The "sniper" of precision medicine: CLL/WM genetic testing

With the continuous development of medical technology, especially genetic testing technology, medical diagnosis and treatment has entered the era of precision medicine from traditional empirical medicine and evidence-based medicine
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As a new type of medical concept and model, precision medicine integrates modern technologies such as genome sequencing, bioinformatics, and big data.
According to the different disease states of patients, it is "tailored" and changed from "symptomatic" medicine to "human" medicine.
To achieve personalized medicine
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Chronic lymphocytic leukemia (CLL) and Waldenstrom's macroglobulinemia (WM) are two chronic lymphoproliferative diseases of B-cells, and the previous treatment effect is not good
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In recent years, with the emergence of the BTK inhibitor ibrutinib, a new treatment pattern has been created
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How to diagnose and treat these two types of diseases more accurately becomes more and more important
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In this issue of "Big Masters "One Hundred Thousands"", Professor Fan Lei from the Department of Hematology, Jiangsu Provincial People's Hospital was invited as the visitor, and Professor Li Jianyong, the leader of the Chinese Chronic Lymphocytic Leukemia Working Group, and the deputy director of the Department of Hematology, Jiangsu Provincial People's Hospital were invited.
As a guest of interview, Professor Xu Wei will discuss with us in depth the "sniper" of precision medicine-CLL/WM genetic testing
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Precision medicine, genes first Professor Fan Lei: Professor Xu, how do you see the value of precision medicine and genetic testing in individualized cancer medicine? In the clinic of Professor Xu Wei, genetic testing is mainly used to assist diagnosis, prognostic stratification and guide treatment
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Taking CLL as an example, the abnormality of TP53 gene and the non-mutation status of IGHV gene are well-known poor prognostic factors
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Other gene mutations, such as NOTCH1, SF3B1, EGR2, BIRC3, BRAF, etc.
, have also been studied in the era of immunochemotherapy
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For high-risk patients, we give priority to new drugs represented by the BTK inhibitor ibrutinib
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With the continuous deepening of research, Ibrutinib combined with BCL2 inhibitors or combined chemotherapy may further improve the prognosis of such patients
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Let's talk about WM.
Whole-genome sequencing found that more than 90% of patients have MYD88L265P gene mutations, and 20%-30% of patients have CXCR4WHIM somatic mutations, which greatly improves the diagnostic level of WM patients
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Although MYD88 mutations also exist in diseases such as CLL and MZL, the incidence is usually less than 10%
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Approximately 50% of MGUS patients carry the MYD88 mutation, and they have a higher risk of switching to WM
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In terms of clinical manifestations, patients with MYD88 mutations are often accompanied by higher tumor burden, manifested as lymphadenopathy and increased IgM levels
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The clinical characteristics of patients with CXCR4 mutations are similar
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Patients with MYD88 and CXCR4 double mutations are clinically more aggressive and have higher levels of IgM
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Patients with neither MYD88 nor CXCR4 mutations have relatively low IgM levels
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In short, genetic testing is a powerful tool to realize "precision medicine
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"
Reasonable choice, scientific testing Professor Fan Lei: Professor Li, as clinicians, how should we conduct scientific genetic testing for CLL patients? Professor Li Jianyong: First of all, choose a reasonable time for testing
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Do not routinely perform genetic testing when there is no indication for treatment
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If the patient's family economy is poor and the prognosis of the disease is not concerned, it can be omitted
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For newly diagnosed/treated patients with indications for treatment, we recommend that relevant genetic testing be perfected before formulating and changing plans, of which TP53 and IGHV genes are the most important
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Secondly, strictly control the quality of specimens
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WM patients often present with low blood picture, if peripheral blood is taken as a test specimen, it is likely to have false negatives
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If necessary, B cells can be purified to increase the positive detection rate
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The peripheral blood of CLL patients has a high proportion of tumor cells, which is more suitable for genetic testing, FISH, and chromosome karyotype analysis than bone marrow blood
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Genetic testing guides CLL decision-making Professor Fan Lei: In the era of new drugs, how does genetic testing guide CLL treatment decision-making? Professor Li Jianyong: For CLL patients with TP53 gene abnormalities, no mutations in IGHV gene, and complex chromosomal karyotype abnormalities, a chemo-free strategy based on new drugs represented by Ibritinib is the first choice
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For CLL patients without adverse prognostic factors, in addition to new drugs, chemoimmunotherapy still has its status
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Other prognostic factors that have not been fully recognized also have certain clinical guidance value
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For example, after NOTCH1 mutation in CLL patients, CD20 expression is low.
At this time, the addition of CD20 monoclonal antibody rituximab may be ineffective, but there are also reports in the literature that the third-generation CD20 monoclonal antibody otuzumab may overcome the poor prognosis of NOTCH1 mutation
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Analyze the current situation and adjust the strategy.
Professor Fan Lei: Professor Xu, the domestic reports that WM’s MYD88 and CXCR4 test positive rates are significantly lower than foreign data.
Please analyze the causes and suggestions for countermeasures
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Professor Xu Wei first tested the type of specimen.
The number of tumor cells in the peripheral blood of WM patients is low, and the patients often show pancytopenia
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The detection rate of selected bone marrow specimens is higher than that of peripheral blood specimens
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The second is the detection method.
If the percentage of tumor cells is less than 20%, first-generation sequencing will often cause false negatives, and second-generation sequencing or ddPCR may achieve a higher detection rate
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Therefore, it is very important to choose suitable specimens and detection methods
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Genotyping drives WM treatment Prof.
Lei Fan: The emergence of ibrutinib has created a new treatment pattern for WM
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Professor Xu, please explain to us how genotyping drives the treatment of WM
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According to WM genotyping, Professor Xu Wei classified the following situations: (1) MYD88L265P/CXCR4WT patients are very sensitive to Ibrutinib, with an effective rate of more than 90% and a PR rate of more than 70%; (2) MYD88L265P/ The response rate of CXCR4WHIM patients to ibrutinib was 70%, and the PR rate was 60%; (3) The ratio of MYD88WT/CXCR4WT patients was less than 10%.
The innovate study found that the combination of ibrutinib and rituximab made these patients gain It has a similar effect to MYD88L265P/CXCR4WHIM/WT patients
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Precision medicine has a long way to go.
Professor Fan Lei: Professor Li, do you have any suggestions and opinions on accelerating the realization of comprehensive precision medicine? Professor Li Jianyong: Precision medicine plays an extremely important role in clinical diagnosis, prognostic evaluation, treatment selection, and further drug development
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However, there are still many problems in China, such as reliance on imports of equipment, instruments and reagents, uneven level of testing companies, lack of standardized management throughout the process, a heavier burden on genetic testing than the common people, and small coverage of medical insurance for new targeted drugs
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The road ahead is a long way to go.
Only by mastering the key core technologies in our own hands can we truly apply precision medicine to clinical practice and benefit our vast numbers of patients
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Conclusion The emergence of precision medicine has updated people's concept of medical care, and more and more people are beginning to benefit from it, especially cancer patients
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Although our country's precision medicine started relatively late and is still in the preliminary stage of development, it is not difficult to foresee that with the joint efforts of all sectors of society, China's precision medicine must have a very broad development space and prospects in the future
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With the help of the precision medicine model, choosing the most efficient, least side-effect, and most beneficial treatment strategy for patients is our ultimate goal, let us look forward to it together
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Professor Li Jianyong, Director of the Department of Hematology, Doctoral Supervisor, and Postdoctoral Cooperative Supervisor of Pukou Chronic Lymphocyte Center, Jiangsu Provincial People's Hospital The fourth chairman of the committee, the fifth honorary chairman, the leader of the lymphoma group, the leader of the Chinese chronic lymphocytic leukemia working group, the vice chairman of the CSCO China Lymphoma Alliance, the deputy leader of the lymphoma group of the Chinese Medical Association Oncology Branch Jiangsu Chairman of the Hematology Branch of the Provincial Geriatrics Association President-elect of the Hematology Branch of the Jiangsu Medical Association Former Chairman of the Hematology Branch of the Jiangsu Medical Association Professor Xu Wei, Chief Physician, Doctoral Supervisor, Deputy Director of the Department of Hematology, Jiangsu Provincial People's Hospital, Deputy Chairman of the Hematological Oncology Committee of the Chinese Anti-Cancer Association, and Leader of the Lymphoma Group, Deputy Chairman of the Lymphoma Professional Committee of the Chinese Geriatric Health Association CSCO Member of the Standing Committee of the Chinese Anti-Lymphoma Alliance Member of the Standing Committee of the Hematology Branch of the Chinese Society of Geriatrics Member and Secretary of the Integrated Hematology Professional Committee of the Integrative Medicine Physician Branch of the Chinese Medical Doctor Association Vice Chairman of the Hematology Society of Jiangsu Medical Association Vice Chairman of the Lymphoma Professional Committee of Jiangsu Research Hospital Association Chairman of the Jiangsu Anti-Lymphoma Alliance Vice Chairman of the Hematological Oncology Committee of the Cancer Society Jiangsu Provincial Anti-Cancer Association Lymphoma Professional Committee Member of the Standing Committee of the Nanjing Hematology Society Professor Fan Lei, Deputy Director, Department of Hematology, Department of Hematology, Jiangsu Provincial People's Hospital, "Leukemia and Lymphoma" and "BLOOD Chinese Edition" and other magazines Oncology Committee Member, Chinese Medical Association Blood Branch 11th Youth Committee, New York Columbia and Cornell University Affiliated New York Presbyterian Hospital Postdoctoral research direction is the precise diagnosis and treatment of lymphatic tumors Editor: Zhang Guixing Liu Hailing stamp "Read the original", we improve together