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1.
Cancer Lett ; 605: 217264, 2024 Sep 25.
Artículo en Inglés | MEDLINE | ID: mdl-39332587

RESUMEN

The consensus in 2018 from The Chinese Society of Haematology (CSH) on the monitoring, treatment, and prevention of leukaemia relapse after allogeneic haematopoietic stem cell transplantation (HSCT) facilitated the standardization of clinical practices in China and progressive integration with the world. To integrate recent developments and further improve the consensus, a panel of experts from the CSH recently updated the following consensus: (1) integrate risk-adapted, measurable residual disease (MRD)-guided strategy on modified donor lymphocyte infusion (DLI) and interferon-α into total therapy, which was pioneered and refined by Chinese researchers; (2) provide additional evidence of the superiority of haploidentical HSCT (the dominant donor source in China) to matched HSCT for high-risk populations, especially for pre-HSCT MRD-positive patients; (3) support the rapid progress of techniques for MRD detection, such as next-generation sequencing (NGS) and leukaemia stem cell-based MRD detection; and (4) address the role of new targeted options in transplant settings. In conclusion, the establishment of a "total therapy" strategy represents a great step forward. We hope that the consensus updated by Chinese scholars will include the latest cutting-edge developments and inspire progress in post-HSCT relapse management.

2.
Leukemia ; 38(11): 2410-2418, 2024 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-39237634

RESUMEN

The phase 3 COMMODORE trial evaluated gilteritinib versus salvage chemotherapy (SC) in a predominantly Asian relapsed/refractory (R/R) FLT3-mutated (FLT3mut+) acute myeloid leukemia (AML) patient population. The primary endpoint was overall survival (OS); secondary endpoints included event-free survival (EFS) and complete remission (CR) rate. As of June 30, 2020 (interim analysis: 32.2 months after study initiation), 234 patients were randomized (gilteritinib, n = 116; SC, n = 118). Median OS was significantly longer with gilteritinib versus SC (9.6 vs. 5.0 months; HR 0.566 [95% CI: 0.392, 0.818]; p = 0.00211) with a median follow-up of 10.3 months. Median EFS was also significantly longer with gilteritinib (2.8 vs. 0.6 months; HR 0.551 [95% CI: 0.395, 0.769]; p = 0.00004). CR rates with gilteritinib and SC were 16.4% and 10.2%, respectively; composite CR rates were 50.0% and 20.3%, respectively. Exposure-adjusted grade ≥3 adverse event (AE) rates were lower with gilteritinib (58.38 events/patient-year [E/PY]) versus SC (168.30 E/PY). Common AEs with gilteritinib were anemia (77.9%) and thrombocytopenia (45.1%). Gilteritinib plasma concentration peaked ~4 h postdose; ~3-fold accumulation occurred with multiple dosing. The COMMODORE trial demonstrated that gilteritinib significantly improved OS and EFS in predominantly Asian patients, validating the outcomes of gilteritinib from the ADMIRAL trial in R/R FLT3mut+ AML.


Asunto(s)
Compuestos de Anilina , Leucemia Mieloide Aguda , Mutación , Pirazinas , Terapia Recuperativa , Tirosina Quinasa 3 Similar a fms , Humanos , Tirosina Quinasa 3 Similar a fms/genética , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidad , Masculino , Femenino , Persona de Mediana Edad , Pirazinas/uso terapéutico , Pirazinas/administración & dosificación , Adulto , Anciano , Compuestos de Anilina/uso terapéutico , Adulto Joven , Tasa de Supervivencia , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/patología , Estudios de Seguimiento , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Resistencia a Antineoplásicos/genética , Pueblo Asiatico/genética , Anciano de 80 o más Años , Pronóstico
3.
J Thorac Dis ; 16(6): 4016-4029, 2024 Jun 30.
Artículo en Inglés | MEDLINE | ID: mdl-38983176

RESUMEN

Background: Invasive fungal disease (IFD) has become a serious threat to human health in China and around the world, with high mortality and morbidity. Currently, the misdiagnosis rate of IFD is extremely high, compounded with the low quality of prescription antifungals and the high incidence of adverse events associated with IFD treatment, resulting in lengthy hospitalization, low clinical response, and high disease burden, which have become serious challenges in clinical practice. Antifungal stewardship (AFS) can not only significantly increase the early diagnosis rate of IFD, reduce inappropriate utilization of antifungal drugs, improve patient prognosis, but can also improve therapeutic safety and reduce healthcare expenses. Thus, it is urgent to identify key AFS metrics suitable for China's current situation. Methods: Based on metrics recommended by international AFS consensuses, combined with the current situation of China and the clinical experience of authoritative experts in various fields, several metrics were selected, and experts in the fields of respiratory diseases, hematology, intensive care units (ICUs), dermatology, infectious diseases, microbiology laboratory and pharmacy were invited to assess AFS metrics by the Delphi method. Consensus was considered to be reached with an agreement level of ≥80% for the metric. Results: Consensus was reached for 24 metrics, including right patient metrics (n=4), right time metrics (n=3), and right use metrics (n=17). Right use metrics were further subdivided into drug choice (n=8), drug dosage (n=4), drug de-escalation (n=1), drug duration (n=2), and drug consumption (n=2) metrics. Forty-six authoritative experts assessed and reviewed the above metrics, and a consensus was reached with a final agreement level of ≥80% for 22 metrics. Conclusions: This consensus is the first to propose a set of AFS metrics suitable for China, which helps to establish AFS standards in China and is also the first AFS consensus in Asia, and may improve the standard of clinical diagnosis and treatment of IFD, and guide hospitals to implement AFS, ultimately promoting the rational use of antifungal drugs and improving patient prognosis.

4.
Front Microbiol ; 15: 1405652, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38962143

RESUMEN

Cytomegalovirus reactivation (CMVr) and bloodstream infections (BSI) are the most common infectious complications in patients after allogeneic haematopoietic stem cell transplantation (allo-HSCT). Both are associated with great high morbidity whilst the BSI is the leading cause of mortality. This retrospective study evaluated the incidence of CMVr and BSI, identified associated risk factors, assessed their impact on survival in allo-HSCT recipients during the first 100 days after transplantation. The study comprised 500 allo-HSCT recipients who were CMV DNA-negative and CMV IgG-positive before allo-HSCT. Amongst them, 400 developed CMVr and 75 experienced BSI within 100 days after allo-HSCT. Multivariate regression revealed that graft failure and acute graft-versus-host disease were significant risk factors for poor prognosis, whereas CMVr or BSI alone were not. Amongst all 500 patients, 56 (14%) developed both CMVr and BSI in the 100 days after HSCT, showing significantly reduced 6-month overall survival (p = 0.003) and long-term survival (p = 0.002). Specifically, in the initial post-transplant phase (within 60 days), BSI significantly elevate mortality risk, However, patients who survive BSI during this critical period subsequently experience a lower mortality risk. Nevertheless, the presence of CMVr in patients with BSI considerably diminishes their long-term survival prospects. This study provides real-world data on the impact of CMVr and BSI following transplantation on survival, particularly in regions such as China, where the prevalence of CMV IgG-positivity is high. The findings underscore the necessity for devising and executing focused prevention and early management strategies for CMVr and BSI to enhance outcomes for allo-HSCT recipients.

5.
Blood ; 144(18): 1951-1961, 2024 Oct 31.
Artículo en Inglés | MEDLINE | ID: mdl-39046786

RESUMEN

ABSTRACT: Although tyrosine kinase inhibitor (TKI) therapy has markedly improved the survival of people with chronic-phase chronic myeloid leukemia (CML), 20% to 30% of people still experienced therapy failure. Data from 1955 consecutive patients with chronic-phase CML diagnosed by the European LeukemiaNet recommendations from 1 center receiving initial imatinib or a second-generation (2G) TKI therapy were interrogated to develop a clinical prediction model for TKI-therapy failure. This model was subsequently validated in 3454 patients from 76 other centers. Using the predictive clinical covariates associated with TKI-therapy failure, we developed a model that stratified patients into low-, intermediate- and high-risk subgroups with significantly different cumulative incidences of therapy failure (P < .001). There was good discrimination and calibration in the external validation data set, and the performance was consistent with that of the training data set. Our model had the better prediction discrimination than the Sokal and European Treatment and Outcome Study long-term survival scores, with the greater time-dependent area under the receiver-operator characteristic curve values and a better ability to redefine the risk of therapy failure. Our model could help physicians estimate the likelihood of initial imatinib or 2G TKI-therapy failure in people with chronic-phase CML.


Asunto(s)
Mesilato de Imatinib , Leucemia Mielógena Crónica BCR-ABL Positiva , Inhibidores de Proteínas Quinasas , Insuficiencia del Tratamiento , Humanos , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/efectos adversos , Persona de Mediana Edad , Masculino , Femenino , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/mortalidad , Anciano , Adulto , Mesilato de Imatinib/uso terapéutico , Anciano de 80 o más Años , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Pirimidinas/uso terapéutico , Pirimidinas/efectos adversos , Adulto Joven , Adolescente , Benzamidas/uso terapéutico , Piperazinas/uso terapéutico , Piperazinas/efectos adversos , Pronóstico , Antineoplásicos/uso terapéutico , Antineoplásicos/efectos adversos
6.
Cell Rep Med ; 5(7): 101645, 2024 Jul 16.
Artículo en Inglés | MEDLINE | ID: mdl-39019012

RESUMEN

Fms-like tyrosine kinase 3 (FLT3) mutations, present in over 30% of acute myeloid leukemia (AML) cases and dominated by FLT3-internal tandem duplication (FLT3-ITD), are associated with poor outcomes in patients with AML. While tyrosine kinase inhibitors (TKIs; e.g., gilteritinib) are effective, they face challenges such as drug resistance, relapse, and high costs. Here, we report that metformin, a cheap, safe, and widely used anti-diabetic agent, exhibits a striking synergistic effect with gilteritinib in treating FLT3-ITD AML. Metformin significantly sensitizes FLT3-ITD AML cells (including TKI-resistant ones) to gilteritinib. Metformin plus gilteritinib (low dose) dramatically suppresses leukemia progression and prolongs survival in FLT3-ITD AML mouse models. Mechanistically, the combinational treatment cooperatively suppresses polo-like kinase 1 (PLK1) expression and phosphorylation of FLT3/STAT5/ERK/mTOR. Clinical analysis also shows improved survival rates in patients with FLT3-ITD AML taking metformin. Thus, the metformin/gilteritinib combination represents a promising and cost-effective treatment for patients with FLT3-mutated AML, particularly for those with low income/affordability.


Asunto(s)
Compuestos de Anilina , Proteínas de Ciclo Celular , Sinergismo Farmacológico , Leucemia Mieloide Aguda , Metformina , Mutación , Quinasa Tipo Polo 1 , Proteínas Serina-Treonina Quinasas , Proteínas Proto-Oncogénicas , Pirazinas , Transducción de Señal , Tirosina Quinasa 3 Similar a fms , Metformina/farmacología , Metformina/uso terapéutico , Tirosina Quinasa 3 Similar a fms/genética , Tirosina Quinasa 3 Similar a fms/metabolismo , Tirosina Quinasa 3 Similar a fms/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Humanos , Animales , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Transducción de Señal/efectos de los fármacos , Pirazinas/farmacología , Pirazinas/uso terapéutico , Compuestos de Anilina/farmacología , Compuestos de Anilina/uso terapéutico , Ratones , Mutación/genética , Línea Celular Tumoral , Tiofenos/farmacología , Tiofenos/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Factor de Transcripción STAT5/metabolismo , Factor de Transcripción STAT5/genética , Femenino , Ensayos Antitumor por Modelo de Xenoinjerto , Masculino , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Serina-Treonina Quinasas TOR/metabolismo
7.
Ann Hematol ; 103(10): 4183-4191, 2024 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-38888616

RESUMEN

Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) has different epidemiology in Chinese vs. Western patients, but there are few studies of CLL/SLL in large populations of Chinese patients. ALPINE is a global phase 3 trial investigating Bruton tyrosine kinase inhibitors zanubrutinib vs. ibrutinib to treat relapsed/refractory (R/R) CLL/SLL. Here we report results from the subgroup of Chinese patients. Adults with R/R CLL/SLL were randomized 1:1 to receive zanubrutinib (160 mg twice-daily) or ibrutinib (420 mg once-daily) until disease progression or unacceptable toxicity. Endpoints included overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety. Data were analyzed descriptively. Ninety patients were randomized in China (zanubrutinib, n = 47; ibrutinib, n = 43). Baseline characteristics were balanced between groups, with fewer male patients in the zanubrutinib vs. ibrutinib group (55.3% vs. 69.8%). Median age was 60.5 years, 11% had del(17p) mutation, and 32% had tumor protein 53 (TP53) mutation. With median 25.3 months follow-up, ORR was 80.9% with zanubrutinib vs. 72.1% with ibrutinib. PFS was improved with zanubrutinib vs. ibrutinib (HR = 0.34 [95% CI, 0.15, 0.77]), and the HR for OS was 0.45 (95% CI, 0.14, 1.50). Rates of Grade ≥ 3 treatment-emergent adverse events (TEAEs; 64.4% vs. 72.1%), AEs leading to discontinuation (6.4% vs. 14.0%), and serious TEAEs (35.6% vs. 51.2%) were lower with zanubrutinib vs. ibrutinib. Zanubrutinib demonstrated improved ORR, PFS, and OS vs. ibrutinib and a more favorable safety profile in patients with R/R CLL/SLL in China. These results are consistent with the full global population of ALPINE. ClinicalTrials.gov: NCT03734016, registered November 7, 2018.


Asunto(s)
Adenina , Leucemia Linfocítica Crónica de Células B , Piperidinas , Pirazoles , Pirimidinas , Humanos , Piperidinas/uso terapéutico , Piperidinas/efectos adversos , Adenina/análogos & derivados , Adenina/uso terapéutico , Masculino , Pirimidinas/uso terapéutico , Pirimidinas/efectos adversos , Pirimidinas/administración & dosificación , Femenino , Persona de Mediana Edad , Anciano , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/mortalidad , Pirazoles/uso terapéutico , Pirazoles/efectos adversos , Pirazoles/administración & dosificación , China/epidemiología , Adulto , Anciano de 80 o más Años , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/efectos adversos , Resultado del Tratamiento , Supervivencia sin Progresión , Agammaglobulinemia Tirosina Quinasa/antagonistas & inhibidores , Resistencia a Antineoplásicos
8.
Haematologica ; 2024 Jun 27.
Artículo en Inglés | MEDLINE | ID: mdl-38934064

RESUMEN

To evaluate the efficacy and safety of flumatinib in the later-line treatment of Chinese patients with Philadelphia chromosome-positive chronic-phase chronic myeloid leukemia (CP-CML previously treated with tyrosine kinase inhibitors (TKIs). Patients with CML-CP were evaluated for the probabilities of responses including complete hematologic response (CHR), cytogenetic response, and molecular response (MR) and adverse events (AEs) after the later-line flumatinib therapy. Of 336 enrolled patients with median age 50 years, median duration of treatment with flumatinib was 11.04 (2-25.23) months. Patients who achieved clinical responses at baseline showed maintenance of CHR, complete cytogenetic response (CCyR)/2-log molecular response (MR2), major molecular response (MMR), and 4-log molecular response or deep molecular response (MR4/DMR) in 100%, 98.9%, 98.6%, and 92.9% patients, respectively. CHR, CCyR/MR2, MMR, and MR4/DMR responses were achieved in 86.4%, 52.7%, 49.6%, and 23.5% patients respectively, which showed the lack of respective clinical responses at baseline. The patients without response at baseline, treated with flumatinib as 2L TKI, having no resistance to prior TKI or only resistance to imatinib, with response to last TKI, and with BCR::ABL ≤10% had higher CCyR/MR2, MMR, or MR4/DMR. The AEs observed during the later-line flumatinib treatment were tolerable and consistent with those reported with the first-line therapy. Flumatinib was effective and safe in patients who are resistant or intolerant to other TKIs. In particular, 2L flumatinib treatment induced high response rates and was more beneficial to patients without previous 2G TKI resistance, thus serving as a probable treatment option for these patients.

9.
Ann Hematol ; 103(7): 2273-2281, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38842566

RESUMEN

While studies have explored the feasibility of switching between various thrombopoietin receptor agonists in treating immune thrombocytopenia (ITP), data on the switching from eltrombopag to hetrombopag remains scarce. This post-hoc analysis of a phase III hetrombopag trial aimed to assess the outcomes of ITP patients who switched from eltrombopag to hetrombopag. In the original phase III trial, patients initially randomized to the placebo group were switched to eltrombopag. Those who completed this 14-week eltrombopag were eligible to switch to a 24-week hetrombopag. Treatment response, defined as a platelet count of ≥ 50 × 109/L, and safety were evaluated before and after the switch. Sixty-three patients who completed the 14-week eltrombopag and switched to hetrombopag were included in this post-hoc analysis. Response rates before and after the switch were 66.7% and 88.9%, respectively. Among those with pre-switching platelet counts below 30 × 109/L, eight out of 12 patients (66.7%) responded, while eight out of nine patients (88.9%) with pre-switching platelet counts between 30 × 109/L and 50 × 109/L responded post-switching. Treatment-related adverse events were observed in 50.8% of patients during eltrombopag treatment and 38.1% during hetrombopag treatment. No severe adverse events were noted during hetrombopag treatment. Switching from eltrombopag to hetrombopag in ITP management appears to be effective and well-tolerated. Notably, hetrombopag yielded high response rates, even among patients who had previously shown limited response to eltrombopag. However, these observations need to be confirmed in future trials.


Asunto(s)
Benzoatos , Hidrazinas , Púrpura Trombocitopénica Idiopática , Pirazoles , Pirazolonas , Receptores de Trombopoyetina , Humanos , Pirazoles/uso terapéutico , Pirazoles/efectos adversos , Pirazoles/administración & dosificación , Masculino , Femenino , Benzoatos/uso terapéutico , Benzoatos/efectos adversos , Benzoatos/administración & dosificación , Púrpura Trombocitopénica Idiopática/tratamiento farmacológico , Púrpura Trombocitopénica Idiopática/sangre , Persona de Mediana Edad , Adulto , Anciano , Hidrazinas/uso terapéutico , Hidrazinas/efectos adversos , Hidrazinas/administración & dosificación , Receptores de Trombopoyetina/agonistas , Pirazolonas/uso terapéutico , Sustitución de Medicamentos , Recuento de Plaquetas , Resultado del Tratamiento , Hidrazonas
10.
Am J Cancer Res ; 14(4): 1649-1661, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38726267

RESUMEN

Adult T-cell leukemia/lymphoma (ATLL) is an aggressive malignancy with a poor prognosis, and there is little data available from the Chinese population. This retrospective study included 115 patients diagnosed with ATLL who were treated across five hospitals in China from June 2011 to December 2022. The median age at diagnosis was 53 years. Several genes involved in T-cell receptor-induced nuclear factor κB (TCR-NF-κB) signaling were commonly mutated, including PLCG1, CIC, PRKCB, CARD11, and IRF4. Eighty-seven patients received chemotherapy. Of these, 13 received a hematopoietic stem cell transplant (HSCT) (allogeneic-HSCT, n=9; autologous-HSCT, n=4) after chemotherapy. Following initial multiagent chemotherapy using EPOCH/CHOEP and other regimens, the overall response rates were 80.6% (complete response [CR], 44.4%) and 42.8% (CR, 14.2%), respectively. The 4-year survival rates (median survival time in days) for EPOCH/CHOEP (n=43), HSCT (n=13), and CHOP-based regimens (n=31) were 12.7% (138), 30.8% (333), and 0% (66), respectively. Lymphadenopathy, EPOCH/CHOEP, and hematopoietic stem cell transplantation were independent prognostic protective factors in patients with aggressive ATLL. Chinese patients exhibit a higher incidence of aggressive-type ATLL, sharing similar genetic alterations with Japanese patients. Etoposide-based chemotherapy (EPOCH or CHOEP) remains the preferred choice for aggressive ATLL, and upfront allogeneic HSCT should be considered in all eligible patients.

11.
Leuk Lymphoma ; 65(9): 1303-1313, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-38767239

RESUMEN

The present study aimed to investigate the real-world results of childhood acute lymphoblastic leukemia (cALL) cases in Fujian, China. The clinical data of 1414 patients with newly diagnosed cALL in Fujian were retrospectively analyzed. Patients were treated according to the Chinese Children Leukemia Group 2008 protocol (CCLG-ALL 2008 group) or Chinese Children's Cancer Group 2015 protocol (CCCG-ALL 2015 group). Cumulative incidence of treatment abandonment (TA) at 5 years was 4.2% ± 0.6% and significantly associated with treatment period and risk stratification. The 5-OS and EFS were significantly higher in the CCCG-ALL 2015 group than in the CCLG-ALL 2008 group. Patients treated with CCCG-ALL 2015 from Fujian Medical Union Hospital had a significantly higher 4-year OS and EFS than did those from the other four hospitals. Real-world TA of cALL greatly decreased, and its long-term survival significantly increased in Fujian, which may be related to optimizing programs, multi-center collaboration, and improving treatment compliance.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiología , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidad , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Femenino , China/epidemiología , Masculino , Niño , Preescolar , Estudios Retrospectivos , Lactante , Resultado del Tratamiento , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Pronóstico , Estudios de Seguimiento , Tasa de Supervivencia
12.
Open Life Sci ; 19(1): 20220848, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38623585

RESUMEN

Bortezomib (BTZ), a proteasome inhibitor, is a promising therapeutic option for multiple myeloma (MM) patients. However, drug resistance often occurs, leading to disease relapse and poor prognosis. In this study, we aimed to identify novel genes associated with drug resistance and investigate their roles in BTZ resistance. Through the screening of 26 genes frequently associated with chemosensitivity or drug resistance, we discovered that KDM4C, a histone demethylase, exhibited increased expression in BTZ-resistant MM cells compared to their sensitive counterparts. Overexpression of KDM4C enhanced the tolerance of a MM cell line to the drug, whereas the knockdown of KDM4C, using shRNA, increased the sensitivity of resistant cells to BTZ treatment. This suggests that KDM4C plays a pivotal role in conferring BTZ resistance. Our study offers fresh insights into BTZ resistance in MM and highlights KDM4C as a potential target for overcoming drug resistance.

13.
Front Oncol ; 14: 1364834, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38651155

RESUMEN

Introduction: An increasing number of cohort studies have shown a correlation between serum bilirubin and tumors, but no definitive causal relationship has been established between serum bilirubin and hematological malignancies.Therefore, the aim of the present study was to assess the causal relationship of serum bilirubin, including total bilirubin (TBIL) and direct bilirubin (DBIL), with hematological malignancies, including leukemia, lymphoma, and myeloma. Methods: We used a genome-wide association study (GWAS) collection of TBIL, DBIL, and hematological malignancies data. Using two-sample Mendelian randomization(MR), we assessed the impact of TBIL and DBIL on hematological malignancies. For this study, the inverse variance weighting method (IVW) was the primary method of MR analysis. In the sensitivity analysis, the weighted median method, MR Egger regression, and MR-PRESSO test were used. To understand the mechanisms behind TBIL and DBIL, we used three different approaches based on screening single nucleotide polymorphisms (SNPs) and their associated genes, followed by bioinformatics analysis. Results: The IVW test results showed evidence of effects of TBIL (odds ratio [OR]: 4.47, 95% confidence interval [CI]: 1.58-12.62) and DBIL (OR: 3.31, 95% CI: 1.08-10.18) on the risk of acute myeloid leukemia (AML).The findings from bioinformatics indicated that TBIL could potentially undergo xenobiotic metabolism through cytochrome P450 and contribute to chemical carcinogenesis. Discussion: In this study, two-sample MR analysis revealed a causal relationship between TBIL, DBIL, and AML.

14.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 32(2): 395-401, 2024 Apr.
Artículo en Chino | MEDLINE | ID: mdl-38660842

RESUMEN

OBJECTIVE: To investigate the correlation of miR-155 expression with drug sensitivity of FLT3-ITD+ acute myeloid leukemia (AML) cell line and its potential regulatory mechanism. METHODS: By knocking out miR-155 gene in FLT3-ITD+ AML cell line MV411 through CRISPR/Cas9 gene-editing technology, monoclonal cells were screened. The genotype of these monoclonal cells was validated by PCR and Sanger sequencing. The expression of mature miRNA was measured by RT-qPCR. The treatment response of doxorubicin, quizartinib and midostaurin were measured by MTT assay and IC50 of these drugs were calculated to identify the sensitivity. Transcriptome sequencing was used to analyze change of mRNA level in MV411 cells after miR-155 knockout, gene set enrichment analysis to analyze change of signaling pathway, and Western blot to verify expressions of key molecules in signaling pathway. RESULTS: Four heterozygotes with gene knockout and one heterozygote with gene insertion were obtained through PCR screening and Sanger sequencing. RT-qPCR results showed that the expression of mature miR-155 in the monoclonal cells was significantly lower than wild-type clones. MTT results showed that the sensitivity of MV411 cells to various anti FLT3-ITD+ AML drugs increased significantly after miR-155 knockout compared with wild-type clones. RNA sequencing showed that the mTOR signaling pathway and Wnt signaling pathway were inhibited after miR-155 knockout. Western blot showed that the expressions of key molecules p-mTOR, Wnt5α and ß-catenin in signaling pathway were down-regulated. CONCLUSION: Drug sensitivity of MV411 cells to doxorubicin, quizartinib and midostaurin can be enhanced significantly after miR-155 knockout, which is related to the inhibition of multiple signaling pathways including mTOR and Wnt signaling pathways.


Asunto(s)
Leucemia Mieloide Aguda , MicroARNs , Compuestos de Fenilurea , Estaurosporina/análogos & derivados , Tirosina Quinasa 3 Similar a fms , MicroARNs/genética , Humanos , Leucemia Mieloide Aguda/genética , Tirosina Quinasa 3 Similar a fms/genética , Línea Celular Tumoral , Transducción de Señal , Doxorrubicina/farmacología , Resistencia a Antineoplásicos , Benzotiazoles/farmacología , Estaurosporina/farmacología , Serina-Treonina Quinasas TOR/metabolismo , Vía de Señalización Wnt
15.
Transl Oncol ; 45: 101952, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38640787

RESUMEN

Solute carrier family 27 member 2 (SLC27A2) is involved in fatty acid metabolism in tumors and represents a prospective target for cancer therapy. However, the role and mechanism of action of SLC27A2 in acute lymphoblastic leukemia (ALL) remain unclear. In this study, we aimed to explore the intrinsic associations between SLC27A2 and ALL and evaluate the prognostic significance, biological functions, and correlation with immune infiltration. We used the transcriptome and clinical data from the TARGET dataset. Differentially expressed genes (DEGs) in the SLC27A2 low- and high-expression groups were analyzed for prognostic implications and functional enrichment. Furthermore, we analyzed the relationship between SLC27A2 gene expression and immune cell infiltration using the ESTIMATE method, which was evaluated using the TIGER platform. Finally, we knocked down SLC27A2 in the Jurkat ALL cell line and conducted cell proliferation, western blotting, flow cytometry, and CCK-8 assays to elucidate the biological function of SLC27A2 in ALL. Patients with ALL who have higher expression levels of SLC27A2 have poorer overall survival and event-free survival. According to gene set enrichment analysis, the DEGs were primarily enriched with immune system processes and the PI3K-Akt signaling pathway. There was an inverse relationship between SLC27A2 expression and immune cell invasion, suggesting involvement of the former in tumor immune evasion. In vitro experiments showed that knockdown of SLC27A2 inhibited cell proliferation and protein expression and altered the Akt pathway, with a reduced proportion of B cells. In conclusion, SLC27A2 plays a vital role in the development of ALL.

16.
Ann Hematol ; 103(7): 2393-2404, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38480542

RESUMEN

This study aimed to analyse the characteristics and treatment outcomes of adult patients with acute lymphoblastic leukaemia (ALL) and construct nomogram predictive models for prognosis prediction. Between January 2017 and June 2022, 462 adult patients with ALL were included in this retrospective analysis. Patients' ages ranged from 14 to 84 years. B-cell origin was observed in 82.7% of these patients, while 17.3% of the cases were of T-cell origin. The BCR/ABL1 fusion gene was detected in 32.9% of those with B-ALL. Complete remission was achieved in 83.7% of the patients after induction chemotherapy. The median disease-free survival (DFS) and overall survival (OS) of patients were 19.0 and 39.1 months, respectively. The 5-year DFS and OS rates were 29.5% and 41.8%, respectively. The BCR/ABL1 fusion gene had a significant adverse impact on DFS and OS when patients were treated with tyrosine kinase inhibitors (TKIs) and chemotherapy; however, this effect was eliminated when patients underwent transplantation. Multivariate analysis identified that age ≥ 35 years, white blood cell count ≥ 30 × 109/L, platelet count < 100 × 109/L, failure to achieve complete remission after induction chemotherapy, positive measurable residual disease (MRD), and absence of transplantation were independent adverse prognostic factors for DFS and/or OS. Nomogram predictive models constructed by the rms package in R software based on these prognostic factors demonstrated precise predictive value. In conclusion, adult patients with ALL experience poor survival. TKIs in combination with transplantation can eliminate the adverse effects of BCR/ABL1 fusion genes on prognosis. Nomogram predictive models were accurate for prognostic prediction and will be useful in clinical practice.


Asunto(s)
Nomogramas , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Adulto , Persona de Mediana Edad , Masculino , Femenino , Anciano , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidad , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Adolescente , Estudios Retrospectivos , Anciano de 80 o más Años , Adulto Joven , Proteínas de Fusión bcr-abl/genética , Resultado del Tratamiento , Tasa de Supervivencia , Supervivencia sin Enfermedad , Pronóstico , Inducción de Remisión
17.
Clin Lymphoma Myeloma Leuk ; 24(6): e257-e266, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38461040

RESUMEN

BACKGROUND: There are limited data comprehensively comparing therapy responses and outcomes among nilotinib, dasatinib, flumatinib and imatinib for newly diagnosed chronic-phase chronic myeloid leukemia in a real-world setting. PATIENTS AND METHODS: Data from patients with chronic-phase CML receiving initial a second-generation tyrosine-kinase inhibitor (2G-TKI, nilotinib, dasatinib or flumatinib) or imatinib therapy from 77 Chinese centers were retrospectively interrogated. Propensity-score matching (PSM) analyses were performed to to compare therapy responses and outcomes among these 4 TKIs. RESULTS: 2,496 patients receiving initial nilotinib (n = 512), dasatinib (n = 134), flumatinib (n = 411) or imatinib (n = 1,439) therapy were retrospectively interrogated in this study. PSM analyses indicated that patients receiving initial nilotinib, dasatinib or flumatinib therapy had comparable cytogenetic and molecular responses (p = .28-.91) and survival outcomes including failure-free survival (FFS, p = .28-.43), progression-free survival (PFS, p = .19-.93) and overall survival (OS) (p values = .76-.78) but had significantly higher cumulative incidences of cytogenetic and molecular responses (all p values < .001) and higher probabilities of FFS (p < .001-.01) than those receiving imatinib therapy, despite comparable PFS (p = .18-.89) and OS (p = .23-.30). CONCLUSION: Nilotinib, dasatinib and flumatinib had comparable efficacy, and significantly higher therapy responses and higher FFS rates than imatinib in newly diagnosed CML patients. However, there were no significant differences in PFS and OS among these 4 TKIs. These real-world data may provide additional evidence for routine clinical assessments to identify more appropriate therapies.


Asunto(s)
Dasatinib , Mesilato de Imatinib , Humanos , Femenino , Masculino , Estudios Retrospectivos , Persona de Mediana Edad , Dasatinib/uso terapéutico , Dasatinib/farmacología , Mesilato de Imatinib/uso terapéutico , Mesilato de Imatinib/farmacología , Adulto , Anciano , Pirimidinas/uso terapéutico , Leucemia Mieloide de Fase Crónica/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacología , Resultado del Tratamiento , Adulto Joven , Adolescente , Benzamidas/uso terapéutico , Anciano de 80 o más Años , Aminopiridinas
18.
Ann Hematol ; 103(4): 1211-1220, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38409598

RESUMEN

This study aimed to examine the characteristics and treatment outcomes of patients with TP53-mutant acute myeloid leukaemia (AML) and to explore potential prognostic factors. This retrospective analysis included 130 patients diagnosed with TP53-mutant AML at the Fujian Medical University Union Hospital between January 2016 and June 2023. Patients' ages ranged from 17 to 80 years, with a median age of 59 years. The proportions of de novo, therapy-related, and secondary AML cases were 71.5%, 7.7%, and 20.8%, respectively. Complex karyotypes were observed in 60.6% of patients, and the proportions of -5 or del(5q), -7 or del(7q), and - 17 or del(17p) were 41.7%, 27.9% and 14.4%, respectively. DNA methylation- and myelodysplasia-related (MR) gene mutations were observed in 36.9% and 25.4% of patients, respectively. These patients showed poor survival, with a median overall survival (OS) of 4.5 months, a 1-year OS rate of 32.5%, a 3-year OS rate of 18.8%, and a 5-year OS rate of 11.3%. The complete response rates for intensive chemotherapy (IC), hypomethylating agent (HMAs)-based therapies, and azacitidine plus venetoclax were 35.7%, 22.2%, and 37.5%, respectively. Patients who did or did not receive allogeneic haematopoietic stem cell transplantation (allo-HSCT) had similar prognoses (median OS: 6.0 vs. 3.9 months; P = 0.6415). Multivariate analysis indicated that MR gene mutations is an independent favorable prognostic factor of OS (HR = 0.366, 95% CI: 0.181-0.738, P = 0.005). In conclusion, patients with TP53-mutant AML have poor prognoses under current treatment strategies and MR gene mutations are associated with a more favorable survival. Therefore, further studies are needed to improve the survival rates in this population.


Asunto(s)
Leucemia Mieloide Aguda , Síndromes Mielodisplásicos , Humanos , Adolescente , Adulto Joven , Adulto , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Estudios Retrospectivos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Mutación , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/terapia , Pronóstico , Proteína p53 Supresora de Tumor/genética
19.
Am J Hematol ; 99(4): 774-779, 2024 04.
Artículo en Inglés | MEDLINE | ID: mdl-38343062

RESUMEN

Jaktinib, a novel JAK and ACVR1 inhibitor, has exhibited promising results in treating patients with myelofibrosis (MF). ZGJAK002 is a Phase 2 trial aimed to assess the efficacy and safety of jaktinib 100 mg BID (N = 66) and 200 mg QD (N = 52) in JAK inhibitor-naive patients with intermediate- or high-risk MF. We herein present the long-term data with a median follow-up of 30.7 months. At data cutoff, 30.3% of patients in 100 mg BID and 28.8% in 200 mg QD were still continuing their treatment. The 100 mg BID group displayed a numerically higher best spleen response compared with the 200 mg QD group (69.7% vs. 46.2%), with 50.4% from the BID and 51.2% from the QD group maintaining spleen responses over 120 weeks. The 36-month survival rates were 78.2% in BID and 73.6% in QD group. The tolerability of jaktinib remained well, and common grade ≥3 adverse drug reactions included anemia (15.2% vs. 21.2%), thrombocytopenia (15.2% vs. 11.5%), and infectious pneumonia (10.6% vs. 1.9%) in BID and QD groups, respectively. By comparing the two groups, the incidence of adverse events (AEs) were similar, except for drug-related serious AEs (24.2% vs. 9.6%) and AEs leading to treatment discontinuation (15.2% vs. 7.7%), which were higher in BID group. The percentages of AEs resulting in death were comparable, with 6.1% in BID and 5.8% in QD group. These analyses further support the long-term durable efficacy and acceptable safety of jaktinib at 100 mg BID and 200 mg QD doses for treating MF.


Asunto(s)
Mielofibrosis Primaria , Humanos , Estudios de Seguimiento , Mielofibrosis Primaria/tratamiento farmacológico , Resultado del Tratamiento
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