Characterization of the phenotypic consequences of the Duffy-null genotype [Retrospective study]

Highlights: 

●       Although it has been proposed that the rs2814778-CC ("Duffy-null") variant is benign, prior studies have shown that the misinterpretation of Duffy-null–associated neutropenia and leukopenia can lead to unnecessary bone marrow biopsies, inequities in cytotoxic and chemotherapeutic treatment courses, under-enrollment in clinical trials, and other disparities.

●       rs2814778-CC is only reproducibly associated with changes in white blood cell count and not with any disease outcomes.

●       Race is not an accurate predictor of Duffy-null–associated benign neutropenia; broad genetic screening of rs2814778 is needed.

●       Short-term solutions could involve Fy(a−b−) phenotyping to better guide clinical interpretations, whereas longer-term goals should focus on developing genotype-specific reference ranges for blood indices that account for broader genetic diversity.

The authors conducted a phenome-wide association study across >1400 clinical conditions to investigate the phenotypic correlates of Duffy-null status in “All of Us” (the Vanderbilt University Medical Center’s Biobank, and the Million Veteran Program). This study reveals that Duffy-null status is only reproducibly associated with changes in white blood cell count, not disease outcomes. They found that Duffy-null–associated neutropenia is, on average, less severe than other neutropenia cases in “All of Us”.

Venetoclax schedule in AML: 7 vs. 14 vs. 21 vs. 28 days [Editorial] 

In this Editorial, the authors share what they have learned from using venetoclax (Ven) in everyday practice. It  includes their thoughts on how genetics can predict how patients with acute myeloid leukemia (AML) will respond to treatment, and what Ven doses to administer to them.

Table 1 in the original paper reviews important findings from past studies comparing Ven dosing schedules. All but one study showed similar rates of complete response (CR) and complete response without count recovery (CRi), with a trend towards lower infection rates with shorter Ven treatment.

The idea that a shorter course of Ven in newly diagnosed AML might be as effective, and less harmful than the standard 28-day dosing is appealing. Also, new combination therapies that use Ven, FLT3 inhibitors, and hypomethylating agents have a shorter Ven schedule to reduce side effects. In their practice, the authors prefer to give Ven every 14 days to patients with suboptimal physiological age, or those at high risk for infectious complications.

Updated Definition and Scoring of Disseminated Intravascular Coagulation in 2025: Communication from the ISTH SSC Subcommittee on Disseminated Intravascular Coagulation [Consensus] 

In this communication, the authors (The International Society on Thrombosis and Haemostasis (ISTH) Scientific and Standardization Committee (SSC) on Disseminated Intravascular Coagulation (DIC) propose a revised definition and updated scoring system for DIC, emphasizing the necessity of tailoring criteria based on the underlying diseases.

DIC: DIC is an acquired life-threatening intravascular event arising from various conditions and characterized by the systemic activation of coagulation with unbalanced fibrinolysis. It is usually accompanied by thrombocytopenia and endothelial damage. DIC can progress from a potentially non-symptomatic early phase to an advanced phase with hemorrhage and/or organ dysfunction.

Early-phase DIC: The activated coagulation status induced by thrombin burst and unbalanced fibrinolysis with endothelial damage. Clinical symptoms can present but it is mainly detected by laboratory tests. Anticoagulant therapy may be effective, but it has not been proven yet. Coagulation and fibrinolysis are disrupted, and clinical symptoms such as bleeding and organ dysfunction become evident. Out-of-range anticoagulant therapy and treatments mainly involve supplementation of coagulation factors and platelets. Synonyms: Non-overt DIC, Subclinical DIC, Compensated DIC.

Late-phase DIC: Coagulation and fibrinolysis are disrupted, and clinical symptoms such as bleeding and organ dysfunction become evident. Out-of-range anticoagulant therapy, and treatments mainly involve supplementation of coagulation factors and platelets. Synonyms: Overt DIC, Decompensated DIC.

Scoring system: Overt DIC 2025 (See Table 1 in the original article).

●       Platelet count (x10⁹/L): <50 = Score 2; ≥50, < 100 = Score 1.

●       D-dimer: > x 7 upper normal limit = Score 3; > x 3 upper normal limit = Score 2.

●       Prothrombin time prolongation / INR (PT-INR): ≥6 sec = Score 2; ≥3 sec, <6 sec = Score 1.

●       Fibrinogen (mg/dL): <100 = Score 1

●       Total score for DIC: ≥5.

Pre-DIC: The earlier stage of early-phase DIC. The patients have risk factors for DIC, and laboratory tests indicate very subtle abnormalities in coagulation, but DIC has not yet developed.

Coagulopathy: Coagulopathy is a general term for a mild to moderate impairment in one or more  elements of coagulation. Phenotypes can be hemorrhagic, thrombotic, or both. Coagulopathy is also used in specific terms like sepsis-induced coagulopathy (SIC) (See Table 1 in the original article) and trauma-induced coagulopathy (TIC);  in these situations, coagulopathy means early-phase DIC.

What is radiation-induced acute myeloid leukemia/can it be accurately identified? [Perspective]

Key points:

●       The terms therapy-related acute myeloid leukemia (AML), radiation-related AML, and secondary AML (implying a prior cause) are often used interchangeably to describe leukemia that develops in an individual exposed to ionizing radiation, usually in the context of radiation therapy. However, details such as age at exposure, latency, dose, dose rate, field, fractionation, and source-term parameters are often unknown or ignored. In addition, there are often concurrent exposure(s) to anticancer drugs known to cause or contribute to the development of leukemia, making the contribution of radiation exposure, if any, less certain.

●       The 2022 5th edition of the World Health Organization Classification of Hematolymphoid Tumors: Myeloid and Histiocytic/Dendritic Neoplasms recommends a category of secondary myeloid neoplasms after cytotoxic therapy in persons with prior exposure to large-field radiation therapy for an unrelated neoplasm. The authors disagree with this designation. Therapy-related AML is no longer an entity in the 2022 International Consensus Classification, but a qualifier added to the diagnosis of AML.

●       Exposure of human cells of various origins to 1 Gy (absorbed dose) results in an average of 2.33 mutations per Gb of DNA, mostly indels (insertions and/or deletions). Ionizing radiation can be a cancer initiator, promoter, or accelerator (see below) depending on several factors such as latency to diagnosis, radiation quality, dose, dose rate, route of exposure, sensitivity of individual cells in the target tissue/organ, tissue kinetics, and cell organization.

●       No genetic alterations or biomarkers specific to radiation-induced cancers, including AML. Therefore, it is unclear how to accurately identify individuals with AML caused or contributed to by radiation exposure.

●       Future studies may identify a mutational signature of radiation-induced AML, bridging epidemiologic findings to insights into the earliest events.

●       At present, radiation-induced AML in humans cannot be accurately identified, and the term should not be used without stating the uncertainty involved.

Genetic subtypes of B-cell acute lymphoblastic leukemia in adults [Review]

Key points: 

●       B-cell acute lymphoblastic leukemia (B-ALL) is a rare malignancy in adults, with outcomes remaining poor, especially compared with children. Over the past 2 decades, extensive whole-genome studies have identified numerous genetic alterations driving leukemia, leading to the recognition of >20 distinct subtypes closely associated with treatment response and prognosis (See Table 1 in the original article).

●       Genetic subtypes are unevenly distributed according to age, with low-risk subtypes (high hyperdiploidy and ETV6::RUNX1) predominant in children. In contrast, the proportion of high-risk subtypes (Ph+, low hypodiploidy, and KMT2A-r) increases with age. See Figure 1 in the original article.

●       The genomic landscape of B-ALL has proven to be so complex, involving numerous genes and types of alterations, that these approaches have become labor-intensive and inefficient. Whole-genome sequencing (WGS) is the only method that provides an exhaustive genome characterization,  but this technology remains costly and resource-intensive, making it currently inaccessible to most diagnostic laboratories. Whole-transcriptome sequencing has the unique advantage of combining gene expression analysis with detecting rearrangements and mutations. Predictive tools have been developed to facilitate subtype allocation without the need for an internal data set. Much more accessible than WGS, its versatility could make it the new standard of care.

●       There is still limited data on how well B-cell–directed therapies work for different B-ALL subtypes. Recent data suggest that some B-ALL subtypes are more likely to resist these therapies. Therefore, comprehensive genomic profiling and a deeper understanding of the determinants of response to B-cell–directed agents will be necessary to establish the foundation of future precision medicine in B-ALL.