Shinya Kimura

Treatment‐free remission (TFR), defined as the maintenance of molecular remission without resumption of therapy after tyrosine kinase inhibitor (TKI) discontinuation, represents the clinical manifestation of functional cure in chronic‐phase chronic myeloid leukemia (CML‐CP), in which durable disease control is maintained without ongoing therapy despite the potential persistence of residual leukemic stem cells (LSCs). Emerging evidence supports a model in which outcomes after TKI discontinuation are determined by the balance between residual LSC persistence and coordinated host immune surveillance. Natural killer (NK)‐cell abundance and maturation have shown the most consistent associations with TFR, while killer immunoglobulin‐like receptor (KIR)‐human leukocyte antigen (HLA) immunogenetics may further influence NK‐cell education and antileukemic activity. Adaptive and regulatory mechanisms—including leukemia‐associated antigen‐specific cytotoxic T lymphocytes, T‐cell receptor repertoire dynamics, T‐cell exhaustion, plasmacytoid dendritic cells, and regulatory T cells—are increasingly implicated in residual disease control. Neutrophil abundance and maturation have also emerged as readily accessible candidate biomarkers. In parallel, persistent LSCs exploit BCR::ABL1‐independent survival programs, immune‐evasion mechanisms, and the protective bone marrow niche, providing a reservoir for molecular relapse. These observations argue against reliance on any single biomarker and instead support integrated models incorporating clinical variables, molecular residual disease, immune competence, immunogenetics, and LSC biology. Most candidate biomarkers remain exploratory and require independent prospective validation. Such multidimensional approaches may enable a transition from empiric TKI discontinuation toward precision, biomarker‐guided TFR and extend durable functional cure to a broader population of patients with CML. Trail Registration: N/A

Objective Generic imatinib has been available for more than a decade, but it remains underutilized in Japan. This study investigated the market trends of imatinib in Japan and explored the reasons for the predominant prescription of Gleevec®. Materials and Methods All-cause healthcare costs and sales data for generic drugs were obtained from publicly available sources. The actual market share of imatinib, which is not available from public sources, was provided by OHARA Pharmaceutical Co., Ltd. The estimated cost reduction resulting from the prescription of the most inexpensive generic drugs was simulated according to the conditions forecasted by Japan's MHLW. Results A generic form of Gleevec® became available in 2014 at 50-55% of the original price. However, Gleevec® remained the market leader, holding 72% of the market share in fiscal year (FY) 2022, owing to the unique universal health insurance and high-cost reimbursement systems that alleviate the financial burden on patients. In October 2024, Japan implemented a Selective Treatment Fee (SENTEI RYOYOHI), which requires patients who opt for the brand-name Gleevec® over its generic counterpart to pay 25% of the cost difference between Gleevec® and the most expensive generic imatinib. Conclusion Although certain patients who opt to use Gleevec® rather than generic imatinib will experience an increase in medical costs, the Selective Care System is an effective solution to protect the endangered national healthcare system in Japan. Ensuring that both individual medical expenditures and net gross national medical expenditures are urgently needed.

Cyclodextrins (CyDs) are cyclic oligosaccharides that form inclusion complexes that allow organic compounds and other substances to be incorporated into their cavities. Hydroxypropyl-β-cyclodextrin (HP-β-CyD) is frequently used to improve the formulation properties of poorly water-soluble drugs because of its aqueous solubility and biocompatibility. Previous studies have demonstrated that the solubility and biocompatibility of poorly water-soluble anti-cancer agents can be improved by complexation with HP-β-CyD, which in some cases enhances their anticancer activity relative to the unmodified drugs. Advances in formulation strategies have enabled more efficient intracellular delivery, improved tissue and cell selectivity, and controlled release. HP-β-CyD has also been investigated as an active pharmaceutical ingredient, with demonstrated efficiency in treating leukemia and breast cancer. For example, folate-conjugated HP-β-CyD exhibits high selectivity for folate receptor-expressing cells and more potent anti-cancer activity than unmodified HP-β-CyD. Autophagy has been suggested to be involved in this mechanism. The continued development of drug-delivery systems that integrate advanced technologies and materials based on HP-β-CyD holds promise for further advances in cancer therapy. These findings indicate a paradigm shift in the role of HP-β-CyD from a formulation additive to an active pharmaceutical ingredient, suggesting broader applications for HP-β-CyD in anticancer treatments.

Numerous strategies exist to isolate hematopoietic stem cells (HSCs) using complex combinations of markers and flow cytometry. However, robust identification of HSCs using imaging techniques is substantially more challenging which has prompted the recent development of HSC reporter mice. To date, very few molecules used in these reporters have been useful for human HSC identification. Here we report that PLXDC2 is a useful marker for both mouse and human cord blood HSCs. Using a green fluorescent protein (GFP) knock-in at the Plxdc2 locus in mice (hereafter denoted as Plxdc2-GFP), we showed that Plxdc2-GFP is highly expressed in HSCs with 1 in 2.8 Plxdc2-GFP⁺CD150⁺ cells giving long-term multi-lineage reconstitution in transplantation. Moreover, we developed a novel human PLXDC2 antibody and showed that human PLXDC2⁺ HSCs have higher long-term multilineage reconstitution ability compared with PLXDC2^- HSCs in a xenograft model. This study identifies PLXDC2 as a highly relevant molecule in HSC identification.

Treatment-free remission (TFR) has become a therapeutic objective for selected chronic-phase chronic myeloid leukemia (CP CML). However, no standardized biomarker is yet in clinical use. In this multi-center study, we explored the potential of bone marrow (BM) cytomorphology given its global accessibility and integral role in clinical diagnostics. We included diagnostic BM aspirate samples of 113 CP CML patients from seven clinical sites having attempted first TKI discontinuation. We digitized cytomorphological slides into 100x-magnified high-resolution images and analyzed these with deep learning-based image analysis. We profiled the BM cytomorphological fingerprint of CP CML patients and recapitulated the known granulocytic predominance and reduction of lymphoid, monocytic and erythroid cells in comparison to an extensive cohort of 942 control BM samples. We discovered neutrophil abundance and granulocytic maturation to associate with sustained TFR. We confirmed these visually and demonstrated their independent impact over known clinical factors. Our study underlines the potential of computational BM cytomorphology to identify novel clinical biomarkers and suggests that granulocytic expansion and maturation at diagnosis could reflect intrinsic disease pathology influencing TFR maintenance.

Background: While tyrosine kinase inhibitor (TKI) discontinuation is an established therapeutic goal, up to 60% of patients relapse after the first attempt. The feasibility of a second or third attempt at TKI discontinuation remains uncertain. Immune surveillance, particularly T‐cell and natural killer (NK) cell responses, may influence treatment‐free remission (TFR), although no definitive biomarkers for predicting sustained TFR have been identified. Methods: This retrospective study included 57 chronic myeloid leukemia (CML) patients who attempted TKI discontinuation. Clinical outcomes after the first, second, and third TFR attempts were analyzed, and T cell receptor (TCR) and B‐cell receptor (BCR) repertoire analyses were conducted on peripheral blood samples from 14 patients to investigate the immune landscape associated with TFR. Results: TFR1 at 1 year was 67.9% (95% confidence interval [CI], 53.9%–78.4%). Sixteen patients attempted a second discontinuation, achieving a 1‐year TFR2 rate of 31.2% (95% CI, 11.4%–53.6%). Patients maintaining BCR::ABL1 mRNA levels below MR ^4.5 at 3 months post‐TKI discontinuation had a significantly lower risk of relapse (HR, 0.099; 95% CI, 0.012–0.829; p = 0.033). TCR repertoire analysis did not reveal distinct clonal expansions of T cells; however, a significant age‐related decline in T‐cell diversity was observed. Conclusion: T‐cell immunity in CML patients who have achieved a deep molecular response (DMR) may closely approximate that observed in healthy individuals.

DNA methylation is an enzyme‐driven epigenetic modification that must be precisely regulated to maintain cellular homeostasis. Aberrant methylation status, especially hypermethylation of the promoter sites of tumor‐suppressor genes, is observed in human malignancies and is a proven target for cancer therapy. The first‐generation DNA demethylating agents, azacitidine and decitabine, are widely used for treating several hematological malignancies. In addition, orally bioavailable prodrugs of azacitidine and decitabine have recently been approved by the FDA. We have developed a silylated derivative of decitabine, OR‐2100, which is resistant to degradation by cytidine deaminase and orally bioavailable. It has efficacy against several human hematological malignancies in xenograft mouse models with less hematotoxicity than decitabine. Since DNA demethylating agents are combined with molecularly targeted drugs in clinical use and trials, we think that the less hematotoxic profile of OR‐2100 makes it suitable for use as a combination therapy. In this article, we review the therapeutic approach in hematological malignancies with the DNA demethylating agent OR‐2100.