Acta Haematologica最新文献

INTRODUCTION Distress negatively affects cancer outcomes. The National Comprehensive Cancer Network (NCCN) recommends screening patients for distress by a self-reported scale (0-10) and to refer those with scores ≥ 4 to supportive services (SS). Little is known about the prevalence of distress and healthcare utilization in classical Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs): polycythemia vera (PV), essential thrombocythemia (ET), myelofibrosis (MF). METHODS We retrospectively identified MPN patients at our center to measure the proportions of patients with distress ≥ 4 evaluated by a SS [chaplaincy, integrative oncology, palliative medicine, psychiatry, psychology, and social work (SW)] or had acute care utilization (ACU; ≥ 1 ED visit or hospitalization) within six months of electronic distress screening (EDS). We also obtained sociodemographic, disease characteristics, and symptom score data to stratify variables associated with distress. RESULTS Among 141 patients (44 PV, 49 ET, 48 MF), the median age was 63 years (range, 25-89). Most patients identified as female (62%), White (77%), and completed EDS within three months of diagnosis (55%). Of 75/141 (53%) who reported distress ≥ 4, only 25/75 (33%) were evaluated by SS, and 23/75 (31%) had ACU within six months of EDS. Patients with distress ≥ 4 evaluated by SS had significantly higher ACU (48% vs. 14%; p=0.009). Distress was associated with higher symptom scores and more ED visits but not gender, race, ethnicity, diagnosis, relationship status, or insurance. CONCLUSION Despite consensus recommendations, most patients with distress ≥ 4 were not evaluated by SS. Future work should identify ways to better use patient-reported outcomes to promote early intervention.

Introduction: Ferroptosis offers novel perspectives for treating multiple blood-related diseases, yet its role in aplastic anaemia (AA) is rare. This study aimed to explore key ferroptosis-related genes (FRGs) in AA using bulk and single-cell RNA sequencing (scRNA-seq) data.

Methods: scRNA-seq and bulk RNA-seq data, along with FRG lists, were obtained from public databases. Differentially expressed FRGs (DEFRGs) between AA and control samples were identified, followed by functional enrichment and protein-protein interaction analyses. Single-cell analyses were conducted to reveal cell types in samples and DEFRGs activity in each cell was assessed. Moreover, DEGs between AA and control samples at the cellular level were explored, followed by integration with DEFRGs to determine common key genes. The KEGG pathway analysis of these genes was performed at the cellular level. Immune infiltration analysis evaluated the relationship between key genes and immune cells.

Results: A total of 38 DEFRGs were identified, enriched in pathways such as the intrinsic apoptotic signalling pathway. scRNA-seq analysis identified seven cell types, with elevated DEFRGs activity in platelets and stromal cells. Key genes DDIT4 and NCF2, identified through integrated analysis, were involved in autophagy, mTOR signalling, and osteoclast differentiation pathways, with their expression positively correlated with activated dendritic cells, in AA samples.

Conclusion: Our findings highlight the roles of DDIT4 and NCF2, in AA progression, providing potential insights for further mechanistic exploration of AA.

Abstract： Introduction: Many reports indicate that the occurrence of multiple myeloma (MM) is closely related to inflammation and immunity. Although the survival rates have been gradually improving in recent years, the cure rate is still not optimistic enough. Therefore, it is necessary to continue exploring the causes of MM. Method: This study utilizes Mendelian randomization (MR) analysis to establish the connection between inflammatory factors, immune cells, and the occurrence of MM. Results: In Mendelian randomization studies, a significant correlation was observed between interleukin-1 receptor antagonist (IL-1Ra), tumor necrosis factor receptor 1 (TNFR1), Memory B cell percentage of B cells (Memory B cell %B cells), and Immunoglobulin D positive, CD24 negative percentage B cells (IgD+ CD24- %B cells) with the onset of MM. In particular, IgD+CD24-%B cells showed a statistically significant inverse relationship with the development of MM (P<0.05, OR<1), whereas IL-1Ra, TNFR1, and Memory B cell %B cells displayed a positive association with the onset of MM (P<0.05, OR>1). These findings contribute valuable insights to the understanding of the pathogenesis of MM. Conclusion：This study emphasizes the significant role of inflammatory factors and immune cells in multiple myeloma (MM) progression. IL-1Ra, TNFR1, and Memory B cell percentages are identified as risk factors, while IgD+ CD24- %B cells may protect against progression, suggesting new immunomodulatory treatment strategies. However, research on IgD+ CD24- %B cells and MM is limited, necessitating future studies to clarify their mechanisms and effects on the tumor microenvironment. There is also an urgent need for clinical trials to assess therapies targeting these cells, as well as long-term follow-ups to understand their dynamic changes in relation to disease progression. Further investigation using animal models is warranted to validate their functional role in MM development.

Introduction: The treatment protocols of adolescent and young adults (AYA) patients with acute lymphoblastic leukemia (ALL) have evolved, with the advent of pediatric-based regimens, measurable residual disease monitoring and mutation analysis. Among the latter, previous reports have identified FLT-3 mutations in up to 5% of pediatric patients, however the full clinical significance of these mutations in the non-pediatric population is still uncertain.

Methods: Our cohort includes AYA patients with ALL treated with the NY-II and BFM protocols at different time periods, allowing analysis of prognostic factors and survival outcomes. Additionally, we analyzed DNA samples for FLT-3 mutations, focusing on the potential prognostic implications and treatment responses within our cohort.

Results: No significant differences were found in overall survival (OS) or progression-free survival (PFS) between the two treatment protocols. However, a higher rate of hematopoietic stem-cell transplantation (HSCT) was noted in the NY-II patients. Older age and high WBC count at presentation were identified as adverse prognostic factors using multivariate analysis. FLT-3 mutations were identified in 4 patients (5%) of the cohort, with only one patient having FLT-3 internal tandem duplication (ITD) mutation and three patients having FLT-3-tyrosine kinase domain (TKD) mutations.

Conclusions: The low rate and variability of FLT-3 mutations in an Israeli cohort precludes broad conclusions regarding their prognostic significance. In our cohort, age and WBC count, but not treatment protocol or FLT-3 mutations influenced survival.

Introduction: Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) is a severe hypersensitivity reaction rarely documented in patients with multiple myeloma (MM).

Methods: In our retrospective study of 108 newly diagnosed MM (NDMM) patients from January 2021 to October 2023, we identified four cases of DRESS. The clinical characteristics such as clinical manifestations, laboratory results, treatment and outcome were analyzed.

Results: These patients presented with fever, persistent and recurrent, along with a widespread red rash characterized by diffuse erythematous macules or papules accompanied by intense itching, desquamation, and other dermatological manifestations. Multi-organ involvement was common, including hepatic impairment, acute kidney injury, and type I respiratory failure, alongside pleural effusion and multiple lymphadenopathy. Laboratory findings revealed elevated eosinophil counts, often exceeding 1.5 × 10^9/L, abnormal liver function tests, acute kidney injury, and inflammatory markers. Anti-MM treatment was promptly suspended, and all patients received corticosteroid therapy. Outcomes varied, with one patient succumbing to myeloma progression, another to multi-organ failure, while the remaining two patients survived.

Conclusion: In NDMM patients undergoing induction therapy, occurrences of DRESS are infrequent but noteworthy, with an incidence higher than observed in the general population. It presents with significant morbidity and mortality, highlighting the crucial need for early recognition and management.

Introduction: Accurate prediction of survival in patients with acute myelogenous leukemia (AML) is challenging. Therefore, we developed a predictive survival model using endocrine-related gene expression to identify an endocrine signature for accurate stratification of AML prognosis.

Methods: RNA matrices and clinical data for AML were downloaded from a training dataset (Gene Expression Omnibus) and two validation datasets (the Cancer Genome Atlas and Therapeutically Applicable Research to Generate Effective Treatments).

Results: In relation to the survival outcome, a risk model was constructed by incorporating seven endocrine-related genes. The model exhibited favorable predictive efficacy in estimating 5-year survival rates, as demonstrated by both the training and validation cohorts. Multivariable analysis revealed that the endocrine signature demonstrated autonomous prognostic significance in the aforementioned cohorts. Prediction accuracy for 5-year overall survival increased using a nomogram combining endocrine risk score and classical prognostic factors compared with using classical prognostic factors alone. The model predictions were confirmed using AML cell lines.

Conclusion: The endocrine-related prognostic model established in this study improves AML survival prediction accuracy.

Introduction: This study aimed to analyze the survival outcomes and adverse events (AEs) associated with the long-term use of tyrosine kinase inhibitors (TKIs) and to assess health-related quality of life (HRQoL) in patients with chronic myeloid leukemia (CML).

Methods: Medical records of 345 patients with CML treated with at least one type of TKI were retrospectively reviewed.

Results: No significant differences in survival were observed based on the number of different TKIs the patients received (p = 0.301) or the sequence of TKIs used (p = 0.770). Among 182 patients treated with nilotinib, 25 experienced cardiovascular events (CVEs). After 10 years of nilotinib treatment, CVEs occurred in 55.2% of patients with ≥2 vascular risk factors. Pleural effusion was observed in 27 of 78 dasatinib-treated patients. In terms of HRQoL, patients treated with nilotinib generally reported higher satisfaction levels than did those treated with imatinib or dasatinib. When stratified by age or duration of TKI treatment, patients aged <60 years or those with a treatment duration of ≥1 year exhibited better satisfaction levels.

Conclusion: Survival outcomes were not affected by history of TKI treatment. Nilotinib is favorable for HRQoL but increases the risk of serious CVEs in patients with vascular risk factors.

Introduction: ETV6::JAK2 is a fusion known to drive acute lymphoblastic leukaemia (ALL) in the presence of other genomic lesions which define the JAK/STAT class of Philadelphia chromosome-like acute lymphoblastic leukaemia (Ph-like ALL). Ph-like ALL comprises approximately 15% of ALL. Patients with mutations or gene fusions signalling through the JAK/STAT pathway have particularly poor prognosis. Emerging treatments targeting JAK2 fusions and mutations are promising, and phase 3 clinical trials are in progress. However, with widespread use of JAK2 inhibitors, it is important to anticipate and manage resistance mechanisms. The JAK2 p.G993A mutation confers resistance in vitro, even to high-dose JAK2 inhibitors such as ruxolitinib. We postulated that direct inhibition of STAT3 and STAT5, downstream from JAK2, may overcome resistance.

Methods: Murine-derived IL-3-dependent Ba/F3 cells were transfected with ETV6::JAK2 containing a p.G993A mutation for this study. These cells were confirmed to demonstrate IL-3 independence and ruxolitinib resistance prior to use in experiments. An inhibitor-response assay was conducted using differing concentrations of SH-4-54 and pimozide (STAT3/5 inhibitors) applied to ETV6::JAK2 p.G993A cells and two control cell lines.

Result: SH-4-54 and pimozide were effective against ETV6::JAK2 p.G993A cells with median lethal doses (LD50) of 296 nM for SH-4-54 and 455 nM for pimozide. Both drugs demonstrated a lesser effect on empty vector Ba/F3 cells, with an LD50 of 371 nM for SH-4-54 and 596 nM for pimozide. Neither drug demonstrated significant effect on non-JAK/STAT-activated KG-1a myeloid cells at doses near the LD50.

Conclusion: SH-4-54 and pimozide both overcame treatment resistance in our in vitro model of JAK/STAT-driven Ph-like ALL with a mutation conferring JAK2 inhibitor resistance. While SH-4-54 demonstrates greater potency than pimozide, pimozide may be a more promising option given its demonstrated safety profile in humans. Direct STAT3 and STAT5 inhibition may be an effective approach for overcoming inevitable JAK2 inhibitor resistance-conferring mutations in patients with the poor prognostic subtype of JAK/STAT class Ph-like ALL.

Introduction: Anal lymphoma (AL) is a rare presentation of extranodal lymphomas, characterized by occurrence in the anal area and largely understudied due to its infrequency. This study aimed to address gaps in knowledge about AL's demographic and clinical profiles, treatments, and survival outcomes, leveraging data from the SEER program.

Methods: We conducted a retrospective analysis of 79 AL cases identified in the SEER database from 2000 to 2022; 36 stage I AL cases were identified and defined as localized primary anal lymphoma (L-PAL). Data on demographics, tumor specifics, treatment modalities, and survival were analyzed using the Kaplan-Meier method and Cox proportional hazards models.

Results: The majority of AL cases were diffuse large B-cell lymphoma (70.9%). Other notable subtypes included anaplastic T-cell lymphoma, marginal zone lymphoma, B-cell non-Hodgkin lymphoma, Burkitt lymphoma/leukemia (each accounting for 6.3%), followed by follicular lymphoma and mantle-cell lymphoma (each at 1.3%). AL primarily affected younger males (median age 50), with a significant majority being Caucasian. Initial stages (I and II) were more commonly observed, and treatments varied, with chemotherapy being most prevalent (67.1%), followed by radiation (30.4%) and surgery (30.4%). The 5- and 10-year overall survival (OS) rates were 59.4% and 44.1%, respectively, while the corresponding cancer-specific survival (CSS) rates were 67.9% and 58.0%, respectively. Age was a significant prognostic factor for OS but not for CSS. Radiotherapy tended to improve CSS in the AL population.

Conclusion: This research corresponds to the first in-depth analysis of AL, highlighting its distinct demographic patterns, clinical features, and responses to various treatments, distinguishing it from other types of anal cancers. Our results underscore the importance of developing specialized diagnostic and treatment strategies. To enhance our understanding and management of this uncommon form of lymphoma, future studies should aim for broader and more collaborative international research efforts.

Introduction: Acute myeloid leukemia (AML) represents a significant burden for patients and their families, and to the healthcare system. This study estimated the total cost of illness associated with newly diagnosed AML patients in Canada.

Methods: The economic burden of AML was estimated using an incidence-based model, analyzing different types of AML cases in Canada. Direct and indirect costs were calculated using scientific literature and Canadian clinical experts' inputs. Patients were categorized depending on their eligibility for intensive chemotherapy (fit and unfit patients) as well as according to age and cytogenetic markers.

Results: The total average cost of AML per patient is estimated to be CAD 178,073 with a cost of CAD 210,983 and CAD 145,163 for fit and unfit patients, respectively. The costs related to treatment represent half of the total average cost (52%), followed by hematopoietic stem cell transplant (23%), best supportive care (16%), productivity loss (6%), and wastage (4%).

Conclusion: For patients with AML, the costs associated with fit patients are higher than unfit patients. Hospitalization and best supportive care costs are key cost drivers for the total costs of fit and unfit patients, respectively. This study highlights that AML is associated with a significant economic burden in Canada.