暂无摘要。

OBJECTIVE: NS-87/CPX-351 is a dual-drug liposomal encapsulation of cytarabine and daunorubicin. NS-87/CPX-351 exerts antileukemic action by maintaining a synergistic molar ratio of cytarabine to daunorubicin of 5:1 within the liposome while in circulation. Patients with high-risk acute myeloid leukemia (AML), which includes therapy-related AML and AML with myelodysplasia-related changes (AML-MRC), have poorer outcomes than those with other AML.
METHODS: This open-label phase 1/2 (P1/2) study was conducted in 47 Japanese patients aged 60-75 years with newly diagnosed high-risk AML to evaluate the pharmacokinetics, safety, and efficacy of NS-87/CPX-351.
RESULTS: In the 6 patients enrolled in the P1 portion, no dose-limiting toxicities (DLTs) were reported, and 100 units/m2 during the induction cycle was found to be acceptable. Cytarabine and daunorubicin had a long half-life in the terminal phase (32.8 and 28.7 h, respectively). In the 35 patients enrolled in the P2 portion, composite complete remission (CRc; defined as complete remission [CR] or CR with incomplete hematologic recovery [CRi]) was achieved in 60.0% (90% CI: 44.7-74.0) of the patients. Adverse events due to NS-87/CPX-351 were well tolerated.
RESULTS: NS-87/CPX-351 can be considered as a frontline treatment option for Japanese patients with high-risk AML.

OBJECTIVE: To explore the role of bone marrow mesenchymal stem cells (BMSC)，an essential element of the bone marrow microenvironment, in multidrug resistance(MDR) of K562 cells, as well as the reversal effect of tetrandrine (TET) on BMSC-mediated MDR and its potential mechanism.
METHODS: A mixed co-culture system and a transwell co-culture system for BMSC and K562 cells were established, and the cells were divided into different groups and treated with daunorubicin (DNR) alone or combined with TET and DNR. The CCK-8 assay was used to detect the proliferation of K562 cells in each group, and the cell inhibition rate was calculated. Cytometric bead array (CBA) was used to detect the expression levels of IFN, IL-2, IL-6 and IL-10 in the supernatant of different groups. RT-qPCR and Western blot were used to detected the expression of STAT3 at mRNA and protein levels, respectively.
RESULTS: Compared with K562+DNR group, the inhibition rate of DNR on K562 cell proliferation in K562+BMSC+DNR group was significantly decreased (P < 0.05), while the levels of IL-6 in the culture supernatant and phosphorylated STAT3 in K562 cells were significantly increased (P < 0.05). Compared with K562+BMSC+DNR group, the inhibition rate of DNR on K562 cell proliferation in K562+BMSC+DNR+TET group was significantly increased (P < 0.05), while the level of IL-6 and phosphorylated STAT3 was significantly decreased (P < 0.05).
CONCLUSIONS: BMSC can promote the drug resistance of leukemia cells, and TET may reverse the BMSC-mediated drug resistance via inhibiting IL-6/STAT3 signaling pathway.
UNASSIGNED: 汉防己甲素对白血病骨髓间充质干细胞相关耐药的影响及其机制研究.
UNASSIGNED: 研究骨髓间充质干细胞（BMSC）是否对白血病的多药耐药有促进作用，并研究汉防己甲素（TET）对BMSC介导的多药耐药（MDR）的影响及其作用机制。.
UNASSIGNED: 构建人骨髓间充质干细胞与白血病K562细胞株的混合共培养体系和Transwell小室共培养体系，并将细胞进行分组，分别给以柔红霉素（DNR）单药干预、TET与DNR联合干预，然后利用CCK-8法检测各组细胞增殖情况，计算细胞抑制率；利用流式细胞术测定各组上清液中IFN、IL-2、IL-6、IL-10的表达水平；利用RT-qPCR和Western blot分别在mRNA和蛋白水平对K562细胞中STAT3的表达进行验证。.
UNASSIGNED: 与BMSC共培养后，DNR对K562细胞增殖的抑制率明显降低（P <0.05），培养上清液中IL-6的水平和K562细胞中磷酸化的STAT3水平显著增加（P <0.05）。加入TET联合干预后，DNR对K562细胞增殖的抑制率显著增加（P <0.05），IL-6和磷酸化的STAT3水平降低（P <0.05）。.
UNASSIGNED: BMSC对白血病细胞的耐药有促进作用，TET可能通过抑制IL-6/STAT3通路从而逆转骨髓微环境介导的耐药作用。.

Failure after hypomethylating agents (HMAs) is associated with dismal outcomes in higher risk myelodysplastic syndromes (HR-MDS) or chronic myelomonocytic leukaemia (CMML). We aimed to evaluate the safety and preliminary activity of lower doses of CPX-351, a liposomal encapsulation of cytarabine and daunorubicin, in a single-centre, phase 1/2 study for patients with HR-MDS or CMML after HMA failure. Four doses of CPX-351 (10, 25, 50 and 75 units/m2 ) administered on Days 1, 3 and 5 of induction and Days 1 and 3 of consolidation were evaluated. Between June 2019 and June 2023, 25 patients were enrolled (phase 1: n = 15; phase 2: n = 10) including 19 (76%) with HR-MDS and 6 (24%) with CMML. Most common grade 3-4 non-haematological treatment-emergent adverse events were febrile neutropenia (n = 12, 48%) and lung infection (n = 5, 20%). Three patients (age >75) experienced cardiac toxicity at the 75 units/m2 dose. Further enrolment continued at 50 units/m2 . Four- and 8-week mortality were 0% and 8% respectively. The overall response rate was 56% with median relapse-free and overall survivals of 9.2 (95% CI 3.2-15.1 months) and 8.7 months (95% CI 1.8-15.6 months) respectively. These data suggest that lower doses of CPX-351 are safe. Further studies are needed to evaluate its activity.

Prior experience indicated that use of higher doses of cytarabine during induction for acute myeloid leukemia (AML) with a histone deacetylase inhibitor resulted in high response rates. S1203 was a randomized multicenter trial for previously untreated patients aged 18-60 with AML which compared daunorubicin and cytarabine (DA), idarubicin with higher dose cytarabine (IA) and IA with vorinostat (IA + V). The primary endpoint was event free survival (EFS). 738 patients were randomized: 261 to each DA and IA arms and 216 to the IA + V arm. 96, 456, and 150 patients had favorable-, intermediate-, and unfavorable-risk cytogenetics, respectively. 152 were NPM1 and 158 FLT3 mutated. The overall remission rate was 77.5% including 62.5% CR and 15.0% CRi. No differences in remission, EFS, or overall survival were observed among the 3 arms except for the favorable cytogenetics subset who had improved outcomes with DA and postremission high dose cytarabine. A trend towards increased toxicity was observed with the IA and IA + V arms. The use of higher dose cytarabine during induction therapy in younger patients with AML, with or without vorinostat, does not result in improved outcomes. (Funded by the US National Institutes of Health and others, ClinicalTrials.gov number, NCT01802333.).

BACKGROUND: Many older patients with acute myeloid leukaemia die or cannot undergo allogeneic haematopoietic stem-cell transplantation (HSCT) due to toxicity caused by intensive chemotherapy. We hypothesised that replacing intensive chemotherapy with decitabine monotherapy could improve outcomes.
METHODS: This open-label, randomised, controlled, phase 3 trial was conducted at 54 hospitals in nine European countries. Patients aged 60 years and older who were newly diagnosed with acute myeloid leukaemia and had not yet been treated were enrolled if they had an Eastern Cooperative Oncology Group performance status of 2 or less and were eligible for intensive chemotherapy. Patients were randomly assigned (1:1) to receive decitabine or standard chemotherapy (known as 3 + 7). For the decitabine group, decitabine (20 mg/m2) was administered for the first 10 days in the first 28-day cycle, followed by 28-day cycles consisting of 5 days or 10 days of decitabine. For the 3 + 7 group, daunorubicin (60 mg/m2) was administered over the first 3 days and cytarabine (200 mg/m2) over the first 7 days, followed by 1-3 additional chemotherapy cycles. Allogeneic HSCT was strongly encouraged. Overall survival in the intention-to-treat population was the primary endpoint. Safety was assessed in all patients who received the allocated treatment. This trial is registered at ClinicalTrials.gov, NCT02172872, and is closed to new participants.
RESULTS: Between Dec 1, 2014, and Aug 20, 2019, 606 patients were randomly assigned to the decitabine (n=303) or 3 + 7 (n=303) group. Following an interim analysis which showed futility, the IDMC recommended on May 22, 2019, that the study continued as planned considering the risks and benefits for the patients participating in the study. The cutoff date for the final analysis presented here was June 30, 2021. At a median follow-up of 4·0 years (IQR 2·9-4·8), 4-year overall survival was 26% (95% CI 21-32) in the decitabine group versus 30% (24-35) in the 3 + 7 group (hazard ratio for death 1·04 [95% CI 0·86-1·26]; p=0·68). Rates of on-protocol allogeneic HSCT were similar between groups (122 [40%] of 303 patients for decitabine and 118 [39%] of 303 patients for 3+7). Rates of grade 3-5 adverse events were 254 (84%) of 302 patients in the decitabine group and 279 (94%) of 298 patients in the 3 + 7 group. The rates of grade 3-5 infections (41% [125 of 302] vs 53% [158 of 298]), oral mucositis (2% [seven of 302] vs 10% [31 of 298]) and diarrhoea (1% [three of 302] vs 8% [24 of 298]) were lower in the decitabine group than in the 3 + 7 group. Treatment-related deaths were reported for 12% (35 of 302) of patients in the decitabine group and 14% (41 of 298) in the 3 + 7 group.
CONCLUSIONS: 10-day decitabine did not improve overall survival but showed a better safety profile compared with 3 + 7 chemotherapy in older patients with acute myeloid leukaemia eligible for intensive chemotherapy. Decitabine could be considered a better-tolerated and sufficiently efficacious alternative to 3 + 7 induction in fit older patients with acute myeloid leukaemia without favourable genetics.
BACKGROUND: Janssen Pharmaceuticals.

1. ABCB1 (P-glycoprotein, MDR1) is one of the most important transporter involved in cancer multi-drug resistance. It also plays a significant role in cancer resistance against anthracyclines, an anticancer group of drugs, including doxorubicin and daunorubicin. Several intracellular enzymes metabolise anthracyclines to carbonyl-reduced, hydroxy metabolites, which have impaired cytotoxic properties. However, metabolite efflux by ABCB1 transporter is not well characterised, while it may be the mechanism responsible for the metabolites\' lack of activity.2. In this study recombinant ABCB1 ATPase transporter assay; anthracyclines accumulation assay in resistant cells overexpressing ABCB1; and molecular modelling were used to investigate anthracyclines: doxorubicin and daunorubicin and their carbonyl-reduced metabolites (doxorubicinol, daunorubicinol) susceptibility for ABCB1-dependent efflux.3. Based on the kinetics parameters of ATPase activity of ABCB1, it was found that daunorubicinol exerted an exceptionally high potential for being effluxed by the ABCB1 transporter. ABCB1 significantly affected the accumulation pattern of studied chemicals in resistant cancer cells. Doxorubicin and daunorubicinol accumulation were influenced by the activity of ABCB1 modulator - valspodar.4. Results indicate that ABCB1 activity affects not only anthracyclines but also their metabolites. Therefore crosstalk between the process of anthracyclines metabolism and metabolite efflux may be the mechanism of impairing anticancer properties of anthracyclines metabolites.

This is the primary report of the randomized, placebo-controlled phase 3 BRIGHT AML 1019 clinical trial of glasdegib in combination with intensive chemotherapy (cytarabine and daunorubicin) or non-intensive chemotherapy (azacitidine) in patients with untreated acute myeloid leukemia. Overall survival (primary endpoint) was similar between the glasdegib and placebo arms in the intensive (n = 404; hazard ratio [HR] 1.05; 95% confidence interval [CI]: 0.782-1.408; two-sided p = 0.749) and non-intensive (n = 325; HR 0.99; 95% CI: 0.768-1.289; two-sided p = 0.969) studies. The proportion of patients who experienced treatment-emergent adverse events was similar for glasdegib versus placebo (intensive: 99.0% vs. 98.5%; non-intensive: 99.4% vs. 98.8%). The most common treatment-emergent adverse events were nausea, febrile neutropenia, and anemia in the intensive study and anemia, constipation, and nausea in the non-intensive study. The addition of glasdegib to either cytarabine and daunorubicin or azacitidine did not significantly improve overall survival and the primary efficacy endpoint for the BRIGHT AML 1019 phase 3 trial was not met. Clinical trial registration: ClinicalTrials.gov: NCT03416179.

Addition of gemtuzumab ozogamicin (GO) to induction chemotherapy improves outcomes in older patients with acute myeloid leukemia (AML), but it is uncertain whether a fractionated schedule provides additional benefit to a single dose. We randomized 852 older adults (median age, 68-years) with AML/high-risk myelodysplasia to GO on day 1 (GO1) or on days 1 and 4 (GO2) of course 1 induction. The median follow-up period was 50.2 months. Although complete remission (CR) rates after course 1 did not significantly differ between arms (GO2, 63%; GO1, 57%; odds ratio [OR], 0.78; P = .08), there were significantly more patients who achieved CR with a measurable residual disease (MRD)<0.1% (50% vs 41%; OR, 0.72; P = .027). This differential MRD reduction with GO2 varied across molecular subtypes, being greatest for IDH mutations. The 5-year overall survival (OS) was 29% for patients in the GO2 arm and 24% for those in the GO1 arm (hazard ratio [HR], 0.89; P = .14). In a sensitivity analysis excluding patients found to have adverse cytogenetics or TP53 mutations, the 5-year OS was 33% for GO2 and 26% for GO1 (HR, 0.83; P = .045). In total, 228 (27%) patients received an allogeneic transplantation in first remission. Posttransplant OS was superior in the GO2 arm (HR, 0.67; P = .033); furthermore, the survival advantage from GO2 in the sensitivity analysis was lost when data of patients were censored at transplantation. In conclusion, GO2 was associated with a greater reduction in MRD and improved survival in older adults with nonadverse risk genetics. This benefit from GO2 was dependent on allogeneic transplantation to translate the better leukemia clearance into improved survival. This trial was registered at www.isrctn.com as #ISRCTN 31682779.

The pivotal RATIFY study demonstrated midostaurin (50 mg twice daily) with standard chemotherapy significantly reduced mortality in adult patients (<60 years) with newly diagnosed (ND) FLT3mut acute myeloid leukemia (AML). Considering that AML often present in older patients who show poor response to chemotherapy, this open-label, multicenter phase 3b trial was designed to further assess safety and efficacy of midostaurin plus chemotherapy in induction, consolidation, and maintenance monotherapy in young (≤60 years) and older (>60 years) patients with FLT3mut ND-AML. Compared with RATIFY, this study extended midostaurin treatment from 14 days to 21 days, substituted anthracyclines (idarubicin or daunorubicin), and introduced variation in standard combination chemotherapy dosing (\"7+3\" or \"5+2\" in more fragile patients). Total 301 patients (47.2% >60 years and 82.7% with FLT3-ITDmut) of median age 59 years entered induction phase. Overall, 295 patients (98.0%) had at least 1 adverse event (AE), including 254 patients (84.4%) with grade ≥3 AE. The grade ≥3 serious AEs occurred in 134 patients. No difference was seen in AE frequency between age groups, but grade ≥3AE frequency was higher in older patients. Overall, complete remission (CR) rate including incomplete hematologic recovery (CR + CRi) (80.7% [95% confidence interval, 75.74-84.98]) was comparable between age groups (≤60 years [83.5%]; >60 to ≤70 years [82.5%]; in patients >70 years [64.1%]) and the type of anthracycline used in induction. CR + CRi rate was lower in males (76.4%) than females (84.4%). Overall, the safety and efficacy of midostaurin remains consistent with previous findings, regardless of age, sex, or induction regimen. The trial is registered at www.clinicaltrials.gov as #NCT03379727.