Can All Thalassemia Patients be Cured? Suradej Hongeng, MD Dept of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University

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1 Can All Thalassemia Patients be Cured? Suradej Hongeng, MD Dept of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University

2 Thalassemia α thalassemia disease Hb bart ( / ) Hb H disease ( /_ α ) β thalassemia disease Homozygous β thalassemia Hb E /ββ thalassemia

3 Clinical heterogeneity in Hb E/β thalassaemia Baseline Hb level in Pediatric Patient with HbE/β Thalassemia >10 Hb (d/dl) V. Viprakasit, unpublished data 2007 Fucharoen S, Winichagoon P. Curr Opin Hematol. 2000;7:

4 Severe Thalassemia Onset of disease at one to three years of age Frequent blood transfusion (monthly) Hepatosplenomegaly Hemoglobin level less than 8 gm/dl (pre-transfusion level) Thalassemic facies

5 Treatments in Severe Thalassemia Palliative treatment Blood transfusion Iron chelation Splenectomy Curative treatment Hematopoietic stem cell transplant (HSCT) Gene therapy

6 HSCT Allogeneic HSCT HLA matching: sibling, unrelated, haploidentical Autologous Source of HSC Bone marrow Peripheral blood Cord blood

7 HSCT in Thalassemia β thalassemia Homozygous β thalassemia HbE/β thalassemia (only severe cases) α thalassemia (rare cases) HbH disease; some α mutations B t H d hi h l l f P tl d Bart s Hydrops; high level of Portland hypertransfusion then followed by HSCT

8 BMT in Thalassemia Risk factors for BMT in thalassemia Chelation Hepatomegaly Liver fibrosis Regular vs Irregular Absent vs Present Absent vs Present Risk classes for BMT in thalassemia Chelation Hepatomegaly Fibrosis Class1 Regular NO NO Class2 Reg/Irreg NO/YES NO/YES Class3 Irregular YES YES Lucarelli G et al. N Engl J Med 1990

9 Dilemma in HSCT in Thalassemia Searching for a suitable donor Class 3 (older patients)

10 HSCT in Thalassemia at Ramathibodi Related n=28, Unrelated n=21 Total 49 patients 92% 82% 82% 71% Overall survival (OS) and thalassemia free survival (TFS) in Thai children Hongeng S et al. Biol Blood Marrow Transplant 2006

11 HSCT in Thalassemia at Ramathibodi Thalassemia ( n = 102 pts) Homozygous β thalassemia 26 pts HbE / β thalassemia 74 pts Alpha thalassemia 2 pts

12 Conditioning Regimens and GVHD Prophylaxis Related group and age < 10 yrs Cyclo 200 mg/kg, Bu mg/kg PO/IV CSA + MTX (CB; pred) Unrelated group and < 10 yrs Cyclo 200 mg/kg, Bu mg/kg PO/IV, Fludara 210 mg/m2 and ATG (Fresenius) 40 mg/kg g FK506 + MTX (CB; Pred) Related and Unrelated age > 10 yrs RIC regimen; Busulfan, Fludara and ATG (Thymoglobulin) CSA or FK MMF

13 TFS 102 Thal Patients at Ramathibodi (Update 2012) Related = 67, Unrelated = % (95%CI:70-93) analysis time (month)

14 OS 102 Thal Patients at Ramathibodi (Update 2011) Related 67, Unrelated Kaplan-Meier survival estimate % (95%CI:77-94) analysis time (month)

15 Results of MRD in HSCT for Thal Patients Reference Patients OS TFS Di Bartolomeo et al Argiolu et al Clift et al Lawson et al Ghavamzadehv et al Denninson et al Lin et al Lee et al Issaragrisil et al

16 Dilemma 1 Searching a suitable donor Unrelated donor Haploidentical donor

17 Unrelated Donor BMT in Thalassemia 68 patients Median age of 15 yrs (2-37 yrs) Conditioning regimens: BUCY 17 (25%) BUTTCY 42 (62%) BUTTFLU 9 (13%) GVHD prophylaxis: CsA+MTX 52 (75%) CsA+MTX+ATG 17 (25%) agvhd gr II-IV 24/59 (40%) cgvhd 10/56 (18%) La Nasa et al. Ann NY Acad Sci 2005

18 Unrelated Donor BMT in Thalassemia Class 1 and 2 30 patients, t median age 8 years agvhd gr II-IV 29% cgvhd 11% Class 3 38 patients, t median age 19 years agvhd gr II-IV 56% cgvhd 27% La Nasa et al. Ann NY Acad Sci 2005

19 OS (Related and Unrelated) Update 2012 at Ramathibodi (n=102) 97%(95%CI:81-99) n = 67 84%(95%CI:57-91) 91) n = 35

20 TFS (Related and Unrelated) Update 2011 at Ramathibodi (n = 102) 94% (95%CI:72-96) n = 65 81% (95%CI:49-84) n = 35

21 Unrelated HSCT at Ramathibodi Previous HLA matching: Intermediate to high resolution: HLA A B DRB1 21 pts: TFS and OS; 71% and 82% Recent HLA matching: Strictly matched high resolution: HLA A B C DRB1 14 pts: TFS and OS = 94%

22 Dilemma 2 Class 3 patients All class 3 patients are the same? What should be done for this group?

23 BMT in Class 1 and class 1 and 2 aged less than 17 years BU 14 mg/kg and CY 200 mg/kg Lucarelli G and Gaziev J. Blood Rev 2008

24 BMT in Class 3 Thalassemia 56 children aged < 17 years 95 children aged < 17 years MRD, BU14CY200 MRD, BU14CY<200 Lucarelli G et al. Blood 1996

25 BMT in Adult Thalassemia 107 patients aged years, MRD BMT Class 2 (n=18), BU14 CY200; class 3 BU14-16 CY Reduced dose intensity of conditioning was not associated with higher rejection rate Adult patients could be given less intensive conditioning to overcome excessive TRM. Gaziev J, et al. Ann N Y Acad Sci 2005

26 Sabloff et al. ICBMTR, Blood 2011

27 Class 3 Patients Definition Older patients Age > 10 yrs Hepatomegaly

28 Class 3 Lucarelli (Age > 10 yrs) Management prior to HSCT Hypertransfusion in order to decrease erythroid expansion especially to decrease spleen size Regular iron chelation for at least 6-12 months Hydroxyurea y (Hb F enhancer) in order to decrease erythroid expansion: 20 mg/kg/day for at least 6-12 months Sodani P et al. Blood 2004 Hongeng S et al. Am J Hematol 2007

29 What Kind of Conditioning Regimen? Myeloablation Reduced intensity Non-ablation

30 Previous RIC Regimen (Early 8 Patients) Busulfan oral (8-12 mg/kg) Fludarabine (210 mg/m 2 ) ATG (Fresinius 20 mg/kg) +TLI 500 cgy + Thiotepa 10 mg/kg + Melphalan 100 mg/m 2 GVHD prophylaxis CSA or FK506 and MMF

31 Am J Hematol, Iannone R, et al. BBMT Horan JT, et al. BMT Jacobsohn DA, et al. Lancet Krishnamurti L, et al. BMT 2006

32 Pretransplant immunosuppression followed by reduced-toxicity conditioning and stem cell transplantation in high-risk Thalassemia: A safe approach to disease control Usanarat Anurathapan, Samart Pakakasama, Nongnuch Sirachainan, Duantida Songdej, Ampaiwan Chuansumrit, Somtawin sirireung, Borje S. Anderson, Suradej Hongeng Dept. Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand

33 Patient Characteristics Twenty-one patients were included in this study. Two out of 21 had second HSCT and 1 had third HSCT. Homozygous β thal = 5; β thal/hbe = 16 Age; median = 16 (10-20) y/o Male 8; Female 13 Splenectomy = 7 (Referral hospital) All patients had liver > 5 cm below costal margin. Ferritin level; median = 3100 ( ) 8350) ng/ml All were class 3 (High risk class 3).

34 Sequential Pretransplant Immunosuppression Fludarabine 40 mg/m 2 x 5 days Dexamethasone 25 mg/m 2 x 5 days 28-day cycle prior to conditioning regimen Ten patients received 1 cycle. Eleven patients received 2 cycles.

35 Conditioning Regimen Fludarabine 35 mg/m 2 ; d-9,-8,-7,-6,-5,-4 Busulfex 130 mg/m 2 ; d-9,-8,-7,-6 ATG (Thymoglobulin) 1.5 mg/kg; d-3,-2,-1

36 Grafts 20 patients received PBSC. 1 patient received BM. Median CD ( ) x10 6 cells/kg MRD 13 MMRD 2 (DRB1) MUD 4 MMUD 2 (C)

37 Survival and Thalassemia-Free Survivals of Patients Treated with Novel Reduced d Toxicity it HSCT % (95% CI, ) Probabi 0.50 lity Years Overall survival Thalassemia Free-survival

38 Conclusions Our novel reduced-toxicity regimen is safe and feasible for HSCT in older thalassemia patients especially high risk class 3 patients. Our patients had a favorable outcome with this approach. Pretransplant & post transplant managements are the key successes for HSCT in older thalassemia patients.

39 Related Donor CBT for Thalassemia Transplant related complications No life threatening infection agvhd 11%, cgvhd 6% 2 yr EFS 79% class1 (89%), class2 (62%) MTX decreased EFS Locatelli F et al. Blood 2003

40 Unrelated Donor CBT for Thalassemia ( n= 35) Jaing et al, BMT 2012

41 UCBT in Thal and SCD Cell dose > 5 x 10(7) /kg; Better outcome Ruggeri et al. EBMT data, BBMT 2011

42 Haploidentical HSCT (34+ selection) 22 pts Myeloablative regimen; Cyclo, Bu, Flu,Thiotepa and ATG GVHD prophylaxis CSA Sodani et al, Blood 2010

43 All Thalassemia Patients may be Cured with HSCT? Probably YES We have performed HSCT in 110 thalassemia patients. With this approach, TFS in related or unrelated in all age group in our center is more than 90%. Currently, we already performed haploindentical HSCT in 3 patients, t 20, 18 and 16 yr-old. All 3 survived without t thalassemia. No major complication except GvHD gr I-II.

44 Cost Uitlity Analysis Study (Markov Model) HSCT vs Hypertransfusion and Chelation Therapy At a societal willingness to pay of 100,000 Thai Baht (1GDP) per QALY gained, matched related donor transplantation was likely to be cost-effectiveness and affordable treatment for young children (age < 10 years) with severe thalassemia in Thailand. BMC Health Services Research: 2010

45 Cost Utility Analysis: Reduced Intensity Hematopoietic Stem Cell Transplantation in Adolescent and Adult Thalassemia Patients Sruamsiri et al. BMC Health Ser Res 2013

46 Results Cost-effectiveness acceptability curve , ,000

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48 Lentiviral vector and transduction - transplantation protocol chs4 Insulator chs4 Insulator SIN + Insulator human β-globin gene cppt/flap 266bp 644bp 845bp 1153bp Ψ + III II I βp HS2 HS3 HS4 3 enhancer RRE β A-T87Q ppt SIN + Insulator Viral titer (cgmp) = 1.1 x 10 8 TU / ml during CD34 + cell transduction Pre-transplant transduction efficiency = 0.6 vector copy / CD34 + cell (qpcr) Dose of CD34+ cells injected = 3.9 x 10 6 CD34 + cells / kg

49 Overview of the clinical protocol CD34+ cells Vector + Cytokines Maximize % Transduced HSCs Bone Marrow Harvest Testing and Release While Frozen (2x10 8 unsorted BM cells/kg kept for rescue) Busulfex Bone Marrow Conditioning Maximize Myeloablation Without Immunosuppression IV Infusion Transduced Cells (> 4x10 6 CD34 + /Kg) (Spontaneous Homing)

50 Conclusion Outcomes of both related- and unrelated-donor dd SCT in children with severe thalassemia seemed to be favorable. We believe the reasons for this favorable result in unrelated transplantation patients is high resolution HLA matching (8/8; ABC and DRB1)

51 Conclusion Pre-transplantation t ti management in class 3 is very important. All thalssemic patients can be cured by HSCT.

52 Acknowledgement Samart Pakakasama Ampaiwan Chuansumrit Nongnuch Sirachainan Usanarat Anurathapan Duanthida Songdej HLA lab and BMT nurses Somtawain Sirirueng Wanpen Pantangkool Saengsuree Jootar AtitU Artit Ungkanont Vinai Suvattee Suthat Fucharoen Surapol Issaragrisil Borje Andrersson Srinakarind Hospital Suandok Hospital Songklanakarin Hospital

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