Haemoglobinophaties EBMT 2011 Data Manager session

Transcription

1 Haemoglobinophaties EBMT 2011 Data Manager session

2 Presentation plan Biological characteristics Clinical characteristics Transplant resuts What is different From transplant in malignancies Between Thalassemia and Sickle Cell Disease (SCD)

3 Hemoglobin One role of blood is to take oxygen from the air in the lungs and deliver it to all parts of the body. The part of the blood that does this job is the red blood cell. Hemoglobin is the part of the red blood cell that carries the oxygen. The most common form of hemoglobin is made up of two parts, alpha globin and beta globin.

4 Hemoglobin Structure Normal adult hemoglobin molecule (HbA) consists of two each of two different types of polypeptide chain. Chains are designated alpha (141 aa) and beta (146 aa)

5 Hemoglobin Structure The four chains are folded and fitted to form a globular tetramer The structure is abbreviated as α2β2

6 Gene Structure

7 Hemoglobinopathies Two types: Expression/ Synthesis Disorders: eg. Thalassemia Structural Variants/ Disorders: eg. Sickle-cell Disease

8 Hemoglobinopathy Genetics Homozygous: Inheritance of two genes from each parent coding for the same type of abnormal hemoglobin Heterozygous: Inheritance of genes from each parent which code for a different type of abnormal hemoglobin each ( normal and abnormal)

9 Hemoglobinopathy Genetics Compound heterozygosis: Inheritance of genes from each parent which code for a different type of abnormal hemoglobin each Β /S Β /E..

10 Haemoglobinopathies epidemiology >330,000 new born with hemoglobinopathy every year 17% Thalassemia (> new born/year) Modell B et al. Global epidemiology of haemoglobin disorders and derived service indicators. Bull World Health Organ 2008;86:480-7.

11 Thalassemia

12 Definition The thalassaemias are a heterogeneous group of haemoglobin disorders with defective synthesis of one or more globin chais resulting in: decreased filling of the red cells with haemoglobin, anaemia. Mutations can occur in any globin gene but only mutations in α and β genes are of known clinical significance.

13 Several types of thalassaemia have been described and named according to the affected globin-chain.

14 As much as 7% of the world s population are carriers of different haemoglobin disorders Carrier frequencies of thalassaemia alleles (%) Region β-thalassaemia α 0 -Thalassaemia α + -Thalassaemia Americas Eastern Mediterranean Europe Southeast Asia Sub-Saharan Africa Western Pacific Weatherall D, et al. Inherited Disorders of Hemoglobin. In: Disease Control Priorities in Developing Countries. 2nd ed. New York: Oxford University Press; 2006: Available from:

15 Classification & Terminology Beta Thalassemia Alpha Thalassemia Normal αα/αα Silent carrier -α/αα Minor -α/-α --/αα Hb H disease --/-α Barts hydrops fetalis --/-- Normal β/β Minor β/β β/β+ Intermedia β+/β+ β /β+ Major β /β

16 Structural variants/ Disorders Types of mutations: - Point mutations - Deletions - Insertions - Frameshift mutations - Chain termination - Fusion polypeptides

17 More than 200 mutations have been so far reported; the large majority are point mutations in functionally important regions of the beta globin gene.

18 β-thalassaemia Adult haemoglobin Alpha/haem aggregates Mutations in the β-globin gene α Haem α α Consequences of reduced β-globin chain production Anaemia Ineffective erythropoiesis Iron overload Erythroid marrow Expansion of splenomegaly Melchiori L, et al. Adv Hematol. 2010;2010: Epub 2010 May 19.

19 Sickle-cell Disease Mutant gene abnormal beta chain Hb S with reduced solubility sickling in reduced form

20 Sickle cell disease is an autosomal recessive genetic disease that results from the substitution of Valine from Glutamic Acid in position 6 of beta globin gene leading to production of defective form of hemoglobin (HB S)

21 Red Blood Cells from Sickle Cell Anemia Deoxygenation of SS erythrocytes leads to intracellular hemoglobin polymerization, loss of deformability and changes in cell morphology. OXY-STATE DEOXY-STATE

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23 Sickle Cells

24 SCD is characterized by generalized vasculopathy

25 CLINICAL AND MEDICAL THERAPY

26 CLINICAL AND MEDICAL THERAPY OF THALASSEMIA MAJOR

27 Course and Treatment Chronic blood transfusion Results in iron overload of major organs resulting in increased morbidit Necessitates the use of chelating agents to remove excess iron

28 Aims of transfusion treatment Normal growth and physical activity Chronic hypoxaemia Compensatory marrow hyperplasia hypervolaemia bone changes extramedullary erythropoiesis Splenomegaly and hypersplenism Gastrointestinal iron absorption Improvement cardiac function

29 Organ systems susceptible to iron overload Clinical sequelae of iron overload Pituitary impaired growth, infertility Thyroid hypoparathyroidism, Heart cardiomyopathy, cardiac Liver hepatic cirrhosis Pancreas diabetes mellitus Gonads hypogonadism Iron overload end-organ iron toxicities are inevitable in the absence of intervention therapy

30 Iron overload Transfusional progressively Iron affects Overload organ in Thalassemia functions 120 Iron (g) Age (years) Hypothyroidism Diabetes Hypogonadism Cardiac arrhythmia Hypoparathyroidism Hepatic Fibrosis --> Cirrhosis Death Cardiac Failure Thalassemia Centre, Dept. of Pediatrics University of Turin, Italy

31 Complication-free survival of Italian β-thalassaemia major patients 1.00 Survival probability Birth cohort p < Age (years) Risk factors for mortality in β-thalassaemia major include :serum ferritin > 2,500 µg/l (HR 3.7), arrhythmia (HR 2.4),male sex (HR 1.9),heart failure (HR 11.3) HR = hazard ratio. Borgna-Pignatti C, et al. Haematologica. 2004;89:

32 Chelation therapy and survival Survival (%) Well-chelated patients Poorly chelated patients Age (years) Brittenham GM, et al. N Engl J Med. 1994;331:

33 CLINICAL AND MEDICAL THERAPY OF SCD

34 SCD MAJOR CLINICAL MANIFESTATIONS Acute painful episodes Neurologic complications Multiorgan failure Psychosocial issues Growth and development Infection Bacteremia Meningitis Bacterial pneumonia Osteomyelitis Cerebrovascular events Bone complications Cardiac complications Myocardial infarction Dermatologic complications Leg ulcers Hepatobiliary complications Pregnancy Priapism Pulmonary complications Oxygen saturation Acute chest syndrome Renal complications Retinopathy Proliferative sickle retinopathy

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37 Kaplan-Meier estimates of the probability of stroke recurrence with chronic blood transfusions compared with historical controls. Verduzco L A, Nathan D G Blood 2009;114: by American Society of Hematology

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39 Effect of Hydroxyurea on Mortality and Morbidity in Adult Sickle Cell Anemia Risks and Benefits, Up to 9 Years of Treatment Martin H. Steinberg, MD et all JAMA, April 2, 2003 Vol 289, No

40 Transplantation for haemoglobinopathies

41 HSCT in Thalassemia - Definition Replacement of a diseased - ineffective erythropoiesis with an effective allogeneic erythropoiesis.

42 HSCT in Thalassemia - Definition Cellular replacement therapy Replacement of the entire hemopoietic system and not only of the diseased erythropoiesis A model of cellular therapy in not malignant disease

43 First HSC transplants for thalassemia Dec 2 nd 1981 in Seattle Dec 17 th 1981 in Pesaro

44 Timeline Showing Numbers of Bone Marrow Transplantations and Advances in the Field, Appelbaum F. N Engl J Med 2007;357:

45 Haemoglobinopathy registry ( ) Pesaro vs. Others OTHERS PESARO PATIENTS YEAR

46 Pesaro experience: thalassaemia-free survival after HSCT from an HLA-identical sibling Results of HSCT in 900 consecutive patients, aged 1 35 years, transplanted in Pesaro since December Thalassaemia-free survival Probability % Years Angelucci E,et al., Haematologica. 2008;93:

47 Pesaro risk classification Three risk factors are used to stratify paediatric patients poor quality of chelation hepatomegaly liver fibrosis Indicators of iron overload and iron-related tissue damage Classification not applicable to adult patients ( 17 years) Lucarelli G, et al., N Engl J Med. 1990;322: Lucarelli G, et al., N Engl J Med. 1993;329: Lucarelli G, et al. Blood. 1999;93:

48 Pesaro experience: results from HSCT across various risk groups Risk OS (%) TFS (%) TRM (%) Low Int High (< 1990) High (> 1990) Adult Optimal medical therapy is key for a successful transplantation 2. High-risk patients had high TRM with the standard conditioning regimen. Using a reduced-intensity conditioning in these patients (Cy dose) decreased TRM, but increased the risk of thalassaemia recurrence 3. Adult patients had a high TRM, but overall a lower risk of thalassaemia recurrence OS = overall survival; TFS = thalassaemia-free survival; TRM = transplantation-related mortality.. Efficacy of hematopoietic cell transplantation in beta thalassemia. In: UpToDate, Basow, DS (Ed), UpToDate,Waltham, MA, 2010.

49 Recent results RISK OS % TFS % TRM % LOWER HIGH RISK OS% TFS% TRM% ADULT Results improved in all patients categories 2. Reducing conditioning regimen intensity in high risk patients decreased TRM but risk of thalassemia recurrence remains relevant. 3. Adult patients still have a high TRM

50 Allogeneic stem cell transplantation in thalassemias Donor type Sibling-matched BMHSC Sibling cord blood HSC Matched unrelated donors Mismatched related donors Unrelated cord blood donors Status Standard Reduced GVHD with similar results Good outcomes, limited donors Promising, but suboptimal Still experimental BMHSC = bone marrow HSC; GVHD = graft-versus-host disease; HSC = haemopoietic stem cells. Angelucci E. Hematol Am Soc Educ Program. 2010;2010:

51 Haemoglobinopathy Registry patients (median age 7 years) outside Pesaro experience (133 Centres, 28 Countries)

52 First HSC transplants for SCD Johnson FL, Look AT, Gockerman J, et al. Bone marrow transplantation in a patient with sickle-cell anemia. N Engl J Med 1984;311: Milpied NHJ, Garand R, David A. Bonemarrow transplantation for sickle-cell anaemia. Lancet (letter) 1988;2: Vermylen C, Fernandez Robles E, Ninane J, et al. Bone marrow transplantation in five children with sickle cell anaemia. Lancet 1988;1:

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54 HSCT : the French experience OS EFS Rejection Cerebral vasculopathy was the principle indication for transplantation (N = 55) Overall survival: 93.1% EFS: 86.1% Cumulative incidence of rejection: 70% at 5 years The estimated 5-year TRM was 6.9%; GVHD was the major cause of TRM Time (years) HSCT is a plausible standard of care for SCD children who are at high risk of stroke EFS = event-free survival; GVHD = graft-versus-host disease; OS = overall survival; RM = transplantation-related mortality. Bernaudin F, et al. Blood. 2007;110:

55 Mixed chimerism

56 Mixed chimerism A permanent co-existence of donor and host hematopoietic cells donor recipient HSCT

57 Mixed chimerism A permanent co-existence of donor and host hematopoietic cells donor recipient HSCT tolerance

58 Patients selection for transplant Thalassemia Major SCD

59 which thalassaemia major patients CAN be considered for transplantation? ALL THOSE WHO ARE TRANSFUSION DEPENDENT

60 which thalassaemia patients SHOULD be considered for transplantation? Young children HLA identical sibling donor Very good matched unrelated donor No organ damage

61 Bone marrow transplant and SCD: Who? <20 yrs with intra-familial HLA-donor (< 18% pts) Severe forms: stroke, severe ACS and chronic pain with failure of HU (parents decision not related to severity of the disease, Kodish, NEJM 1991) When? Before severe organ damage

62 Which SCD patients SHOULD be considered for transplantation? Simptomatic disease Before irreversible tissue damage

63 Gene therapy Challenges Efficient gene transfer and engraftment Sufficient haemoglobin production Advantages no need for matched donor eliminates risks of GVHD and graft rejection

64 Clinical Trial: Gene Transfer of the β 87 lenti-vector into a Hb E-βthalassemia patient promotes transfusion independence Cavazzana-Calvo,Nature2010

65 Thank you for your very kind attention