Gilteritinib-based combination therapy in adult relapsed/refractory FLT3-mutated acute myeloid leukaemia.

Gilteritinib, a potent FMS-like tyrosine kinase 3 (FLT3) inhibitor, was approved for relapsed/refractory (R/R) FLT3-mutated acute myeloid leukaemia (AML) patients but still showed limited efficacy. Here, we retrospectively analysed the efficacy and safety of different gilteritinib-based combination therapies (gilteritinib plus hypomethylating agent and venetoclax, G + HMA + VEN; gilteritinib plus HMA, G + HMA; gilteritinib plus venetoclax, G + VEN) in 33 R/R FLT3-mutated AML patients. The composite complete response (CRc) and modified CRc (mCRc) rates were 66.7% (12/18) and 88.9% (16/18) in patients received G + HMA + VEN, which was higher compared with that in G + HMA (CRc: 18.2%, 2/11; mCRc: 45.5%, 5/11) or G + VEN (CRc: 50.0%, 2/4; mCRc: 50.0%, 2/4). The median overall survival (OS) for G + HMA + VEN, G + HMA and G + VEN treatment was not reached, 160.0 days and 231.0 days. The median duration of remission (DOR) for G + HMA + VEN, G + HMA and G + VEN treatment was not reached, 82.0 days and 77.0 days. Four patients in the G + HMA + VEN group received alloHSCT after remission exhibited prolonged median DOR. The most common grade 3/4 adverse events were cytopenia, febrile neutropenia and pulmonary infection; there were no differences among the three groups. In conclusion, our data demonstrated promising response of G + HMA + VEN combination therapy in R/R FLT3-mutated AML, and it may be considered an effective therapy bridge to transplantation.

Efficacy and safety of venetoclax in patients with relapsed/refractory multiple myeloma: a meta-analysis.

BACKGROUND: Venetoclax is clinically active in treating relapsed/refractory multiple myeloma (RRMM). This study evaluated the efficacy and safety of venetoclax or venetoclax with other agents in treating RRMM. METHODS: PubMed, Web of Science, Embase, and Cochrane Library were comprehensively searched. We included studies investigating the efficacy and safety of venetoclax or venetoclax with other agents in treating RRMM. Overall response rates (ORR), stringent complete response rates (sCR), complete response rates (CR), very good partial response rates (VGPR), partial response rates (PR), stable disease (SD), progressive disease (PD) and adverse events were synthesized using either a random-effects model or a fixed-effects model. RESULTS: A total of 7 clinical trials with 482 patients with RRMM were included. Concerning venetoclax with other agents, the pooled ORR, sCR, CR, VGPR, PR, SD, and PD were 0.76 (95% CIs: 0.62, 0.87), 0.11 (95% CIs: 0.04, 0.21), 0.18 (95% CIs: 0.11, 0.26), 0.16 (95% CIs: 0.12, 0.25), 0.29 (95% CIs: 0.25, 0.34), 0.07 (95% CIs: 0.05, 0.10), and 0.11 (95% CIs: 0.04, 0.23). The overall rate of adverse events ≥ Grade 3 was 0.84 (95% CIs: 0.77, 0.91). The most common non-hematologic adverse events were nausea, diarrhea, fatigue, back pain, and vomiting; hematologic adverse events included thrombocytopenia, neutropenia, anemia, leukopenia, and lymphopenia. CONCLUSIONS: This study indicates that venetoclax alone or in combination with other agents reveals favorable treatment responses and acceptable adverse events in treating RRMM.

Decitabine inhibits the proliferation of human T-cell acute lymphoblastic leukemia molt4 cells and promotes apoptosis partly by regulating the PI3K/AKT/mTOR pathway.

T cell acute lymphoblastic leukemia (T-ALL) is a highly aggressive hematological cancer; however, there is a lack of effective chemotherapeutic or targeted drugs for the treatment of T-ALL. Decitabine is a DNA demethylation agent but it has not been used for T-ALL treatment. Therefore, the present study aimed to assess the inhibitory effect of decitabine on T-ALL molt4 cells and determine its regulatory role in the PI3K/AKT/mTOR pathway. Molt4 cells were stimulated with decitabine in vitro, after which cell proliferation, apoptosis and cell cycle analyses were performed to assess cell viability. Subcellular morphology was observed using transmission electron microscopy. Expression levels of phosphate and tension homology (PTEN), genes involved in the PI3K/AKT/mTOR pathway and the corresponding downstream genes were analyzed using reverse transcription-quantitative PCR and western blotting. The results showed that decitabine induced apoptosis, inhibited proliferation and arrested molt4 cells in the G2 phase. Following decitabine intervention, an increase in the number of lipid droplets, autophagosomes and mitochondrial damage was observed. At concentrations of 1 and 10 µM, decitabine downregulated the expression of PI3K, AKT, mTOR, P70S6 and eukaryotic initiating factor 4E-binding protein 1, which in turn upregulated PTEN expression; however, 50 µM decitabine downregulated PTEN levels. Overall, these results demonstrated that decitabine reduced the viability of molt4 cells partly by inhibiting the PI3K/AKT/mTOR pathway via PTEN, especially at low decitabine concentrations.

The effect of rat nerve growth factor combined with vitamin B on peripheral neuropathy in multiple myeloma patients.

Background: Peripheral neuropathy can induce marked disability and negative effects on quality of life and is the most common therapy-related complication in multiple myeloma patients treated with bortezomib. Currently, there is no useful method to prevent or treat it. So, it is necessary to study the clinical efficacy of rat nerve growth factor combined with vitamin B for the treatment of peripheral neuropathy in multiple myeloma patients. Methods: Sixty multiple myeloma patients who developed peripheral neuropathy after bortezomib-based chemotherapy in Jiaxing First Hospital from October 2015 to May 2018 were randomly divided into treatment and control groups. Changes in serum NGF level and electromyograms before and after treatment were analyzed, and the effects were evaluated via a FACT/GOG-Ntx questionnaire score. Results: After treatment, the NGF level in the treatment group (13.2 ± 3.73 pg/ml) was higher than that in the control group (9.22 ± 2.93 pg/ml, P < 0.05). Improvements in the electromyograms were more pronounced in treatment group than those in the control group, with statistical significance. The FACT/GOG-Ntx questionnaire scores, both in the treatment group and the control group, were decreased (4.00 ± 1.58 vs. 5.20 ± 2.33; P < 0.05), and the alleviation of the symptoms in the treatment group were more obvious. Conclusion: Rat nerve growth factor combined with vitamin B is a safe and effective method for treating peripheral neuropathy in multiple myeloma patients.

Characterization of a 4 lncRNAs-based prognostic risk scoring system in adults with acute myeloid leukemia.

PURPOSE: The study aims to develop a prognostic scoring system based on prognostic lncRNAs for acute myeloid leukemia (AML). METHODS: Based on lncRNA expression profiles downloaded from The Cancer Genome Atlas (TCGA), differentially expressed long noncoding RNAs (DELs) between good prognosis and bad prognosis samples were screened, from which prognosis-related lncRNAs were selected using uni-variate and multi-variate Cox regression analysis. Based on the expression profiles of these signature prognosis-related lncRNAs, a risk scoring system was developed and applied to a training set and validated on a testing set. With sample-matched mRNAs of the signature lncRNAs, lncRNA-mRNA networks were built, followed by function analysis for the mRNAs in these networks. RESULT: Total 66 DELs were identified between good prognosis and bad prognosis samples. Among these DELs, LINC01003, CTD-2234N14, RP1-137K24, and RP11-834C111 were found to be independent predictors of prognosis. A risk scoring system based on the expressions of the 4 signature lncRNAs was developed. Kaplan-Meier survival analysis found that the risk score system could classify patients into high-risk and low-risk groups with significantly different survival outcomes. Function analysis showed that the mRNAs in these lncRNA-mRNA networks were significantly linked to mTOR signaling pathway, apoptosis, Fc epsilon RI signaling pathway, B cell receptor signaling pathway, natural killer cell mediated cytotoxicity, and T cell receptor signaling pathway. CONCLUSION: This study suggested a promising 4 prognostic lncRNAs-based risk scoring system in AML. These 4 lncRNAs may play roles in regulating prognosis partly via mTOR signaling pathway, apoptosis, and some immune-related pathways.