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MINISTRY OF EDUCATION AND TRAINING MINISTRY OF HEATH HANOI MEDICAL UNIVERSITY ====== NGUYEN QUANG HAO RESEARCH ON CLINICAL, LABORATORY CHARACTERISTICS AND OUTCOME OF TREATMENT REGIMENS FOR MYELODYSPLA[.]
MINISTRY OF EDUCATION AND TRAINING MINISTRY OF HEATH HANOI MEDICAL UNIVERSITY ====== NGUYEN QUANG HAO RESEARCH ON CLINICAL, LABORATORY CHARACTERISTICS AND OUTCOME OF TREATMENT REGIMENS FOR MYELODYSPLASTIC SYNDROME AT BACH MAI HOSPITAL AND NATIONAL INSITUTE OF HEMATOLOGY AND BLOOD TRANSFUSION Specialism : Hematology and Blood Transfusion Code : 9720107 ABSTRACT OF THESIS HA NOI - 2022 The thesis has been completed at HANOI MEDICAL UNIVERSITY Supervisors: Assoc Prof Dr Vu Minh Phuong Reviewer 1: Assoc Prof Dr Bach Khanh Hoa Reviewer 2: Assoc Prof Dr Ly Tuan Khai Reviewer 3: Dr Nguyen Van Đo The thesis will be present in front of board of university examiner and reviewer lever at … on … 2022 This thesis can be found at: National Library Library of Hanoi Medical University THE LIST OF PUBLICATIONS RELATED TO THE THESIS Nguyen Quang Hao, Tran Tuan Anh, Nguyen Le Anh, Kieu Ha Trang, Vu Minh Phuong, Vu Duc Binh, Nguyen Ngoc Dung, Duong Quoc Chinh, Bach Quoc Khanh (2019) Application of next-generation sequencing for gene mutation analysis in myelodysplastic syndromes Vietnam Journal of Physiology, No 4: 28-33 Nguyen Quang Hao, Tran Tuan Anh, Luu Thi Thu Huong, Vu Minh Phuong, Vu Duc Binh, Nguyen Ngoc Dung, Nguyen Ha Thanh, Bach Quoc Khanh, Duong Quoc Chinh, (2021), Results of initial treatment Patients with myelodysplastic syndromes subgroup IPSS-R at higher risk by monotherapy with decitabine at the National Institute of Hematology and Blood Transfusion, Vietnam Journal of Physiology, vol 25 N04: 45-52 Nguyen Quang Hao, Ha Hong Quang, Tran Tuan Anh, Vu Duc Binh, Nguyen Ngoc Dung, Duong Quoc Chinh, Nguyen Viet Quyet, Vu Minh Phuong, Le Thi Huong Lan (2022), Characteristics of 139 patients with birth disorders bone marrow treatment at the National Institute of Hematology and Blood Transfusion and Bach Mai Hospital, from 2017 to 2021, Military Medical Journal, No 357: 41-44 BACKGROUND The myelodysplastic syndromes are a heterogeneous group of hematologic disorders of hematopoietic stem cells classified as precancerous chronic blood diseases MDS is characterized by thrombocytopenia, while bone marrow is proliferative, which proves that inefficient hematopoiesis in the bone marrow causes a decrease in the quantity and quality of peripheral blood cells, and one third of them are at risk of turning into blood cells, acute myeloid leukemia Currently, there are only three FDA-approved drugs for the treatment of MDS: Azacitidine, Decitabine, and Lenalidomide, but none of them cures the disease Stem cell transplantation is currently the only treatment that can cure MDS In Vietnam, the studies on MDS are mainly in the direction of describing clinical and subclinical characteristics, focusing mainly on histopathological cytology, some studies refer to cytogenetics Thus, we conducted the study “Research on clinical, laboratory characteristics and outcome of treatment regimens for myelodysplastic syndromes at Bach Mai hospital and National Insitute of Hematology and Blood Transfusion” to address the two following objectives: To study clinical and biological characteristics of myelodyplastic syndrome patinents To evaluate efficiency of supportive care and decitabine for myelodyplastic syndrome * Necessity of the research: The syndrome of myelodysplasia, a group of heterogeneous hematologic disorders of hematopoietic stem cells, has complex causes and pathogenesis The disease is classified according to the international organization and supportive care is combined with drugs that slow the progression of the disease without being curable In Vietnam, the systematic research from clinical, laboratory to treatment is still limited Therefore, this topic is very necessary, has scientific and practical significance, suitable for training majors The research objective is clear and feasible * Contributions of the thesis: This is the first study in Vietnam conducted on a large sample size to analyze clinical and laboratory characteristics and evaluate the effectiveness of two long-term treatment regimens This is also the first study in Vietnam to analyze the characteristics of molecular mutations in patients with myelodysplastic syndromes The results of the thesis have detected gene mutations with prognostic value related to myelodysplastic syndrome This work also demonstrated the effectiveness of the two regimens in improving quality of life and prolonging survival * Thesis structure: The thesis has 126 pages, including: problem statement pages, document overview 33 pages, object and research methods 23 pages, research results 35 pages, discussion 27 pages, Conclusion pages, recommendations page The thesis has 57 tables, 14 charts, 130 references Chapter - OVERVIEW 1.1 History of disease detection In 1976, the first FAB classification of leukemia, which included Myelodysplastic syndromes, was proposed And an extensive revision of the diagnostic and classification system as applicable to MDS was introduced in 1982 Following that, the original World Health Organization - WHO classification was developed in 2000 replace the original definitions given by the FAB Since then the WHO classification has been revised and updated twice in 2008 and 2016 1.2 Epidemiology of MDS According to the WHO report, the incidence is about 3-5 cases per 100,000 people and tends to increase with age The average age is usually 70 years old Data from 2001 to 2003 from the National Cancer Institute's Surveillance, Epidemiology, and End-of-Term Reporting (SEER) program show that 86% of MDS cases were diagnosed in people 60 years of age or older In Vietnam, there are not many reports on the incidence of MDS, especially in the community According to statistics of the National Institute of Hematology and Blood Transfusion, MDS ranks 6th in hematological diseases treated here 1.3 Pathogenesis of MDS To date, there is no satisfactory explanation for the pathogenesis of MDS However, many recent research results have conducted gene sequencing of myeloid cells in MDS cell populations and all detected genetic lesions in these subjects This poses several problems of pathogenesis; one is that MDS is a monoclonal disease of hematopoietic stem cells; The second is that the target cells of MDS vary from patient to patient 1.4 Clinical and laboratory characteristics 1.4.1 Clinical characteristics Clinical manifestations are usually gradual, not aggressive Most of the patients admitted to the hospital because of fatigue, poor diet, blue skin, reduced ability to work, this is a symptom of anemia Some may experience manifestations of hemorrhagic syndrome such as bleeding under the skin, bleeding in the mucous membranes of the mouth, nose, and rarely in the case of internal bleeding Or may experience symptoms of Infectious Syndrome such as fever: usually associated with a decrease in granulocyte count, often indicative of upper respiratory tract, gastrointestinal, urinary tract infections common in women 1.4.2 Laboratory characteristics Morphological and cytological features: Complete blood count showed changes in red blood cells, white blood cells and platelets Many cases showed isolated anemia, others showed isolated leukopenia, thrombocytopenia, or monocytosis without anemia The angiogram usually shows dysplasia in the red and white blood cell lines and may reveal platelet abnormalities Genetic features: Cytogenetic abnormalities account for more than 50% of patients with primary MDS and this number is approximately 80% higher for treatment-related secondary MDS The anomalies del(5q), –7/del(7q), +8 and –Y are most commonly described in MDS Nearly 90% of MDS patients are found to have somatic mutations in at least one gene 1.5 Diagnosis of MDS 1.5.1 Minimal diagnostic criteria Major criteria for the diagnosis of MDS include dysplasia in at least 10% of all cells in a single or multiple cell lines or an increase in erythroblasts greater than 15% or greater than 5% and additional mutations in SF3B1, myeloblasts 5-19% in bone marrow or 2-19% myeloblasts in peripheral blood and characteristic cytogenetic abnormalities associated with MDS 1.5.2 Differential diagnosis Prior to treatment, it is important to differentiate MDS from other causes of cytopenia and dysplasia that may be due to secondary myeloproliferative disorders or pre-MDS conditions, or other monoclonal stem cell disorders 1.5.3 Classification of MDS according to WHO 2016 The 2016 WHO Classification is partially revised to the WHO 2008 This update aims to combine molecular features valuable in diagnosis and treatment with an understanding of the pathogenesis of MDS Important factors in the current MDS classification scheme include the number of dysplastic cell lines, the percentage of blast cells in the peripheral blood and bone marrow, and the presence of less than 15% erythroid erythrocytes in the marrow bone (or less than 5% cyclic erythroblasts if SF3B1 mutation is present), presence of Aure bodies, characteristic cytogenetic abnormalities 1.6 Prognostic factors There are three most commonly used MDS assessment and prognosis systems The revised International Prognostic Scoring System (IPSS-R) and the WHO Classification Based Prognostic Scoring System (WPSS) Significant independent prognostic factors for survival including age, IPSS-R, and molecular mutations such as EZH2, SF3B1, TP53 were associated with lower survival 1.7 Treatment 1.7.1 Supportive care Although there are several supportive treatments for MDS, blood transfusion remains the mainstay of therapy, primarily for many patients Patients receiving red blood cell transfusions at least every weeks have a lower survival rate than those who not require frequent transfusions, which may be due to increased transfusion requirements as a sign of advanced myelosuppression progression and increased risk of comorbidities Hematopoietic growth factors are an integral part of the treatment of MDS In particular, erythropoiesisstimulating agents (ESAs) can reduce the need for transfusion by improving hemoglobin levels, and these agents are generally well tolerated 1.7.2 Demethylating agents Decitabine (5-aza-2'-deoxycytidine) is a DNA methylation inhibitor The role of decitabine has been extensively studied in clinical studies in patients with MDS Current trials of decitabine have shown clinical efficacy (ORR 17% to 32%) in patients with high-risk MDS Optimization of the dosing schedule of decitabine to maximize its inhibitory effect on DNA methylation including its use at low doses, at high dose intensity, and in multiple cycles Chapter - STUDY SUBJECTS AND METHODS 2.1 Study subjects 2.1.1 Study subjects The study subjects were 139 patients diagnosed with primary dysmenorrhea at Bach Mai hospital and the National Institute of Hematology and Blood Transfusion from November 2017 to August 2021 In which, 34 patients were analyzed for molecular genetic characteristics 86 patients were treated and monitored 2.1.2 Study sites The study was carried out at the centers of hematology and molecular genetics of two large hospitals, including: Bach Mai Hospital and National Institute of Hematology and Blood Transfusion 10 Kaplan-Meier method was used to estimate survival and compare using 2-sided log-rank test A p-value less than 0.05 is statistically significant 2.3 Ethics in research The study was approved by the Ethics Committee in Biomedical Research of the Hanoi Medical University, Decision No 77/HĐĐĐĐHYHN dated May 30, 2017 The study was approved by the Ethics Committee in Biomedical Research of the National Institute of Hematology and Blood Transfusion, Decision No 939/QD - HHTM dated May 31, 2019 Chapter - RESULTS 3.1 General characteristics of study subjects General characteristics of gender, the group of patients with myelodysplastic disorder has 74 (53%) male patients and 65 (47%) female patients, the male/female ratio is 1.1 The mean age of patients at the time of diagnosis was 62.6 ± 1.2 According to the WHO 2016 classification, 139 studied patients belonged to disease types In which, the group of patients with MDS-EB-1 and MDS-EB-2 accounted for the highest proportion (25.2% and 28.1%), followed by the group of patients with MDS-MLD (24.5%), MDS-SLD (15.8%), MDSRS (3.6%), MDS del(5q) (2.2%), MDS/MPN has the lowest ratio (0.7%) 11 3.2 Clinical and laboratory characteristics of study subjects The most common symptoms of anemia accounted for 95.7%; followed by infection with 37.4%; bleeding symptoms with 33.1%; Symptoms of hepatomegaly, splenomegaly, weight loss, and peripheral lymphadenopathy are uncommon The mean hemoglobin was 83.1 ± 1.7 (g/L) The mean platelet count was 117.6 ± 13.7 (G/L); mean neutrophil count was 4.6 ± 1.2 (G/L); The average percentage of peripheral blast cells was 2.8 ± 0.4 (%) Dysmorphic disorder of platelets was most common in 65.5% of patients Red blood cell line has disorder in 29.5% of patients, white blood cell line has disorder in 12.9% of patients The main characteristics of myeloid cells were normal density (59.7%), increased cell density was found in 30.2% In the hematopoietic compartment, 4.3% of patients had advanced fibrosis The presence of Alip in the hematopoietic compartment appeared in 5.8% of the patients studied The proportion of patients with chromosomal normality is 70.5% The rate of multiple chromosomal lesions was 17.3% The rate of sex chromosome loss, the rate of del(20q) solitary, the rate of del(5q) alone, and trisomy alone were 2.2% The rate of chromosomal translocation, the rate of -7/del(7q), all accounted for 1.4% Analysis of chromosomal mutations on FISH test with abnormalities: del(5q), del(20q) and TET2 The results showed that the mutant del(5q) alone and del(20q) alone were the highest, having the rate of 7.2% and 2.9%, respectively The rate of TET2 alone and the ratio of combined del(7q) with del(20q) both accounted for 0.7% Regarding 12 molecular genetics, mutations occurred on 17 genes belonging to functional groups of genes Genes with high mutation rates include: ASXL1 (17.6%), RUNX1 (14.7%), TET2 (14.7%), SF3B1 (11.8%) and TP53 (11.8%) The remaining genes have low mutation rates Mutation analysis by functional gene groups showed that RNA splicing and DNA methylation had the highest rate with 26.5% This is followed by Chromatin modification, Transcription regulation, Signal transduction and Tumor suppressor groups with 17.6%, 17.6%, 11.8% and 11.8%, respectively Cohesin complex group has a low rate with 5.9% 3.3 Treatment results 3.3.1 Treatment results 3.3.1.1 Response and survival time of patients treated with supportive care For supportive care, the results of treatment response were as follows: hematological improvement 83.8%, stable disease 2.7% and failure 13.5% Survival time: The supportive care had 23/37 cases of death and 7/37 cases of acute exacerbation The mean OS time was 27.01 ± 2.17 months The mean PFS time was 25.98 ± 2.31 months 3.3.1.2 Response and survival of patients treated with decitabine For the decitabine, the results of the treatment response were as follows: 28.6% complete response, 26.5% partial response, 4.1% complete marrow response, hematological improvement 8, 2%, stable disease 6.1% and failure 26.5% Survival: The decitabine resulted in 26/49 deaths and 14/49 acute exacerbations The mean OS time was 26.03 ± 2.13 13 months The mean PFS time was 24.83 ± 2.25 months 3.3.2 Relevant factors Factors affecting treatment response: For decitabine: The overall response rate in blast rate group ≤ 5% and > 5%, respectively 100% and 53.5% (p = 0) ,03) Molecular genetics: the Cohesin complex group with genetic mutations did not achieve the overall response, while the non-mutant group had an overall response rate of 68.8% (p = 0.048); The DNA methylation with the mutation was 33.3%, and the non-mutant group was 76% (p = 0.022) IPSS-R: treatment response rate in the very high-risk group was significantly lower than in the high- and intermediate-risk group, with p(3)(1) = 0.03, p(3)(2) = 0.03 Multivariate analysis showed that none of the factors had a statistically significant effect on response to treatment Factors affecting survival time: For supportive care, the influencing factors are not statistically significant on OS and PFS time For the decitabine: IPSS-R: The OS time of the very high-risk group was statistically significantly shorter than that of the moderate group, with p(3)(1) < 0.05, p(2)( 1) < 0.05 OS duration of the very high-risk group was significantly shorter than that of the high-risk group, with p(3)(2) < 0.05 Similarly, the time of PFS in the very high-risk group was statistically significantly shorter than in the mean group, with p(3)(1) < 0.05, p(2)(1) < 0.05.; the very high-risk group was significantly shorter than the high-risk group, with p(3)(2) < 0.05 Factors affecting the risk of death: For supportive care, the influencing factors are not statistically significant on the risk of death For decitabine: IPSS-R risk subgroup had a 14 statistically significant effect on the risk of death: the very high risk subgroup increased the risk of death 8,186 times compared with the moderate risk group (p) < 0.001) 3.3.3 Toxicities relating to decitabine For peripheral blood adverse events, the proportions of patients with neutropenia, thrombocytopenia and erythrocytopenia were: 59.2%, 32.6% and 10.2%, respectively There were 11 other common undesirable effects with the following rates: anorexia 36.7%, headache 28.6%, constipation 26.5%, vomiting 22.4%, cough 20.4%, fever 12.2%, diarrhea 16.3%, interstitial pneumonia 16.3%, increased liver enzymes 16.3%, increased blood sugar 20.4% and decreased albumin 18.4% Chapter - CONCLUSIONS 4.1 General characteristics of study subjects In the world, previous reports have recognized MDS as a disease of the elderly with 80-90% of patients diagnosed over 60 years of age The authors Haferlach and Jabbour noted that the mean age at diagnosis of MDS patients was from 70 years old The mean age in the two studies above tends to be slightly higher than in our study, the difference may be due to the characteristics of the aging population in developed countries General characteristics of gender, the group of ED patients has 53% male patients and 47% female patients, male/female ratio is 1.1 Studies around the world have recorded similar rates of disease in men and women Regarding disease classification, the group of patients with MDS-EB-1 and MDS-EB-2 accounted for the highest proportion (25.2% and 28.1%); This is equivalent to 15 the 2016 WHO report, showing that MDS-EB form is found in 40% of cases, MDS-MLD is seen in 30% of cases 4.2 Clinical and laboratory characteristics of study subjects 4.2.1 Clinical characteristics The most common symptom of anemia; followed by infection; bleeding symptoms; Symptoms of hepatomegaly, splenomegaly, weight loss, and peripheral lymphadenopathy are uncommon Anemia is often associated with fatigue, poor appetite, pale skin, reduced working capacity, which directly affects the patient's quality of life Bleeding and infection are two common symptoms that have also been reported in RLS patients in other studies Symptomatic infection is one of the main causes of death in patients with RLS and should be closely monitored during treatment 4.2.2 Laboratory characteristics Similar to the authors Sekeres, Papaemmanuil and Shen, in our study, the hematological parameters including hemoglobin, platelet count, neutrophil count were all lower than the normal limit The literature also noted that the myeloid cell density of patients with MDS was mostly normal or increased Thus, in patients with MDS, the marrow is often rich in cells that exhibit proliferation of immature malignant cells and overwhelm the growth of other normal cell lines in the marrow The cause of the poor marrow cells in patients with MDS is due to the fibrosis of the marrow preventing the correct aspiration of marrow fluid, the narrowing of the hematopoietic compartment in the elderly, and a few cases of true myelocytosis This poses 16 difficulties in the differential diagnosis of MDS from aplastic anemia, bone marrow failure, or other diseases that cause secondary myelosuppression We also recorded 4.3% of patients with advanced fibrogenic hematopoietic compartment Some authors in the world confirmed that myelofibrosis is often related to previous chemotherapy and radiation Our study is similar to the report of author Haferlach (2014) showing that the majority of patients belong to the group with good genetic prognosis Isolated genetic abnormalities encountered a low rate in our study, this result is consistent with the statistics of Meletis (2007) Thus, our results are quite similar to studies in the world, all recorded the rate of chromosomal abnormalities in patients with ED is about 20-40%, of which mainly multiple chromosomal lesions Characteristics of chromosomal abnormalities on FISH test The results of this study are similar to some studies by Sole (2000), Haase (2007), Meletis (2006), all of which recorded a single del(5q) mutation and a single del(20q) mutation to 10% rate Similar to chromosomal abnormalities on tape staining, our results are quite similar to studies around the world However, we have not found similar reports in Vietnam on the rate of chromosomal abnormalities of MDS for comparison Molecular genetic traits The study detected 20/34 patients with at least one gene mutation Studies on gene mutation characteristics have shown that the percentage of patients with at least one gene mutation ranges from 50 to 80% In our study, gene mutations occurred in 17/50 genes Similar 17 to the authors Papaemmanuil noted mutations occurred in 43/111 genes; Author Bejar reported 18/111 genes with mutations According to the statistics of the authors Shallis (2018) and Nybakken (2014) also showed that the genes with the highest rate are ASXL1, RUNX1, TET2 and SF3B1 Our research is similar to other published studies in the world In which, Transcription regulation and Transcription regulation groups were recorded with the highest mutation rate 4.3 Treatment results 4.3.1 Supportive care: response and survival time Analysis of treatment response of adjuvant therapy in 37 low-risk MDS patients showed a hematological improvement rate of 83.8% This result is equivalent to many studies around the world In clinical trials of immunomodulatory drugs, author List recorded a response rate in low-risk MDS patients of 83%, and author Rajkumar reported a hematological improvement rate of 81% For studies using erythrocyte growth promoters, response rates ranged from 20 to 85% Thus, the supportive treatment regimen showed good effect in the group of low-risk MDS patients The mean overall duration of low-risk patients was 27.01 ± 2.17 months Research by author Luăbbert shows that elderly patients treated with supportive care, the survival time can be longer than 30 months 4.3.2 Decitabine: response and survival time For 49 high-risk MDS patients on the decitabine, the overall response rate was 59.2% Our results are similar to studies with the same treatment course of 20 mg/m2/day as by Kantarjian ... that can cure MDS In Vietnam, the studies on MDS are mainly in the direction of describing clinical and subclinical characteristics, focusing mainly on histopathological cytology, some studies... Supportive care Although there are several supportive treatments for MDS, blood transfusion remains the mainstay of therapy, primarily for many patients Patients receiving red blood cell transfusions... laboratory characteristics and outcome of treatment regimens for myelodysplastic syndromes at Bach Mai hospital and National Insitute of Hematology and Blood Transfusion” to address the two following