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Oncotarget Mar 2015This prospective phase II, open label, study was designed to assess the efficacy and safety of D-CAG induction treatment for elderly patients with newly diagnosed AML.
PURPOSE
This prospective phase II, open label, study was designed to assess the efficacy and safety of D-CAG induction treatment for elderly patients with newly diagnosed AML.
EXPERIMENTAL DESIGN
All patients in this study were treated with decitabine of 15 mg/m2 for 5 days and G-CSF for priming, in combination with cytarabine of 10-mg/m2 q12h for 7 days and aclarubicin of 10 mg/day for 4 days (D-CAG).
RESULTS
Among 85 evaluable patients, overall response rate (ORR) and complete remission (CR) were 82.4% and 64.7%, respectively, after 1 cycle of therapy. The ORR in patients aged <70 years was 83.0% and 81.6% in patients aged ≥70 years. There was a significantly longer median overall survival (OS) in patients with response (16 months) than in those without response (7 months, p< 0.0001). The OS for patients aged ≥70 years and 60-69 years was 10 months and 12 months, respectively (p=0.4994). The two-year OS probability was 19.2% and the twenty-month survival rate was 33.8%. Induction mortality of D-CAG treated elderly patients with AML is 4.4%.
CONCLUSION
D-CAG regimen was well tolerated and showed a promising clinic efficacy in elderly patients with AML (≥70 years).
Topics: Aclarubicin; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Azacitidine; Cytarabine; Decitabine; Female; Granulocyte Colony-Stimulating Factor; Humans; Leukemia, Myeloid, Acute; Male; Prospective Studies; Survival Analysis; Treatment Outcome
PubMed: 25749041
DOI: 10.18632/oncotarget.3361 -
RSC Advances Sep 2019Aclarubicin (ACR), an anthracycline anti-tumor agent, is known to play important roles in cancer. Evidence has suggested that ACR has therapeutic effects on rats...
Aclarubicin (ACR), an anthracycline anti-tumor agent, is known to play important roles in cancer. Evidence has suggested that ACR has therapeutic effects on rats intracranially implanted with C6 glioma cells. However, the function and mechanism of ACR in glioma cells remain elusive. In this study, we examined the effects of ACR on glioma cell growth, apoptosis, and DNA damage. Our results showed that treatment with different concentrations of ACR (1, 2, and 5 μM) markedly impeded glioma cell survival, significantly decreased cell proliferation, and increased cell apoptosis and caspase-3 activity. Furthermore, ACR treatment promoted DNA damage through phosphorylation of ATM and CHK1 in U87 and U251 cells. Treatment with ACR also increased sirtuin 1 (SIRT1) expression and inhibited phosphatidylinositol 3'-kinase (PI3K)/AKT pathway activation. Interestingly, we found that AKT overexpression reversed the effects of ACR on glioma cell survival, proliferation, apoptosis, and DNA damage. Thus, our data suggest that ACR induces apoptosis and DNA damage in U87 and U251 cells through the SIRT1/PI3K/AKT signaling pathway.
PubMed: 35529648
DOI: 10.1039/c9ra05572j -
Leukemia Research Oct 2002Aclarubicin (ACLA), which belongs to the antracycline class of antineoplasic agents, has been demonstrated as a differentiating agent for a broad range of human solid...
Aclarubicin (ACLA), which belongs to the antracycline class of antineoplasic agents, has been demonstrated as a differentiating agent for a broad range of human solid tumors and leukemia. By using dihydroethidium as a fluorescent probe, we show the ability of subtoxic (i.e. differentiating) concentration of ACLA to generate reactive oxygen species in both K562 and HL-60 leukemia cell lines. Besides, we have used a calcein-based spectrofluorimetric assay to determine the influence of ACLA treatment on the cellular labile iron pool (LIP). In both cell lines, the LIP level was markedly decreased in the presence of ACLA. Nevertheless, whereas ACLA-induced differentiation was obviously ROS-dependent, the LIP decrease was rather ROS-independent.
Topics: Aclarubicin; Antibiotics, Antineoplastic; Cell Differentiation; Fluorescent Dyes; Free Radicals; HL-60 Cells; Humans; Iron; K562 Cells; Leukemia; Reactive Oxygen Species
PubMed: 12163054
DOI: 10.1016/s0145-2126(02)00030-9 -
Molecular Cancer Jun 2024The efficacy of anthracycline-based chemotherapeutics, which include doxorubicin and its structural relatives daunorubicin and idarubicin, remains almost unmatched in...
The efficacy of anthracycline-based chemotherapeutics, which include doxorubicin and its structural relatives daunorubicin and idarubicin, remains almost unmatched in oncology, despite a side effect profile including cumulative dose-dependent cardiotoxicity, therapy-related malignancies and infertility. Detoxifying anthracyclines while preserving their anti-neoplastic effects is arguably a major unmet need in modern oncology, as cardiovascular complications that limit anti-cancer treatment are a leading cause of morbidity and mortality among the 17 million cancer survivors in the U.S. In this study, we examined different clinically relevant anthracycline drugs for a series of features including mode of action (chromatin and DNA damage), bio-distribution, anti-tumor efficacy and cardiotoxicity in pre-clinical models and patients. The different anthracycline drugs have surprisingly individual efficacy and toxicity profiles. In particular, aclarubicin stands out in pre-clinical models and clinical studies, as it potently kills cancer cells, lacks cardiotoxicity, and can be safely administered even after the maximum cumulative dose of either doxorubicin or idarubicin has been reached. Retrospective analysis of aclarubicin used as second-line treatment for relapsed/refractory AML patients showed survival effects similar to its use in first line, leading to a notable 23% increase in 5-year overall survival compared to other intensive chemotherapies. Considering individual anthracyclines as distinct entities unveils new treatment options, such as the identification of aclarubicin, which significantly improves the survival outcomes of AML patients while mitigating the treatment-limiting side-effects. Building upon these findings, an international multicenter Phase III prospective study is prepared, to integrate aclarubicin into the treatment of relapsed/refractory AML patients.
Topics: Animals; Female; Humans; Male; Aclarubicin; Anthracyclines; Antineoplastic Agents; Leukemia, Myeloid, Acute; Treatment Outcome
PubMed: 38831402
DOI: 10.1186/s12943-024-02034-7 -
Cancer Medicine Aug 2020Adult patients with relapsed or refractory T-cell acute lymphoblastic leukemia (R/R-T-ALL) have extremely poor prognosis, representing an urgent unmet medical need....
Adult patients with relapsed or refractory T-cell acute lymphoblastic leukemia (R/R-T-ALL) have extremely poor prognosis, representing an urgent unmet medical need. Finding an optimal salvage regimen to bridge transplantation is a priority. The CAG (cytarabine, aclarubicin, and G-CSF) regimen was initially used by one group in China, showing unexpectedly promising results in 11 R/R-T-ALL patients. Here, we report the multicenter results of 41 patients who received the CAG regimen as salvage therapy. After one cycle of the CAG regimen, complete remission and partial remission were achieved in 33 (80.5%) and two (4.9%) patients, respectively. Failure to respond was observed in six patients (14.6%). Early T-cell precursor (ETP) (n = 26) and non-ETP (n = 15) patients had a similar CR rate (80.8% vs 80.0%, P = .95). Among 41 patients, allo-HSCT was successfully performed in 27 (66%) patients (22 in CR and 5 in non-CR). With a median follow-up time of 12 months, the estimated 2-year overall survival and event-free survival were 68.8% (95% CI, 47.3%-83.0%) and 56.5% (95% CI, 37.1%-71.9%), respectively. The CAG regimen was well-tolerated, and no early death occurred. Our multicenter results show that the CAG regimen is highly effective and safe, representing a novel choice for adult patients with R/R-T-ALL and providing a better bridge to transplantation.
Topics: Aclarubicin; Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cohort Studies; Cytarabine; Female; Granulocyte Colony-Stimulating Factor; Humans; Male; Middle Aged; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Retrospective Studies; Young Adult
PubMed: 32492289
DOI: 10.1002/cam4.3079 -
Journal of Medicinal Chemistry Aug 2023The anthracycline anti-cancer drugs are intensely used in the clinic to treat a wide variety of cancers. They generate DNA double strand breaks, but recently the...
The anthracycline anti-cancer drugs are intensely used in the clinic to treat a wide variety of cancers. They generate DNA double strand breaks, but recently the induction of chromatin damage was introduced as another major determinant of anti-cancer activity. The combination of these two events results in their reported side effects. While our knowledge on the structure-activity relationship of anthracyclines has improved, many structural variations remain poorly explored. Therefore, we here report on the preparation of a diverse set of anthracyclines with variations within the sugar moiety, amine alkylation pattern, saccharide chain and aglycone. We assessed the cytotoxicity in relevant human cancer cell lines, and the capacity to induce DNA- and chromatin damage. This coherent set of data allowed us to deduce a few guidelines on anthracycline design, as well as discover novel, highly potent anthracyclines that may be better tolerated by patients.
Topics: Humans; Anthracyclines; Doxorubicin; Antibiotics, Antineoplastic; Topoisomerase II Inhibitors; Chromatin; DNA; Neoplasms
PubMed: 37561481
DOI: 10.1021/acs.jmedchem.3c00853 -
Frontiers in Oncology 2022Langerhans cell histiocytosis (LCH) and acute myeloid leukemia (AML) are distinct entities of blood neoplasms, and the exact developmental origin of both neoplasms are...
Langerhans cell histiocytosis (LCH) and acute myeloid leukemia (AML) are distinct entities of blood neoplasms, and the exact developmental origin of both neoplasms are considered be heterogenous among patients. However, reports of concurrent LCH and AML are rare. Herein we report a novel case of concurrent LCH and AML which shared same the driver mutations, strongly suggesting a common clonal origin.An 84-year-old female presented with cervical lymphadenopathy and pruritic skin rash on the face and scalp. Laboratory tests revealed pancytopenia with 13% of blasts, elevated LDH and liver enzymes, in addition to generalised lymphadenopathy and splenomegaly by computed tomography. Bone marrow specimens showed massive infiltration of MPO-positive myeloblasts, whereas S-100 and CD1a positive atypical dendritic cell-like cells accounted for 10% of the atypical cells on bone marrow pathology, suggesting a mixture of LCH and AML. A biopsy specimen from a cervical lymph node and the skin demonstrated the accumulation of atypical cells which were positive for S-100 and CD1a. LCH was found in lymph nodes, skin and bone marrow; AML was found in peripheral blood and bone marrow (AML was predominant compared with LCH in the bone marrow). Next generation sequencing revealed four somatic driver mutations (-G13D, -R140Q, and -F640fs/-I715fs), equally shared by both the lymph node and bone marrow, suggesting a common clonal origin for the concurrent LCH and AML. Prednisolone and vinblastine were initially given with partial response in LCH; peripheral blood blasts also disappeared for 3 months. Salvage chemotherapy with low dose cytarabine and aclarubicin were given for relapse, with partial response in both LCH and AML. She died from pneumonia and septicemia on day 384. Our case demonstrates a common cell of origin for LCH and AML with a common genetic mutation, providing evidence to support the proposal to classify histiocytosis, including LCH, as a myeloid/myeloproliferative malignancy.
PubMed: 36185232
DOI: 10.3389/fonc.2022.974307 -
Oncology Letters Sep 2018The low-dose cytarabine, aclarubicin and granulocyte-colony stimulating factor (G-CSF) (CAG) priming regimen is an effective treatment for patients with relapsed or...
The low-dose cytarabine, aclarubicin and granulocyte-colony stimulating factor (G-CSF) (CAG) priming regimen is an effective treatment for patients with relapsed or refractory acute myeloid leukemia (AML) and advanced myelodysplastic syndrome (MDS). G-CSF influences the bone marrow microenvironment (BMM) by mobilizing regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), as well as by reducing the expression of stromal cell-derived factor-1α (SDF-1α). In the present study, a WEHI-3-grafted BALB/c mouse AML model (AML-M4) was employed to determine how the BMM was altered by different treatment regimens. It was evident that CAG regimen decreased and increased the proportion of Tregs and MDSCs in the bone marrow and spleen, respectively. Furthermore, the CAG regimen downregulated SDF-1α levels in the bone marrow and peripheral blood. However, hematoxylin and eosin staining of the main organs revealed that leukemic cells infiltrated the liver following treatment with the CAG regimen. The present study indicates that the CAG regimen has a positive effect on the immunosuppressive microenvironment in AML and relieves AML-associated BMM immune suppression by decreasing Tregs and MDSCs in the bone marrow and downregulating the SDF-1α/CXCR4 axis in the bone marrow and peripheral blood.
PubMed: 30127892
DOI: 10.3892/ol.2018.9018 -
Cancer Pathogenesis and Therapy Apr 2024Acute myeloid leukemia (AML) is a heterogeneous hematopoietic malignancy whose prognosis is associated with several biomarkers. Decitabine, a deoxyribonucleic acid (DNA)...
BACKGROUND
Acute myeloid leukemia (AML) is a heterogeneous hematopoietic malignancy whose prognosis is associated with several biomarkers. Decitabine, a deoxyribonucleic acid (DNA) methyltransferase (DNMT) inhibitor, combined with cytarabine, aclarubicin hydrochloride, and granulocyte colony-stimulating factor (DCAG), has been used in patients newly diagnosed with AML. This regimen has been especially used in older and fragile patients who are immunocompromised or have co-morbidities, as well as those with specific gene mutations. However, the integration of molecular risk stratification and treatment guidance for the DCAG regimen has not been well defined. Therefore, this study aimed to investigate the genetic mutations associated with AML and establish appropriate treatment strategies for patients newly diagnosed with AML.
METHODS
This study analyzed the clinical data and genetic mutations based on next-generation sequencing (NGS) in 124 newly diagnosed patients with AML who received the DCAG regimen at the People's Liberation Army (PLA) General Hospital from January 2008 to August 2020. Factors associated with the cumulative incidence of relapse (CIR) and leukemia-free survival (LFS) in patients newly diagnosed with AML were analyzed.
RESULTS
The most adverse prognosis of DCAG-treated patients was observed in those with or mutations during univariable analysis, whereas mutation was solely significant in multivariable analysis, with an increased likelihood of CIR ( = 0.001) and reduced LFS duration ( = 0.077). Hyperleukocytosis was maintained as an independent risk factor for increased CIR risk ( = 0.044) and decreased LFS duration ( = 0.042) in multivariable analysis. In this study, we validated the risk classification of patients with AML receiving an epigenetic modifier-based induction regimen across a broad age range.
CONCLUSION
NGS demonstrated a dismal overall outcome in patients with the rare mutations, indicating the need for new therapies that target this high-risk subtype of AML. These results offer a potential molecular stratification and treatment guidance for patients with AML.
PubMed: 38601484
DOI: 10.1016/j.cpt.2023.10.002 -
Anti-cancer Drugs Jan 2022Some previous researches raised the possibility of a novel acute myeloid leukemia (AML) entity presenting cup-like cytomorphology with mutations of both FLT3 and NPM1 or...
Acute myeloid leukemia with cup-like blasts and FLT3-ITD and NPM1 mutations mimics features of acute promyelocytic leukemia: a case of durable remission after sorafenib and low-dose cytarabine.
Some previous researches raised the possibility of a novel acute myeloid leukemia (AML) entity presenting cup-like cytomorphology with mutations of both FLT3 and NPM1 or one of them. However, the clinical implications of this subtype remain unknown. We describe a 63-year-old patient belonging to this distinct AML subtype, who presented similar features of acute promyelocytic leukemia (APL) including nuclear morphology, negative for CD34 and HLA-DR, and abnormal coagulation. He had no response to both arsenic trioxide and CAG regimen (cytarabine, aclarubicin, and G-CSF). Given that the patient carried the FLT3-ITD mutation, we switched to a pilot treatment of FLT3 inhibitor sorafenib combined with low-dose cytarabine (LDAC). To date, the patient achieved durable complete remission over 58 months. These findings suggest that AML with cup-like blasts and FLT3-ITD and NPM1 mutations mimic APL, and the prognosis of this subtype may be improved by sorafenib combined with LDAC.
Topics: Antigens, CD34; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; HLA-DR Antigens; Humans; Leukemia, Myeloid, Acute; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Nucleophosmin; Sorafenib; fms-Like Tyrosine Kinase 3
PubMed: 34459465
DOI: 10.1097/CAD.0000000000001228