homoharringtonine and Blast-Crisis

Omacetaxine mepesuccinate is approved by the Food and Drug Administration in the United States for the treatment of chronic myeloid leukemia in chronic or accelerated phase resistant to two or more tyrosine kinase inhibitors. This review summarizes the mode of action, pharmacokinetics, efficacy and safety of omacetaxine mepesuccinate. Omacetaxine mepesuccinate has activity in chronic myeloid leukemia, especially in the chronic phase, regardless of the presence of ABL1 kinase domain mutations. Omacetaxine mepesuccinate has distinct but manageable adverse events profile. Omacetaxine mepesuccinate is a treatment option for a subset of patients with refractory chronic myeloid leukemia.

Topics: Angiogenesis Inhibitors; Antineoplastic Agents, Phytogenic; Blast Crisis; Codon; Fusion Proteins, bcr-abl; Harringtonines; Homoharringtonine; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Accelerated Phase; Leukemia, Myeloid, Chronic-Phase; Mutation; Treatment Outcome

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Blast Crisis; Female; Harringtonines; Homoharringtonine; Humans; Imatinib Mesylate; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Accelerated Phase; Leukemia, Myeloid, Chronic-Phase; Male; Middle Aged; Neoplasm Staging; Retreatment; Treatment Outcome; Young Adult

The therapeutic response of chronic myelogenous leukemia in myeloid blast crisis (CML-MBC) is very poor.. To explore the therapeutic effect of homoharringtonine (HHT) combined with cytarabine (HA regimen) on CML-MBC and its influence on bone marrow CD34+CD7+ cells.. Thirty-four patients with CML-MBC were treated with the HA regimen and bone marrow CD34+CD7+ cells were assayed prior to and after treatment. Among 33 evaluable patients, the overall hematological response (complete/ partial hematological response and hematological improvement) was 60.1%. Seven patients (21.2%) had a cytogenetic response 12 months after treatment. In the untreated CMLMBC patients, the proportion of bone marrow CD34+CD7+ cells was much higher than in the control group (19.4 ± 7.9 vs. 4.4 ± 1.5%, p < 0.05) and decreased to 14.1 ± 7.1% (p < 0.05) after treatment. Before treatment, the proportion of CD34+CD7+ cells was lower in the patients who had a hematological response to the HA regimen than in the patients who did not respond.. The HA regimen is an effective treatment for CML-MBC and CD34+CD7+ cells may be one of the valuable clinical parameters to assess treatment effectiveness.

Topics: Adolescent; Adult; Antigens, CD34; Antigens, CD7; Antineoplastic Combined Chemotherapy Protocols; Blast Crisis; Bone Marrow; Cell Count; Consolidation Chemotherapy; Cytarabine; Daunorubicin; Drug Resistance, Neoplasm; Female; Follow-Up Studies; Harringtonines; Hematologic Diseases; Homoharringtonine; Humans; Immunophenotyping; Leukemia, Myeloid, Accelerated Phase; Male; Middle Aged; Mitoxantrone; Myeloid Cells; Neoplastic Stem Cells; Remission Induction; Young Adult

We investigated the efficacy of the induction therapy involving granulocyte colony-stimulating factor (G-CSF) and low-dose homoharringtonine as well as standard-dose imatinib, which we called the G-CSF + homoharringtonine + imatinib (GHI) regimen, in patients with chronic myelogenous leukemia (CML) in blast crisis who have failed prior single-agent therapy with imatinib. Twelve patients were enrolled. The GHI regimen consisted in a unique induction course where imatinib was administered at 400 mg day(-1) until remission, together with homoharringtonine (1 mg/m(2) s.c. twice daily for 14 days every 28 days), and G-CSF, which was administered 1 day before chemotherapy (5 µg/kg s.c. daily). Patients who failed to obtain at least a partial hematologic response (PHR) after three courses were taken off study. Patients who responded to induction treatment and who had a matched donor received allogeneic hematopoietic stem cell transplantation (allo-HSCT). The results demonstrates that the GHI regimen re-induce hematologic responses or improve the cytogenetic responses in all evaluable patients. Furthermore, eligible patients have benefited from allo-HSCT after response to this induction treatment. We conclude that the GHI regimen may overcome disease-poor response to conventional doses of imatinib and this approach deserves further evaluation as frontline therapy for newly diagnosed CML.

Topics: Adolescent; Adult; Antineoplastic Agents; Benzamides; Blast Crisis; Drug Therapy, Combination; Female; Granulocyte Colony-Stimulating Factor; Harringtonines; Homoharringtonine; Humans; Imatinib Mesylate; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Male; Middle Aged; Piperazines; Pyrimidines; Treatment Failure; Treatment Outcome; Young Adult

Homoharringtonine (HHT) is a cephalotaxus alkaloid that inhibits the synthesis of proteins leading to apoptosis. Intravenous HHT has demonstrated activity in patients with chronic myeloid leukemia (CML) after failure with interferon.. A Phase I study was completed of subcutaneous (s.c.) HHT in patients with CML in accelerated or blast phases and demonstrated efficacy and good tolerance at the same doses used by intravenous (i.v.) administration. The maximal tolerated dose (MTD) was 1.25 mg/m(2) s.c. twice daily. The cohort was then expanded to treated at the MTD to include patients in late chronic phase CML after imatinib failure. Therapy consisted of an i.v. loading dose of HHT 2.5 mg/m(2) over 24 hours, followed by 1.25 mg/m(2) s.c. twice daily for 14 days every 28 days until remission, then for 7 days every 28 days. Six patients (median age, 53 years) who had failed imatinib were treated and 5 were evaluable. Patients received a median of 4.5 courses of s.c. HHT.. Complete hematologic remission was obtained in all 5 evaluable patients and 3 had cytogenetic (CG) responses: 1 complete and 2 minor. The 2 patients with BCR-ABL kinase domain mutations at the start of therapy with HHT had a CG response and in both instances the mutations became undetectable. All patients developed myelosuppression and 3 had their HHT dose reduced due to prolonged neutropenia. Nonhematologic toxicity was mild and manageable.. Subcutaneous HHT is well tolerated and may have clinical activity in patients with CML after imatinib failure.

Topics: Adult; Aged; Anemia; Antineoplastic Agents, Phytogenic; Benzamides; Blast Crisis; Diarrhea; Dose-Response Relationship, Drug; Drug Administration Schedule; Fatigue; Female; Harringtonines; Homoharringtonine; Humans; Imatinib Mesylate; Injections, Intravenous; Injections, Subcutaneous; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Male; Middle Aged; Nausea; Piperazines; Protein Kinase Inhibitors; Pyrimidines; Treatment Failure; Treatment Outcome

To explore the efficacy of tyrosine kinase inhibitor (TKI) combined with decitabine, homoharringtonine, and interferon regimen as maintenance therapy for blast phase chronic myeloid leukemia (CML-BP).. The clinical data of CML-BP patients who received the first major hematological response after induction therapy at The Affiliated Cancer Hospital of Zhengzhou University from June 2015 to December 2021 were analyzed retrospectively. The event-free survival, duration of remission, and overall survival of patients in TKI combined with decitabine, homoharringtonine, interferon group(. A total of 28 patients were included, with a median age of 46 (24-58) years old. Kaplan-Meier survival analysis showed that patients in TKI combined with decitabine, homoharringtonine, interferon group had longer event-free survival (7.4. The TKI combined with decitabine, homoharringtonine and interferon regimen can significantly prolong the survival of CML-BP patients who obtained the major hematological response compared with TKI combined with conventional chemotherapy regimen.. 酪氨酸激酶抑制剂联合地西他滨、高三尖杉酯碱、干扰素维持治疗慢性髓性白血病急变患者的疗效分析.. 探讨酪氨酸激酶抑制剂（tyrosine kinase inhibitor, TKI）联合地西他滨、高三尖杉酯碱、干扰素方案在慢性髓性白血病急变期（blast phase chronic myeloid leukemia, CML-BP）患者缓解后维持治疗的疗效.. 共纳入28例患者，中位年龄46（24-58）岁。Kaplan-Meier生存分析显示，TKI联合地西他滨、高三尖杉酯碱、干扰素组较TKI联合传统化疗组的无事件中位生存时间（7.4. 对于CML-BP且获得缓解的患者，TKI联合地西他滨、高三尖杉酯碱、干扰素方案较TKI联合传统化疗方案维持治疗可显著延长患者生存.

Topics: Antineoplastic Combined Chemotherapy Protocols; Blast Crisis; Decitabine; Homoharringtonine; Humans; Interferons; Middle Aged; Protein Kinase Inhibitors; Retrospective Studies; Treatment Outcome; Tyrosine Kinase Inhibitors

The aims of this study were to evaluate the feasibility of using the non-clonogenic fluorometric microculture cytotoxicity assay in drug sensitivity testing of tumor cells from patients with chronic myeloid leukemia. In nine samples (six chronic phase, three blast crisis), the drug sensitivities in tumor cells from blood versus from bone marrow and fresh tumor cells versus cryopreserved were compared. In 26 samples obtained in chronic phase (pretreatment), in six samples from patients in blast crisis and in the K 562 cell line, the activity of imatinib alone and in combination with cytarabine, vincristine, daunorubicin, interferon, arsenic trioxide and homoharringtonine was evaluated. All chronic myeloid leukemia chronic phase samples were sensitive to imatinib, with a mean IC50 at 10.3 mumol/l. The chronic myeloid leukemia samples from blast crisis (n=6) were significantly more sensitive to imatinib than the samples from chronic phase (n=26) (P<0.05), with an IC50 mean at 0.4 mumol/l. In blast crisis samples, significant positive interaction effects were observed between imatinib and all other tested drugs except for interferon. In chronic phase samples, interferon, daunorubicin and arsenic trioxide were the drugs with the highest frequency of positive interactions with imatinib (P<0.05). We conclude that the fluorometric microculture cytotoxicity assay may be a useful method for drug sensitivity testing in chronic myeloid leukemia patient samples from both chronic phase and blast crisis, and that testing primary tumor cells may have advantages over cell line studies. Imatinib shows a higher in vitro activity and more positive drug interactions in cells from blast crisis than chronic phase chronic myeloid leukemia patients. Combinations between imatinib and interferon, daunorubicin and arsenic trioxide may be interesting for future clinical trials in patients with chronic myeloid leukemia chronic phase.

Topics: Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Benzamides; Blast Crisis; Cytarabine; Daunorubicin; Feasibility Studies; Harringtonines; Homoharringtonine; Humans; Imatinib Mesylate; In Vitro Techniques; Interferons; K562 Cells; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Oxides; Piperazines; Pyrimidines; Vincristine

Homoharringtonine (HHT) is a cephalotaxine alkaloid that showed clinical efficacy in the chronic phase of chronic myeloid leukemia (Ph1+CML). As a single agent, it resulted in effectively controlling leukocytosis and in producing sporadic karyotypic conversions; its clinical use in combination with interferon (IFN-alpha) for the treatment of CML could thus be considered. In this study we evaluated the growth inhibition and the induction of apoptosis determined by HHT alone and in combination with IFN-alpha and cytosine arabinoside (Ara-C) on normal and CML (both in chronic, CML-CP and in blastic phase; CML-BP) hematopoietic progenitors. HHT is able to determine a dose-dependent cell growth inhibition; evaluation of cytotoxic activity on semisolid cultures showed an activity significantly higher on CML-CP than on normal cells (P = 0.02 for HHT 50 ng/ml and P = 0.01 for HHT 200 ng/ml). HHT exerted a synergistic effect with IFN-alpha, Ara-C and IFN-alpha + Ara-C in inhibiting CML-CP colony growth; the same activity was demonstrated by the combination of HHT with Ara-C and by the triple combination, but not by HHT + IFN-alpha, on normal myeloid progenitors. The triple combination only was able to exert a synergistic effect in CML-BP. The induction of apoptosis resulted HHT dose-dependent in CML-CP and normals; at higher drug concentrations (100-200-1000 ng/ml), HHT induced a significant increase of apoptotic cells (for normals: P = 0.04, P = 0.02 and P = 0.04; for CML-CP: P = 0.01, P = 0.01 and P = 0.04, respectively); no significant changes were observed in CML-BP. In conclusion, the differences in cytotoxic effect and apoptosis induction observed, depending on the various phases of CML, add experimental evidence to the different clinical results between the chronic phase, where the clone is responsive to HHT, and the acute phase, where the drug is ineffective. The in vitro synergism of HHT with Ara-C and IFN-alpha in CML-CP suggests further evaluation in the clinical setting.

Topics: Adult; Antineoplastic Agents, Phytogenic; Apoptosis; Blast Crisis; Bone Marrow; Bone Marrow Cells; Cell Division; Cell Survival; Cells, Cultured; Colony-Forming Units Assay; Cytarabine; Female; Harringtonines; Hematopoietic Stem Cells; Homoharringtonine; Humans; Interferon-alpha; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Male

Continuous infusion of homoharringtonine was administered to 17 children with refractory leukemia. Ten children with acute lymphoblastic leukemia received a total of 18 courses and seven children with acute nonlymphoblastic leukemia had a total of 13 courses. Doses were escalated from 1.65 to 8.5 mg/m2 for 5-10 consecutive days. Side effects included mild nausea and vomiting and transient changes in liver enzymes. Mucositis and diarrhea were more frequently seen at higher dose levels. Grade 3 hypotension and pain were seen at doses of 7 mg/m2 for 10 days. This is considered to be the maximum tolerated dose in this limited phase I trial. None of these previously heavily treated patients achieved a marrow remission.

Topics: Adolescent; Alkaloids; Blast Crisis; Child; Child, Preschool; Female; Harringtonines; Homoharringtonine; Humans; Infant; Leukemia; Leukemia, Lymphoid; Leukemia, Myeloid; Male