Investigational New Drugs最新文献

{"title":"Preclinical evaluation and mechanistic analysis of antitumor effects of the novel anti-CD147 antibody DS-1471a in liver cancer models.","authors":"Hiroshi Yuita, Sadanori Watanabe, Jun Tsukada, Yoshikazu Johmura, Sae Aratani, Hirokazu Ishikawa, Ryuichi Nakamura, Miki Yokoyama, Mari Hashimoto, Hideo Yukinaga, Huynh The Hung, Makoto Nakanishi, Keisuke Fukuchi","doi":"10.1007/s10637-026-01621-3","DOIUrl":"10.1007/s10637-026-01621-3","url":null,"abstract":"<p><p>DS-1471a is a humanized antibody that targets CD147, a transmembrane glycoprotein frequently overexpressed in cancer cells, and has undergone a phase 1 clinical study for advanced solid tumors. To further investigate DS-1471a's therapeutic potential and the underlying molecular mechanisms involved, we examined its efficacy in patient-derived xenograft (PDX) models of liver cancer. DS-1471a exhibited potent antitumor effects in multiple PDX models, with positive correlations observed between DS-1471a efficacy and expression of CD147 and related proteins such as SMAD4, ARF6, and FBXO22. Among these proteins, overexpression of FBXO22, a ubiquitin ligase, enhanced DS-1471a efficacy in liver cancer xenograft models. Mechanistic analysis showed that FBXO22 overexpression was associated with reduced expression of p21/CDKN1A, a cyclin-dependent kinase inhibitor previously characterized as a degradation target of FBXO22, suggesting a potential regulatory relationship between these proteins. Moreover, in tumor models lacking p21, DS-1471a efficacy was also enhanced, whereas DS-1471a-resistant tumors expressed higher levels of p21 protein. Although direct causal relationships remain to be fully established, these results suggest possible mechanisms underlying DS-1471a efficacy involving not only CD147 expression but also FBXO22 and p21. Taken together, these preclinical findings indicate a potential clinical benefit of DS-1471a and provide useful mechanistic insights for liver cancer treatment.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"317-327"},"PeriodicalIF":3.4,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13486073/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148054262","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effector-to-target ratio as a translational bottleneck for CD33 T-cell engagers in acute myeloid leukemia: a quantitative reanalysis of AMG 330.","authors":"Hamid Bellout","doi":"10.1007/s10637-026-01624-0","DOIUrl":"10.1007/s10637-026-01624-0","url":null,"abstract":"<p><p>A common, often unstated paradigm in T-cell engager (TCE) translation assumes that target-antigen density and drug exposure are the main efficacy drivers, with effector context secondary. This paradigm is visible in dose-escalation strategies and in the use of high-E:T screens as principal preclinical assays. We tested whether an alternative, receptor-saturation framework better organizes the published AMG 330 record in acute myeloid leukemia (AML). Receptor-saturation arguments motivate two qualitative expectations: at sufficiently high CD33 densities, EC <math><mmultiscripts><mrow></mrow> <mn>50</mn> <mrow></mrow></mmultiscripts> </math> should show little systematic dependence on additional antigen density, and response should become increasingly constrained by effector availability and functional state. We tested these expectations using two statistical reanalyses of published AMG 330 data-log-linear regression of EC <math><mmultiscripts><mrow></mrow> <mn>50</mn> <mrow></mrow></mmultiscripts> </math> on CD33 density across 11 AML cell lines, and a comparative effect-size analysis of effector-to-target (E:T) ratio versus CD33 expression in 38 primary AML samples-integrated with clinical exposure-response findings and effector-augmenting rescue studies. Both expectations were supported. CD33 density did not significantly predict EC <math><mmultiscripts><mrow></mrow> <mn>50</mn> <mrow></mrow></mmultiscripts> </math> across the 3.9-fold range tested ( <math><mrow><mi>p</mi> <mo>=</mo> <mn>0.13</mn></mrow> </math> ; bootstrap 95% CI on slope includes zero). In primary samples, E:T ratio dominated sustained lysis by approximately an order of magnitude over CD33 expression (92.4 vs. 8.5 percentage points; CD33 effect <math><mrow><mi>p</mi> <mo>=</mo> <mn>0.7</mn></mrow> </math> , not significant). Clinical exposure-response analyses identified baseline E:T ratio and T-cell PD-1 expression as response correlates. A similar target-effector dissociation has been reported in several other TCE programs. The AMG 330 record is more coherently organized by an effector-context framework than by the conventional target-density-and-exposure paradigm. These findings indicate that endogenous-effector assays, paired target-effector biomarkers, and rational effector-support strategies are likely to be clinically informative complements to conventional cell-line potency and dose-escalation approaches in future CD33 TCE development.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"328-336"},"PeriodicalIF":3.4,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148217791","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel EGFR tyrosine kinase inhibitors exhibiting intrinsic fluorescence.","authors":"Amelia Kierasińska-Kałka, Adrianna Rutkowska, Jacek Mularski, Marcin Pacholczyk, Tadeusz Strózik, Joanna Pęciak, Cezary Tręda, Klaudia Waszczykowska, Marta Orlikowska, Dominika Wyrzykowska, Kamil Filiks, Maria Jaskólska, Jakub Bartkowiak, Ewelina Stoczyńska-Fidelus, Piotr Rieske","doi":"10.1007/s10637-026-01625-z","DOIUrl":"https://doi.org/10.1007/s10637-026-01625-z","url":null,"abstract":"<p><p>Kinase inhibitors are commonly used in research and clinical practice. Among them, irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), such as afatinib and osimertinib, constitute an important subclass. The aim of this study was to create an irreversible covalent EGFR TKI exhibiting endogenous fluorescence, i.e., intrinsic fluorescence without the need for additional fluorochromes. These compounds, designated SQI-2, SLT40, and SLT41, were successfully developed and shown to effectively inhibit the EGFR, EGFR^L858R/T790M, and EGFR^vIII kinases. The developed compounds are suitable for a range of cytochemical analyses, including real-time assays. The proposed TKIs may serve as research and diagnostic tools and represent precursors of new types of therapeutic compounds.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148561964","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The novel agent VP79s synergistically enhances venetoclax activity in multiple myeloma cells.","authors":"Yunlong Pei, Jiaxun Wang, Taylor Smith, Martin Sutton, Julie David, Tianyi Gao, Patrick J Hayden, Paul V Browne, Viola Previtali, Marco Minneci, Isabel Rozas, Anthony M McElligott, Daniela M Zisterer","doi":"10.1007/s10637-026-01629-9","DOIUrl":"https://doi.org/10.1007/s10637-026-01629-9","url":null,"abstract":"<p><p>Despite advances in new therapies, multiple myeloma (MM) remains incurable with most patients relapsing or becoming refractory to treatment demonstrating the need for novel therapeutic strategies. We previously identified VP79s, a novel guanidinium-based compound, with potent anti-myeloma activity which targets the dysregulated IL-6/JAK/STAT signalling pathway. Here, we aim to further evaluate the translational potential of VP79s by examining whether it synergises with the BH3 mimetic venetoclax and exploring the mechanisms underlying this effect. The pro-apoptotic effect of VP79s and venetoclax alone or in combination was assessed by annexin V/propidium iodide staining followed by flow cytometry analysis. Western blotting was performed to evaluate the expression level of key pro- and anti-apoptotic members of the Bcl-2 family. BH3 profiling assessed apoptotic priming of cells to a Bim-domain peptide. Co-treatment of NCI-H929 and MM1.S cells with VP79s/venetoclax resulted in a synergistic enhancement of apoptosis which correlated with a decrease in anti-apoptotic Mcl-1 and concurrent increase in pro-apoptotic Bim S. Synergy was not observed in U266B1 cells possibly because these cells demonstrated relative resistance to venetoclax and exhibited a lower level of apoptotic priming in response to a Bim peptide. Importantly, co-treatment of NCI-H929 cells with VP79s and venetoclax was shown to overcome bone marrow stromal cell induced drug resistance. Preliminary findings also indicate that the combination treatment induced an enhanced reduction in viability of ex vivo myeloma patient samples with minimal cytotoxicity toward healthy donor lymphocytes observed. These findings support further preclinical investigation of VP79s in combination with venetoclax as a potential therapeutic strategy in MM.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148470597","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characterizing the post-market safety profile of lazertinib: a pharmacovigilance study of the FDA Adverse Events Reporting System Database.","authors":"Connor Frey","doi":"10.1007/s10637-026-01630-2","DOIUrl":"https://doi.org/10.1007/s10637-026-01630-2","url":null,"abstract":"<p><p>Lazertinib is a third-generation, brain-penetrant, mutant-selective EGFR tyrosine kinase inhibitor approved for first-line treatment of EGFR-mutated non-small cell lung cancer, including in combination with amivantamab. Post-market safety surveillance is important given its recent approval and evolving real-world use. All FAERS reports with lazertinib as the primary suspect drug were extracted. Proportional Reporting Ratios (PRR), Reporting Odds Ratios (ROR), and chi-squared statistics were calculated for each adverse event. Disproportionality signals were defined by PRR ≥ 2, chi-squared ≥ 3.841, and a minimum of 3 reports. A total of 141 lazertinib reports were identified in the FAERS database. Twenty-six adverse events met all signal detection criteria. The strongest signals were observed for paronychia (PRR 132.90, n = 3), dermatitis acneiform (PRR 118.59, n = 4), peripheral sensory neuropathy (PRR 91.97, n = 3), and peripheral neuropathy (PRR 50.09, n = 28). Dermatologic and neurologic adverse events predominated, consistent with the mechanism of EGFR inhibition. FAERS disproportionality analysis identifies a signal profile for lazertinib dominated by EGFR inhibitor-class dermatologic and neurologic toxicities, alongside an infusion-related reaction signal reflecting combination use with amivantamab. The modest report volume warrants cautious interpretation; however, the signal patterns are mechanistically coherent and consistent with the known toxicity profile of third-generation EGFR TKIs.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148420880","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A first-in-human phase 1a study of LP-184, a tumor-site activated novel alkylating agent, in patients with advanced solid tumors.","authors":"Daruka Mahadevan, Jay Parekh, Joseph T Beck, Willam B McKean, Karisa C Schreck, Anthony J Olszanski, Misty D Shields, Vu Phan, John T Hamm, Bruce B Bank, Jianli Zhou, Marc Chamberlain, Kishor Bhatia, Reginald Ewesuedo","doi":"10.1007/s10637-026-01626-y","DOIUrl":"https://doi.org/10.1007/s10637-026-01626-y","url":null,"abstract":"<p><p>LP-184 is a novel acylfulvene pro-drug that alkylates DNA after bioactivation by the intracellular oxidoreductase prostaglandin reductase 1 (PTGR1). In preclinical studies, potent growth inhibition has been observed against a wide variety of solid tumor models, particularly those carrying DNA damage repair deficiency. Here, we report results of the first-in-human dose escalation trial of LP-184 in advanced solid tumors. A dose escalation Bayesian optimal interval design was used with a starting dose of 0.01 mg/kg. Eligible patients with advanced refractory solid tumors were enrolled to receive LP-184 intravenously on days 1 and 8 of each 21-day cycle. Sixty-three patients were enrolled, with a median age of 62 years. Twelve dose levels (DLs) were evaluated with one dose-limiting toxicity (DLT) at DL11 (0.49 mg/kg; grade 4 platelet count decreased) and two DLTs at DL12 (0.61 mg/kg; grade 3 alanine aminotransferase increased and acute liver injury). The most common (≥ 20%) treatment-related adverse events of any grade included nausea, vomiting, fatigue, and platelet count decreased. No treatment-related deaths occurred during the study. Best response to monotherapy LP-184 was stable disease (SD), which was observed in 22 (40%) of the evaluable patients. Three patients experienced SD that lasted more than 12 months. LP-184 was safe and tolerable in the Phase 1a trial in patients with advanced refractory solid tumors. The maximum tolerated dose (MTD) of LP-184 is 0.49 mg/kg. Registry: ClinicalTrials.gov, TRN: NCT05933265, Registration date: June 23, 2023.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148396471","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evaluating pegenzileukin (SAR444245/THOR-707) in combination with pembrolizumab or cetuximab in advanced metastatic gastrointestinal cancer: the PEGATHOR phase 2 study.","authors":"William P Harris, Pilar García-Alfonso, Jean Phillipe Metges, Antonio Cubillo-Gracian, Aziz Zaanan, Lopez Lopez Carlos, Monica Ronzoni, Mariano Ponz-Sarvise, Adyb Baakili, Asma Kefsi, Laurent Andrieu, Maria Agrawal, Wenting Wang, Tobias Paehler, Giovanni Abbadessa, Eric Van Cutsem","doi":"10.1007/s10637-026-01622-2","DOIUrl":"https://doi.org/10.1007/s10637-026-01622-2","url":null,"abstract":"<p><p>Pegenzileukin (SAR444245) is a pegylated recombinant human IL-2 variant designed to expand effector T cells and NK cells without stimulating regulatory T cells. This study evaluated pegenzileukin with pembrolizumab or cetuximab for treating advanced gastrointestinal cancers. A total of 138 patients with advanced gastric cancer (GC), colorectal carcinoma, esophageal squamous cell carcinoma (ESCC), and hepatocellular carcinoma (HCC) were enrolled across seven cohorts in this phase 2 study. Patients received pegenzileukin (24 µg/kg every 3 weeks [Q3W]) with pembrolizumab (200 mg Q3W) or cetuximab (initially 400 mg/m² and then 250 mg/m² weekly). The primary endpoint was the objective response rate (ORR). The secondary endpoints were time to response, response duration, clinical benefit rate, progression-free survival (PFS), and safety. Exploratory biomarker analyses assessed immune cell expansion and cytokine levels. The ORR varied across the cohorts, with the highest in ESCC cohort (1/5; 20.0%) and the lowest in GC Cohort 2 and the HCC cohort (1/19; 5.3% and 1/20; 5.0%, respectively). The median PFS was consistent across the cohorts (1.9-2.1 months). The most common treatment-emergent adverse events were asthenia (Pegenzileukin + pembrolizumab) and infusion-related reactions (Pegenzileukin + cetuximab). The biomarker analyses demonstrated robust expansion of CD8⁺ T cells, CD8⁺ Ki67⁺ T cells, NK cells, and NK Ki67⁺ cells without significant modulation of regulatory T cells. Pegenzileukin with pembrolizumab or cetuximab demonstrated limited efficacy, with a manageable safety profile in advanced GI cancers. The biomarker data supported the mechanism of action involving the upregulation of CD8⁺ T cells and NK cells. ClinicalTrials.gov Identifier: NCT05104567.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-06-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148295068","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characterizing the post-market safety profile of cemiplimab: a pharmacovigilance study of the FDA adverse events reporting system database.","authors":"Connor Frey","doi":"10.1007/s10637-026-01628-w","DOIUrl":"https://doi.org/10.1007/s10637-026-01628-w","url":null,"abstract":"<p><p>Cemiplimab is a fully human PD-1 inhibitor approved for cutaneous squamous cell carcinoma, basal cell carcinoma, and non-small cell lung cancer. Post-market safety surveillance is essential given the broad and evolving indications for immune checkpoint inhibitors. All FAERS reports with cemiplimab as the primary suspect drug were extracted. Proportional Reporting Ratios (PRR), Reporting Odds Ratios (ROR), and chi-squared statistics were calculated for each adverse event. Disproportionality signals were defined by PRR ≥ 2, chi-squared ≥ 3.841, and a minimum of 15 reports. A total of 1,460 cemiplimab reports were identified in the FAERS database. Twenty-two adverse events met all signal detection criteria. The strongest signals were observed for myocarditis (PRR 54.35, n = 40), myositis (PRR 46.10, n = 25), pemphigoid (PRR 36.06, n = 16), and pneumonitis (PRR 19.37, n = 31). Immune-mediated adverse events predominated, consistent with the mechanism of PD-1 blockade. FAERS disproportionality analysis identifies a signal profile for cemiplimab dominated by immune-related adverse events across cardiac, pulmonary, dermatologic, and endocrine systems. These findings are consistent with the known immunotoxicity of PD-1 inhibitors and support heightened clinical vigilance for myocarditis and immune-mediated pneumonitis.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148277468","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical features, diagnosis and prognosis of nivolumab-associated fulminant type 1 diabetes.","authors":"Qiong Liu, Qi Huang, Wei Sun, Zhaoquan Wu, Chunjiang Wang","doi":"10.1007/s10637-026-01627-x","DOIUrl":"https://doi.org/10.1007/s10637-026-01627-x","url":null,"abstract":"<p><p>Fulminant type 1 diabetes (FT1D) is a rare immune-related adverse event associated with nivolumab, and its clinical characteristics remain unclear. This study aims to characterize the clinical features of nivolumab-associated FT1D and to generate evidence to inform its diagnosis and prevention. A systematic search of databases was conducted to identify clinical cases of nivolumab-associated FT1D reported through March 31, 2026. Clinical data for the patients were extracted and subjected to statistical analysis. A total of 59 patients were included, with a median age of 59 years (range 22, 87). The median time to onset of FT1D was 90 days (range 9, 1988) after the initial administration of nivolumab, with a median treatment cycle of 6 cycles (range 1, 136). Polyuria (45.1%), polydipsia (31.4%), weight loss (29.4%), thirst (23.5%), nausea (23.5%), vomiting (21.6%), and fatigue (19.6%) were the main symptoms. The median plasma glucose level at the diagnosis of FT1D was 594 mg/dL (range 208.8, 1652.4), and the median HbA1c was 7.2% (range 5.4, 8.9). Glutamic acid decarboxylase antibody positivity was detected in 23.6% of patients. Following nivolumab discontinuation and initiation of intensive insulin therapy, glycemic control was satisfactorily achieved. FT1D is a rare immune-related adverse event associated with nivolumab. Close plasma glucose monitoring should be maintained both during nivolumab therapy and after drug discontinuation. The possibility of FT1D should be considered in patients presenting with hyperglycemic symptoms and diabetic ketoacidosis. Nivolumab-associated FT1D requires long-term maintenance insulin therapy.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148264450","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Allogeneic hematopoietic stem cell transplantation with liposomal mitoxantrone conditioning for extramedullary leukemia.","authors":"Lei Deng, Xiaolin Yu, Xiaocheng Song, Wenjun Li, Rui Guan, Yixi Hou, Yan Shao, Yuerong Zhao, Qianqian Xiao, Jing Wang, Yue Liu, Bo Xin, Fang Zhou","doi":"10.1007/s10637-026-01623-1","DOIUrl":"https://doi.org/10.1007/s10637-026-01623-1","url":null,"abstract":"<p><p>Leukemia relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the leading death cause, with extramedullary disease history as an independent relapse risk factor in acute leukemia. We analyzed 10 patients with extramedullary disease history who received allo-HSCT with mitoxantrone liposome (Lipo-MIT)-containing conditioning at our center (Dec 2022-Jan 2025). Median age was 39.5 (14-63), 7 had acute myeloid leukemia (AML, including myeloid sarcoma), 2 T lymphoblastic lymphoma/leukemia, and 1 B-cell acute lymphoblastic leukemia. Pre-transplant, 4 were in complete remission (CR) (1 with minimal residual disease [MRD] positivity) and 6 had residual lesions (2 with BM blasts ≥ 5%, 2 with MRD positivity). The conditioning regimen was Lipo-MIT + total body irradiation/busulfan + cyclophosphamide ± cytarabine, with a median Lipo-MIT dose of 26.1 (18.5-28.9) mg/m². Mucosal injury showed a high incidence (9/10) after conditioning, but most were transient and controllable with supportive care. Engraftment succeeded in 9 patients, with a median neutrophil recovery time of 16 (11-21) days and platelet recovery time of 20 (11-39) days. Only 1 patient developed grade 2 skin acute graft-versus-host disease (aGVHD). All 9 engrafted patients achieved complete remission (CR) post-transplantation; one had MRD positivity at + 177 days, which turned negative after chemotherapy combined with donor lymphocyte infusion. One patient relapsed at + 234 days and died at + 272 days. The patient with engraftment failure died at + 346 days due to disease progression, with a history of polycythemia vera complicated by myelofibrosis. Lipo-MIT conditioning shows promising efficacy/safety for allo-HSCT in extramedullary disease patients. Randomized trials are needed.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2026-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148251465","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}