Therapeutic Advances in Hematology最新文献

Background: In haploidentical hematopoietic stem cell transplantation (haplo-HSCT), combining low-dose post-transplant cyclophosphamide (PTCy) with low-dose anti-thymocyte globulin (ATG) is increasingly recognized as a promising approach for graft-versus-host disease (GVHD) prevention.

Methods: This study evaluated 33 patients undergoing haplo-HSCT for hematological disorders, divided into two groups: low-dose ATG/PTCy (n = 17) and PTCy-only (n = 16).

Results: The incidence of grades I-II acute GVHD (aGVHD) was 11.8% in the low-dose ATG/PTCy group compared to 31.3% in the PTCy-only group (p = 0.42). No cases of severe aGVHD (grades III-IV) were reported in either cohort. Moderate chronic GVHD (cGVHD) occurred less frequently in the ATG/PTCy group (28.6%) compared to the PTCy group (100%, p = 0.028). Severe cGVHD was absent in both groups. Non-relapse mortality (NRM) was significantly lower in the ATG/PTCy group compared to the PTCy-only group (17.6% vs 56.3%, p = 0.021). One year overall survival and disease-free survival rates were at 70.6% and 64.7% for ATG/PTCy cohort, versus 56.3% and 50.0% for PTCy-only group. Cytomegalovirus reactivation and relapse were comparable between the groups.

Conclusion: The combination of low-dose ATG and PTCy appears to significantly reduce moderate cGVHD and NRM in haplo-HSCT compared to PTCy alone. To the best of our knowledge, this is the first study directly comparing these two regimens.

Chronic myeloid leukemia (CML) in patients with β-thalassemia major is a rare and concerning occurrence. The longer life expectancy of thalassemia patients, resulting from improved treatment options and better healthcare facilities, has led to the emergence of various health-related issues and complications. We present the case of a 24-year-old female diagnosed with β-thalassemia major at six months of age, who presented with weakness and lethargy in clinic. Investigations, including a bone marrow biopsy, confirmed CML in the chronic phase. Initial management with imatinib resulted in severe thrombocytopenia and failure to achieve a molecular response. The treatment was then switched to Ponatinib, leading to a favorable outcome with early molecular response. This case report highlights the increased risk of hematological malignancies in thalassemia patients and underscores the importance of vigilant monitoring in them. Furthermore, it emphasizes the role and effectiveness of third-generation tyrosine kinase inhibitors in the management of such cases.

Background: The pivotal trial on venetoclax and hypomethylating agents in unfit elderly acute myeloid leukaemia (AML) has got FDA approval. However, Asian patients were under-represented and showed no survival advantage.

Objective: We aimed to compare overall survival and healthcare resource utilisation in elderly patients newly diagnosed with AML, receiving venetoclax with hypomethylating agents versus hypomethylating agents alone.

Design: Target trial emulation.

Methods: Propensity score matching balanced the baseline characteristics. Kaplan-Meier curve and Cox regression compared overall survival. Negative binomial regression assessed healthcare resource utilisation with time offset.

Results: Venetoclax plus hypomethylating agents treatment conferred superior overall survival in patients with AML ⩾60 years old and significantly reduced transfusion requirement compared to those receiving hypomethylating agents alone. The difference was particularly prominent among patients ⩾75 years old.

Conclusion: Compared to hypomethylating agent alone, venetoclax plus hypomethylating agent benefits elderly patients with AML on overall survival and healthcare resource utilisation.

Background: Cytoreductive therapies have been the standard treatment for patients with high-risk polycythemia vera (PV) for decades. However, approximately 24% of patients treated with hydroxyurea will eventually develop resistance or intolerance to hydroxyurea and need second-line (2L) therapy.

Objective: This study compared clinical outcomes of patients with high-risk PV who switched to ruxolitinib as 2L therapy (switchers) versus those who continued first-line (1L) therapy (nonswitchers) after suboptimal response.

Design: This was a retrospective, multicenter, noninterventional study.

Methods: The primary outcome was event-free survival (EFS), defined as the time between the index date and the earliest event of thrombosis, major bleeding, disease progression, or death. Key secondary outcomes included overall survival (OS), time to and rate of disease progression, rate of thrombosis, and change in spleen size.

Results: Overall, 225 patients were included (switchers: 69; nonswitchers: 156). At baseline, >50% of switchers had a prior history of thrombosis (p = 0.006) and PV-related symptoms (p = 0.037) versus nonswitchers. Switchers had a numerically greater reduction in spleen size at 3 years than nonswitchers (-14.4% vs +15.9%; p = 0.107). Compared with nonswitchers, switchers were more likely to experience persistence or presence of new PV-related symptoms as suboptimal response before switching to ruxolitinib (p < 0.001). A greater proportion of nonswitchers required ⩾3 phlebotomies to maintain hematocrit <45% within 1 year (p < 0.001). No significant differences were observed between switchers and nonswitchers in terms of EFS, OS, time to disease progression, and rate of thrombosis. However, switchers had a significantly higher rate of disease progression to myelofibrosis than nonswitchers (p = 0.016).

Conclusion: These data demonstrate the heterogeneity in patient characteristics and type of suboptimal responses between switchers and nonswitchers. The results suggest that patients who switched to ruxolitinib had more severe disease or rapid disease progression and that ruxolitinib may provide some clinical benefit in terms of spleen size reduction and hematocrit control.

Effective strategies to maintain complete remission in adults with acute myeloid leukemia (AML) are critically needed. Early clinical trials aimed at preventing relapse in the postconsolidation phase explored prolonged chemotherapy, single-agent immunotherapy, and hybrid chemo-immunotherapy, but none of these approaches produced practice-changing results. More recent trials have identified efficacious remission maintenance strategies, including (1) midostaurin or quizartinib for patients with FLT3-mutated AML, (2) oral azacitidine for older AML patients, and (3) immunotherapy with histamine dihydrochloride and low-dose interleukin-2 (HDC/IL-2) for younger patients. In this review, we examine key phase III trial and follow-up study results for approved remission maintenance therapies, with a particular focus on HDC/IL-2. We discuss clinical efficacy in relation to patient age and anti-leukemic immunity as well as leukemic cell chemosensitivity, chromosomal integrity, and mutational profiles. Finally, we propose a role for HDC/IL-2 within an evolving landscape of strategies to achieve durable remission in a broader population of AML patients.

Background: Next-generation sequencing (NGS) offers a method for measurable residual disease (MRD) assessment by detecting leukemia-associated genetic mutations.

Objective: This study aimed to evaluate the clinical implications and prognostic value of NGS-based MRD assessment in acute myeloid leukemia (AML).

Design: Sixty-nine adult AML patients were included for NGS (targeted sequencing of AML-related 47 genes), of which 56 patients at initial diagnosis, 69 patients in the first day of consolidation therapy (C1D1), and 51 patients during 2-year MRD monitoring (detection following the C1D1) were enrolled.

Methods: Mutation data were categorized into gene mutations, somatic mutations and somatic mutations excluding clonal hematopoiesis of indeterminate potential (CHIP) for analysis. The study also integrated multiparameter flow cytometry (MFC) and NGS data at C1D1 to evaluate the prognostic significance of combining the two MRD techniques.

Results: Mutation detection rates were 98.21%, 69.57%, and 84.31% for AML patients at initial diagnosis, C1D1 stage, and MRD monitoring, respectively, identified by targeted sequencing. During MRD monitoring, the ETV6 mutation frequency was significantly higher in relapsed patients than in non-relapsed patients (p < 0.05). The mean variant allele frequency (VAF) was significantly higher in the 2-year MRD monitoring period (0.160 ± 0.155) compared to the C1D1 period (0.058 ± 0.087; p < 0.05) in relapsed patients. Survival analysis revealed that patients with a mean VAF (somatic mutations excluding CHIP) ⩽0.004 in the C1D1 stage and ⩽0.020 during MRD monitoring had a better prognosis. Furthermore, the combination of MFC and NGS-based MRD (somatic mutations excluding CHIP) at C1D1 stage showed that patients who were negative for two tests had longer survival than those who were negative for only one.

Conclusion: The combined assessment of MFC-MRD and NGS-MRD status provides a refined prognostic stratification, with the absence of somatic mutations and MFC-MRD negativity correlating with improved progression-free survival, which is expected to improve clinical prognostic assessment of AML patients.

Acquired von Willebrand syndrome (AVWS) is a well-known complication of a monoclonal gammopathy with a potentially severe bleeding tendency. Treatment with von Willebrand factor (VWF)/factor VIII (FVIII) concentrate yields mixed results in controlling the bleeding diathesis, while the use of intravenous immunoglobulins may be effective. However, clear guidelines for the optimal management of AVWS are lacking. Therefore, we retrospectively analyzed the cases of AVWS secondary to monoclonal gammopathy at the University Hospitals of Leuven. We confirm the beneficial effect of intravenous immunoglobulins in IgG-associated AVWS. For IgM-associated AVWS, we observed better results with the administration of VWF/FVIII concentrate or a combination of therapies. Of note, one patient with IgG-associated AVWS did not respond to immunoglobulins and had mutations in the VWF and fibrinogen gamma chain (FGG) genes. This report adds additional cases to the literature of this rare cause of acquired bleeding.

Background: RNA splicing factor (SF) mutations are associated with adverse outcomes in patients with acute myeloid leukemia (AML) and higher-risk myelodysplastic syndromes/neoplasms (HR-MDS). Preclinical data suggest that aberrant RNA splicing can lead to the generation of neoantigens, which renders these tumors more susceptible to immune checkpoint inhibitors. However, dedicated studies on immune checkpoint inhibitors in AML and MDS patients with SF mutations are limited.

Objectives: To characterize the immune and epigenetic landscape of AML and MDS patients with SF mutations.

Design: Post hoc analysis of the impact of RNA SF mutations (defined as any of SF3B1, SRSF2, U2AF1, and ZRSR2) on outcomes of newly diagnosed, older or intensive chemotherapy-ineligible patients with AML or HR-MDS treated with azacitidine ± the anti-PD-L1 antibody durvalumab as part of the randomized, phase II FUSION trial.

Methods: Primary endpoint was the overall response rate (ORR). Flow cytometry and gene expression profiling using bulk RNA sequencing were performed on pretreatment bone marrow aspirate samples.

Results: One hundred twenty-six patients with AML (51 SF-mutant and 75 wild type) and 79 patients with MDS (33 SF-mutant and 46 wild type) were included. ORR was independent of SF mutation status for both AML (SF-mutant: 35.3% vs wild-type: 33.3%; p = 0.47) and MDS patients (51.5% vs 56.5%; p = 0.63). Median overall survival was similar for SF-mutant and wild-type AML (14.9 months vs 12.2 months; p = 0.50) and MDS patients (23.5 months vs 10.6 months; p = 0.16). There were no differences in key cell populations from bone marrow aspirate flow cytometry samples. Gene expression analyses showed an increase in MKI-67 expression in SF wild-type patients, but no differences were observed in several immune-related genes including IL7R and PD-L1.

Conclusion: Addition of durvalumab to azacitidine did not improve ORR or OS among older patients with newly diagnosed AML and HR-MDS independent of SF mutation status.Trial registration: NCT02775903.

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.