Therapeutic Advances in Hematology最新文献

Background: Thrombocytopenia is a common complication following hematopoietic stem cell transplantation, and there is currently no standardized therapeutic approach for its management.

Objectives: This article aims to systematically review the existing clinical treatment regimens for this condition and assess their efficacy.

Design: This is a systematic review and meta-analysis.

Data sources and methods: We conducted a comprehensive literature search in several databases, including PubMed, Web of Science, Cochrane Library, and Embase, up until October 30, 2024. A total of 43 datasets involving 1154 patients were included for further analysis. Therapeutic effectiveness was defined as a patient's platelet count being above 20 × 10⁹/L and being off platelet transfusion for more than 7 consecutive days. Drug response rates and side effect values were statistically calculated.

Results: Our study included a total of 42 articles. The results of our study show that Decitabine and Romiplostim show relatively high effectiveness in treating thrombocytopenia after hematopoietic stem cell transplantation (HSCT), with efficacy rates of 83% (95% CI: 57%-99%) and 87% (95% CI: 69%-98%), respectively. Eltrombopag and Avatrombopag also demonstrated good efficacy, with overall utilities of 68% and 73%. Subgroup analyses revealed that Eltrombopag was particularly effective in adolescent patients compared to adults. Most of the reported side effects were well tolerated, with an overall effect value of 14% (95% CI: 11%-18%, I ² = 41.08%, p = 0.04), and no patients discontinued treatment due to adverse effects. Furthermore, our network meta-analysis suggests that Decitabine-based therapy shows significant efficacy in managing thrombocytopenia after HSCT, although more high-quality clinical trials are needed to validate these conclusions.

Conclusion: Our meta-analysis suggests a significant efficacy of both Romiplostim and Decitabine in the treatment for thrombocytopenia after HSCT, while Eltrombopag showed significantly better efficacy in the pediatric subgroup compared to elder patients, and the side effects of the drugs are within acceptable range.Trial registration: CRD420251000342.

Background: Epigenetic priming prior to chemotherapy represents a promising treatment strategy for refractory or relapsed diffuse large B-cell lymphoma (R/R DLBCL). We conducted a phase II trial to evaluate the efficacy and safety of azacitidine in combination with R-GDP (rituximab/gemcitabine/dexamethasone/cisplatin) in transplant-ineligible R/R DLBCL.

Methods: Fifteen patients were enrolled and treated with azacitidine and R-GDP regimen (NCT03719989). Azacitidine was administered intravenously at a dose of 25 mg/m²/day for 5 days. Each cycle consisted of 21 days, with patients receiving up to a maximum of six cycles. The primary endpoint was the objective response rate, and the secondary objectives were toxicity, progression-free survival (PFS), and overall survival (OS).

Results: Overall, 15 patients were enrolled in the study from March 2019 to August 2023, and the median age was 64 years (range: 41-75). The objective response rate was 66.7% with a complete response rate of 53.3%. The most common grade 3 or higher adverse events were hematologic toxicities, including neutropenia (66.7%) and thrombocytopenia (53.3%). Grade 3 or higher non-hematologic toxicities were rare, and most adverse events were transient and manageable. During a median follow-up of 15.8 months, five patients died, all from DLBCL. The median PFS was 12.6 months, while the median OS was not reached.

Conclusion: Our study suggests that azacitidine followed by R-GDP is an effective and safe strategy for transplant-ineligible patients with R/R DLBCL. This represents the first phase II study to demonstrate the potential of epigenetic priming with azacitidine to enhance chemosensitivity in this patient population.Trial registration: ClinicalTrials.gov identifier: NCT03719989.

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.