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Allogeneic Hematopoietic Stem Cell Transplant in Severe Thalassemia Patients: Time to Transplant

Allogeneic Hematopoietic Stem Cell Transplant in Severe Thalassemia Patients: Time to Transplant. Suradej Hongeng, MD Professor of Pediatrics Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand. Outline. Definition of severe thalassemia

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Allogeneic Hematopoietic Stem Cell Transplant in Severe Thalassemia Patients: Time to Transplant

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  1. Allogeneic Hematopoietic Stem Cell Transplant in Severe Thalassemia Patients: Time to Transplant Suradej Hongeng, MD Professor of Pediatrics Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand

  2. Outline Definition of severe thalassemia Outcome of HSCT thalassemia worldwide Result of unrelated and haploidentical HSCT in thalassemia Result of HSCT in older thalassemia (class 3) Result of cord blood transplant in thalassemia How to define the risk group of thalassemia for HSCT How to improve the outcome HSCT in thalassemia Splenectomy prior to HSCT ??????

  3. 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

  4. Thalassemia α thalassemia disease Hb bart ( _ _ / _ _ ) Hb H disease ( _ _ /_ α ) β thalassemia disease Homozygous β thalassemia Hb E /β thalassemia

  5. Pathophysiology of -Thalassemia/Hb E Disease

  6. b thalassaemia intermedia (Hb E/b thalassaemia) Courtesy of Dr. Vip Viprakasit, Siriraj Hospital, BKK

  7. Hb (d/dL) 0-4 4.1-5 5.1-6 6.1-7 7.1-8 8.1-9 9.1-10 >10 Clinical heterogeneity in Hb E/b thalassaemia Baseline Hb level in Pediatric Patient with HbE/β Thalassemia V. Viprakasit, unpublished data 2007 Fucharoen S, Winichagoon P. Curr Opin Hematol. 2000;7:106-112

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

  9. HSCT in Thalassemia  thalassemia Homozygous β thalassemia HbE/β thalassemia (only severe cases) (Hb level range from 2 gm/dL to 9 gm/dL)  thalassemia ?? HbH and AE Bart’s; some  mutations Bart’s Hydrops; high level of Portland hypertransfusionthen followed by HSCT

  10. Key Issues for HSCT in Thal • Conditioining regimen: Bu + Cy • Donor • Source of HSC • Risk group

  11. Results of MRD in HSCT for Thal Patients

  12. BMT in Thalassemia Risk factors for BMT in thalassemia Chelation Regular vs Irregular Hepatomegaly Absent vs Present Liver fibrosis 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

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

  14. Dilemma 1 Searching a suitable donor Unrelated donor Haploidentical donor

  15. 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

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

  17. Treosulfan, Thiotepa, Fludarabine, ATG (unrelated) Blood; 2012

  18. HSCT in Thalassemiaat 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

  19. HSCT in Thalassemia at Ramathibodi 1989-2011 Thalassemia ( n = 102 pts) Homozygous β thalassemia 26 pts HbE / β thalassemia 74 pts Alpha thalassemia 2 pts

  20. Conditioning Regimens and GVHD Prophylaxis Related group and age < 10 yrs Cyclo 200 mg/kg, Bu 14-16 mg/kg PO/IV CSA + MTX (CB; pred) Unrelated group and < 10 yrs Cyclo 200 mg/kg, Bu 14-16 mg/kg PO/IV, Fludara 210 mg/m2 and ATG (Fresenius) 40 mg/kg FK506 + MTX (CB; Pred) Related and Unrelated age > 10 yrs RIC regimen; Busulfan, Fludara and ATG (Thymoglobulin) CSA or FK 506 + MMF

  21. 1.00 0.75 0.50 0.25 analysis time 0.00 0 50 100 150 200 TFS 102 Thal Patients at Ramathibodi (Update 2012) Related = 67, Unrelated = 35 89% (95%CI:70-93) (month)

  22. OS 102 Thal Patients at Ramathibodi (Update 2012) Related 67, Unrelated 35 92 % (95%CI:77-94) (month)

  23. TFS (Related and Unrelated) Update 2012at Ramathibodi (n = 102) 94%(95%CI:72-96)n = 67 81% (95%CI:49-84) n = 35

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

  25. 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%

  26. Haploidentical HSCT (34+ selection) 31 pts Myeloablative regimen; Cyclo, Bu, Flu,Thiotepa and ATG GVHD prophylaxis CSA Sodani et al, Pediatr Rep 2011

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

  28. BMT in Class 1 and 2 • 515 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

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

  30. BMT in Adult Thalassemia • 107 patients aged 17 – 35 years, MRD BMT • Class 2 (n=18), BU14 CY200; class 3 BU14-16 CY120-160 • 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

  31. High risk; age > 7 and hepatomegaly BBMT; 2007

  32. Sabloff et al. ICBMTR, Blood 2011

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

  34. New Approach for BMT in Children with Class 3 • Protocol 26 • DF 40 mg/kg cont IV, d – 45 to – 11 • PRC every 3 days, Hb 14 – 15 g/dL • HU 30 mg/kg daily • Azathioprine 3 mg/kg daily • FLU 20 mg/m2/d, d – 17 to – 13 • BU14CY160 • 33 class 3 patients • Aged less than 17 years; • 70% of pts age < 10 yr • OS 93%, TFS 83% rejection rate 8% Sodani P et al. Blood 2004

  35. Protocol 26 for BMT in Adult Patients • Protocol 26 in adult thalassemia (n=15) • Decreased CY90 • Decreased TRM from 37% to 27% (still high) • Low rejection rate • Adult patients may be suitable for reduced intensity regimen Gaziev J, et al. Ann N Y Acad Sci 2005

  36. RIC SCT in Thalassemia • A RIC SCT for thalassemia performed by Resnick et al (BMT 2007) • 20 patients, median age 5.6 yrs (2.4 – 23.3 yrs) • 11/20 (55%) at least class 2 • Conditioning regimen • Fludarabine 30 mg/m2/day x 6 days (day -9 to -4) • BU 8 mg/kg (2 pts), 16 mg/kg (6 pts); IVBU 3.2 mg/kg/day x 4 days (day -7 to -4) • ATG-F 10 mg/kg/day x 4 days (day -4 to -1) • Donors: MSD 17, MFD 1, MUD 2 • Stem cells: PBSC 8, BM 12 • GVHD prophylaxis: CsA Resnick et al. BMT 2007

  37. RIC SCT in Thalassemia • 19/20 primary engraftment • Graft rejection = 3 • Stable mixed chimerism = 3 • aGVHD gr I – II = 25% • cGVHD = 25% • Substitution of HD CY by FLU and ATG is effective. • Weekly monitoring chimerism and gradual withdrawal of immunosuppressive • BM is a preferred source in the future (no GVHD from MSD BM) Resnick et al. BMT 2007

  38. Treosulfan, Thiotepa, Fludarabine, ATG (unrelated) Blood; 2012

  39. Our Approach for Patients with Class 3 and Older than 10 yrs

  40. High Risk Class 3 Patients Definition Older patients Age > 10 yrs Hepatomegaly

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

  42. Conditioning Regimen for Patients Older than 10 yrs Past Combination of cyclophosphamide and busulfan Too much alkylating agent regimen Too toxic Long term toxicities; gonadal toxicity ? 2nd malignancies Therefore Finding a novel approach

  43. Patient Characteristics Total 24 patients All patients aged older than 10 yrs. (median 18; range 11-22) All have hepatomegaly; > 5 cms

  44. Previous RIC Regimen(Early 8 Patients) Busulfan oral (8-12 mg/kg) Fludarabine (210 mg/m2) ATG (Fresinius 20 mg/kg) +TLI 500 cGy + Thiotepa 10 mg/kg + Melphalan 100 mg/m2 GVHD prophylaxis CSA or FK506 and MMF

  45. Am J Hematol, 2007 2 Iannone R, et al. BBMT 2003 3 Horan JT, et al. BMT 2005 4 Jacobsohn DA, et al. Lancet 2004 5Krishnamurti L, et al. BMT 2006

  46. TFS and OS of RIT in 24 Thal Patients 92 % (95%CI:50-96)

  47. Novel Reduced Toxicity Regimen for Transplantation in Older Severe Thalassemia Patients: Sequential Immunoablation Suradej Hongeng, Samart Pakakasama, Usanarat Anurathapan, Duantida Songdej, Nongnuch Sirachainan, Ampaiwan Chuansumrit Dept. Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand

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