into the extracellular space and plasma, where they interact with TLR4 (Toll like receptor 4), RAGE (receptor for advanced glycation end products) and CD33. In present studies, we determined the preclinical efficacy of tasquinimod (TQ) against advanced MPN cell lines and patient-derived (PD) CD34+ blastic phase (BP, >5% blasts in PB) MPN cells.

Mortality and relapse dynamics in AML after three years of complete remission.

Patients with AML remain at risk of death after therapy. Our objective was to characterize patients with AML after three years in remission. 453 patients were documented to be alive and in remission 3 years after diagnosis, median follow-up was 7.

Newly diagnosed acute myeloid leukemia in unfit patients: 2026 treatment algorithms.

Management paradigms for newly-diagnosed acute myeloid leukemia (ND-AML) in patients considered unfit to receive intensive chemotherapy have evolved with improved understanding of disease biology. In this setting, management requires clear delineation of goals of therapy that should include preservation of quality-of-life (QoL). Combination of venetoclax (Ven) and a hypomethylating agent (HMA) is the current standard-of-care in most circumstances with flexible options in regard to drug dose and duration of treatment as well as the addition (triplet combinations) or alternative use of targeted therapies, such as inhibitors of FLT3, IDH1, IDH2, or menin for patients with NPM1 or KMT2A rearrangements (KMT2Ar).

Outcomes of patients with newly diagnosed acute myeloid leukemia with FLT3-tyrosine kinase domain mutations: Prognostic implications of NPM1 co-mutation.

Background: The prognostic impact of Fms-like tyrosine kinase 3 (FLT3)-tyrosine kinase domain (TKD) mutation in patients with acute myeloid leukemia (AML) is not well defined. The authors described outcomes of one of the largest cohorts of patients with FLT3-TKD mutated (FLT3-TKD) AML to date.

Methods: This retrospective study included patients with newly diagnosed AML who received frontline treatment at The University of Texas MD Anderson Cancer Center from January 2012 to March 2024 divided into two cohorts: FLT3-TKD AML and nucleophosmin-mutated (NPM1)/FLT3-TKD wild-type (FLT3-TKD) AML.

Contemporary outcomes of octa-nonagenarians with newly diagnosed acute myeloid leukemia.

Background: Octa-nonagenarians with acute myeloid leukemia (AML) represent a high-risk group due to frequently poor performance status, adverse genomics (e.g., TP53 mutations, complex karyotype), a high incidence of secondary AML, and inability to undergo an allogeneic stem cell transplantation.

PPARγ-induced upregulation of fatty acid metabolism confers resistance to venetoclax and decitabine therapy in AML.

The combination of the B-cell lymphoma 2 (BCL2) inhibitor venetoclax (VEN) and the hypomethylating agent decitabine (DEC; VEN/DEC) constitutes a primary therapeutic strategy for treating older adults with acute myeloid leukemia (AML). However, a notable subset of patients exhibits resistance to VEN/DEC, demonstrating either no disease response or relapse after initial remission. This study aimed to elucidate the molecular mechanisms underlying this resistance through analyses of gene expression and DNA methylation profiles.

Long-term results from the AGILE study of azacitidine plus ivosidenib vs placebo in newly diagnosed IDH1-mutated AML.

In the phase 3 AGILE study, after a 12.4-month median follow-up, ivosidenib, a mutant isocitrate dehydrogenase 1 (IDH1) inhibitor, combined with azacitidine significantly improved event-free survival, overall survival (OS), and complete remission rates compared with placebo-azacitidine in patients with newly diagnosed IDH1-mutated acute myeloid leukemia who were unfit for intensive chemotherapy. This post hoc analysis reports long-term follow-up results from AGILE after a median follow-up of 28.

Landscape and clinicopathologic features of RAS pathway mutations in chronic myelomonocytic leukemia.

RAS pathway mutations (RASMT) induce proliferative features and promote transformation in chronic myelomonocytic leukemia (CMML). However, the unique clonal landscape and hierarchy of distinct RASMT remain unexplored. To characterize the landscape, architecture and implications of unique RASMT in CMML we evaluated a cohort of 814 patients with CMML.

Multimodal and Data-Driven Assessment of Myeloid Neoplasms Refines Classification across Disease States.

Unlabelled: The World Health Organization fifth edition and International Consensus Classification for myeloid neoplasms both incorporate empirical numerical thresholds to morphologic and molecular features defining certain disease entities. However, the clinical implications of these thresholds remain unclear. We analyzed a large cohort (N = 6,976) of patients with myeloid neoplasms to evaluate the impact of proposed yet different numerical thresholds for variant allele frequency of genetic mutations or hematologic parameters set forth by the World Health Organization fifth edition and International Consensus Classification for classification of SF3B1-mutated myelodysplastic neoplasms, NPM1-mutated acute myeloid leukemia (AML), and oligomonocytic chronic myelomonocytic leukemia.

Restoring p53 wild-type conformation in TP53-Y220C-mutant acute myeloid leukemia.

TP53-Y220C is a recurrent hotspot mutation in cancers and leukemias. It is observed predominantly in acute myeloid leukemia (AML)/myelodysplastic syndromes among hematological malignancies and is associated with poor outcome. The mutation creates a structural pocket in the p53 protein.

Outcomes of Frontline Triplet Regimens With a Hypomethylating Agent, Venetoclax, and Isocitrate Dehydrogenase Inhibitor for Intensive Chemotherapy-Ineligible Patients With Isocitrate Dehydrogenase-Mutated AML.

Purpose: The development of targeted therapeutics has revolutionized treatment for elderly patients with AML. Two doublet regimens are approved in the frontline setting for intensive chemotherapy (IC)-ineligible AML: venetoclax (VEN) in combination with hypomethylating agent (HMA) therapy and azacitidine (AZA) plus ivosidenib (IVO) specifically for -mutated AML. Although both regimens have improved AML outcomes, most patients will either not respond to frontline therapy or relapse, with dismal salvage outcomes.

A Phase 2 Trial of CPX-351 Combined With Venetoclax in Relapsed or Refractory Acute Myeloid Leukemia.

Outcomes in patients with relapsed/refractory (RR) AML are poor. We sought to investigate if CPX-531 in combination with venetoclax (CPX + VEN) was tolerable and effective in RR AML. This was a single institution phase 1b/2 trial of CPX + VEN.

Characteristics and outcomes of newly diagnosed acute myeloid Leukemia with KMT2A rearrangements.

Acute myeloid leukemia (AML) with KMT2A rearrangement (KMT2Ar) has poor outcomes. We analyzed 1,611 patients with AML and 4.3% demonstrated rearrangements in KMT2A.

BLAST: a globally applicable and molecularly versatile survival model for chronic myelomonocytic leukemia.

We sought to develop a survival model in chronic myelomonocytic leukemia (CMML) that is primarily based on clinical variables and examine additional impact from mutations and karyotype. A total of 457 molecularly annotated patients were considered. Multivariable analysis identified circulating blasts ≥2% (1 point), leukocytes ≥13 × 109/L (1 point), and severe (2 points) or moderate (1 point) anemia as preferred risk variables in developing a clinical risk stratification tool for overall survival (OS), acronymized to "BLAST": low risk (0 points; median, 63 months); intermediate risk (1 point; median, 28 months; hazard ratio [HR], 2.

A Phase I Study of FHD-286, a Dual BRG1/BRM (SMARCA4/SMARCA2) Inhibitor, in Patients with Advanced Myeloid Malignancies.

Purpose: Safety and preliminary clinical activity of FHD-286, a dual BRG1/BRM (Brahma related gene 1/Brahma homolog) inhibitor, were evaluated in patients with relapsed/refractory acute myeloid leukemia or myelodysplastic syndrome.

Patients And Methods: In this multicenter, open-label, phase I, dose-escalation study (NCT04891757), patients received FHD-286 orally once daily at 2.5, 5, 7.

Azacitidine, Venetoclax, and Magrolimab in Newly Diagnosed and Relapsed Refractory Acute Myeloid Leukemia: Phase Ib/II Study and Correlative Analysis.

Purpose: Magrolimab is a monoclonal antibody directed against the macrophage checkpoint CD47 on myeloid leukemia cells that was preclinically synergistic with azacitidine-venetoclax, warranting further clinical evaluation.

Patients And Methods: In this phase Ib/II study, the triplet combination of azacitidine, venetoclax, and magrolimab was evaluated in adult patients with first-line (ineligible for intensive chemotherapy) and relapsed/refractory acute myeloid leukemia. Azacitidine was dosed at 75 mg/m2 for 7 days, venetoclax at 400 mg/day for 28 days, and magrolimab (recommended phase II dose) as follows: 1 mg/kg dose on days 1 and 4, 15 mg/kg on day 8, and 30 mg/kg on days 11, 15, and 22 (cycle 1), followed by 30 mg/kg weekly for cycle 2 and then 30 mg/kg every 2 weeks for cycle 3 and beyond.

Cladribine, idarubicin, and cytarabine (CLIA) for patients with relapsed and/or refractory acute myeloid leukemia: A single-center, single-arm, phase 2 trial.

Background: The treatment of relapsed and/or refractory (R/R) acute myeloid leukemia (AML) remains challenging because of poor responses to chemotherapy. Efforts to improve outcomes have included the use of high-dose cytarabine in combination with nucleoside analogs, such as cladribine. The authors evaluated combined cladribine, idarubicin, and cytarabine (CLIA) in a phase 2 trial of 66 patients with R/R AML.