MINISTRY OF EDUCATION AND TRAINING MINISTRY OF HEALTH HANOI MEDICAL UNIVERSITY LUU HUNG VU STUDY ON TREATMENT OF DIFFUSE LARGE B CELL NON HODGKIN LYMPHOMA WITH CD20(+) BY R CHOP REGIMEN Specialism Onc[.]
MINISTRY OF EDUCATION AND TRAINING MINISTRY OF HEALTH HANOI MEDICAL UNIVERSITY LUU HUNG VU STUDY ON TREATMENT OF DIFFUSE LARGE B-CELL NON-HODGKIN LYMPHOMA WITH CD20(+) BY R-CHOP REGIMEN Specialism: Oncology Code: 9720108 ABSTRACT OF THESIS T HA NOI – 2022 The thesis has been completed at HA NOI MEDICAL UNIVERSITY Supervisors: Supervisor: Assoc Pro Dr Nguyen Quang Tung Dr Pham Xuan Dung Reviewer 1: Reviewer 2: Reviewer 3: The thesis will be present in front of board of university examiner and reviewer lever at on 20 The thesis can be found at: National Library Library of Hanoi Medical University THE LIST OF WORKS HAS PUBLISHED AND RELATED TO THE THESIS Luu Hung Vu (2019) Prognostic significance of MYC, BCL2 and BCL6 gene rearrangements in patients with diffuse large B-cell lymphoma, CD20(+) treated by R-CHOP regimen at Ho Chi Minh City Oncology Hospital Vietnam Journal of Oncology;2(2):330-336 Luu Hung Vu (2019) Evaluating the outcome of diffuse large B-cell lymphoma accompanied by MYC gene mutation treated by R-CHOP regimen at Ho Chi Minh City Oncology Hospital Vietnam Journal of Oncology; 5:141-146 Luu Hung Vu, Phan Minh Chau, Tran Thi Duy Linh et al (2020) Prognostic effects of Germinal Center B-cell-like and non-Germinal Center B-cell-like subtypes in patients with diffuse large B-cell lymphoma, CD20(+) treated with RCHOP regimen Vietnam Journal of Oncology 5(2): 62-68 INTRODUCTION Reason for choosing the investigation topic: Non-Hodgkin’s lymphoma is a common hematologic malignancy, accounting for 90% of all malignant lymphomas According to the 2008 World Health Organization (WHO) classification, diffuse large B-cell lymphoma (DLBCL) is the most common entity of non-Hodgkin's lymphoma, accounting for 30-40% of this whole disease DLBCL belongs to the group of aggressive lymphomas and the clinical prognosis of patients using the International Prognostic Index Regarding the treatment of DLBCL, CHOP regimen has been considered the standard regimen since 1975, with a high complete response rate of 70%, but only 30% of patients have long-term survival In 1997, with the introduction of rituximab, the R-CHOP regimen was considered the gold standard in the treatment of diffuse large B-cell lymphoma, which increased the rate of complete response and survival compared to CHOP alone However, currently only two-thirds of patients with DLBCL are cured with R-CHOP, and these with recurrence often has a poor outcome even with high-dose chemotherapy and autologous stem cell transplantation Abroad, many studies have shown that biological factors adversely affect the treatment outcome of DLBCL with R-CHOP: DLBCL, activated B-cell/ non-germinal center B-cell subtype, or DLBCL with MYC gene rearrangement, or DLBCL with MYC and BCL2/or BCL6 rearrangement (double-hit lymphoma) In contrast, there are almost no studies in the country on DLBCL with MYC, BCL2, BCL6 gene rearrangements treated with R-CHOP regimen That's why we chose this topic with objects: Describing some clinical and laboratory characteristics of patients with DLBCL with CD20(+) treated with R-CHOP regimen Evaluating the treatment results of patients with DLBCL with CD20(+) by R-CHOP regimen and MYC, BCL2, BCL6 gene rearrangement subgroups The dissertation contributions: This is the first study in Vietnam on DLBCL, CD20(+) treated with R-CHOP regimen combined with MYC, BCL2, BCL6 gene rearrangements by FISH test The results of the study are as follows: The total 48 patients, in which 39 cases showed FISH results with MYC, BCL2 and BCL6 gene rearrangement rates of 17.9%, 10.3% and 12.8%, respectively; rearrangement of two genes MYC and BCL2/BCL6 was 5.1% The complete response rate was 70.8% The complete response was significantly associated with lesion size (p < 0.05) The 3-year progression-free survival is 68.6% and the 3-year overall survival is 77% The patients with BCL2 gene rearrangement reduced 3-year progressionfree survival or with MYC gene rearrangement reduced 3-year overall survival compared to others without gene rearrangement, significantly (p < 0.05) Having symptom B, bone marrow involvement, extra-nodal lymphoma ≥ positions, elevated blood LDH and BCL2 gene rearrangement adversely affect progression-free survival (p < 0.05); while having symptom B, bone marrow involvement, elevated blood LDH and MYC gene rearrangement adversely affected overall survival (p < 0.05) Multivariate analysis showed that three factors were significantly associated with reduced overall survival: Having symptom B, increased LDH, and MYC rearrangement The side effects of chemotherapy are mostly grade 01; grade 3-4 neutropenia (31.2%); infection with grade neutropenia (8.3%); severe pneumonia (6.3%); hepatitis B virus reactivation (11.1%) The structure of the thesis: The thesis consists of 120 pages, with the four main chapters: Introduction (2 pages), Literature Overview (35 pages), Research subjects and methods (11 pages), Results (36 pages), Discussion (33 pages), Conclusions and Recommendations (3 pages) The thesis has 59 tables, figures, 14 charts, diagrams, 113 references (12 documents in Vietnamese, 101 documents in English) Chapter 1: LITERATURE OVERVIEW 1.1 Pathology of diffuse large B-cell lymphoma (DLBCL), CD20(+) According to the 2016 WHO classification, the diagnosis of DLBCL, CD20(+) is a combination of four factors:: • Morphology: it is a neoplasm of large B lymphocytes with nuclei equal to or larger than the nuclei of normal macrophages, more than twice the size of normal lymphocytes, accompanied by diffuse growth • Immunophenotype: panel of immunohistochemistry to support diagnosis as recommended by NCCN includes 10 antigens (CD20, CD3, CD5, CD10, CD45, BCL2, BCL6, Ki-67, IRF4/MUM1, MYC) • Genotyping: there are three common translocations in DLBCL, namely MYC, BCL2, BCL6 and detected by FISH technique + MYC gene rearrangement accounts for 5-10% of cases in diffuse large B-cell lymphoma, often in the germinal center subtype, and the prognosis is poor with RCHOP therapy, especially when associated with BCL2/BCL6 gene rearrangement + BCL2 and BCL6 rearrangements: account for 20% and 35% of DLBCL, respectively BCL2 or BCL6 rearrangement may or may not affect the prognosis of DLBCL (due to conflicting results) • Clinical characteristics: Typically, lymph nodes are enlarged, painless, firm, rubbery, appearing in the neck or as a mass in the abdomen Symptom B occurs in 30% of cases Bulky's disease (large lesions > 7.5 cm) accounts for 30% Bone marrow involvement accounts for 15% Other extranodal sites may be encountered (testicles, bones, gastrointestinal tract, skin, liver, breast, nasal cavity ) In addition, according to the WHO 2016 classification, DLBCL should be divided into subgroups: germinal center B-cell subgroup/non-germinal center B-cell subgroup, subgroup with MYC and BCL2/BCL6 gene rearrangements (double-hit lymphoma), MYC and BCL2/BCL6 protein coexpression subtype (double expressor lymphoma) 1.2 Diagnosis Take medical history and perform clinical examination Biopsy Laboratory: CBC, bone marrow aspiration/biopsy, head and neck-thoracicabdominal CT scan, blood LDH, liver-renal-cardiac function, endoscopy, hepatitis B/C virus, lumbar puncture, PET /CT Staging according to the Ann Arbor system (1971): stages I-IV 1.3 Prognosis • Clinical: The International Prognostic Index (IPI) includes five poor prognostic factors (with one factor of point): age > 60, ECOG activity index > 1, stage III-IV, the number of extranodal sites > and increased LDH Patients were classified into four risk groups: low (0-1 points), intermediate-low (2 points), intermediate-high (3 points) and high (4-5 points) 5-year overall survival: was 73% in low-risk group and was 26% in high-risk group • Biomarkers: the following subgroups are considered to have poor outcomes with standard treatment R-CHOP + DLBCL, activated B-cell subtype (also called non-germinal center B-cell subtype): outcomes are worse than germinal center B-cell subtype + DLBCL with MYC rearrangement: worse than without MYC rearrangement + DLBCL with MYC and BCL2/BCL6 gene rearrangements (also known as double hit lymphoma): worse than without rearrangement and worst in DLBCL (recommended intensive therapy such as DA-EPOCH-R) + DLBCL with MYC and BCL2/BCL6 protein co-expression: worse than no co-expression but better than double hit lymphoma 1.4 Treatment 1.4.1 Treatment of new diffuse large B-cell lymphoma (according to NCCN 2021) Stages I-II, there are no large lesions Chemotherapy with cycles of R-CHOP regimen + radiotherapy to lesions 30-36 Gy or Chemotherapy with cycles of R-CHOP regimen radiotherapy to lesions 30-36 Gy or Chemotherapy with cycles of R-CHOP regimen + cycles of rituximab alone (IPI = 0) Stages I-II, with large lesions (lesions ≥ 7.5 cm) Chemotherapy with cycles of R-CHOP regimen radiotherapy to lesions 30-50 Gy Stages III-IV: Chemotherapy with cycles of R-CHOP regimen (assessed after 2-4 cycles by PET/CT) 1.4.2 Prophylactic treatment of the central nervous system (CNS) DLBCL carries a high risk of CNS recurrence when the primary site of injury is the nose, paranasal sinuses, epidural, testis, and breast CNS prophylaxis: pump into the subarachnoid space with methotrexate 10mg/m2, 4-8 doses every week or high-dose methotrexate (33.5g/m2) intravenous infusion for 2-4 cycles during treatment 1.4.3 Treatment of relapsed or refractory DLBCL About 30-40% of advanced-stage diffuse large B-cell lymphomas fail with initial treatment Currently, the most effective are high-dose chemotherapy and autologous stem cell transplantation Pathological Review of Biopsy H&E staining Immunohistochemistry (GCB-NonGCB subtypes) FISH (MYC, BCL2, BCL6) Integrate clinical factors to indentify unique WHO clinipathological entities Diagram 1.1: Current treatment of diffuse large B-cell lymphoma Chapter 2: RESEARCH SUBJECTS AND METHODS 2.1 Research subjects 48 patients were diagnosed with DLBCL, CD20(+) ≥ 16 years old and treated with the R-CHOP regimen at the Department of Internal Hematology, Lymphoma - Ho Chi Minh City Oncology Hospital, since September 1, 2017 to March 31, 2018 2.1.1 Criteria for selection of diseases: • Histopathological diagnosis of DLBCL according to WHO 2016 classification • New disease, not previously treated • Patient age: 16-80 years old • Body activity index according to ECOG 0-1 • Consent to participate in the study and agree to sign the consent form • Treatment with R-CHOP regimen: minimum cycle, maximum cycles 2.1.2 Exclusion criteria: • Heart failure or poor left ventricular function (LVEF < 50%) • Total bilirubin > 1.5 x upper limit of normal (ULN) • AST or ALT > 2.5 x ULN • Creatinine clearance < 50mL/min (according to Cockcroft-Gault formula) • There are serious medical comorbidities; pregnant/lactating women • Concurrent second cancer at the time of diagnosis of DLBCL • Acute lymphoblastic leukemia (lymphoblast/bone marrow ≥ 20%) • Extranodal involvement of the CNS, nose and paranasal sinuses, epidural, breast, kidney, and adrenal glands, or HIV(+) diffuse large B-cell lymphoma Reason: these patients need multimodality combination therapy (chemotherapy + radiotherapy + prevention of central nervous system invasion), not in the study target 2.2 Research Methods 2.2.1 Study design: prospective, clinical intervention without control 2.2.2 Sample size: The sample size is calculated by the formula: p (1-p) n = Z21-/2 (p)2 n: Required research sample size; p: Overall survival rate of years according to study by Habermann et al = 67% = 0.67; 1-p = – 0.67 = 0.33; Z: The scale corresponds to the desired statistical significance; : error type = 5% = 0.05; 2-side test Z (look up table) = 1.96; : Desired relative deviation, choose = 0,2; Work out: n = 47.3 So choose a sample size of 48 patients 2.2.3 Research process: 2.2.3.1 Procedure for diagnosis and treatment of patients with DLBCL, CD20(+) at the Department of Internal Hematology and Lymphoma - Ho Chi Minh City Oncology Hospital • Take medical history and physical examination • Biopsy • Diagnostic pathology - Morphology: Tissue samples were dewaxed, laminated, H & E stained and morphologically read If results are positive for diffuse large Bcell lymphoma, immunohistochemistry is used to confirm the diagnosis; if lymphoma, epithelial cancer or mesothelioma cannot be distinguished, immunohistochemistry is used to confirm the diagnosis with LCA, EMA and CK antigens to differentiate - Immunohistochemistry: Assisted immunohistochemistry set of 10 CDs, namely CD3, CD5, CD10, CD20, BCL2, BCL6, CYCLIN D1, MUM1, Ki67 and MYC An immunohistochemistry result is considered positive when the antigen-antibody reaction is staining > 30% of cells - Fluorescence in situ hybridization (FISH): looks for MYC, BCL2 and BCL6 gene rearrangements using four probes MYC, BCL2, BCL6 and IgH Then, examine over 100 tumor cells in the mesenteric phase of mitosis Single-gene rearrangement is considered positive when the cell nucleus shows a gene translocation that changes the double color signal by > 1020% of cells Laboratory Treatment - Chemotherapy: R-CHOP regimen x cycles Patients with stage IV (lymphomas involve bone marrow, liver ), treatment has not changed - R-CHOP regimen (cycle of 21 days): Rituximab 375 mg/m2 i.v day (brand name drug or biosimilar) Cyclophosphamide 750 mg/m2 i.v day (brand name drug) Doxorubicin 50 mg/m2 i.v day (generic class 1) Vincristine 1.4 mg/m2 i.v day (generic class 1) 10 Diagram 2.2: Summary of studying the process for patients with DLBCL, CD20(+) treated by R-CHOP regimen at Ho Chi Minh City Oncology Hospital 2.2.5 Methods of data collection and processing Collect patient information through medical records Enter and process data using SPSS 23.0 software for Windows 2.2.6 Time and place of study The study period: the starting time of the study is September 1, 2017 and the end of the study is September 1, 2021 The study location: 11 The patient was clinically examined, performed a biopsy, tested and treated at Ho Chi Minh City Oncology Hospital For fluorescence in situ hybridization (FISH) test: the block borrowed from the Department of Pathology of Ho Chi Minh City Oncology Hospital was transferred to the Molecular Biology Laboratory of a private hospital, and then FISH test was performed at the Center for Molecular Biology of Ho Chi Minh City University of Medicine and Pharmacy (a private hospital affiliated with the University) 2.2.7 Research ethics: The R-CHOP regimen has proven to be effective and safe, and is commonly used by centers around the world and in the country for patients with DLBCL There are volunteer forms to participate in the study for the patients to read and sign to confirm after listening to the consultation on diagnosis and treatment of this disease The study was approved by the Ethics Committee of Hanoi Medical University and the Ethics Committee of Oncology Hospital There is no cost to the patient for the FISH test (PhD student’s own expenses) Chapter 3: RESEARCH RESULTS By studying the 48 patients with diffuse large B-cell non-Hodgkin lymphoma, CD20(+) of which 39 cases gave FISH test results, we obtained the following results:: 3.1 Some clinical and paraclinical characteristics of patients with diffuse large B-cell non-Hodgkin lymphoma CD20(+) 3.1.1 Characteristics of studied patients Gender Male = 27 cases (56.3%) female = 21 cases (43.7%) Male: female ratio = 1.3:1 Age The youngest patient's age is 17 years old, the oldest patient's age is 73 years old, the mean age is 52.7 years old First symptom Large peripheral lymph nodes are common 87.5% (42 cases), other symptoms (fever, difficulty swallowing, abdominal pain) account for 12.5% 12 Time of disease onset (is the time from the time the patient has the first symptoms to the time of hospital admission) Most 1-3 months: 70.8% (34 cases), > months: 29.2% Symptom B Having symptom B accounts for 31.3% (15 cases) Lymph node involvement Common cervical lymphadenopathy 87.5% (42 cases); the rest are axillary lymph nodes 47.9%, abdominal lymph nodes 43.8%, inguinal lymph nodes 25%, mediastinal lymph nodes 22.9% Extra-nodal lymphoma Waldeyer's tonsillar ring accounted for the highest 52.2% (12/23 cases); next to gastrointestinal tract 12.4% (stomach 17.4%, colon 8.7%, small intestine 4.3%), spleen 4.3%, liver 4.3%, lungs 4.3%, bone marrow 4.3% Size of lesion < cm: 83.3% (40 cases); 4-7.5 cm: 8.3% and > 7.5 cm: 8.3% Staging Stage I: 6.3%, Stage II: 50% (24 cases), Stage III: 37.5%, Stage IV: 6.3% Analysis of the relationship between Stage and symptom B: Having B symptoms in stage I-II was 10.4% (5 cases) and stage III-IV was 20.8% (10 cases), the difference is statistically significant (2 test, p = 0.03) Blood LDH before treatment LDH increased (> 240 U/L) accounted for 47.9% (23 cases) International prognostic index Low risk: 50% (24 cases), intermediate-low risk: 27.1%, intermediate-high risk: 20.8%, high risk: 2.1% Germinal center B-cell (GCB) and non-GCB subtypes GCB: 43.7%, non-GCB: 52.1% (25 cases), not graded: 4.2% MYC and BCL2/BCL6 protein co-expression subtypes With co-expression: 70.8% (24 cases), no co-expression: 25%, no subgroup: 4.2% Rate of MYC, BCL2, BCL6 gene rearrangement of 39 patients 13 BCL2 gene rearrangement: cases (10.3%) Rearrangement of two genes MYC and BCL2: case (2.6%) BCL6 gene rearrangement: cases (12.8%) MYC gene rearrangement: cases (17.4%) Rearrangement of two genes MYC and BCL6: case (2.6%) Diagram 3.1: Rate of MYC, BCL2, BCL6 gene rearrangement in 39 studied patients 3.1.2 Characteristics of patients with MYC, BCL2, BCL6 rearrangements Table 3.1: Characteristics of two patients with two-gene rearrangements Patients with MYC and Patients with MYC Characteristics BCL2 gene and BCL6 gene rearrangements rearrangements Gender Male Male Age 51 59 Symptom B None None Blood LDH Increased Increased Stage III II International Intermediate-low Low Prognostic Index Subgroup GCB Unclassified Protein expression MYC (-), BCL2 (-) MYC (-), BCL6 (+) The characteristics of patients with MYC, BCL2, BCL6 gene rearrangements were not different from those without gene rearrangements (2 test, p > 0.05) Features of rearrangement of two genes MYC and BCL2/BCL6 according to table 3.1 14 3.2 Treatment results 3.2.1 Response rate 3.2.1.1 Response rates of 48 studied patients Methods of treatment Chemotherapy accounted for 95.8% (46 cases), chemotherapy + radiotherapy 4.2% (2 cases) Number of chemotherapy cycles Full cycles: 87.5% (42 cases); 1-5 cycles: 12.5% Actual dose of chemotherapy 100% theoretical dose: 62.5% (40 cases), 85-95% theoretical dose: 25%, 75-80% theoretical dose: 12.5% Response after cycles Complete response (CR): 10.4% (5 cases), Uncertain complete response: 4.2% (2 cases), partial response: 79.1%, disease stable: 4.2%, progressive disease: 2.1% Overall complete response: 14.6% Response at the end of treatment (treatment response) Complete response (CR): 66.6% (32 cases), Uncertain complete response: 4.2% (2 cases), partial response: 22.9%, disease stable: 4.2%, progressive disease: 2.1% Overall complete response: 70.8% Analysis of the relationship between treatment response and lesion size: < cm (91.2%); 4-7.5 cm (2.9%); > 7.5 cm (5.9%), the difference is statistically significant (2 test, p = 0.005) Analysis of the relationship between treatment response and stage, International Prognostic Index, actual dose of chemotherapy: no difference (p > 0.05) 3.2.1.2 Response rates of 39 patients with FISH results Treatment response to common gene rearrangement Complete response + Totally uncertain response: no gene rearrangement 70%; rearrangement of one gene 23.3%; rearrangement of genes 6.7%, the difference is not statistically significant (2 test, p = 0.93) Response to treatment by MYC, BCL2, BCL6 gene rearrangements Complete response + Totally uncertain response: 16.7% with MYC rearrangement, 83.3% without rearrangement (p = 0.64); with BCL2 rearrangement 6.7%, without rearrangement 93.3% (p = 0.23); with BCL6 rearrangement 16.7%, without rearrangement 83.3% (p = 0.63) 3.2.2 The 3-year progression-free and overall survival rate 15 3.2.2.1 The 3-year progression-free survival rate Entire studied patients Number of patients (progression-free): 48 40 35 33 33 Chart 3.1: Kaplan-Meier curve shows progression-free survival of 48 studied patients Mean progression-free survival = 35.4 months (95% CI: 30.5-40.4) Estimated 3-year progression-free survival rate = 68.6% Patients with and without BCL2 gene rearrangement The 3-year progression-free survival: with BCL2 rearrangement = 25% < no rearrangement = 74.2%, significant difference (Log Rank test: p = 0.04) Patients with MYC gene rearrangement, or BCL6 gene, or two MYC and BCL2/BCL6 genes did not affect progression-free survival compared to patients without gene rearrangement (Log Rank test: p > 0.05) Univariate analysis showed that there were five poor prognostic factors: presence of B symptoms, bone marrow involvement, extranodal lesion ≥ positions, elevated blood LDH and BCL2 gene rearrangement had significant effects progressive-free survival of studied patients (Log Rank test: p < 0.05) Multivariate by Cox regression analysis with factors above: none of the factors were significantly associated with reduced progression-free survival of studied patients (p > 0.05) 3.2.2.2 The 3-year overall survival rate 16 Entire study patients Number of patients (alive/censored): 48 43 40 37 37 Chart 3.2: The Kaplan-Meier curve shows overall survival of the studied patient Mean overall survival = 39.0 months (95% CI: 34.7-43.2) Estimated 3-year overall survival rate = 77% Patients with and without MYC gene rearrangements The 3-year overall survival: with rearrangement MYC = 42.9% < no rearrangement = 87.5%, significant difference (Log Rank test: p = 0.007) Patients with BCL2 gene rearrangement, or BCL6 gene, or two genes MYC and BCL2/BCL6 did not affect overall survival compared with patients without gene rearrangement (Log Rank test: p > 0.05) Univariate analysis showed that four poor prognostic factors: having B symptoms, bone marrow involvement, elevated blood LDH and having MYC gene rearrangement had significant effects on overall survival of studied patients (tested) Log Rank: p < 0.05) Multivariable by Cox regression analysis showed that three factors associated with significant reduction in overall survival of patients were: presence of symptom B (HR: 0.024), elevated blood LDH (HR: 0.123) and MYC gene rearrangement (HR: 0.024) 3.2.3 Side effects of chemotherapy in studied patients 3.2.3.1 Side effects during infusion 17 Table 3.2: Side effects during infusion of studied patients Cycle Cycle Cycle Cycle Cycle Cycle Adverse events Number of cases/total number of patients (%) 2/47 1/46 2/45 1/44 2/42 Fever < 38oC 5/48 (4.2) (2.2) (4.4) (2.3) (4.8) (10.4) Mild chills 1/47 0/46 1/45 0/44 0/42 2/48 (2.1) (0) (2.2) (0) (0) (4.2) Mild stuffy 2/47 1/46 1/45 0/44 1/42 2/48 nose (4.2) (2.2) (2.2) (0) (2.4) (4.2) Slight pain at 1/48 0/47 1/46 0/45 1/44 1/42 the injection (2.1) (0) (2.2) (0) (2.3) (2.4) site 2/47 1/46 1/45 2/44 1/42 Mild nausea 5/48 (4.2) (2.2) (2.2) (4.5) (2.4) (10.4) Comment: common in cycle and related to rituximab 3.2.3.2 Hematological side effects Leukopenia: grade 0-1 (41.7%), grade (27.1%), grade 3-4 (31.2%) Neutropenia: grade 0-1 (45.8%), grade (22%), grade 3-4 (31.2%) Anemia: grade 0-1 (50%), grade (47.9%), grade 3-4 (2.1%) Thrombocytopenia: grade 0-1 (79.1%), grade (18.8%), grade 3-4 (2.1%) 3.2.3.3 Extra-hematological side effects Increased AST/ALT: grade 0-1 (62.5%), grade (37.5%), Increased blood creatinine, no decrease in GFR: grade 0-1 (100%) Left ventricular dysfunction: grade 0-1 (95.8%), grade (4.2%), Vomiting: grade 0-1 (83.3%), grade (16.7%), Diarrhea: grade 0-1 (91.7%), grade (8.3%), Sensory nerve disorders: grade 0-1 (66.6%), grade (31.3%), grade (2.1%) 3.2.3.3 Infectious side effects Infection with neutropenia: grade (8.3%-4 cases) Severe pneumonia: grade (4.2%), grade 4-5 (2.1%-1 cases) Hepatitis B virus reactivation: grade (2.1%-1 cases) ... DLBCL should be divided into subgroups: germinal center B- cell subgroup/non-germinal center B- cell subgroup, subgroup with MYC and BCL2/BCL6 gene rearrangements (double-hit lymphoma), MYC and BCL2/BCL6... CD20(+) by R-CHOP regimen and MYC, BCL2, BCL6 gene rearrangement subgroups The dissertation contributions: This is the first study in Vietnam on DLBCL, CD20(+) treated with R-CHOP regimen combined... group • Biomarkers: the following subgroups are considered to have poor outcomes with standard treatment R-CHOP + DLBCL, activated B- cell subtype (also called non-germinal center B- cell subtype):