Therapeutic Advances in Hematology最新文献

Background: Adults with relapsed or refractory (R/R) B-cell precursor acute lymphoblastic leukemia (BCP-ALL) have dismal prognoses, underscoring the need for effective salvage therapies. Inotuzumab ozogamicin (INO) and blinatumomab (BLIN) have demonstrated efficacy in achieving complete remission (CR) and measurable residual disease (MRD) response.

Objectives: We tried to evaluate the clinical outcomes and toxicities of INO in adults with R/R BCP-ALL.

Design: Prospective observational multicenter study.

Methods: A total of 100 patients (25 Ph-positive, 75 Ph-negative) received INO (0.8 mg/m² on week 1; 0.5 mg/m² on weeks 2-3) for the initial cycle, followed by 0.5 mg/m² dosing in subsequent cycles. Allogeneic hematopoietic cell transplantation (allo-HCT) was planned after remission.

Results: Among the cohort, 7 patients were primary refractory (4 post-BLIN), 36 relapsed after chemotherapy (23 post-BLIN), and 57 relapsed after allo-HCT (23 post-BLIN). Extramedullary relapse occurred in 39% of patients. After the first cycle, 60% achieved CR or CR with incomplete hematologic recovery; the overall best response rate after two cycles was 67%, with MRD negativity achieved in 63.1%. Thirty-nine patients (58.2%) underwent allo-HCT. Early mortality occurred in 12%, and hepatic veno-occlusive disease/sinusoidal obstruction syndrome was observed in 10%. With a median follow-up of 31.5 months, the 3-year overall survival was 21.3% in the entire cohort and 37.6% among transplanted patients.

Conclusion: INO represents a potent salvage option for R/R BCP-ALL. However, substantial toxicities highlight the critical need for careful patient selection and dose optimization strategies to maximize its therapeutic benefit.

Trial registration: This study was registered in Clinical Research Information Service (CRIS #KCT0010009) which is connected to WHO ICTRP (Operated by Korea Centers for Disease Control and Prevention, Ministry of Health and Welfare, Republic of Korea).

Background: Outcomes for primary central nervous system lymphoma (PCNSL) have been improved with high-dose methotrexate (HD-MTX)/Thiotepa-based chemotherapy followed by autologous stem cell transplantation. In limited-resource settings, HD-MTX/Ifosfamide plus whole brain radiotherapy (WBRT) has become the local standard of care.

Objectives: This study investigated the real-world effectiveness, neurocognitive functions, and health-related quality of life (HRQoL) of HD-MTX/Ifosfamide in newly diagnosed PCNSL patients.

Design: A single-center retrospective and prospective study.

Methods: Newly diagnosed PCNSL patients treated with HD-MTX (±Ifosfamide) between 2011 and 2024 were analyzed for treatment effectiveness using binary logistic regression and a Cox regression model. The age range- and education-matched PCNSL and non-central nervous system (CNS) lymphoma patients in first remission were assessed using standardized cognitive tests and European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30/BN20 questionnaires. The categorical data and continuous data were calculated with the Chi-square test or Fisher's exact test and analysis of variance, respectively.

Results: Among 94 PCNSL patients, 56 patients received HD-MTX/Ifosfamide (median age 56 (range 16-69) years; 68% Eastern Cooperative Oncology Group (ECOG) 0-1) and 38 patients received HD-MTX monotherapy (median age 66 (range 51-82) years; 63% ECOG ⩾2). HD-MTX/Ifosfamide demonstrated a significantly longer event-free survival (39 months vs 8 months, p = 0.021) than HD-MTX monotherapy. Poor performance status (ECOG ⩾2) was associated with inferior response (54.8% vs 78.8%, p = 0.013) and overall survival (hazard ratio 2.4 (95% confidence interval 1.57-4.56), p = 0.007). Patients who received WBRT consolidation had a superior 2-year progression-free survival (74.5% vs 35.6%, p < 0.001). Comparing neurocognitive tests in 20 PCNSL and 20 non-CNS lymphoma survivors showed no difference in overall scores, but trends toward lower attention and executive function scores in the PCNSL group. Most (16/20) PCNSL survivors received WBRT. Compared to non-CNS lymphoma survivors, PCNSL survivors reported significantly lower HRQoL, particularly in physical functioning, which might be attributed to residual neurological deficits.

Conclusion: This study supports HD-MTX/Ifosfamide as an effective, well-tolerated regimen for younger, fit PCNSL patients. WBRT remains a valuable consolidation therapy to prevent recurrence without a pronounced decline in cognitive function. However, PCNSL survivors may experience subtle declines in attention, executive function, and HRQoL.

Background: FIBTEM, a rotational thromboelastometry (ROTEM) component, assesses fibrin-based clot firmness and indirectly measures fibrinogen function. It offers faster turnaround time compared to the Clauss method for fibrinogen quantification, which may support early coagulation assessment in critically ill patients with sepsis.

Objectives: Our study aims to evaluate the correlation between FIBTEM parameters and fibrinogen levels and predict the possibility of hyperfibrinogenemia using FIBTEM parameters in patients with sepsis.

Design: A retrospective secondary analysis of a prospective observational study.

Methods: Patients diagnosed with sepsis were recruited and admitted to the University Medical Center Ho Chi Minh City intensive care unit from June 2020 to December 2021. The international normalized ratio, activated partial thromboplastin time, platelet counts, fibrinogen levels, and FIBTEM parameters (A5, A10, A20, and maximum clot firmness (MCF)) were assessed for each patient. The correlations among laboratory parameters were assessed using the Pearson's correlation coefficient. Predicted values of fibrinogen and FIBTEM were analyzed using simple linear regression, Bland-Altman plots, and Lin's concordance correlation coefficient (CCC). The area under the receiver operating characteristic curve (AUC) and Kappa coefficients were calculated.

Results: The median age of 159 patients with sepsis was 69. Males represented 51.6% of the participants. The percentage of patients with comorbidities was 88.1%. The mean plasma fibrinogen level was 5.4 ± 1.8 g/L. Fibrinogen levels were strongly correlated with FIBTEM parameters (p < 0.01 for all values), including A5 (r = 0.701), A10 (r = 0.717), A20 (r = 0.723), and MCF (r = 0.735). MCF could not predict exact fibrinogen levels (CCC = 0.703). The AUC of the MCF to predict hyperfibrinogenemia was 0.905 (95% CI: 0.866-0.945), with a sensitivity of 85.5%, a specificity of 83.1%, and a Kappa coefficient of 0.69 at the optimal cut-off value of 22.5 mm.

Conclusion: FIBTEM MCF could be a practical, rapid, surrogate tool for detecting hyperfibrinogenemia in sepsis and may help guide early clinical decisions before fibrinogen test results are available, although further validation in larger studies is required.

Background: Acquired aplastic anemia (AA) is rare bone marrow failure syndrome characterized by pancytopenia due to immune-mediated destruction of hematopoietic stem and progenitor cells, and leads to an increased risk of bleeding and infectious complications. The first-line treatment option for individuals with severe AA who are ineligible for allogeneic hematopoietic stem cell transplantation is triple therapy, comprised equine anti-thymocyte globulin, calcineurin inhibitor (CNI), and eltrombopag (EPAG). However, this approach is associated with considerable treatment-related complications, requires close inpatient monitoring as well as specialized care and expertise, limiting its feasibility in less-experienced centers. Emerging evidence suggests that double therapy with CNI and EPAG combination reduces the transfusion burden in severe AA.

Objective: Evaluate the real-world effectiveness of CNI and EPAG combination therapy in reducing transfusion burden among adults with AA.

Methods: We conducted a retrospective cohort study using Blue Cross Blue Shield Axis Database to examine the change in transfusion requirements in adult patients with newly diagnosed AA who have received combination therapy with CNI and EPAG. Individuals were stratified into baseline transfusion-independent, low, and high transfusion subgroups. Transfusion requirements were reassessed after 6 months from initiation of double therapy.

Results: The majority of the 153 identified patients with AA started therapy shortly after diagnosis and were adherent to treatment and monitoring during the initial 6 months. Among patients with baseline transfusion requirements (97; 63.4%), 66% achieved TI status. Additionally, 75.5% of patients with a high baseline transfusion burden demonstrated a ⩾50% reduction in transfusion requirements.

Conclusion: These findings underscore the efficacy and feasibility of double therapy with CNI and EPAG for adults with AA in the real-world setting, offering an alternative for patients when triple therapy is not possible.

Background: Patients with transfusion-dependent thalassemia frequently experience significant psychological distress, with high rates of anxiety and depression reported. Despite this, the psychological status of thalassemia patients after hematopoietic stem cell transplantation (HSCT) remains less explored. Gaining insights into the symptoms of depression and anxiety in this population is crucial, as it can inform tailored support and improve quality of life.

Objectives: This study aimed to assess the prevalence of anxiety and depression in post-HSCT thalassemia patients and to identify potential risk factors.

Design: This was a cross-sectional study.

Methods: A cross-sectional study involved 170 transfusion-dependent thalassemia patients who underwent HSCT from January 2017 to November 2022. The Hospital Anxiety and Depression Scale (HADS), a self-report questionnaire, was used to evaluate the levels of anxiety and depression.

Results: The prevalence of anxiety and depression was 11.2% and 8.8%, respectively. Patients with a history of splenectomy and those with chronic graft-versus-host disease (cGVHD) exhibited significantly higher HADS scores (p < 0.01). Correlation analysis revealed positive associations between these variables and HADS scores, with correlation coefficients of 0.256 for splenectomy with HADS-Anxiety (HADS-A) and 0.227 with HADS-Depression (HADS-D) scores. For cGVHD, the correlation coefficients were 0.290 with HADS-A and 0.388 with HADS-D scores.

Conclusion: The study revealed the psychological burden faced by post-transplant thalassemia patients, particularly those with a history of splenectomy and cGVHD. These findings underscore the need for targeted psychological support and interventions for this vulnerable patient group.

Background: Detection of measurable residual disease (MRD) is becoming the standard of care in the prognostication of acute myeloid leukaemia post-chemotherapy, but its role in early post-haematopoietic stem cell transplantation (HSCT) is less defined.

Objectives: This study aims to examine the role of MRD detection by molecular tools in early post-HSCT settings and its significance in prognostication among other clinicopathologic factors.

Design: It is a retrospective cohort study.

Methods: We examined MRD early post-HSCT (median: 26 days) in patients receiving allogeneic HSCT at complete remission by droplet digital PCR or next-generation sequencing targeting leukaemia-associated mutations. The effect of MRD positivity and other clinicopathologic variables on post-HSCT leukaemia-free survival (LFS), overall survival (OS) and cumulative incidence of relapse (CIR) were investigated.

Results: One hundred fifty-nine patients were included, and the median follow-up time was 6 years. Early post-HSCT MRD positivity was observed in 36% patients and was associated with higher CIR (37.1% vs 13.2% at third year, p = 0.0005), inferior LFS (median: 3.8 years vs not reached, p = 0.002) and OS (median: 10.6 years vs not reached, p = 0.019). It was the only significant factor associated with inferior post-HSCT LFS, CIR and OS in both univariate and multivariate analyses.

Conclusion: This study demonstrated that early MRD positivity was predictive of a higher risk of relapse, and inferior LFS and OS post-HSCT. This information laid the foundation for designing MRD-guided strategies early post-HSCT to prevent haematological relapse.

The first gene therapy products for hemophilia A and B have recently been approved by the regulatory authorities. Although this is an important milestone for people with hemophilia, there is still a need to further improve on the efficacy, safety, and stability of expression and to ultimately include pediatric patients before the onset of arthropathy and other complications caused by uncontrolled bleeding. To overcome some of the limitations of conventional gene therapy strategies, gene editing is currently being explored in preclinical studies. Gene editing allows for targeted modifications of the human genome with unprecedented specificity based on zinc finger nuclease, meganuclease, transcription activator-like endonuclease, or clustered regularly interspaced short palindromic repeats (CRISPR) technologies that induce double-strand DNA breaks (DSB). Next-generation gene editing strategies, such as those dependent on CRISPR-derived base or prime editors, allow targeted genetic modification independent of the induction of DSBs, offering a potential safer alternative. Sustained efficacy and production of factor VIII or factor IX can be achieved after gene editing in patient-derived cells or in adult or newborn hemophilia A or B mouse models. These preclinical studies pave the way toward phase I/II clinical trials in patients with severe hemophilia. The potential risk of undesired off-target modifications of the human genome and adverse immune reactions, and the need for efficient delivery of the gene editing components, need to be rigorously addressed before the promise of gene editing for hemophilia can ultimately be fulfilled.

Background: The therapeutic use of immunoglobulin (IG) is increasing and accounts for the largest expenditure in the Canadian Blood Services budget. However, more granular data on IG utilization is limited.

Objective: To describe IG treatment indications, dosing characteristics, and clinical outcomes in patients enrolled in the Ontario IG Treatment (ONIT) program, a government-funded pilot clinical program with a case registry.

Methods: A longitudinal descriptive study was conducted on ONIT registry participants from June 1, 2020 to March 31, 2024.

Results: Six hundred ninety-three consenting participants were included; 429 (61.9%) were female; median [Q1, Q3] age was 62 [47, 71] years; 47 (6.8%) passed away during the study period. Of 693, 658 (94.9%) were receiving IG treatment: 544 (82.7%) on SCIG and 114 (17.3%) on IVIG. Treatment indications were primary immune deficiency (PID) (299, 43.1%), secondary immune deficiency (SID) (348, 50.2%), and immune-mediated disease (IMD) (46, 6.7%). The median dose was 0.48 [0.42, 0.57] and 0.52 [0.44, 0.64] g/kg/4 weeks, for SCIG and IVIG, respectively. Seventy-three patients transitioned from IVIG to SCIG, with the dose adjusted to clinical response. The IVIG:SCIG conversion ratios were 1:1, 1:0.9, and 1:1.2 for PID, SID, and IMD, respectively. Only 33 (5.0%) stopped IG during the study. There was a 78.4% reduction in infections and over 90% reduction in emergency room visits and hospitalizations in PID and SID. Most patients (89.4%) reported improved health after starting IG therapy.

Conclusion: The study provides insights into the current landscape of IG utilization, which may inform health system research and support healthcare delivery planning.

Background: Gene therapy has emerged as a transformative treatment for hemophilia, offering the potential for durable factor expression after a single administration. Since 2019, multiple gene therapies have been approved for adults with hemophilia A and B. However, the adoption of gene therapy into clinical practice has been slow, and provider preparedness remains uncertain.

Objective: To assess current knowledge, perceptions, and clinical preparedness regarding hemophilia gene therapy among international healthcare professionals.

Methods: An anonymous online survey was distributed internationally from August 24, 2023 to January 24, 2024 through four professional organizations. The 24-question survey included items on demographics, perceptions of gene therapy, and knowledge-based questions. Descriptive statistics were used to analyze responses.

Results: A total of 327 participants from 66 countries responded. Top concerns with current therapies included dosing burden, inhibitor risk, and venous access. Only 7.5% of respondents were extremely familiar with regulatory guidance on gene therapy, and 35.6% were not comfortable answering patient questions about trials. Perceived barriers to adoption included uncertainty about durability, immune responses, eligibility, and cost.

Conclusion: While clinical integration of gene therapy for hemophilia is advancing, this survey highlights persistent gaps in provider knowledge and confidence, especially related to regulatory guidance and clinical trial data. Targeted education and training initiatives are needed to support informed implementation of gene therapy in diverse clinical settings.

Background: Solitary plasmacytoma (SP) is a rare plasmacytoma. Research on clinical characteristics and prognostic factors for SP is very limited.

Objective: This study aimed to evaluate the clinical attributes and prognostic indicators for individuals afflicted with SP.

Design: We retrospectively analyzed the clinical parameters and survival data of 49 patients diagnosed with SP from three centers between the year 2009 and 2024.

Methods: The Kaplan-Meier curves were constructed to compare the survival outcomes. The independent risk factors were determined based on the Cox proportional hazards model.

Results: Among the 49 patients with SP, 30 (61.2%) were classified as solitary bone plasmacytoma (SBP), while 19 (38.8%) had solitary extramedullary plasmacytoma (SEP). Anatomically, SEPs predominantly localized to the upper aerodigestive tract (47.4%), whereas SBPs exhibited a predilection for the axial spine (30.0%) and appendicular long bones (20.0%). Survival analysis revealed significantly reduced progression-free survival (PFS) in the SBP cohort compared to SEP patients (p = 0.0002), though no statistically significant difference in overall survival was observed between groups (p = 0.1012). Radiotherapy in conjunction with surgery or chemotherapy did not substantially enhance the outcome of the patients with SP. Multivariate Cox regression analysis identified SBP subtype (hazard ratio (HR) = 0.068, 95% confidence interval (CI): 0.008-0.537, p = 0.011) and elevated Ki67 expression (HR = 4.545, 95% CI: 1.005-20.542, p = 0.049) as independent prognostic factors for inferior PFS. Notably, SBP patients with Ki67 expression exceeding 35% demonstrated the poorest clinical outcomes.

Conclusion: The prognosis of patients with SBP was poorer than that with SEP. Patients with SBP exhibiting Ki67 expression exceeding 35% had the poorest outcome.