[Rinsho ketsueki] The Japanese journal of clinical hematology最新文献

A 54-year-old woman presented with a chief concern of right back pain that had persisted for 3 weeks. Laboratory tests revealed pancytopenia, liver dysfunction, and coagulation abnormalities. She had hepatomegaly and splenomegaly but no lymphadenopathy. No abnormal cells were detected in the bone marrow or on a liver biopsy. Epstein-Barr virus (EBV) DNA levels in the peripheral blood were high at 6.44 log IU/ml, and clonality of EBV-infected cells was confirmed by Southern blot hybridization with a probe targeting the EBV terminal repeat. EBV-infected NK cells were detected using the magnetic bead method. This led to a diagnosis of EBV-associated lymphoproliferative disease (EBV-LPD). As pancytopenia and coagulation abnormalities induced by the development of hemophagocytic syndrome continued to worsen after steroid therapy, we performed intensive chemotherapy followed by umbilical cord blood transplantation. After transplantation, EBV-DNA levels in the peripheral blood were undetectable, with complete donor chimerism. In the present case, the rapid disease progression with an extremely high EBV-DNA level indicated a poor prognosis. Intensive chemotherapy followed by upfront allogeneic hematopoietic cell transplantation may be necessary in patients with rapidly progressing EBV-LPD.

Evaluation of genetic alterations is important for diagnosis, treatment selection, and prognostic assessment in hematological malignancies, but no comprehensive genomic profiling (CGP) assays for hematological malignancies have been approved for manufacturing and marketing in Japan. We have developed a CGP assay for the analysis of genetic alterations (specifically, mutations, structural variations, and fusion genes) in 452 genes, along with a corresponding analysis and reporting system that runs on Amazon Web Services. This CGP assay, named HemeSight®, successfully detected genetic alterations with an allele frequency of 5-10% in limit of detection testing using non-clinical samples. In testing using human clinical samples, it showed high positive percent agreement (94.4% for mutations, 94.7% for IGH rearrangements [structural variations], and 100% for fusion genes) compared with established clinical tests.

Asciminib is a first-in-class allosteric inhibitor that specifically targets the myristoyl pocket of BCR::ABL1 and has shown efficacy in patients with chronic myeloid leukemia (CML) who are resistant or intolerant to prior tyrosine kinase inhibitors (TKIs). Despite its unique mechanism of action, several resistance mechanisms to asciminib have been identified. BCR::ABL1 kinase domain mutations, including A337V, C464W, and compound mutations involving T315I, can interfere with asciminib binding or allosteric regulation. Additionally, BCR::ABL1 transcript variants lacking the SH3 domain, such as e13a3 and e14a3, exhibit primary resistance by disrupting the autoinhibited conformation required for asciminib activity. Non-BCR::ABL1 mechanisms that also contribute to resistance include overexpression of efflux transporters such as ABCG2 and P-glycoprotein, which reduce intracellular drug accumulation. Moreover, novel insertion mutations like p.I293_K294insSLLRD have been shown to impair the allosteric inhibition of ABL1. Combination therapies with ponatinib or other agents, as well as newer TKIs like olverembatinib, have demonstrated potential in overcoming resistance in preclinical and clinical models. Understanding these diverse resistance mechanisms is critical for optimizing asciminib-based treatment strategies and guiding the development of effective combination therapies for patients with resistant CML.

Treatment strategies for chronic myeloid leukemia (CML) have changed significantly with the development of new tyrosine kinase inhibitors (TKIs). Due to its extreme rarity, pediatric CML has historically been managed based on evidence in adult patients. However, as the unique biological and clinical characteristics of pediatric CML have become increasingly apparent, the need for pediatric-specific treatment guidelines is now widely recognized. This review outlines the treatment of pediatric CML as of 2025, with a focus on clinical trial results from Japan and the latest consensus guidelines issued by the International Pediatric CML Working Group.

Recent advances in molecular genetic research, driven by the development of genomic analysis technologies, have significantly improved treatment outcomes for leukemia. In recent years, mounting evidence indicates that germline genetic background influences drug sensitivity and the risk of adverse effects, underscoring the growing importance of personalized treatment strategies. In particular, the NUDT15 polymorphism, which determines sensitivity to 6-mercaptopurine, has garnered significant attention. Notably, a low-activity variant of this polymorphism, prevalent in Asian countries, has been shown to substantially increase the risk of bone marrow suppression and other adverse effects. Pre-treatment analysis of the NUDT15 polymorphism has demonstrated utility in dose adjustment, helping to mitigate the risk of treatment-related toxicities. Studies have also explored the relationship between genetic background and late complications of leukemia treatment. Optimization of therapeutic strategies based on pharmacogenetic insights holds promise for minimizing complications while maximizing treatment efficacy for each individual patient.

Recent advances in cancer therapy have improved the long-term outcomes of cancer patients, increasing the importance of managing cardiovascular complications arising not only from cancer itself but also from chemotherapy, radiation therapy, and immunotherapy. In the field of hematology, there are serious concerns about cardiovascular complications of various chemotherapeutic agents such as anthracyclines, immunomodulatory drugs, BCR-ABL tyrosine kinase inhibitors, proteasome inhibitors, and immune checkpoint inhibitors. Chemotherapy has a wide variety of effects on the cardiovascular system, and the molecular mechanisms underlying the cardiovascular toxicities of individual molecularly targeted agents remain to be precisely defined. This "Onco-Cardiology" approach is expected to enhance interdisciplinary collaboration between oncology/hematology and cardiology specialists across clinical practice, research, and education to protect cancer patients and survivors from cardiovascular complications.

Multiple myeloma (MM) is characterized by several cytogenetic abnormalities that occur at various time points during the disease course. Cytogenetic abnormalities in MM cells are critical intrinsic factors that determine tumor characteristics, and reflect sensitivity to key drugs including proteasome inhibitors, immunomodulatory drugs, and anti-CD38 monoclonal antibodies. Venetoclax, a first-in-class BCL-2 inhibitor, is currently under investigation for the treatment of t (11;14) MM. Some cytogenetic abnormalities may also be associated with poor response to BCMA-targeting bispecific antibodies and CAR-T therapy. The biological and clonal heterogeneity of MM complicates treatment stratification according to biology and risk. Consequently, cytogenetic abnormalities play an important role in treatment stratification for this heterogenous disease, and precision medicine based on cytogenetic abnormalities can be expected eventually.

A 56-year-old woman with mixed-phenotype acute leukemia underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT). She developed grade 2 acute graft-versus-host disease (GVHD), which subsequently improved, but did not develop chronic GVHD. Immunosuppressive therapy was discontinued 7 months after allo-HSCT, with no relapse of GVHD. However, around the same time, the patient began experiencing generalized fatigue, left eyelid ptosis, and right upper limb finger extensor weakness. Further examinations led to a diagnosis of Hashimoto's disease and multifocal motor neuropathy (MMN). Although neurological impairment was progressive, muscle strength improved after treatment with high-dose intravenous immunoglobulin therapy for MMN and blinatumomab for post-transplant relapse of MPAL. The clinical course suggests that MMN developed after allo-HSCT as an immune-mediated neuropathy involving donor lymphocytes. It may be appropriate to consider MMN as a differential diagnosis for peripheral neuropathy occurring after discontinuation of immunosuppressive agents or in association with autoimmune disease.

Acute myeloid leukemia (AML) is common in elderly adults and is a genetically heterogeneous disease. Many factors such as adverse chromosomal and/or genetic abnormalities contribute to disease risk, along with defining features related to antecedent hematologic disorders and a history of exposure to radiation or cytotoxic agents in the case of secondary AML. The "7+3" regimen combining cytarabine and anthracycline, along with its reduced-dose variant, was once the only first-line treatment option for AML in Japan. However, treatment options have expanded in recent years to include azacitidine with or without venetoclax, as well as CPX-351 and quizartinib combination chemotherapy. Nevertheless, there are still many high-risk conditions with a low chance of cure even with these new drugs or allogeneic transplantation, and many other issues remain to be addressed. This article outlines the current best treatment options and future prospects for high-risk disease types.