2022
EHA Annual Meeting
From June 9 to 12, 2022, the 27th European Hematology Annual Meeting (EHA) was held online + offline. The meeting brought together blood cancer experts from all over the world and announced a number of blockbuster studies. result. Professor Liu Hui of Beijing Hospital and his team have a study on the apoptosis of acute myeloid leukemia (AML) cells induced by the CDK7 inhibitor THZ1, which was selected for the poster presentation of this EHA conference. Yimaitong specially invited Professor Liu Hui conducted an interview to explain the significance of the research and share the changes translational medicine has brought to hematological tumors.
Yimaitong: AML is a heterogeneous hematological malignant tumor with poor overall prognosis, and most of the patients are elderly. Could you please talk about the progress in the treatment of elderly AML and what unmet clinical needs there are?
Professor Liu Hui
Compared with young patients, elderly AML patients have poorer general conditions and more comorbidities. Most of them cannot tolerate intensive chemotherapy and are difficult to treat. In addition, in terms of disease characteristics, elderly AML patients have a higher proportion of unfavorable karyotypes and genetic mutations. More complex. In recent years, with the emergence and application of a variety of new drugs, the treatment of AML has made rapid progress. When clinicians now formulate treatment plans, they not only need to consider whether the patient can tolerate high-intensity induction chemotherapy, but also must take into account the patient's disease characteristics - cytogenetics and molecular genetics to determine whether it can be applied. New, lower-intensity treatment options.
The National Comprehensive Cancer Network (NCCN) guidelines recommend that patients aged ≥60 years undergo a comprehensive geriatric assessment (CGA) to determine whether elderly AML patients can tolerate intensive chemotherapy. CGA aims to conduct objective, quantifiable, and reproducible assessments of the elderly from multiple aspects through a series of scoring scales, thereby predicting chemotherapy tolerance and guiding doctors in treatment selection for patients. The assessment content includes patient age, comorbidities, concomitant medications, living status, mental status, nutritional status, social support, etc. For patients who are not suitable for intensive chemotherapy, venetoclax combined with hypomethylating agents (HMA) is currently the preferred treatment option for the treatment of elderly AML. In a phase III clinical study comparing venetoclax + azacitidine (AZA) with azacitidine alone in elderly AML patients who were not suitable for standard chemotherapy, the median survival of the combination group (14.7 months vs. 9.6 months) and complete remission rate (CR+CRi: 66.4% vs. 28.3%) were better than those of the single-agent azacitidine group. In a phase III clinical study comparing venetoclax + low-dose cytarabine (LDAC) with LDAC alone, the median survival time (8.4 months vs. 4.1 months) and complete response rate (CR) of the combination group were +CRi: 48% vs. 13%) was better than LDAC single-agent group. In addition to venetoclax-based combination therapy and single-agent demethylation therapy, small molecule targeted drugs can be selected based on the patient's mutation spectrum, such as FLT3 inhibitors, IDH inhibitors, SMO inhibitors, and anti-CD47 monoclonal antibodies.
Although my country has made important progress in the diagnosis and treatment of AML in the elderly, it should be noted that AML is still incurable in most cases. The median duration of CR+CRi of venetoclax combined with HMA is only 11.3 months, and patients will relapse after disease remission, so it is necessary to explore new drugs.
Yimaitong: You and your team reported a study on the CDK7 inhibitor THZ1 inducing apoptosis in AML cells at this EHA meeting. Could you please explain this study in detail and talk about the results of this study on AML? What does treatment mean?
Professor Liu Hui
In this study, we found that THZ1, a covalent inhibitor of CDK7, reduced the viability of AML cells (THP1, MOLM-13, OCI-AML3) and induced cell apoptosis in a dose- and time-dependent manner. . THZ1 reduces the expression of phosphorylated CDK1 and CDK2, arresting the cell cycle in the G0/G1 phase; inhibits the phosphorylation of CTD Ser2, Ser5, and Ser7 of RNA Pol II, thereby inhibiting the global transcription of cells. The combined treatment of AZA and THZ1 synergistically inhibited AML cell viability, promoted AML cell apoptosis, and significantly down-regulated the expression of the anti-apoptotic protein MCL1.RNA sequencing results showed that the combination of AZA and THZ1 significantly inhibited the expression of MYC and its target genes. We then demonstrated the inhibitory effect of the combination on c-MYC at the protein level and mRNA level. c-MYC is a well-known tumor gene that regulates a variety of biological processes by targeting downstream genes, including cell growth , cell cycle and metabolism. Previous studies have proven that high expression of c-MYC is associated with the occurrence of AML and drug resistance. related. Inhibiting the expression of c-MYC is a promising therapeutic approach. Our study demonstrates the effectiveness of CDK7 inhibitors alone and in combination with , azacitidine and in AML at the cellular level, which may provide new options for the treatment of AML.
Additionally, the MOLM-13 cell line used in this study harbors the FLT3-ITD mutation, a common driver mutation associated with poor prognosis in AML patients. Despite various dual or triple combination therapies with FLT3 inhibitors, including chemotherapy + FLT3 inhibitors and HMA + venetoclax ± FLT3 inhibitors, the prognosis of patients with FLT3-ITD remains poor. Our data suggest that THZ1 has potential therapeutic value against FLT3-ITD-positive leukemia cells and enhances the antileukemic activity of AZA.
Yimaitong: Since the concept of translational medicine was proposed by the National Institutes of Health (NIH) in 2003, what changes have been brought to the research on hematological tumors? Can you briefly talk about it?
Professor Liu Hui
Translational medicine aims to break the barriers between basic medicine and drug research and development, clinical medicine, and establish a two-way connection between laboratory and clinic. The translational medicine model is mainly divided into two categories: T1 and T2. T1 is "from laboratory to bedside" (bench to bedside), which mainly transforms basic research into clinical application fields (including medical treatment, prevention, and nursing) to provide diagnosis and treatment of diseases. Provide more advanced concepts, methods, tools and methods to improve the prevention, diagnosis and treatment of clinical diseases. T2 stands for "evidence based implementation and sustainability". Clinical researchers provide timely feedback on clinical issues and transfer clinical issues to corresponding basic fields for in-depth research. Translational medicine applies scientific research results to clinical practice and collects clinical trial data to feed back into basic research, achieving a win-win situation between clinical practice and scientific research.
Thanks to the rapid development of translational medicine, the diagnosis and treatment of hematological tumors have undergone tremendous changes. Taking AML as an example, next-generation sequencing technology has detected more than ten high-frequency AML mutation genes, among which FLT3-ITD mutations can be found in 30% of AML patients. The high relapse rate and low remission rate after relapse have become a sign of poor prognosis in AML. . The combination of the first-generation FLT3 inhibitor sorafenib and the second-generation quizartinib with chemotherapy has increased the response rate of rescue treatment of refractory and relapsed AML from 10-20% to 30-54%, achieving a breakthrough from the laboratory to the clinic. Transformation. Furthermore, during the treatment of AML with venetoclat combined with HMA, it was found that FLT3-ITD mutations are related to resistance to venetoclat combination. This problem was transformed into basic research to explore the role of FLT3-ITD mutations in secondary resistance. The role played in the medicine achieves the transformation from clinical to laboratory. Translational medicine has promoted individualized treatment under the guidance of " precision medicine ", which has greatly promoted the development of hematological tumors and brought good news to patients with hematological tumors.
In addition, the study published by our team at this year's EHA conference started from clinical problems to be solved and explored new AML therapeutic drugs, proving the effectiveness of CDK7 inhibitors alone and in combination with AZA in AML cells. effectiveness, providing a preclinical research basis for the application of CDK7 in AML. We will further conduct animal experiments to verify the effectiveness and toxicity of the combination of AZA and THZ1 in vivo. On this basis, the research results can be further applied in clinical practice to realize the transformation of scientific research results into clinical practice.
Professor Liu Hui
Director of the Hematology Department of Beijing Hospital, MD, Chief Physician, Doctoral Supervisor
Member of the Red Blood Cell Disease Group of the Hematology Branch of the Chinese Medical Association
Member of the Lymphoma Group of the Hematology Branch of the Chinese Medical Association
Central Health Care Consultation Expert
Standing Member and Deputy Director-General of the Hematology Branch of the Chinese Gerontological Society
Member of the China Anti-Lymphoma Alliance
Standing Member of the Clinical Oncology Committee of the Chinese Association of Women Physicians
Member of the Hematology Committee of the Chinese Association of Women Physicians
Member of the Hematology Branch of the Beijing Medical Association
Executive director of the Hematology Specialist Branch of the Beijing Medical Doctor Association
Main research directions: clinical and research on hematological tumors in the elderly
Correspondence editorial board member of "Chinese Journal of Hematology", editorial board member of "Leukemia. Lymphoma", "Clinical Drugs" Journal of Therapy " Editorial Board
Editor: Quinta
Reviewer: Professor Liu Hui
Typesetting: Wenting
Execution: siqili
