Đánh giá kết quả điều trị u lympho ác tính không hodgkin tế bào b tái phát bằng phác đồ GDP và ghép tế bào gốc tạo máu tự thân TT TIENG ANH

MINISTRY OF MINISTRY OF EDUCATION AND TRAINING HEALTH HANOI MEDICAL UNIVERSITY NGUYEN VAN HUNG EVALUATION OF TREATMENT RESULT FOR RELAPSED B CELL NON-HODGKIN LYMPHOMA WITH GDP REGIMEN AND AUTOLOGOUS HEMATOPOIETIC STEM CELL TRANSPLANTATION Specialization : Hematology and blood transfusion Code : 62720151 SUMMARY OF MEDICAL DOCTORAL THESIS HANOI – 2021 The Work has been completed at: HANOI MEDICAL UNIVERSITY Science Mentors: Prof Pham Quang Vinh PhD Nguyen Tuan Tung Reviewer 1: Assoc Prof., Dr Ly Tuan Khai Reviewer 2: PhD Nguyen Thanh Binh Reviewer 3: Assoc Prof., Dr Bui Thi Mai An The thesis has been defended at university-level Thesis Evaluation Council held in Hanoi Medical University At, (am/pm), / /2021 (date) This thesis is found at: - National Library; - Hanoi Medical University Library THE LIST OF AUTHOR’S PUBLICATED WORKS RELATED TO THE THESIS Nguyen Van Hung, Nguyen Tuan Tung, Vu Van Truong (2018) Reseach on ratio of Peripheral Blood Cell and Bone Marrow in Non Hodgkin Lymphoma Patients in Bach Mai Hospital Vietnam Medical Journal, vol 467, 678 – 686 Nguyen Van Hung, Nguyen Tuan Tung, Pham Quang Vinh (2020) Reseach on treatment results for B cell lymphoma relapse with GDP regimen Journal of Medical Research, Hanoi medical university, no 132, vol 8, 190-197 Nguyen Van Hung, Nguy Thi Van, Nguyen Tuan Tung (2020) Preniminary results of autologous hematopoetic stem cell transplantation for non-Hodgkin lymphoma at Bach Mai hospital Vietnam Medical Journal, vol 496, 850 -859 Nguyen Van Hung, Nguyen Tuan Tung, Pham Quang Vinh (2021) Reseach results of autologous stem cell transplant for B cell lymphoma relapse at Bach Mai Hospital Journal of Medical Research, Hanoi medical university, no 140 (4), 171- 17 INTRODUCTION Non-Hodgkin lymphoma (NHL) is a group of malignancies of the lymphaid system According to GLOBOCAN, in 2020 the new-get NHL rates in the world and Vietnam were: 19.81/100.000 and 10.07/100.000 people, ranked 12th among the most popular cancers Although there are many progresses of diagnosis and treatment, the disease will still come back At the relapsed stage, treatment is more difficult, low response rate, short survival time The autologous stem cell transplantation (ASCT) has been effective in the treatment of relapsed NHL However, in order to have ASCT treatment, the patient will first have to be treated with chemotherapy, achieved partial response or more and collected enough ctem cells (SC) Some multichemotherapy regimens with the addition of Rituximab if the tumor cells are positive for CD20 are often used such as: DHAP, ICE, ESHAP These regimens have much toxicity In the world, many countries have used GDP regimen (Gemcitabine, Cisplastin, Dexamethazone) adding Rituximab if CD20 positive to treat relapsed NHL and have good results, low toxicity, lower payment for treatment In 2012, the Center of Hematology and Blood Transfusion - Bach Mai Hospital deployed SCT and used the GDP protocol to treat relapsed Bcell NHL Therefore, we proceed the research with two objectives: Objectives of the study: To evaluate the treatment results, adverse effects of GDP regimen (addition Rituximab if tumor cells are positive for CD20) and autologous hematopoietic stem cell transplantation for relapsed Non-Hodgkin lymphoma B cells; To study on some factors which have affection on the treatment results of GDP regimen and autologous hematopoietic stem cell transplantation in relapsed B cell Non-Hodgkin lymphoma patients NEW FINDINGS OF THE THESIS This is the first study about the application of the GDP regimen addition Rituximab if the tumor cells are positive for CD20 and the ASCT to treat relapsed B-cell non-Hodgkin lymphoma The results of the study: After cycles, the overall response rate: 47/61 (77.1%), complete response: 31,2% Twelve patients received ASCT After finishing the treatment: + The rate complete response of group only treatment with GDP regimen was 19/35 (54,3%) patients, the rates of progression-free survival and overall survival after years: 18.1% and 36.4% + The ASCT group, the rate complete response was 11/12 patients (before ASCT 9/12), the rates of the progression-free survival and overall survival after years: 48.5% and 61.4% The ASCT group had a longer overall survival time than the only treatment with GDP regimen group with p = 0.049 From these initial achievements, the study has opened up a new option in the treatment of relapsed B-cell non-Hodgkin lymphoma THESIS STRUCTURES Structure of the thesis: The thesis was presented on 142 pages, including itroduction part (2 pages), literature review (36 pages), subject and methodology (23 pages), results (43 pages), discussion (35 pages), conclusion (2 pages) and recommendation (1 pages) There were 53 tables, 24 figures and image There were 169 referrence sources, in which are 17 in Vietnamese and 152 in English Chapter OVERVIEW 1.1 NON - HODGKIN LYMPHOMA 1.1.1 Definition NHL is a group of malignancies of the lymphaid system characterized by abnormal spread of lymph nodes and possibly extranodal tissues 1.1.2 Epidemiology, causes and pathogenesis According to GLOBOCAN in 2020, the incidence rates in the world and Vietnam are: 19.81/100.000 and 10.07/100.000 people The average age is 60 years old, The rate at Male is higher than Female Risk factors of NHL: virus, bacteria (EBV, HP), radiation, autoimmune disease, immunodeficiency and t(14;18); t(11;14); t(2;5)… 1.1.3 Clinical features a B symptoms: have one of the symptoms: loss of more than 10 percent of body weight over months; fever; drenching night sweats b Physical symptoms: lymphadenopathy – usually bilaterally symmetricial Extranodal are primary or secondary 1.1.4 Subclinical features a Cytology, histopathology of node/tumor immunohistochemistry: identify and classify B lymphocytes, T cells or T/NK cells b Bone marrow aspiration and biopsy: to evaluate tumor cell invasion into bone marrow and to rule out lymphoid malignancies c Other tests: complete blood count , LDH, calci, ferritin, uric, liver function, kidney function d Immunoassay: t(14;18), t(11;14), gene: BCL2, BCl6, MYC… e Diagnostic imaging: X-ray, ultrasound, CT scanner, PET - CT 1.1.5 Classification of NHL: In 1832, Thomas Hodgkin who first described the malignant lymphoma There were various classifications: Gall, Rappaport, working formulation In 2001, World Health Organization (WHO) published the classification, updated in 2008, 2016 1.1.6 Staging: According to the Ann-Arbor staging system 1.1.7 Prognostic factors: According to International Prognostic Index (IPI) 1.1.8 Treatments of non-Hodgkin's lymphoma a Chemotherapy: CHOP/CHOP-like regimens for - cycles, addition Rituximab if tumor cells are possitive for CD20 b Immunotherapy: monoclonal antibodies such as Rituximab, chimeric antigen receptor (CAR) T cells c Stem cell transplantation: relapsed/refractory case, high malignancy 1.1.9 Assessment of response to treatment: according to the criteria of National Comprehensive Cancer Network (NCCN) 2004 1.2 STEM CELL TRANSPLANTATION THERAPY FOR NONHODGKIN LYMPHOMA 1.2.1 History of stem cell transplantation (SCT) In 1957, Edonnall Thomas performed the first therapy in treatment of acute leukemia In 1978, Appelbaum FR treated malignant lymphoma with ASCT therapy In Vietnam, SCT has been performed since 1995 Now, it is performing at the hospitals with over 1000 cases of SCT Bach Mai Hospital has been proceeded SCT since 2012 with over 100 cases 1.2.2 Principle of hematopoietic stem cell transplantation: SC (CD34+) have the ability to migrate from the peripheral blood to the bone marrow, multiply, and differentiate into mature blood cells High-dose chemotherapy combined with autologous SCT allows the maximum exclusion of cancer cells, to minimize the possibility of relapse 1.2.3 Indications for ASCT in NHL: Age ≤ 65 years old, respond to chemotherapy, ASCT for patients with relapse/refactory, high malignancy, high risk for early relapse 1.2.4 Stem cells sources for ASCT: there are two main sources: SC from bone marrow and peripheral blood In the world and Vietnam, mainly use SC from peripheral blood (99%) because of this source has more advantages than bone marrow source Use G-CSF, GM-CSF to mobilize SC into peripheral blood 1.2.5 Conditioning regimens for SCT: have many regimens such as: BEAM, LEED, BucyE, etc, BucyE regimen is used in Vietnam 1.2.6 Stem cells transferred to patients: stem cells are infused into the patient by catheter after 24 hours conditioning has been completed 1.2.7 Follow-up after ASCT: caring level I in a positive pressure room, following test: peripheral blood cells, ure/creatinine, AST/ALT, glucose, electrolytes, CRPhs/Procalcitonin, blood product transfusion, white blood cell stimulation by G-CSF 1.2.8 Evaluation of graft growth: neutrophil count > 0.5 G/l, platelet count > 20 G/l in days (no platelet transfusion) 1.2.9 Common complications after ASCT: a Ulcers of the oral mucosa, diarrhea, decreased blood cells, pneumonia b.Grafting syndrome: symptoms may include high fever, erythema, pulmonary infiltrates, pulmonary venous obstruction, heart failure, diarrhea, weight gain, multi-organ failure c Hepatic veno-occlusive disease: Usually occur three weeks after transplantation g Secondary cancers: myeloproliferative disorders, leukemia, other cancers 1.3 RELAPSED NON HODGKIN LYMPHOMA 1.3.1 Definition of relapsed NHL: according to the criteria of NCCN 2004 1.3.2 Characteristics of relapsed NHL: often relapsed in the first two years, the mechanism is that cells, which are not affected by chemicals, will accumulate and re-grow 1.3.3 Treatment of relapsed NHL: difficult to treat many countries choose chemotherapy to qualify for ASCT Second line regimen: DHAP, ESHAP, ICE often toxic GDP regimem: response rate is not lower than other regimens but less toxicity, low treatment cost 1.3.4 Research on the treatment of relapsed NHL 1.3.4.1 Studies on the treatment of relapsed NHL with chemotherapy In the NCIC - CTG LY.12 study, the response rate of R-GDP in relapsed/refractory DLBCL was: 47% not lower than the R-DHAP regimen: 44% , lower toxicity and treatment costs Diego Villa's study, 141 relapsed NHL treated with R-GDP, response rate: 76%, 112 got ASCT In the study by Francesco Ghio (2016), 45 patients with DLBCL relapse were treated with regimen R - GDP, the RR was 15/45 (33.3%) Dittrich, the GDP regimen is no less effective than other regimens, but the toxicity, especially toxicity to the hematopoietic system, is much lower 1.3.4.2 Studies on treatment of relapsed NHL with ASCT a Follicular lymphoma (FL) In the GELA/GOELAMS study (2011) on 175 cases of relapsed follicular lymphoma (FL), the 3-year overall survival rate was higher in the SCT group than the non-ASCT group (92% vs 63%), with p = 0,0003 Freedman 153 FL relapse, the probability of disease-free survival, the 8-year overall survival is 42% and 66% Andrew M Evens, SCT for 136 relapsed/refractory FL treated with Rituximab, probability of disease-free survival, 3-year overall survival: 78%, 92% Thus, both before and after the period of Rituximab, ASCT for patients with relapsed/drug-resistant FL is highly effective b Diffuse Large B Cell Lymphoma (DLBCL) Study of PARMA group (1995), 215 relapsed NHL, cycles of DHAP regimen, 109 patients responded, divided into groups Group 1: 54 patients, continued treatment with DHAP regimen, the CR rate was 44% Group 2: 55 patients with ASCT, the CR rate was 84% Probability of 5-year disease-free survival in the ASCT group was 46%, the non ASCT group was 12%, with p < 0.001 The 5-year overall survival probability in the ASCT group was 53% and the non ASCT group was 32% with p = 0.038 Study Nicolas mounier (2012), ASCT for 470 relapsed DLBCL, 119 (25%) were treated with rituximab, the average duration of the first-time treatment was 11 months As a result, the probability of overall survival and disease free survival after years is: 63% and 48% The mean disease - free survival time was 51 months, much higher than the time of first treatment with p < 0.01 Chapter SUBJECT AND METHOD OF THE STUDY 2.1 SUBJECT OF THE STUDY Including 61 patients with relapsed B - cell NHL who were treated with GDP regimen at the Center of Hematology and Blood Transfusion - Bach Mai Hospital from January 2013 to June 2020(retropective study 21 patients, prospective study 40 patients), 59 patients with positive CD20 tumor cells were treated with Rituximab In which: - 61 patients were treated for cycles with GDP regimen or GDP regimen addition Rituximab if tumor cells are possitive for CD20 - 12 patients were ASCT after treated the GDP regimen addition Rituximab if tumor cells are possitive for CD20 - 35 patients non-ASCT treated with GDP regimen or GDP regimen addition Rituximab if tumor cells are possitive for CD20 during 4-6 cycles - 14 patients did not respond, switched to another regimen, in which patients progressed and died after treatment cycles 2.1.1 Eligibility criteria 2.1.1.1 Age: ≥16 years old 2.1.1.2 Definitive diagnosis: diagnosis and classification of WHO 2008 2.1.1.3 Diagnosis of relapse: according to NCCN 2014 criteria 2.1.1.4 Treatment: GDP regimen addition Rituximab if tumor cells are possitive for CD20 2.1.1.5 Patients with ASCT add the following criteria: ≤ 65 years old, PR/CR 2.1.2 Exclusion criteria: have neurological, mental, heart, liver, kidney diseases, contraindications to chemotherapy and ASCT The patients and their family disagree, did not fully complete the treatment course 2.2 METHOD OF THE STUDY 2.2.1 Study design: uncontested clinical intervention with follow up, retropective and prospective study 2.2.2 Formula for calculating sample size: convenient sampling 10 c Stem cell storage and preservation: SC are preserved, stored at 1960C at Stem Cell Bank, National Institute of Hematology Blood Transfusion d Conditioning before autologous SCT: BEAM or BuCyE regimen e Stem cell transfusions to patients: SC transfusion on day Monitor vital signs and early complications such as allergies, anaphylaxis f Follow-up after ASCT: highest level care in a positive pressure room, daily test: peripheral blood cells, ure/creatinine, electrolytes, CRPhs/Procalcitonin, blood product transfusion, white blood cell stimulation by G-CSF when needed g Anti- infection: use combination antibiotics if there is an infection h Nutrition: about 2000 Kcal/day, add intravenous if needed 2.3.2.6 Follow-up after treatment: re-examination after month, every months for the next years, every months in subsequent years 2.3.3 Evaluation criteria: 2.3.3.1 Graft growth assessment: is counted as graft growth when neutrophil > 0.5 G/l and platelet > 20 G/l for days (Carreras E.) 2.3.3.2 Evaluation of treatment results a Overall response assessment: after cycles and finish of treatment, according to 2014 NCCN criteria b Assessment of survival time: call to record patient information If the patient died, write down the time and cause of death Calculation of survival time after treatment by Kaplan - Meier method c Comparison of treatment results by prognostic factors: age, gender, disease stage, disease type, subgroup, IPI score, time to relapse, LDH, Ferritin, CD5, MYC, BCL2, BCL6 2.3.3.3 Evaluation of unwanted effects: calculated the unwanted effects per total treatment cycles according to the levels of WHO Clinical: vomiting, nausea, inflammation of the oral mucosa, diarrhea, chills; hematopoietic system, liver, kidney 2.3.4 Research materials: peripheral blood, marrow fluid bone marrow biopsy, lymph nodes/tumors for hematology, biochemistry, pathology testing 11 2.3.5 Research tools and instruments 2.3.5.1 Research instruments: XN1000 cell counter, CS 2500 coagulation machine, Hitachi biochemistry machine, Nikon - Japan microscope, Cope Spectra and Optia Spectra, Flow cytometry machine (Navios-Ex) 2.3.5.2 Chemicals and biological products: chemicals of hematology, biochemistry, microbiology, pathology, diagnostic imaging 2.3.6 Testing techniques and evaluation standards: testing techniques, evaluation criteria for hematology, biochemistry, microbiology, pathology, and electro-optical indicators are performed according to the procedures of the Ministry of Health, Bach Mai Hospital 2.4 DATA ANALYSIS AND PROCESSING Using SPSS 22.0 software to process research data 2.4.1 Method of describing the results: quantitative variables expressed in X ± SD, qualitative variables presented as a percentage with decimal places 2.4.2 Comparison of results: survival time according to Kaplan – Meier, using Log-rank test to evaluate the difference Use test χ2 to test statistical significance when comparing proportions, if the value is small, use χ2 (Yates) The comparison was statistically significant when p < 0.05 2.5 ETHICAL ISSUE OF THE STUDY The outline of the study was approved by the ethics committee of Hanoi Medical University according 87/HĐĐĐHYHN Decision No 925/KCB - NV (12/9/2012) of the Ministry of Health agreed to give Bach Mai Hospital hematopoietic stem cell transplantation for lymphoma Patients and their families agreed to participate in the study Patients’ information is confidential Research results serve the treatment and care of people's health Patients with ASCT are approved by the ASCT committee of Bach Mai Hospital 12 STUDY ALGORITHMS 61 patients B Cell NHL relapsed Clinical examination, subclinical examination, classification staging, prognosis Treatment regimem GDP x 2cyles, adding Rituximab if CD20 (+) Bo Evaluation of response to treatment according to the standards of NCCN 2014 47 patients responded (19 CR, 28 PR) 35 patients non ASCT 12 patients ASCT 14 patients failed to responded Change to another regimen Stop studying Treatment continues regimen GDP 4-6 cycles Mobilize, collection, ASCT Evaluation of response (19 CR, 16 PR) After ASCT 30 days (11 CR, PR) Monitor, survival time find factors related to results Monitor, survival time, find factors related to results 13 Chapter STUDY RESULTS 3.1 CHARACTERISTICS OF STUDY PATIENT GROUP 3.1.1 Characteristics age, gender, classification, survival time The mean age: 55.9 years old; group ≥ 60: 37.7%; male/female =2.87 Transform 5/61 (8.2%) The DLBCL is the highest: 59.0%; non - GCB: 66.7% The rate patients relapsed < 24 months: 59.0% 3.1.2 Stage, prognostic index, clinical and subclinical symptoms: - Stage IV: 77.0%; IPI = points: 68.9% - The rate of lymphadenopathy, liver and spleen enlargement: 88.5%, 16.4 and 32.8% Primary extranodal: 32.8%, gastrointestinal: 5/20 patients - The rate of bone marrow invasion, anemia, leukopenia, and thrombocytopenia: 34.4%; 54.1%; 18.0% and 24.6% - Hepatitis B: 19.7%; increase in urea/creatinine: 39.3%/14.8%; increase in AST/ALT: 31.1%/11.5%, increase LDH, Ferritin: 9.8%/59.0% - The rates positive for CD20, CD5, BCL2, BCL6, CD10: 96.7%, 33.3%; 82.5%; 28.6%; 27.8% - DLBCL group, expression double hit (MYC + BCL2/BCL6): 4/10 (40%); expression triple hit (MYC + BCL2 + BCL6): 2/10 (20%) 3.2 TREATMENT RESULTS, ADVERSE EFFECTS OF GDP REGIMEN AND AUTOLOGOUS HEMATOPOIETIC STEM CELL TRANSPLANTATION FOR NON-HODGKIN LYMPHOMA B CELLS RELAPSE 3.2.1 Treatment results Table 3.1 Results after cycles and the end of treatment Result of treatment Complete Response Partial Response Stable disease Progressive disease Progressive /death Total After cycles (n=61) n 19 28 61 % 31,2 45,9 11,5 8,2 3,3 100,0 Finish of treatment (n=47 Non - ASCT ASCT (n = 35) (n=12) n Tỷ lệ n % 19/35 54,3 11/12 91,7 16/35 45,7 1/12 8,3 0 0 0 0 0 0 35 100,0 12 100,0 14 Autologous stem cell transplantation (ASCT) Overall response rate: 47/61 (77.1%), in which CR: 31,2% - 35 patients non ASCT, treatment GDP regimes - 11/12 ASCT patients are overall response 3.2.2 Results of treatment after cycles of the two groups 3.2.2.1 Treatment results of the group Non - ASCT (n=35) Table 3.2 Response rate to GDP regimen of non-ASCT group Time Response Complete Response Partial Response Total After cycles n % 25,7 26 74,3 35 100,0 Finish of treatment n % 19 54,3 16 45,7 35 100,0 After cycles, the complete response rate: 19/35 (54.3%) patients 3.2.2.2 Treatment results of ASCT group a General characteristics of patients with ASCT Table 3.3 Some characteristics of patients with ASCT Characteristics of transplant patients Average age ± SD (Min – Max) Male Gender Female Diffuse large B cell lymphoma Small B cell Mantle cell lymphoma Classification Marginal zone B-cell Follicular lymphoma Stage II Stage III Stage Stage IV Yes B symptoms No score IPI score – score Invasion Bone marrow invasion No invasion Number of patients 48,3 ± 10,4 (34 -64) 1 6 15 b Features of stem cell mobilization and collection (CD34+) Stem cell count: 8.4 ± 6.1 (3.1 – 21,5)106/kg body weight; 11/12 patients mobilized with G-CSF, 01 patient used G-CSF + Cyclophosphamide c Time to graft growth, hospital stay and use of G-CSF The time to grow grafts with neutrophils and platelets: 10.5 ± 1.2 and 13.3 ± 2.6 days Use of G-CSF and hospital stay: 12.2 ± 1.9 and 33.8 ± 5.4 days d Results 30 days after ASCT After 30 days of autologous hematopoietic stem cell transplant, the rate of complete response was 11/12 patients (pre-transplant was 9/12) 3.2.2.3 Survival time in the ASCT group and the non- ASCT group After years: ASCT: 48,5 % Non - ASCT: 18,1% After years: ASCT: 61,4% Non - ASCT: 36,4% PFS: ASCT group: 44,4 ± 8,3 month Non–ASCT group: 32,8 ± 3,7 month OS: ASCT group: 56,1 ± 7,1 month Non– ASCT group: 42,8 ± 4,6 month Progression-free survival Overall survival Chart 3.1 Survival time after treatment of GBTG group (n=12) PFS after ASCT were: 44.4 ± 8.3 months and non – ASCT: 32,8 ± 3,7 months; the probability of PFS years of ASCT group: 48,5%, Non – ASCT group were: 18,1%, with p = 0,099 OS after ASCT were 56,1 ± 7,1 months, and non – ASCT: 42,8 ± 4,6 month The probability OS after years were 61.4% and 36,4%, the difference is statistically significant with p = 0.049 3.2.3 Unwanted effects Symptoms of vomiting - nausea grade I and II are: 41.4% and 25.1%; Other symptoms are rare Common leukopenia, neutrophils 16 grade III: 36.7% and 33.5% Common Anemia is grade II: 34.7% Thrombocytopenia was more common in grade III: 31.9% The rate of treatment cycles that did not affect the renal function of urea/creatinine were: 85.7% and 82.1%, the rate with liver function (normal AST/ALT) was: 82.1% and 80.5% In the ASCT group, vomiting: 12/12 patients, 10/12 patients had diarrhea, 10/12 patients had oral mucosal ulcers 10/12 patients decreased hemoglobin grade III, Both 12/12 had leukopenia, grade IV thrombocytopenia 10/12 patients did not increase urea/creatinine, 6/12 patients did not increase AST/ALT, the rest only increased AST/ALT level I, infection: 6/12 (50%) 3.3 SOME FACTORS AFFECT TREATMENT RESULTS OF GDP AND AUTOLOGOUS HEMATOPOIETIC STEM CELL TRANSPLANTATION 3.3.1 Factors affecting the results of treatment regimen GDP 3.3.1.1 Result value with a number of factors Non-statistical difference in outcomes with several prefixes such as: age, gender, time to relapse, disease stage, IPI score, LDH 3.3.1.2 Treatment results with concentration Ferritin Table 3.4 Response rate to ferritin Ferritin level Result After cycles n =61 The end of treatment n =35 Complete response Partial response Stable disease Progressive disease p Complete response Partial response p Ferritin ≤ 400 Ferritin > 400 n = 25 Percent n = 36 Percent 12 48,0 19,4 32,0 20 55,6 8,0 13,9 12,0 11,1 0,123 n = 12 Percent n = 23 Percent 75,0 10 43,5 25,0 13 56,5 0,046 At the end of treatment, the rate CR in the high ferritin group: was lower than the normal ferritin group (43.5% compare to75.0%), p = 0.046 The difference is statistically significant with p = 0.046 17 3.3.1.3 Survival according to response level The overall survival after treatment in the CR group was 52.1 ± 4.6 months, and the PR group was 31.7 ± 4.7 months, with p = 0.066 3.3.2.3 Comparison of treatment results with prognostic factors of DLBCL a Survival according to BCL6 (n = 16) BCL6 (-): 46,6 ± 7,2 month (95% CI: 32,5 – 60,8) BCL6 (-): 58,2 ± 6,8 month (95%:CI: 44,8 – 7,5) BCL6 (+): 22,7 ± 5,1 month (95% CI: 12,7 – 32,6) BCL6 (+): 25,1 ± 5,1 month (95%CI: 15,0 – 35,2) Progression-free survival Overall survival Chart 3.2 Extra life time with BCL6 imprint The group of patients with diffuse large B-cell type, BCL6positive had a shorter progression-free survival time after treatment than the BCL6-negative group (22.7 ± 5.1 months versus 46.6 ± 7,2 months, with p = 0.035 In Cox regression analysis, the BCL6 group (+) increased the risk of recurrence 4,132 times c Survival according to dual gene expression (n=8) Table 3.5 Survival according to dual gene expression Dual gene expression Finish of treatment Number of patients with relapse Progression-free survival (month) Index p Number of patients who died Overall survival Index p Positive 3/3 (100%) 10,0 ± 2,0 Negative 1/5 Not estimated yet 0,039 3/3 (100%) 1/5 18,5 ± 10,5 Not estimated yet 0,046 18 All 3/3 patients with dual gene expression (MYC and BCL2 and/or BCL6) had relapsed and died at the time of study 3.3.2 Some factors affect the results of ASCT Table 3.6 Progression-free survival and overall survival after stem cell transplantation according to several prognostic factors (n = 12) Prognosis factors Group (Patient) ≤ 60 (n = 10) Age Kind of disease IPI score ± SD OS p 46,5 ± 8,7 > 60 (n = 2) (n = 8) ± SD Hasn’t relapsed 45,0 ± 5,3 Hasn’t died 40,5 ± 16,3 DLBCL (n = 6) 38,3 ± 7,1 0,844 56,3 ± 12,8 44,8 ± 6,1 0,473 Others (n = 6) 56,0 ± 13,9 ≤ (n = 4) 42,8 ± 8,9 0,805 60,4 ± 9,5 42,8 ± 8,9 0,671 > (n = 8) 45,1 ± 10,2 B symtomps Yes 31,0 ± 10,4 Invasion of marrow Yes Relapsed time ≤ 24 months (n=9) 36,5 ± 6,5 > 24 months (n= 3) 57,0 ± 0,0 (n = 3) 0,913 56,9 ± 8,0 60,0 ± 6,6 0,083 No (n = 9) (n = 6) 59,1 ± 10,3 0,142 18,0 ± 4,2 37,0 ± 4,6 38,0 ± 3,7 0,437 No (n = 6) 0,65 45,9 ± 4,6 0,514 Female (n = 4) p 55,2 ± 7,5 0,56 Male Gender PFS 42,0 ± 16,2 0,835 54.6 ± 10,3 0,176 42.3 ± 11,3 0,531 60,1 ± 8,3 Initially, the patient groups were recorded with factors such as: other disease forms (cystic form, capsular cell, small cell ), no B symptoms, no bone marrow invasion, recurrence time after 24 months with progression-free survival and mean overall survival over 40 months However, the difference was not statistically significant with p > 0.05 19 Chapter DISCUSSION 4.1 COMMON CHARACTERISTICS OF THE RESEARCH GROUP The study of 61 patients relapsed B cell NHL showed that the average age was 55.9 (29 - 80) years old, the male/female ratio ≈ 2.87 This result is similar to other studies and as in the literature The rate DLBCL highest: 59.0%, non-GCB: 66.7% Transformation was 8.2%, lower than that of Rania Hafez's study The mean PFS stage I was: 26.5 ± 3.1 months, (9 - 170) Mainly patients are stage IV and III (77.0% and 14.8%), the most common IPI score is and points (68.8 % and 9.8%), equivalent to the study of Alden A Monica, Heba Sheha… The B symptoms, lymphadenopathy, and extranodal nodes were: 75.9%, 84.5% and 91.4 %, this result is similar to that of Nguyen Lan Phuong and Rania Hafez About subclinical, the rate of bone marrow invasion, anemia, leukopenia, and thrombocytopenia: 34.4%; 54.1%; 25.9% and 19% are equivalent to the studies of Musa F Alzahrani (Canada), Conlan, Bloomfield (USA) The rate of increase of ure and creatinine was: 39.3% and 14.8%, the rate of increase of AST/ALT was 31.1%/11.5%; LDH,Ferritin increase was 9.8% and 59.0% The percentage of patients who had CD20, CD5 positive is 96.7%, 69.1%; 4/10 patients had MYC positive, equivalent to the study at the early stage of diagnosis 4.2 TREATMENT RESULTS, UNWANTED EFFECTS OF GDP REGIMEN AND AUTOLOGOUS STEM CELL TRANSPLANTATION FOR NON HODGKIN LYMPHOMA B CELLS RELAPSE 4.2.1 Overall treatment results after cycles and after treatment ends The results of the study in table 3.1 show that, after cycles, 47/61 patients, corresponding to 77.1%, had a response, in which the CR was 31.2% and the PR was 45.9% This result is equivalent to some 20 other studies such as those of Nguyen Lan Phuong at National Institute of Hematology and Blood Transfusion.,12 patients received ASCT, 35 people still continue to treatment with the GDP 4-6 cycles 4.2.2 Results of treatment after cycles of the two groups 4.2.2.1 Group only treated with GDP regimen At the end of treatment, the rate CR was 19/35 patients (54.3%) This result is equivalent to some other studies such as those of Nguyen Lan Phuong, Michel Crum, Rania Hafez, Diego Villa, Francesco and not lower to other second-line regimens such as DHAP, ESHAP or ICE 4.2.2.2 Results of stem cell transplantation 12 patients receiving ASCT have characteristics: the mean age was 48.3 ± 10.4 years old (34 - 64 years old), lower than the research group because Bach Mai Hospital and other ASCT centers choose the age under 65 years old Currently, in the world, centers have raised the age for transplantation higher (over 70 years old) as reported by Ajay K.Gopal and Jantunen E The DLBCL is the majority 6/12 (50.0%), spreading stage is 11/12 patients (91.7%), IPI score 3-4 points is 8/12 patients (66.7%), symptoms B is 9/12, bone marrow invasion is 6/12 (50%) The count of SC CD34 (+) collected was 8.4 ± 6.1 *106/kg body weight (3.1 - 21.5), in which 11/12 patients mobilized by G-CSF alone, this result also equivalent to some authors mobilizing after GDP regimen such as Jean - Philippe Adam, Gokamen and higher than the authors mobilizing stem cells after other regimens such as DHAP, ESHAP, ICE ASCT results: the time for grafting of neutrophils and platelets is 10.2 days and 13.3 ± 2.6 days, this result is similar to other authors such as Bach Quoc Khanh, Jeong Eun Kim, Jacqueline Sapelli MD 21 The hospital stay was 33.8 days After ASCT, the rate CR is 11/12 patients (before ASCT is 9/12) 4.2.2.3 Survival time of the two groups PFS and OS mean after ASCT is: 44.4 ± 8.3 and 56.1 ± 7.1 months The probability of PFS and OS after treatment at years is: 72.7% and 81.8%; at years are: 48.5% and 61.4% Thus, for patients receiving autologous hematopoietic stem cell transplantation, there was a marked improvement in progression-free survival and overall survival This result is equivalent to some other studies such as Nicolas mounier (2012) 4.2.3 Unwanted effects With the GDP regimen, the common clinical symptoms are vomiting - nausea, rarely diarrhea, ulcers of the oral mucosa, chills and infectious fever Grade IV leukopenia encountered 26.7%, and grade IV thrombocytopenia was only 8.8%, GDP regimen was less toxic to liver and kidney function This result is also equivalent to many authors of GDP regimens experiencing less toxicity and lower costs For ASCT, the common clinical symptoms are vomiting (100%); diarrhea, mouth ulcers (83,3%), infection rate: 6/12 patients lower than other authors as Bach Quoc Khanh, Jeong Eun Kim, Jacqueline Sapelli ASCT shows safety with liver and kidney function 4.3 EFFECTS OF SOME FACTORS ON THE TREATMENT RESULTS OF GDP AND STEM CELL TRANSPLANTATION 4.3.1 Factors affecting the treatment outcome of GDP regimen The results of the study did not show any difference in treatment results with a number of prognostic factors such as: age, sex, time to relapse, IPI and symptoms B, LDH The results of the study in Table 3.3 show that after the end of treatment, the rate of OS in the 22 group with low ferritin concentration is 75%, with p = 0.046 compared with the group of patients with high ferritin concentration The pass passis only 40.7% There has not been any difference in treatment results with prognostic factors in DLBCL such as subgroup, CD10, CD5 markers The PFS after treatment of the group BCL6 (-) was 46.6 ± 7.2 months with (95% CI: 32.5 – 60.8 months) was 22.7 ± 5.1 months longer than the positive BCL6 group with (95% CI: 12.7 – 32.6 months), this difference is statistically significant with p = 0.035, Cox regression analysis showed that BCL6 (+) increased the risk of recurrence 4.132 times This result is similar to Suli's study showing that positive BCL6 is a poor prognostic factor regardless of race or detection method Although the number of patients is still small, initially found that the bad prognostic factors include positive BCL2, double gene expression, it is necessary to study with a larger number of patients and longer follow-up time to come up with results 4.3.2 A number of factors affect the outcome of ASCT At the time of the study, there were deaths, of which patient died from kidney cancer, patient died from biliary tract infection and patient did not achieve a complete response after transplantation, death from progressive disease Due to the small number of patients, the follow-up time is not long enough, so there are no prognostic factors affecting the results of autologous hematopoietic stem cell transplantation However, in Table 3.6, initially recorded groups of patients with factors such as: other disease form, no B symptoms, no bone marrow invasion, time to relapse after 24 months, and PFS averaged over 40 months Hasan's study, the factors that adversely affect the outcome of autologous 23 hematopoietic stem cell transplantation are advanced age (> 45 years old), the time from achieving a complete response to stem cell transplantation Arboe's study showed that the factors affecting the progression-free survival time included: lesions on an extranodal site, persistent disease, having relapsed more than times before Factors affecting overall survival were: advanced age (>58 years), lesions on an extranodal site, persistent disease CONCLUSION Results of treatment, unwanted effects of GDP regimen and autologous hematopoietic stem cell transplantation After cycles of treatment: The rate of patients with response was 77.1%, the CR are: 31.2% In which: 35 patients non- ASCT treatment with the GDP regimen 12 patients received ASCT After finishing treatment: - The non - ASCT group, the rate CR was 19/35 patients, the rates of progression-free survival and overall survival after years: 18.1% and 36.4% - The ASCT group, the rate CR was 11/12 patients (before ASCT: 9/12 patients, the rates of the progression-free survival and overall survival after years: 48.5% and 61.4% - The ASCT group had a longer overall survival time than the untransplanted group with p = 0.049 Unwanted effects: - Unwanted effects when treated with the common GDP regimen are: nausea - vomiting grade I, II (41.4% and 25.1%); very rarely diarrhea, chills, inflammation of the oral mucosa Leukopenia, thrombocytopenia grades III - IV are: 63.4% and 40.7% of cycles The 24 rate of cycles that did not affect urea/creatinine renal function were 85.7% and 82.1%, respectively, the rate of cycles without increasing AST/ALT was 82.1 and 80.5% - Unwanted effects when autologous stem cell transplantation are: vomiting - sadness occurs in 100% of patients The rate of oral mucosal ulcers and diarrhea are 83% The percentage of patients who did not increase urea/creatinine was 83.0%; without increasing AST/ALT is 58.3% Infection rate is 6/12 patients (50.0%) Some factors affect treatment results Factors affecting the treatment outcome of GDP regimen: - The group of patients with high ferritin reduced the rate of CR compared with the group of normal Ferritin (43.5% versus 75.0%) - In the group of diffused large B cells, positive BCL6: reduced progression-free survival time after treatment compared with the negative BCL6 group (22.7 ± 5.1 months vs 46.6 ± 7.2 months) with p = 0.035 BCL6 positivity increases the risk of recurrence 4,132 times - All 3/3 patients with dual gene expression (MYC and BCL2 and/or BCL6) had relapsed and died at the time of study Factors affecting the outcome of autologous hematopoietic stem cell transplantation: No prognostic factors have been reported to have a statistically significant influence on the outcome of autologous hematopoietic stem cell transplantation ... Library; - Hanoi Medical University Library THE LIST OF AUTHOR’S PUBLICATED WORKS RELATED TO THE THESIS Nguyen Van Hung, Nguyen Tuan Tung, Vu Van Truong (2018) Reseach on ratio of Peripheral Blood... results of autologous hematopoetic stem cell transplantation for non -Hodgkin lymphoma at Bach Mai hospital Vietnam Medical Journal, vol 496, 850 -859 Nguyen Van Hung, Nguyen Tuan Tung, Pham Quang... node/tumor immunohistochemistry: identify and classify B lymphocytes, T cells or T/NK cells b Bone marrow aspiration and biopsy: to evaluate tumor cell invasion into bone marrow and to rule out lymphoid