PRELIMINARY STUDY OF IMMUNE TOLERANCE INDUCTION IN THE TREATMENT OF PAEDIATRIC HAEMOPHILIA A WITH INHIBITORS By, DR AZMANIRA BINTI AZIZ Dissertation Submitted in Partial Fulfilment of the Requirement for the Degree of Master of Medicine (Transfusion Medicine) UNIVERSITI SAINS MALAYSIA ADVANCED MEDICAL AND DENTAL INSTITUTE (AMDI) 2017
35
Embed
PRELIMINARY STUDY OF IMMUNE TOLERANCE INDUCTION … filepreliminary study of immune tolerance induction in the treatment of paediatric haemophilia a with inhibitors by, dr azmanira
This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
Transcript
PRELIMINARY STUDY OF IMMUNE TOLERANCE
INDUCTION IN THE TREATMENT OF PAEDIATRIC
HAEMOPHILIA A WITH INHIBITORS
By,
DR AZMANIRA BINTI AZIZ
Dissertation Submitted in
Partial Fulfilment of the Requirement for the Degree of
Master of Medicine (Transfusion Medicine)
UNIVERSITI SAINS MALAYSIA
ADVANCED MEDICAL AND DENTAL INSTITUTE (AMDI)
2017
ii
DECLARATION
I hereby declare that this thesis represents my own work and all the sources had been
quoted and acknowledged by means of complete references. This thesis has been sent
to Universiti Sains Malaysia for the degree of Masters of Medicine in Transfusion
Medicine and it is not to be sent to any other universities. With that, this research might
be used for consultation and will be photocopied as reference.
_________________________
Dr Azmanira binti Aziz
PIPM 0007/13
iii
ACKNOWLEDGEMENT
In the name of Allah, the Most Compassionate, the Most Merciful. The
salutation is upon His Messenger Muhammad S.A.W., His family and His
companions. It is an honour for me, to thank the following individuals who have
contributed in this thesis possible.
1. Dr Abdul Rahim Hussein, Supervisor, Senior Medical Lecturer and Haemato-
pathologist from Advanced Medical and Dental Institute,Universiti Sains
Malaysia. This thesis would not have been possible without the guidance,
encouragement and support from him.
2. Dato’ Dr Faraizah Abdul Karim, Co-supervisor and Senior Consultant
Haemato-pathologist from National Blood Centre. Her guidance, support,
valuable comment, suggestion, advices and endless helped to complete this
thesis.
3. Assoc Prof. Dr.Wan Mohd Zahiruddin Wan Mohammad, Dr Noorsuzana binti
Mohd Shariff, Dr Sabrizan bin Osman, Mr Nizuwan bin Azman for their
helped especially in statistical analysis and data interpretation to provide a good
and quality thesis.
4. Staffs at Haemophilia clinic, National Blood Centre for their kindness and help
searching for the information and patient’s record.
5. I am grateful to my husband, children, parents, in laws and siblings, their
sacrifice, love, caring, patient and understanding to pursue this thesis.
6. My fellow colleagues from the Master of Transfusion Medicine for their
continuous support gave me the strength and confidence to complete the thesis.
Last of all, I offer my regards and blessings to all of those who supported me in
any respect during the completion of the thesis.
iv
TABLE OF CONTENTS
Page
DECLARATION ii
ACKNOWLEDGEMNT iii
TABLE OF CONTENTS iv
LIST OF TABLES viii
LIST OF FIGURES ix
ABBREVIATIONS ix
LIST OF APPENDICES xi
ABSTRAK xii
ABSTRACT xiv
CHAPTER 1 : INTRODUCTION
1.1 Overview of Haemophilia A 1
1.1.1 Pathophysiology of Haemophilia A 1
1.1.2 Clinical Presentation of Haemophilia A 2
1.1.3 Diagnosis of Haemophilia A 4
1.1.4 Treatment of Haemophilia A 4
1.1.5 Complication of Replacement Therapy 6
1.2 Overview of Inhibitor Development 6
1.2.1 Method of Analysis for Inhibitor Development 8
v
1.3 Overview Management of Inhibitor 8
1.4 Justification and benefits of research study 11
1.5 Objectives of the study 13
1.5.1 General objective 13
1.5.2 Specific objectives 13
1.6 Hypothesis of research study 13
1.7 Conceptual Framework 14
CHAPTER 2 : LITERATURE REVIEW
2.1 Treatment for Haemophilia A 15
2.2 Treatment for Haemophilia A with inhibitor 18
2.3 Review of Immune tolerance induction therapy 21
CHAPTER 3 : METHODOLOGY
3.1 Study Design 26
3.2 Study Location 26
3.3 Subjects 27
3.3.1 Inclusion Criteria 27
3.3.2 Exclusion Criteria 28
3.3.3 Immune Tolerance Induction Protocol 28
3.4 Sample Size Calculation 28
3.5 Sampling Method 30
vi
3.6 Study Duration 30
3.7 Data Resources 30
3.8 Data Extraction Tool 30
3.8.1 Flowchart of the study 32
3.9 Statistical Analysis 33
3.10 Operational Definition 33
3.11 Ethical Issues 35
CHAPTER 4 : RESULT
4.1 Introduction 36
4.2 Descriptive analysis 36
4.2.1 Patient demographics and clinical characteristics among
patients on ITI therapy in National Blood Centre, Kuala Lumpur
36
4.2.2 Treatment outcomes 42
4.2.3 Factors associated with ITI outcomes 43
4.3 Statistical analysis 45
4.3.1 Association between patient’s and treatment characteristics
with ITI outcomes
45
CHAPTER 5 : DISCUSSION
5.1 Patients demographics and clinical characteristics 48
5.2 The outcomes of immune tolerance induction therapy 51
vii
5.3 Factors associated between patients and treatment characteristics
with ITI outcomes
53
CHAPTER 6: CONCLUSION, LIMITATION AND RECOMMENDATION
6.1 Conclusion 59
6.2 Limitation 60
6.3 Recommendation 60
6.4 Recommendation for future research 61
REFERENCES 63
APPENDICES 72
Appendix 1 Approval from Human Research Ethics Committee
(HREC), Universiti Sains Malaysia (USM)
73
Appendix 2 Extension of Approval from Human Research Ethics
Committee (HREC) , Universiti Sains Malaysia (USM)
76
Appendix 3 Approval from Medical and Ethics Committee, Ministry of
Health
78
Appendix 4 Extension of Approval from Medical and Ethics
Committee, Ministry of Health
80
Appendix 5 Proforma 81
viii
LIST OF TABLES
List of Tables Page
Table 1.1 Relationship of Bleeding Severity to Clotting Factor Level 2
Table 1.2 Sites of Bleeding in Haemophilia 3
Table 1.3 Approximate Bleeding Frequency at Different Sites 3
Table 1.4 Suggested Plasma Factor Peak Level and Duration of Administration
(When there is no significant resource Constraint) for On Demand
Therapy
5
Table 1.5 Characteristics and Outcome of Reported ITI Protocol 10
Table 2.1 ITI protocol used in NBCKL for severe haemophilia A with inhibitor 23
Table 2.2 Outcome Definition 24
Table 3.1 Sample size calculation for factors associated with ITI outcomes. 29
Table 4.1 Summary of patient demographics and clinical characteristics 37
Table 4.2 Characteristic of patient’s age with the disease and treatment 40
Table 4.3 Characteristic of inhibitor level in patient with ITI therapy in NBCKL 41
Table 4.4 Factors associated with ITI outcomes 43
Table 4.5 Association between patient’s and treatment characteristics with ITI
outcomes
45
ix
LIST OF FIGURES
List of Figures Page
Figure 1.1 Conceptual framework for this study 14
Figure 3.1 Flowchart of study 32
Figure 4.1 Number of cases based on ethnicity. 38
Figure 4.2 Cumulative exposure days to FVIII
replacement therapy
39
Figure 4.3 Number of patients based on ITI outcomes 42
x
ABBREVIATIONS
AMDI Advanced Medical and Dental Institute
aPCC Prothrombin complex concentrates
aPTT and activated partial thromboplastin time
BBIS Blood Bank Information System
BIA Bethasda Inhibitor Assay
BU Bethesda Unit
CDC Centers for Disease Control and Prevention
CNS Central nervous system
CVAD Central venous access device
ED Exposure day
FEIBA Factor eight inhibitor bypassing activity
FIX Factor IX
FIXa factor IX activated
FVIII Factor VIII
FVIIIa VIII activated
GITR Germany Immune Tolerance Registry
HLA Human leukocyte antigen
HREC Human Research Ethics Committee
IITR International Immune Tolerance Registry
IQR Interquartile range
xi
ITI Immune tolerance induction
IU
ml
International Unit
millilitres
NAITR North American Immune Tolerance Registry
NBCKL National Blood Centre Kuala Lumpur
pdFVIII Plasma derived FVIII
PROFIT Prognostic Factors in Immune Tolerance
PT prothrombin time
rFVIIa, Recombinant activated factor VII
rFVIII Recombinant Factor VIII
SIPPET Survey of Inhibitors in Plasma-Products Exposed Toddlers
US United State
USM Universiti Sains Malaysia
vWF von Willebrand Factor
WHO World Health Organisation
xii
ABSTRAK
Kajian awal Induksi Toleransi Imun (ITI) dalam Rawatan
Pediatrik Hemofilia A dengan Inhibitor
Pengenalan
Pembentukan antibodi terhadap Factor VIII konsentrat atau lebih dikenali sebagai
inhibitor adalah salah satu komplikasi utama dalam perawatan untuk pesakit hemofilia
A. Sejak 30 tahun yang lalu, Induksi Toleransi Imun (ITI) digunakan untuk menyahkan
inhibitor dan memulihkan farmakokinetik factor VIII (FVIII) kepada normal. ITI
adalah pilihan terbaik jangka panjang untuk menyahkan inhibitor, dengan kadar
kejayaan yang tinggi dicapai antara 60% hingga 90%. Kajian ini bertujuan mengkaji
demografi pesakit, ciri-ciri klinikal dan hasil toleransi terapi ITI di Pusat Darah
Negara.
Kaedah
Kajian keratan rentas retrospektif telah dijalankan dengan mengumpulkan data
sejumlah 18 pesakit kanak-kanak hemofilia A yang teruk dengan inhibitor yang
menjalani ITI di Pusat Darah Negara daripada tahun 2002 sehingga 30 Jun 2016. Data
– data berkaitan pesakit diambil daripada fail pesakit dan dimasukkan ke dalam borang
kaji selidik yang telah diselaraskan. Antara data yang diambil termasuk demografi
pesakit, jenis gen mutasi FVII, jenis FVIII konsentrat, dos FVIII, sejarah paras puncak
inhibitor pesakit, paras inhibitor pesakit sebelum, pada permulaan dan semasa
perawatan ITI. ITI yang berjaya ditakrifkan apabila paras inhibitor telah negatif, aras
xiii
pemulihan FVIII kembali normal dan ketiadaan kesan amnestik apabila terdedah
kepada rawatan FVIII berikutnya.
Keputusan.
Sejumlah 12 daripada 18 pesakit (66.6%) telah berjaya menyahkan inhibitor. Kajian ini
juga menunjukkan terdapat statistik yang signifikan dengan sejarah paras inhibitor
puncak sebelum memulakan terapi ITI (p = 0.015) , paras inhibitor sebelum ITI ( p =
0.036), paras inhibitor ketika permulaan ITI (p = 0.010), paras puncak inhibitor semasa
ITI (p = 0.018), dan tempoh antara pengesanan inhibitor sehingga ITI diberi dengan
hasil akhir rawatan.
Kesimpulan.
Kajian ini menunjukkan bahawa terapi ITI boleh menjadi rawatan yang berkesan untuk
menghapuskan inhibitor. Antara faktor-faktor kejayaan ITI termasuk sejarah paras
puncak inhibitor yang rendah sebelum ITI (<200BU / ml), paras inhibitor yang rendah
sebelum dan permulaan ITI(<10BU/ml). Tempoh yang lebih singkat untuk memulakan
terapi ITI selepas pengesanan inhibitor juga mempengaruhi hasil rawatan ITI dengan
kejayaan yang lebih tinggi. Oleh yang demikian, kajian ini merupakan kajian awal yang
baik untuk memberi kefahaman dalam pemilihan pesakit mendapatkan rawatan ITI di
Malaysiaagar hasil yang sukses dapat diperolehi.
Kata kunci: hemofilia, inhibitor, factor VIII, induksi toleransi imun, paras inhibitor
xiv
ABSTRACT
Preliminary Study of Immune Tolerance Induction in the Treatment of Paediatric
Haemophilia A with Inhibitor
Introduction
One of the primary complications in the treatment of haemophilia A patient is the
development of inhibitor. Over the last 30 years, Immune Tolerance Induction (ITI) has
been used to eliminate inhibitor as well as to restore FVIII pharmacokinetics. ITI is the
best long term device in eliminating inhibitors with its success rate varying from 60%
to 90%. The purpose of this study is to investigate the patient’s demography, clinical
characteristics and the result from ITI therapy at the National Blood Centre.
Method
This cross sectional retrospective study is undertaken by reviewing the files of 18
severe haemophilia A paediatric patients with inhibitors who underwent ITI therapy at
the National Blood Centre from 2002 till June 2016. All information had been obtained
from the patient’s file and entered into a standardized research proforma. The data were
included patient’s demographics, type of FVIII gene mutation, type of FVIII product,
FVIII dosing, inhibitor history, inhibitor level during ITI, duration of ITI therapy and
the outcomes. The successful outcome was defined as negative titre inhibitors, FVIII
level were normalized and no trace of amnestic upon subsequent FVIII exposure.
xv
Result
Twelve (66.6%) patients out of 18 from this study successfully eliminated inhibitors.
This study also demonstrated that statistically there was a significant association with
the historical peak inhibitor before start ITI (p = 0.015), peak of inhibitor during ITI (p
= 0.018), inhibitor titre before ITI (p = 0.036), inhibitor at the start of ITI (p = 0.011)
and the duration between inhibitor detection and the start of ITI (p = 0.046) with the
final outcome of ITI therapy.
Conclusion
This study has demonstrated that ITI therapy can be an effective treatment and can be
accepted as inhibitor eliminator. The successful ITI factors includes the history of low
inhibitor titre peak prior to therapy (< 200BU/ml), low inhibitor titre peak during ITI,
low inhibitor titre before and at the beginning of ITI (<10BU/ml). The shorter duration
of starting ITI therapy after inhibitor detection could influence the ITI outcome with
higher success rate. This is a good preliminary study that provides an understanding
and helping the physicians in patient selection to start ITI therapy for a better success