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Objective:To explore the clinical short-term efficacy of venetoclax (Ven) combined with azacitidine (AZA) in treatment of newly treated and relapsed/refractory patients with acute myeloid leukemia (AML).Methods:The data of 18 newly treated and relapsed/refractory patients with AML who received Ven+AZA treatment in Suzhou Traditional Chinese Medicine Hospital Affiliated to Nanjing University of Chinese Medicine from April 2020 to June 2022 were retrospectively analyzed. The complete remission or complete remission with incomplete recovery of blood cell count (CR/CRi) and objective remission rate (ORR) [calculated as CR/CRi+partial remission (PR)] were analyzed in newly treated and relapsed/refractory patients or patients with different gene mutations. The patients were followed up until June 30, 2022, and the overall survival (OS) of relapsed/refractory patients was analyzed. The occurrence of adverse reactions was summarized.Results:The median age of the 18 patients was 58 years old (23-81 years old), 8 were males and 10 were females; 6 were newly treated and 12 were relapsed/refractory; the median follow-up time was 3 months (1-15 months). In 6 newly treated patients, after the first cycle of Ven+AZA, 5 cases achieved CR/CRi, and the ORR was 83.3% (5/6). In 12 relapsed/refractory patients, after the first cycle of Ven+AZA, 5 cases achieved CR/CRi, 3 achieved PR, and the ORR was 66.7% (8/12). Among the 18 patients, 7 cases had FLT3-ITD/TKD mutation, after the first cycle of Ven+AZA, 1 case achieved CR/CRi, 1 case achieved PR, and the ORR was 28.6% (2/7); 3 cases had NPM1 mutation combined with FLT3-ITD/TKD mutation, 1 case achieved CR/CRi, and the ORR was 33.3% (1/3); 4 cases had IDH1/2 mutation, and 3 cases of them combined with FLT3-ITD/TKD mutation, all of which were non-remission, and the other 1 relapsed/refractory patient combined with K/NRAS mutation achieved CR/CRi; among the 4 cases with K/NRAS mutation, 2 cases combined with FLT3-ITD/TKD mutation, including 1 case of NR and 1 case of PR, and the other 2 cases achieved CR/CRi, the ORR was 75.0% (3/4). Of the 12 relapsed/refractory patients, 6 died by the end of follow-up, with a median OS time of 2.6 months (1- 8 months), including 4 cases of disease progression and 2 cases of disease relapse; the 6 surviving patients had stable disease. All the 18 patients had ≥grade 3 hematologic adverse reactions, and non-hematologic adverse reactions included lung infection, nausea, vomiting and diarrhea.Conclusions:Ven+AZA treatment for newly treated and relapsed/refractory AML patients results in a high response rate with tolerable adverse reactions, but it is not effective in AML patients with FLT3-ITD/TKD mutation.
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Objective:To investigate clinical efficacy and safety of venetoclax (VEN)-based regimens in the treatment of acute myeloid leukemia (AML).Methods:The clinical data of 41 AML patients treated with venetoclax-based regimens from January 2021 to December 2021 in Ruijin Hospital North of Shanghai Jiao Tong University School of Medicine were retrospectively analyzed. The treatment regimens included VEN+demethylating drugs ± gene mutation inhibitors or VEN+chemotherapy with a median number of 2 courses (1- 5 courses).Results:The median age of all patients was 60 years (18-73 years), and there were 24 males and 17 females. After 1 course of VEN-based therapy, 22 (53.7%) patients achieved complete remission (CR) or morphological complete remission without complete blood count recovery (CRi), including 5 patients achieving minimal residual disease (MRD) negative. After 2 courses of treatment, of 17 patients available for efficacy evaluation, 7 patients achieved MRD negative. Among 20 relapsed/refractory AML patients, 9 cases achieved CR/CRi after 1 course of treatment, of which 1 patient had MRD negative. Among 21 patients initially treated and re-treated, 13 cases achieved CR/CRi and 1 case achieved partial remission after 1 course of treatment, of which 4 cases had MRD negative.Conclusions:VEN-based treatment regimens for AML have a high remission rate and tolerable adverse effects.
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The anti-apoptotic protein bcl-2, a key regulator of the intrinsic apoptotic pathway, is frequently overexpressed in cells of hematologic malignancies, and the small molecule inhibitor venetoclax that targets this apoptotic pathway has shown promising efficacy in the treatment of chronic lymphocytic leukemia and small lymphocytic lymphoma. The survival and prognosis of patients with acute myeloid leukemia who are of advanced age or who are unsuitable for strong induction chemotherapy because of comorbidities also have significantly improved, but some patients develop progressive drug resistance during the course of venetoclax treatment, which affects the efficacy of medical therapy. This article reviews the action mechanism, therapeutic progress and resistance mechanism of venetoclax in hematologic malignancies.
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OBJECTIVE@#To investigate the efficacy and safety of venetoclax (VEN) combined with demethylating agents (HMA) in the treatment of relapsed/refractory acute myeloid leukemia (R/R AML).@*METHODS@#The clinical data of 26 adult R/R AML patients who received the combination of VEN with azacitidine (AZA) or decitabine (DAC) in Huai'an Second People's Hospital from February 2019 to November 2021 were retrospectively analyzed. The treatment response, adverse events as well as survival were observed, and the factors of influencing the efficacy and survival were explored.@*RESULTS@#The overall response rate (ORR) of 26 patients was 57.7% (15 cases), including 13 cases of complete response (CR) and CR with incomplete count recovery (CRi) and 2 cases of partial response (PR). Among the 13 patients who got CR/CRi, 7 cases achieved CRm (minimal residual disease negative CR) and 6 cases did not, with statistically significant differences in overall survival (OS) and event-free survival (EFS) between the two groups (P=0.044, 0.036). The median OS of all the patients was 6.6 (0.5-15.6) months, and median EFS was 3.4 (0.5-9.9) months. There were 13 patients in the relapse group and refractory group, respectively, with response rate of 84.6% and 30.8% (P=0.015). The survival analysis showed that the relapse group had a better OS than the refractory group (P=0.026), but there was no significant difference in EFS (P=0.069). Sixteen patients who treated for 1-2 cycles and 10 patients who treated for more than 3 cycles achieved response rates of 37.5% and 90.0%, respectively (P=0.014), and patients treated for more cycles had superior OS and EFS (both P<0.01). Adverse effects were mainly bone marrow suppression, complicated by various degrees of infection, bleeding, and gastrointestinal discomfort was common, but these could be all tolerated by patients.@*CONCLUSION@#VEN combined with HMA is an effective salvage therapy for patients with R/R AML and is well tolerated by patients. Achieving minimal residual disease negativity is able to improve long-term survival of patients.
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Adult , Humans , Retrospective Studies , Neoplasm, Residual/drug therapy , Bridged Bicyclo Compounds, Heterocyclic/adverse effects , Recurrence , Leukemia, Myeloid, Acute/drug therapy , Antineoplastic Combined Chemotherapy Protocols/therapeutic useABSTRACT
Artificial intelligence-aided drug discovery (AIDD) is a new version of computer-aided drug discovery (CADD). AIDD is featured in significantly promoting the performance of conventional CADD. AI markedly enhances the learning ability of CADD. In the 1960s, CADD was established from conventional QSAR approaches, which mainly used regression approaches to derive substructure-activity relationship for compounds with a common scaffold, and guide drug molecular design, figure out the binding features of drugs, and identify potential drug targets. Since the 1990s, structural biology has provided three-dimensional structures of drug targets, enabling drug discovery based on target structure (SBDD), fragment-based drug discovery (FBDD), and structure-based virtual screening (SBVS) with CADD approaches. In the past 30 years, many first in class (FIC) and best in class (BIC) drugs were discovered with CADD. Now, AIDD will further revolutionize CADD by reducing human interventions and mining big chemical and biological data. It is expected that AIDD will significantly enhance the abilities of CADD, virtual screening and drug target identification. This article tries to provide perspectives of CADD and AIDD in medicinal chemistry with case studies.
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Objective:To compare the efficacy and safety of venetoclax (VEN) combined with azacitidine (AZA) versus CAG regimen combined with decitabine (DAC) in elderly patients with relapsed acute myeloid leukemia (AML).Methods:From January 2018 to August 2020, the clinical data of forty-five elderly patients with relapse AML at the First Affiliated Hospital of Soochow University were retrospectively analyzed, including 31 males and 14 females. The median age was 66 (60-80) years old. Eighteen patients were administrated with VEN and AZA, while the other 27 were in CAG with DAC. The complete remission (CR) rate, partial remission (PR) rate, total remission rate (ORR), adverse events and overall survival (OS) were compared between the two groups.Results:At the end of the treatment, the ORR in VEN with AZA group was 77.8% (14/18); including 11 CR and 3 PR. In CAG with DAC group, the ORR was 37.0% (10/27); including 8 CR and 2 PR ( P=0.007). Subgroup analysis suggested that VEN with AZA had a higher ORR in patients stratified as intermediate and poor-risk ( P=0.013) or with DNA methylation mutations ( P=0.007). Main adverse events in both groups were bone marrow suppression, infections, nausea and vomiting, anorexia and fatigue. Grade Ⅲ-Ⅳ cytopenia developed in lower incidence of VEN with AZA group, such as leukopenia (66.7% vs. 100%, P=0.002), anemia (50.0% vs. 92.6%, P=0.002), thrombocytopenia (72.2% vs. 96.3%, P=0.031) and neutropenia (61.1% vs. 92.6%, P=0.014). In addition, less grade Ⅲ-Ⅳ infections occurred in VEN with AZA group (66.7% vs. 33.3%, P=0.028), as well as grade Ⅲ-Ⅳ gastrointestinal events (40.7% vs. 11.1%, P=0.032), grade Ⅲ-Ⅳ fatigue (55.6% vs.11.1%, P=0.003) compared with CAG with DAC group. The 1-year OS in VEN with AZA group versus CAG with DAC group was 42.9% and 31.6% respectively ( P=0.150). Conclusion:VEN combined with AZA proves favorable efficacy and tolerablity in elderly patients with relapsed AML.
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Objective: To explore the safety and short-term efficacy of venetoclax combined with azacitidine (Ven+AZA) in previously untreated patients unfit for standard chemotherapy and patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) in China. Methods: A retrospective study was conducted in 60 previously untreated patients unfit for standard chemotherapy and patients with R/R AML who received Ven+ AZA (venetoclax, 100 mg D1, 200 mg D2, 400 mg D3-28; azacitidine, 75 mg/m(2) D1- 7) at the Peking University Institute of Hematology from June 1, 2019 to May 31, 2021. The incidence of adverse events, complete remission (CR) /CR with incomplete hematological recovery (CRi) rate, objective remission rate (ORR) , and minimal residual disease (MRD) status in patients with different risk stratification and gene subtypes were analyzed. Results: The median age of the patients was 54 (18-77) years, 33 (55.0%) were males, and the median follow-up time was 4.8 (1.4-26.3) months. Among the 60 patients, 24 (40.0%) were previously untreated patients unfit for standard chemotherapy, and 36 (60.0%) were R/R patients. The median mumber cycles of Ven+AZA in the two groups were both 1 (1-5) . According to the prognostic risk stratification of the National Comprehensive Cancer Network, it was divided into 8 cases of favorable-risk, 2 cases of intermediate risk, and 14 cases of poor-risk. In previously untreated patients unfit for standard chemotherapy, after the first cycle of Ven+AZA, 17/24 (70.8%) cases achieved CR/CRi, 3/24 (12.5%) achieved partial remission (PR) , and the ORR was 83.3%. Among them, nine patients received a second cycle chemotherapy and two received a third cycle. Among CR/CRi patients, 8/17 (47.1%) achieved MRD negativity after two cycles of therapy. In the R/R group, after the first cycle of Ven+AZA, 21/36 (58.3%) cases achieved CR/CRi (7/21 achieved MRD negativity) , 3 achieved PR, and the ORR was 66.7%. Among R/R patients, 12 were treated for more than two cycles. There were no new CR/CRi patients after the second treatment cycle, and 14 cases (66.7%) achieved MRD negativity. According to the time from CR to hematological recurrence, the R/R group was divided into 12 cases in the favorable-risk group (CR to hematological recurrence ≥18 months) and 24 in the poor-risk group (CR to hematological recurrence<18 months, no remission after one cycle of therapy, and no remission after two or more cycles of therapy) . Eleven of 24 (45.8%) cases achieved CR/CRi after one cycle of Ven+AZA in the poor-risk R/R group, and 10 of 12 (83.3%) achieved CR/CRi in the favorable-risk R/R group, which was significantly superior to the poor-risk group (P=0.031) . After one cycle of treatment, 13 patients with IDH1/2 mutations and 4 that were TP53-positive all achieved CR/CRi. The CR/CRi rate of 18 patients with NPM1 mutations was 77.8%. Five patients with RUNX1-RUNX1T1 combined with KIT D816 mutation (two initial diagnoses and three recurrences) had no remission. Ven+ AZA was tolerable for AML patients. Conclusion: Ven+AZA has acceptable safety in previously untreated patients unfit for standard chemotherapy, patients with R/R AML can achieve a high response rate, and some patients can achieve MRD negativity. It is also effective in NPM1-, IDH1/IDH2-, and TP53-positive patients. The long-term efficacy remains to be observed.
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Aged , Humans , Male , Middle Aged , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Azacitidine/therapeutic use , Bridged Bicyclo Compounds, Heterocyclic/therapeutic use , Leukemia, Myeloid, Acute/genetics , Retrospective Studies , SulfonamidesABSTRACT
Objective:To investigate the therapeutic effect of venetoclax combined with azacitidine in treatment of myelodysplastic syndromes (MDS) complicated with monoclonal globulinemia of unknown significance (MGUS).Methods:The clinical data of a patient with MDS complicated with MGUS in the Second People's Hospital of Shenzhen in December 2020 were retrospectively analyzed, and the literatures were reviewed.Results:According to results of bone marrow smear, cytogenetics, and next-generation sequencing, the patient was diagnosed as MDS and MGUS complicated with ASXL1, RUNX1, EZH2, STAG2 mutations as well as t(11;14). No response was observed after 2 courses of azacitidine and 1 course of azacitidine plus HAG. Later the patient achieved complete remission and negative RUNX1 and STAG2 mutations after a course of venetoclax combined with azacitidine. Meanwhile, M protein exhibited a decrease more than 50%. To date, the patient was still in complete remission.Conclusions:The regimen of venetoclax combined with azacitidine shows a significant efficacy and good tolerance to patient with co-occurrence of MDS and MGUS with t(11; 14).
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Objective:To investigate the efficacy of venetoclax-based combined regimen in treatment of adult patients with acute myeloid leukemia (AML).Methods:The data of 50 adult AML (non-acute promyelocytic leukemia) who received venetoclax-based combined regimen in the First Affiliated Hospital of Xiamen University, Dongguan People's Hospital, the First Hospital of Longyan City, Jieyang People's Hospital from December 2018 to May 2021 were retrospectively analyzed. Different doses venetoclax combined with demethylation drugs or low-dose chemotherapy regimen were used to analyze the therapeutic efficacy. The related factors influencing efficacy were analyzed by using logistic regression.Results:The composite complete remission (CR) rate of 50 AML patients was 62.0% (31/50), the overall response rate (ORR) was 76.0% (38/50); 28 patients achieved effectiveness [CR and partial remission (PR)] after the first cycle and could achieve effectiveness by 3 courses of treatment at the latest. Among 50 patients, 28 cases were newly diagnosed AML, the composite CR rate was 60.8% (17/28), ORR was 78.6% (22/28); 22 cases were recurrent and relapsed, the composite CR rate was 63.6% (14/22), ORR was 72.7% (16/22); and there was no statistically significant difference of ORR between the both groups ( χ2 = 0.23, P = 0.743). Logistic regression multivariate analysis showed age was the only independent influencing factor for the treatment effectiveness ( OR = 8.451, 95% CI 1.306-54.697, P = 0.025). The median duration time of patients receiving venetoclax treatment regimen was 4.5 months (1.1-15.0 months); 16 cases who had treatment effectiveness finally relapsed, the median time of maintaining effectiveness was 5 months (1.1-11.0 months). Additionally, the common treatment-related adverse reactions included bone marrow suppression after treatment, followed by some gastrointestinal reactions like nausea, vomiting and stomachache. In addition, no patient stopped medication for more than 1 week due to bone marrow suppression related complications. Conclusion:Venetoclax-based combined regimen shows a good short-term efficacy in treatment of AML. It is also effective and tolerable for elderly patients receiving reduced dose therapy.
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Objective:To explore the application of venetoclax in transplantation of patients with refractory acute myeloid leukemia (AML).Methods:The diagnosis and treatment process of a patient with refractory AML who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) under venetoclax and hypomethylating agents bridging myeloablative preconditioning regimen after induction therapy failure in the First Affiliated Hospital of Soochow University in March 2020 were retrospectively analyzed.Results:The patient was a 28-year-old female who was diagnosed with refractory AML. The patient was initially given induction chemotherapy with IA (idarubicin+cytarabine) (3+7) regimen, but the disease did not relieve, then the induction chemotherapy with CLAG (cladribine+cytarabine+granulocyte colony stimulating factor) regimen was given, but the disease still did not relieve. After chemotherapy with venetoclax and hypomethylating agents bridging myeloablative preconditioning regimen, salvage haploid allo-HSCT was performed. Re-examination of bone marrow showed remission, and implantation was successful. The patient was followed up for 100 days and had sustained remission, and no transplantation complications occurred.Conclusion:For refractory AML patients who have failed primary induction therapy, the use of venetoclax and hypomethylating agents bridging myeloablative preconditioning regimen can be used as a preferred solution for salvage allo-HSCT.
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ABSTRACT Background: Older patients with acute myeloid leukemia are particularly difficult to treat, as they have a high risk of comorbidities, poor performance status and less tolerability to chemotherapy, as well as a more aggressive disease biology, responsible for the resistance to treatment. There is a need to explore novel therapeutic agents that are more effective and tolerable. Venetoclax, a BCL-2 inhibitor is a promising agent, as BCL-2 overexpression is present in 84% of acute myeloid leukemia patients at diagnosis and 95% of patients at relapse and has been associated with leukemia cell survival, chemotherapy resistance and poor prognosis. Objective: To review the available data about venetoclax in acute myeloid leukemia and how it can influence the treatment in older patients. Methods: Using the Pubmed database, we selected 29 articles published within the last 15 years, considering preclinical and clinical trials and review studies that combined venetoclax with acute myeloid leukemia. Results: Venetoclax has demonstrated promising results in preclinical and clinical trials, especially in patients with poor prognosis and the IDH mutation, with an excellent side-effect profile. However, resistance seems to develop rapidly with venetoclax monotherapy, because of antiapoptotic escape mechanisms. Conclusions: While the results with the use of venetoclax seem encouraging, it is not likely that targeting a single pathway will result in long-term disease control. The solution includes the use of combined therapy to block resistance mechanisms and enhance apoptosis, by reducing MCL-1, increasing BIM or inhibiting the complex IV in the mitochondria.
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Leukemia, Myeloid, Acute , Genes, bcl-2 , BH3 Interacting Domain Death Agonist Protein , Molecular Targeted Therapy , Azacitidine/therapeutic use , Decitabine/therapeutic useABSTRACT
Conventional combination therapies have not resulted in considerable progress in the treatment of acute myeloid leukemia (AML). Elderly patients with AML and poor risk factors have grave prognosis. Midostaurin has been recently approved for the treatment of FLT-3-mutated AML. Venetoclax, a BCL-2 inhibitor, has been approved for the treatment of relapsed and/or refractory chronic lymphoid leukemia. Clinical trials on applying venetoclax in combination with cytarabine and other agents to treat various hematological malignancies are currently underway. Here, we present a case of a male patient with poor performance status and who developed AML following allogeneic hematopoietic stem cell transplant for high-risk myelodysplasia. The patient with high risk AML achieved complete response to the combined treatment regimen of low-dose cytarabine and venetoclax. Furthermore, we reviewed current clinical trials on the use of venetoclax for hematological malignancies.
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Aged , Humans , Male , Bridged Bicyclo Compounds, Heterocyclic , Combined Modality Therapy , Cytarabine , Fatal Outcome , Hematopoietic Stem Cell Transplantation , Leukemia, Myeloid, Acute , Drug Therapy , Genetics , Recurrence , Remission Induction , SulfonamidesABSTRACT
Objective To investigate the effect of venetoclax on RNA expression and cytokines release in lymphocytes isolated from acute myeloid leukemia(AML) patients. Methods MTT method was performed to study the apoptosis of AML cells and optimize the concentration of venetoclax.The gene markers expression and cytokines production before and after venetoclax treatment were examined by RT-PCR and ELISA methods,respectively. Results After chemotherapy,the expression of tumor associated inhibitory genes including BCL-2(P<0.05),SIRPα(P<0.05),CD47(P<0.05),PDL-1(P<0.05),PDL-2 (P<0.01),and EZH2(P<0.05) were significantly decreased when venetoclax reached 300 nmol·L-1.In addition,the expression levels of the activated molecules significantly increased,such as TRAIL(P<0.01) and TNF-α(P<0.01).The ELISA results showed that the release of human TNF-α and IFN-γ have significantly increased. Conclusion Venetoclax,which is a chemotherapeutic drug,can be used as tumor targeting drug.It can promote apoptosis in AML patients by regulating the genes expressions related to malignancy and cytokines production.
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OBJECTIVE: To investigate the in-vitro release behavior of venetoclax preparations, the pharmacokinetic processes and the correlations between in-vitro release and in-vivo absorption of venetoclax in Beagle dogs. METHODS: The dissolution curves of venetoclax preparations in different dissolution media were studied. HPLC method was established for the determination of venetoclax in Beagle dogs, and the pharmacokinetics were studied for commercial venetoclax tablets in Beagle dogs under fed and fasted states.The IVIVC study was carried out by linear regression of cumulative in-vitro drug release and in-vivo absorption accumulation percentage data. RESULTS: The in-vitro release behavior among venetoclax formulation in 4 dissolution media were significant difference. The simple, accurate and rapid analysis method for venetoclax blood samples was established. The fed group and the fasted group AUC0→∞ were (32.38±5.87) and (27.70±6.32) mg·h·L-1, the concentration of peak were (4.04±0.78) and (3.72 ±0.69) μg·mL-1, the peak time were (6.01±1.04) and (4.27±0.92) h, respectively, and there was obvious difference (P<0.05) in AUC0→∞ and the peak time between two group. Percentage of in-vivo absorption was in good agreement with in-vitro release in pH 6.8 0.2%SDS media. CONCLUSION: The study shows that food could improve the bioavailability of venetoclax formulation; 0.2%SDS pH 6.8 media (paddle, 75 r·min-1) is the in-vivo release of venetoclax associated with the in-vitro release condition.