British Journal of Haematology最新文献

IKZF1 mutations are recurrent alterations in acute myeloid leukaemia (AML), and hotspot point mutation, N159S, has recently been associated with unique gene expression and adverse risk. To better understand the molecular and clinical associations of IKZF1 N159S-mutated AML, we performed a pooled analysis of 4136 AML patients. IKZF1 N159 mutations were found in 39 patients (0.94%) in a dominant clonal constellation, indicating early genetic events. N159S mutations were associated with aberrant karyotype, significantly higher rates of myelodysplasia-related gene mutations, ELN2022 adverse risk and a particularly poor outcome, supporting the classification of IKZF1 N159S-mutated AML as a rare molecular subtype with adverse prognosis.

Chemotherapy-induced thrombocytopenia (CIT) is a common clinical problem in patients with solid tumour malignancies. Unlike nadir CIT which often resolves by the start of the following chemotherapy cycle, persistent CIT results in unacceptably low platelet counts at the beginning of a cycle lasting throughout multiple chemotherapy cycles, resulting in bleeding as well as chemotherapy treatment delays, dose reductions and discontinuation. Persistent CIT can be managed with thrombopoietin receptor agonist support in the context of a clinical trial or off-label use of romiplostim if a trial is not available.

Germline variants in DDX41 (DDX41^MT-germline predisposition syndrome [GPS]) are associated with predisposition to haematological malignancies (HM), including lymphoid and myeloid neoplasms (MN). We retrospectively analysed the clinical and molecular features of 195 patients diagnosed and treated at Mayo Clinic with DDX41^MT-GPS. Patients with germline DDX41 pathogenic variants (42.3%) and variants of unknown significance (VUS, 57.6%) were included. The median age was 68.6 years (16.2-93.4). Ninety-two per cent were Caucasian, 64.1% were male and 30.8% had a family history of HM. There were 92 distinct germline variants among our cohort, and the most common was p.Met1? (15.9%), followed by p.Asp140Glyfs*2 (9.2%). Clinical diagnoses included asymptomatic carriers (10.2%), clonal cytopenia of undetermined significance (CCUS, 6.1%), myeloproliferative neoplasms (6.7%), myelodysplastic syndrome (40.5%), acute myeloid leukaemia (20.5%), lymphoid neoplasms (9.2%), plasma cell dyscrasias (6.1%) and solid tumours (22.5%). Patients with MN were older (median age 70 vs. 63.5 years) and more likely to be male (M:F ratio 2.3 vs. 1.0) and most patients (78.8%) with MN had a normal karyotype. The most common somatic variants involved DDX41 (34.4%), followed by TET2 (11.2%), DNMT3A (9.6%) and ASXL1 (9.2%). In summary, we have comprehensively described the spectrum of clinical phenotypes within the Mayo Clinic DDX41^MT-GPS cohort.

Germline homozygous loss-of-function mutations in TET2 result in significant childhood immunodeficiency that resembles autoimmune lymphoproliferative syndrome and predisposes one to lymphoma. The implications of heterozygous variants are less well understood. We describe four patients with heterozygous germline loss-of-function TET2 mutations who presented with B-cell lymphoma on a background of chronic lymphadenopathy and autoimmune features. This expands the association of germline TET2 mutations with lymphoma and an autoimmune lymphoproliferative syndrome-like phenotype to the heterozygous state. Assessment for TET2 mutations and germline origin should be considered in the appropriate context, as recognition of these variants may have implications on patient care.

In high-income countries, individuals with sickle cell disease (SCD) almost universally survive into adulthood, but transfer to adult SCD care is fraught. The young adult clinic (YAC) at our sickle cell centre was designed to provide developmentally appropriate, expert SCD care to young adults with SCD aged 18-30 years. In this retrospective cohort study, we measured YAC appointment attendance and scheduling attempts based on patient referral source and demographic characteristics. Between 1 March 2019 and 30 September 2023, 89% (170/192) of referred patients attended a YAC appointment, and 97% (77/79) of patients referred from paediatric SCD care attended a YAC appointment. Most patients attended their first scheduled appointment (61%, 105/170). Among rescheduled patients, the mean number of scheduling attempts before attendance was 2.9 (standard deviation 1.5). During the 55-month study period, this cohort had five deaths (3%) and seven successful haematopoietic stem cell transplants (4%). These results indicate that healthcare systems designed to meet the needs of young adults with SCD enable successful participation in adult SCD care. Resources to build robust adult SCD care systems are desperately needed, alongside research regarding optimal approaches to integrating young people into adult SCD care.

Although CD20xCD3 bispecific antibodies (BsAbs) have demonstrated transformational activity in diffuse large B-cell lymphoma (DLBCL), some patients fail to respond and others relapse. To begin to explore possible limitations, we compared the in vitro activity of four CD20xCD3 biosimilar BsAbs against four DLBCL cell lines with CD20 expression ranging over a 100-fold. All four biosimilar BsAbs demonstrated superior in vitro activity to rituximab, with biosimilar glofitamab consistently being the most potent. Moreover, biosimilar glofitamab and odronextamab retained significant activity in the presence of low-level CD20 expression. Finally, one DLBCL cell line exhibited intrinsic resistance to all four CD20xCD3 BsAbs despite inducing marked T-cell and NK-cell activation.

The peripheral blood lymphocyte-to-monocyte ratio (LMR) has been shown to predict outcomes in follicular lymphoma (FL). Among 1018 patients from the RELEVANCE trial (for previously untreated, high tumour burden FL), the median LMR was 2.5 (range, 0.3-93.5) and an LMR cut-off of 2 was mostly associated with survival end-points. Patients with an LMR ≤2 (n = 372; 37%) were older and had higher risk disease. An LMR ≤2 was associated with a shorter progression-free survival (PFS) (hazard ratio [HR] = 1.39, p = 0.002) and overall survival (OS) (HR = 1.44, p = 0.049). The association of the LMR with PFS was significant in the rituximab plus chemotherapy arm (p = 0.01) and inconclusive in the rituximab plus lenalidomide arm (p = 0.08). Within the three Follicular Lymphoma International Prognostic Index risk categories, the LMR retained its association with PFS only in the low-risk group (p = 0.03). An LMR ≤2 was also associated with a higher risk of progression of disease within 24 months of treatment initiation (univariable odds ratio (OR) = 1.84, p < 0.001; multivariable OR = 1.58, p = 0.02). In conclusion, the LMR is an easily accessible parameter informative of outcomes in FL patients in need of treatment, being especially helpful in otherwise low-risk patients. Whether the incorporation of immunomodulators such as lenalidomide will reduce its negative prognostic value needs to be further investigated.

Patients with haematological malignancies (HMs) are highly vulnerable to COVID-19 due to their immunocompromised status, which leads to prolonged viral clearance and severe outcomes. Nirmatrelvir/ritonavir has shown efficacy in reducing severity and mortality in high-risk COVID-19 outpatients, but its effectiveness in hospitalized HM patients remains unclear. We conducted a retrospective study to assess the effectiveness of nirmatrelvir/ritonavir on mortality and viral clearance in hospitalized HM patients with mild-to-moderate COVID-19 during China's first COVID-19 surge. Mortality rate and viral clearance time were the primary end-points. Cox proportional hazards models were used to detect factors associated with mortality and viral clearance. A total of 116 HM patients, with a median age of 47.2 years, hospitalized for a minimum of 5 days with mild-to-moderate COVID-19, were included in this study. There was no difference in the 90-day mortality rate between HM patients treated with nirmatrelvir/ritonavir within 5 days and those not treated (4.9% vs. 5.3%, p = 1.000). Nirmatrelvir/ritonavir use within 5 days reduced the time to viral clearance (hazard ratio [HR] = 1.59, 95% confidence interval [CI] 1.04-2.42). Nirmatrelvir/ritonavir use within 5 days in hospitalized HM patients with mild-to-moderate COVID-19 does not reduce mortality but accelerates viral clearance.

The outcome of B-cell non-Hodgkin lymphoma (B-NHL) in children and adolescents has improved significantly over recent decades due to risk-adapted strategies and the use of immunotherapy. However, refractory or relapsed (R/R) B-NHL remains extremely difficult to cure (<30%). This retrospective study of 45 patients with R/R B-NHL reflects the limited benefit associated with reintroducing rituximab in second-line strategies, the importance of achieving complete remission before stem cell transplantation and the potential role of TP53 as a biomarker in R/R B-NHL. TP53 mutations were identified in 44% of tumours and associated with a worse 3-year overall survival (15% vs. 80%; p = 0.048).