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Background The efficacy of hetrombopag in Chinese patients with immune thrombocytopenia (ITP) has been demonstrated in a randomized, double-blind, placebo-controlled, multicenter, phase III trial (NCT03222843). Objective This study aimed to report comprehensive data on a ≤6-week dose tapering to withdrawal (Stage 3) and an additional 24-week long-term extension period (Stage 4) in this phase III trial. Patients/methods Patients who fulfilled the screening criteria were eligible to enter Stage 3 or 4. During Stage 3, hetrombopag was gradually tapered to withdrawal. During Stage 4, hetrombopag treatment was initiated at 2.5, 3.75, 5, or 7.5 mg once daily. The efficacy endpoints during Stage 3 or 4 and the safety profile during the entire treatment period were reported. Results Among 194 patients who entered Stage 3, 171 (88.1%) relapsed. The median time to the first relapse since the start of Stage 3 was 15.0 days (95% CI, 14.0-16.0). In Stage 4, 144 (42.5%) patients responded at ≥75% of their assessments and 254 (74.9%) patients achieved platelet count ≥30×109 /L at least once, which was at least twice their baseline platelet count in the hetrombopag group (n=339). The most common adverse events were upper respiratory tract infection (53.1%), thrombocytopenia (27.1%), and urinary tract infection (21.2%) in the hetrombopag group. Conclusion The majority of patients who experienced dose tapering to withdrawal experienced a relapse. Long-term treatment with hetrombopag was effective in increasing and maintaining platelet count within the desired range in Chinese adults with ITP. Hetrombopag was well tolerated.

There is still a great demand in the clinic for the drugs which can overcome a variety of imatinib resistant ABL mutants. Starting from a type I inhibitor axitinib, which has been reported to overcome ABL-T315I mutant induced resistance, through a structure guided drug design approach and binding mode switch strategy, we have discovered a novel type II ABL inhibitor 24 (CHMFL-ABL-121), which significantly improved the inhibitory activity against ABL wt and a broad spectrum of mutants including the most prevalent imatinib-resistant gatekeeper mutant T315I. 24 exhibited IC50 values of 2 nM and 0.2 nM against purified inactive ABL wt and T315I kinase protein respectively and inhibited the proliferation of the established CML cell lines with GI50 at single digit nM. In cellular context, 24 strongly affected BCR-ABL mediated signaling pathways and induced apoptosis as well as arrested cell cycle at G0/G1 phase. In the in vivo study, 50 mg/kg/day dosage of 24 displayed TGI of 52% in the TEL-ABLT315I-BaF3 cell inoculated allograft mouse model without obvious toxicity.

Long non-coding RNA CRNDE and DNA methylation play a vital role in the occurrence and development of chronic lymphocytic leukemia (CLL). This study attempted to investigate the biological role of CRNDE methylation in CLL. The expression and methylation levels of CRNDE in CLL cell lines (MEC-1 and HG3) before or after methylation inhibitor (5-Aza-2'-deoxycytidine, 5-Aza-CdR) treatment was detected by quantitative real-time PCR or methylation-Specific PCR. The relationship among CRNDE, miR-28 and NDRG2 was verified by luciferase reporter assay. The effect of CRNDE overexpression and 5-Aza-CdR treatment on cell proliferation and apoptosis of MEC-1 and HG3 cells were assessed by CCK8 and flow cytomery. Compared with normal B lymphocytes, CRNDE was down-regulated and the methylation level of CRNDE was increased in MEC-1 and HG3 cells. Then, 5-Aza-CdR treatment caused an increase of CRNDE expression in MEC-1 and HG3 cells by demethylation. The overexpression or demethylation of CRNDE inhibited cell proliferation and promoted apoptosis in MEC-1 and HG3 cells by up-regulating CRNDE expression. Moreover, CRNDE functioned as a competing endogenous RNA to repress miR-28, which controlled its down-stream target NDRG2. CRNDE overexpression inhibited cell proliferation and promoted apoptosis via miR-28/NDRG2 axis in CLL. In conclusion, our data elaborated that CRNDE expression was regulated by DNA methylation, and the protective effect of CRNDE on CLL was attributed to the inhibition of proliferation in CLL via miR-28/NDRG2 axis. Thus, this work highlights a novel competing endogenous RNA circuitry involving key regulators of CLL.

Acute myeloid leukemia (AML) is one of the most common, complex, and heterogeneous hematological malignancies in adults. Despite progresses in understanding the pathology of AML, the 5-year survival rates still remain low compared with CML, CLL, etc. The relationship between genomic features and drug responses is critical for precision medication. Herein, we depicted a picture for response of 145 drugs against 33 primary cell samples derived from AML patients with full spectrum of genomic features assessed by whole exon sequencing and RNA sequencing. In general, most of the samples were much more sensitive to the combinatorial chemotherapy regimens than the single chemotherapy drugs. Overall, these samples were moderately sensitive to the Traditional Chinese Medicine (TCM) and the targeted drugs. In the weighted gene coexpression network analysis (WGCNA), the TCM and targeted therapies displayed similar genetic signatures in the gene module correlation. Meanwhile, the expression of miRNAs, lncRNAs, and mRNAs did not display apparent gene module correlations among those different types of therapies. In addition, the combinatorial chemotherapy bear more module correlations than the single drugs. Interestingly, we found that the gene mutations and drug response were not enriched in any WGCNA module analysis. Most of the sensitive drug response biomarkers were enriched in the ribosome, endocytosis, cell cycle, and p53 associated signaling pathways. This study showed that gene expression modules might show better correlation than gene mutations for drug efficacy predictions.