Yanli Sun

Background: Umbralisib, a dual PI3Kδ/CK-1ϵ inhibitor, has shown clinical activity in various hematologic malignancies. However, a systematic assessment of its efficacy and safety is still lacking. This study provides a comprehensive evaluation based on current clinical evidence. Methods: A comprehensive search was conducted in PubMed, Embase, Web of Science, CNKI, and ClinicalTrials.gov for studies involving umbralisib in hematologic malignancies (up to March 14, 2025). Two investigators independently screened eligible studies and extracted data. Efficacy outcomes and adverse events (AEs) were analyzed using meta-analytic methods. The review protocol was registered in PROSPERO (registration number: CRD420251018098). Results: Umbralisib monotherapy was associated with frequent hematologic AEs such as thrombocytopenia, neutropenia, and anemia, along with common non-hematologic toxicities including diarrhea, nausea, and fatigue. Liver enzyme elevation and diarrhea represented the more severe AEs. Combination therapy showed a distinct AE profile, with infusion reactions and infections being more prominent, but generally demonstrated fewer severe toxicities. In terms of efficacy, monotherapy yielded a modest objective response rate, while combination regimens achieved substantially higher response rates, including improved complete and partial response outcomes. Conclusion: Umbralisib shows promising efficacy in hematologic malignancies such as MZL, FL, and DLBCL, though its clinical use is limited by frequent AEs. Combination therapy offers better response rates and appears to alleviate some of the severe toxicities seen with monotherapy. Further studies are needed to optimize combination strategies, explore alternative administration routes, and refine dosing approaches. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/ , identifier CRD420251018098.

Background: Tirabrutinib is a potent, irreversible, and highly selective Bruton’s tyrosine kinase (BTK) inhibitor that has demonstrated significant therapeutic activity in patients with relapsed or refractory B-cell lymphoma. However, the safety and efficacy of tirabrutinib monotherapy have not been systematically assessed. This meta-analysis aims to assess the safety and efficacy of tirabrutinib monotherapy in patients with B-cell lymphoma.Methods: We conducted a comprehensive literature search in Embase, PubMed, Web of Science, and Cochrane Library databases to identify prospective clinical trials evaluating tirabrutinib monotherapy in B-cell lymphoma. Data on efficacy and safety were extracted and analyzed.Results: A total of seven studies were included in the meta-analysis. The clinical trials primarily involved patients with chronic lymphocytic leukemia (CLL), primary central nervous system lymphoma (PCNSL), mantle cell lymphoma (MCL), and Waldenström’s macroglobulinemia (WM). The pooled overall response rate (ORR) was 72.5%, with complete response (CR) rate of 18.6%, stable disease (SD) rate of 13.8%, and partial response (PR) rate of 41.1%. The highest median progression-free survival (mPFS) was observed in patients with CLL, reaching 38.5 months. Neutropenia was the most common adverse event (AE), both all grades and grade ≥3. Additionally, a high incidence of skin-related AEs was reported.Conclusion: Tirabrutinib monotherapy demonstrates a manageable safety profile and promising efficacy in patients with B-cell lymphoma. However, these findings need to be confirmed by larger and higher-quality randomized controlled trials in the future. Further research should also explore the long-term effects and potential benefits of combination therapies involving tirabrutinib.Systematic Review Registration: Identifier CRD42024552721.

Acute myeloid leukemia (AML) represents a hematological malignancy that arises from the abnormal proliferation of progenitor cells or myeloid hematopoietic stem. The current standard treatments for AML include chemotherapy and hematopoietic stem cell transplantation. However, chemotherapy suffers from high toxicity and a shortage of hematopoietic stem cell donors, which significantly shortens patient survival. A new type of cell death, disulfidptosis, has shown potential in medicine. However, its specific biological mechanism of action in AML is currently unclear. This research developed a prognostic model of disulfidptosis-related long non-coding RNAs (DRLs) based on 132 AML patients with GDC TCGA Acute myeloid leukemia (LAML). In this model, eight DRLs: AL049835.1, EXOC3-AS1, AC009237.14, LINC00944, AP002761.4, LINC00926, AC010247.2, and AC099811.5 were included. Patients with high-risk AML evaluated based on the model had shorter survival, significant infiltration of monocytes and M2 macrophages, and elevated transcriptional levels of immune checkpoint genes. In addition, AML was classified into three subtypes according to the model, and patients in different subtypes showed different overall survival (OS) and drug sensitivity. Overall, we formulated a pioneering prognostic model utilizing DRLs, achieving precise AML outcome predictions. The correlations between the DRL prognostic models and the AML immune microenvironment, drug sensitivity, and tumor subtype were explored. In addition, further studies on the molecular mechanisms of key biomarkers, such as LINC00944 and LINC00926, will greatly contribute to our understanding of AML pathogenesis and drug resistance mechanisms in the future.

Introduction: FLT3 mutations are closely associated with the occurrence of hematological and solid malignancies, especially with acute myeloid leukemia. Currently, several FLT3 inhibitors are in clinical trials, and some have been applied in clinic. However, the safety, efficacy and pharmacodynamics of these FLT3 inhibitors have not been systemically analyzed before.Methods: We searched and reviewed clinical trial reports on the monotherapy of 13 FLT3 inhibitors, including sorafenib, lestaurtinib, midostaurin, gilteritinib, quizartinib, sunitinib, crenolanib, tandutinib, cabozantinib, pexidartinib, pacritinib, famitinib, and TAK-659 in patients with hematological and solid malignancies before May 31, 2023.Results: Our results showed the most common adverse events (AEs) were gastrointestinal adverse reactions, including diarrhea, hand-foot syndrome and nausea, while the most common hematological AEs were febrile neutropenia, anemia, and thrombocytopenia. Based on the published data, the mean overall survival (OS) and the mean progression-free survival (PFS) were 9.639 and 5.905 months, respectively. The incidence of overall response rate (ORR), complete remission (CR), partial response (PR), and stable disease (SD) for all these FLT3 inhibitors was 29.0%, 8.7%, 16.0%, and 42.3%, respectively. The ORRs of FLT3 inhibitors in hematologic malignancies and solid tumors were 40.8% and 18.8%, respectively, indicating FLT3 inhibitors were more effective for hematologic malignancies than for solid tumors. In addition, time to maximum plasma concentration (T_max) in these FLT3 inhibitors ranged from 0.7-12.0 hours, but the elimination half-life (T_1/2) range was highly variable, from 6.8 to 151.8 h.Discussion: FLT3 inhibitors monotherapy has shown significant anti-tumor effect in clinic, and the effectiveness may be further improved through combination medication.

Acute myeloid leukemia (AML) is one of the malignant hematological cancers with high mortality. Finding a more effective and readily available treatment is of the utmost importance. Here, we aimed to identify the anti-leukemia effect of a natural small molecule compound honokiol on a panel of AML cell lines, including THP-1, U-937, and SKM-1, and explored honokiol’s potential biological pathways and mechanisms. The results showed that honokiol decreased the viability of the targeted AML cells, induced their cell cycle arrest at G0/G1 phase, and inhibited their colony-formation capacity. Honokiol also triggers a noncanonical ferroptosis pathway in THP-1 and U-937 cells by upregulating the level of intracellular lipid peroxide and HMOX1 significantly. Subsequent studies verified that HMOX1 was a critical target in honokiol-induced ferroptosis. These results reveal that honokiol is an effective anti-leukemia agent in AML cell lines and may be a potential ferroptosis activator in AML.

Background: The upregulated expression of BET proteins is closely associated with the occurrence and development of hematological malignancies and solid tumors. Several BET inhibitors have been developed, and some have been in phase I/II of clinical trials. Here, the safety, efficacy, and pharmacodynamics of ten BET inhibitors currently in clinical trials were evaluated.Methods: We retrieved and reviewed published reports on the clinical trials of twelve BET inhibitors including AZD5153, ABBV-075, BMS-986158, CPI-0610, GSK525762, OTX-015, PLX51107, INCB054329, INCB057643, FT-1101, CC-90010, and ODM-207 for patients with hematological malignancies and solid tumors and summarized their published target genes.Results: In the monotherapy of BET inhibitors, the most common and severe (grade ≥3) hematological adverse events (AEs) are thrombocytopenia, anemia, and neutropenia. The most common non-hematological syndromes are diarrhea, nausea, fatigue, dysgeusia, and decreased appetite, while the most severe AE is pneumonia. Additionally, T_max of these BET inhibitors was between 0.5–6 h, but the range for T_1/2 varied significantly. According to published data, the rates of SD, PD, CR and PR were 27.4%, 37.6%, 3.5%, and 5.7%, respectively, which is not very satisfactory. In addition to BRD4, oncogene MYC is another common target gene of these BET inhibitors. Ninety-seven signaling pathways may be regulated by BET inhibitors.Conclusion: All BET inhibitors reviewed in our study exhibited exposure-dependent thrombocytopenia, which may limit their clinical application. Moreover, further efforts are necessary to explore the optimal dosing schemes and combinations to maximize the efficacy of BET inhibitors.