CD7 expression and its prognostic significance in acute myeloid leukemia patients with wild-type or mutant CEBPA / 中华血液学杂志

Objective: To analyze the prognostic value of CD7 expression in newly diagnosed acute myeloid leukemia (AML) patients, and to further explore the correlation between CD7 expression and CEBPA mutation, and to clarify the prognostic value of CD7(+) in AML patients with wild-type (WT) or mutant-type (MT) CEBPA. Methods: The clinical data of 298 newly diagnosed non-M(3) AML patients between January 2010 and December 2016 were analyzed retrospectively. The clinical characteristics and prognosis of CD7(+) and CD7(-) patients were respectively compared in all patients, and in patients with WT and MT CEBPA. The relationship between CD7 expression and CEBPA mutation was determined by chi-square, and the effects of CEBPA mutation on survival and prognosis in CD7(+) group by Kaplan-Meier method. Results: In CD7(+) group, the frequencies of CEBPA mutation were 10.1% (single site) and 33.9% (double site) , significantly higher than those of the CD7(-) group (5.3% and 4.2%) (P=0.000) . Subgroup prognostic analysis showed a lower CR rate (P=0.001) and a higher RR (P=0.023) in CD7(+) group comparing to those of CD7(-) group in AML patients with wild type CEBPA. There were no statistical difference between CD7(+) group and CD7(-) group in overall survival (OS) and disease free survival (P>0.05) , while in the CEBPA mutant group the CD7(+) group has higher OS (P=0.019) and DFS (P=0.010) . Based on the CD7 expression and CEBPA mutation, 298 cases were divided into 3 subgroups, named as CD7(+)-CEBPA MT group, CD7(-) and CD7(+)-CEBPA WT group. The 3-year OS of the 3 groups were 80.2%, 48.0% and 30.6%, respectively (P<0.001) , and the 3-year DFS were 74.1%, 37.4% and 22.2%, respectively (P<0.001) . Conclusion: The CEBPA mutation rate was higher in CD7(+) AML patients then that of CD7(-) patients. CD7 expression has opposite prognostic significance in AML patients carrying the wild-type or mutant-type CEBPA. Based on CD7 expression and CEBPA mutation, a new risk stratification model can be established, which is helpful to guide the clinical individualized treatment for AML patients.

Comparison of the Curative Efficacy of Elderly Patients with High-Risk MDS and MDS-Transformed AML between Decitabine Combined with Low-Dose CEG Regimen and Decitabine Combined with Low-Dose CAG Regimen / 中国实验血液学杂志

OBJECTIVE@#To evaluate the efficacy of decitabine combined with low-dose CEG regimen (DCEG) and decitabine combined with low-dose CAG regimen (DCAG) in the treatment of elderly patients with MDS and MDS-transformed acute myeloid leukemia (AML).@*METHODS@#A prospective study was conducted in 7 medical centers, 45 patients with MDS (≥ 60 years old) and MDS-transformed AML from October 2016 to January 2019 were enrolled, with the median age of 68.5 years old. The risk stratification of patients was poor or very poor, according to IPSS-R score. The treament results of decitabine combined with CEG and decitabine combined with CAG were compared.@*RESULTS@#The comparison of the two regiem showed that the DCEG regimen had advantages on total effective rate (ORR, 86.4% vs 47.8%, respectively), overall survival time (OS) (10.0 months vs 6.0 months, respectively) and progression-free survival time (PFS) (9.0 months vs 3.0 months, respectively). About 50% of MDS patients treated by DCEG regimen achieved PR or CR, with a median OS of 31 months. Multivariate analysis showed that patients with PR or CR after induction therapy and DCEG regimen had longer survival time (31months). The incidence of bone marrow suppression, infection and treatment-related mortality rate were similar between the two groups.@*CONCLUSION@#Decitabine combined with CEG regimen could improve the survival of patients with high-risk MDS and MDS-transformed AML. The conclusion of the reaserch needs to be validated by a larger prospective randomized clinical trial.

Apoptosis of acute myeloid leukemia HL-60 cells induced by CDK inhibitor SNS-032 and its molecular mechanisms / 浙江大学学报·医学版

<p><b>OBJECTIVE</b>To investigate the effects of cycle-dependent kinase (CDK) inhibitor SNS-032 on apoptosis in human acute myeloid leukemia (AML) HL-60 cells and its molecular mechanisms.</p><p><b>METHODS</b>Cultured AML HL-60 cells were treated with various concentrations of SNS-032. Cell apoptosis was determined with flow cytometry;cell viability was measured by MTT assay; the profiles of microRNA expression of HL-60 cells were analyzed by microRNA microarray;the protein expressions of JAK2/STAT3 pathway were detected by Western blotting.</p><p><b>RESULTS</b>Apoptosis of AML HL-60 cells was induced by SNS-032; the rate of apoptosis was (5.9±1.7)%, (12.1±3.1)% and (59.4±3.6)% when HL-60 cells were treated with 0,100 and 200 nmol/L SNS-032. MicroRNA microarray analysis revealed that the levels of miR-30a, miR-183, miR-20b, miR-26b, miR-20a, miR-589, miR-107, miR-181a, miR-106a, miR-17 and miR-378c were down-regulated by SNS-032,whereas the levels of miR-320a and miR-H7* were up-regulated. Western blotting showed that SNS-032 strongly inhibited phosphorylation of STAT3 and protein expression of JAK2,C-MYC and MCL-1.</p><p><b>CONCLUSION</b>CDK inhibitor SNS-032 can induce apoptosis of AML HL-60 cells, which is associated with the inhibition of MCL-1,C-MYC and JAK2/STAT3, and down-regulation of miR-17-92 family.</p>

Itraconazole for secondary prophylaxis of invasive fungal infection in patients undergoing chemotherapy and stem cell transplantation / 中华血液学杂志

<p><b>OBJECTIVE</b>To evaluate the efficacy and safety of itraconazole for secondary prophylaxis of previous proven or probable invasive fungal infection (IFI) in patients undergoing chemotherapy or allogeneic hematopoietic stem cell transplantation (HSCT) in agranulocytosis state.</p><p><b>METHODS</b>A phase IV prospective, open-label, multicenter trial was conducted to evaluate itraconazole (200 mg q12h intravenously d1-2, 200 mg/d) as secondary antifungal prophylaxis in patients (18-65 years old) undergoing chemotherapy or HSCT with previous proven or probable IFI. Itraconazole was started when patients' neutrophils＜1.5 × 10⁹/L, and stopped when chemotherapy patients' neutrophils ＞0.5 × 10⁹/L and stem cell transplant recipients' neutrophils＞1.0 × 10⁹/L. The primary end-point of the study was the incidence of proven, probable or possible IFI.</p><p><b>RESULTS</b>Seventy one patients from November 2008 to September 2010 were enrolled in the trial. The median duration of itraconazole prophylaxis was 14 (4-35) days. No patients died of drug-related toxicity within trial. Five cases occurred IFI during the trial. The cumulative incidence of invasive fungal disease was 7.0%. One patient was withdrawn from the study due to treatment-related adverse events (liver malfunction and severe phlebitis).</p><p><b>CONCLUSION</b>Itraconazole appears to be safe and effective for secondary prophylaxis of systemic fungal infection after chemotherapy and allogeneic HSCT. The observed incidence of 7.0% is considerably lower than the relapse rate reported in historical controls, suggesting that itraconazole is a promising prophylactic agent in this population.</p>

Roles of microvesicles in tumor progress and its clinical application / 浙江大学学报·医学版

Microvesicles transport special proteins, micro RNA and DNA segments, which provides new access to intercellular communication. Tumor-derived membrane microvesicles (TMV) are involved in the tumor progress by transporting tumor-derived proteins, delivering microRNA to surrounding normal cells to alter their phenotype and promoting reverse transcription to interfere gene stability and to create tumor microenvironment. TMV also play crucial roles in tumor angiogenesis and matrix degradation, which facilitates malignant cell metastasis. TMVs are also involved in escaping immunological surveillance by intensifying the function of suppressor T cell and inducing apoptosis of cytotoxic T cells. On the other hand, microvesicles carry tumor antigens and can be used for development of tumor vaccines; some new vaccines such as AEX and DEX are under early clinical trials. Circulating microRNA and DNA segments in body fluid can be a new potential biomarker for cancer diagnosis and prognosis. Purification of microvesicles needs to be further improved, which is important for identification of microvesicles and their subtypes.

Candida tropicalis arthritis in a patient with acute leukemia / 中国实验血液学杂志

Candida arthritis in patient with hematological malignancy is rare. A case of Candida tropicalis arthritis of knee occurred in a patient with acute monocytic leukemia was reported during the recovery phase of post chemotherapy myelosuppression and agranulocytosis. The patient was diagnosed as Candida tropicalis arthritis of knee according to the Candida tropicalis isolated from the synovial fluid. Itraconazole and amphotericin B were intravenously injected for therapy for 4 - 5 weeks based on the susceptibility test in vitro, which showed better efficacy. But the arthritis relapsed at 4 - 6 weeks after the drug withdrawal. The curative effect was found in patient after treatment with fluconazole injection and articular cavity douching with amphotericin B for 8 weeks. In conclusion, although Candida arthritis in patient with hematological malignancy is rare, it still occurred in the patient with hypoimmunity. The treatment emphasis showed be placed on the full dosage and full treatment course of antifungal agent.

Study on unrelated donor allogeneic bone marrow transplantation with Bu-CY2 conditioning regimen for myelodysplastic syndrome / 浙江大学学报·医学版

<p><b>OBJECTIVE</b>To evaluate the efficacy and safety of Bu-CY(2) conditioning regimen on allogeneic bone marrow transplantation (BMT) with unrelated donor for myelodysplastic syndrome.</p><p><b>METHODS</b>Six patients received chemotherapy regimen of busulfan (Bu) and cyclophosphamide (CY) before allogeneic BMT (Bu 4 mg . kg(-1) . d(-1), -7 d - -4 d, CY 60 mg . kg(-1) . d(-1), -3 d - -2 d). Mycophenolate mofetil combined with cyclosporin A and methotrexate was used for prevention of acute graft-versus-host disease after transplantation. Lipo prostaglandin E(1)was used in prophylactic regimen for hepatic veno-occlusive disease.</p><p><b>RESULT</b>Neutrophil count began to be higher than 0.5 x 10(9)/Lat the 18th day after BMT. Platelet count began to be higher than 20 x 10(9)/Lat the 21st day after BMT. Disease-free survival in the six patients was 27 months.</p><p><b>CONCLUSION</b>Bu-CY(2) conditioning regimen on allogeneic bone marrow transplantation with unrelated donor is an effective therapy for patients with myelodysplastic syndrome.</p>

The relationship between expression of the vascular endothelial growth factor and acute leukemia subtype / 中华血液学杂志

<p><b>OBJECTIVE</b>To investigate the relationship between expression of vascular endothelial growth factor (VEGF) and pathogenesis of acute leukemia (AL).</p><p><b>METHODS</b>VEGF mRNA expression was analysed by using semi-quantitative RT-PCR technique. VEGF level of culture supernatant of the bone marrow mononuclear cell (BMMNC) was detected by ELISA. The influence of culture supernatant of the BMMNC on proliferation of human umbilical vein endothelial cell line huECV304 in vitro was determined by MTT assay.</p><p><b>RESULTS</b>The median VEGF/beta-actin expression level of BMMNC in newly diagnosed untreated AL group was higher (0.86) than that in remission group (0.41) and normal control group (0.39) (P < 0.01, both), but was no difference from the relapse group (1.02, P > 0.05). Among the patients with newly diagnosed untreated AL, VEGF/beta-actin level in AML (1.03) was statistically higher than that in ALL (0.61) (P < 0.05). The VEGF level in 72 h culture supernatant of BMMNC was higher in newly diagnosed untreated AL group (91.48 ng/L) than in remission group (31.91 ng/L) and normal control group (28.71 ng/L) (P < 0.01). In ALL group (32.76 ng/L), the VEGF level of 72 h culture supernatant was much lower than that in AML group (173.49 ng/L) (P < 0.01). The proliferation of huECV304 cells after co-cultured with the 72 h culture supernatant of AML BMMNC with addition of anti-VEGF antibody was inhibited notably compared with culture supernatant alone (P < 0.01). However, no such result was found in ALL group (P > 0.05).</p><p><b>CONCLUSION</b>The mRNA expression and secretion of VEGF in AML cells were higher than those in ALL cells. The regulators that participated angiogenesis were different in ALL and AML patients.</p>

A comparison of clinical outcomes between HLA allele matched and 1 - 2 alleles mismatched unrelated allogeneic bone marrow transplantations / 中华血液学杂志

<p><b>OBJECTIVE</b>To compare the clinical outcomes between HLA allele matched (HLA-M) and 1 approximately 2 alleles disparity mismatched (HLA-mis) unrelated allogeneic bone marrow transplantation (URD-BMT).</p><p><b>METHODS</b>Thirty-nine patients received HLA-M and 21 received HLA-mis URD-BMT for the treatment of acute leukemia, chronic myeloid leukemia in chronic phase (CP) and myelodysplastic syndromes (MDS) in our hospital between November 1998 and December 2002. Conditioning regimen was Bu 16 mg/kg plus CTX 120 mg/kg, and mycophenolate mofetil (MMF), CsA and MTX were given to prevent aGVHD.</p><p><b>RESULTS</b>Thirty-eight of the HLA-M group and 18 of the HLA-mis group were engrafted successfully. The median follow-up duration was 11 (2.5 - 52.0) months for HLA-M group and 9 (2 - 46) months for HLA-mis group. The 3-year probabilities of disease-free survival (DFS) for HLA-M and HLA-mis group were (79.2 +/- 7.1)% and (45.8 +/- 15.5)%, respectively (P < 0.05). Grade II - IV aGVHD occurred in 10 (26.3%) patients in HLA-M group and 6 (33.3%) in HLA-mis group, respectively (P > 0.05).</p><p><b>CONCLUSION</b>URD-BMT is an effective modality for the treatment of leukemia and MDS. The outcome after URD-BMT can be optimized by matching the HLA-A, B and DR alleles between the donor and recipient.</p>

Treatment of childhood leukemia with unrelated donor allogeneic bone marrow transplantation / 中华儿科杂志

<p><b>OBJECTIVE</b>Allogeneic bone marrow transplantation has been established as a standard method for the treatment of a range of malignant and non-malignant hematologic diseases in children. Unfortunately, fewer than 30% of patients have a human leukocyte antigen (HLA)-matched sibling. Advances in our understanding of the HLA system and the development of large international donor registries encourage the increasing use of unrelated donors as an alternative source of stem cells. The purpose of this study was to evaluate the clinical efficacy and safety of unrelated donor allogeneic bone marrow transplantation (URD-BMT) for the treatment of childhood leukemia.</p><p><b>METHODS</b>Six patients with leukemia received URD-BMT. Two of them suffered from chronic myeloid leukemia (CML), 3 suffered from acute lymphocytic leukemia (ALL) and 1 suffered from acute promyelocytic leukemia (APL) (CR2). All cases were facilitated by Tzu Chi Marrow Donor Registry (TCTMDR). The high resolution DNA test for classIand II was carried out in HLA typing of all donor-receiver pairs. HLA allele matched in three cases, mismatched with one locus in two cases and with two loci in one case. All patients were prepared with cyclophosphamide (CY) 60 mg/kg/day for 2 days (total dose 120 mg/kg) and busulfan (Bu) 1 mg/kg x 4/day for 4 days (total dose 16 mg/kg). Mycophenolate mofetil (MMF), CsA and MTX were given to prevent acute graft-versus-host-disease (aGVHD). CsA of 3 mg/kg/d was continuously given by i.v. infusion, and then 6mg/kg/d by oral. The blood CsA concentration was 200 - 300 ng/ml. MTX was given at the dosage of 15 mg/m(2) on d 1 and 10 mg/m(2) on d 3, 6,9 or 11. MMF was given at the dosage of 0.25 - 0.5 g/d from day 0 to day 120. Prostaglandin E1 was given to prevent the hepatic veno-occlusive disease (VOD), Ganciclovir was used to prevent CMV infection until the CMV antigenemia became negative.</p><p><b>RESULTS</b>Analysis of DNA short tandem repeats showed total engraftment of donor marrow after transplantation in all cases. The median time when granulocyte exceeded 0.5 x 10(9)/L was 14.5 (13 - 18) days, platelets exceeded 20 x 10(9)/L was 16 (14 - 23) days. The acute GVHD grade II-IV occurred in 2 of 6 (33.3%) patients. There were 3 cases with chronic GVHD and none of them developed with the extensive chronic GVHD. All patients were alive in disease-free situation now with median follow-up 412 (187 - 1338) days.</p><p><b>CONCLUSION</b>URD-BMT is an effective method for the treatment of childhood leukemia.</p>

Treatment of one case of adult chronic myelogenous leukemia by two units of unrelated umbilical cord blood transplantation / 中国实验血液学杂志

To explore the hematopoietic reconstitution and transplantation-related complications of two units of unrelated umbilical cord blood combined transplantation for the treatment of adult hematologic malignancies, one adult patient with chronic myelogenous leukemia received two units of unrelated umbilical cord blood combined transplantation. The conditioning regimen was busulfan and cyclophosphamide (Bu-Cy). GVHD prophylaxis regimen consisted of mycophenolate mofetil (MMF), cyclosporine A (CsA) and methotrexate (MTX). The patient received total nucleated cells 4.63 x 10(7)/kg with CD34+ cells 8.34 x 10(5)/kg. Engraftment was documented by the analysis of short tandem repeat with polymerase chain reaction (STR-PCR). The results showed that the STR-PCR analysis for peripheral blood at day 31, 46 and 71 after transplantation suggested that one of two units of cord blood were completely engrafted. The ANC > 0.5 x 10(9)/L in the patient occurred at day 23, blood platelet counts > 20 x 10(9)/L at day 33 and > 50 x 10(9)/L at day 47. The Philadelphia chromosome and bcr/abl fusion gene of the patient also turned to negative after engraftment. Acute GVHD grade II occurred at day 13 and cured after treatment. It is concluded that umbilical cord blood can be used in adult hematopoietic stem cell transplantation. Two or more units umbilical cord blood combined transplantation might be the way to solve the problem of the low counts of nucleated cells when be used for adult.