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Hemorrhage is the typical manifestation of APL-related coagulopathy while thrombosis is infrequently reported. In a retrospective analysis with 33 patients with hyperleukocytic APL, we found 6 out of 33 hyperleukocytic APL patients presented with thrombosis rather than hemorrhage. A notable feature in these high-risk APL patients with thrombosis is that there were no significant abnormalities in fibrinogen (FIB), prothrombin time (PT) and activated partial thromboplastin time (APTT). Compared with the normal ranges, both the high-risk APL patients with thrombosis and the high-risk APL patients with hemorrhage had a significant increase in fibrinogen degradation product (FDP) and d-dimer levels. However, the group with hemorrhage had noticeably higher plasma levels of FDP and d-dimer than the group with thrombosis. To find a close relationship between coagulation markers and the onset of thrombotic events in patients with high-risk APL, the potential effects of FDP/FIB and d-dimer/FIB ratios as risk markers were investigated. We demonstrated that FDP/FIB and d-dimer/FIB ratios in the patients with high-risk APL with thrombosis showed higher ratios than the normal range but significantly lower ratios than the patients with high-risk APL-related hemorrhage. Our data demonstrated that the alteration in FDP/FIB and d-dimer/FIB ratios have more significant relevance than the levels of FIB, FDP or d-dimer as potential factors for predicting thrombosis and may help with designing more appropriately risk-adapted treatment protocols or personalized therapy.

There is still a lack of effective treatments for elderly AML/MDS patients, especially those with TP53 mutation. We conducted a prospective, multicenter clinical trial to evaluate decitabine and etoposide based regimen in elderly AML/MDS patients and found the median OS of TP53 mutation AML/MDS was improved to 31 months. Moreover, the administration of decitabine and etoposide greatly reduced TP53 mutant AML tumor burden in NSG mice model. Decitabine and etoposide induced significant apoptosis and differentiation of TP53 mutant myeloid tumor cells in vitro. RNA sequencing data and CRISPR-Cas9 gene editing indicated that drug-induced apoptosis and differentiation, were predominantly dependent on Notch1 signaling pathway. We also found that normal p53 function could inhibit Notch1 activation, whereas decitabine and etoposide could activate Notch1 in dysfunctional TP53 mutant AML/MDS. These findings indicate that treatment of elderly AML/MDS patients may need to be developed into a more precise, personalized chemotherapy in the future.

We have demonstrated that 12-0-tetradecanoylphorbol-13-acetate (TPA) combined with vitamin D 3 (VD 3 ) and cytosine arabinoside (Ara C) is effective and feasible for chronic myelogenous leukemia (CML) in blastic phase (BP). In the current study, the efficacy of TPA combined with inhibitor imatinib mesylate (imatinib) was investigated in patients with CML in BP that was resistant to standard-dose imatinib (400 mg/day). The results suggested that TPA combined with imatinib (400 mg/day) might overcome disease-poor response to conventional doses. So this approach deserves further evaluation as frontline therapy for newly diagnosed CML.