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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

1 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

2 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

3 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 twofollowing objectives:

1 To study clinical and biological characteristics of

myelodyplastic syndrome patinents

2 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 2 pages, document overview 33 pages, object and research methods 23 pages, research results 35

recommendations 1 page The thesis has 57 tables, 14 charts,

130 references

Chapter 1 - 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

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 8 weeks have a lower survival rate than those who do 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, erythropoiesis-stimulating agents (ESAs) can reduce the need for transfusion

by improving hemoglobin levels, and these agents are generally well tolerated

1.7.2 Demethylating agents

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 2 - 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

hepatomegaly, splenomegaly Peripheral blood cell and bone marrow indices, bone marrow histopathological characteristics, chromosomal changes and gene mutations

2.2.2.2 Variables to evaluate treatment outcome

Treatment response variables (complete response rate, partial response rate, bone marrow complete response rate, relapse rate, ), overall survival, progression-free survival

2.2.3 Laboratory applied in the study

2.2.3.1 Specimen sampling techniques: Peripheral blood

sampling, bone marrow aspiration and bone marrow biopsy (*)

2.2.3.2 Cytological testing techniques: The technique of

staining the blood and bone marrow specimens of Giemsa (*) Iron erythrocyte staining (Perls staining) (*) Technique for processing bone marrow biopsies and staining HE (Hemophylic eosin) bone marrow histology specimens (*)

2.2.3.3 Cytogenetic testing: Technique to extract DNA and

RNA from bone marrow aspirate (*) Technique of culture and analysis of marrow chromosomes (*) FISH (Fluorescent in-situ

hybridization) technique: fluorescence in situ hybridization (*) identifies some abnormalities: del(5q), -7/del(7q), del(20q)

2.2.3.4 Molecular genetic testing techniques: Gene sequencing on

the NGS-Illumina system (according to the NIHBT's process)

2.2.4 Treatment

2.2.4.1 Supportive care

Supportive care, including: transfusion of blood products, use of antibiotics in case of infection, growth factors that stimulate the flow of red blood cells, granulocytes Evaluation after each course of treatment: level of response, unwanted effects The assessment of treatment response was performed for the first time after 8 weeks Antibiotics are indicated in the presence of an infection Iron excretion occurs when serum ferritin levels are > 1000 µg/L Use growth promoting factors (Epo ± G-CSF) Indications for transfusion of red blood cells: when the hemoglobin concentration is < 80 g/l Indication for platelet transfusion: platelet count < 20 G/L or < 50 G/L with bleeding

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 3 - 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 7 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%), MDS-

RS (3.6%), MDS del(5q) (2.2%), MDS/MPN has the lowest ratio (0.7%)