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1.
Mol Cancer ; 23(1): 120, 2024 Jun 04.
Article in English | MEDLINE | ID: mdl-38831402

ABSTRACT

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.


Subject(s)
Aclarubicin , Anthracyclines , Leukemia, Myeloid, Acute , Animals , Female , Humans , Male , Aclarubicin/pharmacology , Aclarubicin/therapeutic use , Anthracyclines/therapeutic use , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/pharmacology , Antineoplastic Agents/adverse effects , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/mortality , Treatment Outcome
2.
Curr Med Sci ; 43(6): 1151-1161, 2023 Dec.
Article in English | MEDLINE | ID: mdl-38057538

ABSTRACT

OBJECTIVE: Preclinical evidence and clinical trials have suggested synergistic effects of epigenetic modifiers in combination with cytotoxic agents for the treatment of leukemia. However, their efficacy in patients with relapsed/refractory acute myeloid leukemia (R/R AML) remains unclear. METHODS: Clinical data of R/R AML patients who received a CDCAG regimen (chidamide, decitabine, cytarabine, aclarubicin, and granulocyte colony-stimulating factor) from July 1, 2018 to October 31, 2021 at our center were retrospectively assessed, and the safety and efficacy of the CDCAG regimen were evaluated. Patients were followed up until November 30, 2021, with a median follow-up of 21.6 months (95% CI: 10.0-33.2 months). RESULTS: A total of 67 patients were enrolled. Two patients died within 3 weeks after the initiation, and therefore only 65 patients underwent the assement for clinical response and survival. It was found that 56.9% patients achieved complete remission with a median overall survival (OS) of 9.6 months. The median OS of responders was 25.9 months, while that of non-responders was 5.0 months (P<0.0001). Patients with gene mutations had a superior overall response rate (ORR) (80.4% vs. 45.5%, P=0.043) compared to those without gene mutations. The presence of DNA methyltransferase 3 A (DNMT3A), ten-eleven translocation-2 (TET2), and isocitrate dehydrogenase 1/2 (IDH1/2) mutations did not affect the response rate (88.2% vs. 68.9%, P=0.220) and reflected a better OS (not attained vs. 9.0 months, P=0.05). The most common non-hematologic adverse events were pulmonary infection (73.1%), followed by febrile neutropenia (23.9%) and sepsis (19.4%). CONCLUSIONS: 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.


Subject(s)
Cytarabine , Leukemia, Myeloid, Acute , Humans , Cytarabine/therapeutic use , Retrospective Studies , Decitabine/therapeutic use , Granulocyte Colony-Stimulating Factor/therapeutic use , Aclarubicin/therapeutic use , Treatment Outcome , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/genetics
3.
Med Oncol ; 40(2): 77, 2023 Jan 10.
Article in English | MEDLINE | ID: mdl-36625951

ABSTRACT

Chemotherapy followed by donor lymphocyte infusion (DLI) is a promising treatment for relapsed acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, the best strategy for administering this therapy is still unclear. This study sought to explore the efficacy and safety of chidamide and CAG (cytarabine, aclarubicin, and granulocyte colony-stimulating factor) (CCAG) regimen followed by DLI in relapsed AML/MDS after allo-HSCT. This was a single-arm, phase II trial in patients with relapsed AML/MDS after allo-HSCT. CCAG regimen followed by DLI was given according to the inclusion and exclusion criteria. Twenty adult patients were enrolled. The median follow-up time was 12 months. The complete remission (CR) rate was 45% and the partial remission (PR) rate was 5%. The 1-year overall survival (OS) was 56.7% (95% confidence interval (95% CI), 31.6-75.6%), and the median OS was 19 months. The 1-year relapse-free survival (RFS) was 83.3% (95% CI, 27.3-97.5%). Patients relapsing more than 6 months after HSCT and achieving CR/PR after CCAG plus DLI regimen attained significantly higher survival rates. The cumulative incidence of grade III-IV acute graft-versus-host disease (aGVHD) was 9.4%. There was no treatment-related mortality (TRM). These data suggest that CCAG plus DLI regimen is safe and induces durable remission and superior survival in patients with relapsed AML/MDS after allo-HSCT. Trial registration number: ChiCTR.org identifier: ChiCTR1800017740 and date of registration: August 12, 2018.


Subject(s)
Graft vs Host Disease , Hematopoietic Stem Cell Transplantation , Leukemia, Myeloid, Acute , Myelodysplastic Syndromes , Adult , Humans , Aclarubicin/therapeutic use , Leukemia, Myeloid, Acute/drug therapy , Cytarabine/adverse effects , Hematopoietic Stem Cell Transplantation/adverse effects , Myelodysplastic Syndromes/drug therapy , Granulocyte Colony-Stimulating Factor , Lymphocytes , Recurrence , Graft vs Host Disease/etiology
4.
Oxid Med Cell Longev ; 2022: 8212286, 2022.
Article in English | MEDLINE | ID: mdl-35873796

ABSTRACT

Objective: The prognosis of children with refractory acute myeloid leukemia (AML) is poor. Complete remission (CR) is not always achieved with current salvage chemotherapy regimens before transplantation, and some patients have no chance of transplantation. Here, we aimed to describe a new regimen of conventional chemotherapy drugs (homoharringtonine, cladribine , and aclarubicin (HCA)) for refractory AML and its mechanism in vitro. Methods: We retrospectively collected the clinical data of 5 children with primary refractory AML using HCA as reinduction chemotherapy, and CR rates, adverse reactions, and disease-free survival (DFS) were analyzed. The effects of homoharringtonine, cladribine, and aclarubicin alone or in combination on the proliferation of HL60 and THP1 cells were analyzed by CCK-8 assay. Furthermore, CCK-8 was used to determine the effects of HCA, alone or in combination with apoptosis inhibitors, necroptosis inhibitors, ferroptosis inhibitors, or autophagy inhibitors, on the proliferation of HL60 and THP1 cells and to screen for possible HCA-mediated death pathways in AML cells. The pathway of HCA-mediated AML cell death was further verified by Hoechst/PI staining, flow cytometry, and Western blotting. Results: After 2 cycles of conventional chemotherapy, none of the 5 children with AML achieved CR and were then treated with the HCA regimen for two cycles, 4 of 5 achieved CR, and another child achieved CR with incomplete hematological recovery (CRi). After CR, 3 children underwent hematopoietic stem cell transplantation (HSCT), and only 2 of them received consolidation therapy. As of the last follow-up, all 5 patients had been in DFS for a range of 23 to 28 months. The inhibition rate of homoharringtonine, cladribine, and aclarubicin in combination on HL60 and THP1 cells was significantly greater than that of a single drug or a combination of two drugs. We found that inhibitors of apoptosis and necroptosis were able to inhibit HCA-mediated cell death but not ferroptosis or autophagy inhibitors. Compared with the control group, the number of apoptotic cells in the HCA group was significantly increased and could be reduced by an apoptosis inhibitor. Western blot results showed that PARP, caspase-3, and caspase-8 proteins were activated and cleaved in the HCA group, the expression of Bax was upregulated and that of Bcl-2 was downregulated. The expression of apoptosis-related proteins could be reversed by apoptosis inhibition. Compared with the control group, the expression levels of the necroptosis-related proteins RIP1, RIP3, and MLKL were downregulated in the HCA group but were not phosphorylated. The necroptosis inhibitor increased the expression of RIP1 but caused no significant changes in RIP3 and MLKL, and none were phosphorylated. Conclusions: 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.


Subject(s)
Aclarubicin , Cladribine , Homoharringtonine , Leukemia, Myeloid, Acute , Aclarubicin/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Child , Cladribine/therapeutic use , Granulocyte Colony-Stimulating Factor , Homoharringtonine/therapeutic use , Humans , Leukemia, Myeloid, Acute/drug therapy , Retrospective Studies
5.
Anticancer Drugs ; 33(7): 614-621, 2022 08 01.
Article in English | MEDLINE | ID: mdl-35324522

ABSTRACT

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal types of cancer, mainly due to its delayed diagnosis and lack of effective therapeutic options. Therefore, it is imperative to find novel treatment options for PDAC. Here, we tested a series of conventional chemotherapeutics together with anthracycline compounds as single agents or in combination, determining their effectivity against established commercial and patient-derived, low-passage PDAC cell lines. Proliferation and colony formation assays were performed to determine the anticancer activity of anthracyclines; aclarubicin and doxorubicin, on commercial and patient-derived, low-passage PDAC cell lines. In addition, the effect of standard-of-care drugs gemcitabine and individual components of FOLFIRINOX were also investigated. To evaluate which mechanisms of cell death were involved in drug response, cleavage of poly(ADP-ribose)polymerase was evaluated by western blot. Aclarubicin showed superior antitumor activity compared to other anthracyclines and standard of care drugs (gemcitabine and individual components of FOLFIRINOX) in a patient-derived, low-passage PDAC cell line and in commercial cell lines. Importantly, the combination of gemcitabine and aclarubicin showed a synergistic effect at a dose range where the single agents by themselves were ineffective. In parallel, evaluation of the antitumor activity of aclarubicin demonstrated an apoptotic effect in all PDAC cell lines. Aclarubicin is cytotoxic for commercial and patient-derived low-passage PDAC cell lines, at doses lower than peak serum concentrations for patient treatment. Our findings support a (re)consideration of aclarubicin as a backbone of new combination regimens for pancreatic cancer patients.


Subject(s)
Antineoplastic Agents , Carcinoma, Pancreatic Ductal , Pancreatic Neoplasms , Aclarubicin/pharmacology , Aclarubicin/therapeutic use , Anthracyclines/pharmacology , Anthracyclines/therapeutic use , Antibiotics, Antineoplastic/pharmacology , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Apoptosis , Carcinoma, Pancreatic Ductal/metabolism , Cell Line, Tumor , Cell Proliferation , Cytotoxins/pharmacology , Cytotoxins/therapeutic use , Humans , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/metabolism , Pancreatic Neoplasms
6.
Clin. transl. oncol. (Print) ; 23(1): 48-57, ene. 2021.
Article in English | IBECS | ID: ibc-220449

ABSTRACT

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 (AU)


Subject(s)
Humans , Male , Female , Adult , Middle Aged , Aged , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/mortality , Induction Chemotherapy/methods , Antineoplastic Agents, Phytogenic/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Cytarabine/therapeutic use , Aclarubicin/therapeutic use , Retrospective Studies , Risk Factors , Retreatment , Remission Induction
8.
Clin Transl Oncol ; 23(1): 48-57, 2021 Jan.
Article in English | MEDLINE | ID: mdl-32458310

ABSTRACT

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.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Homoharringtonine/therapeutic use , Induction Chemotherapy/methods , Leukemia, Myeloid, Acute/drug therapy , Aclarubicin/adverse effects , Aclarubicin/therapeutic use , Aged , Antineoplastic Agents, Phytogenic/administration & dosage , Antineoplastic Agents, Phytogenic/adverse effects , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Cytarabine/adverse effects , Cytarabine/therapeutic use , Drug Administration Schedule , Female , Granulocyte Colony-Stimulating Factor/adverse effects , Granulocyte Colony-Stimulating Factor/therapeutic use , Homoharringtonine/adverse effects , Humans , Induction Chemotherapy/adverse effects , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/mortality , Male , Middle Aged , Progression-Free Survival , Remission Induction , Retreatment/methods , Retrospective Studies , Risk Factors , Salvage Therapy , Single-Blind Method , Time Factors , Treatment Failure
10.
Clin Epigenetics ; 12(1): 132, 2020 09 01.
Article in English | MEDLINE | ID: mdl-32873343

ABSTRACT

BACKGROUND: Epigenetic mechanisms play an important role in the chemoresistance of acute myeloid leukemia (AML). The clinical response to epigenetic modifier-based chemotherapy in patients with relapsed/refractory AML (r/r AML) is unclear. This multicenter clinical trial evaluated the safety and efficacy of epigenetic modifiers (chidamide and decitabine) in combination with aclarubicin, cytarabine, and granulocyte colony-stimulating factor (G-CSF) in patients with r/r AML. RESULTS: Adult patients with r/r AML were treated with chidamide, decitabine, cytarabine, aclarubicin, and G-CSF (CDCAG). The primary measures were overall response (OR), overall survival (OS), and safety. Next-generation sequencing was performed to analyze the correlation between gene mutations and response. A total of 93 patients with r/r AML were enrolled. Overall, 24 patients had a complete remission (CR) and 19 patients achieved CR with incomplete blood count recovery (CRi). The overall response rate (ORR) was 46.2%. The overall survival of these 43 patients who achieved CR/CRi was significantly longer than that of patients who failed to achieve remission (563 vs 152 days, P < 0.0001). Of the patients with mutations in epigenetic and transcription factor-related genes, but without internal tandem duplications in FMS-like tyrosine kinase3 (FLT3-ITDs), 55.6% achieved CR/CRi, whereas the ORR was 28.2% for patients with mutations in other genes. CONCLUSIONS: The CDCAG regimen was well tolerated and effective in r/r AML. Patients with epigenetic and transcription factor-related gene mutations, but without FLT3-ITD mutations, may benefit from this regimen. TRIAL REGISTRATION: Clinical Trials, NCT02886559 . Registered 01 September 2016.


Subject(s)
Aclarubicin/therapeutic use , Aminopyridines/therapeutic use , Benzamides/therapeutic use , Cytarabine/therapeutic use , Decitabine/therapeutic use , Granulocyte Colony-Stimulating Factor/therapeutic use , Leukemia, Myeloid, Acute/drug therapy , Adolescent , Adult , Antibiotics, Antineoplastic/therapeutic use , Antimetabolites, Antineoplastic/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Disease-Free Survival , Female , Humans , Male , Middle Aged , Remission Induction , Treatment Outcome , Young Adult
11.
Oncologist ; 25(11): e1663-e1670, 2020 11.
Article in English | MEDLINE | ID: mdl-32845551

ABSTRACT

LESSONS LEARNED: Studies targeting cladribine in combination with granulocyte colony-stimulating factor, low-dose cytarabine, and aclarubicin (C-CAG) regimen in relapsed and refractory acute myeloid leukemia (R/R AML) are limited. The complete remission rate after two cycles of C-CAG regimen was 67.6%, and 1-year overall survival and disease-free survival rates were 59.7% and 72.9%, respectively. The C-CAG regimen is significantly effective against R/R AML with a low hematological toxicity and thus serves as an alternative treatment for R/R AML. BACKGROUND: The optimal salvage chemotherapy regimen for relapsed and refractory acute myeloid leukemia (R/R AML) remains uncertain. Therefore, a phase II study was conducted for the prospective evaluation of the efficacy and safety of the purine analog cladribine in combination with granulocyte colony-stimulating factor (G-CSF), low-dose cytarabine, and aclarubicin (C-CAG) regimen for patients with R/R AML. METHODS: A total of 34 patients received C-CAG regimen for salvage treatment as follows: cladribine 5 mg/m2 , days 1-5; G-CSF 300 µg, days 0-9; aclarubicin 10 mg, days 3-6; cytarabine 10 mg/m2 every 12 hours, subcutaneously, days 3-9; 4 weeks per cycle. Patients were allowed to withdraw from the study if complete remission (CR) was not achieved after two courses of chemotherapy. If conditions were right, the patients achieving CR were recommended to receive allogeneic hematopoietic stem cell transplantation. Otherwise, they were treated for a total of six cycles unless disease progression or unacceptable side effects were observed or they withdrew their consent. RESULTS: All patients received at least two cycles of C-CAG regimen chemotherapy. After two cycles of C-CAG, 23 patients (67.6%) achieved CR, and 5 patients had partial remission (14.7%). At a median follow-up of 15 months (range, 3-38 months), the 1-year overall survival (OS) and disease-free survival (DFS) rates were 59.7% (95% confidence interval [CI], 42.6%-76.8%) and 72.9% (95% CI, 54.3%-91.5%), respectively. The most common adverse effect was myelosuppression. Nonhematological toxicities were mild, and no treatment-related deaths occurred. CONCLUSION: Preliminary data indicate that the C-CAG regimen chemotherapy is significantly effective against R/R AML with a high remission rate and a low hematological toxicity. Thus, it may serve as an alternative treatment for R/R AML.


Subject(s)
Aclarubicin , Cladribine , Cytarabine , Leukemia, Myeloid, Acute , Aclarubicin/therapeutic use , Adolescent , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Cladribine/therapeutic use , Cytarabine/therapeutic use , Female , Granulocyte Colony-Stimulating Factor/therapeutic use , Humans , Leukemia, Myeloid, Acute/drug therapy , Male , Middle Aged , Prospective Studies , Treatment Outcome , Young Adult
13.
Cancer Med ; 9(15): 5327-5334, 2020 08.
Article in English | MEDLINE | ID: mdl-32492289

ABSTRACT

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.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/genetics , Aclarubicin/pharmacology , Aclarubicin/therapeutic use , Adolescent , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Cohort Studies , Cytarabine/pharmacology , Cytarabine/therapeutic use , Female , Granulocyte Colony-Stimulating Factor/pharmacology , Granulocyte Colony-Stimulating Factor/therapeutic use , Humans , Male , Middle Aged , Retrospective Studies , Young Adult
14.
Aging (Albany NY) ; 12(7): 5792-5811, 2020 04 01.
Article in English | MEDLINE | ID: mdl-32238611

ABSTRACT

We evaluated the risk status and survival outcomes of 125 elderly acute myeloid leukemia (AML) patients treated with decitabine in combination with low-dose cytarabine, aclarubicin, and G-CSF (D-CAG). The risk status was evaluated by determining the frequency of recurring gene mutations using next-generation sequencing (NGS) analysis of 23 selected genes and cytogenetic profiling of bone marrow samples at diagnosis. After a median follow-up of 12 months (range: 2-82 months), 86 patients (68.8%) had achieved complete remission after one cycle of induction, and 94 patients (75.2%) had achieved it after two cycles. The median overall survival (OS) and disease-free survival (DFS) were 16 and 12 months, respectively. In 21 AML patients aged above 75 years, the median OS and DFS were longer in the low- and intermediate-risk group than the high-risk group, but the differences were not statistically significant. The median OS and DFS were similar in patients with or without TET2, DNMT3A, IDH2, TP53 and FLT3 mutations. Multivariate analysis showed that patient age above 75 years, high-risk status, and genetic anomalies, like deletions in chromosomes 5 and/or 7, were significant variables in predicting OS. D-CAG regimen tends to improve the prognosis of a subgroup of elderly patients with high-risk AML.


Subject(s)
Aclarubicin/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Cytarabine/therapeutic use , Decitabine/therapeutic use , Granulocyte Colony-Stimulating Factor/therapeutic use , Leukemia, Myeloid, Acute/drug therapy , Age Factors , Aged , Aged, 80 and over , Disease-Free Survival , Female , Humans , Leukemia, Myeloid, Acute/mortality , Male , Middle Aged , Prognosis , Survival Rate , Treatment Outcome
15.
Int J Cancer ; 146(5): 1457-1467, 2020 03 01.
Article in English | MEDLINE | ID: mdl-31344264

ABSTRACT

It remains unclear whether there is a relationship between therapeutic effects of hypomethylating agents (HMAs) and epigenetic modifier gene mutations (EMMs) in patients with cytogenetically intermediate-risk acute myeloid leukemia (IR-AML). Based on targeted-capture sequencing, we retrospectively analyzed the correlation between EMMs and prognosis in 83 IR-AML patients treated with decitabine in combination with cytarabine, aclarubicin hydrochloride and granulocyte colony-stimulating factor (DCAG, n = 35) or "7 + 3" induction regimens (n = 48). In the multivariate analyses, EMM (+) patients did not show any statistically significant difference in remission rates from EMM (-) patients in the DCAG group (p > 0.05), but achieved inferior complete remission (CR; p = 0.03) and overall remission rates (ORR; p = 0.04) after the first course of standard induction regimens (p < 0.05). In the EMM (-) cohort, the DCAG group showed the tendency of adverse total CR (p = 0.06). Besides, DCAG group with EMMs achieved the best survival outcome independent of baseline characteristics, whereas it was opposite in EMM (+) patients receiving standard induction regimens (p < 0.05). Additionally, in the EMM (+) cohort, the survival rate of isolated DCAG group was statistically similar to that of the combination of standard chemotherapies and allogeneic hematopoietic stem cell transplantation (allo-HSCT) (p > 0.40), whereas patients who received only standard regimens had the worst survival rate (0.0%, p < 0.01). It can be concluded that the EMMs might be regarded as the potentially predictive biomarkers of better response to DCAG in IR-AML patients.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacology , Biomarkers, Tumor/genetics , Drug Resistance, Neoplasm/genetics , Epigenesis, Genetic/genetics , Genes, Modifier/genetics , Leukemia, Myeloid, Acute/drug therapy , Aclarubicin/pharmacology , Aclarubicin/therapeutic use , Adolescent , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Cytarabine/pharmacology , Cytarabine/therapeutic use , DNA Methylation/drug effects , Decitabine/pharmacology , Decitabine/therapeutic use , Disease-Free Survival , Female , Granulocyte Colony-Stimulating Factor/pharmacology , Granulocyte Colony-Stimulating Factor/therapeutic use , Humans , Kaplan-Meier Estimate , Karyotyping , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/mortality , Male , Middle Aged , Mutation , Prognosis , Remission Induction/methods , Retrospective Studies , Survival Rate , Young Adult
17.
Medicine (Baltimore) ; 97(39): e12102, 2018 Sep.
Article in English | MEDLINE | ID: mdl-30278488

ABSTRACT

To assess treatment response and overall survival (OS) in refractory or relapsed acute myeloid leukemia (R/R AML) patients treated by different common salvage chemotherapy regimens.Medical records data from 142 R/R AML patients were reviewed in this retrospective study. Patients were treated with regimens based on the following drugs: cytarabine, granulocyte colony-stimulating factor (G-CSF), and fludarabine (FLAG) (n = 46); cytarabine and G-CSF in addition to aclarubicin or daunorubicin (CAG/DAG) (n = 30); cytarabine, G-CSF, and cladribine (CLAG) (n = 27); cytarabine, etoposide, and mitoxantrone (MEA) (n = 17); cytarabine plus idarubicin, daunorubicin, or mitoxantrone (IA/DA/MA) (n = 12); and homoharringtonine, cytarabine, and aclarubicin or daunorubicin (HAA/HAD) (n = 10).A total of 43 (35.2%) patients achieved complete remission (CR), 60 (49.2%) patients achieved overall remission rate (ORR), and 18 (14.8%) patients received allogeneic hematopoietic stem cell transplantation (allo-HSCT) after CR. Median OS was 8.0 (95% CI 6.6-9.4) months with a 1-year OS rate of (29.9 ±â€Š3.9)% and 3-year OS rate of (11.1 ±â€Š3.6)%. No difference of CR (P = .621), ORR (P = .385), and allo-HSCT (P = .537) achievement was observed among different chemotherapy regimens. Interestingly, we observed that the CLAG-based regimen did not affect CR (P = .165), while it achieved a numerically higher ORR (P = .093) and was an independent factor for prolonged OS (P = .016). No other regimens were determined to be correlated with CR, ORR, or OS.FLAG-, CAG/DAG-, CLAG-, MEA-, IA/DA/MA- and HAA/HAD-based regimens were found to achieve similar CR rates, while the CLAG-based regimen achieved numerically higher ORR rates and significant favorable OS. Therefore, CLAG-based regimens should be a prioritized treatment option for R/R AML patients.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Leukemia, Myeloid, Acute/drug therapy , Salvage Therapy/methods , Aclarubicin/adverse effects , Aclarubicin/therapeutic use , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Cladribine/adverse effects , Cladribine/therapeutic use , Cohort Studies , Cytarabine/adverse effects , Cytarabine/therapeutic use , Daunorubicin/adverse effects , Daunorubicin/therapeutic use , Etoposide/adverse effects , Etoposide/therapeutic use , Female , Granulocyte Colony-Stimulating Factor/adverse effects , Granulocyte Colony-Stimulating Factor/therapeutic use , Harringtonines/adverse effects , Harringtonines/therapeutic use , Humans , Leukemia, Myeloid, Acute/mortality , Male , Middle Aged , Mitoxantrone/adverse effects , Mitoxantrone/therapeutic use , Retrospective Studies , Salvage Therapy/adverse effects , Survival Rate , Treatment Outcome , Vidarabine/adverse effects , Vidarabine/analogs & derivatives , Vidarabine/therapeutic use , Young Adult
18.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 24(3): 698-701, 2016 Jun.
Article in Chinese | MEDLINE | ID: mdl-27342493

ABSTRACT

OBJECTIVE: To study the curative effect of HAG and CAG regimens for patients with acute myelocytic leukemia (AML) and high/medium-risk myelodysplastic syndrome (MDS). METHODS: Fifty two patients from January 2010 to January 2014 were enrolled in this study, 32 were diagnosed with AML and 20 with MDS. All the patients were divided into 2 groups: 26 in HAG group (26 cases) and another 26 in CAG group (26 cases). The bone marrow examination, remission rate, PFS, OS and side reaction rates were compared between 2 groups. RESULTS: After treatment, the bone marrow hyperplasia and juvenile cells were decreased significantly. In HAG group, the remission rate was 57.69% and that was 76.92% in CAG group, the difference between these 2 groups was statistically significant (P<0.05), but the survival time was not statistically significant different between 2 groups (P>0.05). The incidence of side reaction in HAG group was 11.54%, that in CAG group was 7.69%, there was no statistically significant difference (P>0.05). CONCLUSION: Both CAG and HAG regimens have shown significant curative effects for acute myelocytic leukemia and high/medium-risk myelodysplastic syndrome.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Leukemia, Myeloid, Acute/drug therapy , Myelodysplastic Syndromes/drug therapy , Aclarubicin/therapeutic use , Bone Marrow Examination , Cytarabine/therapeutic use , Granulocyte Colony-Stimulating Factor/therapeutic use , Humans , Remission Induction
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