Haematologica最新文献

Non-tuberculous mycobacterial infection (NTM) is rare in healthy children, with lymphadenitis being the most common presentation. Immunocompromised populations are known to be at high risk, but the clinical picture of NTM infection in pediatric hematology/oncology patients is unclear. In this nationwide retrospective analysis of patients under the age of 40 treated in Japanese pediatric hematology/oncology departments who developed NTM infection between January 2010 and December 2020, 36 patients were identified: 21 patients with hematopoietic stem cell transplantation (HSCT) and 15 non-transplant patients. Post-transplant patients were infected with NTM at 24 sites, including the lungs (N=12), skin and soft tissues (N=6), bloodstream (N=4), and others (N=2). Nine of 12 patients with pulmonary NTM infection had a history of pulmonary graft-versus-host disease (GvHD), and rapid-growing mycobacteria (RGM) were isolated from 5 of them. In non-transplant patients, the primary diseases were acute lymphoblastic leukemia (ALL; N=5), inborn errors of immunity (IEI; N=6), and others (N=4). All cases of ALL had bloodstream infections with RGM, whereas all cases of IEI were infected with slow-growing mycobacteria (SGM). In summary, 3 typical clinical scenarios for pediatric hematology/oncology patients have been established: RGM-induced pulmonary disease in patients with pulmonary GvHD, RGM bloodstream infection in patients with ALL, and SGM infection in patients with IEI. Our findings suggest that NTM must be regarded as a pathogen for infections in these high-risk patients, especially those with pulmonary GvHD, who may require active screening for NTM.

Allopurinol can be used in maintenance therapy (MT) for pediatric acute lymphoblastic leukemia (ALL) to mitigate hepatic toxicity in patients with skewed 6-mercaptopurine metabolism. Allopurinol increases the erythrocyte levels of thioguanine nucleotides (e-TGN), which is the proposed main mediator of the antileukemic effect and decreases methyl mercaptopurine (e-MeMP) levels, associated with hepatotoxicity. We investigated the effects of allopurinol in thiopurine methyltransferase (TPMT) wild-type patients without previous clinical signs of skewed 6-mercaptopurine metabolism. Fifty-one patients from Sweden and Finland were enrolled in this prospective before-after trial during ALL MT. Mean e-TGN increased from 280 nmol/mmol hemoglobin (Hb) after 12 weeks of standard MT to 440 after 12 weeks of MT with addition of allopurinol 50 mg/ m2 (P<0.001). Mean e-MeMP decreased simultaneously from 9,481 nmol/mmol Hb to 2,791 (P<0.001) and mean alanine aminotransferase declined by almost 50%. Primary endpoint, defined as e-TGN >200 nmol/mmol Hb, was reached for 91% of the patients after 12 weeks of allopurinol (week 25) compared to 67% before (week 13) (P<0.001). This level was chosen as the median e-TGN in a previous NOPHO ALL-2008 study was just below 200 nmol/mmol Hb. During weeks on allopurinol a slightly higher proportion of the patients had a white blood cell count within target 1.5-3.0×109/L. Allopurinol did not increase severe adverse events and no life-threatening events were reported. In conclusion, allopurinol add-on treatment is safe and leads to increased e-TGN and reduced e-MeMP also in ALL-patients without previous signs of skewed thiopurine metabolism and is a promising approach to increase antileukemic effect and reduce toxicity.

Aplastic anemia (AA) is a disease characterized by failure of hematopoiesis, bone marrow aplasia, and pancytopenia. It can be inherited or acquired. Although acquired AA is believed to be immune-mediated and random, new evidence suggests an underlying genetic predisposition. Besides confirmed genomic mutations that contribute to inherited AA (such as pathogenic mutations of TERT and TERC), germline variants, often in heterozygous states, also play a not negligible role in the onset and progression of acquired AA. These variants, associated with inherited bone marrow failure syndromes and inborn errors of immunity, contribute to the disease, possibly through mechanisms including gene homeostasis, DNA repair, and immune injury. This article explores the nuanced association between acquired AA and germline variants, detailing the clinical significance of germline variants in diagnosing and managing this condition. More work is encouraged to better understand the role of immunogenic pathogenic variants and whether somatic mutations participate as secondary "hits" in the development of bone marrow failure.

The current clinical management of extranodal natural killer (NK)/T-cell lymphoma (ENKTL) primarily depends on conventional chemotherapy and radiotherapy, underscoring the need for innovative therapeutic strategies. This study explores the clinical significance and therapeutic implication of c-MYC (MYC) in ENKTL. Initially, we identified MYC protein overexpression in approximately 75% of cases within a large cohort of 111 patients. MYC overexpression was strongly correlated with lymphoma cell proliferation and poor clinical outcomes. Intriguingly, integrating MYC expression into the prognostic index of NK cells lymphoma with Epstein-Barr virus (PINK-E) prognostic model significantly enhanced its predictive power. Subsequently, we implemented MYC knockdown in NK malignancy cell lines with MYC overexpression, resulting in significant viability reduction. RNA sequencing used to determine MYC function revealed a high overlap with canonical MYC-regulated genes and enrichment in metabolism and cell cycle regulation. Integrative analysis of the RNA-sequencing data upon MYC knockdown with gene expression profiles of primary ENKTL cases identified a subset of genes closely associated with MYC overexpression. Among these, CDK4 emerged as a potential therapeutic target, and its inhibition not only abrogated MYC function but also decreased MYC expression in NK malignancy cells. Furthermore, the clinical-grade CDK4/6 inhibitor palbociclib exhibited a potent anti-tumor effect in xenograft mouse models, especially when combined with gemcitabine. In summary, our study firmly establishes MYC as an oncogene with prognostic significance in ENKTL and highlights CDK4 inhibition as a promising therapeutic strategy for treating ENKTL with MYC overexpression.

Venous thromboembolism (VTE) is a complex disease that can be classified into two subtypes: deep vein thrombosis (DVT) and pulmonary embolism (PE). Previous observational studies have shown associations between lipids and VTE, but causality remains unclear. Hence, by utilizing 241 lipid-related traits as exposures and data from the FinnGen consortium on VTE, DVT, and PE as outcomes, we conducted two-sample Mendelian randomization (MR) analysis to investigate causal relationships between lipids and VTE, DVT and PE. The MR results identified that fatty acid (FA) unsaturation traits (ratio of bis-allylic bonds to double bonds in lipids, and ratio of bis-allylic bonds to total fatty acids in lipids) were associated with VTE (odds ratio [OR]=1.21, 95% confidence interval [CI]: 1.15-1.27; OR=1.21, 95% CI: 1.13-1.30), DVT (OR=1.24, 95% CI: 1.16-1.33; OR= 1.26, 95% CI: 1.16-1.36) and PE (OR=1.18, 95% CI: 1.08-1.29; OR=1.18, 95% CI: 1.09-1.27). Phosphatidylcholines (PC) exhibit potential causal effects on VTE and PE. PC acyl-alkyl C40:4 (PC ae C40:4) was negatively associated with VTE (OR=0.79, 95% CI: 0.73-0.86), while PC diacyl C42:6 (PC aa C42:6) and PC acyl-alkyl C36:4 (PC ae C36:4) were positively associated with PE (OR=1.44, 95% CI: 1.20-1.72; OR=1.22, 95% CI: 1.10-1.35). Additionally, we found that medium LDL had a protective effect on VTE. Our study indicates that higher FA unsaturation may increase the risk of VTE, DVT, and PE. Different types of PC have either promotive or inhibitory effects on VTE and PE, contributing to a better understanding of the risk factors for VTE.

Patients with primary immune thrombocytopenia (ITP) suffer from reduced survival and quality of life, but the underlying reasons for this are largely undescribed. Mental health and the use of psychotropic drugs in ITP is unknown. We investigated the risk of hospital-registered mental health events including fatigue and the use of psychotropic drugs in adult patients with ITP compared with the general population, using nationwide registry-data. We identified 3,749 patients with ITP and 149,849 age- and sex-matched general population comparators in the Danish Health Registries in the period 1997-2016. The median age was 60 years (interquartile range [IQR], 40-73) and 53% were women. We followed the individuals for incident mental health events and estimated the use of psychotropic drugs over calendar-years and in temporal relation to diagnosis of ITP. The first year cumulative incidence of any mental health event was 2.3% (95% confidence interval [CI]: 1.9-2.9) in patients and 0.7% (95% CI: 0.6-0.7) in comparators, yielding an adjusted cause-specific hazard ratio (csHR) of 3.57 (95% CI: 2.84-4.50). The corresponding estimates for depression were 1.2% (95% CI: 0.9-1.6) and 0.3% (0.3-0.4) respectively, with an adjusted csHR of 3.53 (95% CI: 2.56-4.85). We found similar findings for anxiety and fatigue, but risks generally diminished after 1-5 years. The use of opioids, antidepressants, and benzodiazepines increased in temporal relation to diagnosis of ITP. The risk of mental health events and the use of psychotropic drugs is higher in adult patients with ITP compared with the general population, and has a temporal relation to diagnosis of ITP emphasizing that mental health in ITP is a concern.