homoharringtonine and Leukemia--Myeloid--Acute

In China, the combination of homoharringtonine, cytarabine, and G-CSF (HAG) has been extensively applied for treatment of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS).. We performed a meta-analysis of 2,314 patients (AML, n = 1754; MDS, n = 560) to determine the overall safety and efficacy of this regimen.. The complete response (CR) rate of AML patients (53%) was significantly higher than that of MDS/transformed-AML patients (45%; P = 0.007). The CR rate of patients with newly diagnosed AML (62%) was significantly higher than in patients with relapsed/refractory AML (50%; P = 0.001). There were no significant difference in CR rates between elderly AML patients (54%) and all AML patients (P = 0.721). When compared with non-HAG regimens for AML/MDS induction therapy, the CR rate of patients treated with HAG was significantly higher than in treated with intensive chemotherapy (P = 0.000). No significant differences in CR rates were observed between patients treated with HAG and those treated with CAG (cytarabine, aclarubicin, G-CSF) regimens (P = 0.073). HAG regimen was well tolerated, with early death (ED) in 2%, grade IV myelosurrpression in 52% and infection in 50%. Reports of ED and rates of myelosuppression were reduced as compared with intensive chemotherapy (P = 0.000 and P = 0.000, respectively).. The HAG regimen is an effective and safe regimen for the treatment of AML and MDS, and appears to be more effective and better tolerated than intensive chemotherapy. Future randomized controlled trials and further meta-analyses are strongly needed to confirm its efficacy and safety, especially in comparison with intensive chemotherapy.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Cytarabine; Female; Granulocyte Colony-Stimulating Factor; Harringtonines; Homoharringtonine; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Myelodysplastic Syndromes; Survival Analysis; Treatment Outcome; Young Adult

The present meta-analysis provides an overview on the effectiveness of homoharringtonine (HHT) combination regimens to treat acute myeloid leukemia (AML). Because most of these studies were performed in China, Chinese published clinical studies were used for the analysis. A search for studies from 2006 to 2013 of regimens containing HHT for AML treatment was performed using published studies and Chinese databases in Mandarin. The complete response (CR) and overall response (OR) rates were analyzed, and the fixed effects model and random effects model (REM) were calculated. The heterogeneity of the studies was calculated using Q homogeneity statistics. The meta-analysis included 21 studies (n = 1310, n = 229 pediatric, and n = 216 elderly). HHT was given in combination with cytarabine, daunorubicin, idarubicin, aclacinomycin, mitoxantrone, or granulocyte colony-stimulating factor. Heterogeneity was seen in all analyzed pools, but it was most pronounced in retrospective studies. Overall, the REM showed a CR rate of 65.2%. However, in studies in which HHT-containing regimens were compared to regimens without HHT, the CR rates were 69.1% in randomized trials and 62.8% in retrospective studies. Additionally, in studies with exclusively elderly patients, the CR rate was considerably lower than it was for the studies with mixed age populations (47.5% vs. 65.2%). Higher overall CR rates for HHT-containing regimens in AML treatment in the Chinese studies suggest that HHT could be an active agent in the management of AML. Additional clinical trials are warranted to evaluate the efficacy of HHT in AML treatment.

Topics: Age Factors; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; China; Databases, Factual; Harringtonines; Homoharringtonine; Humans; Leukemia, Myeloid, Acute; Treatment Outcome

Topics: Antineoplastic Combined Chemotherapy Protocols; Clonal Evolution; Cytarabine; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Granulocyte Colony-Stimulating Factor; Harringtonines; Homoharringtonine; Humans; Leukemia, Myeloid, Acute; Treatment Outcome

HHT, one of the alkaloids from a Chinese natural plant, Cephalotaxus, has shown its potential in leukemia treatment. This compound demonstrated strong growth-inhibiting activities in vitro and in animal experiments, and obtained encouraging results in some clonal proliferative disease such as in chronic myeloid leukemia (CML) and in polycythemia vera. Evidences also confirmed HHT as an apoptosis inducer in tumor cell lines and fresh cells from cancer patients. The CR rate reported with HHT-based regimen in acute nonlymphocytic leukemia showed no statistic differences from that with DNR-based regimen, although the case number was limited. While used in clinical trial, the drug often cause noticeably cardiovascular disturbances if be given rapidly by intravenous infusion. Myelosuppression is the common complication in HHT-based chemotherapy. Although with the anti-growth activity in vitro and praisable achievement in acute and chronic myeloid leukemia treatment, the drug shows no beneficial effect in lymphocytic leukemia and solid tumors. The underlying mechanism for the discrepancy of efficacy keeps unknown. This review will present with the preclinical research data including the action mechanism, pharmacokinetics and drug resistance of HHT as well as the result from the clinical trial with HHT in China and the United States.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Cardiovascular Diseases; Cell Proliferation; Cephalotaxus; Clinical Trials as Topic; Harringtonines; Homoharringtonine; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Acute; Polycythemia

Individualized chemotherapy, which is at the forefront of acute myeloid leukemia (AML) treatment, has moderately improved outcomes over the past decade. Monitoring the peripheral blood blast burden during induction by flow cytometry has shown significant value in the evaluation of treatment responses. Our previous study reported the day 5 peripheral blast clearance rate (D5-PBCR) as an indicator of early treatment response, and D5-PBCR (+) patients showed poor outcomes. We performed the present phase 2 trial of early intervention in D5-PBCR (+) patients with homoharringtonine (HHT) introduced in the traditional induction regimen with anthracycline and cytarabine. The primary endpoint was complete remission (CR). This study enrolled 151 patients, 65 patients were D5-PBCR (+) and 55 patients completed induction with HHT addition. The overall CR rate after one course of induction was 84.4%, with 87.5% and 80.0% for the D5-PBCR (-) and D5-PBCR (+) groups, respectively. The incidence of grade 3/4 adverse events was comparable between the two groups. At the median follow-up of 53.1 months, median overall survival (OS) was not reached in the entire cohort, and median event-free survival (EFS) was 42.2 months. Neither the OS nor EFS showed significant differences between the D5-PBCR (-) and D5-PBCR (+) groups. Compared to historical data, significant improvements in both OS (p = .020) and EFS (p = .020) were observed in the D5-PBCR (+) group. In conclusion, optimization of induction chemotherapy with idarubicin and cytarabine according to D5-PBCR is feasible in patients with newly diagnosed AML. The addition of HHT demonstrated a good efficacy and safety profile.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Female; Homoharringtonine; Humans; Idarubicin; Induction Chemotherapy; Leukemia, Myeloid, Acute; Male; Middle Aged; Treatment Outcome

Topics: Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; CASP8 and FADD-Like Apoptosis Regulating Protein; Cyclophosphamide; Cytarabine; Daunorubicin; Down-Regulation; Drug Eruptions; Hidradenitis; Homoharringtonine; Humans; Incidence; Leukemia, Myeloid, Acute; Mercaptopurine; Myeloid Cell Leukemia Sequence 1 Protein; Neoplasm Proteins; Neutrophils; Protein Kinase Inhibitors; Sweat Glands

The present study aimed to investigate the efficacy and severity of adverse effects of HCAG and CAG re-induction chemotherapy in elderly low- and intermediate-risk group patients diagnosed with acute myeloid leukemia (AML) following induction failure.. A total of 94 AML patients were enrolled in the study, of whom 46 were treated with HCAG chemotherapy, while 48 were treated with CAG chemotherapy.. The complete remission (CR) was 39.6% in the patients with HCAG, while the CR was 33.3% in the CAG group. The overall remission (ORR) was 63.0% and 43.5% in patients of the HCAG and CAG groups, respectively (P = 0.038). The median survival time of progression free survival (PFS) was 8.0 (95% CI 3.843-10.157) months in the HCAG group and 7.0 (95% CI 2.682-13.318) months in the CAG group (P = 0.032). A total of 31 patients in the HCAG group suffered from grade 4 hematological toxicity, whereas 29 patients were treated with CAG (P = 0.622). A total of 27 (58.7%) cases indicated apparent pulmonary infection in the HCAG group, while 25 (52.1%) were noted with this complication in the CAG group (P = 0.519). Oral cavity toxicity was evident for 13 (28.3%) and 11 (23.0%) cases in the HCAG and CAG groups, respectively (P = 0.216).. The HCAG regimen was more effective than the CAG regimen in elderly low- and intermediate-risk group patients diagnosed with acute myeloid leukemia although the HCAG regimen exhibited similar toxicity with that of the CAG group.

Topics: Aclarubicin; Aged; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Drug Administration Schedule; Female; Granulocyte Colony-Stimulating Factor; Homoharringtonine; Humans; Induction Chemotherapy; Leukemia, Myeloid, Acute; Male; Middle Aged; Progression-Free Survival; Remission Induction; Retreatment; Retrospective Studies; Risk Factors; Salvage Therapy; Single-Blind Method; Time Factors; Treatment Failure

Omacetaxine mepesuccinate (OME) has antileukemic effects against acute myeloid leukemia (AML) carrying an internal tandem duplication of Fms-like tyrosine kinase 3 (FLT3-ITD). A phase 2 clinical trial was conducted to evaluate a combination treatment of sorafenib and omacetaxine mepesuccinate (SOME).. Relapsed or refractory (R/R) or newly diagnosed patients were treated with sorafenib (200-400 mg twice daily) and OME (2 mg daily) for 7 (first course) or 5 days (second course onward) every 21 days until disease progression or allogeneic hematopoietic stem cell transplantation (HSCT). The primary endpoint was composite complete remission, which was defined as complete remission (CR) plus complete remission with incomplete hematologic recovery (CRi). Secondary endpoints were leukemia-free survival (LFS) and overall survival (OS).. Thirty-nine R/R patients and 5 newly diagnosed patients were recruited. Among the R/R patients, 28 achieved CR or CRi. Two patients showed partial remission, and 9 patients did not respond. Among the 5 newly diagnosed patients, 4 achieved CR, and 1 achieved CRi. The median LFS and OS were 5.6 and 10.9 months, respectively. Prior Fms-like tyrosine kinase 3 (FLT3) inhibitor exposure (P = .007), 2 or more inductions (P = .001), and coexisting IDH2 (P = .008) and RUNX1 mutations (P = .003) were associated with lower CR/CRi rates. HSCT consolidation and deep molecular responses (defined as an FLT3-ITD variant allelic frequency [VAF] ≤ 0.1% or a nucleophosmin 1 [NPM1] mutant VAF ≤ 0.01%) were associated with better OS and LFS. Prior FLT3 inhibitor exposure and 2 or more inductions were associated with inferior LFS.. SOME was safe and effective for R/R and newly diagnosed FLT3-ITD AML.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Disease Progression; Disease-Free Survival; Drug Administration Schedule; Drug Resistance, Neoplasm; Drug Synergism; Exons; Female; fms-Like Tyrosine Kinase 3; Gene Duplication; Hematopoietic Stem Cell Transplantation; Homoharringtonine; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Neoplasm Recurrence, Local; Nucleophosmin; Remission Induction; Sorafenib; Transplantation, Homologous; Young Adult

Homoharringtonine (HHT), a plant alkaloid from Cephalotaxus harringtonia, exhibits a unique anticancer mechanism and has been widely used in China to treat patients with acute myeloid leukemia (AML) since the 1970s. Trial SCMC-AML-2009 presented herein was a randomized clinical study designed based on our previous findings that pediatric AML patients younger than two years old may benefit from HHT-containing chemotherapy regimens. Patients randomized to arm A were treated with a standard chemotherapy regimen comprising mainly of anthracyclines and cytarabine (Ara-C), whereas patients in arm B were treated with HHT-containing regimens in which anthracyclines in all but the initial induction therapy were replaced by HHT. From February 2009 to November 2015, 59 patients less than 2 years old with de novo AML (other than acute promyelocytic leukemia) were recruited. A total of 42 patients achieved a morphologic complete remission (CR) after the first course, with similar rates in both arms (70.6% vs.72.0%). At the end of the follow-up period, 40 patients remained in CR and 5 patients underwent hematopoietic stem cell transplantation in CR, which could not be considered as events but censors. The 5-year event-free survival (EFS) was 60.2%±9.6% for arm A and 88.0%±6.5% for arm B (P= 0.024). Patients in arm B experienced shorter durations of leukopenia, neutropenia, and thrombocytopenia and had a lower risk of infection during consolidation chemotherapy with high-dosage Ara-C. Consequently, the homoharringtonine-based regimen achieved excellent EFS and alleviated hematologic toxicity for children aged younger than 2 years with de novo AML compared with the anthracycline-based regimen.

Topics: Anthracyclines; China; Cytarabine; Disease-Free Survival; Female; Hematopoietic Stem Cell Transplantation; Homoharringtonine; Humans; Infant; Leukemia, Myeloid, Acute; Male; Neoadjuvant Therapy; Remission Induction

The aim of the present study was to investigate the efficacy and adverse effects of HCAG and FLAG re-induction chemotherapy in acute myeloid leukemia (AML) patients of low- and intermediate-risk groups following induction failure.. A total of 98 AML patients were enrolled. Among these subjects, 47 patients were treated with HCAG chemotherapy, while 51 patients were treated with FLAG chemotherapy.. The complete remission (CR) and overall remission (OFF) were 24% and 38%, respectively in patients with HCAG induction chemotherapy, while the corresponding percentages were 28% and 42% in subject receiving FLAG chemotherapy. The median survival time of progress-free survival (PFS) was 29.8 (95% CI 23.749-35.851) months in the HCAG group and 30.8 (95% CI 21.728-39.872) months in the FLAG group (P = 0.620). A total of 42 patients in the HCAG group suffered from grade 4 hematological toxicity, while this adverse reaction was noted for all patients who were treated with FLAG chemotherapy (P = 0.023). A total of 19 cases indicated apparent nonhematological toxicity in the HCAG group, while only 40 (78.4%) were noted with these adverse reactions in the FLAG group (P = 0.000).. The HCAG regimen exhibited a similar effect compared with the FLAG regimen in low- and intermediate-risk groups, although the HCAG regimen significantly decreased the toxicity compared with that noted in the FLAG regimen group.

Topics: Aclarubicin; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Drug Administration Schedule; Female; Granulocyte Colony-Stimulating Factor; Homoharringtonine; Humans; Induction Chemotherapy; Leukemia, Myeloid, Acute; Male; Middle Aged; Progression-Free Survival; Prospective Studies; Risk; Single-Blind Method; Treatment Failure; Vidarabine

An in vitro drug-screening platform on patient samples was developed and validated to design personalized treatment for relapsed/refractory acute myeloid leukemia (AML). Unbiased clustering and correlation showed that homoharringtonine (HHT), also known as omacetaxine mepesuccinate, exhibited preferential antileukemia effect against AML carrying internal tandem duplication of fms-like tyrosine kinase 3 (FLT3-ITD). It worked synergistically with FLT3 inhibitors to suppress leukemia growth in vitro and in xenograft mouse models. Mechanistically, the effect was mediated by protein synthesis inhibition and reduction of short-lived proteins, including total and phosphorylated forms of FLT3 and its downstream signaling proteins. A phase 2 clinical trial of sorafenib and HHT combination treatment in FLT3-ITD AML patients resulted in complete remission (true or with insufficient hematological recovery) in 20 of 24 patients (83.3%), reduction of ITD allelic burden, and median leukemia-free and overall survivals of 12 and 33 weeks. The regimen has successfully bridged five patients to allogeneic hematopoietic stem cell transplantation and was well tolerated in patients unfit for conventional chemotherapy, including elderly and heavily pretreated patients. This study validated the principle and clinical relevance of in vitro drug testing and identified an improved treatment for FLT3-ITD AML. The results provided the foundation for phase 2/3 clinical trials to ascertain the clinical efficacy of FLT3 inhibitors and HHT in combination.

Topics: Adult; Aged; Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Cell Culture Techniques; Cell Line, Tumor; Cluster Analysis; Drug Evaluation, Preclinical; Drug Synergism; Female; fms-Like Tyrosine Kinase 3; Gene Duplication; Harringtonines; Homoharringtonine; Humans; Leukemia, Myeloid, Acute; Male; Mice; Middle Aged; Models, Biological; Niacinamide; Phenylurea Compounds; Protein Biosynthesis; Remission Induction; Sorafenib; Treatment Outcome; Young Adult

To assess the efficacy and toxicity of HAA regimen (Homoharringtonine 4 mg/m(2)/day, days 1-3; cytarabine 150 mg/m(2)/day, days 1-7; aclarubicin 12 mg/m(2)/day, days 1-7) as a salvage therapy in the treatment of refractory and/or relapsed acute myeloid leukemia (AML), 46 patients with refractory and/or relapsed AML, median age 37 (16-65) years, participated in this clinical study. The median follow-up was 41 (10-86) months. Eighty percent of patients achieved complete remission (CR), and the first single course of re-induction HAA regimen resulted in CR rate of 76.1 %. The study protocol allowed two courses of induction. The CR rates of patients with favorable, intermediate and unfavorable cytogenetics were 90 %, 88.9 %, and 37.5 %, respectively. For all patients, the estimated 3-year overall survival (OS) rate was 42 %, and the estimated relapse free survival (RFS) at 3 years for the 36 CR cases was 49 %. The toxicities associated with HAA regimen were acceptable. HAA is a good choice in cases with refractory/relapsing AML for salvage chemotherapy, preferably with a high-efficacy and low-toxicity profile.

Topics: Aclarubicin; Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Chemical and Drug Induced Liver Injury; Combined Modality Therapy; Cytarabine; Disease-Free Survival; Drug Resistance, Neoplasm; Female; Follow-Up Studies; Harringtonines; Heart Diseases; Homoharringtonine; Humans; Kaplan-Meier Estimate; Kidney Diseases; Leukemia, Myeloid, Acute; Leukemia, Myelomonocytic, Acute; Male; Middle Aged; Recurrence; Remission Induction; Salvage Therapy; Stem Cell Transplantation; Young Adult

Homoharringtonine-based induction regimens have been widely used in China for patients with acute myeloid leukaemia. However, their efficacy has not been tested in a multicentre randomised controlled trial in a large population. We assessed the efficacy and safety of homoharringtonine-based induction treatment for management of newly diagnosed acute myeloid leukaemia.. This open-label, randomised, controlled, phase 3 study was done in 17 institutions in China between September, 2007, and July, 2011. Untreated patients aged 14-59 years with acute myeloid leukaemia were randomly assigned (by a computer-generated allocation schedule without stratification) to receive one of three induction regimens in a 1:1:1 ratio: homoharringtonine 2 mg/m(2) per day on days 1-7, cytarabine 100 mg/m(2) per day on days 1-7, and aclarubicin 20 mg/day on days 1-7 (HAA); homoharringtonine 2 mg/m(2) per day on days 1-7, cytarabine 100 mg/m(2) per day on days 1-7, and daunorubicin 40 mg/m(2) per day on days 1-3 (HAD); or daunorubicin 40-45 mg/m(2) per day on days 1-3 and cytarabine 100 mg/m(2) per day on days 1-7 (DA). Patients in complete remission were offered two cycles of intermediate-dose cytarabine (2 g/m(2) every 12 h on days 1-3). The primary endpoints were the proportion of patients who achieved complete remission after two cycles of induction treatment and event-free survival in the intention-to-treat population. The trial is registered in the Chinese Clinical Trial Register, number ChiCTR-TRC-06000054.. We enrolled 620 patients, of whom 609 were included in the intention-to-treat analysis. 150 of 206 patients (73%) in the HAA group achieved complete remission versus 125 of 205 (61%) in the DA group (p=0.0108); 3-year event-free survival was 35.4% (95% CI 28.6-42.2) versus 23.1% (95% CI 17.4-29.3; p=0.0023). 133 of 198 patients (67%) in the HAD group had complete remission (vs DA, p=0·20) and 3-year event-free survival was 32.7% (95% CI 26.1-39.5; vs DA, p=0.08). Adverse events were much the same in all groups, except that more patients in the HAA (12 of 206 [5.8%]) and HAD (13 of 198 [6.6%]) groups died within 30 days than in the DA group (two of 205 [1%]; p=0.0067 vs HAA; p=0.0030 vs HAD).. A regimen of homoharringtonine, cytarabine, and aclarubicin is a treatment option for young, newly diagnosed patients with acute myeloid leukaemia.. Chinese National High Tech Programme, Key Special Research Foundation of the Ministry of Science and Technology of China, National Nature Science Foundation of China, National Clinical Key Specialty Construction Project.

Topics: Adolescent; Adult; Antineoplastic Agents, Phytogenic; Female; Follow-Up Studies; Harringtonines; Homoharringtonine; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Neoplasm Staging; Prognosis; Remission Induction; Survival Rate; Young Adult

The purpose of the study was to compare the antitumor efficacy and safety profile of high-dose homoharringtonine as induction and post-induction therapy compared to either standard-dose homoharringtonine or daunorubicin in elderly patients with newly diagnosed acute myeloid leukemia. A total of 254 patients, age range 60-77 years received induction and post-induction therapy containing daunorubicin, standard-dose homoharringtonine, or high-dose homoharringtonine. After one course of induction therapy, the overall complete remission rate was similar between treatment arms (58.7%, P = .92). Among 161 patients with acute myeloid leukemia (non-M5 subtype), estimated median overall survival was 39, 29, and 37 months, respectively, in the daunorubicin, standard-dose homoharringtonine, and high-dose homoharringtonine treatment groups (P = .53). In the 93 patients with acute myeloid leukemia-M5 subtype, there was a significant difference in estimated median overall survival: 24, 24, and 52 months, respectively, in the daunorubicin, standard-dose homoharringtonine, and high-dose homoharringtonine treatment groups (P = .003). There was no significant difference in drug-related adverse events between treatment arms. High-dose homoharringtonine does not clearly increase the complete remission rate of elderly patients with acute myeloid leukemia. However, in the subset of elderly patients with acute monocytic leukemia, high-dose homoharringtonine as a first-line regimen prolonged overall survival with minimal toxicity.

Topics: Aged; Antineoplastic Agents; China; Daunorubicin; Female; Harringtonines; Homoharringtonine; Humans; Induction Chemotherapy; Kaplan-Meier Estimate; Leukemia, Myeloid, Acute; Male; Middle Aged; Proportional Hazards Models

The purpose of this study was to assess the efficacy and toxicity of HAI regimen [(homoharringtonine 2.5 mg/(m(2)×d), days 1 - 7; cytarabine 150 mg/(m(2)×d), days 1 - 7; idarubicin 9 mg/(m(2)×d), days 1 - 7)] for induction treatment of newly diagnosed acute myeloid leukemia (AML) (except acute promyelocytic leukemia). 31 patients with newly diagnosed AML, aged 39 (14 - 58) years, were enrolled in this clinical study. The complete remission (CR) rate, especially after one course, the overall survival (OS) rate and relapse free survival (RFS) rate were estimated. The outcomes were compared between different prognostic groups according to World Health Organization (WHO) classification, genetics and initial WBC count. Safety was evaluated using standard WHO criteria. The results showed that 26 patients (84%) achieved CR after 1 course of induction. The CR rate for the patients with favorable, intermediate and unfavorable cytogenetics was 90%, 88% and 60% respectively. All 7 patients with a high initial WBC count (≥ 100×10(9)/L) obtained CR, while 19 out of 24 without a high initial WBC count obtained CR. With a median follow-up of 15(range 2-56) months, the estimated 3-year OS rate for all patients and the patients with CR was 44% and 52% respectively. The 3-year RFS rate was 51%. The patients receiving induction chemotherapy died of the chemotherapy. Profound myelosuppression was seen in all patients after the HAI induction with the median duration of neutropenia (ANC < 0.2×10(9)/L) of 16 (6 - 24) days. As the most common toxicity, severe infections (grade III-IV) involved in all the patients and the duration of febris was 6 (1 - 36) days. The incidence of septemia and invasive fungus infection were 19.4% and 45.2% respectively. The incidence of non-infection fever, increased glutamic-pyruvic transaminase (GPT), diarrhea, increased bilirubin and oral cavity mucositis were 6.5%, 6.5%, 3.2%, 3.2%, 3.2% respectively, as the more frequent severe non-hematological toxicities. It is concluded that HAI regimen is a high efficient induction schedule for the newly diagnosed AML, and archive the higher CR rate after one course than DNR/Ara-C standard induction regimen. Side effects are acceptable, except severe infection.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Female; Harringtonines; Homoharringtonine; Humans; Idarubicin; Induction Chemotherapy; Leukemia, Myeloid, Acute; Male; Middle Aged; Young Adult

To evaluate the effectiveness and toxicity of the regimen combined homoharringtonine, low-dose cytarabine with G-CSF or GM-CSF (HAG regimen) in treating patients with relapsed or refractory AML, geriatric AML and advanced myelodysplastic syndromes (MDS).. Forty patients with AML or advanced MDS were treated with HAG regimen for remission induction and consolidation therapy. All of them were followed up till April 2006. Results 20 of them (50%) achieved complete remission (CR), including 46.2% patients with relapsed or refractory AML, 60% elderly patients with primary AML who were either untreated or treated with only one course of induction therapy previously, and 66.7% patients with MDS-RAEB. After a follow-up of 6- 47 (median 23) months from the date of remission, the median times of relapse-free survival and overall survival were (7.0 +/- 1.1) and (28 +/- 12.3) months, respectively. Myelosuppression was the most significant toxicity. The incidences of infection and hemorrhage which exceed grade II were 43.8% and 37.5%, respectively. Non-hematologic adverse effects were minimal.. The HAG regimen presented effective and well-tolerated. It seems promising for the treatment of relapsed or refractory AML, geriatric AML and advanced MDS.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Female; Follow-Up Studies; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Harringtonines; Homoharringtonine; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Myelodysplastic Syndromes; Neoplasm Recurrence, Local; Young Adult

This study was aimed to investigate the efficacy of moderate intensity regimen, CHG (homoharringtonine, cytarabine and granulocyte colony-stimulating factor (G-CSF)) on the patients with high-risk MDS or MDS-transformed acute myeloid leukemia. 30 newly diagnosed adult patients with high-risk MDS or MDS-transformed AML were enrolled in this clinical trial to evaluate the efficacy of sequential low-dose homoharringtonine/cytarabine chemotherapy combined with G-CSF priming. Homoharringtonine and Ara-C were injected intravenously at doses of 1 mg and 25 mg daily for 14 consecutive days respectively, G-CSF was injected subcutaneously once daily at a dose of 300 microg on 12 hours prior to chemotherapy and continued given until the end of chemotherapy or when the peripheral WBC count reached > 20 x 10(9)/L. This regimen was given only for one course, and followed by conventional chemotherapy as maintenance or consolidation therapy when CR achieved. 33 patients with high- risk MDS and MDS-transformed AML were injected aclarubicin/Ara-C intravenously at doses of 10 mg and 25 mg for 8 and 14 consecutive days respectively, G-CSF was used at the same dose and the same way as the CHG regimen. 33 patients with high-risk MDS and MDS-transformed AML were treated with HHT/Ara-C intravenously at doses of 2 - 3 mg and 100 - 150 mg daily for 7 consecutive days respectively, G-CSF was injected when WBC count was below 4 x 10(9)/L, and it was stopped to be used when WBC count was > 4 x 10(9)/L. The results showed that (1) 14 patients achieved complete remission (CR) (46.67 %) and 7 patients achieved partial remission (PR) (23.33 %) with one course of CHG regimen, total effective rate was 70%; 14 patient achieved CR (42.4%) and 9 patients achieved PR (27.3%) with one course of CAG regimen, total effective rate was 69.7%; 7 patient achieved CR (33.3%) and 3 patients achieved PR (9.1%) with one course of HA regimen, total effective rate was 42.4%. There was no statistical difference between the effective rate of CHG and CAG, but difference was significant between CHG and HA. (2) Agranulocytosis (neutrophil < 0.5 x 10(9)/L) occurred in 12 cases (40%) of CHG-treated patients with a mean 8 days of agranulocytic period, so the infectious complications were less serious and tolerable without treatment-related death. (3) Among 14 out of 30 patients with CR, 9 relapsed, the mean duration from CR to replace was 8.2 months. All relapsed patients reusing CHG regimen did not achieved CR ag

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Female; Granulocyte Colony-Stimulating Factor; Harringtonines; Homoharringtonine; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Myelodysplastic Syndromes; Young Adult

A total of 32 patients (25 with advanced MDS and 7 with t-AML) were enrolled in this study to evaluate the efficacy and toxicity of the low-dose cytarabine and homoharringtonine in combination with granulocyte colony-stimulating factor (G-CSF) (CHG protocol) in patients with advanced myelodysplastic syndromes (MDS) or MDS-transformed acute myeloid leukemia (t-AML). All the patients were administered the CHG regimen comprising low-dose cytarabine (25 mg/day, intravenous continuous infusion, days 1-14), homoharringtonine (1 mg/day, intravenous continuous infusion, days 1-14), and G-CSF (300 microg/day, subcutaneous injection, days 0-14, interrupted when the peripheral white blood cell count reached >20 x 10(9)/L). The overall response rate was 71.9% after the administration of one course of the CHG regimen. Of the 32 patients, 15 (46.9%) achieved complete remission (CR) and 8 (25%) achieved partial remission (PR). This regimen was followed by a post-remission therapy that included conventional chemotherapy, when CR was achieved. Of the patients with CR who just received post-remission regimens as homoharringtonine and cytarabine (HA) and daunorubicin and cytarabine (DA) 6 relapsed rapidly and just had a mean 6.1 months of CR. Otherwise, the other 8 out of 14 patients with CR alternatively received subsequent chemotherapy, which combined mitoxantrone, idarubicin, pirarubicin, or aclarubicin with cytarabine. The mean CR duration of the 8 patients had reached 10.6 months, and 5 of the 8 still kept a continuous CR. The median overall survival (OS) was 18.2 months. There were no statistically significant differences for CR, PR, and OS when the patients were grouped by age, blasts in bone marrow, and karyotypes, respectively. No treatment-related deaths were observed. Myelosuppression was mild to moderate, and no severe non-hematological toxicity was observed. Thus, a CHG priming regimen as an induction therapy was well tolerated and effective in patients with advanced MDS or t-AML. Stronger and alternative subsequent chemotherapy is necessary for patients with CR to maintain longer CR and better OS.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cell Transformation, Neoplastic; Cytarabine; Disease Progression; Dose-Response Relationship, Drug; Female; Granulocyte Colony-Stimulating Factor; Harringtonines; Homoharringtonine; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Myelodysplastic Syndromes; Neoadjuvant Therapy; Treatment Outcome; Young Adult

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; China; Cytarabine; Disease-Free Survival; Etoposide; Female; Harringtonines; Homoharringtonine; Humans; Leukemia, Myeloid, Acute; Male; Neoplasm Recurrence, Local; Survival Analysis; Treatment Outcome

Homoharringtonine (HHT) is a plant alkaloid that is derived from a Chinese evergreen tree. Its mechanism of action is thought to be by inhibition of protein, DNA, and RNA synthesis by inhibition of chain initiation. The treatment of acute myelogenous leukemia (AML) in children, has been hampered by few new effective agents developed in the past 30 years. Significant numbers of children still die of this disease. The purpose of this study is to evaluate the efficacy and toxicity of HHT for the therapy of refractory AML in children.. Patients entered the study and were treated with HHT 7mg/m(2)/day for 10 days. The cycles could be repeated every 21 days depending on recovery from myelosuppression.. Thirty-seven patients entered the study, with twenty-eight evaluable for response. Complete response was obtained in four and a partial response in one (response rate 5/28 = 18%). Significant toxicities included prolonged severe myelosuppression in all responsive patients and neuropathogenic pain in two patients. The median duration of response was 62 days with a range of 28-126 days.. HHT has activity against chemotherapy resistant AML in children, with tolerable toxicity. This agent warrants further clinical evaluation in combination with other agents or perhaps biologic response modifiers which will hopefully lead to useful therapeutic options. Med Pediatr Oncol 2001;37:103-107.

Topics: Adolescent; Antineoplastic Agents, Phytogenic; Child; Child, Preschool; Disease Progression; Drug Resistance, Neoplasm; Female; Harringtonines; Homoharringtonine; Humans; Infant; Infusions, Intravenous; Leukemia, Myeloid, Acute; Male; Neutropenia; Thrombocytopenia; Treatment Outcome

Current anti-leukemic chemotherapy in patients with myelodysplastic syndromes (MDS) and MDS evolving to acute myeloid leukemia (AML) is associated with low response rates and high treatment-related toxicity. Homoharringtonine (HHT) is a novel cephalotaxime alkaloid with reported efficacy in relapsed and de novo AML and more recently, chronic myeloid leukemia. Although its mechanism(s) of action is not completely understood, in vitro studies have demonstrated both cytotoxic and differentiating activity in leukemic cells, as well as intra-cellular changes suggestive of apoptotic cell death. In a phase II trial, HHT was administered at a dose od 5 mg/m2 by 24-h continuous infusion daily for 9 days to patients with MDS and MDS evolving to AML (MDS/AML). Twenty-eight patients (MDS 16, MDS/AML 12) with a median age of 67 years (range 23-83) were entered. A complete remission was achieved in seven patients, a partial remission was achieved in one patient for an overall response rate of 28% (8/28). There were four of 13 responders in MDS/AML patients and four of 15 in patients with MDS. The median duration of complete response was 7 months (range 2-10). Significant myelosuppression was universal and resulted in a high incidence of induction deaths (13/28) due to neutropenic-related infections. Extramedullary toxicity was mild and consisted of hypo-tension, fluid retention, hypoglycemia, diarrhea, nausea and vomiting. HHT given in this dose and schedule demonstrated limited activity in MDS and MDS/AML and was associated with prolonged pancytopenia and marrow hypoplasia in many patients. Administration of HHT at a lower dose or in combination with hematopoietic growth factors may lead to better results, but treatment with HHT as single agent at this dose and schedule is not currently recommended for these patients.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Phytogenic; Drug Administration Schedule; Female; Harringtonines; Homoharringtonine; Humans; Infusions, Intravenous; Leukemia, Myeloid, Acute; Male; Middle Aged; Myelodysplastic Syndromes; Neutropenia; Remission Induction

Homoharringtonine (HHT) is a cephalotaxine alkaloid with reported efficacy in acute myelogenous leukemia (AML). In a phase II trial, we evaluated HHT 5 mg/m2 by continuous infusion daily for 9 days in patients with relapsed or refractory acute leukemia and blastic phase of chronic myelogenous leukemia (BLCML). Sixty-six patients were entered. There were 40 males and 26 females with a median age of 41 years (range 15-81). Of 43 patients with relapsed AML, seven achieved a complete remission (16%, 95% confidence interval 5%-27%). Although 11 patients with AML primarily resistant to an anthracycline/cytarabine combination did not respond, two of three patients primarily resistant to low-dose cytarabine achieved complete remission. No patients with acute lymphoblastic leukemia, biphenotypic leukemia, or BLCML responded. Hypotension during the administration of HHT was the most difficult toxicity encountered, requiring multiple interruptions of therapy in several patients and the administration of intravenous saline. Fluid retention and weight gain occurred in 29% of patients. Transient asymptomatic hyperglycemia was observed in 63% of patients. Other toxicity was mild and included nausea and vomiting, diarrhea, mucositis, hepatic dysfunction, and cardiac arrhythmias. As expected, severe myelosuppression occurred in all patients. HHT is well tolerated, but with unique problems associated with administration. It has demonstrable efficacy in pre-treated patients with AML, but its role in the treatment of this disease remains to be defined.

Topics: Antineoplastic Agents, Phytogenic; Harringtonines; Homoharringtonine; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Acute; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recurrence

Homoharringtonine (HHT) is one of several cephalotaxine alkaloids that has shown clinical efficacy in patients with acute myelogenous leukemia (AML). In a phase I trial we evaluated cytarabine 100 mg/m2 by continuous infusion daily for 7 days in combination with four dose levels of HHT ranging from 1.5-5 mg/m2 by continuous infusion daily for 7 days to see if an effective regimen could be developed. Twenty-two patients with relapsed and/or primary refractory AML were treated. Seventeen males and five females were treated, with a median age of 40 years (range 19-63). There were five remissions in 14 patients with relapsed AML and none of eight responders in patients with primary refractory AML. None of the three patients treated at 1.5 mg/m2 dose level of HHT responded. Of three patients treated at the 3 mg/m2 dose level, there was one complete remission. At both 4 mg/m2 and 5 mg/m2, two of eight patients achieved complete remission. Four of the five remissions occurred in patients with acute promyelocytic leukemia. Drug induced pancytopenia was universal, and hypotension and fluid retention were more common at the higher dose levels. Other toxicity was mild and included nausea, vomiting, diarrhea, and mucositis. No significant hepatic, renal, or cardiac toxicity was seen. We conclude that the dose of HHT 4 mg/m2 for 7 days by continuous infusion in combination with cytarabine is safe for patients with AML; and this combination is appropriate for a phase II evaluation.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Dose-Response Relationship, Drug; Female; Harringtonines; Homoharringtonine; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Recurrence

Acute myeloid leukemia (AML) remains a threatening disease due to severe complications, drug resistance, and high recurrence rates. Many drug combinations have demonstrated enhanced therapeutic effects in clinical practice. However, it requires complicated dosing regimens and is accompanied by increased toxicity. This study explored the combined effect of two therapeutic agents, daunorubicin (DNR) and homoharringtonine (HHT) in cell viability, apoptosis, and cell cycle in vitro and verified their synergistic effect. We encapsulated the two drugs into liposomes to construct a folic acid-modified co-delivery system (FA-DH-LP) to achieve an effective and safe therapeutic strategy. The FA-DH-LP was prepared by film hydration method. The resultant FA-DH-LP was homogeneously spherical and showed good blood compatibility with high encapsulation efficiency for DNR and HHT. The FA-DH-LP exhibited higher cellular uptake in HL60 and K562 cells and enhanced cytotoxicity than DNR/HHT co-delivery liposomes without folic acid modification (DH-LP) in vitro. In the HL60 subcutaneous xenotransplantation model, FA-DH-LP showed improved tumor targeting ability, anti-leukemia activity and safety profile superior to free combinational drugs and DH-LP after 18-day treatment. The results demonstrated that FA-DH-LP might present a promising delivery strategy to improve the efficacy of the two combinational chemotherapeutics while reducing toxicity.

Topics: Cell Line, Tumor; Daunorubicin; Folic Acid; Homoharringtonine; Humans; Leukemia, Myeloid, Acute; Liposomes

Bromodomain-containing protein 4 (BRD4) inhibitors have been clinically developed to treat acute myeloid leukemia (AML), but their application is limited by the possibility of drug resistance, which is reportedly associated with the activation of the WNT/β-catenin pathway. Meanwhile, homoharringtonine (HHT), a classic antileukemia drug, possibly inhibits the WNT/β-catenin pathway. In this study, we attempted to combine a novel BRD4 inhibitor (ACC010) and HHT to explore their synergistic lethal effects in treating AML. Here, we found that co-treatment with ACC010 and HHT synergistically inhibited cell proliferation, induced apoptosis, and arrested the cell cycle in FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD)-positive AML cells in vitro, and significantly inhibiting AML progression in vivo. Mechanistically, ACC010 and HHT cooperatively downregulated MYC and inhibited FLT3 activation. Further, when HHT was added, ACC010-resistant cells demonstrated a good synergy. We also extended our study to the mouse BaF3 cell line with FLT3-inhibitor-resistant FLT3-ITD/tyrosine kinase domain mutations and AML cells without FLT3-ITD. Collectively, our results suggested that the combination treatment of ACC010 and HHT might be a promising strategy for AML patients, especially those carrying FLT3-ITD.

Topics: Animals; Apoptosis; beta Catenin; Cell Line, Tumor; fms-Like Tyrosine Kinase 3; Homoharringtonine; Humans; Leukemia, Myeloid, Acute; Mice; Mutation; Nuclear Proteins; Protein Kinase Inhibitors; Transcription Factors

Identifying therapeutic targets and prognostic biomarkers significantly contributes to individualized treatment of acute myeloid leukemia (AML). Dihydropyrimidinase-like 2 (DPYSL2) expression was decreased in homoharringtonine (HHT)-resistant AML cells, which were established by our group. DPYSL2 plays an important role in axon growth and has oncogene effect in glioblastoma. However, little research has been conducted to investigate the function of DPYSL2 in AML pathogenesis.. Auto-docking was used to reveal the targeting relationship between HHT and DPYSL2. Overall survival (OS), event-free survival (EFS), and relapse-free survival (RFS) were used to evaluate the prognostic impact of DPYSL2 for AML. ShRNA was used to knockdown the expression of SPATS2L. Apoptosis was assessed by flow cytometry. In vivo growth and survival were assessed using a xenotransplantation mice model. RNA sequencing was performed to elucidate the molecular mechanisms underlying the role of SPATS2L in AML and were confirmed by Western blot.. We found DPYSL2 was the target of HHT. Next, we found AML cell lines and patients had higher DPYSL2 expression levels than the normal samples. Further multivariate analysis demonstrated that high DPYSL2 expression was an independent poor prognostic factor for OS, EFS, and RFS in AML. Inhibition of DPYSL2 expression suppressed cell growth, induced apoptosis in AML cell lines, and prolonged the survival of AML xenograft NCG mice. Through RNA-seq analysis from TCGA and our data, the JAK2/STAT3/STAT5-PI3K P85/AKT/GSK3b axis was thought to be the critical pathway in regulating DPYSL2 in AML development.. We first time confirmed that DPYSL2 was a target of HHT and played an oncogene role in AML by regulating JAK/STAT signaling pathway. Therefore, DPYSL2 could serve as a novel prognostic marker and therapeutic target for AML treatment.

Topics: Animals; Biomarkers; Cell Line, Tumor; Homoharringtonine; Humans; Leukemia, Myeloid, Acute; Mice; Prognosis

Spermatogenesis associated serine rich 2 like (SPATS2L) was highly expressed in homoharringtonine (HHT) resistant acute myeloid leukemia (AML) cell lines. However, its role is little known in AML. The present study aimed to investigate the function of SPATS2L in AML pathogenesis and elucidate the underlying molecular mechanisms.. Overall survival (OS), event-free survival (EFS), relapse-free survival (RFS) were used to evaluate the prognostic impact of SPATS2L for AML from TCGA database and ourcohort. ShRNA was used to knockdown the expression of SPATS2L. Apoptosis was assessed by flow cytometry. The changes of proteins were assessed by Western blot(WB). A xenotransplantation mice model was used to evaluate in vivo growth and survival. RNA sequencing was performed to elucidate the molecular mechanisms underlying the role of SPATS2L in AML.. SPATS2L expression increased with increasing resistance indexes(RI) in HHT-resistant cell lines we had constructed. Higher SPATS2L expression was observed in intermediate/high-risk patients than in favorable patients. Meanwhile, decreased SPATS2L expression was observed in AML patients achieving complete remission (CR). Multivariate analysis showed high SPATS2L expression was an independent poor predictor of OS, EFS, RFS in AML. SPATS2L knock down (KD) suppressed cell growth, induced apoptosis, and suppressed key proteins of JAK/STAT pathway, such as JAK2, STAT3, STAT5 in AML cells. Inhibiting SPATS2L expression markedly enhanced the pro-apoptotic effects of traditional chemotherapeutics (Ara-c, IDA, and HHT).. High expression of SPATS2L is a poor prognostic factor in AML, and targeting SPATS2L may be a promising therapeutic strategy for AML patients.

Topics: Animals; Homoharringtonine; Humans; Janus Kinases; Leukemia, Myeloid, Acute; Mice; Prognosis; Signal Transduction; STAT Transcription Factors; STAT5 Transcription Factor

Acute myeloid leukemia (AML) is a heterogeneous disease and about one third of AML patients carry nucleophosmin (NPM1) mutation. Because 95% mutations give NPM1 an additional nuclear export signaling (NES) and dislocate NPM1 in cytoplasm (NPMc

Topics: Cell Nucleus; Cytoplasm; Homoharringtonine; Humans; Leukemia, Myeloid, Acute; Mutation; Nuclear Proteins

The majority of RUNX1 mutations in acute myeloid leukemia (AML) are missense or deletion-truncation and behave as loss-of-function mutations. Following standard therapy, AML patients expressing mtRUNX1 exhibit inferior clinical outcome than those without mutant RUNX1. Studies presented here demonstrate that as compared with AML cells lacking mtRUNX1, their isogenic counterparts harboring mtRUNX1 display impaired ribosomal biogenesis and differentiation, as well as exhibit reduced levels of wild-type RUNX1, PU.1, and c-Myc. Compared with AML cells with only wild-type RUNX1, AML cells expressing mtRUNX1 were also more sensitive to the protein translation inhibitor homoharringtonine (omacetaxine) and BCL2 inhibitor venetoclax. Homoharringtonine treatment repressed enhancers and their BRD4 occupancy and was associated with reduced levels of c-Myc, c-Myb, MCL1, and Bcl-xL. Consistent with this, cotreatment with omacetaxine and venetoclax or BET inhibitor induced synergistic in vitro lethality in AML expressing mtRUNX1. Compared with each agent alone, cotreatment with omacetaxine and venetoclax or BET inhibitor also displayed improved in vivo anti-AML efficacy, associated with improved survival of immune-depleted mice engrafted with AML cells harboring mtRUNX1. These findings highlight superior efficacy of omacetaxine-based combination therapies for AML harboring mtRUNX1.

Topics: Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Core Binding Factor Alpha 2 Subunit; Drug Synergism; Homoharringtonine; Humans; Leukemia, Myeloid, Acute; Mutation; Protein Synthesis Inhibitors; Proto-Oncogene Proteins c-bcl-2; Sulfonamides

We analyzed the treatment effects of chidamide and decitabine in combination with a HAG (homoharringtonine, cytarabine, G-CSF) priming regimen (CDHAG) in acute myeloid leukemia (AML) patients with TP53 mutation. Seven TP53 mutated AML patients were treated with CDHAG. The treatment effects were assessed using hemogram detection and bone marrow aspirate. The possible side effects were evaluated based on both hematological and non-hematological toxicity. Four of the seven patients were classified as having achieved complete remission after CDHAG treatment; one patient was considered to have achieved partial remission, and the remaining two patients were considered in non-remission. The overall response rate (ORR) to CDHAG was 71.4%. Regarding the side effects, the hematological toxicity level of the seven patients ranged from level III to level IV, and infections that occurred at lung, blood, and skin were recorded. Nausea, vomiting, liver injury, and kidney injury were also detected. However, all side effects were attenuated by proper management. The CDHAG regimen clearly improved the ORR (71.4%) of TP53-mutated AML patients, with no severe side effects.

Topics: Adult; Aged; Aminopyridines; Antimetabolites, Antineoplastic; Benzamides; Cytarabine; Decitabine; Female; Granulocyte Colony-Stimulating Factor; Homoharringtonine; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Mutation; Remission Induction; Retrospective Studies; Treatment Outcome; Tumor Suppressor Protein p53

The prognostic factors to stratify acute myeloid leukaemia (AML) with double-mutated CCAAT/enhancer-binding protein alpha (CEBPAdm) into different risk groups remains to be determined. In this retrospective study, we evaluated 171 consecutive patients with newly diagnosed AML with CEBPAdm by a Cox proportional hazards regression model. In univariate analyses, colony stimulating factor 3 receptor (CSF3R) and Wilms tumour 1 (WT1) mutations were associated with poor relapse-free survival (RFS). The induction regimens including homoharringtonine (omacetaxine mepesuccinate) or intermediate-dose cytarabine was associated with favourable RFS and overall survival (OS). The induction regimen including both homoharringtonine and intermediate-dose cytarabine was associated with the most favourable RFS (3-year RFS 84.7%) and OS (3-year OS 92.8%) compared to the conventional cytarabine and daunorubicin regimen (3-year RFS 27.7%, hazard ratio [HR] 0.126, 95% confidence interval [CI] 0.051-0.313, Wald p < 0.001; and 3-year OS 56.4%, HR 0.179, 95% CI 0.055-0.586, Wald p = 0.005). In multivariate analyses, the induction regimen including intermediate-dose cytarabine (HR 0.364, 95% CI 0.205-0.646, Wald p < 0.001) and CSF3R mutations (HR 2.667, 95% CI 1.276-5.572, Wald p = 0.009) were independently associated with RFS. Taken together, we found that induction regimen and CSF3R mutations were independent prognostic factors for AML with CEBPAdm.

Topics: CCAAT-Enhancer-Binding Protein-alpha; CCAAT-Enhancer-Binding Proteins; Cytarabine; Homoharringtonine; Humans; Leukemia, Myeloid, Acute; Mutation; Neoplasm Recurrence, Local; Prognosis; Receptors, Colony-Stimulating Factor; Retrospective Studies

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Female; Homoharringtonine; Humans; Induction Chemotherapy; Leukemia, Myeloid, Acute; Male; Middle Aged; Nuclear Proteins; Prognosis; Remission Induction; Retrospective Studies; Young Adult

Despite advances in targeted agent development, effective treatment of acute myeloid leukemia (AML) remains a major clinical challenge. The B-cell lymphoma-2 (BCL-2) inhibitor exhibited promising clinical activity in AML, acute lymphoblastic leukemia (ALL) and diffuse large B-cell lymphoma (DLBCL) treatment. APG-2575 is a novel BCL-2 selective inhibitor, which has demonstrated anti-tumor activity in hematologic malignancies. Homoharringtonine (HHT), an alkaloid, exhibited anti-AML activity.. The synergistic effects of APG-2575 and HHT were studied in AML cell lines and primary samples. MTS was used to measure the cell viability. Annexin V/propidium iodide staining was used to measure the apoptosis rate by flow cytometry. AML cell xenografted mouse models were established to evaluate the anti-leukemic effect of BCL-2 inhibitor, HHT and their combination in vivo. Western blot was used to determine the expression of related proteins.. APG-2575 showed comparable anti-leukemic effect to the FDA-approved BCL-2 inhibitor ABT-199 in vitro and in vivo. Combined treatment of HHT with APG-2575 synergistically inhibited AML cell growth and engraftment. Mechanistically, HHT promoted degradation of myeloid cell leukemia-1 (MCL-1), which was reported to induce BCL-2 inhibitor resistant, through the PI3K/AKT/GSK3β signaling pathway.. Our results provide an effective AML treatment strategy through combination of APG-2575 and HHT, which is worthy of further clinical research.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Drug Synergism; Homoharringtonine; Leukemia, Myeloid, Acute; Mice; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-bcl-2

The prognosis of children with refractory acute myeloid leukemia (AML) is poor. Complete remission (CR) is not always achieved with current salvage chemotherapy regimens before transplantation, and some patients have no chance of transplantation. Here, we aimed to describe a new regimen of conventional chemotherapy drugs (homoharringtonine, cladribine , and aclarubicin (HCA)) for refractory AML and its mechanism in vitro.. We retrospectively collected the clinical data of 5 children with primary refractory AML using HCA as reinduction chemotherapy, and CR rates, adverse reactions, and disease-free survival (DFS) were analyzed. The effects of homoharringtonine, cladribine, and aclarubicin alone or in combination on the proliferation of HL60 and THP1 cells were analyzed by CCK-8 assay. Furthermore, CCK-8 was used to determine the effects of HCA, alone or in combination with apoptosis inhibitors, necroptosis inhibitors, ferroptosis inhibitors, or autophagy inhibitors, on the proliferation of HL60 and THP1 cells and to screen for possible HCA-mediated death pathways in AML cells. The pathway of HCA-mediated AML cell death was further verified by Hoechst/PI staining, flow cytometry, and Western blotting.. After 2 cycles of conventional chemotherapy, none of the 5 children with AML achieved CR and were then treated with the HCA regimen for two cycles, 4 of 5 achieved CR, and another child achieved CR with incomplete hematological recovery (CRi). After CR, 3 children underwent hematopoietic stem cell transplantation (HSCT), and only 2 of them received consolidation therapy. As of the last follow-up, all 5 patients had been in DFS for a range of 23 to 28 months. The inhibition rate of homoharringtonine, cladribine, and aclarubicin in combination on HL60 and THP1 cells was significantly greater than that of a single drug or a combination of two drugs. We found that inhibitors of apoptosis and necroptosis were able to inhibit HCA-mediated cell death but not ferroptosis or autophagy inhibitors. Compared with the control group, the number of apoptotic cells in the HCA group was significantly increased and could be reduced by an apoptosis inhibitor. Western blot results showed that PARP, caspase-3, and caspase-8 proteins were activated and cleaved in the HCA group, the expression of Bax was upregulated and that of Bcl-2 was downregulated. The expression of apoptosis-related proteins could be reversed by apoptosis inhibition. Compared with the control group, the expression levels of the necroptosis-related proteins RIP1, RIP3, and MLKL were downregulated in the HCA group but were not phosphorylated. The necroptosis inhibitor increased the expression of RIP1 but caused no significant changes in RIP3 and MLKL, and none were phosphorylated.. HCA, as a new regimen of conventional drugs, was a safe and efficacious reinduction salvage strategy in children with refractory AML before HSCT. HCA exhibits the synergistic growth inhibition of AML cells and induces cell death mainly through apoptosis.

Topics: Aclarubicin; Antineoplastic Combined Chemotherapy Protocols; Child; Cladribine; Granulocyte Colony-Stimulating Factor; Homoharringtonine; Humans; Leukemia, Myeloid, Acute; Retrospective Studies

Topics: Antineoplastic Combined Chemotherapy Protocols; Azacitidine; Cytarabine; Homoharringtonine; Humans; Leukemia, Myeloid, Acute; Remission Induction; Salvage Therapy; Treatment Outcome

Our objective is to retrospectively analyze the response to low dose of homoharringtonine (HHT) and cytarabine-based priming induction regimens in patients above 70 years with. We retrospectively analyzed these very elderly newly diagnosed patients with AML and high-risk MDS, who received low dose of HHT and cytarabine-based priming induction regimens between March 2006 and September 2019.. Of the 24 patients, 11 patients (47.8%) achieved complete remission (CR) and 3 (13%) partial remission, and the overall response rate was 60.9%. The estimated median overall survival (OS) time was 12 months and the 1-year OS rate was 47.8%. Patients without CR and Charlson's Comorbidity Index > 2 may be the two independent prognostic factors. The median OS was significantly higher for patients with CR after induction chemotherapy than those without CR (22.93. Our study provides a hint of the efficacy of low dose of HHT and cytarabine-based priming induction regimens for patients aged over 70 years with

Topics: Age Factors; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Female; Homoharringtonine; Humans; Induction Chemotherapy; Leukemia, Myeloid, Acute; Male; Myelodysplastic Syndromes; Retrospective Studies; Survival Analysis; Treatment Outcome

Acute myeloid leukemia (AML) with FLT3 internal tandem duplication (FLT3-ITD) has a dismal prognosis. FLT3 inhibitors have been developed to treat patients with FLT3-ITD AML; however, when used alone, their efficacy is insufficient. FLT3 inhibitors combined with chemotherapy may be a promising treatment for FLT3-ITD AML. Homoharringtonine (HHT) is a classical anti-leukaemia drug with high sensitivity to FLT3-ITD AML cells. Here, we showed that HHT synergizes with a selective next-generation FLT3 inhibitor, quizartinib, to inhibit cell growth/viability and induce cell-cycle arrest and apoptosis in FLT3-ITD AML cells in vitro, significantly inhibit acute myeloid leukemia progression in vivo, and substantially prolong survival of mice-bearing human FLT3-ITD AML. Mechanistically, HHT and quizartinib cooperatively inhibit FLT3-AKT and its downstream targets GSK3β, c-Myc, and cyclin D1, cooperatively up-regulate the pro-apoptosis proteins Bim and Bax, and down-regulate the anti-apoptosis protein Mcl1. Most strikingly, HHT and quizartinib cooperatively reduce the numbers of side-population (SP) and aldehyde dehydrogenase (ALDH)-positive cells, which reportedly are rich in LSCs. In conclusion, HHT combined with quizartinib may be a promising treatment strategy for patients with FLT3-ITD AML.

Topics: Adolescent; Adult; Aged, 80 and over; Animals; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Benzothiazoles; Cell Line, Tumor; Drug Delivery Systems; Drug Synergism; Female; fms-Like Tyrosine Kinase 3; Homoharringtonine; Humans; Leukemia, Myeloid, Acute; Male; Mice; Mice, Inbred NOD; Mice, Transgenic; Middle Aged; Phenylurea Compounds; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-myc; Xenograft Model Antitumor Assays

Acute myeloid leukemia (AML) is a group of heterogeneous hematologic malignancies correlates with poor prognosis. It is important to identify biomarkers for effective treatment of AML. Kinases participate in many regulatory pathways and biological activities in AML. Previous studies demonstrated that MAP4K1, a serine/threonine kinase, was associated with immune regulation and cancer progression. However, its role and mechanism in acute myeloid leukemia (AML) have not been explored.. RNA-seq profiling was performed for Homoharringtonine (HHT)-resistant and Homoharringtonine (HHT)-sensitive cell lines. Bioinformatic tools were used for differential analysis. Cell culture and transfection, Cell proliferation, apoptosis and Cell cycle assay, Quantitative RT-PCR, and Western blotting analysis were used to explore biological phenotypes in vitro.. We found that MAP4K1 was highly expressed in HHT-induced resistant AML cell lines. In addition, overexpression of MAP4K1 in AML cells induced resistance of AML cells against HHT. Not only that, the findings of this study showed that overexpression of MAP4K1 was an independent risk factor that predicts poor prognosis of AML. Further, In vitro studies showed that MAP4K1 modulated cell cycle through MAPK and DNA damage/repair pathways. Therefore, MAP4K1 is a potential target for developing therapies for AML.. This study demonstrates that MAP4K1 not only regulates HHT resistance but also independently predicts AML prognosis. In addition, understanding the regulatory mechanism of MAP4K1 reveals novel treatment strategies for resistant and refractory AML. Fundings: This work was supported by the National Natural Science Foundation of China (NSFC) (Grant No.81800199, 81670124, 82070118) and the Natural Science Foundation of Zhejiang Province (LY20H080008).

Topics: Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Biomarkers, Tumor; Cell Line, Tumor; Cell Proliferation; DNA Damage; DNA Repair; Drug Resistance, Neoplasm; Homoharringtonine; Humans; Leukemia, Myeloid, Acute; MAP Kinase Signaling System; Mice; Protein Serine-Threonine Kinases; THP-1 Cells; Transcriptome

Topics: Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Homoharringtonine; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; mRNA Cleavage and Polyadenylation Factors; Oncogene Proteins, Fusion; Receptors, Retinoic Acid; Retinoic Acid Receptor gamma

Topics: DNA; Epigenome; Homoharringtonine; Humans; Leukemia, Myeloid, Acute; Mixed Function Oxygenases; Proto-Oncogene Proteins; Sp1 Transcription Factor

Drug-induced pancreatitis (DIP) is a kind of acute pancreatitis with a relatively low incidence. There are many cases of acute pancreatitis (AP) caused by chemotherapeutic agents that have been reported. However, few reports focus on the combination of chemotherapeutic agents that induce acute pancreatitis. This article aims to retrospectively analyze a case of DIP and to explore the relationship between chemotherapeutic agents and acute pancreatitis.. Here, we report a 35-year-old Chinese female patient who was diagnosed as acute myeloid leukemia with BCR/ABL expression. After induction chemotherapy of daunorubicin and cytarabine, bone marrow aspiration showed: Acute myeloid leukemia-not relieved (AML-NR). Then the regimen of homoharringtonine, cytarabine and dasatinib was started. The patient developed abdominal pain on the 14th day of chemotherapy. Laboratory tests showed elevated serum amylase (AMY) and lipase (LIPA). Computed tomography (CT) of the abdomen revealed a swollen pancreas with blurred edges and thickened left prerenal fascia.. The patient was diagnosed as DIP by the symptoms of upper abdominal pain and the change of CT images. Other common causes of AP were excluded meanwhile.. The chemotherapy was stopped immediately. And after fasting, fluid infusion and inhibiting the secretion of the pancreas, the symptoms were relieved.. DIP relapsed when the regimen of aclacinomycin + cytarabine + G-CSF + dasatinib regimen (G-CSF (400ug/day, day 1 to 15), cytarabine (30 mg/day, day 2 to 15), aclacinomycin (20 mg/day, day 2 to 5)and dasatinib (140 mg/day, continuously)) was given, and was recovered after treatment for AP was performed.. To choose the best treatment plan for patients, clinicians should raise awareness of DIP, and should know that chemotherapeutic agents can induce pancreatitis and the combination of chemotherapeutic agents may increase the risk of drug-induced pancreatitis.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Dasatinib; Daunorubicin; Female; Homoharringtonine; Humans; Leukemia, Myeloid, Acute; Pancreatitis; Tomography, X-Ray Computed

Refractory acute myeloid leukemia (AML) remains a challenging hematological malignancy to treat, due to the development of drug resistance, severe complications, and relapse in chemotherapies. Free-drugs combination has demonstrated enhanced therapeutic efficacy in AML, while it requires complicated administration regimens and brings added toxicity. To tackle this complex disease, in this work two clinically applied therapeutics, doxorubicin and homoharringtonine, were assembled into one polymeric micelle to form a co-delivery system (DHM) to facilitate a novel and simple administration regimen. The DHM was systematically investigated in the drug-resistant AML cell line HL60/A as well as in the AML1-ETO

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Doxorubicin; Homoharringtonine; Leukemia, Myeloid, Acute; Mice

Some acute myeloid leukemia (AML) patients are unresponsive to treatment or have remission followed by worsening of disease (known as relapsed/refractory AML [R/RAML]) after standardized treatment. The CAG/HAG regimen is not often used clinically because heterogenous patient responses, resistance, and hematopoietic bone marrow dysfunction have been reported with its use. We present 2 cases of R/RAML treated with a new combined therapy (venetoclax+ hypomethylating agents [HMAs]) in which the HAG dose was adjusted and effective in the first course of treatment.. Case 1 involved a 23-year-old man who had suffered from AML for >4 years, and his FLT3 mutation status was positive at the initial diagnosis. After the first course of treatment with the standard-dose "Da" plan, the patient experienced complete remission. During the subsequent courses of treatment, the patient experienced 6 recurrences and was treated with the "ID Ara-C + MIT + sidaaniline" and "CAG + sidaaniline" regimens. However, the disease did not respond. Case 2 involved a 26-year-old man who received chemotherapy with the "Da," "ID Ara-C," "decitabine + half-dose CAG," and "HAE" regimens. In this patients, remission could not be achieved. Reintroduction of the "ia" scheme also failed after treatment in our hospital.. Two patients were diagnosed with R/RAML.. The patient in case 2 received chemotherapy interventions, whereas the patient in case 1 refused to receive medical services at our hospital.. The patient in case 1 was discharged after complete response treatment due to economic reasons and relapsed 2 months later. The patient ultimately died of infection and heart failure. The patient in case 2 is receiving a second cycle of chemotherapy.. We recommend the "venetoclax + HMAs combined with dose-adjusted CAH/HAG" regimen as an effective treatment for adult R/RAML.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Azacitidine; Bridged Bicyclo Compounds, Heterocyclic; Cytarabine; Decitabine; Drug Combinations; Fatal Outcome; Granulocyte Colony-Stimulating Factor; Homoharringtonine; Humans; Leukemia, Myeloid, Acute; Male; Neoplasm Recurrence, Local; Sulfonamides; Young Adult

More than half of the patients with acute myeloid leukemia (AML) fail to achieve long-term disease-free survival with current therapies and novel therapeutic strategies are urgently needed. The effects of homoharringtonine (HHT) on the growth of AML cell lines and primary leukemia cells were examined using MTT, colony formation assay. The effects of HHT on both eukaryotic translation initiation factor 4E (eIF4E) and phospho-eIF4E(p-eIF4E) were examined through western blot and immunofluorescence staining. HHT selectively reduced levels of p-eIF4E and its downstream oncoprotein Mcl-1, and potently inhibited

Topics: Apoptosis; Cell Line, Tumor; Eukaryotic Initiation Factor-4E; Homoharringtonine; Humans; Leukemia, Myeloid, Acute; Peptide Initiation Factors

Collaboration of c-KIT mutations with AML1-ETO (AE) has been demonstrated to induce t(8; 21) acute myeloid leukemia (AML). Targeted therapies designed to eliminate AE and c-KIT oncoproteins may facilitate effective treatment of t(8; 21) AML. Homoharringtonine (HHT) features activity against tumor cells harboring c-KIT mutations, whereas oridonin can induce t(8; 21) AML cell apoptosis and AE cleavage. Therefore, studies should explore the efficacy of combination therapy with oridonin and HHT in t(8; 21) AML. In this study, we investigated the synergistic effects and mechanism of oridonin combined with HHT in t(8; 21) AML cell line and mouse model. The two drugs synergistically inhibited cell viability and induced significant mitochondrial membrane potential loss and apoptosis. Oridonin and HHT induced significant downregulation of c-KIT and its downstream signaling pathways and promoted AE cleavage. HHT increased intracellular oridonin concentration by modulating the expressions of MRP1 and MDR1, thus enhancing the effects of oridonin. The combination of oridonin and HHT prolonged t(8; 21) leukemia mouse survival. In conclusion, oridonin and HHTexert synergistic effects against t(8; 21) leukemia in vivo and in vitro, thereby indicating that their combination may be an effective therapy for t(8; 21) leukemia.

Topics: Animals; Apoptosis; Cell Line, Tumor; Cell Proliferation; Cell Survival; Chromosomes, Human, Pair 21; Chromosomes, Human, Pair 8; Diterpenes, Kaurane; Drug Synergism; Female; Homoharringtonine; Humans; Leukemia, Myeloid, Acute; Mice; Mice, Inbred BALB C; Oncogene Proteins, Fusion; Proto-Oncogene Proteins c-kit; Signal Transduction; Translocation, Genetic

Relapse of minimal residual disease (MRD) is a major problem after conventional chemotherapy in patients with acute myeloid leukemia (AML). The bone marrow stroma can protect AML cells from insults of chemotherapy, partly contributing to AML relapse. Arsenic trioxide (ATO) is the main component of arsenical traditional Chinese medicines and has been widely used for the treatment of hematologic malignancies particularly acute promyelocytic leukemia over the past three decades. ATO acts through a direct arsenic binding to cysteine residues in zinc fingers located in promyelocytic leukemia protein (PML), thus killing the leukemia stem cells (LSCs). Our prior study has demonstrated that adhesion to stroma cells could render AML cells resistant to ATO but the detailed mechanism remains to be explored. Here, we report that the adhesion-induced resistance to ATO is related to the up-regulation of myeloid cell leukemia-1 (Mcl-1). Homoharringtonine (HHT) can potentiate the anti-leukemia effects of ATO on adhered AML cells by suppressing Mcl-1 through glycogen synthase kinase-3β (GSK3β). Furthermore, a potentiating effect of HHT on ATO was also observed in primary AML cells and AML xenografted tumors. Thus, these data indicate that HHT could enhance ATO anti-leukemia activity both in vitro and in vivo.

Topics: Adult; Aged; Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Cell Adhesion; Cell Line, Tumor; Coculture Techniques; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Drug Synergism; Female; Homoharringtonine; Humans; Leukemia, Myeloid, Acute; Male; Mice, SCID; Middle Aged; Xenograft Model Antitumor Assays; Young Adult

Acute myeloid leukemia (AML) is a malignantly clonal and highly heterogeneous disease. Although the treatment of AML has brought promising outcomes for younger patients, prognosis of the elderly remains dismal. Innovative regimens are increasingly necessary to be investigated.. We present an 86-year-old AML patient with fever, cough, and sputum production.. A diagnosis of AML with maturation (AML-M2) and AML1/ETO was made.. The patient was treated with a regimen of Homoharringtonine coupled with arsenic trioxide.. The AML-M2 patient with AML1/ETO achieved incomplete remission, but showed few toxic side effects and improved survival. Besides, we analyzed the dynamic counts of complete blood cells during the treatment. The count of white blood cell had a positive correlation with the percentage of blast cells (r = 0.65), both of which had a negative correlation with the percentage of segmented neutrophils (r = -0.63, -0.89).. Homoharringtonine and arsenic trioxide may induce both the apoptosis and differentiation of leukemic cells in AML-M2 with AML1/ETO.

Topics: Aged, 80 and over; Antineoplastic Agents; Apoptosis; Arsenic Trioxide; Cell Differentiation; Core Binding Factor Alpha 2 Subunit; Drug Therapy, Combination; Homoharringtonine; Humans; Leukemia, Myeloid, Acute; Male; Oncogene Proteins, Fusion; RUNX1 Translocation Partner 1 Protein

Ibrutinib, an inhibitor of Bruton tyrosine kinase (BTK), has shown promising pharmacologic effects in acute myeloid leukemia (AML). In this study, we report that abivertinib or AC0010, a novel BTK inhibitor, inhibits cell proliferation, reduces colony-forming capacity, and induces apoptosis and cell cycle arrest in AML cells, especially those harboring FLT3-ITD mutations. Abivertinib was also found to be more sensitive than ibrutinib in treating AML. We demonstrate that in addition to targeting the phosphorylation of BTK, abivertinib also targeted the crucial PI3K survival pathway. Furthermore, abivertinib suppressed the expression of p-FLT3 and the downstream target p-STAT5 in AML cells harboring FLT3-ITD mutations. Moreover, in vitro and in vivo data revealed synergistic activity between abivertinib and homoharringtonine (HHT), a natural plant alkaloid commonly used in China, in treating AML cells with or without FLT3-ITD mutations. Collectively, these preclinical data suggest that abivertinib may be a promising novel agent for AML, with potential for combination treatment with HHT. Clinical studies on abivertinib-involved therapy are planned.

Topics: Agammaglobulinaemia Tyrosine Kinase; Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Biomarkers, Tumor; Cell Cycle; Cell Proliferation; Drug Synergism; fms-Like Tyrosine Kinase 3; Gene Expression Regulation, Neoplastic; Homoharringtonine; Humans; Leukemia, Myeloid, Acute; Mice; Mice, Inbred NOD; Mice, SCID; Mutation; Pyrimidines; Signal Transduction; STAT5 Transcription Factor; Tumor Cells, Cultured; Tumor Suppressor Proteins; Xenograft Model Antitumor Assays

Harringtonine (HT) is a naturally occurring alkaloid isolated from the plant genus Cephalotaxus. It possesses antileukemic activity and has been clinically utilized for the treatment of acute leukemia and lymphoma. Sodium periodate (NaIO

Topics: Alkaloids; Antibodies, Monoclonal; Apoptosis; Cell Line, Tumor; Cell Proliferation; Cephalotaxus; Harringtonines; HL-60 Cells; Humans; Leukemia, Myeloid, Acute; Leukemia, Promyelocytic, Acute; Lymphoma; Periodic Acid

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; China; Cytarabine; Female; Granulocyte Colony-Stimulating Factor; Harringtonines; Hematopoietic Stem Cell Transplantation; Homoharringtonine; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Remission Induction; Retrospective Studies; Transplantation, Homologous

Homoharringtonine (HHT) has long and widely been used in China for the treatment of acute myeloid leukemia (AML), the clinical therapeutic effect is significant but the working mechanism is poorly understood. The purpose of this study is to screen the possible target for HHT with virtual screening and verify the findings by cell experiments. Software including Autodock, Python, and MGL tools were used, with HHT being the ligand and proteins from PI3K-Akt pathway, Jak-stat pathway, TGF-β pathway and NK-κB pathway as the receptors. Human AML cell lines including U937, KG-1, THP-1 were cultured and used as the experiment cell lines. MTT assay was used for proliferation detection, flowcytometry was used to detect apoptosis and cell cycle arrest upon HHT functioning, western blotting was used to detect the protein level changes, viral shRNA transfection was used to suppress the expression level of the target protein candidate, and viral mRNA transfection was used for over-expression. Virtual screening revealed that smad3 from TGF-β pathway might be the candidate for HHT binding. In AML cell line U937 and KG-1, HHT can induce the Ser423/425 phosphorylation of smad3, and this phosphorylation can subsequently activate the TGF-β pathway, causing cell cycle arrest at G1 phase in U937 cells and apoptosis in KG-1 cells, knockdown of smad3 can impair the sensitivity of U937 cell to HHT, and over-expression of smad3 can re-establish the sensitivity in both cell lines. We conclude that smad3 is the probable target protein of HHT and plays an important role in the functioning mechanism of HHT.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Cell Line, Tumor; Cell Proliferation; G1 Phase Cell Cycle Checkpoints; Harringtonines; Homoharringtonine; Humans; Leukemia, Myeloid, Acute; Phosphorylation; RNA Interference; RNA, Small Interfering; Smad3 Protein; THP-1 Cells; Transforming Growth Factor beta; U937 Cells

Acute myeloid leukemia (AML) is a highly heterogeneous disease and internal tandem duplication mutation in FMS-like tyrosine-kinase-3 (FLT3-ITD) has a negative impact on outcome. Finding effective treatment regimens is desperately needed. In this study, we explored the inhibitory effect and mechanism of homoharringtonine (HHT) in combination with ibrutinib on FLT3-ITD mutant AML cells. Consequently, we observed a synergistic inhibitory effect when ibrutinib was combined with HHT to inhibit cell proliferation, induce apoptosis and arrest cell cycle at G0/G1 phase in MV4-11 and MOLM-13 leukemia cells. Our results indicate that the mechanisms of the combination effect are mainly via regulating the STAT5/Pim-2/C-Myc pathway, AKT pathway and Bcl-2 family, activating p21WAF1/CIP1 and inhibiting CCND/CDK complex protein. Interestingly, synergistic cytotoxicity of ibrutinib and HHT was dependent on both FLT3 and BTK. Here we provide a novel effective therapeutic approach for the treatment of AML patients with FLT3-ITD mutation.

Topics: Adenine; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Blotting, Western; Cell Line, Tumor; Cell Proliferation; Drug Synergism; fms-Like Tyrosine Kinase 3; Gene Knockdown Techniques; Harringtonines; Homoharringtonine; Humans; Leukemia, Myeloid, Acute; Mutation; Piperidines; Polymerase Chain Reaction; Pyrazoles; Pyrimidines

The methylation inhibitor decitabine (DAC) has great therapeutic value for myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). However, DAC monotherapy is associated with relatively low rates of overall response and complete remission. Previous studies have shown promising results for combination treatment regimens including DAC. Homoharringtonine (HHT), an alkaloid from Chinese natural plants and Cephalotaxus, has demonstrated potential for leukemia treatment. Our studies have suggested that the combination of DAC and HHT has synergistic effects for inhibiting the viability of SKM-1 and Kg-1a cells. This combination leads to enhanced inhibition of colony formation and apoptosis induction compared with DAC alone in SKM-1 but not Kg-1a cells. Only high-dose DAC and HHT significantly up-regulate caspase-3 and caspase-9 and inhibit BCL-XL in the SKM-1 cell line. The combined effects of DAC plus HHT on apoptosis may not only depend on regulation of the apoptosis-related genes we examined but others as well. HHT had no demethylation effects, and HHT in combination with DAC had no enhanced effects on hypomethylation and DNMT1, DNMT3A and DNMT3B mRNA expression in SKM-1 cells. Overall, these results suggest that DAC used in combination with HHT may have clinical potential for MDS treatment.

Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Azacitidine; Cell Proliferation; Decitabine; Harringtonines; Homoharringtonine; Humans; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Tumor Cells, Cultured

Homoharringtonine combined aclarubicin and cytarabine (HAA) has been demonstrated to achieve a high remission rate and provide a survival advantage in acute myeloid leukemia (AML). To investigate whether HAA is an ideal induction regimen for t(8;21)AML, we retrospectively analyzed the data of 140 patients from the last 8 years in our center. When achieving complete remission (CR), the post-remission treatment was administered as a minimal residual disease-directed risk-stratification treatment protocol. The RUNX1/RUNX1T1 transcript level was assessed by RT-qPCR. The last follow-up was conducted in October 2015. In total, thirty patients received an HAA regimen as the induction treatment. The CR rate after one cycle of the HAA regimen was 93.3% (28/30). One patient achieved partial remission, and one had no response. No patients died during induction treatment. The median fold decrease of the RUNX1/RUNX1T1 transcript level was 200 (1-358000), and 16.7% (5/30) patients achieved >3 log decrease after one cycle of the HAA regimen. The estimated 4-year disease-free survival and overall survival were 89.9% and 90.8%, respectively. We concluded that the HAA regimen is highly effective as the first course of induction therapy for t(8;21) AML, and this needs to be confirmed in a large population in the future.

Topics: Aclarubicin; Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Chromosomes, Human, Pair 21; Chromosomes, Human, Pair 8; Core Binding Factor Alpha 2 Subunit; Cytarabine; Female; Follow-Up Studies; Harringtonines; Homoharringtonine; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Staging; Oncogene Proteins, Fusion; Prognosis; Real-Time Polymerase Chain Reaction; Remission Induction; Retrospective Studies; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; RUNX1 Translocation Partner 1 Protein; Survival Rate; Translocation, Genetic; Young Adult

To estimate the long-term outcomes and the prognostic factors of homoharringtonine, cytarabine, daunorubicin or idarubicin (HAD/HAI) as induction chemotherapy in de novo acute myeloid leukemia (AML).. The CR rate, overall survival (OS) rate, relapse free survival (RFS) rate were retrospectively assayed in 143 de novo AML patients who received the HAD/HAI induction chemotherapy. The outcomes were compared among prognostic groups according to world health organization (WHO) classification, genetic prognosis and initial white blood cell (WBC) count. The role of consolidation chemotherapy consisting of middle-dosage Ara-C (MD-Ara-C) on long term survival was evaluated.. Of 143 patients, 112 (78.3%) achieved CR after the first course of HAD/HAI induction treatment, and early death occurred in only one case. Notably, the CR rate of patients with an initial WBC count ≥100×10(9)/L was not significantly different from those with an initial WBC count<100× 10(9)/L (70.4% vs 80.2%, P=0.266). The CR rate for the patients with favorable, intermediate and unfavorable integrated genetics risk factors was 93.7%, 71.4% and 61.3%, respectively, the difference between groups was statistically significant (P=0.001). Patients with FLT3-ITD mutation obtained similar CR rate (70.6%) to that of patients with FLT3 wild type (79.3%, P=0.528).The estimated 5-year OS rate and 5-year RFS rate for all patients was 40.0% and 37.0%, respectively, with a median follow-up of 24 (range 1-104) months. The median survival time was 30 [95%CI (12, 48)] months. 5-year OS and 5-year RFS of the 96 patients who achieved CR after first course chemotherapy without undergoing allo-HSCT in complete remission was 47.0% and 38.0%, respectively. 5-year OS was significantly higher in MD-Ara-C consolidation group than in no MD-Ara-C consolidation group among CR patients without allo-HSCT (58.0%, 19.0%, respectively, P=0.004). In patients who obtained CR after first course and received MD-Ara-C consolidation without allo-HSCT, the 5-year OS of patients with hyperleukocytosis was not significantly lower than that of patients without hyperleukocytosis (55.5%, 58.8%, respectively,P=0.419). FLT3-ITD mutation patients showed similar 5-year OS to that of wild type FLT3 patients (51.4%, 60.2%, respectively, P=0.482). And furthermore, 5-year OS of favorable, intermediate and unfavorable integrated genetics groups were 59.1%, 62.5%, 51.9%, respectively (P=0.332) in this subgroup.. HAD/HAI induction chemotherapy with sequential consolidation of MD-Ara-C could obtain satisfactory CR rate and long-term survival rate in de novo AML, especially for patients with hyperleukocytosis or FLT3-ITD mutation. It yet remains to be verified by large sample, prospective studies.

Topics: Cytarabine; Daunorubicin; Harringtonines; Homoharringtonine; Humans; Idarubicin; Induction Chemotherapy; Leukemia, Myeloid, Acute; Leukocyte Count; Prognosis; Prospective Studies; Remission Induction; Retrospective Studies; Survival Rate

To evaluate the efficacy and safety of the HAA regimen (homoharringtonine,cytarabine and aclarubicin)as salvage chemotherapy in the treatment of refractory/relapsed acute myeloid leukemia (AML).. We retrospectively analyzed 64 patients with refractory/relapsed AML who received the HAA regimen as salvage chemotherapy. The complete remission (CR)rate was analyzed. Kaplan-Meier method was used to estimate overall survival (OS) and relapse free survival (RFS), and the differences were compared by Log-rank test.. The overall CR rate was 70.1%, and 67.1% of the patients attained CR after the first induction course. The early death rate was 0. The median follow-up time was 61 (range:6-120) months. The estimated 3-year OS rate was 46.8% and the estimated 3-year RFS rate was 42.8%. The CR rates of patients with favorable/intermediate and unfavorable cytogenetics were 76.4% and 33.3%, respectively. The 3-year OS of favorable/intermediate and unfavorable group were 53.7% and 10.0%, respectively. The median survival time of unfavorable group was only 8 months. The side effects associated with the HAA regimen were tolerable, in which the most common toxicities were myelosuppression and infection.. HAA regimen is associated with a higher rate of CR and longer-term survival and its toxicity can be tolerated. The regimen is suitable for refractory/relapsed AML patients with favorable or intermediate risk .

Topics: Aclarubicin; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Harringtonines; Homoharringtonine; Humans; Leukemia, Myeloid, Acute; Recurrence; Remission Induction; Retrospective Studies; Salvage Therapy; Survival Rate

As sensitization of leukemia cells with granulocyte colony-stimulating factor (G-CSF) can enhance the cytotoxicity of chemotherapy in myeloid malignancies, a pilot study was conducted in order to evaluate the effect of G-CSF priming combined with low-dose chemotherapy in patients with higher risk myelodysplastic syndrome (MDS). The regimen, G-HA, consisted of cytarabine (Ara-C) 7.5mg/m(2)/12h by subcutaneous injection, days 1-14, homoharringtonine (HHT) 1.5mg/m(2)/day by intravenous continuous infusion, days 1-14, and G-CSF 150mg/m(2)/day by subcutaneous injection, days 0-14. 56 patients were enrolled, 34 patients (61%, 95% confidence interval: 51.44-70.56%) achieved complete remission (CR). Median duration of neutropenia was 7days (ranging from 2 to 16days). Grade 1-2 nonhematologic toxicities were documented, including nausea and vomiting (5%), liver function abnormality (5%), and heart function abnormality (2%). No central nervous system toxicity was found. Mortality within the first 4 weeks was 4%. The G-HA regimen is effective in remission induction for higher risk MDS patients and well tolerated due to the acceptable toxicity in maintenance therapy in the patients who cannot undergo Hematopoietic cell transplantation (HCT).

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Female; Granulocyte Colony-Stimulating Factor; Harringtonines; Homoharringtonine; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Myelodysplastic Syndromes; Neutropenia; Pilot Projects; Remission Induction; Risk; Young Adult

The treatment of young patient with acute myeloid leukemia (AML) has improved dramatically during the past several decades. However, management of elderly patients with AML still remains a challenge. A total of 56 elderly patients with de novo AML were treated with homoharringtonine and cytarabine in combination with granulocyte colony-stimulating factor (HCG). The overall response rate was 75% (60.7%% complete response [CR] and 14.3% partial response). Fourteen (25%) of the 56 patients showed no response. A higher CR rate was observed in patients aged < 70 years, with better-risk or intermediate-risk karyotype and with NPM1 mutations. To the date of the last follow-up, the median overall survival (OS) was 12.0±1.7 months. There were significant correlations of OS with age, initial karyotype, performance status and gene mutations (NPM1,FLT-ITD and DNMT3A) at diagnosis. The early death rate was 7.1%. Hematologic toxicity was well tolerated; and severe non-hematologic toxicity was not observed.

Topics: Age Factors; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Female; Granulocyte Colony-Stimulating Factor; Harringtonines; Homoharringtonine; Humans; Karyotyping; Leukemia, Myeloid, Acute; Male; Middle Aged; Mutation; Nucleophosmin; Survival Analysis; Treatment Outcome

To explore the clinical efficacy and adverse effects of GHA(G-CSF+homoharringtonin+cytarabine C) and new combined priming chemotherapeutic regimens(GHAA/GHTA) with high efficacy and low toxicity for treatment of relapsed and refractory acute myeloid leukemia(AML) and myelodysplastic syndrome(MDS), and to analyze the relation of above-mentioned regimens with the expression of co-stimuolating molecule B7.1.. Standard GHA regimen consisting of G-CSF: 100 µg/(m2·d) subcutaneous injection, d 0-14; homoharringtonine: 1.0 mg/(m2·d) intravenous drip, d 1-14; Ara-C: 7.5-10 mg/(m2·d) subcutaneous injection, q12h, d 1-14. Other regimens as GHAA/GHTA were combined respectively with aclarubicin 20 mg d 1-7, or pirarubicin 20 mg d 1-7. 74 patients with refractory AML and 46 patients with MDS received these priming chemotherapy. The clinical efficacy and toxicity of above-mentioned priming chemotherapy were compared with 56 patients received routine chemotherapy (MA/TAE) respectively. And the expression of costimulatory molecule B7.1 on leukemia cells in patients of different subtypes was also detected by immunofluoressence and its relationship with clinical efficiency was explored.. (1) for AML patients treated with priming chemotherapy, the total remission was 67.56% (CR 54.05%, PR 13.51%), which was much higher than that of patients received routine chemotherapy (P<0.05). The CR rate of AML-M2 and AML-M5 group (65.51%, 61.90% respectively) was much higher than that of AML other subtypes (P<0.05), and the longest remission period lasted for 4 years; (2) for MDS patients treated with priming chemotherapy, the total remission was 60.87% (CR 45.65%, PR 15.22%), which was also significantly higher than that of patients received routine chemotherapy (P<0.05); (3) in comparison with patients received standard GHA priming regimen, the remission rate of combined priming chemotherapy GHAA/GHTA was significantly higher both in patients with AML (85.18%) and MDS (81.25%); (4) side effects after chemotheropy, including granulocyte deficiency, thrombocytopenia and anemia etc, lasted for 7-14 days; the severe infection rate was 1%, there were no severe bleeding, digest effect and damage of function in heart, liver and kidney. The therapy-related mortality was zero. Compared with routine chemotherapy, priming chemotherapy proved significantly safe and effective (P<0.05); (5) the expression rate of costimulatory molecule B7.1 showed large variance between AML and MDS, it was higher in AML-M2/AML-M5 and lower in AML of other subtypes (P<0.05). In the same case, B7.1 expression was positive correlated with efficiency of priming chemotherapy.. GHA priming chemotherapy, as well as other combination regimens GHAA/GHTA, are well-tolerated, effective regimens for refractory AML and advanced MDS, without severe side effects and therapy-related mortality. Especially the new regimens GHAA/GHTA has better efficacy, which are proved more efficient than conventional GHA. Efficiency of priming chemotherapy is positive correlated with B7.1 expression, its mechanism will be further explored.

Topics: Aclarubicin; Antineoplastic Combined Chemotherapy Protocols; B7-1 Antigen; Cohort Studies; Cytarabine; Doxorubicin; Granulocyte Colony-Stimulating Factor; Granulocytes; Harringtonines; Homoharringtonine; Humans; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Recurrence; Thrombocytopenia

The present study aimed to explore the changes in serum endostatin and fibroblast growth factor 19 (FGF-19) in acute myeloid leukemia patients, and to determine their effects on chemotherapeutic sensitivity. Sixty acute myeloid leukemia patients and 30 healthy controls were included in the study. Patient serum endostatin and FGF-19 levels were measured on admission, and then, standard chemotherapy was administered. The patients were divided into 2 groups according to chemotherapeutic effects: 21 patients in the chemotherapeutic sensitivity group (complete remission + partial remission) and 39 in the chemotherapeutic resistance group (no remission + degradation). A receiver operating characteristic (ROC) curve was used to analyze the relationship of serum endostatin and FGF-19 levels with chemotherapeutic sensitivity in acute myeloid leukemia patients. The levels of serum endostatin and FGF-19 in acute myeloid leukemia patients before chemotherapy were significantly higher than those in the control group. Moreover, these levels significantly decreased after chemotherapy (P < 0.01). The levels of serum endostatin and FGF-19 in the chemotherapeutic sensitivity group were lower than those in the chemotherapeutic resistance group, both before and after chemotherapy (P < 0.05 and P < 0.01, respectively). ROC curve analysis showed that the predictive values of endostatin and FGF-19 were good, and there was no significant difference between these results. In conclusion, serum endostatin and FGF-19 can be used as predictors of chemotherapeutic sensitivity for acute myeloid leukemia patients, and may be important for determining prognosis.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Pharmacological; Case-Control Studies; Cytarabine; Daunorubicin; Drug Resistance, Neoplasm; Endostatins; Female; Fibroblast Growth Factors; Gene Expression; Harringtonines; Homoharringtonine; Humans; Idarubicin; Leukemia, Myeloid, Acute; Male; Middle Aged; Prognosis; Remission Induction; ROC Curve; Treatment Outcome

Single‑agent histone deacetylase (HDAC) inhibitors have exhibited marked antileukemic activity in preclinical and clinical studies and have undergone trials in combination with standard chemotherapeutics. However, the mechanisms of action of combination therapies are not completely understood. In the present study, a novel strategy for treatment of acute myeloid leukemia (AML) was identified, in which the chemotherapeutic agent, homoharringtonine (HHT), was combined with suberoylanilide hydroxamic acid (SAHA), a pan‑HDAC inhibitor. A synergistic effect was observed when HHT was added to SAHA to induce apoptosis in Kasumi‑1 and THP‑1 leukemia cells. This combination was found to significantly enhance the activation of caspase‑8 and ‑9 compared with treatment with each drug separately. Notably, while SAHA induced upregulation of death receptor 4 (DR4) and DR5, HHT upregulated tumor necrosis factor‑related apoptosis-inducing ligand (TRAIL) expression in a dose‑dependent manner. In addition, the synergistic effect between HHT and SAHA was blocked partially using a specific anti‑TRAIL antibody. The combination therapy was also found to significantly inhibit the growth of leukemia xenografts in vivo with enhanced apoptosis. These results indicate that, by regulating the induction of TRAIL and activation of the TRAIL apoptotic pathway, it is possible to administer HHT at low concentrations in combination with SAHA as an effective therapeutic approach for the treatment of AML.

Topics: Animals; Apoptosis; Caspase 8; Caspase 9; Cell Line, Tumor; Cell Proliferation; Drug Synergism; Drug Therapy, Combination; Female; Harringtonines; Histone Deacetylase Inhibitors; Homoharringtonine; Humans; Hydroxamic Acids; Leukemia, Myeloid, Acute; Mice; Mice, SCID; Receptors, Death Domain; Receptors, TNF-Related Apoptosis-Inducing Ligand; TNF-Related Apoptosis-Inducing Ligand; Transplantation, Heterologous; Vorinostat

Topics: Antineoplastic Agents, Phytogenic; Female; Harringtonines; Homoharringtonine; Humans; Leukemia, Myeloid, Acute; Male

In this study, we confirmed that combining HHT with ACR can result in synergistic cytotoxicity to AML cells in vitro and in vivo. Combining HHT and ACR simultaneously inhibited PI3K/AKT and WNT/β-catenin signaling in AML cells. Significant increases in growth inhibition and apoptosis were induced by an AKT inhibitor when the WNT3A gene of THP-1 cells was silenced. HHT+ACR could synergistically induce the apoptosis of CD34(+)/CD38(-) primary AML cells. These results highlight β-catenin and AKT are promising targets for combination therapy for AML.

Topics: Aclarubicin; Animals; Antineoplastic Agents; Apoptosis; beta Catenin; Caspases; Cell Line, Tumor; Cell Proliferation; Disease Models, Animal; Drug Synergism; Female; Gene Silencing; Glucose; Harringtonines; Homoharringtonine; Humans; Leukemia, Myeloid, Acute; Mice; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-bcl-2; Signal Transduction; Wnt Proteins; Xenograft Model Antitumor Assays

Topics: Aclarubicin; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Granulocyte Colony-Stimulating Factor; Harringtonines; Homoharringtonine; Humans; Leukemia, Myeloid, Acute; Treatment Outcome

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Endostatins; Female; Granulocyte Colony-Stimulating Factor; Harringtonines; Homoharringtonine; Humans; Kaplan-Meier Estimate; Leukemia, Myeloid, Acute; Male; Prognosis; Salvage Therapy; Treatment Outcome

To establish a homoharringtonine (HHT)-resistant SKM-1 cell line and explore its biologic characteristics and mechanisms for drug resistance.. The HHT-resistant SKM-1 cell line was established by repeatedly exposing the cells to comparatively large doses of HHT with a short-time duration, and gradually elevating the drug concentration to an endurable level. The morphology of the resistant and parental cell lines was observed through optical microscope. The MTT assay was used to determine the doubling time and the resistance index to draw growth curve. The immunophenotype, cell cycle distribution and DNR accumulation between SKM-1 and SKM-1/HHT were analyzed by flow cytometry, and the karyotypes by R-banding. Semi-quantitative real-time PCR was performed to evaluate the expression levels of mdr1, MRP and topo-IIa.. The HHT-resistant cell line SKM-1/HHT was eventually established following 7-month drug induction. Both the resistant and the parental cell lines were similar with regard to morphology and immunophenotype. The karyotypes of the former was more complicated with differences located in chromosome 20, X, 4, 5, 9 and 11. The resistant cell line had more G(1) phase cells (64.04% vs 41.91%), less S phase cells (34.92% vs 53.53%), and less G(2) phase cells (1.04% vs 4.56%) compared with the parental cell line. The SKM-1/HHT cell line showed significant drug resistance to HHT, VCR, DNR and etoposide, the resistance indices of HHT, VCR, DNR and etoposide were 17.94, 8.75, 5.99 and 13.76 respectively. DNR accumulation was impaired in SKM-1/HHT cell line as less fluorescence of DNR (698 ± 36 vs 858 ± 54). The expression of mdr1 increased dramatically in the resistant cell line, its 2(-ΔCt) value was 20.1 higher than that of the parental cell line \\[(3.42 ± 0.46)×10(-2) vs (0.17 ± 0.01)×10(-2), P < 0.05\\], while MRP also increased in the resistant by 3.56 folds \\[(4.77 ± 0.87)×10(-3) vs (1.34 ± 0.56)×10(-3), P < 0.05\\]; However there was a slightly decrease of topo-IIa, the ratio of the resistant to the parental calculated by their 2(-ΔCt) values was 0.619:1 \\[(1.91 ± 0.30)×10(-4) vs (3.08 ± 0.21)×10(-4), P < 0.05\\].. A HHT-resistant cell line SKM-1/HHT was established. The prominent overexpression of mdr1 may be the main cause for multidrug resistance.

Topics: Cell Line, Tumor; Drug Resistance, Neoplasm; Harringtonines; Homoharringtonine; Humans; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes

To investigate the effect of homoharringtonine (HHT) on leukemic stem-like cells (LSC) in human acute myeloid leukemia (AML) cell lines.. The phenotypes of AML cell lines U937,Kasumi-1,and KG-1 cells were analyzed by flow cytometry (FACS). The effect of HHT on leukemia stem-like cells with immunophenotype of CD34(+)CD38(-)CD96(+) was detected with FACS. Cell growth was measured by MTT assay. Activation of Caspase pathway and expression of apoptosis-related regulator proteins were examined by Western blotting.. FACS demonstrated that the 69% of KG-1 cells expressed LSC phenotype CD34(+)CD38(-)CD96(+), while 26.7% on Kasumi-1 cells expressed this marker. In contrast,U937 cells showed CD96 negative. HHT significantly inhibited cell growth of KG-1 cells with an IC(50) of 16.9 ng/ml at 48 h. The ratio of CD34(+)CD38(-)CD96(+) cells decreased from 63.6% to 17.1% after HHT treatment. Enhanced apoptosis was demonstrated in HHT group evidenced by strong activation of Caspase-9,Caspase-3 and PARP.HHT treatment resulted in down-regulation of expression of anti-apoptotic protein BCL-2 and phosphorylated-Akt.. HHT can effectively kill the leukemic stem-like cells in human AML cell line KG1 by inhibiting cell growth and inducing apoptosis which is associated with activation of Caspase pathway and down-regulation of anti-apoptotic proteins and phosphorylated-Akt.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Caspase 3; Caspase 9; Cell Line, Tumor; Cell Proliferation; Gene Expression Regulation, Neoplastic; Harringtonines; Homoharringtonine; Humans; Leukemia, Myeloid, Acute; Neoplastic Stem Cells

To explore the effect of low dose of homoharringtonine (HHT) and cytarabine (Ara-c) combined with granulocyte colony-stimulating factor (G-CSF) priming (HAG regimen) on relapsed or refractory acute myeloid leukemia (AML).. Sixty-seven patients with relapsed or refractory acute myeloid leukemia (AML) were enrolled. All the patients were treated with HAG regimen (HHT 1.5 mg/m(2)/day, 1-14d; Ara-C 7.5 mg/m(2)/12 h, 1-14d; G-CSF 150 μg/m(2)/day, according to the counting of the peripheral white blood cells). Blood cell counting, liver, kidney function, ECG and myocardial enzymes were monitored regularly.. Thirty-five of 67 (52.2%) patients achieved complete remission (CR) and 8/67 (11.9%) partial remission (PR). The overall response rate was 64.1%. Myelosuppression was the most frequently observed adverse effect. Sixty of 67 (89.5%) patients suffered from grade 1-4 adverse effects of hematologic toxicity (according to World Health Organization criteria) and non-hematologic toxicity was mild.. In conclusion, HAG regimen was effective and tolerated well in refractory or relapsed AML. As a promising regimen for relapse or refractory AML, further observations should be made.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Female; Granulocyte Colony-Stimulating Factor; Harringtonines; Homoharringtonine; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Receptors, CXCR4; Recurrence

To explore the efficacy and safety of HAA regimen (homoharringtonine, cytarabine and aclarubicin) in the treatment of 150 newly diagnosed adult acute myeloid leukemia (AML).. All patients entered the study from May 1999 to June 2008 were treated with HAA regimen. Cox-survival analysis was used to estimate the survival rate and differences between M(1)/M(2) and M(4)/M(5) were compared with 2-sided log-rank test.. Out of the 150 patients, 121 (81%) achieved complete remission (CR). After the first course, CR rate was 68%. The CR rates of 97%, 84% and 38% were achieved in patients with favorable, intermediate and unfavorable cytogenetics, respectively. For the patients with CR, the median follow-up time was 16.5 (1.5 - 100.5) months, and the estimated 3-year survival rate was 45%. The estimated 3-year relapse free survival rate was 52% for the 121 patients with CR.. HAA regimen may be an efficacious and safe regimen with a good toleration in the induction therapy for newly diagnosed AML, and a high CR rate could be achieved with only one or two courses.

Topics: Aclarubicin; Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Disease-Free Survival; Female; Harringtonines; Homoharringtonine; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Survival Rate; Treatment Outcome; Young Adult

Homoharringtonine (HHT) is one of several cephalotaxine alkaloids that has shown clinical efficacy in the treatment of acute myeloid leukemia (AML). The purpose of this study was to evaluate the efficacy and toxicity of HHT for de novo pediatric AML. Patients entered in this study were treated with a regimen including HHT 3.5 mg/m(2) day for 9 days for 6-8 cycles after induction and consolidation with cytarabine plus daunorubicin (DA). One hundred and seventy-one eligible patients, with a median age of 7.58 years, were enrolled. Complete response was obtained in 140/171 (81.9%) cases within 60 days (2 cycles) after DA induction. The 5-year event-free survival was 52.75%. Severe myelosuppression was seen in all patients, with an average minimum WBC count of 686/μl. Following the HHT-including regimen, one patient suffered severe pancreatitis, and a second with a history of congenital hepatitis B suffered liver failure. No significant drug-induced hypotension, fluid retention, hyperglycemia, or cardiac toxicity was detected in this study. Other toxicities, including nausea, vomiting, diarrhea, and mucositis, were mild. HHT-including protocols may emerge as useful therapeutic options in future clinical trials.

Topics: Adolescent; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; China; Clinical Chemistry Tests; Cytarabine; Daunorubicin; Disease-Free Survival; Drug Administration Schedule; Female; Harringtonines; Hematologic Tests; Hepatitis B; Homoharringtonine; Humans; Infant; Leukemia, Myeloid, Acute; Liver Failure; Male; Pancreatitis; Remission Induction; Secondary Prevention

To evaluate the efficacy and toxicity of CHG regimen (low-dose cytarabine, homoharringtonine with G-CSF priming) as an induction chemotherapy for elderly patients with high-risk MDS or acute myeloid leukemia transformed from MDS (MDS-AML).. Thirty-three untreated patients (21 high-risk MDS and 12 MDS-AML) were enrolled in this study. Each patient was administered with the CHG regimen comprised of low-dose cytarabine (25 mg/day, days 1-14) and homoharringtonine (1 mg/day, days 1-14) by intravenous continuous infusion in combination with G-CSF (300 μg/day) by subcutaneous injection from day 0 until neutrophil count recovery to 2.0 × 10(9)/L.. The overall response rate (OR) was 66.7% after one course of the CHG regimen with 19 patients reaching CR (57.6%) and 3 patients reaching partial remission (PR) (9.1%). The median overall survival (OS) was 15.0 months. Patients with normal serum lactate dehydrogenase (LDH) appeared longer median OS when compared to patients with high LDH level (18 months vs. 5 months, P = 0.011). Grade 3/4 thrombocytopenia occurred in 28% of patients, neutropenia in 34%. No treatment-related deaths occurred during the induction therapy.. These data suggest that the CHG priming regimen is effective and safe as a novel induction therapy for elderly patients with high-risk MDS and MDS-AML. The results need to be conformed in further study involving a larger cohort of patients.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Female; Granulocyte Colony-Stimulating Factor; Harringtonines; Homoharringtonine; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Myelodysplastic Syndromes; Risk

Acute myeloid leukemia (AML) arises from genetic changes at the level of stem cell, various mutations have been elucidated, including AML1-ETO fusion gene has been shown as the representative target of cellular transformation for LSCs originating from hematopoietic stem cells (HSCs) compartment. LSCs resemble HSCs with respect to self-renewal capacity and chemotherapy-resistance. However, LSCs possess specific cell-surface markers, they are proposed to reside within the CD34(+)/CD38(-)/CD123(+) compartment. And the interaction mediated by adhesion molecules between LSCs and niche played a role in chemoresistance of LSCs. Therefore, study on the LSCs surface makers related to niche is helpful for the potential target therapy in the future. In this study, the proportions of CD34(+)/CD38(-)/CD123(+) LSCs compartment co-expressing the three adhesion molecules, N-Cadherin, Tie2 and CD44, respectively, from AML patients before and after chemotherapy were analyzed. We demonstrated N-Cadherin and Tie2 positive CD34(+)/CD38(-)/CD123(+) LSCs populations could be enriched by chemotherapy. Furthermore, AML1/ETO fusion signals and MDR1 expression were detected on the CD34(+)/CD38(-)/CD123(+) LSCs populations expressing N-Cadherin and Tie2. Therefore, N-Cadherin and Tie2 are probably the potential markers for identification of LSCs.

Topics: Adolescent; ADP-ribosyl Cyclase 1; Adult; Antigens, CD34; Cadherins; DNA Primers; DNA, Complementary; DNA, Neoplasm; Female; Flow Cytometry; Harringtonines; Homoharringtonine; Humans; Hyaluronan Receptors; In Situ Hybridization, Fluorescence; Interleukin-3 Receptor alpha Subunit; Leukemia, Myeloid, Acute; Male; Middle Aged; Prognosis; Receptor, TIE-2; Reverse Transcriptase Polymerase Chain Reaction; RNA, Neoplasm; Stem Cells

The response to remission induction in elderly patients with acute myeloid leukemia (AML) remains poor. The purpose of this paper is to evaluate the efficacy and toxicity of a plant alkaloid, homoharringtonine, in combination with cytarabine as an induction therapy for AML in elderly patients (> or =60 years).. Twenty-three patients were treated with the HA regimen consisting of homoharringtonine (2 mg/m2/day for 7 days) and cytarabine (Ara-C, 100 mg/m2/day for 7 days). The overall response rate was 56.5% with complete remission (CR) rate of 39.1% and partial remission of 17.4%. There was no early death in this cohort of patients. The estimated median overall survival (OS) time of all patients was (12.0 +/- 3.0) months. The estimated OS time of the CR patients was 15 months. The estimated one-year OS rate of all patients treated with HA protocol was (49.3 +/- 13.5) %. The estimated one-year OS rate of the CR patients was (62.5 +/- 17.1) %.. HA is a suitable induction regimen for elderly patients with AML, with relatively low toxicity and reasonable response rate.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; China; Cytarabine; Drug Administration Schedule; Harringtonines; Homoharringtonine; Humans; Leukemia, Myeloid, Acute; Middle Aged; Remission Induction; Retrospective Studies; Survival Analysis

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.. 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.. 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.. HAA regimen is a safe, efficacious, and well-tolerable induction therapy for newly diagnosed AML.

Topics: Aclarubicin; Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Female; Harringtonines; Homoharringtonine; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Retrospective Studies; Treatment Outcome; Young Adult

Homoharringtonine (HHT) was efficient in therapying patients with acute myeloid leukemia (AML) in China, but little is known about the mechanism of its action. As the abnormal activation of JAK2 associated pathway is important to AML, we try to explore the effect of HHT on JAK2-STAT pathway in AML cells, thus supplying theoretical basis for wider use of HHT.. The cell viability was tested by MTT. Apoptosis was tested by flow cytometry. RT-PCR was used to measure the expression of JAK2, STAT5 and the effect gene Bcl-xL. The signal proteins such as p-JAK2, p-STAT5, p-AKT, p-ERK activated by abnormal activated JAK2 were tested by Western blotting.. HHT obviously inhibited the viability of primary AML cells and AML cell lines HEL, K562 and HL-60 cells, AnnexinV-PI double staining confirmed early apoptosis in a dose-dependent manner. In immunoblotting analysis, when AML cells were affected by HHT for 6 h (much ahead of the time when apoptosis could be induced). The expressions of p-JAK2, p-STAT5, and p-AKT were down-regulated, while the total JAK2, STAT5 and AKT protein levels were stable. There were no changes in p-ERK and BcL-xL proteins. When it prolonged to 24 h, Bcl-xL decreased obviously. Similar results were obtained by using JAK2 specific inhibitor AG490.. HHT possibly acts as a broad-spectrum PTK inhibitor and inhibits the phosphorylation of the signal proteins caused by oncogenic proteins such as JAK2V617F, BCR/ABL, thus blocking the survival and proliferative signal pathway of malignant cells.

Topics: Amino Acid Substitution; Antineoplastic Agents, Phytogenic; Apoptosis; bcl-X Protein; Cell Survival; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Fusion Proteins, bcr-abl; Harringtonines; HL-60 Cells; Homoharringtonine; Humans; Janus Kinase 2; K562 Cells; Leukemia, Myeloid, Acute; Mutation, Missense; Oncogene Protein v-akt; Phosphorylation; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Signal Transduction; STAT5 Transcription Factor; Tyrphostins

This study was purposed to explore the clinical efficiency and side effects of GHA (G-CSF, homoharringtonine and low-dose cytarabine) priming chemotherapy for patients with refractory acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), and its relationship with B7.1 expression. 79 cases of refractory AML and 21 cases of MDS were treated with GHA standard priming chemotherapy. Clinical efficiency, side effects, and therapy-relevant mortality were observed in comparison with MA therapy. Expression of costimulatory molecule B7.1 was detected by immunofluorescence and its relationship with clinical efficiency was explored. The results showed that the remission rate in AML was 60.7% (complete remission rate was 43% and partial remission rate was 17.7%), and that was 52.4% in MDS. The incidence of granulocyte deficiency was 25% during 3.5 days. The severe infection rate was 3%, without severe bleeding, with mild digest effect, and slight damage of function in heart, liver, and kidney. The therapy-related mortality was zero. The higher CR rate was in AML-M(2) and AML-M(5) (60.9%, 61.9%), and the longest remission period was 4 years; expression rate of costimulatory molecule B7.1 displayed large variance (0% - 66.7%) and had positive correlation with efficiency of priming chemotherapy. The rate of B7.1 expression was higher in AML-M(2) and AML-M(5) and lower in other AML groups and normal control. It is concluded that GHA priming chemotherapy can be used to treat refractory AML and MDS, without severe side effects, toxicity and therapy-related mortality. It is a new chemotherapy protocol with better effect and low toxicity. Efficiency of GHA priming chemotherapy may be correlated with B7.1 expression. Its mechanism is worthy to be further explored.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; B7-1 Antigen; Cytarabine; Female; Granulocyte Colony-Stimulating Factor; Harringtonines; Homoharringtonine; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Myelodysplastic Syndromes; Treatment Outcome

The impact of the percentage of residual leukemic cells (RLCs) at the end of first course of induction chemotherapy (T1) or during aplasia (T2) on complete remission (CR) rate, disease-free survival (DFS), and overall survival (OS) were retrospectively analyzed in 72 cases of de novo acute myeloid leukemia (AML) treated with HAD (homoharringtonine, cytosine arabinoside, and daunorubicin) regimen. The patients were separated into two subgroups by a cutoff of 10% bone marrow leukemic cells at T1 or T2 time point. The CR rate, DFS, and OS were significantly different between the two groups. We further confirmed that the percentage of RLCs at T1 or T2 is an independent prognostic factor of AML.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Disease-Free Survival; Female; Harringtonines; Homoharringtonine; Humans; Leukemia, Myeloid, Acute; Male; Metabolic Clearance Rate; Middle Aged; Prognosis; Retrospective Studies; Survival Analysis

As sensitization of leukemic cells with granulocyte colony-stimulating factor (G-csf) can enhance the cytotoxicity of chemotherapy in acute myeloid leukemia (AML), a pilot study was conducted in order to evaluate the effect of G-csf priming combined with low-dose chemotherapy in patients with relapsed and refractory AML. The regimen, G-HA, consisted of cytarabine 7.5 mg/m2/12 hr by subcutaneous injection, days 1-14, homoharringtonine 1.5 mg/m2/day by intravenous continuous infusion, days 1-14, and G-csf 150 microg/m2/day by subcutaneous injection, days 0-14. Thirty-six AML patients were enrolled, 23 refractory and 13 relapsed. Eighteen patients (50%, 95% confidence interval: 33-67%) achieved complete remission (CR) with a median CR duration of 7.2 months, and two elderly patients continued a regimen of maintenance therapy and remained in remission for 26.3 and 14.1 months, respectively, as of last follow-up. Eight patients (22%) experienced neutropenia (median duration: 6 days; range: 2-22 days). Thirteen of the 36 (36%) developed severe infections. Grade 1-2 nonhematologic toxicities were documented, including nausea and vomiting (20%), liver function abnormality (6%), and heart function abnormality (6%). No central nervous system and kidney toxicity was observed. The G-HA regimen is effective in remission induction for refractory and relapsed AML patients and well tolerated in maintenance therapy in some subgroups of elderly patients. Further studies are necessary to elucidate optimum dose and schedule for this regimen to enhance the treatment efficacy of relapsed or refractory AML patients.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials, Phase I as Topic; Cytarabine; Female; Granulocyte Colony-Stimulating Factor; Harringtonines; Homoharringtonine; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Neutropenia; Retrospective Studies; Treatment Outcome

One hundred and ninety-six untreated de novo acute myeloid leukemia (AML) patients were treated with homoharringtonine + cytosine arabinoside (HA) based induction therapy composed of three chemotherapeutic drugs (HAD/M, D-daunorubicin-DNR, M-mitozantrone-MTZ) used in our hospital for the past 12 years. The patient population was relatively young (median age 37, oldest patient 67), and patients were excluded if they had prior MDS or prior chemotherapy or radiotherapy. Complete remission (CR) rate, disease free survival (DFS) and overall survival (OS) of the patients were calculated. One hundred and fifty-three patients who had karyotype results were divided into four groups according to Southwestern Oncology Group (SWOG) criteria. Differences of CR rate, DFS and OS of different groups were evaluated. The CR rate of all 196 cases was 153/196 (78.1%), and 95.3% of these were within 1 - 2 courses. Median DFS of the 153 CR patients was 23.8 (range from 1.0 to 153) months. DFS rates at 3 years and 5 years were 41.1% and 35.9%, respectively. The median OS of 196 patients was 19.3 (0.5 - 154) months. The probabilities of 3-year and 5-year OS were 31.5% and 29.2%, respectively. CR rate, DFS and OS of the different cytogenetic risk groups were also be analyzed. According to SWOG criteria, patients were classified into favorable, intermediate, adverse and unknown (a group where the meaning of chromosomes are unclear) groups. CR rate, median DFS and OS were 91.9%, 90.8 months and 94.4 months for the favorable group; 86.4%, 22.0 months and 22.8 months for the intermediate group; 59.4%, 9 months and 10.5 months for the adverse group; 76.0%, 22.0 months, 16.1 months for the unknown group, respectively. The differences among the four groups were statistically significant (P = 0.001, 0.0033, 0.0001). We conclude that triple-drugs induction regimens based on HA (HAD/M) are highly effective in adult AML in China. Cytogenetics is the important prognostic factor. SWOG karyotype subtyping criteria was appropriate for our patients, the prognosis of the unknown group was similar to that of the intermediate group.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; China; Cytarabine; Cytogenetic Analysis; Daunorubicin; Female; Harringtonines; Homoharringtonine; Humans; Karyotyping; Leukemia, Myeloid, Acute; Male; Middle Aged; Mitoxantrone; Prognosis; Remission Induction; Retrospective Studies; Survival Analysis

Homoharringtonine (HHT), a natural alkaloid extracted from various Cephalotaxus species, exerts its antitumoral and anti-angiogenic activity through an inhibition of protein synthesis and the promotion of apoptosis. ChemGenex Pharmaceuticals Ltd, in collaboration with Stragen Group, is developing omacetaxine mepesuccinate, a semisynthetic formulation of HHT, as a potential treatment for chronic myelocytic leukemia (CML), myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML). In preclinical studies, omacetaxine mepesuccinate induced apoptosis in leukemia cell lines. Results from phase II clinical trials revealed omacetaxine mepesuccinate to be active in patients with CML that was resistant to tyrosine kinase inhibitor (TKI) therapy, including those patients who carry the BCR-ABL1T315I mutation, which is highly insensitive to the TKIs imatinib, nilotinib and dasatinib; the therapeutic was also generally well tolerated. Phase II and III clinical trials are underway to assess the activity of omacetaxine mepesuccinate, either alone or in combination with TKIs or other cytotoxic drugs, in patients with CML that is resistant to TKI therapy. Phase I and II clinical trials for omacetaxine mepesuccinate in the treatment of AML and MDS are also ongoing; intravenous, subcutaneous and oral formulations of the drug are being developed. Omacetaxine mepesuccinate appears to hold potential for the treatment of CML and, in particular, imatinib-resistant CML; the development of alternative formulations of the therapeutic further expands the potential for success in drug development.

Topics: Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Clinical Trials as Topic; Drug Evaluation, Preclinical; Harringtonines; Homoharringtonine; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Acute; Leukemia, Promyelocytic, Acute; Myelodysplastic Syndromes; Patents as Topic; Structure-Activity Relationship; Treatment Outcome

Cancer dose-finding trials aim at assessing the maximum tolerated dose (MTD) of a new treatment or combination. Owing to ethical constraint, they are based on adaptive designs, sequentially allocating patients to increased doses on the basis of previous responses. More recently, the concept of MTD has been extended to the largest concept of most successful or most desirable dose, based on efficacy criterion under toxicity restrictions. The aim of this paper is to present three main approaches proposed to estimate such a dose, in the setting of Phase I/II trials. Two case-studies allow to illustrate these new approaches.

Topics: Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Harringtonines; Homoharringtonine; Humans; Interferon alpha-2; Interferon-alpha; Leukemia, Myeloid, Acute; Maximum Tolerated Dose; Melanoma; Recombinant Proteins; Research Design

To assess the efficacy and toxicity of HAA regimen (homoharritonine 4 mg/m2/day, days 1-3; cytarabine 150 mg/m2/day, days 1-7; aclarubicin 12 mg/m2/day, days 1-7) as an induction therapy in the treatment of de novo acute myeloid leukemia (AML), 48 patients with newly diagnosed AML, aged 35 (14-57) years, were entered into this clinical study. The median follow-up was 26 months. Eighty-three percent of patients achieved complete remission (CR), and the first single course of induction HAA regimen resulted in CR rate of 79%. The CR rate of 100, 82 and 33% were achieved in patients with favorable, intermediate and unfavorable cytogenetics, respectively. For all patients who achieved CR, the median time from the initiation of the induction therapy to the evaluation of the remission status was 32 days. For all patients, the estimated 3 years overall survival (OS) rate was 53%, whereas for patients with M5, the estimated OS rate at 3 years was 75%. The toxicities associated with HAA regimen were acceptable, and the most common toxicity was infection. This study suggested that HAA regimen might be a well-tolerable, effective induction regimen in young adult patients with AML.

Topics: Aclarubicin; Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Female; Follow-Up Studies; Harringtonines; Homoharringtonine; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged

Homoharringtonine (HHT) is a plant alkaloid with antileukemia activity that is currently being used for treatment of acute, chronic leukemias and MDS. In this study, we show that HHT can induce apoptosis in a variety of human myeloid leukemia cell lines (U937, HL-60, HEL, THP, and K562). U937 and HL60 cells undergo rapid apoptosis on treatment with HHT, as indicated by increased annexin V binding capacity, caspase-3 activation, and cleavage of poly(ADP-ribose) polymerase (PARP). In addition, the expression of bax is upregulated during HHT-induced cell death, whereas the expression of bcl-2 is only slightly decreased. Importantly, treatment of primary leukemic cells, obtained from acute myeloid leukemia patients, resulted in rapid apoptosis. Thus, our data provide the mechanism of HHT and justify the use of HHT in the treatment of human myeloid leukemia.

Topics: Annexin A5; Apoptosis; bcl-2-Associated X Protein; Blotting, Western; Caspase 3; Caspases; Cell Division; Gene Expression; Harringtonines; Homoharringtonine; Humans; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Poly(ADP-ribose) Polymerases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Reverse Transcriptase Polymerase Chain Reaction; Tumor Cells, Cultured

To investigate the potentiated effects of total saponins of Panax Ginseng (TSPG) on inhibition of leukemic progenitor cells by cytotoxic drugs in acute myelocytic leukemia.. Using bone marrow culture of colony forming unite-acute myeloid leukemia (CFU-AML) method, the sensitivity of leukemic cells obtained from 18 patients to homoharringtonin (HHr), cytarabine (Ara), adriamycin (Adr) and etoposide (VP-16) were detected separately.. TSPG alone (20 micrograms/ml) could stimulate proliferation of CFU-AML obviously, and increase the colony numbers by 37.98% over the non-TSPG control (P < 0.01). In the presence of TSPG, the inhibition rates of CFU-AML of HHr, Ara, Adr and VP-16 were 51.2%-62.0% respectively, which were significantly higher than 30.4%-47.4% of non-TSPG control (all P < 0.01). In the combination of TSPG with cytotoxic drugs, the leukemic progenitor cells became more sensitive to cytotoxic drugs, CFU-AML colony numbers at 1.84-2.23 fold as more as those of non-TSPG control were inhibited by HHr, Ara, Adr and VP-16. Sensitivity test of 17 among 72 drugs reversed from resistant (suppression rate less than 30%) to sensitive (suppression rate more than 30%) by TSPG.. TSPG could drive non-cycling leukemic progenitors to enter cell cycle, and thereby enhance their susceptibility to cytotoxic drugs.

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Drug Resistance, Neoplasm; Drug Synergism; Female; Ginsenosides; Harringtonines; Homoharringtonine; Humans; Leukemia, Monocytic, Acute; Leukemia, Myeloid, Acute; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Panax; Saponins; Tumor Cells, Cultured; Tumor Stem Cell Assay

To explore the methods of combined chemosensitivity test in vitro.. The chemosensitivity of leukemia cells to 7 kinds of combined chemotherapy regimens, including DA, HA, AA, MA, HAD, HAA and HAM, was estimated in 79 patients with ANLL by MTT assay in vitro. The ratios of drug combinations at which synergistic interactions between drugs are to the highest levels were determined by using Chou's "median effect analysis".. There were 67 S(sensitive)/S, 9 R(resistant)/R, 2 R/S, 1 S/R(in vitro/in vivo) in 79 patients. The general, positive and negative coincident rates of in vitro with in vivo, specificity and sensitivity were 96.2%, 98.5%, 81.8%, 88.9% and 97.1%, respectively.. This method is better than the single drug test, and it is more useful to find drug resistant patients.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Cells; Cytarabine; Daunorubicin; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Harringtonines; Homoharringtonine; Humans; Leukemia, Myeloid, Acute; Middle Aged; Mitoxantrone; Tumor Cells, Cultured

The in vitro induced differentiation of a number of human leukemia cell lines by chemical inducers not only provides a valuable model system for the study on the mechanism of hematopoietic cell proliferation and differentiation at both cellular and molecular levels, but also reveals a new prospect in the treatment of leukemia. In order to find out the possibility of applying inducing agents to the patients with various types of leukemia, the bone marrow cells in primary culture from 50 patients with leukemia were tested for their inducibility in response to the inducers. Only M3 leukemia bone marrow cells can be markedly induced by retinoic acid to the myeloid terminal cells with positive NBT reduction while the cells of other types respond with uncertainty. TPA is able to cause a macrophage-like differentiation in bone marrow cells of all types of leukemia except M1. However, the leukemic cells of chronic myelogenous leukemia in lymphocytic blast crisis will lose response to TPA. The cultured bone marrow cells of acute lymphocytic leukemia respond neither to retinoic acid nor to TPA. Homoharringtonine, a chemotherapeutic drug used in the so-called HOAP regimen for acute nonlymphocytic leukemia, seems to possess the capability of inducing HL-60, the promyelocytic leukemia cell line, to NBT positive myeloid terminal cells, although the inducing effect is weaker than retinoic acid.

Topics: Adolescent; Adult; Aged; Bone Marrow; Child; Female; Harringtonines; Homoharringtonine; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Acute; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Tetradecanoylphorbol Acetate; Tretinoin; Tumor Cells, Cultured

Bone marrow cells from 33 patients with AML were cultured in vitro using PHA-LCM. The test consisted of two phases: an initial liquid phase and then a semi-liquid phase as described by Dicke et al. Drug sensitivity test for homoharringtonine (H) and cytarabine (A) were performed with clonogenic assay. All patients were treated with these drugs. The results showed that PHA-induced leukemic colonies (CFU-AML) varied from 0 to 812/2 x 10(5) cells (median 175). Three patterns of cell growth were recognized in analysis: high degree (7 patients) with more than 250 CFU-AML colonies, median degree (17 patients) with 50-250 and low, degree with 0 to 49 colonies (9 patients). Drug sensitivity was closely related to the cell growth patterns as evaluated with the clinical outcome. Patients with "high" growth pattern needed more sensitive drugs. When clonogenic assay showed "low" growth pattern, all patients responded to H and A very well regardless the degree of drug sensitivity. Most patients with M3 had high or median growth patterns and relatively low sensitivity to HA. Only one of the six patients with M3 got remission.

Topics: Alkaloids; Bone Marrow; Colony-Forming Units Assay; Cytarabine; Harringtonines; Homoharringtonine; Humans; Leukemia, Myeloid, Acute; Prognosis; Tumor Stem Cell Assay

Thirty-one patients with a diagnosis of refractory acute myelogenous leukemia received homoharringtonine as their first (15 patients) or second (16 patients) salvage therapy. Homoharringtonine was given as a continuous infusion of 2.5 mg/m2 daily for 15 to 21 days to 13 patients (schedule 1), and of 3.0 mg/m2 daily for 15 days in 18 patients (schedule 2). Overall, one patient achieved complete remission (3%), and three (10%) had a hematologic improvement with normalization of the marrow and peripheral blood picture except for persistent thrombocytopenia. Six patients (19%) demonstrated prolonged myelosuppression, three (23%) on schedule 1 and three (17%) on schedule 2. Cardiovascular complications were minimal consisting of hypotension in one patient (3%) and supraventricular arrhythmias in two patients (6%). Hyperglycemia was observed in 42% of patients and was significant in 10%. The authors conclude that homoharringtonine, at the dose schedule investigated, has definite but low antileukemic efficacy. The low-dose continuous infusion schedule was associated with prolonged myelosuppression but no serious cardiovascular complications. The role of such therapy in myeloproliferative disorders, especially chronic myelogenous leukemia, deserves consideration.

Topics: Adult; Aged; Alkaloids; Bone Marrow; Combined Modality Therapy; Drug Administration Schedule; Drug Evaluation; Harringtonines; Homoharringtonine; Humans; Infusions, Intravenous; Leukemia, Myeloid, Acute; Middle Aged; Recurrence; Remission Induction

Single-agent homoharringtonine (HH) was evaluated as induction therapy in 20 patients with advanced acute nonlymphocytic leukemia (ANLL) in a pilot study of the Eastern Cooperative Oncology Group (ECOG). HH was given by continuous intravenous (i.v.) infusion at 3.5 mg/m2 on the first day and at 6.0 mg/m2/day on days 2-8. Fourteen men and six women with a median age of 43 years were treated. Sixteen patients had clearing of peripheral blasts, 10 patients achieved marrow hypoplasia, and 2 patients had progressive disease. No complete remission occurred. Drug-induced hypotension was the most significant toxicity, causing a delay in treatment in 8 patients. The median survival was 15 weeks (range 1-65 weeks) from the start of HH treatment. Despite a definite antileukemic effect, HH as a single agent cannot be recommended as a useful salvage regimen in patients with far advanced ANLL.

Topics: Adolescent; Adult; Aged; Alkaloids; Antineoplastic Agents; Drug Evaluation; Harringtonines; Homoharringtonine; Humans; Leukemia, Myeloid, Acute; Middle Aged; Remission Induction

Topics: Alkaloids; Animals; Cell Line; Colony-Forming Units Assay; Harringtonines; Homoharringtonine; Humans; Leukemia L1210; Leukemia, Myeloid, Acute; Melanoma; Mice; Tumor Stem Cell Assay