Hemoglobin disorder Most common monigenetic disorder: 5% of the world population with globin gene variant

Transcription

1 Jean Hugues Dalle 4th EBMT training course for pediatricians and pediatric nurses on HSCT in children and adolescents: interactive educational EBMT PDs course. Bucarest, May 2013

2

3 Rationnal Thalassemia: Hemoglobin disorder Most common monigenetic disorder: 5% of the world population with globin gene variant 80 million people with β Thalassemia births a year with major thalassemia Initially from (sub) tropic area Now worldwide

4 From Beta thalassemia Always severe phenotype

5 Erythroïd hyperplasia (BM and extrabm) Hemolytic anemia neffective rythropoiesis Iron overload ±Hepatitis C Chronic transfusions Multiple organ damages: Heart, Liver, Endocrine deficiencies

6 < 50% of patients still remain alive after 35 year of age Survival Probability Log rank test: p< Age (years) Borgna 2010

7 To avoid early death: Chronic transfusion Substitutive therapy HSCT from full matched compatible donor Only curative therapy Multi disciplinary and long life follow up

8 Balance HSCT Curative therapy Risk of death during procedure Risk of GvHD Risk of long term sequelaes Transfusion program + Iron chelation Subtitutive therapy Risk of viral infections (hepatitis C +++) Risk of allo immunisation Risk of toxicity Renal failure BM failure ( ) Cost +++

9 The problem of the costs Medical therapy HSCT Gene therapy Direct costs in Italy (transfusion + chelation with DFO) Acute Leukemia. Euro Study. Median value =14,916 /year = 94,350 (CV 40%) Manipulated stem cell??????? Scalone L et al. Curr Med Res Opin 2008;24: Orsi C et al Bone Marrow Transplant 2007; 40: Personal information

10 Angelucci E Hematology 2010;2010: Factors that must be considered for individual decision making about HSCT for thalassemia.

11 1981 : First HSCT for thalassemia Seattle group 14 month old girl HLA identical sister Successful outcome Pesaro group 16 year old heavely transfused thalassemia patient HLA identical brother Rejection

12 First report and results Lucarelli et coll., NEJM patients < 17 years of age OS: 82% EFS: 75% Multivariate analysis for 116 pts Highly homogeneous patient group and therapy Bu14 + Cy200 GvHD prophylaxis: CSA + MP ±ATG

13 Pesaro score Risk Factors Risk Classes Class 1 Class 2 Class 3 Chelation Regular Regular/ Irregular Hepatomegaly > 2 cm Liver Fibrosis (biopsy) No No/Yes Yes No No/Yes Yes Irregular OS 94% 80% 61% EFS 94% 77% 53% Recurrence 0% 9% 16%

14 HSCT from related donors for Class 1 & Class 2 patients under 17y.o. About 515 classes 1 2 patients under 17 years of age In order to decrease the rate of rejection: + Thiotepa for patients less than 4 years and short course MTX

15 HSCT from related donors for Class 3 patients under 17y.o. Bu14 + Cy200: high TRM Bu14 + Cy 120 to 160: Better overall survival (53 to79%) Higher rejection rate (7 to 30%) Protocol 26 from 1997 Azathioprine 3mg/kg/d from D 45 Hydroxyurea 30mg/k/d from D 45 Hypertransfusion regimen (Hb>14g/dl) + continuous chelation Growth factors twice weekly Fludarabine 20mg/m²/d from D 17 to D 13 Bu14 + Cy 160

16 About 73 class 3 patients under 17 y.o

17 HSCT from related donors for adult patients (Gaziev et al, Ann NY Acd Sc 2005) Modified protocol 26: Cy 90

18 HSCT results from 10/10 MUD in very genetically stable population All patients, n=68

19 HSCT results from 10/10 MUD in very genetically stable population Class 1 2 patients Class 3 patients

20 Table 2. HSCT in Thalassemia ( ) Author and year # OS TFS TRM 1 Galambrun C et al years : 86.8% 15 years 69.4% 15 years 12% 2 Yesilipek MA et al year : 85% 1 year 68% 1 year 7.75% 3 Li C. et al years: 91% 3 years 3 years 8% 87% 4 Choudhary D. et al % 71.4% 21.4% 5 Bernardo ME et al years: 93% 5 years 7% 84% 6 Sabloff M et al years: Intermediate risk :91% High risk 64% 5 years Intermediate risk :88%, High risk: 62% Intermediate risk:5/75 High risk 23/64 7 Ghavamzadeh A. et al years: PBSCs 83% BM 89% 2 years PBSCs 76% BM 76% 1 year PBSC 14% BM9% 8 Iravani M. et al years: 80% 4.1 years: 65% 4.1 years 7/52 9 Irfan M. et al years: BM: 73% PBSCs: 65% 5 years BM: 67% PBSCs: 55% 100 days: 10/56 10 Kabbara N et al years: 95% 6 years: 86% 4% 11 Ullah K. Et al years: 79% 6 years: 75% 20.8% 12 Di Bartolomeo P. et al years: 89.2% 20 years: 85.7% 1 year 8.7% 13 Gaziev J. et al years: 66% 12 years: 62% 37% 14 Lawson SE et al years : 94.5% 8 years :81.8% 5,4% 15 Gaziev J years: 91% 3 years: 87% 100 days 3% Article reporting series of patients partially or fully already reported have been excluded.

21 Sickle Cell Disease

22 S/S > S βthal > S/C Very wide phenotype, including into a same family From

23 Epidemiology In North America: About 8% of African American people carry sickle cell gene (1/400) In Sub Saharian Africa 10% to 30% of people have Sickle cell trait or disease because of protective effect against malaria in endemic regions that leads to positive selection for the gene mutation. In France 1/3360 live births ( 380/y) 1/950 live births in Paris and sub urban area (250 à 270/y)

24

25 Challenge Sickle Cell Disease Low early mortality but high morbidity risk Wide phenotype Stem cell transplantation Only curative therapy Toxicity risks (GVHD, gonadic failure) but offers hope of cure and better quality of life Donor availability Cost Alternative treatments Transfusion program Viral infections Allo immunization Hydroxyurea Toxicity Compliance (availability)

26 >25 year experience with SCT for SCD patients Two first reports one SCD leukemic patient successfully transplanted in US 5 SCD patients successfully engrafted in Belgium

27 elated Myeloablative Stem Cell ransplantation o Cure Sickle Cell Anemia: Update of French esults rançoise Bernaudin et al, for the SFGM-TC

28 Our first experience, reported in Blood 2007, included 87 consecutive severe SCA patients transplanted in France between 1988 and Dec 2004 the introduction of rabbit anti thymocyte globulin (ATG) in the conditioning regimen in 2000 allowed a significant reduction of the rejection rate from 22.6% to 3% Global results were similar to worldwide experience

29 Transplantation procedure HbS < 30% Myelo ablative Conditioning Regimen BU CY ( ) 4/12 unstable chimerism, rejection BU CY rabbit ATG (Thymoglobulin 20 mg/kg) Busulfan Day 10 to 7 Oral 485 mg/m2 (>= 16 mg/kg) Intravenous > 2001 CY 200 mg/kg ( 50 mg/kg/d x 4: day 5 to 2) Rabbit ATG 20 mg/kg (5 mg/kg x 4 day 6 to 3)

30 Transplantation procedure (2) GVHD prophylaxis (6 9 months) CSA MTX for BMT and CSA alone for CBT Seizure prevention Clonazepam during conditioning and CSA therapy Hemoglobin maintained 9 11g/dl Platelet count > 50,000/mm3 Arterial hypertension strictly controlled Magnesium deficiency promptly corrected After 2002, CSA replaced by MMF in case of GVHD requiring steroids

31 onsecutive Geno identical myeloablative SCT for CD (n=161) SFGM TC data in Promise Follow Up stopped on 21 March 2010 Conditioning Regimen: BU CY without ATG n= 17 with ATG n=144 BM n=121, CB n=21

32 Indications (n=144) Cerebral vasculopathy 89 Overt Strokes 39 TIA 3 Stenoses +/ silent strokes 20 Abnormal TCD 9 Silent stokes ± anemia, cogn.deficit 18 Erythroid polyalloimmunisation 4 3 VOC/yr ± ACS 41 Osteonecrosis 7 1 ALL, 1 AML 2 TRJV > 2.5 m/sec 1

33 Events (n=9) Non engraftment (n=2) Rejections (n=1) at 3.2 years post transplant Deaths (n=6) Sepsis during aplasia (n=1) Hemorrhagic stroke (n=1) at day32 in a patient with severe Moya Moya syndrome Extensive GVHD (n=4) death at 2, 4 12, 30 months post transplant obliterans bronchiolitis (n=2) Aspergillosis, CMV, adenovirus..

34 Survival at 5 years: 95% (SE: 2%) Survival probability (%) Years post-transplant mber at risk

35 100 Rejection probability (%) Rejection at 5 years : 2.8% (SE: 1.7%) Years post-transplant mber at risk

36 Event-free Survival probability (%) Event free (Disease free) Survival at 5 years 92.2% (SE: 2.6%) Event free (Disease free) Survival at 5 years 92.2% (SE: 2.6%) Years post-transplant Number at risk

37 100 EFS at 5y: 95.8% (SE 2.5%) EFS at 5y: 95.8% (SE 2.5%) Event-Free Survival probability (%) Log Log Rank: Rank: p= p= EFS at 5 y: 73.9% (SE 9.2%) Year of Transplant 0= < = > Years post-transplant umber at risk roup: roup:

38 Event-Free Survival probability (%) EFS EFS at at 5 years: years: 90.2% 90.2% (SE (SE 6.6%) 6.6%) vs vs 92.4% 92.4% (SE (SE 2.9%) 2.9%) Log Rank: p=0.53 NS Cell Source Cord Blood BM or PBC Years post-transplant mber at risk roup: cord blood roup: other

39 100 Event-Free Survival probability (%) Age at Transplant < 16 years (n=132) > 16 years (=12) Years post-transplant

40

41 Umbilical Cord Blood Transplantation for Children with Thalassemia and Sickle Cell Disease Annalisa Ruggeri et al for the Eurocord Registry, CIBMTR and the New York Blood Center. BBMT 2012

42 Unrelated volunteer donor SCD patients : < 1% of full matched unrelated availability On going multicenter trial in US Thalassemia: MUD from Sardegna for Thal patient from Sardegna different combination

43 Haplo identical HSCT Bolanos Meade et al, Blood patients 14 haplo id donor 3 SC patients?

44 No death

45 Reduced toxicity / Reduced intensity conditioningr regimen Flu based conditioning regimen (Cy substitution) Threo based conditioning regimen (Bu substitution) Main concern: rejection / engraftment failure, including secondary engraftment

46 Clinical Trial: Gene Transfer of the β 87 lenti vector into a Hb E βthalassemia patient promotes transfusion independence

47 Expert meeting report on Hematopoietic stem cell transplantation in thalassemia major and sickle cell disease: Indications and Management Recommendations from the EBMT. Emanuele Angelucci, Susanne Matthes Leodolter, Ayad Achmed, Donatella Baronciani, Françoise Bernaudin, Sonia Bonanomi, Maria Domenica Cappellini, Jean Hugues Dalle, Paolo Di Bartolomeo, Cristina Díaz de Heredia, Roswitha Dickerhoff, Claudio Giardini, Eliane Gluckman, Naynesh Karmani, Milen Minkov, Franco Locatelli, Vanderson Rocha, Jan Smiers, Isabelle Thuret, Isaac Yaniv, Marina Cavazzana Calvo, Christina Peters

48 Recommendations for Thalassemia Young patients with TM with an available HLA identical sibling should be offered HSCT as soon as possible before development of iron overload and iron related tissue damage. HLA genoidentical CB and BM are equally effective stem cell sources provided the CB unit has an adequate number of nucleated cells (i.e. greater than 3.5x10 7 /kg) HSCT from an HLA mismatched family member in TM should still be considered an experimental approach to be conducted only in the context of well designed controlled trials. If a well matched unrelated donor is available, allogeneic HSCT is a suitable option for a child with life long control of iron overload and absence of iron related tissue

49 Recommendations for Thalassemia The unrelated volunteer must be selected using highresolution molecular typing for both HLA class I and II loci and according to stringent criteria of compatibility with the recipient. UCBT in thalassemia is an option to be considered a promising approach if the CB unit is HLA matched and contains an appropriate cell number. This type of transplantation should be performed in the context of a well controlled clinical trial in centers with specific UCBT programs. An ablative conditioning regimen (without radiation) should always be used for standard transplantation.

50 Recommendations for Thalassemia Reduced toxicity regimens are under investigation and may be used in the context of clinical trials. Use of fludarabine instead of cyclophosphamide can reduce the risk of undue extramedullary toxicity. Any prospective attempt to induce stable mixed chimerism should be considered experimental. The combination of cyclosporine and short course methotrexate represents the gold standard for GvHD for HSCT from MSD. Whether mono or polyclonal antibodies like ATG or alemtuzumab could contribute to better GVHDprevention in the context of MSD HSCT. For GVHD prevention in the UD HSCT setting antibodies are

51 Recommendations for Sickle cell disease Young patients with symptomatic SCD requiring intensification treatment such as Hydroxyurea or transfusion program who have a HLA matched sibling donor should be transplanted as early as possible, preferably at pre school age Unmanipulated bone marrow or umbilical cord blood (whenever available) from matched related donors are the recommended stem cell sources and therefore the cryopreservation of sibling umbilical cord blood should be encouraged and performed routinely.

52 Recommendations for Sickle cell disease (2) SCT from unrelated marrow or cord blood donors should only be considered in the context of welldesigned controlled trials.

53 Recommendations for Sickle cell disease (3) The gold standard for conditioning in patients with SCD is busulfan, cyclophosphamide and ATG. The promising disease and GvHD free survival rates reported in some small studies following RIC should be validated by larger prospective trials.

54 Recommendations for Sickle cell disease (4) The use of ATG and post transplantation cyclosporine A plus MTX is the gold standard for patients with SCD following myeloablative conditioning. RIC regimens and the use of Campath 1H instead of ATG should be evaluated in prospective trials.

55 Acknwoledgments Georgio Dini Christina Peters Constantin Arion Anita Colita Inge Hirsh