Therapeutic Advances in Hematology最新文献

Background: Patients with chronic myeloid leukemia (CML) are currently experiencing intolerance or lack of efficacy with previous tyrosine kinase inhibitors (TKIs) and benefit from asciminib as a novel TKI.

Objectives: The purpose of this meta-analysis was to evaluate the efficacy and safety of asciminib as a second-line or beyond second-line treatment for patients with CML.

Design: A systematic review and meta-analysis.

Data sources and methods: We searched four databases (PubMed, Cochrane, Web of Science, and EMBASE) for relevant literature from the inception of the databases to February 4, 2024. Two authors independently performed data extraction to assess the efficacy of asciminib using metrics such as the rate of major molecular response (MMR) and the safety of asciminib using the rate of adverse event (AE). We also performed a subgroup analysis based on the reason for starting asciminib. Data were analyzed using either a fixed-effects model or a random-effects model to calculate the rate of MMR and the rate of AEs. We also assessed the quality of the studies by selecting appropriate tools according to the type of included studies.

Results: We included 8 studies involving a total of 691 patients. The overall MMR rate for patients with CML treated with asciminib was 46.9% (95% CI: 39.8-54.0, p < 0.05). AEs were reported in five studies, with a combined rate of 79.2% (95% CI: 46.6-98.7, p < 0.05) for all grades and 39.5% (95% CI: 17.6-61.3, p < 0.05) for grade ⩾3 AEs. Thrombocytopenia was the most common AE, with a combined rate of 22.5% (95% CI: 18.8-26.3, p < 0.05) for all grades.

Conclusion: Asciminib is effective in the treatment of patients with CML, and the most common AE during treatment is thrombocytopenia.

Background: Cancer drug development is a complex and costly process. Selinexor is a drug that received accelerated approval as a new treatment for relapsed or refractory diffuse-large B-cell lymphoma and multiple myeloma. Despite initially showing promise in treating these conditions, it has shown high-grade toxicity in clinical trials. Hence, an analysis is needed to assess the clinical trial portfolio of selinexor.

Objectives: This investigation aims to evaluate published clinical trials of selinexor to assess its risk/benefit in terms of response and survival outcomes as well as its toxicity.

Design: Cross-sectional.

Methods: We conducted a cross-sectional investigation by searching databases for published clinical trials that used a response criteria pertaining to selinexor administration in adults. In a masked, duplicate manner, we extracted trial characteristics, median progression-free survival (PFS), overall survival (OS), objective response rates (ORR), and Grade 3-5 adverse events (AEs).

Results: Of the 753 articles identified, 40 were included in our final sample. The trials reporting PFS data using control arms showed a median difference in PFS by 4.4 months, favoring the selinexor treatment arm. However, trials that reported OS data with control arms indicated that selinexor showed a worse median difference in OS (-2.4 months) than the control arms. Among the 53 measurements reporting ORR, the weighted median ORR was 36.4%, and the median difference ORR (4.8%) favored selinexor. Additionally, 4153 cumulative Grade 3-5 AEs were reported.

Conclusion: In comparison to a control arm, selinexor increases PFS and induces response, suggesting drug activity. However, acceptable Grade 3-5 AEs or improvement of OS was not seen across a single indication, suggesting a poor pretest probability. Our risk/benefit analysis of selinexor provides valuable insight into the unfavorable outcomes of the drug and increased high-grade AEs. Hence, further testing of selinexor should be carefully scrutinized and contextualized with the portfolio of data we present.

Pegylated interferons alfa are increasingly used in patients with myeloproliferative neoplasms (MPN) due to their potential disease-modifying effect. Ropeginterferon alfa-2b has been approved for patients with polycythemia vera (PV) with no symptomatic splenomegaly as first-line cytoreductive therapy, based on the results of the PROUD-PV/CONTINUATION-PV studies, documenting significantly higher rates of complete hematologic response (CHR) compared with hydroxyurea from 2-year timepoint onward. Although safety profile of pegylated interferons is overall good, interferon-related toxicities can occur. Focus of this article is on interferon-mediated autoimmune diseases. We describe two patients with PV treated with pegylated interferons alfa, one patient developed a cutaneous, paranasal sarcoidosis without any systemic symptoms and was successfully treated with topical steroids. The other patient developed widespread psoriatric skin lesions, which were treated with moderate effect with topical therapy with calcipotriene and betamethasone dipropionate foam, antidry calm lotion and in the course of the disease with ultraviolet light therapy (UVB). Only with methotrexate she achieved a nearly complete remission of the psoriasis. In both patients pegylated interferon was continued in view of the CHR and therefore the beneficial effect on MPN. We review the pertinent literature on the management of interferon-mediated autoimmune diseases in patients with MPN. As there is little published evidence on that topic, we propose multidisciplinary clinical practice recommendations based on available evidence and clinical experience in the management of patients with MPN treated with pegylated interferon alfa.

Background: Haploidentical hematopoietic stem cell transplantation (haplo-HSCT) is a common alternative for patients with hematological malignancies. Epstein-Barr virus (EBV) reactivation is a common complication post-transplantation, but its impact on immune reconstitution and survival remains unclear.

Objective: To compare immune reconstitution and survival between patients with and without EBV reactivation after haplo-HSCT.

Design: A retrospective study was conducted involving 322 patients aged 18-60 years, diagnosed with hematological malignancies, who underwent haplo-HSCT at our center from January 2018 to December 2021.

Methods: Data analysis was performed using SPSS (version 24.0) and R4.3.0 software. Statistical methods included Chi-square tests for qualitative variables, independent t tests for continuous variables, Kaplan-Meier method for survival analysis, and logistic regression for risk factor analysis.

Results: After a median of 58 days posttransplant, 176 patients (54.6%) had EBV reactivation, but only 5 patients developed posttransplant lymphoproliferative disorder. Logistics multivariate analysis showed EBV IgA-negative donor, cytomegalovirus (CMV) reactivation, and graft-versus-host disease (GVHD) prophylaxis with anti-thymocyte globulin (ATG) were independent risk factors of EBV reactivation. Then a risk factor prediction model for EBV reactivation after transplantation was established based on the multivariate regression. The analysis based on the generalized linear mixed model showed dramatic improvements in the reconstitution of CD8⁺CD45RO⁺ memory T-cells and CD16⁺CD56⁺ NK cells of the EBV-reactivated group. There was no statistical difference in overall survival (p = 0.26), relapse-free survival (p = 0.72), GVHD-relapse free survival (p = 0.44), cumulative incidence of relapse (Gray's test p = 0.72), and transplant-related mortality (Gray's test p = 0.066) between patients with and without EBV reactivation.

Conclusion: Our study showed EBV IgA-negative donor, CMV reactivation, and GVHD prophylaxis with ATG were independent risk factors of EBV reactivation. Posttransplant EBV reactivation had no significant influence on the outcomes of patients, but its impact on immune reconstitution might be complicated. The predictive model based on the study could direct our attention toward patients at high risk of EBV reactivation.

Core-binding factor acute myeloid leukemia (CBF-AML) is a subtype of AML characterized by specific genetic rearrangements, including t(8;21) and inv(16), which are associated with a relatively favorable prognosis with relapse rates around 30%. The mutational profiling of CBF-AML is highly heterogeneous in pediatrics, with mutations in the tyrosine kinase pathway (including KIT, FLT3, and N/KRAS), epigenetic regulators, cohesin, and additional cytogenetic abnormalities. The identification of high-risk mutations, such as those in KIT and FLT3, underscores the need for targeted therapies and highlights the importance of high-throughput sequencing technologies, providing critical insights into the prognosis and informing treatment strategies. Integrating targeted agents with existing treatment protocols has the potential to enhance treatment efficacy and significantly improve patient outcomes. However, CBF-AML presents significant heterogeneity in both pathophysiology and clinical characteristics, with cooperating cytogenetic mutations, leading to difficulties and uncertainties in the prognosis and treatment of CBF-AML in pediatrics. Given the relapse rates and the significant impact of specific mutations on prognosis, there is a critical need for improved risk stratification and personalized treatment approaches in pediatric CBF-AML. Ongoing research and clinical trials focusing on the molecular and genetic profiling of pediatric CBF-AML will be essential for developing more effective and targeted therapies, ultimately improving patient outcomes. This review summarizes the molecular genetics profiling in CBF-AML among pediatrics, targeting its effect and interactions on prognosis and treatment to provide an overview for further research based on mutations among CBF-AML in pediatrics.

Background: Hereditary haemorrhagic telangiectasia (HHT) is a genetic vascular disorder characterised by telangiectases, which cause nasal and gastrointestinal (GI) bleeding, and visceral arteriovenous malformations. Since 2012 bevacizumab, a monoclonal antibody targeting vascular endothelial growth factor, has been a promising treatment for HHT-related bleeding and was evaluated in the phase II BABH study.

Objective: To follow and describe evolution and treatments of patients with HHT post-BABH study.

Design: This study is a 1-year, multi-centre descriptive study.

Methods: We collected clinical (nose and GI bleeding, red blood cell transfusions) and biological (haemoglobin and ferritin levels) data and treatment information.

Results: Of 22 patients included across 4 centers, 15 received bevacizumab. Among them, 12 (86%) had a >50% decrease in the number of RBC units transfused 3 months post-treatment. Mean haemoglobin levels increased from 83.08 to 105.98 g/L.

Conclusion: Bevacizumab effectively reduces RBC transfusions and is efficient for treating severe bleeding in patients with HHT.

Trial registration: This trial was registered with the ClinicalTrials.gov Identifier #NCT06039124.

Acute myeloid leukemia (AML), the most common type of leukemia in adults, is a highly heterogeneous and aggressive hematologic malignancy. Since the 20th century, the combination of cytosine arabinoside and anthracyclines has been the most common chemotherapy drug used to treat patients with AML. Although, new targeted medicines have emerged, such as midostaurin and gilteritinib targeting FMS-like tyrosine kinase 3 (FLT3), ivosidenib (isocitrate dehydrogenase 1 (IDH1) inhibitor) and enasidenib (IDH2 inhibitor) targeting IDH, and gemtuzumab ozogamicin targeting CD33, which have changed the treatment strategies of AML. But, until now, hematopoietic stem cell transplantation remains the best treatment option in most cases. However, treatment resistance and relapse are still the major consequences of disease progression in AML, highlighting the urgent need for novel therapeutic approaches. As an alternative, chimeric antigen receptor (CAR)-T cells are engineered T-cells developed as a breakthrough in cancer therapy in recent years, and explored and used in various tumor types. In particular, it has achieved remarkable efficacy in the field of relapsed and refractory B lymphocyte tumors. This review mainly summarizes and discusses the research progress and the clinical application of CAR-T cell immunotherapy in AML in recent years.

Background: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is crucial for treating high-risk hematological cancers. Posttransplant infections are a leading cause of mortality and morbidity, especially before engraftment. This study evaluated the effects of granulocyte transfusion (GT) therapy on neutrophil and platelet (PLT) engraftment in patients with febrile neutropenia during the pre-engraftment phase following allo-HSCT with a control group.

Methods: We retrospectively analyzed 56 patients who underwent allo-HSCT from January 2019 to January 2024, dividing them into two groups: those who received GT (GTG) and those who did not (non-GTG).

Results: A total of 76 GTs were administered to 28 patients with febrile neutropenia during the pre-engraftment period. The median granulocyte dose was 5.4 × 10⁸/kg. Median engraftment times in the GTG were 13 days for both PLT and neutrophil engraftment, compared to 15.5 days (PLT) and 19 days (neutrophil) in the non-GTG (p < 0.001 for neutrophil and p = 0.007 for PLT). Additionally, 89.3% of patients in the GTG showed improved infection status. Overall survival (OS) at 2 year was 61.4% for GTG and 73.2% for non-GTG, respectively. No significant difference in OS between the groups (p > 0.05). In the non-GTG, the OS rate was 47.5%, with no significant difference in OS and mortality rates between the groups. GT did not affect the incidence of graft-versus-host disease or cytomegalovirus infection.

Conclusion: This study is the first to include a control group and demonstrate a statistically significant association between GT therapy in the pre-engraftment period and shortened engraftment times in allo-HSCT recipients.

Aims: It was aimed at measuring the comorbidities of chronic myeloid leukemia (CML) patients at the time of diagnosis with different comorbidity indices and evaluating their effects on disease prognosis.

Methods: The comorbidities of the patients were retrospectively screened and calculated in three different comorbidity indices: the ACE-27 Comorbidity Index, the Age-adjusted Charlson Comorbidity Index, and the Elixhauser Comorbidity Index. C-statistic was used to evaluate the ability of comorbidity indices to discriminate mortality. The relationship between the calculated scores and overall survival (OS) was evaluated with the Kaplan-Meier curve. Mortality risk was analyzed with a multivariate Cox regression model.

Results: A total of 218 CML patients were evaluated, and 211 chronic-phase patients were included in this study. The median age of the patients was 56 years (21-89), and 53% were female. As initial tyrosine kinase inhibitors, 201 (95%) patients were treated with imatinib, 10 (5%) patients with nilotinib. The median follow-up was 94.50 (9-201) months. The median OS was not reached. The most common comorbid conditions were hypertension 23% (n = 48), weight loss 19% (n = 40), diabetes mellitus 13% (n = 27), and cardiovascular disease 9% (n = 19). C-statistic values were 0.76 for ACE-27, 0.41 for ACCI, and 0.32 for ECI scores. In the Cox regression model including comorbidity scores, mortality risk was higher in patients with moderate ACE-27 score (HR: 148.05; 95% CI: 7.89-2751.53; p = 0.012), severe ACE-27 score (HR: 232.36; 95% CI: 14.20-4793.20; p = 0.001), ECOG 3 score (HR: 34.62; 95% CI: 2.67-447.36; p = 0.007), and high ELTS score (HR: 27.52; 95% CI: 1.34-543.68; p = 0.031).

Conclusion: This study showed that the ACE-27 Comorbidity Index is effective in predicting prognosis in CML patients. Therefore, comorbid conditions should be used more frequently as a prognostic marker at the time of diagnosis.

Background: To evaluate the potential clinical value of cerebrospinal fluid (CSF) circulating tumor DNA (ctDNA) in the diagnosis and monitors the central nervous system (CNS) lymphomas.

Methods: This was a prospective study of 17 consecutive patients with B-cell lymphoma: 10 patients with CNS lymphomas and 7 patients with B-cell lymphomas at high clinical risk of CNS relapse. Genomic profiles were performed on the CSF and plasma samples of patients by next-generation sequencing.

Results: In patients with CNS lymphomas, ctDNA was detected in 70.0% of CSF and 60.0% of plasma. The detection rate and gene mutation abundance of CSF were higher than plasma (p = 0.016). CSF had a unique genetic profile. Furthermore, we newly found that gene mutations consistent with plasma or lymphoma-related were also detected in the CSF of the high-risk group without CNS involvement. Analysis of paired plasma and CSF samples from three patients at different time points, changes of CSF ctDNA abundance occurred at the same time or earlier than clinical disease changes, which could timely monitor the therapeutic response and relapse trend.

Conclusion: The detection rate of ctDNA in CSF is higher than that in plasma. The dynamic monitoring of ctDNA in CSF has hint significance for therapeutic response of CNS lymphoma patients.