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OncoTargets and Therapy 2023The prognosis of patients with unfit or relapsed/refractory (R/R) AML remains poor. Venetoclax (VEN) has been shown to exhibit anti-leukemia stem cell activity; however,...
PURPOSE
The prognosis of patients with unfit or relapsed/refractory (R/R) AML remains poor. Venetoclax (VEN) has been shown to exhibit anti-leukemia stem cell activity; however, few studies have been published on the efficacy and safety of VEN combined with both hypomethylating agents (HMAs) and low-dose chemotherapy for patients with unfit or R/R AML.
METHODS
This study retrospectively analyzed the clinical characteristics, treatment details, safety profile and clinical outcomes of patients with unfit or R/R AML treated with VEN+ HMAs+ half-dose CAG (LDAC, aclarubicin and granulocyte colony-stimulating factor).
RESULTS
A total of 24 AML patients were involved in the study, of whom 13 (54.2%) were in the unfit group, and 11 (45.8%) were in the R/R group. and (8/24, 33.3%) were the most common gene aberrations. Patients in the R/R group were found to be more likely to carry (5/11, 45.5%) compared with the unfit group (0/13, 0%) ( = 0.006). The ORR observed during the study was 83.3% (20/24; 14 CR, 2CRi, 4PR). In the unfit group, 11/13 (84.6%) patients achieved cCR (10 CR and 1 CRi); while 5/11 (45.5%) R/R patients achieved response (4 CR and 1 CRi). CR was observed in all AML patients with (5/5), (3/3), (3/3) and (3/3). The most common adverse events (AEs) during VEN+ HMAs+ half-dose CAG therapy were persistent cytopenias and infections.
CONCLUSION
The results of this study confirm that VEN+ HMAs+ half-dose CAG is associated with promising efficacy (even high-risk molecular patterns) and tolerable safety profile in patients with unfit or R/R AML. Yet, the study involves only a small sample size, which should not be overlooked. As such, further studies on the efficacy of VEN combined with HMAs and half-dose CAG regimen in AML patients are essential.
PubMed: 37334144
DOI: 10.2147/OTT.S405611 -
Indian Journal of Cancer 2019Acute myeloid leukemia (AML) patients with non-remission (NR) after the first cycle of standard induction chemotherapy remain a challenge owing to poor response and...
Efficacy of high-dose cytarabine and aclarubicin in combination with G-CSF regimen compared to intermediate/high-dose cytarabine and standard-dose cytarabine induction regimen for non-remission acute myeloid leukemia.
BACKGROUND
Acute myeloid leukemia (AML) patients with non-remission (NR) after the first cycle of standard induction chemotherapy remain a challenge owing to poor response and tolerance to re-induction regimen. We retrospectively evaluated the efficacy and safety of three regimens in AML patients refractory to the first course of standard induction regimen.
MATERIALS AND METHODS
The three regimens consisted of (1) High-dose cytarabine, aclarubicin and granulocyte colony-stimulating factor (HD-CAG) regimen (n = 44); (2) intermediate/high-dose cytarabine (I/HDAC) regimen (n = 30); and (3) standard-dose cytarabine (SDAC) combination regimen that was identical to the first course of standard induction regimen (n = 27).
RESULTS
Results indicated that after the second course, the overall response (OR), i.e., complete remission [CR]+partial remission [PR]) rates in HD-CAG was higher than in the I/HDAC group (84.1% vs. 56.7%, P = 0.009), whereas the CR rates among 3 groups were not statistically different (P = 0.541). Meanwhile, the proportion of subjects reporting certain adverse effects in the HD-CAG group was lower than the I/HDAC or SDAC groups. There were no significant differences in overall survival (OS) and disease-free survival (DFS) rates among the 3 groups (P = 0.881 and P = 0.872, respectively).
CONCLUSION
Our preliminary results indicate that HD-CAG regimen may represent a better alternative option for AML patients with NR after the first course of standard induction chemotherapy.
Topics: Aclarubicin; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Disease-Free Survival; Dose-Response Relationship, Drug; Female; Granulocyte Colony-Stimulating Factor; Humans; Induction Chemotherapy; Leukemia, Myeloid, Acute; Male; Middle Aged; Remission Induction; Retrospective Studies
PubMed: 31062738
DOI: 10.4103/ijc.IJC_392_18 -
OncoTargets and Therapy 2019The chemotherapeutic regimen DCAG (decitabine with cytarabine, aclarubicin hydrochloride, and granulocyte colony-stimulating factor) is effective for elderly patients...
Clinical efficacy of decitabine in combination with standard-dose cytarabine, aclarubicin hydrochloride, and granulocyte colony-stimulating factor in the treatment of young patients with newly diagnosed acute myeloid leukemia.
The chemotherapeutic regimen DCAG (decitabine with cytarabine, aclarubicin hydrochloride, and granulocyte colony-stimulating factor) is effective for elderly patients with acute myeloid leukemia, but recommendations for young patients remain controversial. This study investigated the tolerance and efficacy of DCAG for patients with newly diagnosed acute myeloid leukemia (aged 14-60 years). The clinical features or molecular markers that may predict response to DCAG were identified. One-hundred sixty-one consecutive patients with newly diagnosed acute myelogenous leukemia received DCAG or standard (idarubicin plus cytarabine, IA) induction chemotherapy (n=64 and 97, respectively). The rates of complete remission after the first cycle, overall survival (OS), and event-free survival (EFS) were comparable. After the second cycle, the complete remission rate of the DCAG group (54.7%) was significantly lower than that of the reference (78.35%, =0.005). The following were associated with significantly worse OS, and EFS, in the DCAG group: Eastern Cooperative Oncology Group (ECOG) score ≥3 and no response after the second induction therapy; and FLT3-ITD. The multivariate analysis showed the DCAG group with significantly shorter OS associated with ECOG ≥3 and FLT3-ITD. In the DCAG group, after the first cycle of induction chemotherapy the median recovery times of neutrophils and platelets were 15.8 and 13 days. The DCAG and IA groups were similar with regard to complete remission rate after the first cycle, OS, and EFS. The complete remission rate after the second cycle of the DCAG was significantly lower than that of the IA. Grade 4 neutropenia and thrombocytopenia were a major adverse event associated with DCAG.
PubMed: 31303761
DOI: 10.2147/OTT.S200005 -
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 -
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 -
BioRxiv : the Preprint Server For... Jan 2023Anthracyclines are a class of widely prescribed anti-cancer drugs that disrupt chromatin by intercalating into DNA and enhancing nucleosome turnover. To understand the...
Anthracyclines are a class of widely prescribed anti-cancer drugs that disrupt chromatin by intercalating into DNA and enhancing nucleosome turnover. To understand the molecular consequences of anthracycline-mediated chromatin disruption, we utilized CUT&Tag to profile RNA polymerase II during anthracycline treatment in cells. We observed that treatment with the anthracycline aclarubicin leads to elevated levels of elongating RNA polymerase II and changes in chromatin accessibility. We found that promoter proximity and orientation impacts chromatin changes during aclarubicin treatment, as closely spaced divergent promoter pairs show greater chromatin changes when compared to codirectionally-oriented tandem promoters. We also found that aclarubicin treatment changes the distribution of non-canonical DNA G-quadruplex structures both at promoters and at G-rich pericentromeric repeats. Our work suggests that the anti-cancer activity of aclarubicin is driven by the effects of nucleosome disruption on RNA polymerase II, chromatin accessibility and DNA structures.
PubMed: 36712130
DOI: 10.1101/2023.01.09.523323 -
Medicine Mar 2023This study aimed to explore the effects of recombinant human thrombopoietin (rhTPO) on platelet recovery in decitabine, cytarabine, aclarubicin, and G-CSF (DCAG)-treated...
BACKGROUND
This study aimed to explore the effects of recombinant human thrombopoietin (rhTPO) on platelet recovery in decitabine, cytarabine, aclarubicin, and G-CSF (DCAG)-treated patients with intermediate-high-risk myelodysplastic syndrome/hypo proliferative acute myeloid leukemia.
METHODS
Recruited patients were at a ratio of 1:1 into 2 groups: the rhTPO group (DCAG + rhTPO) and control group (DCAG). The primary endpoint was the time for platelets to recover to ≥ 20 × 109/L. The secondary endpoints were the time for platelets to recover to ≥ 30 × 109/L and ≥ 50 × 109/L, overall survival (OS), and progression-free survival (PFS).
RESULTS
The time required for platelet recovery to ≥ 20 × 109/L, ≥30 × 109/L, and ≥ 50 × 109/L in the rhTPO group was significantly shorter (6.5 ± 2.2 vs 8.4 ± 3.1 days, 9.0 ± 2.7 vs 12.2 ± 3.9 days, 12.4 ± 4.7 vs 15.5 ± 9.3 days, respectively; all P < .05 vs controls). The amount of platelet transfusion in the rhTPO group was smaller (4.4 ± 3.1 vs 6.1 ± 4.0 U, P = .047 vs controls). The bleeding score was lower (P = .045 vs controls). The OS and PFS were significantly different (P = .009 and P = .004). The multivariable analysis showed that age, karyotype, and time for PLT recovery to ≥ 20 × 109/L were independently associated with OS. Adverse events were similar.
CONCLUSIONS
This study suggests that rhTPO leads to a faster platelet recovery after DCAG treatment, reduces the risk of bleeding, reduces the number of platelet transfusions, and prolongs the OS and PFS.
Topics: Humans; Thrombopoietin; Blood Platelets; Recombinant Proteins; Myelodysplastic Syndromes; Leukemia, Myeloid, Acute
PubMed: 37000082
DOI: 10.1097/MD.0000000000033373 -
Frontiers in Bioengineering and... 2024Daunorubicin and doxorubicin, two anthracycline polyketides produced by , are potent anticancer agents that are widely used in chemotherapy, despite severe side...
Daunorubicin and doxorubicin, two anthracycline polyketides produced by , are potent anticancer agents that are widely used in chemotherapy, despite severe side effects. Recent advances have highlighted the potential of producing improved derivatives with reduced side effects by incorporating l-rhodosamine, the -dimethyl analogue of the native amino sugar moiety. In this study, we aimed to produce -dimethylated anthracyclines by engineering the doxorubicin biosynthetic pathway in the industrial strain G001. To achieve this, we introduced genes from the aclarubicin biosynthetic pathway encoding the sugar -methyltransferases AclP and AknX2. Furthermore, the native gene for glycosyltransferase DnrS was replaced with genes encoding the aclarubicin glycosyltransferases AknS and AknT. Additionally, the gene for methylesterase RdmC from the rhodomycin biosynthetic pathway was introduced. A new host was engineered successfully, whereby genes from the aclarubicin pathway were introduced and expressed. LC-MS/MS analysis of the engineered strains showed that dimethylated sugars were efficiently produced, and that these were incorporated ino the anthracycline biosynthetic pathway to produce the novel dimethylated anthracycline -dimethyldaunorubicin. Further downstream tailoring steps catalysed by the cytochrome P450 monooxygenase DoxA exhibited limited efficacy with -dimethylated substrates. This resulted in only low production levels of -dimethyldaunorubicin and no -dimethyldoxorubicin, most likely due to the low affinity of DoxA for dimethylated substrates. G001 was engineered such as to produce -dimethylated sugars, which were incorporated into the biosynthetic pathway. This allowed the successful production of -dimethyldaunorubicin, an anticancer drug with reduced cytotoxicity. DoxA is the key enzyme that determines the efficiency of the biosynthesis of -dimethylated anthracyclines, and engineering of this enzyme will be a major step forwards towards the efficient production of more -dimethylated anthracyclines, including -dimethyldoxorubicin. This study provides valuable insights into the biosynthesis of clinically relevant daunorubicin derivatives, highlighting the importance of combinatorial biosynthesis.
PubMed: 38481571
DOI: 10.3389/fbioe.2024.1363803 -
Cancer Chemotherapy and Pharmacology 1993Aclarubicin is an anthracycline antibiotic that differs from doxorubicin in its structure, mechanism of action, and preclinical toxicity profile, especially its reduced... (Clinical Trial)
Clinical Trial
Aclarubicin is an anthracycline antibiotic that differs from doxorubicin in its structure, mechanism of action, and preclinical toxicity profile, especially its reduced cardiotoxicity. We therefore conducted a side-by-side in vivo and in vitro trial of this agent in metastatic breast-cancer patients and their biopsied tumor specimens, respectively. Aclarubicin (100 mg/m2) was given by intravenous infusion every 3 weeks to 22 patients with objectively measurable metastatic breast cancer, 15 of whom had not previously received doxorubicin. The dose-limiting toxicity consisted primarily of leukopenia and severe nausea and vomiting. No objective response was observed in the 19 evaluable patients. After disease progression, 10 of the 15 doxorubicin-naive patients were treated with doxorubicin; 6 patients achieved a partial response, including 4 who responded to doxorubicin alone and 2 who responded to doxorubicin in combination with thiotepa and vinblastine. Tumor specimens were obtained from 14 of the 22 patients prior to the start of therapy and were tested for in vitro sensitivity to aclarubicin and doxorubicin using a soft agar colony-forming assay. Adequate colony growth occurred in 9 of 14 cultured tumor specimens. All 9 specimens, including 3 obtained from doxorubicin-naive patients, demonstrated in vitro resistance to aclarubicin. In all, 1 of 3 specimens taken from doxorubicin-naive patients demonstrated in vitro sensitivity to doxorubicin, whereas 6 tumor specimens obtained from patients who had undergone prior doxorubicin therapy demonstrated in vitro resistance. The patient whose tumor demonstrated in vitro doxorubicin sensitivity responded to a doxorubicin regimen after failing aclarubicin treatment; in vitro doxorubicin resistance correlated with clinical resistance in all cases. We conclude that aclarubicin is inactive in metastatic breast cancer at the dose and schedule used. Side-by-side in vivo and in vitro trials are feasible and could be useful in the development of investigational agents with activity greater than that of aclarubicin and, particularly, in the evaluation of analogs of clinically active drugs.
Topics: Aclarubicin; Adult; Aged; Breast Neoplasms; Doxorubicin; Drug Resistance; Female; Humans; In Vitro Techniques; Middle Aged; Neoplasm Metastasis; Treatment Outcome; Tumor Stem Cell Assay
PubMed: 8453689
DOI: 10.1007/BF00685040 -
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