OBJECTIVE: To investigate the effect of chromosomal karyotype on the prognosis of patients with acute promyelocytic leukemia (APL) in condition of the maintenance treatment based on arsenic trioxide. METHODS: The patients with acute promyelocytic leukemia for last 12 years in our hospital were retrospectively collected. The patients mainly treated with arsenic trioxide in maintenance protocol were selected and followed up. All the patients were divided into 3 groups according to cytogenetic data: single t (15; 17) group, t (15; 17) with additional chromosomal abnormality (ACA) group, and normal karyotype group. Then, the prognostic significance of ACAs and complex karyotype were investigated in APL patients. RESULTS: There were 57 cases in the single t (15; 17) group, in which 8 cases died in the first month after induction treatment with early mortality rate of 14%. There were 21 patients in t (15; 17) with ACA group, in which 4 cases died in the first month with early mortality rate of 19%. There were 15 cases in normal chromosome group, in which 5 cases died in the first month with the early mortality rate of 33.3%. There was no statistical difference in the early mortality among 3 groups. All the remaining 76 patients achieved complete hematological remission. These patients were followed up. The median follow-up time was 43.9 months. Among them, only 2 patients in single t (15; 17) group and 1 patient in t (15; 17) with ACA group relapsed. No patient relapsed in normal karyotype group. The relapse rate was 3.5% in single t (15; 17) group and 4.2% in t (15; 17) with ACA group, respectively. There was no statistical difference in the overall survival and disease-free survival rates among 3 groups. Further analysis showed that the patients with complex chromosome karyotypes had lower relapse-free survival rates, but overall survival rates were not significantly different in 3 group. CONCLUSION In general, ACA can not affect the prognosis of patients with acute promyelocytic leukemia in condition of the maintenance treatment based on arsenic trioxide, but the complex chromosomal karyotype may reduce the relapse-free survival rates.
Arsenic Trioxide ; therapeutic use ; Humans ; Karyotype ; Leukemia, Promyelocytic, Acute ; drug therapy ; Prognosis ; Remission Induction ; Retrospective Studies ; Treatment Outcome ; Tretinoin

OBJECTIVE: To explore the treatment of children with high-risk acute promyelocytic leukemia (APL), aiming to improve the prognosis. METHODS: The clinical datas of 24 children with high-risk APL in our hospital from January 2015 to June 2021 were retrospectively analyzed. RESULTS: The main manifestations of 24 children (including 15 males and 9 females) were purpura, gingiva bleeding and nasal hemorrhage, with a median age of 7 years old and a median leukocyte count of 28.98 (10-232)×10⁹/L, including 15 cases with leukocyte count between 10×10⁹/L and 50×10⁹/L, 2 cases between 50×10⁹/L and 100×10⁹/L, and 7 cases >100×10⁹/L. The leukocyte count of 2 cases in 3 children admitted from 2015 to November 2016 was >100×10⁹/L, in which 1 case was first treated with homoharringtonine for cytoreduction, 7 days later treated with all-trans retinoic acid (ATRA) after genetic diagnosis, then died of differentiation syndrome and pulmonary hemorrhage after 3 days. The other one was treated with reduced ATRA+daunorubicin+arsenic trioxide (ATO) for induction, then achieved complete remission. The third one with leukocyte count 12×10⁹/L had cerebral hemorrhage before admission and died on the 7th day of treatment. The remaining 21 children were treated with chemotherapy according to the APL regimen for children in South China, including 14 cases with leukocyte count between 10×10⁹/L and 50×10⁹/L, 2 cases between 50×10⁹/L and 100×10⁹/L, and 5 cases >100×10⁹/L. In the 5 children with leukocyte count >100×10⁹/L, 1 case died of cerebral hemorrhage on the second day of oral ATRA before the addition of anthracyclines, 3 cases died of cerebral hemorrhage after the addition of anthracyclines to chemotherapy on the second day of oral ATRA, and another one developed differentiation syndrome after the addition of mitoxantrone on the second day of oral ATRA, then achieved complete remission after ATRA reduction chemotherapy and survived without disease till now. In the 2 children with leukocyte count between 50×10⁹/L and 100×10⁹/L, 1 case died of cerebral hemorrhage on the second day of oral ATRA before the addition of anthracyclines. All the children were followed up until 1st August, 2021, with a median follow-up time of 40 months, including 7 deaths and 1 recurrence in maintenance therapy who achieved second remission after chemotherapy, 14 cases survived in 3 years and 13 cases survived without event. The 7 dead children had a median time from treatment to death of 5 days, including 1 case with leukocyte count between 10×10⁹/L and 50×10⁹/L, 1 case between 50×10⁹/L and 100×10⁹/L, and 5 cases >100×10⁹/L. CONCLUSION High-risk APL children with leukocyte count >100×10⁹/L have a high mortality rate. Gradual addition of chemotherapy starting at small doses and early addition of ATO may help to improve the prognosis.
Male ; Female ; Humans ; Child ; Leukemia, Promyelocytic, Acute/drug therapy* ; Retrospective Studies ; Arsenic Trioxide/therapeutic use* ; Tretinoin/therapeutic use* ; Remission Induction ; Anthracyclines/therapeutic use* ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use* ; Treatment Outcome

Promyelocytic leukemia (PML) protein, a tumor suppressor, plays an important role in patients with acute promyelocytic leukemia (APL) receiving arsenic trioxide (AsO) therapy. APL is a M3 subtype of acute myeloid leukemia (AML), which is characterized by expression of PML-RARα (P/R) fusion protein, leading to the oncogenesis. AsO is currently used as the first-line drug for patients with APL, and the mechanism may be:AsO directly binds to PML part of P/R protein and induces multimerization of related proteins, which further recruits different functional proteins to reform PML nuclear bodies (PML-NBs), and finally it degraded by SUMOylation and ubiquitination proteasomal pathway. Gene mutations may lead to relapse and drug resistance after AsO treatment. In this review, we discuss the structure and function of PML proteins; the pathogenesis of APL induced by P/R fusion protein; the involvement of PML protein in treatment of APL patient with AsO; and explain how PML protein mutations could cause resistance to AsO therapy.
Antineoplastic Agents ; therapeutic use ; Arsenic Trioxide ; therapeutic use ; Drug Resistance, Neoplasm ; genetics ; Humans ; Leukemia, Promyelocytic, Acute ; drug therapy ; Mutation ; Oncogene Proteins, Fusion ; metabolism ; Promyelocytic Leukemia Protein ; chemistry ; genetics ; metabolism

OBJECTIVE: To investigate the effect of dihydroartemisinin (DHA) combined with arsenic trioxide (ATO) on the viability and apoptosis of acute myeloid leukemia (AML) FLT3-ITD mutant cell line MOLM13 and its mechanism. METHODS: MOLM13 cells were treated with DHA or ATO alone or in combination. The viability of MOLM13 cells was detected by CCK-8 assay, cell proliferation was observed by colony formation assay, cell apoptosis and reactive oxygen species (ROS) level were measured by flow cytometry, and the expression levels of proteins related to apoptosis were detected by Western blot. RESULTS: Compared with the control group, treatment with DHA and ATO alone or in combination could inhibit cell proliferation, activate ROS formation, and finally induce cell apoptosis. DHA in combination with ATO produced a synergistic effect. Western blot analysis showed that DHA combined with ATO could significantly upregulate the level of c-PARP and activate apoptosis via inhibition of Mcl-1 and FLT3-ITD. CONCLUSION DHA combined with ATO induces the apoptosis of FLT3-ITD AML cell line MOLM13 by inhibiting Mcl-1 pathway and activating FLT3-ITD protein degradation.
Apoptosis ; Arsenic Trioxide/therapeutic use* ; Artemisinins/therapeutic use* ; Cell Line, Tumor ; Humans ; Leukemia, Myeloid, Acute/drug therapy* ; Myeloid Cell Leukemia Sequence 1 Protein ; Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use* ; Reactive Oxygen Species/therapeutic use* ; Sincalide/therapeutic use* ; fms-Like Tyrosine Kinase 3