International Journal of Hematology最新文献

Mixed phenotype acute leukemia (MPAL) is a rare and aggressive form of leukemia with a poor prognosis and no established treatment. In this study, we established a novel leukemic cell line, JMPAL-1, from a specimen of a 69-year-old patient with Philadelphia chromosome-positive MPAL. Flow cytometry showed that JMPAL-1 expresses B-cell markers but not myeloperoxidase. A genomic analysis of JMPAL-1 cells revealed the BCR::ABL1 fusion gene, missense mutation in PAX5, homozygous deletion of CDKN2A/CDKN2B, and BRAF amplification. This cell line was stroma-dependent in proliferation and required co-culturing with mouse bone marrow-derived mesenchymal cells (9-15C). Knowing the differences between JMPAL-1 and patient leukemia cells may improve understanding of the in vivo versus in vitro behavior of leukemia, clonal selection, and transformation. The stroma-dependent growth pattern of JMPAL-1 also provides a unique platform to study tumor-stromal interactions and their role in leukemic cell survival and drug resistance. Our study highlights the importance of establishing preclinical models such as JMPAL-1 and performing detailed cytogenetic analysis to develop targeted therapies in line with the pathogenesis of the disease.

To clarify karyotype evolution of myelodysplastic syndrome or acute myeloid leukemia with TP53 mutations (MDS/AML-TP53), we analyzed G-banding of bone marrow aspiration samples of eight patients with MDS/AML-TP53 and visualized the evolutions as phylogenetic trees. With very few exceptions, the initial roots of these trees and all branches longitudinally had -5/5q- and -7/7q- in common. Time series data of the karyotypes obtained in six patients showed highly complex karyotype evolutions, such as combined branched, linear, parallel, and macro-evolutions. In two patients, numerous branches appeared as the initial transformation. As for aneuploidy, chromosome loss was more common than chromosome gain as previously reported. Structural and numerical chromosomal abnormalities were often deleted as karyotype evolution progressed. Among these karyotype evolutions, loss of translocated chromosomes with break sites at or near the centromeres frequently caused monosomies of two chromosomes involved in the translocation. G-banding enables analysis and visualization of karyotype evolutions as phylogenetic trees because it offers the properties of both single-cell and whole-chromosome analysis. Our research has led us to propose G-banding as a new interpretation method for classical karyotype analysis.

Zanubrutinib is a selective second-generation Bruton tyrosine kinase inhibitor approved in various B-cell malignancies globally. The phase 1/2 BGB-3111-111 study evaluated the efficacy and safety of zanubrutinib 160 mg twice daily orally in Japanese patients with treatment-naive or relapsed/refractory mature B-cell malignancies. Here, efficacy results from Part 2 in chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL; n = 19) and Waldenström macroglobulinemia (WM; n = 19), and safety results from Parts 1 (N = 6) and 2 (N = 49) are presented, with the first dose between 30 January, 2020, and 31 October, 2022. As of 10 May, 2023, investigator-assessed overall response rates were 100% (19/19) and 94.7% (18/19) in CLL/SLL and WM, respectively, with median follow-up of 27.9 and 26.8 months; 24-month progression-free survival rates were 71.4% and 100% in treatment-naive and relapsed/refractory CLL/SLL and 83.9% and 100% in treatment-naive and relapsed/refractory WM, respectively. In patients with B-cell malignancies, any-grade treatment-emergent adverse events (TEAEs) occurred in 53 (96.4%) and serious TEAEs in 18 (32.7%). Common TEAEs were platelet count decreased (18.2%), pyrexia (18.2%), COVID-19 (14.5%), and neutrophil count decreased (12.7%). With median follow-up > 2 years, zanubrutinib demonstrated durable efficacy in Japanese patients with CLL/SLL or WM and a favorable safety profile consistent with global phase 3 studies.

Disseminated intravascular coagulation (DIC) is a severe condition characterized by systemic, persistent activation of coagulation in the presence of an underlying disease, leading to the formation of microthrombi in small blood vessels. In DIC, fibrinolysis is also activated alongside coagulation, but the extent of fibrinolysis varies significantly depending on the underlying condition. The classification of DIC types is crucial not only for understanding the pathophysiology involved, but also for selecting appropriate treatment strategies. Internationally, DIC is often associated with sepsis, typically presenting with ischemic organ damage. However, it is important to recognize that some forms of DIC exhibit minimal ischemic organ damage but severe bleeding symptoms. When diagnosing and treating DIC, considering the underlying condition and disease type can lead to better clinical outcomes. This underscores the need for DIC management guidelines that are based on an understanding of the underlying disease. The newly released "Clinical Practice Guidelines for Management of Disseminated Intravascular Coagulation in Japan 2024" offer the first comprehensive guidelines for detailed management based on specific underlying conditions, providing a groundbreaking contribution to the global DIC clinical community.

High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) is a standard treatment for relapsed diffuse large B cell lymphoma (DLBCL). The BEAM regimen is widely used, but the MEAM regimen is more common in Japan due to the unavailability of carmustine. This retrospective analysis evaluated the efficacy of the thiotepa and busulfan (TT/BU) regimen compared with other regimens in 27 patients with systemic DLBCL who underwent ASCT at our institution from December 2013 to March 2022. Fourteen patients received the TT/BU regimen, while 13 received alternative regimens. The TT/BU regimen demonstrated superior progression-free survival (PFS) and overall survival (OS) compared to other regimens, with a 3 year PFS of 84.4% and OS of 91.7%. The TT/BU group also had fewer severe adverse events, particularly regarding renal function. Our findings suggest that the TT/BU regimen is a well-tolerated and effective alternative for relapsed/refractory DLBCL and provide valuable insights for future treatment strategies.

Eltrombopag (EPAG), an oral thrombopoietin receptor agonist, has shown excellent efficacy in patients with aplastic anemia (AA) alone or in combination with immunosuppressive therapy. EPAG also has the unexpected ability to chelate polyvalent cations, including iron. However, the association between long-term EPAG use and iron deficiency anemia (IDA) remains unclear. To address this, we retrospectively evaluated the incidence and characteristics of EPAG-induced IDA (E-IDA) in patients with AA at our institution. Of the 36 patients with AA receiving EPAG, six (17%) developed E-IDA without evidence of bleeding, with a median onset of 1142.5 days (range, 389-1442 days) after EPAG administration. The cumulative dose of EPAG was significantly higher in patients with E-IDA than in those without E-IDA (P = 0.04). In 4 patients, E-IDA occurred after hemoglobin levels improved above 10 g/dl; this was considered recurrent anemia. In the other 2 patients, E-IDA occurred when hemoglobin levels remained below 10 g/dl; this was considered resistant anemia. After oral iron supplementation, all patients achieved hemoglobin levels higher than their peak levels prior to the onset of E-IDA. E-IDA should be considered when patients with AA treated with EPAG longer than 1 year develop recurrent or resistant anemia.

Diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) are the most common histological types of B-cell lymphoma, but have significantly different pathological and biological characteristics. In recent years, understanding of the genetic abnormalities and microenvironmental structures of these lymphomas has progressed, and various molecular targeted drugs and immunotherapies have been introduced into clinical practice. Therefore, accurate understanding of etiology and its clinical relevance is required for the appropriate management of these lymphomas.

Hereditary protein C (PC) deficiency is an inherited thrombophilic disorder caused by variants in the PC gene (PROC). We identified a novel PROC variant, c.302G>T, p.Cys101Phe (C101F), in a patient with type I PC deficiency. We analyzed the intracellular dynamics of the C101F variant of PC (PC-C101F) to elucidate the pathogenic mechanism underlying this condition. Wild-type PC (PC-WT) and PC-C101F were transiently expressed in HEK293 cells for expression and functional analyses. The PC antigen levels in the cell lysate and culture supernatant of PC-C101F-expressing cells were significantly lower than those of PC-WT-expressing cells. In cycloheximide (CHX) chase experiments, the intracellular PC antigen level gradually decreased in PC-C101F-expressing cells, but remained stable at 0 and 6 h in the presence of CHX/MG132. No significant difference in co-localization with the endoplasmic reticulum was observed between PC-C101F and PC-WT. 101Cys forms a disulfide bond with 106Cys, which is crucial for maintaining the conformation of PC. PC-C101F likely results in protein misfolding and proteasomal degradation, leading to type I PC deficiency. These findings highlight the importance of cysteine residues in the three-dimensional structure of PC and provide insight into the mechanism of type I PC deficiency.