The Effects of Decitabine Combined with All-Trans Retinoic Acid on the Number of Immune Cells in Myeloid Neoplasms / 中国实验血液学杂志

OBJECTIVE@#To investigate the effects of decitabine (DEC) combined with all-trans retinoic acid (ATRA) on the number of immune cells, efficacy and adverse reactions in the treatment of myeloid neoplasms patients.@*METHODS@#Eighty-four patients with myeloid tumors, including AML, MDS-EB-1 or MDS-EB-2 treated by the regimen containing decitabine in our hospital from January 2009 to October 2019 were enrolled and retrospectively analyzed, among the patients, 21 patients treated with DEC alone, 24 patients treated with DEC combined with ATRA (DEC/ATRA) and 39 patients treated with DEC combined with G-CSF priming regimen (DEC/priming). The changes of peripheral blood immune cell levels before and after treatment of the patients between the three groups were compared, and the differences in clinical efficacy and adverse reactions of the patients between the three groups were also compared.@*RESULTS@#There was no statistical differences in the number of immune cells among the patients in the three groups before treatment (P>0.05). NK cell levels decreased significantly in the patients in DEC and DEC/ATRA group after treatment (P<0.05); After treatment, the levels of CD8+ and CD3+T cells in the patients treated by DEC /priming regimen significantly increased (P<0.05), while the levels of CD3-HLA-DR+ B cells significantly decreased (P<0.05). The overall response rate (ORR) of the patients in DEC/ATRA group (75%) and DEC/priming group (74.36%) was significantly higher than 42.86% in DEC monotherapy group, and the differences showed statistically significant (P<0.05), while the ORR between the patients in DEC/ATRA and DEC/priming group showed no statistic differences (P>0.05). There were no statistical differences in overall survival (OS) and incidence of bleeding between the patients in the three groups (P>0.05). The incidences of grade 3 to 4 bone marrow suppression and the infection rate of the patients in DEC monotherapy and DEC/ATRA group were significantly lower than that in DEC/priming regimen group after treatment (all P<0.05), however, there was no statistical difference between DEC monotherapy and the DEC/ATRA group.@*CONCLUSION@#The efficacy of DEC/ATRA on myeloid neoplasms is comparable to that of DEC/priming regimen, and the anti-myeloid tumor effect of DEC/ATRA regimen may be related to the regulation of NK cells and T cells.

Comparison of the efficacy and safety between decitabine combined with all-trans retinoic acid or half dose priming regimen in the treatment of elderly patients with myelodysplastic syndromes and acute myeloid leukemia / 医学研究生学报

Objective Decitabine (DAC) combined with the half dose priming regimen (HDPR) is a common treatment of myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) in the elderly. This study was to compare the clinical effect and safety of DAC combined with all-trans retinoic acid (ATRA) versus DAC plus HDPR in the treatment of MDS with excess of blasts (MDS-EB) or AML in elderly patients. Methods We retrospectively analyzed 48 elderly patients (≥60 years) with myeloid neoplasms (AML, MDS-EB-1 or MDS-EB-2) ineligible for standard chemotherapy treated in our hospital from January 2014 to October 2018, 22 by DAC+ATRA (group A) and the other 26 by DAC+HDPR (group B). We compared the overall response rate (ORR), overall survival (OS) and adverse events between the two groups of patients. Results No statistically significant difference was observed between groups A and B in ORR (86.4% vs 76.9%, P = 0.643) or median OS (26.2 vs 24.9 mo, P = 0.920). The median time to response was significantly longer in group A (2 courses) than in B (1 course) (P = 0.006). Compared with group A, group B showed remarkably lower incidence rates of grade-3 to -4 cytopenia (54.5% vs 84.6%, P = 0.029) and infection (45.5% vs 76.9%, P = 0.037), longer duration of neutropenia (P < 0.05), and higher volumes red blood cell infusion and platelet infusion (P < 0.05). There was no statistically significant difference in the incidence rate of bleeding between the two groups (P = 0.643). Conclusion DAC+ATRA and DAC+HDPR have comparable clinical effects on myeloid neoplasms in elderly patients, but the former is safer and better tolerated while the latter can achieve a more rapid response.

All-Trans Retinoic Acid and Decitabine Synergistically Induce Anti-Leukemia Effect on U937 Cell Line and Newly Diagnosed Elder AML Patients / 中国实验血液学杂志

<p><b>OBJECTIVE</b>To investigate the effect of all transretinoicacid(ATRA) combined with decitabine (5-Aza-2'-deoxycytidine;DAC) on DNA methylation and gene expression of p16INK4a (p16) and retinoic acid receptor β (RARβ), and to explore their combined anti neoplastic effect on U937 cells and newly diagnose delder acute myeloid leukemia(AML) patients.</p><p><b>METHODS</b>The expression levels of p16 and RARβ were determined by qRT-PCR and Western blot. Methylation-specific PCR was used to analyze their methylation status. WST-1 and flow cytometry were performed to detect growth inhibition, differentiation, apoptosis and cell cycle of U937 cells respectively.</p><p><b>RESULTS</b>The expression p16 and RARβ was down-regulated by promoter hypermethylation in newly diagnose delder AML patients and U937 cells. Combination treatment of ATRA and DAC induced DNA hypomethylation as well as gene expression of p16 and RARβ, which contributed to the growth inhibition, differentiation, apoptosis and cell cycle arrest of U937 cells. In addition for elder AML patients intolerable to standard chemotherapy, the combination regimen of ATRA and DAC showed antineoplastic activity accompamied by up-regulation of p16 and RARβ expression and decrease of bone marrow blast, moreover the parients showed good tolerence to the reginen.</p><p><b>CONCLUSION</b>The regimen of ATRA combined with DAC as the combination therapeutic strategy for inducing differentiation and demethylation possesses the anti-AML potency, and contributes to optimizing the therapeutic strategy for elder AML patients and promoting the clinical prognosis.</p>

Autologous Peripheral Blood Hematopoietic Stem Cell Transplantation with IBu Precondition Regimen in Treatment for 11 Patients with Low to Intermediate Risk Acute Myeloid Leukemia / 中国实验血液学杂志

<p><b>OBJECTIVE</b>To evaluate safety and efficacy of autologous peripheral blood hematopoietic stem cell transplantation (auto-PBHSCT) with IBu precondition regimen consisting of high-dose idarubicin (IDA) and busulphan (Bu) for treatment of patients with low and intermediate risk acute myeloid leuekmia (AML).</p><p><b>METHODS</b>A total of 11 patients with AML (5 low and 6 intermediate risk patients) treated with auto-PBHSCT with IBu precondition regimen (IDA 20 mg/m, continuous i.v. from d-13 to d-11, Bu 0.8 mg/kg/q6h i.v. for 2h, from d-5 to d-2) from March 2011 to July 2014 were analyzed retrospectively. Adverse effects and transplantation-related mortality (TRM) were evaluated. Kaplan-Meier analysis was performed to calculate the overall survival (OS), disease-free survival (DFS) and cumulative relapse rate (RR). Cox regression was performed for univariate analysis for DFS.</p><p><b>RESULTS</b>Among the 11 patients, 10 patients obtained hematopoietic reconstitution, 1 patient died during transplantation, thus the TRM was 9.1%. The adverse effects were well tolerated. With median follow-up of 31.6 (8.7-52.5) months, 7 patients (63.3%) were alive, including 6 patients (54.5%) in continuous complete remission (CR). Median OS and DFS were not reached. The 3-year OS, DFS and RR were (57.7±16.3)%, (52.5±17.6)% and 47.5%, respectively. Univartiate analysis indicated that the age, sex, interval between diagnosis and transplantation, white blood cell count at diagnosis, risk-grouping (low or intermediate risk), disease status before transplantation (CR1 or CR2), and count of mononuclear cells for infusion all can not influence DFS(P>0.05, respectively).</p><p><b>CONCLUSION</b>The treatment of auto-PBHSCT with IBu precondition regimen for low to intermediate risk AML patients is safe and effective.</p>

MicroRNA-10a expression in FAB different subtype of acute myeloid leukemia and its relationship with drug resistance / 中国实验血液学杂志

<p><b>OBJECTIVE</b>This study was to investigate the expression of miR-10a in the different FAB subtype of acute myeloid leukemia (AML) and its relationship with drug resistance.</p><p><b>METHODS</b>Forty de novo patients with AML, 16 patients with non-malignant hematologic disease and three AML cell lines HL-60, U937 and HL-60/ADR were enrolled in this study, the MiR-10a expression in bone marrow mononuclear cells of above-mentioned patients and 3 AML cell lines was detected by TaqMan RT-PCR. The correlation of miR-10a with clinicopathological factors of AML patients was analyzed.</p><p><b>RESULTS</b>The miR-10a expression level in HL-60 cell line was higher than that in U937 cell line (P = 0.039). And its expression level in de novo AML patients was higher than that in patients with non-malignant hematologic disease (P < 0.01). FAB-AML-M3 patients exhibited higher expression of miR-10a than that in M1, M2 and M4 (P < 0.05); HL-60/ADR cell line showed higher miR-10a expression than that in HL-60 cell line (P < 0.01) . Except M3, the patients without CR (non-CR) after the first cycle of chemotherapy showed a higher level of miR-10a as compared with CR patients (P < 0.01).</p><p><b>CONCLUSION</b>The high expression of miR-10a may be closely related to over-proliferation of promyelocyte and drug resistance of acute myeloid leukemia cells, except M3.</p>

Clinical study on platelet engraftment by thrombopoietin in patients with hematological malignancies after allogeneic hematopoietic stem cell transplantation / 中华血液学杂志

<p><b>OBJECTIVE</b>To evaluate the efficacy and safety of thrombopoietin (TPO) on platelet engraftment in hematological malignancies patients after allogeneic haematopoietic stem cell transplantation (allo-HSCT).</p><p><b>METHODS</b>One hundred and twenty patients were enrolled in a multicenter, open-label, randomized, controlled clinical trial, and were randomized into 4 treatment groups following allo-HSCT. Group A was the control arm without TPO, while group B, C and D were trial arms with received 300 U×kg(-1)×d(-1) of TPO starting from day +1, +4 and +7, respectively. A total of 89 cases were evaluated, of which 22 cases in group A, 23 in group B, 20 in group C and 24 in group D. Efficacy evaluation (the time of platelet engraftment, the number of platelet transfusion) and safety evaluation \[adverse events, routine blood tests, liver and renal function, coagulation function and occurrence of graft-versus-host disease (GVHD)\] were observed.</p><p><b>RESULTS</b>The median platelet engraftment time in experimental groups (groups B, C and D) were on day (13.17 ± 2.89), day (12.15 ± 2.08), day (12.33 ± 1.76), respectively, and that in control group was on day (14.82 ± 5.05). There was statistically significant difference between two groups (P = 0.029), There were no statistically significant difference in the average amount of platelet transfusion, platelet engraftment time, and platelet nadir value among the 3 experimental groups. No significant adverse events were observed in experimental groups.</p><p><b>CONCLUSIONS</b>TPO administration following allo-HSCT for patients with hematologic malignancies appears to shorten platelet engraftment time. TPO given starting from day +7 is effective and safe.</p>

Effect of recipient mouse splenocytes taken orally by donor mouse on GVHD after splenocyte transplantation / 中国实验血液学杂志

This study was aimed to explore whether the GVHD in mice can be ameliorated and the GVL effect in mice can be reserved by transfusion of lymphocytes of donors fed with recipient splenocytes effect. Male (DBA-2) mice (H-2(d)) as donors were fed with BALB/c splenocytes, DBA-2 splenocytes, bovine serum albumin, or regular chow, every other day. Induction of tolerance was assessed by a mixed lymphocyte reaction (MLR). Female (BALB/c) mice (H-2(d)) as recipients received total body irradiation (TBI) of 6.0 Gy ((60)Cogamma-ray) followed by inoculation of 3 x 10(3) P388 mouse leukemia cells on the same day. Subsequently, tail vein injection of 2 x 10(7) splenocytes supplied by DBA-2 was undertaken. Control groups were fed identically without leukemia cell inoculation. The results showed that GVHD was significantly ameliorated and CD4(+)/CD8(+) ratio increased in recipient-mice transplanted with splenocytes of tolerated donors, compared with control animals. There was no significant difference in survival rate between different groups of recipients inoculated with leukemia cell. It is concluded that the peroral recipient-mouse splenocytes can ameliorate GVHD without hampering effect on GVL.

Selective elimination of alloreactive donor lymphocytes by using TBI and cyclophosphamide / 中国实验血液学杂志

This study was aimed to investigate a new method of avoiding graft-vs-host disease (GVHD) through selective elimination of alloreactive donor lymphocytes by using total body irradiation (TBI) and cyclophosphamide (Cy). Female (BALB/c x C57BL/6) F1 mice (H-2(d/b)) as recipients received (60)Co gamma-ray sublethal TBI of 4 Gy on day 0 followed by being inoculated with P388D1 leukemia cell line on day 1, injection of allogeneic splenocytes from C57BL/6 male mice (H-2(b)) was carried out for induction of graft-vs-leukemia (GVL) effect prior to stem cell transplantation (SCT), intraperitoneally injection of cyclophosphamide (Cy) (200 mg/kg) and TBI (9 Gy) was given on day 6. One day later, treated mice were rescued with bone marrow hematopoietic stem cells from (BALB/c x C57BL/6) F1 male mice (H-2(d/b)). The results showed that recipients had no occurrence of leukemia and GVHD through selective elimination of alloreactive donor lymphocytes by Cy and TBI, survived more than 210 days, the complete-donor chimerism occurred on day 21 after transplantation. The ratio of chimerism descended subsequently, but still displayed mixed-chimerism at 90 days. Control mice died of GVHD, leukemia or other death-related-transplantation within 20 to 36 days (P<0.01). It is concluded that to induce GVL effects by MHC mismatched splenocytes given before syngeneic bone marrow transplantation followed by selective elimination of alloreactive donor lymphocytes through TBI and Cy, graft-vs-host disease was thus avoided.