Therapeutic Efficacy of VICP+L-ASP/TKI on Adult Patients with B-ALL / 中国实验血液学杂志

<p><b>OBJECTIVE</b>To evaluate the therapeutic efficacy of VICP+L-ASP/TKI on adult patients with B-ALL and to explore the influence factors.</p><p><b>METHODS</b>Forty-one adult B-ALL patients treated with VICP+L-ASP/TKI from August 2008 to June 2014 were following-up. The complete remission(CR) rate, toxicity, overall survival(OS) and event free survival(EFS) after induction treatment were analyzed, the therapeutic outcome of patients between different risk stratification subgroups was compared, the influence of standardized consolidatory and maintaining treatment as well as allogeneic hematopoietic stem cell transplantation(allo-HSCT) on survival time was analyzed.</p><p><b>RESULTS</b>The early death not occurred in 41 patients with B-ALL including 37 cases with CR; the CR rate of 1 course treatment was 90.2%. The follow-up time lasted to March 17, 2015, the median follow-up time was 25(9-79) months; the 1 year OS rate was 75.3%, the EFS rate was 58.3%. Analysis of risk factors showed that the initial WBC count over 30×10/L, LDH over 250 U/L and minimal residual disease(MRD) over 10after treatment were poor prognostic factors. After remission, the standardized consolidatory treatment or allo-HSCT according to the "2012 China adult ALL diagnosis and treatment expert consensus" could improve long-term survival, 3 years OS rate was 73.8% and 61.5% respectively, 3 years EFS were 63.5% and 65.7% respectively. The main toxic and side effects were hematologic reactions, the hematologic adverse reaction of IV grade was observed in 97.6%(40/41) during induction treatment.</p><p><b>CONCLUSION</b>Induction chemotherapy based on VICP+L-ASP/TKI and standardized consolidatory after remission according to the "2012 China adult acute lymphoblastic leukemia diagnosis and treatment expert consensus" can improve the therapeutic efficacy. The allo-HSCT should be actively performed for B-ALL paients with high risk(elevated initial WBC count and LDH level); at some time, the regularly monitoring MRD and adjusting therapeutic protocol according to monitoring result can promote the prognosis of adult B-ALL patients.</p>

Matrine and CYC116 synergistically inhibit growth and induce apoptosis in multiple myeloma cells / 中国结合医学杂志

<p><b>OBJECTIVE</b>To investigate whether CYC116 can potentiate matrine-dependent growth inhibition and apoptosis in multiple myeloma (MM) cells.</p><p><b>METHODS</b>The dose response relationship of matrine to dexamethasone-resistant and dexamethasone-sensitive MM cells was first established. Myeloma RPMI8226 cells were treated with matrine alone or combined with CYC116 for 24 h. Cell proliferation was measured using an MTT assay and apoptosis induction was evaluated by flow cytometry. Activation of the caspase pathway and expression of apoptosis regulator proteins were detected by Western blotting.</p><p><b>RESULTS</b>Matrine significantly induced growth arrest and apoptosis in both drug-resistant and drug-sensitive MM cells. Treatment with the combination of matrine and CYC116 had a stronger cytotoxic effect on MM cells than did single drug treatments. Enhanced apoptosis observed following the combined treatment of matrine and CYC116 was associated with higher levels of activation of caspase-9, caspase-3, and poly adenosine diphosphate ribose polymerase (PARP) and down-regulation of the anti-apoptotic proteins Bcl-2 and Mcl-1 and the signaling proteins p-Akt and nuclear factor κB (NF-κB).</p><p><b>CONCLUSION</b>CYC116 enhances the growth inhibitory and apoptotic effects of matrine on MM cells.</p>

Apoptosis of multiple myeloid cells induced by polysaccharides extracts from Hedyotis diffusa and its mechanism / 中华血液学杂志

<p><b>OBJECTIVE</b>To explore the proliferation inhibition and apoptosis effects of polysaccharides extracts from Hedyotis diffusa (PEHD) on multiple myeloma (MM) cell line RPMI 8226 cells in vitro, so as to provide experimental theory for the clinical application in the treatment of MM.</p><p><b>METHODS</b>MTT assay was used to examine the effects of PEHD on cell growth. The apoptotic cells were analyzed by flow cytometry with AnnexinⅤ/PI staining. Hoechst staining was used to observe the morphological changes of RPMI 8226 cell apoptosis. The expression levels of caspase-3,-8,-9, PARP, nucleoprotein NF-κB protein and other channel protein were assayed by Western blotting method.</p><p><b>RESULTS</b>The growth of RPMI 8226 cells were suppressed after treatment with PEHD, the highest inhibition rate reached to 92.3%, the results in the doses from 1 to 4 mg/ml showed a dose-and-time-dependent manner. The proportion of apoptotic cells in 1, 2 and 3 mg/ml PEHD treatment groups for 24 h were 22.52%, 62.31% and 69.94%, respectively, and significantly higher than that of control 8.93%. After treated with PEHD, apoptotic body appeared in RPMI 8226 cells nucleus and the number of apoptotic body increased in a dose-dependent manner. With the increasing of PEHD concentration, the expression of caspase-8,-9,-3 and PARP protein increased. The expression of Mcl-1, Bcl-xl, Bid and Bim protein decreased gradually, but the expression of Bax, Bak and Bad protein increased, and the expression of p-AKT protein (60 kDa) and NF-κB obviously decreased.</p><p><b>CONCLUSION</b>PEHD could inhibited the growth of RPMI 8226 cells and displayed a dose-and-time-dependent manner, its mechanism may involve cell apoptosis induction, which was associated with the activation of caspase-8, caspase-9, and caspase-3 protein and the down-regulation of p-AKT and NF-κB protein expression.</p>

Efficacy and safety of the HAA regimen as induction chemotherapy in 236 de novo acute myeloid leukemia / 中华血液学杂志

<p><b>OBJECTIVE</b>To evaluate the efficacy and safety of the HAA regimen (homoharringtonine, cytarabine and aclarubicin) as induction chemotherapy in de novo acute myeloid leukemia (AML).</p><p><b>METHODS</b>The efficacy and safety of 236 de novo AML patients who received the HAA regimen as induction chemotherapy were retrospectively analyzed. The complete remission (CR) rate was assayed. Kaplan-Meier method was used to estimate overall survival (OS) and relapse free survival (RFS), and the differences were compared by Log-rank test.</p><p><b>RESULTS</b>The overall CR rate was 78.0%, and 65.7% of the patients attained CR in the first induction cycle. The early death rate was 4.7%. The median followup time was 41(1-161) months. The estimated 5-year OS and 5-year RFS rates were 44.9% and 45.5%, respectively. The CR rates of patients with favorable, intermediate and unfavorable cytogenetics were 92.9%,78.6%and 41.7%, respectively. The 5-year OS of favorable and intermediate group were 61.1% and 45.1%, respectively. The 5- year RFS of favorable and intermediate group were 49.0% and 45.4%, respectively. The median survival time of unfavorable group was only 5 months. The side effects associated with the HAA regimen were tolerable, in which the most common toxicities were myelosuppression and infection.</p><p><b>CONCLUSION</b>The HAA regimen is associated with a higher rate of CR and longer survival time and its toxicity could be tolerated.</p>

Clinical study of Philadelphia chromosome-positive adult acute lymphoblastic leukemia / 中华血液学杂志

<p><b>OBJECTIVE</b>To study the clinical characteristics, risk factors and therapeutic outcome of Philadelphia chromosome-positive adult acute lymphoblastic leukemia (Ph(+)aALL).</p><p><b>METHODS</b>The clinical data of 117 newly diagnosed adults with Ph(+)ALL in our hospital between January 1995 and December 2009 were retrospectively analyzed. And their prognoses were followed up.</p><p><b>RESULTS</b>There were 117(16.1%) of 727 aALL patients diagnosed as Ph(+)aALL. Among the 117 cases, 64.1% patients were classified as pre-B immunophenotype and 31.3% as common B immunophenotype, 37.5% patients with co-expression of myeloid antigens (CD13 or CD33), and 98.4% patients with positive CD34. The complete remission (CR) rate after 1 or 2 cycles of induction chemotherapy was 62.2% in Ph(+)aALL group versus 82% in Ph(-)aALL group (P = 0.000). The median disease-free survival time of Ph(+) group was 6 months and the median survival time was 9 months. Sole karyotype abnormality subgroup t(9;22) accounted for 53% of all Ph(+)aALL patients and additional karyotype abnormality subgroup, t(9;22) plus other chromosome variation, accounted for 47%. Patients in sole karyotype abnormality subgroup had slightly lower CR rate (59.6% vs 62.5%, P = 0.768), longer median survival time (7 months vs 4 months, P = 0.158), and higher 3-year overall survival rate (27.3% vs 14.4%, P = 0.271). For the myeloid antigen co-expressed patients and the only lymphocytic antigen expressed ones, CR rate was 56.0% and 61.5% (P = 0.750), the median survival time was 5 months and 4 months (P = 0.182), and the 3-year overall survival rate was 16.0% and 15.0% (P = 0.354), respectively. In the imatinib plus combination chemotherapy treatment group, 81.3% patients achieved CR, compared with that of 58.3% in patients treated with only traditional combination chemotherapy (P = 0.083). The median survival time was 9.5 months and 6 months (P = 0.003) in these two subgroup, and 3-year overall survival rate was 52.2% and 10.3% (P = 0.029), respectively. For the patients receiving allo-HSCT after CR and that receiving traditional consolidation chemotherapy, the median survival time was 15 months and 6 months (P = 0.000), and the 3-year overall survival rate was 62.0% and 10.3% (P = 0.000), respectively. For the patients receiving imatinib as consolidation-maintenance treatment and that receiving allo-HSCT, the median survival time was 12 months and 15 months (P = 0.300), and the 3-year overall survival rate was 64.7% and 62% (P = 0.505), respectively.</p><p><b>CONCLUSION</b>Of all adult ALL patients, the Ph(+) subgroup accounted for about 16.1%, which have unfavorable prognosis such as lower CR rate and shorter survival duration under traditional chemotherapy. Neither additional chromosome abnormalities to t(9;22) nor co-expression of myeloid antigen had negative effect on CR rate and survival duration. Addition of imatinib to the therapy was beneficial to improve the CR rate and survival duration. Either receiving imatinib as consolidation-maintenance treatment or allo-HSCT after complete remission can improve long-term survival rate of Ph(+) adult ALL group significantly.</p>

Effects of fludarabine on apoptosis and gene expression profile in multiple myeloma cells / 中华血液学杂志

<p><b>OBJECTIVE</b>To investigate the in vitro effects of fludarabine on apoptosis and gene expression profile in human multiple myeloma (MM) cells.</p><p><b>METHODS</b>Cell growth was measured by a MTT assay. Cells apoptosis was evaluated by flow cytometry. The activation of caspase cascade was determined by Western blot analysis. The expression profile of apoptosis-related genes in human MM cells was detected by cDNA expression array system.</p><p><b>RESULTS</b>The growth of RPMI8226 and KM3 cells was suppressed by fludarabine treatment in a dose and time-dependent manner. After treatment with fludarabine for 24 h, the IC(50) for RPMI8226 cells was 2.13 µg/ml, and 0.36 µg/ml for KM3 cells. Apoptotic cells of RPMI8226 and KM3 increased in a dose- dependent manner after exposure to fludarabine for 24 h. Western blot analysis showed the activation of caspase-3 and PARP in the MM cells treated with fludarabine. The cDNA expression array showed that multiple pathways were involved in the apoptosis induced by fludarabine. Among 97 apoptosis-related genes, 25 genes were differently expressed and 13 expressions were up-regulated in fludarabine treated group, involving in Bcl-2 pro-apoptotic gene, tumor necrosis factor (TNF) and its receptor superfamily gene, and caspase recruitment domain family, 12 genes expression down-regulated, including Bcl-2 antiapoptotic gene, TNF superfamily and its receptor related factor gene and apoptosis inhibitor protein family.</p><p><b>CONCLUSION</b>Fludarabine can significantly inhibit MM cell growth and induce apoptosis in vitro. The multiple pathways may be involved for the apoptosis in MM cells.</p>

HAA regimen as induction chemotherapy for newly diagnosed acute myelogenous leukemia / 中华血液学杂志

<p><b>OBJECTIVE</b>To analyse the outcome of newly diagnosed adult acute myeloid leukemia (AML) patients treated with HAA (homoharringtonine, cytarabine and aclarubicin) regimen and explore the efficacy and safety of this regimen.</p><p><b>METHODS</b>Eighty patients were treated with HAA regimen. The complete remission (CR) rate was observed. Kaplan-Meier method was used to estimate relapse free survival (RFS) rate and the differences were compared with 2-sided log-rank test.</p><p><b>RESULTS</b>Of the 80 patients, 65 (81%) attained CR and the CR rate after the first course of induction was 75%. For the CR patients, the median follow-up was 26 (2 -69) months, and the estimated 3-year overall survival (OS) rate was 51% and the estimated 3-year RFS was 53%. For the AML-M5 and AML-M /M2 patients the CR rate was 74% and 87% and 3 year RFS of CR patients was 75% and 37%, respectively. The CR rate of 100%, 83% and 20% was achieved in patients with favorable, intermediate and unfavorable cytogenetics, respectively. The 3 year OS for favorable and intermediate group was 76% and 50% respectively. The median survival time of unfavorable group was only 6 months.</p><p><b>CONCLUSION</b>HAA regimen is a safe, efficacious, and well-tolerable induction therapy for newly diagnosed AML.</p>

Clinical study of amphotericin B in the treatment of invasive fungal infection in 111 hematological disorder patients with neutrocytopenia / 中华血液学杂志

<p><b>OBJECTIVE</b>To compare the differences in clinical therapeutic effect and safety between amphotericin B and its liposome form in treating invasive fungal infection (IFI) in hematological disorder with neutrocytopenia.</p><p><b>METHODS</b>Of 111 patients with IFI, 82 were treated with amphotericin B and 29 with amphotericin B liposome. The mean cumulative dose of amphotericin B was 617 (60-1895) mg and the mean course was 18 (7-60) d, and those for amphotericin B liposome was 925 (140-3420) mg and 13 (7-50) d, respectively.</p><p><b>RESULTS</b>The total effective rates of amphotericin B and its liposome groups were 69% and 58%, respectively (P>0.05). The adverse effect rates of chill and fever in amphotericin B and its liposome groups were 21% and 10% (P>0.05), hypopotassemia 34% and 14% (P=0.03), hepatic impairment 22% and 17% (P>0.05), and renal impairment 9% and 3%, respectively (P>0.05).</p><p><b>CONCLUSION</b>The therapeutic effect for IFI of amphotericin B and its liposome was similar. The severe adverse reaction of amphotericin B liposome was slightly lower than that of amphotericin B.</p>

Biological features of dendritic cells derived from chronic myeloid leukemia cells in vitro / 浙江大学学报·医学版

<p><b>OBJECTIVE</b>To induce primary chronic myeloid leukemia (CML) cells into dendritic cells (DCs).</p><p><b>METHODS</b>Bone marrow mononuclear cells (MNCs) were isolated from 13 CML patients and peripheral blood MNCs from 5 healthy donors. The isolated MNCs were co-cultured with rhGM-CSF 1,000 U/ml, rhIL- 4,500 U/ml and TNF-alpha 50 U/ml for 10 days. The morphological features were observed by Wright's staining,inverted microscope and electron microscope. CD(80), CD(86), CD(83), CD(1a) and HLA-DR expression were assayed by flow cytometry, cytogenetic analysis was performed by fluorescence in-situ hybridization(FISH). The concentration of IL-12 was measured by ELISA and the function of antigen presenting was tested by mixed lymphocyte reaction (MLR).</p><p><b>RESULT</b>After being cultured with cytokines, the typical dendritic appearance with delicate membrane projections was observed. The CD(80), CD(86), CD(83), CD(1a) and HLA-DR markers and capacity of stimulating allogeneic T cells were upregulated significantly. FISH confirmed that the DCs were generated from leukemic origin and CML DCs could secrete higher level of IL-12 than CML MNCs. There were no differences in morphology and immunophenotype expression between DCs derived from CML and those from normal individuals. However, DCs from CML patients displayed weaker activity than that of normal individuals when tested in MLR.</p><p><b>CONCLUSION</b>CML cells could be induced into leukemia-DCs by co-culture with cytokines.</p>

Cytogenetic and clinical analysis of -7/7q- abnormalities in acute leukemia and myelodysplastic syndrome / 中国实验血液学杂志

The objective was to study the incidence and prognosis significance of -7/7q- abnormalities in acute leukemia and myelodysplastic syndrome. Conventional cytogenetic analysis of R-band was used to test -7/7q- chromosome abnormalities in 410 patients with acute leukemia (AL), in 71 cases of myelodysplastic syndrome (MDS) and in 36 cases of chronic myelogenous leukemia in accelerated phase (CML-AP). The results showed that the incidences of -7/7q- abnormalities in AL, MDS and CML-AP patients were 4.88%, 9.86% and 8.33% respectively. The -7/7q- abnormalities could be found in acute myeloblastic leukemia (AML) and acute lymphocytic leukemia (ALL), incidences of which were 4.70% and 6.25% (P > 0.05) respectively. 9 cases had -7 or 7q- as the sole chromosome abnormalities, 22 cases showed other additional chromosome abnormalities: -X, -5, +8, t(3; 3), t(11;16) and t(2;11). Monosomy -7 and 7q- abnormality clone was found in one patient with MDS-RAEB, and the number of cells with -7 abnormality was greater than that of 7q- abnormality cells. Four patients acquired CR among 7 patients with ALL after chemotherapy, but 2 out of 13 patients with AML achieved CR while 6 out of 7 patients with MDS transformed into AL. No patients with CML-AP achieved CR. In conclusion, -7/7q- is a frequent aberration in hematologic malignancies as well as AML and ALL. The monosomy -7 and 7q-abnormalities were detected in the same patient. The patients with -7/7q- abnormalities show poor prognosis.