International Journal of Hematology最新文献

Mutation profiling by next-generation sequencing (NGS) has facilitated understanding of the molecular pathogenesis of acute myeloid leukemia (AML), and has been incorporated into the new disease classification (International Consensus Classification; ICC) and risk classification (European LeukemiaNet [ELN] 2022; ELN2022). We compared disease subtypes between the previous disease classification (4th edition of the WHO classification; WHO-4) and the ICC in 91 patients with AML diagnosed at our institution. We also compared disease risk classifications using the previous risk classification (ELN2017) and the ELN2022. Targeted sequencing of bone marrow samples was conducted at Kyoto University. We found that entities under AML with recurrent genetic abnormalities were well-established, with almost no change from the WHO-4 to the ICC. In contrast, 16.7% of cases of AML, not otherwise specified in the WHO-4 were reclassified into AML with mutated TP53, and 36.7% were reclassified into AML with myelodysplasia-related gene mutations or cytogenetic abnormalities per the ICC. Meanwhile, the ELN2017 and ELN2022 showed no difference in concordance indexes in multivariate Cox regression analysis for progression-free and overall survival. The superiority of the ELN2022 over the ELN2017 could not be confirmed in our single-center retrospective study, and further investigation including multicenter prospective studies is needed.

Previously, we reported the efficacy and safety of tazemetostat in Japanese patients with relapsed/refractory follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) harboring the EZH2 mutation in a multicenter, open-label, phase II study. Here, we present a follow-up analysis of tazemetostat at a long-term median follow-up of 35.0 months. Twenty patients were enrolled: 17 in the FL cohort and three in the DLBCL cohort. In the FL cohort, the objective response rate was 70.6%, consistent with the primary analysis, and the median progression-free survival (PFS) was not reached. The 24-month and 36-month PFS rates were 72.1% (95% confidence interval [CI] 41.5%-88.6%) and 64.1% (95% CI 33.7%-83.4%), respectively. The median duration of treatment was 30.2 months. After the primary analysis at a median follow-up of 12.9 months, grade 1-2 urinary tract infection, peripheral motor neuropathy, and hypogammaglobulinemia newly emerged, but the incidence of adverse events (AEs) did not increase notably during this follow-up period. No unexpected grade ≥ 3 treatment-related AEs were reported. Long-term oral monotherapy with tazemetostat showed favorable efficacy and safety profiles, indicating that it may be a useful third-line or later treatment option for patients with relapsed/refractory FL harboring the EZH2 mutation. Trial registration: ClinicalTrials.gov: NCT03456726.

Acute lymphoblastic leukemia (ALL) relapsed after allogeneic hematopoietic cell transplantation (allo-HCT) has a catastrophic prognosis. Blinatumomab, a CD3/CD19-directed bispecific T cell engager, is reportedly effective for advanced B-cell ALL (B-ALL), even after allo-HCT. However, the efficacy of blinatumomab in extramedullary relapse (EMR) is controversial. Donor lymphocyte infusion (DLI) is another immunological treatment worth considering for ALL relapsed after allo-HCT. We report the case of a 56-year-old woman with B-ALL. Allo-HCT was performed during the second complete remission (CR). Thirteen months after allo-HCT, isolated EMR (iEMR) of B-ALL developed without bone marrow lesions. A third CR was achieved with 2 cycles of blinatumomab. An additional four cycles each of blinatumomab and DLI were then administered. The patient did not develop graft-versus-host disease and has confirmed 2-year treatment-free remission without a second allo-HCT. Therefore, blinatumomab was considered an effective salvage therapy for iEMR of B-ALL after allo-HCT, because iEMR could have a lower tumor burden than that seen in systemic relapse, and low tumor burden was a prognostic factor for response to blinatumomab. Furthermore, immunological consolidation therapies could only provoke graft-versus-leukemia effects if the imbalanced effector/target ratio was restored and the tumor burden was lowered through immunosurveillance.

Venetoclax was approved for relapsed/refractory chronic lymphocytic leukemia (R/R CLL) and small lymphocytic leukemia (SLL) in Japan in September 2019; however, clinical data in Japanese patients are limited. This all-case post-marketing surveillance assessed efficacy and safety in Japanese patients with R/R CLL/SLL who started venetoclax treatment between November 2019 and August 2020. Overall, the safety and efficacy analysis sets included 129 and 114 patients, respectively. The overall response rate (ORR) was 57.0%; ORRs were higher in patients with versus without concomitant rituximab (65.4% vs. 54.7%), and in patients with 1 versus ≥ 2 prior lines of therapies (72.5% vs. 44.4%). Adverse events (AEs) were reported in 66.7% of patients (86/129); the most common AEs were neutrophil count decreased (22.5%), white blood cell count decreased (7.8%), and tumor lysis syndrome (TLS; 6.2%). AEs of special interest (TLS, myelosuppression, and infection) were manageable in clinical practice in Japan. Venetoclax is efficacious and safe for R/R CLL/SLL patients in the real-world setting in Japan. ClinicalTrials.gov ID: NCT04198415.

We describe a 67-year-old patient with hemophilia A and inhibitors (PwHA-I) receiving emicizumab prophylaxis who underwent surgical treatment for pseudoaneurysm. He was treated with a bolus infusion of recombinant factor VIIa (rFVIIa; 79 μg/kg) immediately before surgery, and a second dose of rFVIIa after an initial treatment on day 1. A third rFVIIa bolus was infused 17 h after the second dose on day 2, and the treatment was continued every 24 h on day 3 and day 4. Treatment with rFVIIa was discontinued on day 4. No perioperative bleeding or thrombotic events were observed. Coagulation potentials at 8 h after rFVIIa administration determined by clot waveform analysis (CWA) and thrombin generation assay (TGA) were within near-normal ranges, and results at 17 h after rFVIIa administration showed coagulation function comparable to that in the patient without rFVIIa. Our experimental data suggest that the coagulation potential in FVIII-deficient plasma spiked with both 0.28 µg/mL (11.2 μg/kg) rFVIIa and emicizumab was equivalent to or greater than that spiked with 2.2 µg/mL (90 μg/kg) rFVIIa alone. Thus, administration of rFVIIa every 8 h may be feasible for managing perioperative treatment in emicizumab-treated PwHA-I.

Acute myeloid leukemia (AML) is a heterogeneous disease characterized by various molecular abnormalities that significantly impact its pathogenesis and prognosis. Currently, the prognosis of AML patients is stratified on the basis of co-existing chromosomal and genetic abnormalities. AML patients with NPM1 or CEBPA mutations, which are frequently identified in cytogenetically normal AML, are classified in the favorable-risk group, although approximately 40% of patients relapse. Similarly, a clinical high-risk group has been identified among patients with acute promyelocytic leukemia, but the underlying molecular abnormalities remain unclear. FLT3 mutations frequently overlap in these favorable-risk AMLs, including core binding factor AML, and their prognostic impact is still controversial. As such, further risk stratification and treatment optimization based on various molecular abnormalities are warranted to improve the prognosis of favorable-risk AMLs. These molecular abnormalities are also considered therapeutic targets, and targeted therapies have been developed over the years. In recent years, several targeted agents have been approved and demonstrated to improve the prognosis of AML. However, resistance to targeted therapies is also a challenge. This Progress in Hematology features current trends and challenges in favorable-risk AML and FLT3 mutations that are frequently identified in these patients.

Romiplostim, a thrombopoietin (TPO) receptor agonist, is a clinically approved drug that is clearly effective in reconstituting hematopoiesis in refractory aplastic anemia and　idiopathic thrombocytopenic purpura. However, the mechanism underlying its biological effect is unknown, and its differences from other TPO receptor agonists remain unclear. Therefore, we determined the in vitro expansion effect of romiplostim on human CD34 + hematopoietic stem and progenitor cells (HSPCs) versus recombinant human TPO (rhTPO) and another clinically available drug, eltrombopag. We also performed single-cell RNA-seq to determine effects of romiplostim on CD34 + HSPCs at the molecular level. The maximum expansion effect of romiplostim on total CD34 + cells, CD34 + CD38 + progenitor cells, and CD34 + CD38 - immature cells was comparable to that of rhTPO, but higher than that of eltrombopag, particularly on CD34 + CD38 - immature cells. Single-cell RNA-seq analysis revealed that both romiplostim and eltrombopag induced signatures driven by rhTPO, but romiplostim induced molecular changes related to RHOA signaling in the most primitive HSPC subsets that were partially driven or not driven by eltrombopag. Additionally, romiplostim did not induce TFRC expression as was observed with eltrombopag. In conclusion, romiplostim expands and affects human HSPCs similar to rhTPO, but partially different from eltrombopag in terms of induction of gene expression.

Infertility is a common issue that threatens couples worldwide. Infertility can result from the male or female partner alone, or both partners. It can be due to multiple factors related to the patient's overall health or lifestyle. Causes related to patient health can be systemic or related to gonadal dysfunction. One of the systematic causes can be hematological. The two most common hemoglobinopathies that are thought to cause infertility, especially male infertility, are sickle cell disease (SCD) and thalassemia major (TM). These two hemoglobinopathies cause male infertility through pathophysiological alterations. Specifically, they alter the oxygen carrying ability of red blood cells (RBCs), causing tissue hypoxia that affects the normal physiological process of spermatogenesis, eventually inducing infertility. Semen analyses and other systemic blood testing can be used to investigate male infertility. Both hemoglobinopathies can be helped by blood transfusions, which can then alleviate male infertility. This paper aims to explore the relationship between hemoglobinopathies (SCD and TM) and their role in contributing to male infertility, in addition to the role of blood transfusions in addressing male infertility by correcting the root cause.

The treatment of acute promyelocytic leukemia (APL) has evolved with the introduction of all-trans retinoic acid (ATRA) and subsequent arsenic trioxide (ATO), particularly in standard-risk APL with an initial white blood cell count (WBC) < 10,000/μL, where a high cure rate can now be achieved. However, for some patients with risk factors, early death or relapse remains a concern. Insights from the analysis of patients treated with ATRA and chemotherapy have identified risk factors such as WBC, surface antigens, complex karyotypes, FLT3 and other genetic mutations, p73 isoforms, variant rearrangements, and drug resistance mutations. However, in the ATRA + ATO era, the significance of these risk factors is changing. This article provides a comprehensive review of APL risk factors, taking into account the treatment approach, and explores the challenges associated with APL treatments.

Nucleophosmin 1 (NPM1) mutation is one of the most prevalent genetic mutations in adult acute myeloid leukemia (AML) and is particularly predominant in AML with a normal karyotype. NPM1 is a chaperone protein that plays various roles in several cellular processes. Wild-type NPM1 is normally localized to the nucleus, whereas mutant NPM1 proteins exhibit altered cytoplasmic localization. Clinically, AML with mutated NPM1 without FLT3-ITD is associated with a higher complete remission rate and improved overall survival. AML with mutated NPM1 is categorized as a distinct genetic entity in the World Health Organization classification of hematopoietic malignancies due to its unique clinical and biological features. However, the precise roles of NPM1 in normal hematopoiesis and in AML development remain unclear. Recent studies have revealed various clinical applications of NPM1 mutations in AML treatment, particularly in measurable residual disease analyses that target mutant NPM1 transcripts and in potential therapeutic applications of menin inhibitors and XPO-1 inhibitors for AML with mutated NPM1. Thus, NPM1 mutation is highly significant in AML classification, prognosis, response assessment, and molecular targeted therapies. Here, we review recent progress in clinical and biological aspects of AML with mutated NPM1 including molecular targeted therapy.