British Journal of Haematology最新文献

We evaluated the tolerability and efficacy of pegylated interferon alfa-2B (peg-IFNα; PegIntron, MSD) combined with nilotinib in the Australasian Leukaemia and Lymphoma Group CML11 (Pinnacle) study. This phase II study started patients on nilotinib 300 mg twice daily. Subcutaneous peg-IFNα was added at 30-50 50 μg/week from 3 months until 24 months as tolerated. Sixty patients were enrolled with a median age of 48.5 years (range 19-72); 45% were female. With a median follow-up of 60 months, 40 patients (67%) remain on study. The proportion of patients who received ≥50% and ≥85% of their assigned peg-IFNα doses were 58% and 35% respectively. Common reasons for peg-IFNα discontinuation were mood disturbance (5), thyroid disease (4) and myalgia (4). The cumulative incidence of Major Molecular Response (MMR, BCR::ABL1≤0.1%) was 87% by 12 months; Molecular Response 4.5 (MR4.5, BCR::ABL1≤0.0032%) incidence at 24 and 60 months was 55% and 82% respectively. Thirty-seven patients (62%) had MR4.5 for >24 months, 14 of whom attempted treatment-free remission (TFR); 13 remained in TFR at a median follow-up of 32 months. CML11 demonstrated that peg-IFNα with nilotinib leads to high rates of molecular response, with tolerability similar to prior studies. Trial registration ANZCTRN12612000851864.

Allogeneic haematopoietic stem cell transplantation (ASCT) is a curative treatment for acute myeloid leukaemia (AML) but carries a high risk of gonadotoxicity. Ovarian tissue cryopreservation (OTC) offers a fertility preservation option, yet its safety in AML remains uncertain due to the risk of leukaemic cell reintroduction. The FERTILAM pilot study evaluated measurable residual disease (MRD) in ovarian tissue collected at complete remission (CR) from nine AML patients undergoing OTC before ASCT. MRD was assessed using patient-specific clonal markers via droplet digital polymerase chain reaction on DNA and RNA from bone marrow (BM), ovarian cortex and medulla. At CR, MRD-DNA was detected in ovarian cortex of four of nine patients, all with concurrent MRD positivity in BM. Three patients were negative in both BM and ovarian tissue. Paired cortex/medulla analyses showed concordant MRD-DNA results in five of six patients. BM MRD-RNA and MRD-DNA were fully concordant, whereas two discrepancies were observed between MRD-DNA and MRD-RNA in ovarian tissue. These findings suggest potential leukaemic cell persistence in ovarian tissue despite CR and highlight the need for sensitive molecular assays to assess safety prior to ovarian tissue transplantation.

Girls and women with bleeding disorders (GWBD) comprise more than half of all registered patients with bleeding disorders in the UK National Haemophilia Database. The gynaecological care of GWBD, until recently, has not been prioritised despite high health burdens, where four of every five patients experience heavy menstrual bleeding (HMB). We report the results of a national survey exploring gynaecological health-care services offered across haemophilia centres in the United Kingdom, with a focus on HMB. We combine these results with a retrospective cohort analysis of individual patient care records, across a 3-year period. Of 65 haemophilia centres, 41 responded, covering 90% of the UK GWBD population. Six hundred and ninety-seven individual patient care records were included, from 13 centres. Our results show that immediate clinical care offered to GWBD experiencing HMB is adequate, despite infrastructure deficiencies (such as lack of joint-gynaecology input and few centres having named clinical leads for GWBD). We recommend several areas for immediate prioritisation within haemophilia centres which will improve the equity of care for GWBD. These include direct access to gynaecological services; universal testing of iron status; and more broadly, a shift towards clinical practices that recognise and address the impact HMB has on patients' psycho-social, sexual and overall quality of life.

The British Osteonecrosis Study (BONES) is the first multicentre prospective study assessing bone health and vertebral fractures in patients aged 10-24 in the United Kingdom undergoing treatment for acute lymphoblastic leukaemia (ALL) or lymphoblastic lymphoma (LBL). Sixty-one patients were recruited from three tertiary centres in the United Kingdom. Dual-energy X-ray absorptiometry (DXA) scans with vertebral fracture analysis were performed within 4 weeks of diagnosis and annually for 3 years. Subjective pain assessments were performed at the same time points. Bone mineral density (assessing total body less head (TBLH)) significantly reduced after 2 years, compared to baseline (estimate = -0.964, 95% CI [-1.357, -0.572]), with the greatest decrease occurring within the first year. Vertebral fracture prevalence was 4.9%, with two further patients experiencing incident vertebral fractures. All vertebral fractures occurred in male patients, 75% of whom were British Asian. Back pain was not a predictor of low bone mineral density (BMD) or vertebral fractures. We report a lower vertebral fracture prevalence in patients aged 10-24 with ALL than has been previously reported in a cohort of younger patients. Male British Asian patients appeared to be at higher risk of vertebral fractures in our study. BMD and pain were not predictors of vertebral fractures.

The response to salvage chemotherapy in relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) is poor, and data on circulating tumour deoxyribonucleic acid (ctDNA) in this setting are limited. We evaluated ctDNA dynamics in 29 patients with relapsed or refractory DLBCL who received platinum-based salvage chemotherapy at the University Medical Center Groningen. In total, 124 plasma samples were analysed using low-coverage whole-genome sequencing to detect copy number alterations (CNAs) and targeted sequencing with a 115-gene panel for single- and multi-nucleotide variants (SNVs/MNVs). The complete response rate at the end of treatment was 55%, with a 1-year progression-free survival of 31%. At the R/R baseline, defined as the time after confirmation of relapse or refractory status and prior to initiation of salvage chemotherapy, CNAs were detected in 15 patients, SNVs in 27 and MNVs in 21. Patients with treatment failure had higher fraction of genome altered (FGA) and ctDNA levels at baseline. Low FGA combined with low metabolic tumour volume (MTV) at baseline was associated with favourable outcome. Clearance of all baseline SNVs at interim evaluation correlated with improved response, while persistence predicted failure (p < 0.05). Two of three patients with complete metabolic response at the end of treatment and detectable ctDNA relapsed, indicating ctDNA as a sensitive marker of minimal residual disease. These findings indicate the value of ctDNA profiling as a prognostic biomarker and as a tool for response-adapted treatment strategies in R/R DLBCL.

Evidence suggests that iron deficiency may reduce sickle cell disease (SCD) complications by decreasing sickle haemoglobin polymerization through reduced red cell haemoglobin concentration. The aim is to investigate the effects of iron deficiency in SCD patients. We reviewed clinical and laboratory data from 512 patients (408 HbSS, 104 HbSC) at King's College Hospital (2008-2020). Outpatient data were collected from patients with no blood transfusions or hydroxyurea (hydroxycarbamide) use in the prior 90 days. Patients were categorized as hypoferritinaemic (<45 μg/L), normoferritinaemic (45-800 μg/L) or hyperferritinaemic (>800 μg/L) and analysed for laboratory markers and clinical complications. In HbSC patients, hypoferritinaemia was associated with significantly fewer hospital admissions and inpatient days per year compared to normoferritinaemia. Although this was not seen in HbSS patients, hypoferritinaemia correlates with lower haemolysis and inflammation markers, with no differences in total haemoglobin or erythropoietin in both groups. In HbSS patients, haemoglobin F was significantly lower in hypoferritinaemic compared to normoferritinaemic patients. Iron deficiency may reduce inflammation and haemolysis in both HbSS and HbSC, with clinical benefits demonstrable in HbSC. Low ferritin levels were not associated with increased anaemia, suggesting improved red cell survival. Iron-restricted erythropoiesis may benefit SCD patients in certain circumstances.

Myelodysplastic syndromes (MDS) are heterogeneous stem cell disorders with a 30%-40% risk of transformation to acute myeloid leukaemia (AML). This study characterised the genetic and clinicopathological features of 437 newly diagnosed MDS patients. A predictive model for AML transformation was developed, which identified the bone marrow blast percentage, KRAS, STAG2 and TP53 mutations as significant predictors of disease progression. Novel prognostic models for overall survival (OS) and progression-free survival (PFS) were established and validated. The OS model incorporated age, sex and mutations in TP53, NF1, SRSF2, CSF3R, ETV6, CEBPA, BCOR, TET2, JAK2 and SF3B1. The PFS model incorporated age, sex, bone marrow blast percentage and mutations in STAT3, TP53, NF1, CEBPA, ETV6, CALR, DNMT3A, IDH2, GATA2, BCOR, JAK2, TET2 and SF3B1. These models stratify patients into favourable, intermediate-1, intermediate-2 and adverse risk groups, demonstrating superior risk stratification compared to the Revised/Molecular International Prognostic Scoring System (IPSS-R/M). This work provides the first genomic characterisation of a diagnosed MDS cohort in China and establishes the first risk prediction model for MDS-to-AML transformation, alongside novel prognostic models for OS and PFS. These tools offer improved prognostic prediction and potential guidance for therapeutic strategies in Chinese patients with MDS.

B-cell acute lymphoblastic leukaemia (B-ALL) in adolescents and adults remains challenging due to high relapse rates and suboptimal outcomes. Although minimal residual disease (MRD) and cytogenetic risk classification are independent prognostic indicators for B-ALL in adolescents and adults, their combined utility remains under explored. This retrospective study analysed 609 adolescent and adult patients with B-ALL to evaluate the integrated prognostic value of MRD at end of induction (MRD1) and after first consolidation (MRD2), combined with cytogenetic risk stratification (standard risk [SR] vs. poor risk [PR]). Although cytogenetic risk alone was not an independent prognostic factor, MRD positivity at either time point significantly predicted inferior 5-year RFS and OS in PR patients. Allogeneic haematopoietic stem cell transplantation (allo-HSCT) improved outcomes overall; however, PR patients with MRD2 positivity remained at high risk of relapse post-transplant. Multivariate analysis identified MRD1 and MRD2 as independent predictors of both relapse (RFS HR = 2.048) and mortality (OS HR = 1.979) in PR patients (all p < 0.01). These results demonstrate that combining MRD assessment with cytogenetic risk improves risk stratification, precisely identifying poor-risk patients with persistent MRD who may benefit from treatment intensification, including novel strategies post-transplant.