aclarubicin

P2, N=106, Not yet recruiting, Jiangsu Province Hospital; Jiangsu Province Hospital

After a regimen of ruxolitinib, VICLP (Vincristine, Idarubicin, Cyclophosphamide, Prednisone, Peg-asparaginase) regimen, high-dose cytarabine, and methotrexate regimens, the patient's bone marrow condition partially resolved. However, when the disease relapsed four months later, despite attempts with selinexor, venetoclax, and CAG(aclarubicin hydrochloride, Algocytidine, Granulocyte Stimulating Factor) chemotherapy, the leukocytes and peripheral blood primitive cells reduced, but the bone marrow did not achieve remission. This pathogenesis may be related to microenvironmental immune escape under prolonged inflammatory stimulation and gene disruption affecting protein function due to colony-stimulating factor 3 receptor gene (CSF3R) mutations. For this type of disease, early intervention may delay disease progression.

Doxorubicin, daunorubicin, epirubicin, and idarubicin have been in clinical use for decades, but their application remains complicated by treatment-related toxicities and drug resistance. Among these, N,N-dimethyl-idarubicin and anthracycline (composed of the idarubicin aglycon and the aclarubicin trisaccharide) stand out, due to their histone eviction-mediated cytotoxicity toward doxorubicin-resistant cells. Our findings thus uncover understudied anthracycline variants warranting further investigation in the quest for safer and more effective anticancer agents that circumvent cellular export by ABCB1.

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. NGS demonstrated a dismal overall outcome in patients with the rare PTPN11 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.

NCOR1::GLYR1 gene is considered as the pathogenic factor for the MDS/MPN patient with neutropenia.

The FLT3 inhibitor gilteritinib was administered for reinduction therapy after failure of chemotherapy with a combination of venetoclax, decitabine, aclarubicin, cytarabine and granulocyte colony-stimulating factor. Similar cases of Sweet syndrome following FLT3 inhibitor therapy for acute myeloid leukemia were reviewed. Attention should be given to this rare complication when FLT3 inhibitors are used for acute myeloid leukemia therapy, and appropriate treatments need to be administered in a timely manner.

To achieve this, we introduced genes from the aclarubicin biosynthetic pathway encoding the sugar N-methyltransferases AclP and AknX2. DoxA is the key enzyme that determines the efficiency of the biosynthesis of N,N-dimethylated anthracyclines, and engineering of this enzyme will be a major step forwards towards the efficient production of more N,N-dimethylated anthracyclines, including N,N-dimethyldoxorubicin. This study provides valuable insights into the biosynthesis of clinically relevant daunorubicin derivatives, highlighting the importance of combinatorial biosynthesis.

Recently, several DNA intercalators have attracted much interest given their ability to inhibit RNA Polymerase I transcription (BMH-21), evict histones (Aclarubicin) or induce chromatin trapping of FACT (Curaxin CBL0137)...These DNA intercalators have a cumulative impact on general transcription machinery by inducing accumulation of topological defects and impacting nuclear chromatin. Therefore, their cytotoxic capabilities may be the result of compounding deleterious effects on chromatin homeostasis.

The CDCAG regimen was effective and well-tolerated in R/R AML patients, increasing the potential for allogeneic hematopoietic stem cell transplantation. Moreover, patients with DNMT3A, TET2, and IDH1/2 mutations might benefit from this regimen.

Out of the total, 7 patients were treated with CAG/HAG regimen (C: aclarubicin 6mg d1-14, H: homoharringtonine 1mg/m 2d1-14, A: cytarabine 10mg/m 2 q12h d1-14, and G: Granulocyte Colony-stimulating Factor 200mg/m 2 d1-14 ), 8 patients with decitabine (20mg/m 2 d1-5), 11 patients with decitabine and CAG/HAG, 4 patients with AML-like chemotherapy (Daunorubicin+cytarabine+etoposide ) or other. Decitabine combined with CAG/HAG improve the response rate of advanced pediatric MDS. Chemotherapy bridged hematopoietic stem cell transplantation significantly improves the prognosis of advanced pediatric MDS.

The selinexor-containing regimens used in this study were either selinexor (35mg/m 2 biw) alone or in combination with other drugs (decitabine, azacytidine, venetoclax, low-dose cytarabine, and CAG (cytarabine, aclarubicin, G-CSF) regimen). Selinexor-containing regimens have been shown to be effective and well tolerated in post-transplant AML/MDS patients with MRD-positive, including those who have failed first-line preemptive treatment.

In conclusion, HMAs plus modified priming regimens might be a potential alternative therapeutic approach for patients with ND AML, but VEN-based regimens presented predominance in specific molecular subgroups. Molecular characteristics contribute to guiding choice of treatment.

P2, N=200, Recruiting, Chinese PLA General Hospital

P2, N=200, Recruiting, Chinese PLA General Hospital

Cells were treated with adriamycin (ADR), etoposide, aclacinomycin and daunorubicin. Additionally, NOD2 silencing or NF-κB signaling pathway inhibition increased the apoptotic rate. The results of this study indicate that NOD2 promotes cell apoptosis and reduces the drug resistance of CLL by inhibiting the NF-κB signaling pathway.

The HAA regimen as first induction chemotherapy resulted in a higher CR/CRi rate in AML patients with RUNX1::RUNX1T1, especially those harboring KIT and non-D816 KIT mutation, and a more favorable RFS compared with the IA regimen. The efficacy between the two regimens did not differ in those with CBFB::MYH11.

P3, N=50, Recruiting, Shanxi Bethune Hospital | Phase classification: P1 --> P3

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). 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.

The common grades 3-4 adverse events were nausea (100%), thrombocytopenia (39%) and neutropenia (37.5%). The CAG regimen may have activity in CBF-AML patients and could provide a new option for patients who have a poor molecular response to high/intermediate-dose cytarabine.

P3, N=170, Recruiting, The First Affiliated Hospital with Nanjing Medical University | Trial primary completion date: Feb 2023 --> Jun 2023

Venetoclax combined with chemotherapy or azacytidine or low-dose cytarabine has shown efficacy in adults with AML...Patients received induction treatment with venetoclax (100 mg on day 2, 200 mg on day 3, and 300 mg on days 4–10), homoharringtonine (2 mg/m² on days 1–5), cytarabine (100 mg/m² on days 1–5), and aclarubicin (12 mg/m² on days 1–5) (VHAA regimen)... The VHAA regimen represents an effective induction therapy for newly diagnosed adults with acute myeloid leukaemia, which resulted in a high rate of composite complete remission. These findings showing a safe strategy to incorporate venetoclax combined homoharringtonine-based induction regimens to treat newly diagnosed acute myeloid leukaemia.

After diagnosis, 4 cases received IAE induction regimen (idarubicin, cytarabine and etoposide), 1 case received MAE induction regimen (mitoxantrone, cytarabine and etoposide), 1 case received DAH induction regimen (daunorubicin, cytarabine and homoharringtonine) and 1 case received DAE induction regimen (daunorubicin, cytarabine and etoposide)...Four cases who did not achieved complete remission received CAG (aclarubicin, cytarabine and granulocyte colony-stimulating factor), IAH (idarubicin, cytarabine and homoharringtonine), CAG combined with cladribine, and HAG (homoharringtonine, cytarabine and granulocyte colony-stimulating factor) combined with cladribine reinduction therapy, respectively, all 4 cases reached complete remission...Low remission rate by chemotherapy only and very high recurrence rate indicate its high malignancy and poor prognosis. Early HSCT after the first complete remission can improve its prognosis.

Cases of remission following vit C supplementation have been reported (Foster M, Antioxidants, 2018; Das A, Blood Cancer J, 2019) and a small study showed that the addition of vit C to decitabine/AraC/aclarubicin/G-CSF improved outcome compared to DCAG (Zhao H, Leuk Res 2018). Normal Vit D levels can be restored before transplant, which may be important. The potential impact of vit C/D supplementation in AML with NPM1 mutations needs further studies and pave the way for exploratory analyses to explain how the VDR pathway and/or vit C activity may interact with the biology of NPM1 mutation.

There was no early death. In conclusion, DAC+HAAG regimen is effective and well-tolerated as induction therapy in patients with newly diagnosed AML.

Homoharringtonine- (HHT-) based HHT, aclarubicin, and cytarabine (HAA) induction regimen is the first-line therapy for nonelder acute myeloid leukemia (AML) patients in China. In addition, these two genes have prognostic significance for AML patients. Taken together, we successfully constructed HHT-resistant cell lines with dynamic RIs and explored the resistance mechanisms, which will help identify new drugs for HHT-resistant AML patients.

P=N/A, N=132, Recruiting, Institute of Hematology & Blood Diseases Hospital | Trial completion date: Dec 2022 --> Dec 2024 | Trial primary completion date: Dec 2021 --> Dec 2024

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.

Herein, we found that the erythroid differentiation inducers activin A and aclacinomycin A induced expression of erythroid markers (α-globin, ζ-globin, GATA-1, and glycophorin A) and simultaneously reduced CD69 levels in K562 CML cells. These results suggest that CD69 inhibits activin A induction of erythroid differentiation-mediated CML cell sensitivity to imatinib via MT2A. Therefore, activin A induction of erythroid differentiation sensitizes BCR-ABL-positive cells to imatinib by downregulating the erythroid differentiation suppressors CD69 and MT2A.

The patients received Azacytidine 75 mg/m 2 subcutaneously daily, day 1-7 or Decitabine 20 mg/m 2 intravenously daily, day 1-5 plus CAG regimen (cytarabine 100 mg intravenously every 12 hours, day 1-5; aclarubicin 20 mg intravenously daily, day 1-5; and concurrent use of G-CSF 5 mg/kg/day subcutaneously) with Tislelizumab 200 mg beginning on the next day after chemotherapy was stopped and every 4 weeks thereafter. IRAEs are mild, low-grade. Special attention needs to be paid to patients who have an increased risk of developing graft-versus-host disease.

P3, N=170, Recruiting, The First Affiliated Hospital with Nanjing Medical University

She did not achieve CR by salvage chemotherapy with cytarabine-aclarubicin-G-CSF regimen. Finally, the patient died of the uncontrolled primary disease. This is a case in which comprehensive gene mutation analysis was useful in determining a treatment strategy.

The patient was resistant to venetoclax combined with decitabine, homoharringtonine, aclarubicin, cytarabine and granulocyte colony stimulating factor (G-CSF), high-dose cytarabine combined with cladribine, G-CSF, chidamide and CD38 CART therapy...Grade 3 cytokine release syndrome with high fever and hypotension were observed, which was relived by tocilizumab and dexamethosone. No organ dysfuction and immune effector cell-associated neurotoxicity syndrome were observed. In general, we showed for the first time that the nanobody derived CD7-CART with PEBL technology was a potent and safe salvage therapy in a relapsed/refractory ETP-ALL/LBL patient with high tumor burden.

A total of 331 patients with AML who were treated with intensive chemotherapy (young patients, n=179) or D-CAG regimen (older patients, n=152) were enrolled in this study.The young patients received IA regimen (idarubicin 10-12 mg/m 2 on days 1 to 3 and cytarabine 100 mg/m 2 /d on days 1 to 7) as induction...The D-CAG regimen (decitabine 15 mg/m 2 intravenously on days 1-5, cytarabine 10 mg/m 2 subcutaneous injection twice daily on days 3-9, aclarubicin 8-10 mg/m 2 /d on days 3-6, and G-CSF 300 μg/d for priming until white blood cell count was >20×10 9 /L) was given to the older patients... Intensive chemotherapy had little effect on the prognosis of intermediate- or high-risk young patients who did not undergo allo-HSCT. Patients harboring FLT3-ITD , DNMT3A , IDH2 , TP53 and DNA methylation associated mutations were found to benefit more from the D-CAG regimen in comparison to intensive chemotherapy.

Selected therapeutics were standard chemotherapy (n = 182, 84.3%, including CAG regimen; cytarabine, aclarubicin and G-CSF), hypomethylating agents or low-dose cytarabine (n = 19, 8.8%), and best supportive care (n = 15, 6.9%). PB or BM-WT1 low in intermediate-risk AML was associated with a poor prognosis. In standard-risk AML, WT1 mRNA may be a useful pan-marker to predict prognosis at diagnosis.

P3, N=315, Recruiting, CSPC ZhongQi Pharmaceutical Technology Co., Ltd. | Not yet recruiting --> Recruiting

He had no response to both arsenic trioxide and CAG regimen (cytarabine, aclarubicin, and G-CSF). 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.

P3, N=315, Not yet recruiting, CSPC ZhongQi Pharmaceutical Technology Co., Ltd.

No abstract available

Then, we screened a chemical library of > 1500 FDA-approved drugs and > 25,000 novel compounds in the ZINC database to find established drugs targeting BRAF47-438del and PIK3R1-G376R mutated proteins. Results Several compounds (including anthracyclines) bound with higher affinities than the control drugs (sorafenib and vemurafenib for BRAF and PI-103 and LY-294,002 for PIK3R1). Aclarubicin revealed higher cytotoxicity than both sorafenib and vemurafenib, whereas idarubicin and daunorubicin revealed higher cytotoxicity than LY-294,002. Liposomal formulations of anthracyclines may be suitable to cross the blood brain barrier. Conclusions In conclusion, we identified novel small molecules via a drug repurposing approach that could be effectively used for personalized glioblastoma therapy especially for patients carrying BRAF47-438del and PIK3R1-G376R mutations.