___________________________________________________MANAGEMENT OF THALASSAEMIA REP ORT MANAGEMENT OF THALASSAEMIA HEALTH TECHNOLOGY ASSESSMENT UNIT MEDICAL DEVELOPMENT DIVISION health MINISTRY OF HEALTH MALAYSIA MOH/PAK/77.03 (TR) i ___________________________________________________MANAGEMENT OF THALASSAEMIA EXECUTIVE SUMMARY 1. BACKGROUND Thalassaemias and Sickle cell disorder, are the commonest human inherited haemoglobin disorders that can be treated effectively, and also prevented at community level. Thalassaemia is the commonest single gene disorder in Malaysia and a paradigm of monogenetic diseases. In 1995, it was estimated that about 8,000 persons were afflicted with HbE beta Thalassaemia, and 8,000 with Homozygous beta-Thalassaemia, about 40% of whom were dependent on regular blood transfusions for survival (Kaur, 1995). In addition, the carrier rate for beta Thalassaemia and HbE is estimated to be 3-5%. Besides blood transfusion, another curative option is the use of haemopoietic stem cell transplantation. In Malaysia, it is currently being offered to potential patients with suitable donors at two centres, namely, University Malaya Medical Centre and the Paediatrics Institute, Kuala Lumpur Hospital. 2 OBJECTIVE To determine the safety, effectiveness, cost implications as well as ethical, legal and social implications of management of Thalassaemia. 3. SCOPE This assessment does not include diagnosis of Thalassaemia, as well as antenatal screening for Thalassaemia that has already been assessed previously under antenatal screening. 4. RESULTS There is sufficient evidence that a screening and prevention programme is effective for the control of β-thalassaemia trait. The options for effective screening include screening of 15-16 year old school students, pre-marital screening, and screening of relatives of known carriers. Screening tests include MCH and osmotic fragility test. The complications of Thalassaemia include Hepatitis B and Hepatitis C, cardiac complications like heart failure, short stature, pubertal delay, and osteoporosis. Other less common complications include diabetes mellitus. With respect to blood transfusion, there is sufficient evidence to conclude that leukocyte reduced red cells, produced either in the blood bank or using bed-side filters, are effective in reducing transfusions reactions, the better the filter, the greater the reduction in transfusion reactions. The use of neocytes for transfusion can decrease blood requirement, but is costly. For the treatment of Thalassaemia by chelation therapy, there is sufficient evidence that Desferrioxamine and Deferiprone are effective in preventing or improving serious complications of the disease. There is sufficient evidence that sibling donor bone marrow transplantation is safe and effective, and more cost effective compared to blood transfusion therapy. There is also evidence of effectiveness of bone marrow transplantation from unrelated and alternative donors, cord blood transplantation and peripheral blood stem cell transplantation. Modulators of fetal hemoglobin synthesis like Hydroxyurea, Butyrates, 5 Azacytidine and Erythropoietin is still largely experimental and cannot replace the need for regular blood transfusions and regular chelation therapy. Gene therapy to replace bone marrow transplant seems to be possible. There is insufficient evidence on the effectiveness of other treatment modalities like nutrition support and vitamins. 5. RECOMMENDATION It is recommended that a screening and prevention programme for the control of β-thalassaemia trait be instituted. Screening of school students and screening of relatives of known carriers should be carried out. Pre-marital and prenatal screening services should be offered for those who request for it. ii ___________________________________________________MANAGEMENT OF THALASSAEMIA Thalassaemic children on blood transfusion should receive leukocyte-reduced red cells for. All blood should be screened for ABO and Rh (D) compatibility, while Rh (C and E) and Kell is not recommended because of high cost involved. For Chelation therapy, it is recommended that Desferrioxamine and Deferiprone be used to prevent or improve serious complications of the Thalassaemia. Bone Marrow Transplantation should be offered to patients as soon as possible especially if there is a HLA compatible sibling/ family member. Bone marrow transplantation from unrelated and alternative donors, cord blood transplantation and peripheral blood stem cell transplantation services can also be offered where indicated. There is insufficient evidence to recommend other treatment modalities. iii ___________________________________________________MANAGEMENT OF THALASSAEMIA EXPERT COMMITTEE 1. Dr Wong Swee Lan Cahirman Head & Consultant Paediatrician Institute of Paediatric Kuala Lumpur Hospital 2. Dr Ng Hoong Phak Consultant Paediatrician Sarawak Umum Hospital 3. Dr Tam Pui Ying Consultant Paediatrician Sultanah Aminah Hospital 4. Dr Hung Liang Choo Consultant Paediatrician Institute of Paediatric Kuala Lumpur Hospital 5. Dr Zulaiha Muda Consultant Paediatrician Institute of Paediatric Kuala Lumpur Hospital 6. Dr Safiah Bahrin Principal Assistant Director Family Health Development Divison 7. Dr Balveer Kaur Consultant Paediatric Haematology Ipoh Hospital 8. Prof Dr Rahman Jamal Consultant Paediatrician University Kebangsaan Malaysia Hospital 9. Prof Dr Thong Meow Keong Consultant Paediatrician University Malaya Medical Centre 10 Prof Dr E George Unit Haematology University Putra Malaysia Project Coordinators 1. Dr S Sivalal Head, Health Technology Assessment Unit Deputy Director Medical Development Division Ministry of Health Malaysia 2. Ms Sin Lian Thye Nursing Officer Health Technology Assessment Unit Ministry of Health Malaysia iv ___________________________________________________MANAGEMENT OF THALASSAEMIA TABLE OF CONTENTS EXECUTIVE SUMMARY i EXPERT COMMITTEE iv TABLE OF CONTENTS v 1 BACKGROUND 1 2 OBJECTIVE 1 3 SCOPE 1 4 TECHNICAL FEATURES 1 4.1 Screening Program 1 4.2 Treatment 2 4.2.1 Blood transfusion 2 4.2.2 Chelation therapy 3 4.2.3. Haemopoitic stem cell transplantation 4 4.2.4. Other treatment modalities 4 (i) Augmentation of Fetal Hemoglobin Synthesis 4 (a) Hydroxyurea 4 (b) 5 Azacytidine 4 (c) Butyrates 4 (d) Erythropoietin 5 (e) Combination Agents 5 (ii) Gene Therapy 5 (iii) Others 5 5 METHODOLOGY 5 6 RESULTS & DISCUSSION 5 6.1 Screening and Prevention of Thalassaemia 5 6.1.1 Effectiveness 6 6.1.2 Target population for screening 7 (i) School students 7 (ii) Premarital screening programme 7 (iii) Inductive or cascade screening programme 7 6.1.3 Cost effectiveness - Thalassaemia prevention programme 7 6.1.4 Laboratory tests for Thalasseamia screening 8 6.1.5 Ethical, legal and social issues in genetic screening 8 Ethical issues 8 Legal issues 8 Social issues 9 Genetic Counselling 9 CONCLUSION 9 6.2 Complications of Thalasssemia 10 6.2.1 Hepatitis C, hepatitis B and HIV 10 6.2.2 Cardiac complications 10 6.2.3 Short stature in patients with Thalassaemia 10 6.2.4 Pubertal delay in patients with Thalassaemia 11 6.2.5 Diabetes Mellitus in patients with Thalassaemia 11 6.2.6 Osteoporosis in Thalassaemia patients 11 6.3 Treatment 12 6.3.1 Blood transfusion 12 (i) Type of Blood Products. 12 v ___________________________________________________MANAGEMENT OF THALASSAEMIA (a) Leukocyte Reduced Red Cells 12 (b) Neocytes 12 (ii) Transfusion regimes 13 (a) Pretransfusion Haemoglobin (Hb) Level 13 (b) Transfusion interval 13 (iii) Compatibility testing 13 (iv) Cost 14 6.3.2 Chelation Therapy 14 (i) Safety 14 (ii) Effectiveness 15 The Impact of Iron-Chelating Therapy on 15 Cardiac Disease and Survival The impact of iron-chelating therapy in 15 liver disease Impact of iron-chelating therapy on 15 endocrine function and growth Impact on quality of life 16 Impact on Bone Marrow Transplantation 16 patients Compliance with Deferoxamine and 16 alternatives to subcutaneous infusion (iii) Cost effectiveness 17 6.3.3 Oral Deferioximine(L1) 17 (i) Safety 17 (ii) Dose and route of administration 17 iii) Effectiveness 17 CONCLUSIONS 18 6.3.4 Transplantation 18 (i) Safety 18 (ii) Effectiveness 18 Sibling donor bone marrow transplantation 18 Bone marrow transplantation from 20 unrelated donors and alternative donors Cord blood transplantation 20 Peripheral blood stem cell transplantation 20 CONCLUSION 21 63.5 Other treatment modalities 21 (i) Augmentation of Fetal Hemoglobin 21 Synthesis (a) Hydroxyurea 21 (b) 5 Azacytidine 21 (c) Butyrates 21 (d) Erythropoietin 21 (e) Combination Agents 21 (f) Other agents 22 (ii) Gene Therapy 22 (iii) Nutrition, Vitamins Support 22 (iv) Psychological therapy 22 CONCLUSION 22 vi ___________________________________________________MANAGEMENT OF THALASSAEMIA 7 CONCLUSION 23 8 RECOMMENDATION 24 8.1 Prevention and screening programme 24 8.2 Treatment 24 8.2.1 Blood Transfusion 24 8.2.2 Chelataion therapy 24 8.2.3 Bone Marrow transplantation 24 8.2.4 Other treatment modalities 24 9 REFERNCES 25 EVIDENCE TABLE 38 LIST OF TABLE Table 1 : Bone Marrow Transplantation inpatients with Thalassaemia 18 Table 2: Reported Transplants for Thalassaemia and Probabilities of 18 Survival and Disease Free Survival in Various International Centres Table 3 : Comparison of survival rates between BMT and conventional 19 therapy at the age of 25 years Appendix 1 METHODOLOGY 128 . 1 Screening and Prevention 2 Complications 3 Treatment 3.1 Blood transfusion 3.2 Chelation Therapy (i) Desferrioxamine (ii) Deperine (L1) 3.3 Haemopoietic Stem Cell Transplantation