COHEM Barcellona 2012 Hemoglobinopathies debate

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2 COHEM Barcellona 2012 Hemoglobinopathies debate September 8, 2012: h. 10:30-12:00 Hall: A Is it justified to perform BMT in hemoglobinopathies using unrelated and/or partially mismatched donors?

3 HSCT indication in Hemoglobinopathies Disease Indication Problem Experience Thalassemia Major Transfusion dependency High success of medical therapy SCD Complication Unpredictability of disease course. Low treatment possibility for severe complications Large (>3000 HSCTs) Limited (500 HSCTs)

4 HSCT for thalassemia HSCT is a today - worldwide available - high success curative procedure for thalassemia (> 3000 HSCTs) HLA identical sibling HSCT HLA well match unrelated donor HSCT HLA matched unrelated cord blood HSCT HLA mismatch related donor transplant Reduced intensity HSCT Accepted Accepted Experimental Experimental Experimental ASH Education Book, 2010 vol no

5 HSCT for SCD HSCT is a today available - high success curative procedure for SCD ( 500 HSCTs performed) HLA identical sibling HSCT HLA well match unrelated donor HSCT HLA matched unrelated cord blood HSCT HLA mismatch related donor transplant Reduced intensity HSCT Accepted Experimental Experimental Experimental Accepted

6 Is it justified to perform BMT in hemoglobinopathies using unrelated and/or partially mismatched donors? Thalassemia MUD transplant Haplo identical transplant Sickle cell disease MUD transplant Haplo identical transplant

7 Is it justified to perform BMT in hemoglobinopathies using unrelated and/or partially mismatched donors? Thalassemia

8 Kaplan Meier survival curves, after the first decade of life by birth cohort Survival Probability Log-rank test: p< Age (years) Borgna 2010

9 Available evidence

10 Results of hemopoietic stem cell transplantation in 900 consecutive patients, aged 1-35 years, transplanted from an HLA identical sibling in Pesaro since December 1981 Haematologica 2008;93: Copyright 2008 Ferrata Storti Foundation

11 HSCT in Thalassemia Recent results RISK OS % TFS % TRM % LOWER HIGH RISK OS% TFS% TRM% ADULT Blood 2010;115: ,Biol Blood Marrow Transplant 2010;16: Blood 2004; 104: , Ann N Y Acad Sci 2010; 1202: Bone Marrow Transplant 2007; 40: ,Ann N Y Acad Sci 2005; 1054:

12 Thalassemia Survival and Donor EBMT data HSCTs centers, 28 countries Patients Events 2-yrs. psu p-value MSD ±0.01 <0.001 MFD ±0.04 MUD ±0.04 MMFD ±0.07 MMUD ±0.05

13 Available evidence for Matched Unrelated Donor and haploidentical donor Transplantation in Thalassemia

14 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 Died na 13 2 years OS na 77% 2 years Thal FS 87% na 1 Biol Blood Marrow Transplant 2010; 16: Bone Marrow Transplant 2010; 45: 378.

15 Matched unrelated donor transplant in Thalassemia 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 complications. The unrelated volunteer must be selected using high-resolution 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 in the context of a well-controlled clinical trial in centers with specific UCBT programs.

16 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:

17 Haplo identical transplant on Thalassemia 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.

18 Is it justified to perform BMT in hemoglobinopathies using unrelated and/or partially mismatched donors? Sickle Cell Disease

19 Sickle Cell Disease SCD is associated with substantial morbidity leading to both reduced quality of life and shortened life expectancy. Although survival has improved significantly in the last two decades and 94% of children with SCD now survive until the age of 18 years mortality dramatically increases once patients reach adulthood. SCD-associated morbidity and mortality in young adults is largely due to as-yet unpreventable complications such as Priapism, Avascular necrosis Chronic pulmonary impairment, Hypertension, Stroke Recurrent veno-occlusive crises.

20 Available evidence

21 Sickle Cell Disease Comparison of Kaplan-Meier estimates of EFS in patients receiving transplants before (n = 43) and after January 2000 (n = 44): respectively 76.7% and 95.3% at 5 years (P = 0.26). EFS = 95.3% 2007 by American Society of Hematology Bernaudin F et al. Blood 2007;110:

22 EBMT Registry : Overall Survival SCT (all age groups) in the pair-wise comparison SCT is significantly different to all other groups (unknown/missing not included for evaluation of p-values Patients Events 2-yrs. psu p-value Thalassemia ±0.01 <0.001 SCD ±0.01 other ±0.23 unkown/missing ±0.05

23 EBMT Registry : Event Free Survival SCT (all age groups) 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 p-value Thalassemia ±0.01 <0.001 SCD SCT ± other other ± unkown/missing unkown/missing ± ±0.05..

24 Available evidence for Matched Unrelated Donor and haploidentical donor HSCT in SCD

25 Unrelated Cord Blood Transplant So far a total of 32 patients with SCD transplanted with an unrelated CB unit have been published,18 of them following a reduced-intensity conditioning with an overall survival :91% disease-free survival :50% Main reason of failure :rejection. Ruggeri et al: BBMT 2011, Adamkiewitz TV. Pediatric transplantation 2007; 11: Kamani NR et al. BBMT 2012

26 Even if results comparable to those obtained in TM can be expected, there are no firm data on outcome of HSCT from matched unrelated donors for SCD, and therefore, the advantages and disadvantages of this option cannot be adequately addressed. So far no data on haplo-identical HSCT in SCD have been published

27 SCD associated morbidity and mortality in young adults is largely due to as yet unpreventable complications.

28 Indication for standard HSCT in SCD Stroke or central nervous system event lasting longer than 24 hours, acute chest syndrome with recurrent hospitalizations or previous exchange transfusions; recurrent vaso-occlusive pain (more than 2 episodes per year over several years) or recurrent priapism; impaired neuropsychological function and abnormal cerebral MRI scan; Stage I or II sickle lung disease; sickle nephropathy (moderate or severe proteinuria or a glomerular filtration rate 30 to 50% of the predicted normal value); bilateral proliferative retinopathy and major visual impairment in at least one eye; osteonecrosis of multiple joints; red-cell alloimmunization during long-term transfusion therapy) and should be performed only in the context of controlled trials in experienced centers.

29 Indication for unrelated or haploidentical HSCT Recurrence of stroke despite transfusion program Worsening cerebral vasculopathy despite transfusion program Severe erythroid allo immunization

30 Conclusions 1

31 Is it justified to perform BMT in hemoglobinopathies using unrelated and/or partially mismatched donors? Thalassemia MUD transplant: YES In child with life-long control of iron overload and absence of ironrelated tissue complications. If a wellmatched unrelated-donor is available with less stringent compatibility criteria If correct medical therapy is not feasible

32 Is it justified to perform BMT in hemoglobinopathies using unrelated and/or partially mismatched donors? Thalassemia Haplo identical transplant = YES If correct medical therapy is not feasible. Only inside controlled clinical trials

33 Is it justified to perform BMT in hemoglobinopathies using unrelated and/or partially mismatched donors? Sickle cell disease. MUD transplant = YES In patients with symptomatic untreatable disease Well matched Cord blood

34 Is it justified to perform BMT in hemoglobinopathies using unrelated and/or partially mismatched donors? Sickle cell disease Haplo identical transplant: YES in un treatable SCD patients inside clinical trials (autologous BM back up) when it is impossible to find an acceptable unrelated donor.

35 Conclusions 2

36 Thalassemia Direct cost of medical therapy in Italy: Chelation (Deferoxamine) + transfusions in 2006 =14,916 Scalone L et al. Curr Med Res Opin 2008;24:

37 SCD It has been calculated that patients with SCD in the USA need more than hospital admissions per year with admission associated costs of approximately USD per SCD-patient per year. in the Florida Medicaid program during the lifetime cost of care for SCD is averaging $460,151 per patient with SCD Steiner CA, Miller JL. Sickle Cell Disease Patients in U.S. Hospitals, 2004: Statistical Brief # Kauf TL, Coates TD, Huazhi L, Mody-Patel N, Hartzema AG. The cost of health care for children and adults with sickle cell disease. Am J Hematol. 2009;84:

38 HSCT for not malignant disease HSCT from sibling donors for non malignant diseases: USD USD per expected life year in case of HSCT in infancy. Matthes-Martin S, Potschger U, Barr R, et al. Costs and Cost- Effectiveness of Allogeneic Stem Cell Transplantation in Children Are Predictable. Biol Blood Marrow Transplant

39 Cost-effectiveness of HSCT VS Medical care in Thalassemia and SCD. USD per expected life year.

40 Hemoglobinopathies 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.

41 Thank you for your attention