Company name Novartis Disclosures of: Emanuele Angelucci Research support Employee Consultant Stockholder Speakers bureau Advisory board Chair of TELESTO pro Other
EBMT 2012 Educational Session Haemoglobinopathy and HSCT Thalassemia
Treatment options for Thalassemia Major 1. Transfusions and iron chelation 2. Transplantation 3. Gene Therapy 3
Survival Probability Kaplan-Meier survival curves, after the first decade of life by birth cohort 1.00 85-96 80-84 75-79 0.75 70-74 0.50 65-69 60-64 0.25 Log-rank test: p<0.0001 0.00 0 5 10 15 20 25 30 35 40 45 50 Age (years) Borgna 2010
Clinical Trial: Gene Transfer of the b 87 lenti-vector into a Hb E-b-thalassemia patient promotes transfusion independence Cavazzana-Calvo,Nature2010
Thalassemia epidemiology >330,000 new born with hemoglobinopathy every year 17% Thalassemia (> 23.000 new born/year) Modell B et al. Global epidemiology of haemoglobin disorders and derived service indicators. Bull World Health Organ 2008;86:480-7.
HSCT in Thalassemia
First HSC transplants for thalassemia Dec 2 nd 1981 in Seattle Dec 17 th 1981 in Pesaro
Results of HSCT in 900 consecutive patients, aged 1-35 years, transplanted from an HLA identical sibling in Pesaro since December 1981 Haematologica 2008;93:1780-1784
Probability Results of HSCT in 115 consecutive patients, aged 1-28 years, transplanted from an HLA identical sibling in Pescara since May 1983. 1.0 OS (89.2%) 0.8 DFS (85.7%) 0.6 0.4 Median follow-up 15 years (1-24) 0.2 0.0 n patients at risk (OS) n patients at risk (DFS) 0 4 8 12 16 20 Years from BMT 115 100 99 75 44 11 115 96 95 71 41 11 Am J Hematol 2008;83:528-530
Outcome prediction (HLA identical sibling HSCT)
Pesaro risk classification Three risk factors stratified pediatric patients in 3 risk groups N Engl J Med 1990; 322: 417-21. N Engl J Med 1993; 329:840-5. Chelation Hepatomegaly Liver fibrosis No risk factor Low risk 1-2 risk factors Intermediate risk 3 risk factors High risk
Pesaro risk classification Three risk factors stratified pediatric patients in 3 risk groups N Engl J Med 1990; 322: 417-21. N Engl J Med 1993; 329:840-5. Chelation Hepatomegaly Liver fibrosis Iron overload. Iron related tissue damage. Classification not applicable to adults patients ( 17 years) Blood. 1999 Feb 15;93(4):1164-7
Pesaro results RISK REGIMEN OS % TFS % TRM % LOW Bu 14 Cy 200 94 87 6 INT Bu 14 Cy 200 84 81 15 HIGH (<1990) Bu 14 Cy 200 50 47 47 HIGH (>1990) Bu 14 Cy 120-160 79 58 18 ADULT Bu 14 Cy 120-160 66 62 34 1. Optimal medical therapy is the key for a successful transplant 2. High risk patients had high TRM with standard Bu-Cy 3. Reducing conditioning regimen intensity (Cy dose) decreased TRM but amplified risk of thalassemia recurrence 4. Adult patients had a high TRM and limited risk of thalassemia recurrence Efficacy of hematopoietic cell transplantation in beta thalassemia In: UpToDate, Basow, DS (Ed), UpToDate, Waltham, MA, 2010. Ann N Y Acad Sci 2010; 1202:141-8.
Recent preparative regimens Regimen Patients ref iv targeted busulfan + Cy 200 ± thiotepa Lower risks Blood 2010;115: 4597-604. Biol Blood Marrow Transplant 2010;16: 622-8 Pre-conditioning treatment with hypertransfusion and chelation + hydroxyurea, azathioprinine and fludarabine. Preconditioning treatment with hypertransfusion and chelation + hydroxyurea, azathioprinine and fludarabine. + targeted iv busulfan + Cy 160 High risk Blood 2004; 104: 1201-3 High risk Blood 2010;115: 4597-604) Biol Blood Marrow Transplant 2010;16: 622-8. Thiotepa treosulfan fludarabine all Ann N Y Acad Sci 2010; 1202: 141-8. Busulfan (iv busulfan) / fludarabine all Bone Marrow Transplant 2007; 40: 957-64 Preconditioning treatment with hypertransfusion and chelation, hydroxyurea, azathioprinine and fludarabine. Iv targeted busulfan + Cy 90 Adult Ann N Y Acad Sci 2005; 1054: 196-205 1. Introduction of new drugs 2. Intensity reduction in high risk and adult patients
Recent results RISK OS % TFS % TRM % LOWER 96-97 86-91 3 HIGH 87-96 66-80 12 RISK OS% TFS% TRM% ADULT 67 67 27 1. Basic concept from Pesaro experience were confirmed 2. Results improved in all patients categories 3. Reducing conditioning regimen intensity in high risk patients decreased TRM but risk of thalassemia recurrence remains relevant. 4. Adult patients still have a high TRM
Research developments
Research developments Alternative source of stem cell Peripheral blood Cord blood Alternative donors Matched unrelated Mismatched related Unrelated cord blood
Probability MUD transplant in thalassemia. GITMO study 132 patients. Median age 14 (1-35) Overall survival = 85,5% Thalassaemia-free survival = 77,4% Mortality = 14,5% COMPATIBILITY: complete identity high resolution HLA typing for class I (A, B, C) and class II (DrB1, DqB1, DpB1). Rejection = 10,7% Months after transplantation Courtesy by Franco Locatelli GITMO study. N. Y. Acad. Sci. 2005
Mismatched related. Haploidentical transplant 22 patients. Median age 7 (range 3-14) Patients (# 22): 2 low risk 6 intermediate risk Outcome (#22) 2 infection related deaths 6 thalassemia recurrences Blood 2010;115:1296-1302
Unrelated cord blood transplant Taiwan Study 1 Retrospective - multicenter EBMT- CIBMTR 2 Patients 32 low risk 51 Median age 5 years 5 years Alive and cured 27 16 Died na 13 2 years OS na 77% 2 years Thal FS 87% na 1 Biol Blood Marrow Transplant 2010; 16: 102-7. 2 Bone Marrow Transplant 2010; 45: 378.
Is HSCT the worldwide diffuse standard of cure for Thalassemia Major? The EBMT Hemoglobinopathy Registry
EBMT Registry 134 Centers, 28 Countries Patients with Haemoglobinopathies N = 3821 Patients transplanted between 1/1/2000 and 12/31/2010 N = 1953 Patients with thalassemia N =1493
EBMT Registry : THALASSEMIA Number of identical sibling transplants per Countries 5% 1% 6% 2% 35% Italy 4% 2% 4% 3% 2% France Germany 9% UK 18% Turkey Iran 7% 2% Turkey Iran Netherlands UK Italy Spain Israel Saudi Arabia Greece Jordan Algeria Others
EBMT REGISTRY: HSCT and age 200 180 160 140 120 100 80 < 18 yrs > 18yrs 60 40 20 0 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010
Overall Survival HSCT 2000-2010 (1493 patients all age groups. Median age = 7 years) in the pair-wise comparison SCT is significantly different to all other grou (unknown/missing not included for evaluation of p-values Patients Events 2-yrs. psu Thalassemia 1493 154 0.88±0.01
Event Free Survival - HSCT 2000-2010 (1493 patients all age groups. Median age = 7 years) all 3 pair-wise comparison are significant (Bonferoni) (unknown/missing not included for evaluation of p-values Events: Relapse (=significant worsening)/additional diagnosis or death??? please approve??? Patients Events 2-yrs. pefs Thalassemia 1493 253 0.81±0.01
Thalassemia - Survival and Donor HSCT 2000-2010 (1493 patients all age groups. Median age = 7 years) Patients Events 2-yrs. psu p-value MSD 1061 88 0.91±0.01 <0.001 MFD 127 11 0.88±0.04 MUD 111 20 0.82±0.04 MMFD 57 8 0.83±0.07 MMUD 99 23 0.74±0.05
Thalassemia - EFS and Donor HSCT 2000-2010 (1493 patients all age groups. Median age = 7 years) Patients Events 2-yrs. pefs p-value MSD 1061 151 0.83±0.01 <0.001 MFD 127 22 0.78±0.05. MUD 111 26 0.77±0.04. MMFD 57 20 0.61±0.08. MMUD 99 29 0.67±0.05.
Thalassemia Survival and age HSCT 2000-2010 (1493 patients) Patients Events 2-yrs. psu p-value < 2 years 96 5 0.94±0.03 <0.001 2-5 years 388 26 0.92±0.02. 5-10 years 473 50 0.88±0.02. 10-14 years 248 14 0.94±0.02. 14-18 years 154 27 0.78±0.04. >18 years 133 31 0.77±0.04.
Thalassemia - EFS and age HSCT 2000-2010 (1493 patients) Patients Events 2-yrs. pefs p-value < 2 years 96 9 0.90±0.03 0.001 2-5 years 388 59 0.82±0.02. 5-10 years 473 75 0.81±0.02. 10-14 years 248 36 0.83±0.03. 14-18 years 154 38 0.70±0.04. >18 years 133 35 0.74±0.04.
Thalassemia Survival and age Match Sibling Donor (# 1061) Patients Events 2-yrs. psu p-value < 2 years 66 3 0.95±0.03 <0.001 2-5 years 266 13 0.94±0.02. 5-10 years 352 33 0.90±0.02. 10-14 years 197 8 0.96±0.02. 14-18 years 97 14 0.82±0.04. >18 years 82 16 0.80±0.05.
Thalassemia Event Free Survival and age Match Sibling Donor (# 1061) Patients Events 2-yrs. pefs p-value < 2 years 66 4 0.93±0.03 0.019 2-5 years 266 32 0.86±0.03. 5-10 years 352 52 0.83±0.02. 10-14 years 197 24 0.86±0.03. 14-18 years 97 20 0.74±0.05. >18 years 82 18 0.76±0.05
The problem of the costs
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;24:1905 17 Orsi C et al Bone Marrow Transplant 2007; 40: 643-9 Personal information
SCD as emerging problem of public health in non endemic areas Weatherall DJ et al. Bulletin WHO 79: 704, 2001; Modell B et al Bulletin WHO 86: 480, 2008
Conclusions
Conclusions - 1 HSCT is a today - worldwide available - high success curative procedure for thalassemia Well defined accepted and experimental approaches HLA identical sibling HSCT HLA well match unrelated donor HSCT HLA identical sibling cord blood HSCT HLA matched unrelated cord blood HSCT HLA mismatch related donor transplant Accepted Accepted Accepted Experimental Experimental ASH Education Book, 2010 vol. 2010 no. 1 456-462
Conclusions - 2 Optimal medical therapy is the key for a successful transplant Best results have been reported in young well chelated children HSCT is cost-effective
Conclusions - 3 Any new developing, intent to cure, procedure should demonstrate at least its equivalence to HSCT
Conclusion 2. Factors that must be considered for individual decision making about HSCT for thalassemia Angelucci, E. Hematology 2010;2010:456-462 Copyright 2010 American Society of Hematology. Copyright restrictions may apply.
Acknowledgements EBMT PDWP Peters Christina Elarouci Nabila Ruiz Elvira Carmen Baronciani Donatella Cagliari Businco Cancer Centre Hematology group All Hospital colleagues and personal Di Bartolomeo Paolo Locateli Franco Kabbara Nabil
Thank you for your attention