Blood Advances

Immunoglobulin light-chain amyloidosis (AL) has been reported to be associated with multiple myeloma (MM) in approximately 10-15% of cases, with the two conditions often coexisting. Understanding the interaction between these diseases is vital for improving patient outcome and developing targeted treatments. Our study investigates cellular heterogeneity in immunoglobulin light-chain amyloidosis (AL) and coexisting multiple myeloma (MM) or monoclonal gammopathy of undetermined significance (MGUS)...

Backgroundacute promyelocytic leukemia (APL) is a subtype of acute myeloid leukemia (AML) marked by a high incidence of coagulopathy. Podoplanin (PDPN), a glycoprotein involved in platelet activation through interaction with CLEC-2, has been recently identified on leukemic promyelocytes and suggested as a potential contributor to APL coagulopathy. Identification of novel biomarkers and therapeutic targets for APL coagulopathy can potentially improve the outcomes of this condition. Aimto explore...

HighlightsO_LISingle-cell RNA sequencing of bone marrow from TP53-mutated AML patients showed a decrease in cells expressing anti-apoptotic genes like BCL2 and MCL1 after venetoclax and azacitidine treatment. C_LIO_LIImmune cells increased both in number and in gene expression levels associated with cytotoxicity post venetoclax combination therapy, verifying immune recovery. C_LIO_LIResidual AML cells expressed CD47 and CLL1, suggesting a role for ancillary treatment targeting antigens expressed...

Despite promising anti-leukemic activity of MCL-1 inhibitors in preclinical studies of acute myeloid leukemia (AML), their progress through clinical evaluation has in part been challenged by limited knowledge of patient subgroups suitable for treatment. To stratify patients with AML for MCL-1 inhibitor-based treatment, we evaluated the sensitivity of 42 primary AML samples to MCL-1 inhibitor MIK665 (S64315) and contrasted their molecular profiles. We observed that MIK665 sensitive samples had a ...

IntroductionIncluding of proliferative parameters in the routine clinical flow-cytometry (FC) workup may be important for better evaluation of prognosis and risk assessment in patients with myelodysplastic syndromes (MDS). However, supportive data are still contradicting. AimTo assess the levels of FC based proliferative parameters in patients with MDS using propidium Iodide, and to study their correlation with risk assessment and the incidences of CD34+ blasts and CD16- and CD16+ granulocytes....

BackgroundChronic Eosinophilic Leukemia, Not Otherwise Specified (CEL-NOS), a rare and intricate hematological disorder characterized by uncontrolled eosinophilic proliferation, presents clinical challenges owing to its infrequency. This study aimed to investigate the epidemiology and develop a prognostic nomogram for CEL-NOS patients. MethodsUtilizing the Surveillance, Epidemiology and End Results (SEER) database, CEL-NOS cases diagnosed between 2001 and 2020 were analyzed for incidence rates,...

PurposeEvaluating the safety and tolerability of 5-FU-miR-15a (CR-001) in adults with relapsed or refractory acute myeloid leukemia (R/R AML) in a phase I dose-escalation study (EudraCT number: 2021-006332-46). Patients and MethodsA standard 3+3 dose-escalation study design was employed. Patients received intravenous (IV) administrations of the synthetic double-stranded mimic of miR-15a (miRNA) CR-001 of 7.5 mg, 11.25 mg, 15 mg and 18.75 mg/administration, weekly dosing. Each patient was dosed ...

BackgroundCoagulopathy and associated bleeding and venous thromboembolism (VTE) are major causes of morbidity and mortality in patients with acute leukemia. The underlying mechanisms of these complications have not been fully elucidated. ObjectivesTo evaluate the associations between biomarker levels and bleeding and VTE in acute leukemia patients. Patients/MethodWe examined plasma levels of activators, inhibitors and biomarkers of the coagulation and fibrinolytic pathways in patients [≥]18...

Accurate classification and risk stratification is critical for clinical decision making in AML patients. In the newly proposed World Health Organization (WHO) and International Consensus classifications (ICC) of hematolymphoid neoplasms, the presence of myelodysplasia-related (MR) gene mutations is included as one of the diagnostic criteria of AML, myelodysplasia-related (AML-MR), largely based on the assumption that these mutations are specific for AML with an antecedent myelodysplastic syndro...

Nucleophosmin-1 (NPM1) mutations define a major molecular subtype of acute myeloid leukemia (AML) and is generally associated with favorable prognosis. However, the impact of myelodysplasia-associated mutations (MDSm+) on patient outcomes within this subgroup remains uncertain. We retrospectively analyzed 271 NPM1-mutated AML patients from three independent cohorts (SWOG, Fred Hutch, and Beat AML) to assess the prognostic significance of MDSm+ and its interaction with age. MDSm+ occurred in 17% ...

PurposeHCT is vital for treating hematological malignancies, relying on HLA matching between unrelated patient-donor pairs to significantly reduce adverse outcomes. Recent studies recognize the potential impact of HLA-DPB1 mismatches on HCT outcomes. Multiple approaches focus on finding better-tolerated HLA-DPB1 mismatches. Additionally, recent studies suggest matching at noncoding HLA sequence may improve HCT outcomes. This study aims to evaluate different approaches for categorizing DPB1 misma...

The epiCMIT (epigenetically-determined Cumulative MIToses) mitotic clock traces B-cell mitotic history via DNA methylation changes in heterochromatin and H3K27me3-containing chromatin. While high scores correlated with poor outcomes in CLL and MCL, its prognostic significance in SMZL remains unknown. Derived from 142 SMZL cases using DNA methylation microarrays, epiCMIT values were correlated with genomic, transcriptomic, and clinical data. EpiCMIT as a continuous variable was significantly high...

DIRECT was a prospective, multisite study assessing the feasibility and utility of circulating tumor DNA (ctDNA) in 188 patients with aggressive B-cell non-Hodgkin lymphoma using a lymphoma-customized assay and open-source pipeline. CtDNA fraction assessed by copy number alterations in pre-treatment plasma identified high-risk patients more effectively than existing clinical risk scores. In 74.5% of cases ctDNA was equivalent or superior to biopsy for genetic profiling. Patients not suitable for...

Occasional complete responses to immune checkpoint inhibitor therapies suggest that acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) are immune-sensitive when appropriately targeted. Here, we analyzed AML/MDS patients treated with anti-TIM3 sabatolimab and decitabine in a phase Ib clinical trial (NCT03066648) using single-cell RNA and T cell receptor (TCR) sequencing and functional co-culture assays. Unlike T cell restricted CTLA4 and PD1, TIM3 was broadly expressed across natural...

Monosomy 7 and deletion of the q arm of chromosome 7 (-7/-7q) are high-risk markers in myelodysplastic syndromes (MDS). We previously showed that blasts with -7/-7q from patients with acute myeloid leukemia (AML) are exceptionally sensitive to NAMPT inhibitors, with the sensitivity caused by NAMPT gene haploinsufficiency as a result of - 7/-7q. The objective of this study was to investigate whether blasts from patients with -7/-7q MDS are similarly susceptible to NAMPT inhibition. We first asses...

The myelodysplastic syndrome (MDS) is a heterogeneous group of clonal disorders of hematopoietic progenitor cells related to ineffective hematopoiesis and an increased risk of transformation to acute myelogenous leukemia. MDS is divided into categories, namely lineage dysplasia (MDS-SLD), MDS with ring sideroblasts (MDS-RS), MDS with multilineage dysplasia (MDS-MLD), MDS with excess blasts (MDS-EB). The International Prognostic Classification System (IPSS) ranks the patients as very low, low, in...

NPM1-mutated AML is one of the largest entities in international classification systems of myeloid neoplasms, which are based on integrating morphologic and clinical data with genomic data. Previous research, however, indicates that bulk transcriptomics-based subtyping may improve prognostication and therapy guidance. Here, we characterized the heterogeneity in NPM1-mutated AML by performing single-cell RNA-sequencing and spectral flow cytometry on 16 AML belonging to three distinct subtypes pre...

BackgroundPatients with relapsed/refractory multiple myeloma (RRMM) and high-risk genetic abnormalities such as del(17p) and TP53 mutation have poor response to standard therapies and shorter survival compared to patients without these aberrations. Here, we investigated the activity and mechanism of action of peptide-drug conjugate melphalan flufenamide (melflufen) in TP53 wild type (TP53wt) and mutant (TP53mut) myeloma models and assessed the efficacy of melflufen in patients with del(17p) and/...

Recent genomic studies in adult and pediatric acute myeloid leukemia (AML) demonstrated recurrent in-frame tandem duplications (TD) in exon 13 of upstream binding transcription factor (UBTF). These alterations, which account for ~4.3% of AMLs in childhood and up to 3% in adult AMLs under 60, are subtype-defining and associated with poor outcomes. Here, we provide a comprehensive investigation into the clinicopathological features of UBTF-TD myeloid neoplasms in childhood, including 89 unique ped...

BACKGROUNDPatients with refractory thrombocytopenia (RT) are not sensitive to conventional therapies, such as platelet transfusions and thrombopoietin receptor agonists (TPO-RAs). The persistently high risk of life-threatening hemorrhage in this population highlights the urgent need for novel therapeutic strategies. Megakaryocyte (MK)-based therapies have emerged as a promising alternative, as MKs are the natural precursor cells responsible for platelet production. However, whether allogeneic MK...