Homoharringtonine Attenuates Dextran Sulfate Sodium-Induced Colitis by Inhibiting NF-κB Signaling.

Homoharringtonine (HHT) exhibits an anti-inflammatory activity. The potential protective effects and mechanisms of HHT on dextran sulfate sodium- (DSS-) induced colitis were investigated. DSS-induced colitis mice were intraperitoneally injected with HHT. Body weight, colon length, disease activity index (DAI), and histopathological change were examined. The relative contents of interleukin- (IL-) 1ß, tumor necrosis factor- (TNF-) α, IL-6, and the chemokine (C-C motif) ligand 2 (CCL2) in the colon tissues and HHT-treated RAW264.7 cells were detected with the enzyme-linked immunosorbent assay. In the meantime, the levels of p-p65 and p-IκBα were detected by Western blot. The proportion of macrophages (CD11b+F4/80+) in the colon tissues was detected by flow cytometry. HHT alleviated DSS-induced colitis with downregulated TNF-α, IL-1ß, IL-6, and CCL2 expression; reduced activation of nuclear factor-kappa B (NF-κB) signaling; and diminished proportion of recruited macrophages in colon tissues. It was further testified that HHT inhibited lipopolysaccharide-induced macrophage activation with reduced activation of NF-κB signaling. In addition, HHT inhibited the M1 polarization of both human and mouse macrophages, while HHT did not affect the differentiation of human CD4 T cells into Th17, Th1, or Treg cells and did not affect the proliferation and migration of human colon epithelial cells. In summary, HHT attenuates DSS-induced colitis by inhibiting macrophage-associated NF-κB activation and M1 polarization, which could be an option for the treatment of ulcerative colitis.

Optimization of idarubicin and cytarabine induction regimen with homoharringtonine for newly diagnosed acute myeloid leukemia patients based on the peripheral blast clearance rate: A single-arm, phase 2 trial (RJ-AML 2014).

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.

Comparison of efficacy of HCAG and CAG re-induction chemotherapy in elderly low- and intermediate-risk group patients diagnosed with acute myeloid leukemia.

PURPOSE: 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. METHODS: 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. RESULT: 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). CONCLUSION: 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.

Acute pancreatitis induced by combination chemotherapy used for the treatment of acute myeloid leukemia: A case report.

RATIONALE: 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. PATIENT CONCERNS: 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. DIAGNOSIS: 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. INTERVENTIONS: The chemotherapy was stopped immediately. And after fasting, fluid infusion and inhibiting the secretion of the pancreas, the symptoms were relieved. OUTCOMES: 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. LESSONS: 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.

Sorafenib and omacetaxine mepesuccinate as a safe and effective treatment for acute myeloid leukemia carrying internal tandem duplication of Fms-like tyrosine kinase 3.

BACKGROUND: 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). METHODS: 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). RESULTS: 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. CONCLUSIONS: SOME was safe and effective for R/R and newly diagnosed FLT3-ITD AML.

The efficacy and toxicity of the CHG priming regimen (low-dose cytarabine, homoharringtonine, and G-CSF) in higher risk MDS patients relapsed or refractory to decitabine.

PURPOSE: Myelodysplastic syndromes (MDSs) refractory or relapsed after hypomethylating agents (HMAs) remain a therapeutic challenge. The CHG regimen has been demonstrated to be effective in initially treating higher risk MDS. The current study evaluated the efficacy and toxicity of the CHG regimen in patients who were resistant to decitabine. METHODS: Patients with higher risk MDS relapsed or refractory to decitabine were enrolled in this study. Each patient received the CHG regimen (cytarabine (25 mg/day, days 1-14) and homoharringtonine (1 mg/day, days 1-14) intravenously with G-CSF (300 µg/day) subcutaneously from day 0 until neutrophil count recovery to 2.0 × 109 cells/L). Next gene sequencing with a 31-gene panel was carried out in patients. RESULTS: Thirty-three patients were enrolled, including 12 relapsed and 21 refractory cases. The overall response rate (ORR) was 39.4% (13 of 33), with 9 (27.3%) achieving complete remission (CR), 2 having marrow CR (mCR), and 2 achieving partial remission (PR). The CR rate was higher in patients harboring fewer gene mutations (0-1) (55.6%) than in those with more gene mutations (> 1) (12.5%) (p = 0.021). The median overall survival (OS) of the 33 patients was 7.0 months. Patients who achieved a response had significantly longer survival times than were found in those without a response (21.0 M vs. 4.0 M, p < 0.0001). The regimen was endurable for most of the patients. CONCLUSIONS: The CHG priming regimen provided a safe and effective salvage regimen for higher risk MDS patients who were resistant to decitabine. Further studies involving larger samples will be needed. Clinical trial No. ChiCTR-ONC-11001501.

Comparison of efficacy of HCAG and FLAG re-induction chemotherapy in acute myeloid leukemia patients of low- and intermediate-risk groups.

PURPOSE: 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. METHODS: 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. RESULT: 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). CONCLUSION: 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.

A phase II study of omacetaxine mepesuccinate for patients with higher-risk myelodysplastic syndrome and chronic myelomonocytic leukemia after failure of hypomethylating agents.

The outcome of patients with myelodysplastic syndromes (MDSs) after failure of hypomethylating agents (HMAs) failure is poor with a median overall survival (OS) of only 4-6 months. Omacetaxine mepesuccinate (OM) is safe and effective in myeloid malignancies but has not been studied in MDS with HMA failure. We conducted a phase II study of OM in patients with MDS or chronic myelomonocytic leukemia (CMML) who had previously failed or been intolerant to HMAs. Patients received OM at a dose of 1.25 mg/m2 subcutaneously every 12 hours for 3 consecutive days on a 4- to 7-week schedule. The primary endpoints were the overall response rate (ORR) and OS. A total of 42 patients were enrolled with a median age of 76 years. The ORR was 33%. Patients with diploid cytogenetics were more likely to respond to OM than were those with cytogenetic abnormalities (58% vs 23%, respectively; P = .03). Overall, the median OS was 7.5 months and 1-year OS rate was 25%. Patients with diploid cytogenetics had superior OS to those with cytogenetic abnormalities (median OS 14.8 vs 6.8 months, respectively; P = .01). Two patients had ongoing response to OM of 2 years or longer (both MDS with diploid cytogenetics and RUNX1 mutation). The most common grade ≥ 3 adverse events were infections in 11 patients (26%), febrile neutropenia in 4 (10%), and hemorrhage in 3 (7%). Overall, OM was safe and active in patients with MDS or CMML who experienced HMA failure. These results support the further development of OM in this setting.