Outcomes of Patients After Allogenic Hematopoietic Cell Transplantation With Decitabine-containing Conditioning Regimen and Acetylcysteine Treatment
Phase: PHASE3
Conditions: Engraft Failure, Relapse, GVHD
Sponsor: The First Affiliated Hospital of Soochow University

 
 
 
 
 
 
 
Study Protocol 
 
 
 
Outcomes of patients after allogenic hematopoietic cell 
transplantation with decitabine-containing conditioning 
regimen and acetylcysteine treatment 
 
 
 
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Apr. 25, 2021 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
Table of Contents 
Protocol Summary ............................................................................................ 4 
Background ...................................................................................................... 6 
Engraftment of HSCs ................................................................................... 6 
GVHD and Relapse ...................................................................................... 7 
Reference ..................................................................................................... 9 
Rationale of this study .................................................................................... 11 
Study objectives ............................................................................................. 11 
Primary objective and primary endpoint ..................................................... 11 
Secondary objectives and secondary endpoints: ....................................... 12 
Research design ............................................................................................ 12 
Type of study .............................................................................................. 12 
Experimental diagram ................................................................................ 12 
Subject selection ............................................................................................ 12 
Inclusion criteria.......................................................................................... 13 
Exclusion criteria ........................................................................................ 13 
Treatment Allocation .................................................................................. 13 
Procedures for randomization .................................................................... 13 
Dosage and administration ......................................................................... 13 
Study process ................................................................................................ 15 
Screening phase (3 days) .......................................................................... 15 
Study period (365 days) ............................................................................. 15 
Termination phase ...................................................................................... 16 
Follow-up phase (3 years) .......................................................................... 16 
Safety evaluations .......................................................................................... 16 
Safety endpoints ......................................................................................... 16 
Clinical symptoms ....................................................................................... 17 
Laboratory examination .............................................................................. 17 
Adverse event ................................................................................................ 17 
Definition and record of an adverse event .................................................. 17 
Classification of adverse event severity ..................................................... 17 
Relevance .................................................................................................. 18 
Serious adverse event ................................................................................ 18 
Definition of an unexpected adverse event: ............................................... 19 
Expected adverse events ........................................................................... 19 
Procedures of all adverse event ................................................................. 19 
Monitoring committee ................................................................................. 20 
Statistical methods ......................................................................................... 20 
Sample size estimation .............................................................................. 20 
Statistical analysis ...................................................................................... 21 
Management of product quality complaint ..................................................... 21 
Procedures ................................................................................................. 21 

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Study drug information ................................................................................... 22 
Ethical statement ........................................................................................... 22 
Ethical principles ........................................................................................ 22 
Information and informed consent .............................................................. 22 
Withdrawal from the study .......................................................................... 23 
Identity and privacy of patients ................................................................... 23 
Responsibility of independent ethics committee ........................................ 24 
Responsibility of investigator ......................................................................... 25 
Publications .................................................................................................... 26 
Organization and responsibility ...................................................................... 26 
Appendix ........................................................................................................ 28 
Appendix 1. The score of bleeding ............................................................. 29 
Appendix 2. ECOG score ........................................................................... 30 
Appendix 3. Criteria for IBMTR severity index for acute GVHD ................. 31 
Appendix 4. Criteria of chronic GVHD ........................................................ 32 
Appendix 5: Patient consent form for study participation ........................... 33 

 
Protocol Summary 
Study centers 
The First Affiliated Hospital of Soochow University, Suzhou 215006, China;  
Principal Investigator 
Yue Han, MD, PhD; Depei Wu, MD, PhD. 
Methodology 
A prospective, randomized clinical trial. 
Primary objective 
To assess hematopoietic reconstitution, GVHD and relapse rate after allo-
HSCT with decitabine containing conditioning regimen and acetylcysteine 
treatment 
Secondary objectives 
To evaluate the survival of patients after allo-HSCT with decitabine based 
conditioning regimen and acetylcysteine treatment 
Inclusion criteria 
1) Diagnosed as hematopoietic malignancy; 
2) Achieved complete remission since the last chemotherapy; 
3) Age 10-70 years； 
4) Be willing to receive allo-HSCT, with HLA matched related or HLA 
matched unrelated, or HLA mismatched related donor. 
Exclusion criteria 
1) Active infections, severe organ damage (cardiac, renal and/or hepatic 
dysfunction greater than grade 2 according to the Common Terminology 
Criteria for Adverse Events V5.0), or any other conditions that make 
patients ineligible for allo-HSCT;  
2) Allergic to acetylcysteine or decitabine； 
Intervention  
1) Arm A: Acetylcysteine (1.2g twice a day, oral, from day -10 of conditional 
regimen to day 180 after HSCT). Conditional regimen: decitabine (20mg/m2 
intravenously from day -10 to day -8 of conditional regimen); semustine 250 
mg/m²/day on day -9; cytarabine 2 g/m² every 12 hours on day -8; busulfan 
3.2mg/kg/day on day -7 to -5; cyclophosphamide 1.8g/m²/day on day -4 to -
3; anti-thymocyte globulin (2mg/kg/d on day -5 to day -2) and 
mycophenolate (500mg, oral, twice a day from day -8) were usually added 
for transplants with unrelated donor or HLA mismatched donor.  
 
2) Arm B: Conditional regimen: semustine 250 mg/m²/day on day -9; 
cytarabine 2 g/m² every 12 hours on day -8; busulfan 3.2mg/kg/day on day -

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7 to -5; cyclophosphamide 1.8g/m²/day on day -4 to -3; anti-thymocyte 
globulin (2mg/kg/d on day -5 to day -2) and mycophenolate (500mg, oral, 
twice a day from day -8) were usually added for transplants with unrelated 
donor or HLA mismatched donor.  
Total number of patients: 100 
Total duration of the study: 4 years 
 

Background 
Allogeneic hematopoietic stem cell transplantation(allo-HSCT) is the curative 
treatment for hematological malignancy. Relapse, graft versus host disease 
(GVHD) and graft failure remain the main causes of treatment failure.  
Engraftment of HSCs 
Engraftment is the process by which hematopoietic stem cells (HSCs) make 
their way (homing) to free bone marrow niches where they can find optimal 
conditions to survive and proliferate. Once they have reached the BM 
microenvironment, HSC have to proliferate to generate all hematopoietic cell 
subsets [1]. A fundamental goal for successful engraftment is that the 
transplanted HSC are capable of sustaining long-term effective 
hematopoiesis; production of red blood cells, white blood cells, and platelets; 
and their release to peripheral blood [2].  
Various definitions of engraftment exist in the literature. Engraftment is most 
commonly defined as the first of three consecutive days of achieving a 
sustained peripheral blood neutrophil count of >0.5 × 109/L [3]. Platelet 
engraftment is usually defined as independence from platelet transfusion for 
at least 7 days with a platelet count of more than >20 × 109/L [4]. The two 
major factors affecting engraftment are the graft source and the hematopoietic 
stem cell transplant conditioning regimen.  
Emerging evidence from mouse studies has suggested that effective 
hematopoiesis depends on a particular bone marrow microenvironment in 
which HSCs reside. The bone marrow microenvironment is a cellular system 
within the marrow that serves as a vital and dynamic support system which 
supports hematopoiesis. It is composed of several different cell types 
(endothelial cells, stromal cells, etc) as well as cytokines and matrix proteins 
that are essential for the proliferation and differentiation of hematopoietic stem 

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and progenitor cells and the maturation of lineage specific precursor cells. In 
patients undergoing HCT, the homeostasis of bone marrow microenvironment 
is damaged by the intensive conditioning treatments and alloreactivities 
associated with allogeneic transplantation.  
Acetylcysteinee (NAC), a ROS scavenger, has been widely used as an 
exogenous antioxidant [5-7]. Emerging evidence from in vitro and murine 
studies showed that NAC could enhance defective HSCs by repairing 
dysfunctional bone marrow endothelial cells of thrombocytopenia patients 
after HSCT. NAC has been also proved to overcome the exhaustion of HSCs 
and enhance the engraftment of HSCs [6-8].  
Decitabine, a hypomethylating agent, can incorporate into deoxyribonucleic 
acid (DNA) and subsequently bind to DNA methyltransferase (DNMT) 
covalently, and is widely used for patients with AML and MDS. Our recent 
study showed decitabine could restore bone marrow microenvironment by 
repairing endothelial cells and endothelial progenitor cells, as well as 
cytokines and chemokines which are crucial to HSCs proliferation and 
differentiation, thereby promote platelet recovery after HSCT [9].  
 
GVHD and Relapse 
Decitabine therapy was shown to be associated with reduced incidence of 
GVHD, lower relapse rate, and increased overall survival of patients after 
HSCT in several studies [10-12]. It was found to be involved in various 
immune modulatory effects. Decitabine could induce immunosuppressive 
effects by increasing the number of regulatory T cells with upregulation of the 
expressions of Foxp3 and HLA-G [13-16]. Besides, it was shown to exert a 
protective role after HSCT by modulating the proliferation and differentiation of 
T cells in a TET2-dependent way. Furthermore, decitabine could alleviate 
tissue damage by inhibiting the production of proinflammatory cytokines, such 
as interferon γ and tumor necrosis factor β [17].  

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Decitabine was also used as salvage therapy for relapse after allo-HSCT in 
many studies [18-23]. It may upregulate the expressions of antioncogenes 
that are silenced because of hypermethylation [24], and further remodel 
specific immune responses by inducing the expression of tumor-associated 
antigen, restoring the expression of HLA class I antigen, upregulating the 
expressions of costimulatory molecules expression, inducing heterogeneous 
expression of killer immunoglobulin-like receptor (KIR) genes, and promoting 
enrichment or differentiation of tumor-derived APCs [25-28]. In summary, 
decitabine exerts its antitumor effects via direct cytotoxicity and strengthened 
tumor immunity, without sacrificing its GVHD protective effects.  
In summary, we will conduct this prospective and randomized clinical trial, to 
evaluate the hematopoietic reconstitution, GVHD and relapse rate of patients 
after allo-HSCT with decitabine containing conditional regimen and NAC 
treatment.  
 

 
Reference 
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after allogeneic hematopoietic stem cell transplantation. Expert Opin Emerg 
Drugs. 2013; 18(2): 173–192. 
2. Locatelli F, Lucarelli B, Merli P. Current and future approaches to treat graft 
failure after allogeneic hematopoietic stem cell transplantation. Expert Opin 
Pharmacother. 2014; 15(1): 23–36.  
3. Wolff SN. Second hematopoietic stem cell transplantation for the treatment 
of graft failure, graft rejection or relapse after allogeneic transplantation. Bone 
Marrow Transplant. 2002; 29(7): 545–552.  
4. Teltschik HM, Heinzelmann F, Gruhn B, et al. Treatment of graft failure with 
TNI-based reconditioning and haploidentical stem cells in paediatric patients. 
Br J Haematol. 2016; 175(1): 115-122. 
5. Bao XM, Wu CF, Lu GP. Atorvastatin inhibits homocysteine-induced 
oxidative stress and apoptosis in endothelial progenitor cells involving Nox4 
and p38MAPK. Atherosclerosis. 2010; 210(1): 114-121. 
6. Ito K, Hirao A, Arai F, et al. Reactive oxygen species act through p38 
MAPK to limit the lifespan of hematopoietic stem cells. Nat Med. 2006; 12(4): 
446-451. 
7. Hu L, Cheng H, Gao Y, et al. Antioxidant N-acetyl-L-cysteine increases 
engraftment of human hematopoietic stem cells in immune-deficient mice. 
Blood. 2014; 124(20): e45-e48. 
8. Cai H, Harrison DG. Endothelial dysfunction in cardiovascular diseases: the 
role of oxidant stress. Circ Res. 2000; 87(10): 840-844. 
9. Yaqiong T, Jia C, Qifa L, et al. Low-dose decitabine for refractory prolonged 
isolated thrombocytopenia after HCT: a randomized multicenter trial. Blood 
Adv. 2021; 5(5): 1250-1258. 
10. Iskra Pusic, Jaebok Choi, Mark A Fiala, et al. Maintenance Therapy with 
Decitabine after Allogeneic Stem Cell Transplantation for Acute Myelogenous 
Leukemia and Myelodysplastic Syndrome. Biol Blood Marrow Transplant. 
2015; 21(10): 1761-1769. 
11. Wang QY, Li Y, Liang ZY, et al. Decitabine-Containing Conditioning 
Regimen for Allogeneic Hematopoietic Stem Cell Transplantation in Patients 
with Intermediate- and High-Risk Myelodysplastic Syndrome/Acute Myeloid 
Leukemia: Potential Decrease in the Incidence of Acute Graft versus Host 
Disease. Cancer Manag Res. 2019; 11: 10195-10203. 
12. Cao Y, He Y, Zhang SD, et al. Conditioning Regimen of 5-Day Decitabine 
Administration for Allogeneic Stem Cell Transplantation in Patients with 
Myelodysplastic Syndrome and Myeloproliferative Neoplasms. Biol Blood 
Marrow Transplant. 2020; 26(2): 285-291. 

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13. Choi J, Ritchey J, Prior JL, et al. In vivo administration of hypomethylating 
agents mitigate graft-versus-host disease without sacrificing graft-versus-
leukemia. Blood. 2010; 116(1): 129–139.  
14. Fransolet G, Ehx G, Somja J, et al. Azacytidine mitigates experimental 
sclerodermic chronic graft-versus-host disease. J Hematol Oncol. 2016;9(1): 
53.  
15. Landman S, Cruijsen M, Urbano PCM, et al. DNA methyltransferase 
inhibition promotes Th1 polarization in human CD4(+) CD25(high) FOXP3(+) 
regulatory T cells but does not affect their suppressive capacity. J Immunol 
Res. 2018; 2018: 4973964.  
16. Stamou P, Marioli D, Patmanidi AL, et al. Simple in vitro generation of 
human leukocyte antigen-G-expressing T-regulatory cells through 
pharmacological hypomethylation for adoptive cellular immunotherapy against 
graft-versus-host disease. Cytotherapy. 2017; 19 (4): 521–530.   
17. Li X, Mei Q, Nie J, et al, Decitabine: A promising epi-immunotherapeutic 
agent in solid tumors. Expert Rev Clin Immunol. 2015; 11(3): 363–375.  
18. El-Cheikh J, Massoud R, Fares E, et al. Low-dose 5-azacytidine as 
preventive therapy for relapse of AML and MDS following allogeneic HCT. 
Bone Marrow Transplant. 2017; 52(6): 918–921. 
19. Craddock C, Jilani N, Siddique S, et al. Tolerability and clinical activity of 
post-transplantation azacitidine in patients allografted for acute myeloid 
leukemia treated on the RICAZA trial. Biol Blood Marrow Transplant. 2016; 
22(2): 385–390. 
20. de Lima M, Giralt S, Thall PF, et al. Maintenance therapy with low-dose 
azacitidine after allogeneic hematopoietic stem cell transplantation for 
recurrent acute myelogenous leukemia or myelodysplastic syndrome: a dose 
and schedule finding study. Cancer. 2010; 116(23): 5420–5431. 
21. Han S, Kim YJ, Lee J, et al. Model-based adaptive phase I trial design of 
post-transplant decitabine maintenance in myelodysplastic syndrome. J 
Hematol Oncol. 2015; 8: 118. 
22. Oshikawa G, Kakihana K, Saito M, et al. Post-transplant maintenance 
therapy with azacitidine and gemtuzumab ozogamicin for high-risk acute 
myeloid leukaemia. Br J Haematol. 2015; 169(5): 756–759. 
23. Pusic I, Choi J, Fiala MA, et al. Maintenance therapy with decitabine after 
allogeneic stem cell transplantation for acute myelogenous leukemia and 
myelodysplastic syndrome. Biol Blood Marrow Transplant. 2015; 21(10): 
1761–1769. 
24. Goodyear OC, Dennis M, Jilani NY, et al. Azacitidine augments expansion 
of regulatory T cells after allogeneic stem cell transplantation in patients with 
acute myeloid leukemia (AML). Blood. 2012; 119(14): 3361–3369.  
25. Chan HW, Kurago ZB, Stewart CA, et al. DNA methylation main- tains 
allele-specific KIR gene expression in human natural killer cells. J Exp Med. 
2003; 197(2): 245–255.  

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26. Coral S, Sigalotti L, Gasparollo A, et al. Prolonged upregulation of the 
expression of HLA class I antigens and costimulatory molecules on melanoma 
cells treated with 5-aza-2ʹ-deoxycytidine (5-AZA-CdR). J Immunother. 1999; 
22(1): 16–24.  
27. Hambach L, Ling KW, Pool J, et al. Hypomethylating drugs convert HA-1 
negative solid tumors into targets for stem cell based immunotherapy. Blood. 
2009; 113(12): 2715–2722.  
28. Krishnadas DK, Bao L, Bai F, et al. Decitabine facilitates immune 
recognition of sarcoma cells by upregulating CT antigens, MHC molecules, 
and ICAM-1. Tumor Biol. 2014; 35 (6): 5753–5762.  
 
Rationale of this study 
Ø Relapse, graft versus host disease (GVHD) and graft failure are the main 
causes of treatment failure of allo-HSCT. 
Ø The bone marrow microenvironment plays an important role in supporting 
hematopoietic reconstitution. NAC and decitabine could potentially promote 
engraftment by restoring bone marrow microenvironment. 
Ø Decitabine was found to be involved in various immune modulatory effects, 
and be associated with reduced incidence of GVHD and lower relapse rate. 
Study objectives 
Primary objective and primary endpoint 
Primary objective: 
This study aims to validate the outcome of patients after allo-HSCT with 
decitabine containing conditional regimen and NAC treatment. 
Primary endpoint: 
The primary endpoint is the hematological engraftment, GVHD and relapse 
rate after HSCT. 

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Secondary objectives and secondary endpoints: 
To evaluate the survival of patients after HSCT. 
Research design 
Type of study  
This is a prospective, open-label, randomized clinical trial. 
 
Experimental diagram 
The overall design of the study is shown in Figure 1. 
 
Figure 1. The flow chart of the conditioning regimen. 
Notes: CCNU: semustine; Dec: decitabine; Bu: busulfan; CTX: cyclophosphamide; Ara-C: 
cytarabine; MTX: methotrexate; CsA: cyclophosphamide; TPO, recombinant human 
thrombopoietin.  
 
 
Subject selection 

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Inclusion criteria 
Ø Diagnosed as hematopoietic malignancy; 
Ø Achieved complete remission since the last chemotherapy; 
Ø Age 10-70 years； 
Ø Be willing to receive allo-HSCT, with HLA matched related or HLA matched 
unrelated, or HLA mismatched related donor. 
Exclusion criteria 
Ø Active infections, severe organ damage (cardiac, renal and/or hepatic 
dysfunction greater than grade 2 according to the Common Terminology 
Criteria for Adverse Events V5.0), or any other conditions that make 
patients ineligible for allo-HSCT;  
Ø Allergic to acetylcysteine or decitabine. 
Treatment Allocation 
Subjects will be randomized after the investigator has verified that all eligibility 
criteria have been met. Subjects will be randomized in a 1:1 ratio to either 
Arm A or Arm B. 
Procedures for randomization 
Completely randomized block design method was performed to assign the 
patients into the 2 arms. For each study site, we produced the random series 
and corresponding assigning arm A and B. 
Dosage and administration 
Treatment: 
Arm A: Acetylcysteine (1.2g twice a day, oral administration, from day -10 to 
day 365 after HSCT). Conditional regimen: decitabine (20mg/m2 intravenously 
from day -10 to day -8 of conditional regimen); semustine 250 mg/m2/day on 
day -9; cytarabine 2 g/m2 every 12 hours on day -8; busulfan 3.2mg/kg/day on 
day -7 to -5; cyclophosphamide 1.8g/m2/day on day -4 to -3; cyclosporin A: 

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3mg/kg/d from day -8. Anti-thymocyte globulin (2mg/kg/d on day -5 to day -2) 
and mycophenolate (500mg, oral, twice a day from day -8) were usually 
added for transplants with unrelated donor or HLA mismatched donor. 
Arm B: Conditional regimen: semustine 250 mg/m2/day on day -9; cytarabine 
2 g/m2 every 12 hours on day -8; busulfan 3.2mg/kg/day on day -7 to -5; 
cyclophosphamide 1.8g/m2/day on day -4 to -3; cyclosporin A: 3mg/kg/d from 
day -8. Anti-thymocyte globulin (2mg/kg/d on day -5 to day -2) and 
mycophenolate (500mg, oral, twice a day from day -8) were usually added for 
transplants with unrelated donor or HLA mismatched donor. 
Note:  
Ø Donor for allogeneic HCT was selected based on the results of human 
leukocyte antigen (HLA) typing, age, sex, and health status, etc. Generally, 
HLA-matched related younger male donor was prioritized and alternative 
donor including HLA haplo-identical donor and HLA-matched unrelated 
donor were chosen according to the institutional guidelines. Grafts from 
bone marrow or peripheral blood were regularly primed by granulocyte 
colony stimulating factor (G-CSF) before collecting. 
Ø Prophylactic platelet transfusion is required for no-bleeding patients with 
platelet counts lower than 20×109/L and those with bleeding and platelet 
counts lower than 30×109/L. For those with severe anemia (hemoglobin ≤ 
60 g/L), washed red blood cells should be given. Platelet and red blood 
cells should be irradiated with Co60 before transfusion for those share ABO 
inconsistency between donor and recipient. 
Ø Decitabine treatment should be suspended when some non-hematologic 
toxicities appear as follows: 
• Serum creatinine ≥ 2.0mg/dL; 
• Serum aminotransferase or total bilirubin higher than 2 fold the upper-limit 
of normal level. 
Concomitant therapy 

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Except the study drug, other therapies (including immunosuppressant, 
antibiotics, proton-pump inhibitor, diuretic, nutritional therapy, etc) must be 
recorded in the eCRF for the main study treatment period. 
Study process 
Screening phase (3 days) 
Ø Inclusion /Exclusion Criteria 
Ø Demographic data: age, sex, nationality, address, contact information. 
Ø General information: past history, allergic history, previous disease and 
status, complications, previous treatment. 
Ø Physical examination: height, body weight, blood pressure, body 
temperature, heart rate, body surface area, respiratory and cardiovascular 
system examination, nervous system examination, Eastern Cooperative 
Oncology Group (ECOG) score, etc. 
Ø Laboratory examination: 
• Blood analysis: blood routine test, blood biochemistry, virological testing, T-
lymphocyte subsets. 
• BM examination: marrow morphology examination, minimal residual 
disease, chromosome，mutational analyses, gene rearrangement 
detection and donor chimerism. 
Ø Electrocardiogram test. 
Study period (365 days) 
Ø Drugs will be given based on the protocol;  
Ø Blood routine test and blood biochemistry will be performed once a day and 
once a week from day -10 to day 90, and once a week and once a month 
from day 90 to day 360, respectively. For patients with poor graft function, 
prolonged intensive monitoring of blood is recommended.  

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Ø Bone marrow examination will be performed once a month, including 
marrow morphology, minimal residual disease, chromosome, mutational 
analyses, gene rearrangement detection and donor chimerism. 
Ø Important vital signs will be recorded. 
Ø Adverse events will be recorded and managed according to this protocol. 
Termination phase 
Ø Physical examination: height, body weight, blood pressure, body 
temperature, heart rate, body surface area, respiratory and cardiovascular 
system examination, nervous system examination, ECOG score, etc. 
Ø Laboratory examination: 
• Blood analysis: blood routine test, blood biochemistry, virological testing, T-
lymphocyte subsets. 
• BM examination: marrow morphology examination, minimal residual 
disease, chromosome，mutational analyses, gene rearrangement 
detection and donor chimerism. 
Ø Electrocardiogram test. 
Follow-up phase (3 years)  
Ø Routine blood examination will be repeated once every 1 month; 
Ø The changes of other complications; 
Ø Survival will be long-term recorded until death.  
Safety evaluations 
Safety and tolerability are assessed throughout the study.  
Safety endpoints 
White blood cell count, hemoglobin, liver function, renal function. 

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Clinical symptoms: 
Newly occurred symptoms during the study period: fever, nausea, cough, 
somnolence, depression, constipation, diarrhea, petechia, edema, pharyngitis, 
pulmonary edema, atrial fibrillation, tachycardia, mycobacterium avium 
complex infectious, hyperglycemia, neutropenia, anemia. 
Laboratory examination 
Blood routine test, blood biochemistry, virological testing, electrocardiogram, 
etc. 
Adverse event 
Definition and record of an adverse event 
Adverse events are defined as any harmful medical manifestations occurring 
in a person who participates in a biomedical research whether this 
manifestation is related to the research or the product used in the research. 
An adverse effect may be any unfavourable or unexpected sign (including 
abnormal laboratory results), any symptom or temporary disorder associated 
with the use of the product, with or without relation to the product. 
The clinically significant abnormality must be reported as an adverse event 
(AE) in the eCRF, and AE is supposed to record the time of occurrence, the 
stage of severity, the duration of time, measures and outcomes.   
Classification of adverse event severity  
Every case report is performed by the grade of severity about drug adverse 
reactions： 
Ø Mild: usually transient symptoms unaffecting the daily life; 
Ø Moderate: symptoms probably affecting the daily life; 
Ø Severe: symptoms seriously affecting the daily life. 

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Relevance  
Ø Definite relevance: The adverse event is clearly related to the 
investigational agent. For example, an event that follows a reasonable 
temporal sequence from administration of the study intervention abides by 
a known or expected response pattern to the suspected intervention, which 
improves by stoppage and reappears through repeated exposures, but is 
unable to be reasonably explained by the known characteristics of the 
subject’s clinical state; 
Ø Possible relevance: An adverse event that follows a reasonable temporal 
sequence from administration of the study intervention abides by a known 
or expected response pattern to the suspected intervention, which can be 
easily induced by various other factors; 
Ø Irrelevance: The adverse event is clearly uncorrelated with the research 
agent or procedure. For example, there exists another plausible cause, 
and/or a clinically plausible temporal sequence is inconsistent with the 
onset of the event and the study intervention and/or a causal relationship is 
considered biologically implausible. 
Serious adverse event: 
A serious adverse event (SAE) event is defined as the event with one of the 
following consequences:  
Ø Death; 
Ø Life-threatening condition;  
Ø Hospitalization or extension of hospitalization; 
Ø Temporary or permanent disability; 
Ø Congenital anomaly or malformation; 
Ø Important medical events: although the event caused by the drug which 
may endanger the subjects may not be life-threatening and result in death 
or require hospitalization, medical or surgical intervention requires to be 

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taken to prevent one of the outcomes based on the appropriate medical 
judgment.  
Definition of an unexpected adverse event: 
An unexpected adverse event of the product is defined as the event with the 
nature, severity or course non-corresponding to the product information 
mentioned in the summary when it is authorized or in the investigator's 
brochure when it is not authorized. 
Expected adverse events: 
Ø Due to other non-hematological toxicity 
Liver dysfunction; 
Renal dysfunction; 
Ø Related to the hematological disease 
   Death 
Ø Related to drug allergy 
Erythra, edema, pruritus, swelling, etc. 
Procedures of all adverse event 
Investigators must immediately take necessarily measures at once to protect 
subjects’ safety, when serious adverse events occur. Furthermore, all adverse 
events should be followed up and investigated, and detailed records are 
supposed to be made and signed. 
All serious and non-serious AEs and special situation will be reported from the 
signature to completion of the subject’s last study-related procedure (which 
may include the follow-up contact for safety). SAEs must be reported using 
the Serious Adverse Event Form. The sponsor will evaluate any safety 
information that is spontaneously reported by an investigator beyond the time 
frame specified in the protocol. 

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All AEs, regardless of the severity or presumed relationship with the study 
treatment, must be recorded in the source document and eCRF using medical 
terminology. Whenever possible, diagnosis should be made when signs and 
symptoms are caused by the common etiology. Investigators must record 
their opinions on the relationship between AEs and the study treatment in the 
eCRF. All measures required for (serious) AEs must be recorded in the 
source document and reported according to sponsor instructions. 
Monitoring committee 
A safety committee comprised of 3 persons independent of the trial will be 
organized and will meet to check the safety related to the study treatment 
during the study. In terms of the overall mortality of each arm and serious 
adverse events, review will be performed by the independent safety 
committee. The committee is responsible for 
hemovigilance/pharmacovigilance of the study and acts as an additional 
warning sign against hemovigilance/pharmacovigilance of the study. 
Statistical methods 
Statistical analysis will be done by the sponsor or under the authority of the 
sponsor. A general description of the statistical methods to be used to analyze 
the efficacy and safety data is outlined below. Baseline for all analyses will be 
the day of randomization unless otherwise specified. 
Sample size estimation 
We used the formula of sample size estimate when comparing the 
independent rates more two groups. The sample size for each group at least 
was 50, and the total sample size should at least be 100. 

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Statistical analysis 
Completely randomized block design method was performed to assign 
the patients into the 2 arms. Numerical data was presented as medians with 
interval quartile range (IQR), and categorical data were shown as proportions. 
One-way ANOVA was used to compare the difference for the means among 3 
treatment arms. Chi-square test or Wilcoxon rank test was used to compare 
the difference for the proportions between 2 treatment arms. Kaplan-Meier 
method was performed to estimate the 1-year survival rate for the 2 arms 
respectively and log-rank test to compare their difference for the survival 
curves. Cox model and logistic model were used to estimate independent 
association for the HR (hazard ratio), OR (odds ratio) and 95% CI (confidence 
interval) among the treatment arms. A significance level was set as a 2-tailed 
P value of < .05. All the analyses used the SPSS 19.0 (SPSS Inc.).   
Management of product quality complaint 
A product quality complaint (PQC) is defined as any suspicion of a product 
defect related to manufacturing, labeling, or packaging, ie, any dissatisfaction 
relative to the identity, quality, durability, or reliability of a product, including its 
labeling or package integrity. PQCs may have an impact on the safety and 
efficacy of the product. Timely, accurate, and complete reporting and analysis 
of PQC information from clinical studies are crucial for the protection of 
subjects, investigators, and the sponsor, and are mandated by regulatory 
agencies worldwide.  
Procedures 
All initial PQCs must be reported to the sponsor by the investigational staff 
within 24 hours after being made aware of the event. 
If the defect is combined with an SAE, the investigational staff must report the 
PQC to the sponsor according to the SAE reporting timelines. A sample of the 

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22 
suspected product should be maintained for further investigation if requested 
by the sponsor. 
Study drug information 
Ø Decitabine is a kind of white sterile lyophilized powder, placed in a clear, 
colorless vial. Each 20 mL vial contains 25 mg decitabine.  
Ø NAC is an effervescent tablet containing 600 mg for each pill. 
Ethical statement 
Ethical principles 
The study should be carried out in accordance with Helsinki declaration 
proposed by World Medical Association and subsequent amendments and 
approved by the Independent Ethics Committee (IEC) before implementation. 
Information and informed consent  
Ø All the patients who agree to participate should be asked to sign the 
informed consent form to prove their approval for participation in this study. 
The informed consent form must be signed and dated personally by the 
patients and investigators. 
Ø Before obtaining the informed consent, the investigators must provide 
sufficient information to the patients who are potential participants in this 
study:  
• The investigators should orally inform the patients of all the relevant 
circumstances of this study;  
• The information provided to patients must be fully and easily understood by 
non-professionals, so that they can make a decision according to their own 
willingness based on their full understanding of this study;  

Vision 1.0 
 
23 
• Additionally, the patients voluntarily participate in the study, and are free to 
quit from the study at any time, without any reasons. The subsequent 
treatment of patients is not under the influence of unwilling to participate or 
quitting from the study.  
Ø All the patients who agree to participate should be asked to sign the 
Informed Consent Form (ICF) to prove their approval for participation in this 
study. The ICF must be signed and dated personally by the patients and 
the investigators;  
Ø The signed ICF will be kept in the Data Center and must be safely kept for 
future review at any time throughout the study. 
Withdrawal from the study  
The main withdrawal criteria are as following:  
Ø Changes in the patient’s condition after inclusion, which suggests that the 
study protocol is unsuitable for the patient;  
Ø Severe complications affecting the implementation of the study treatment;  
Ø Patients who are confirmed to require emergency treatment due to other 
diseases after inclusion;  
Ø Treatment unmated with the study protocol;  
Ø Patients who voluntarily quit or discontinue any examination, treatment and 
monitoring required by the study for personal reasons at any stage after 
inclusion in this study. The PI also has the right to withdraw patients from 
the study if he/she feels that the withdrawal is in the best interests of the 
patients. 
Identity and privacy of patients  
Ø After obtaining an ICF, each enrolled patient is assigned a subject number 
(allocation number). This number will represent the identity of the patient 
during the study and for the retrieving of dedicated clinical research 
database;  

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24 
Ø Throughout the study, several measures will be taken to minimize any 
breaches of personal information, including:  
• Only the PI and co-investigators will be able to link to the research data of 
the patients to themselves through the identifiable table after authorization;  
• Collection, transmission, handling and storage of the study data must 
comply with the data protection and privacy regulations. 
Responsibility of independent ethics committee  
The responsibilities of independent ethics committee include: 
Ø Review of this study;  
Ø Evaluate this study to determine if risks to which patients are exposed have 
been duly minimized and whether these risks are reasonable compared to 
expected benefits;  
Ø Check the study protocol and relevant documents (patient information 
sheet, ICF, CRF, etc.) submitted by the Research Committee before 
beginning of the study;  
Ø Provide the written proof of ethical review opinions, the written proof of the 
date of the review meeting, the written proof of the members presenting at 
the meeting and voting members, the written proof of recording of the 
reviewed versions of study protocol, ICF and other related documents, and 
if possible, a copy of the minutes, to the Research Committee. The study 
can begin only after obtaining the written proof of favorable 
opinions/approval of the IEC;  
Ø Supervise the legitimacy of the process of informed consent;  
Ø Ensure the safety of patients during the research process by examining the 
reported safety information. The investigators should report to the IEC on 
any therapeutic complications which may affect the safety of patients. 
When complications that affect the patient safety occur, the IEC should 
inform PI to withdraw patients from the study and use any possible 

Vision 1.0 
 
25 
treatment to cure patients. If the PI decides not to withdraw patients from 
the study, he should provide a written proof of explanation to the IEC;  
Ø Review the reasonableness of the costs incurred by patients in the course 
of the study through a selective check for hospitalization expenses. When 
the patient has indications for off-label use of drugs, the IEC will receive the 
notice and the description of relevant situation from the investigators. The 
IEC should record the relevant records;  
Ø Review the revisions of the study protocol, and any changes must be 
approved by the IEC before they are adopted. Unless the change is 
necessary to eliminate an immediate hazard to the patients, in which case 
the IEC should be informed as soon as possible;  
Ø Review the progress of the study annually and the close-out report 
submitted by the Research Committee at the end of the trial. 
Responsibility of investigator 
The responsibilities of investigators are as follows: 
Ø Investigators, participated in the clinical trial, should be obtained certificate 
for assistant practicing doctor, resigned and attended the training of the 
GCP guidelines and the correlation of laws and regulations, possessed 
specialty, qualification and ability in clinical trial. 
Ø Subjects are adequately recruited by the investigator during required time 
according to the clinical trial，and operation capacity and possibility to be 
qualified the item should be evaluated by the previous working experience.  
Ø Investigators are familiar with clinical trial protocols and execute instruction 
strictly according to the protocols and case report form. 
Ø In all adverse events, subjects must be taken appropriate therapies and 
made a contact with the investigator as soon as possible. Investigators will 
take responsibilities of relevant medical decision of clinical trial to ensure 
subjects that is taken adequate medical treatment. 

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26 
Ø Any information on the case report form possesses original data, to ensure 
the case history and case report form filled in truly, accurately, completely， 
timely, regularly and legally. 
Ø Subjects will be illustrated the relevant situation where the clinical trial is 
fully consent by Ethics Committee. The informed consent will be acquired 
and, during the process, it must meet the specification. 
Ø Supervision and inspection will be received by supervisor and inspector 
assigned by sponsor to ensure the quality of clinical trial.  
Ø Any advices and suggestions focused on the study protocols might be 
submit to the principal institution of clinical research, and made a 
discussion with sponsor and coordination institutions to decide whether 
adopting the above advice or suggestions, during the clinical trial executed 
by each institutions.  
Publications 
Ø All the data collected during this study are the property of the study sponsor 
and cannot be communicated in any case to a third party without the written 
agreement of the investigator. 
Ø Any publication or communication (oral or written) will be decided from a 
common agreement between the investigators and will respect the 
international recommendations: "Uniforms Requirements for Manuscripts 
Submitted to Biomedical Journals" 
(http://www.cma.ca/publications/mwc/uniform.htm): notably, an authorship 
will be proposed to each clinical center participating in the study and to 
each member of the steering committee according to his/her actual 
participation. 
Organization and responsibility  

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27 
The Research Committee is responsible for developing study protocol, auditing 
patient eligibility and guiding interpretation of informed consent. It is also 
responsible for collection of complication reports, guiding diagnosis and 
treatment of complications and emergency intervention for serious 
complications, as well as approving the content and distribution of all 
publications related to the study.

 
Appendix  
Appendix 1. The score of bleeding 
Appendix 2. ECOG score 
Appendix 3. Criteria for IBMTR severity index for acute GVHD 
Appendix 4. NIH global severity of chronic GVHD 
Appendix 5. Patient consent form for study participation 
 
 
 
 
 
 
 
 
 
 
 
 

 
Appendix 1. The score of bleeding* 
 
Grade  
Manifestation 
Score 0 
No bleeding. 
Score 1 
Occult bleeding in secretion, including mild petechia or minimal 
vaginal bleeding.  
Score 2 
Minor bleeding without the requirement of RBC transfusion, such 
as ecchymosis, epistaxis, line oozing, vaginal bleeding, skin 
bleeding, mild hematemesis, melena, mild hematuria. 
Score 3 
Bleeding that can cause a rapid fall of hematocrit and needs one 
or more units of RBC transfusion per day over the expected rate 
of an individual, or fail to obtain a post-transfusion increment at 
active bleeding. 
Score 4 
Life-threatening bleeding, defined as either massive bleeding 
causing severe hemodynamic compromise or bleeding into a 
vital organ, such as intracranial hemorrhage, pericardial 
hemorrhage, diffuse alveolar hemorrhage.  
 
Minor bleeding signified bleeding less than a week of daily score 2;  
Moderate bleeding was defined as more than a week of daily score 2, or 1–2 
days of score 3 (within 7 days); 
Severe bleeding included score 3 for 3 or more days, or any score 4. 
 
Notes: RBC=red blood cell; * Nevo S, Swan V, Enger C, et al. Acute bleeding after bone 
marrow transplantation (BMT)- incidence and effect on survival. A quantitative analysis in 
1,402 patients. Blood. 1998;91(4):1469-77. 
 

 
Appendix 2. ECOG score* 
Grade 
Performance status 
0 
Fully active, able to carry on all pre-disease performance without 
restriction. 
1 
Able to move freely and take mild physical activity, such as 
housework and office work, but restricted in severe physical activity.  
2 
Able to move freely and take care of himself, but loss of work 
capability; doing activities for more than half of the waking hours. 
3 
Capable of taking care of himself partially, confined to the bed or chair 
for more than half of the waking hours.  
4 
Completely disabled, unable to take care of himself and totally 
confined to the bed or chair. 
5 
Dead 
 
Notes: ECOG=Eastern Cooperative Oncology Group; * Oken M, Creech R, Tormey D, et al. 
Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin 
Oncol. 1982;5:649-655. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
Appendix 3. Criteria for IBMTR severity index for acute GVHD* 
 
Skin involvement 
 
Liver involvement 
 
Gastrointestinal involvement 
Index 
Stage 
(max.) 
Rash 
range 
Stage 
(max.) 
Total bilirubin 
(μmol/L) 
 
Stage 
(max.) 
Volume of diarrhea 
(ml/d) 
A 
1 
<25% 
 
0 
<34 
 
0 
<500 
B 
2 
25%- 50% 
or 
1-2 
34-102 
or 
1-2 
550-1 500 
C 
3 
>50% 
or 
3 
103-255 
or 
3 
>1 500 
D 
4 
Bullae 
or 
4 
>255 
or 
4 
Severe pain and 
ileus 
 
Notes: GVHD=graft-versus-host disease; *Rowlings PA, Przepiorka D, Klein JP, et al. IBMTR 
Severity Index for grading acute graft-versus-host disease: retrospective comparison with 
Glucksberg grade. Br J Haematol. 1997;97(4):855-64. 
 

 
Appendix 4. Criteria of chronic GVHD* 
 
Severity  
Manifestation 
Mild 
1 or 2 Organs involved with no more than score 1 plus 
Lung score 0. 
Moderate 
3 or More organs involved with no more than score 1 
OR 
At least 1 organ (not lung) with a score of 2 
OR 
Lung score 1  
Severe 
At least 1 organ with a score of 3 
OR 
Lung score of 2 or 3  
Notes: GVHD=graft-versus-host disease; In skin: higher of the 2 scores to be used for 
calculating global severity. In lung: FEV1 is used instead of clinical score for calculating global 
severity. If the entire abnormality in an organ is noted to be unequivocally explained by a non-
GVHD documented cause, that organ is not included for calculation of the global severity. If 
the abnormality in an organ is attributed to multifactorial causes (GVHD plus other causes) 
the scored organ will be used for calculation of the global severity regardless of the 
contributing causes (no downgrading of organ severity score). * Jagasia MH, Greinix HT, 
Arora M, et al. National Institutes of Health Consensus Development Project on Criteria for 
Clinical Trials in Chronic Graft-versus-Host Disease: I. The 2014 Diagnosis and Staging 
Working Group report. Biol Blood Marrow Transplant. 2015;21(3):389-401. 

 
Appendix 5: Patient consent form for study participation 
Title: Outcomes of patients with hematopoietic malignancy after allogenic 
hematopoietic cell transplantation with decitabine-containing conditioning 
regimen and acetylcysteine 
Investigator OR 
institution Name 
 
Study Site  
Patient Name 
 
Please tick each box below o if you have known the corresponding 
statement.    
                                    (to be completed by the patient) 
o What you should know about a research study  
Someone will explain this research study to you.  
Ø 
A research study is something you volunteer for.  
Ø 
Presence or absence of participation in the research study is up to you.  
Ø 
You can choose not to take part in the research study.  
Ø 
You can agree to take part now and later change your mind.  
Ø 
Whatever you decide it will not be held against you.  
Ø 
You can feel free to ask all the questions that you want before you decide . 
o What is the purpose of this study?  
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the main 
curative treatment for hematological malignancy. Relapse, graft versus host 
disease (GVHD) and graft failure are the main causes of treatment failure. 
NAC was found to be able to enhance defective HSCs by repairing 
dysfunctional bone marrow endothelial cells, and overcome the exhaustion of 
HSCs and enhance the engraftment of HSCs. Decitabine could restore bone 
marrow microenvironment by repairing endothelial cells and endothelial 
progenitor cells, as well as cytokines and chemokines which are crucial to 
HSCs proliferation and differentiation, thereby promote platelet recovery after 
HSCT. Besides, decitabine therapy was shown to be associated with reduced 
incidence of GVHD, lower relapse rate, and increased overall survival in 
several studies. Thereby we will conduct this clinical trial to evaluate the 
hematopoietic reconstitution, GVHD and relapse rate of patients with 

Vision 1.0 
 
34 
hematological malignancy after allo-HSCT with decitabine containing 
conditional regimen and NAC treatment. 
 
o Why have I been chosen? 
We are inviting patients who 
Ø 
Diagnosed as hematopoietic malignancy; 
Ø 
Achieved complete remission since the last chemotherapy; 
Ø 
Age 10-70 years； 
Ø 
Be willing to receive allo-HSCT, with HLA matched related or HLA 
matched unrelated, or HLA mismatched related donor. 
o Do I have to take part?  
Ø 
Participation in the study is entirely voluntary.  
Ø 
You will be given sufficient time to consider whether you want to participate 
in the study.  
Ø 
Non-participation in the study will not affect your future care that you will 
receive from your medical and nursing team in our hospital. 
Ø 
If you decide to join the study, you will be asked to sign an informed 
consent form.  
Ø 
You are free to withdraw from this research at any time and without giving 
a reason. Any of your current medical care and future treatment in our 
hospital will not be affected. 
o What will happen to me if I take part?  
All patients who agree to take part and provide a written informed consent form 
will be included into this study.  
If you are included in this research, you will be randomly assigned into the one of 
two treatment groups. Randomization means that neither you nor your doctor will 
be able to select which treatment you will receive. We will use a computer to 
allocate you to one of this two groups with equal chances of each treatment 
approach being the one you will receive. This procedure will ensure that the 
number of patients in each of the two treatment groups is similar.  
Ø If you are assigned in the group A:  
You will be treated with decitabine (20mg/m2 intravenously from day -10 to day -
8 of conditional regimen) plus NAC (1.2g twice a day, oral administration, from 
day -10 to day 180 after HSCT), together with modified Bu/Cy regimen. 

Vision 1.0 
 
35 
Ø If you are assigned in the group B:  
You will be treated with modified Bu/Cy regimen without decitabine and NAC. 
Your doctors will introduce the detailed treatment procedures to you. You are free 
to ask any question about the treatments you may have. 
o How long will I be in the study 
If you participate in this study, you will receive therapy for 1 year. Follow up 
will continue indefinitely, for as long as 3 years or longer. 
You can stop participating at any time. However, if you decide to stop 
participating in the study, we encourage you to talk to the researcher and 
your regular doctor first.  
o What are the risks of the study? 
Ø 
Potential adverse event of decitabine includes:  
• Other non-hematological toxicity: 
Liver dysfunction; 
Renal dysfunction; 
• Drug allergy 
Erythra, edema, pruritus, swelling, etc 
Ø 
Others: 
There also may be other unexpected complications or discomforts that we 
cannot predict.  
Your doctors will do their best to prevent complications and to treat them if 
occur. You will receive the best medical care available during and after the 
study and in the unlikely event of an injury arising from taking part in this 
study, you will be provided with the necessary care. 
oAre there benefits you to taking part in the study? 
You’ll get free treatment of decitabine and NAC (Group A) and free test of blood 
and bone marrow (all participants). Another possible benefit you may 
experience from this research includes better hematopoietic reconstitution and 
lower rates of GVHD and relapse, and prolongation of survival time. However, 
there is no guarantee that each patient will benefit from the treatment in this 
research.  
Furthermore, the results obtained from this study may be useful in guiding the 
treatment for patients with such disease in the future. 

Vision 1.0 
 
36 
 
o What are my responsibilities in this study?  
If you choose to take part in this study, you will need to:  
Ø 
Keep your study appointments.  
Ø 
Tell your doctor about:  
• All medications and supplements you are taking;  
• Any discomforts or complications you suspect;  
• Any doctors’ visits or hospital stays outside of this study;  
• Whether you have been or are currently in another research study.  
o How will my privacy be protected?  
Your health information, such as your response to the treatment, results of 
study tests, and medicines you took, will be kept by the data center of this 
research. This information is strictly confidential. However, your name and 
contact information will not be put in the database. If information from this study 
is published or presented at scientific meetings, there will be no personally 
identifiable information.  
o What happens if I change my mind during the study?  
We would certainly recommend that you continue the study, however, 
participation in the study is voluntary and you may stop the participation at any 
time that you wish without losing any of your rights as a patient here. Your 
treatment at our hospital will not be affected in any way. The PI of this study 
also has the right to withdraw patients from the study if he feels that the 
withdrawal is in your best interests. Your follow-up information will still be kept 
by doctor after you have stopped participating in the research. 
oWhom do I call if I have questions or problems? 
For information about your disease and research-related injury, you may 
contact:  
Name (institution) :                         Telephone Number:          
For information about this study, you may contact:  
Name (institution) :                         Telephone Number:          
For information about your rights as a research subject, you may contact:  
Name (institution) :                         Telephone Number:          

 
Signature page 
 
 
 
 
I have read all the above, asked questions, and received answers 
concerning areas I did not understand. I have had the opportunity to take 
this consent form home for review or discussion.  
I willingly give my consent to participate in this program. Upon signing this 
form I will receive a copy. I may also request a copy of the protocol (full 
study plan).  
 
Patient 
signature  
 
Name 
(print) 
 
Date 
signed 
 
 
Investigator (institution) Statement and Signature  
to be completed by the person taking consent 
 
I have discussed this clinical research study with the patient and/or his or 
her authorized representative using a language that is understandable and 
appropriate. I believe that I have fully informed the participant of the nature 
of this study and the possible benefits and risks of taking part. I believe the 
participant has understood this explanation.  
 
Investigator OR 
institution signature 
 
Name 
(print) 
 
Date 
signed