Download - Allogeneic Hematopoietic Stem Cell Transplant in Severe Thalassemia Patients: Time to Transplant
![Page 1: Allogeneic Hematopoietic Stem Cell Transplant in Severe Thalassemia Patients: Time to Transplant](https://reader036.vdocuments.us/reader036/viewer/2022062408/56813c00550346895da55a41/html5/thumbnails/1.jpg)
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
![Page 2: Allogeneic Hematopoietic Stem Cell Transplant in Severe Thalassemia Patients: Time to Transplant](https://reader036.vdocuments.us/reader036/viewer/2022062408/56813c00550346895da55a41/html5/thumbnails/2.jpg)
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 ??????
![Page 3: Allogeneic Hematopoietic Stem Cell Transplant in Severe Thalassemia Patients: Time to Transplant](https://reader036.vdocuments.us/reader036/viewer/2022062408/56813c00550346895da55a41/html5/thumbnails/3.jpg)
Severe Thalassemia
Onset of disease at one to three years of ageFrequent blood transfusion (monthly)HepatosplenomegalyHemoglobin level less than 8 gm/dL
(pre-transfusion level)Thalassemic facies
![Page 4: Allogeneic Hematopoietic Stem Cell Transplant in Severe Thalassemia Patients: Time to Transplant](https://reader036.vdocuments.us/reader036/viewer/2022062408/56813c00550346895da55a41/html5/thumbnails/4.jpg)
Thalassemia
α thalassemia disease
Hb bart ( _ _ / _ _ )
Hb H disease ( _ _ /_ α )
β thalassemia disease
Homozygous β thalassemia
Hb E /β thalassemia
![Page 5: Allogeneic Hematopoietic Stem Cell Transplant in Severe Thalassemia Patients: Time to Transplant](https://reader036.vdocuments.us/reader036/viewer/2022062408/56813c00550346895da55a41/html5/thumbnails/5.jpg)
Pathophysiology of -Thalassemia/Hb E Disease
![Page 6: Allogeneic Hematopoietic Stem Cell Transplant in Severe Thalassemia Patients: Time to Transplant](https://reader036.vdocuments.us/reader036/viewer/2022062408/56813c00550346895da55a41/html5/thumbnails/6.jpg)
thalassaemia intermedia (Hb E/ thalassaemia)
Courtesy of Dr. Vip Viprakasit, Siriraj Hospital, BKK
![Page 7: Allogeneic Hematopoietic Stem Cell Transplant in Severe Thalassemia Patients: Time to Transplant](https://reader036.vdocuments.us/reader036/viewer/2022062408/56813c00550346895da55a41/html5/thumbnails/7.jpg)
Clinical heterogeneity in Hb E/ thalassaemia
V. Viprakasit, unpublished data 2007Fucharoen S, Winichagoon P. Curr Opin Hematol. 2000;7:106-112
0-4 4.1-5 5.1-6 6.1-7 7.1-8 8.1-9 9.1-10 >10 Hb (d/dL)
Baseline Hb level in Pediatric Patient with HbE/β Thalassemia
![Page 8: Allogeneic Hematopoietic Stem Cell Transplant in Severe Thalassemia Patients: Time to Transplant](https://reader036.vdocuments.us/reader036/viewer/2022062408/56813c00550346895da55a41/html5/thumbnails/8.jpg)
Treatments in Severe Thalassemia
Palliative treatment Blood transfusion Iron chelation SplenectomyCurative treatment Hematopoietic stem cell transplant (HSCT)
Gene therapy
![Page 9: Allogeneic Hematopoietic Stem Cell Transplant in Severe Thalassemia Patients: Time to Transplant](https://reader036.vdocuments.us/reader036/viewer/2022062408/56813c00550346895da55a41/html5/thumbnails/9.jpg)
HSCT in Thalassemia thalassemiaHomozygous β thalassemiaHbE/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
hypertransfusion then followed by HSCT
![Page 10: Allogeneic Hematopoietic Stem Cell Transplant in Severe Thalassemia Patients: Time to Transplant](https://reader036.vdocuments.us/reader036/viewer/2022062408/56813c00550346895da55a41/html5/thumbnails/10.jpg)
Key Issues for HSCT in Thal
• Conditioining regimen: Bu + Cy• Donor• Source of HSC• Risk group
![Page 11: Allogeneic Hematopoietic Stem Cell Transplant in Severe Thalassemia Patients: Time to Transplant](https://reader036.vdocuments.us/reader036/viewer/2022062408/56813c00550346895da55a41/html5/thumbnails/11.jpg)
Results of MRD in HSCT for Thal Patients
Reference Patients OS TFS
Di Bartolomeo et al. 111 90 86
Argiolu et al. 37 88 88
Clift et al. 68 94 81
Lawson et al. 54 95 82
Ghavamzadehv et al. 60 83 73
Denninson et al. 50 76 68
Lin et al. 28 86 82
Lee et al. 44 86 82
Issaragrisil et al. 21 70 53
![Page 12: Allogeneic Hematopoietic Stem Cell Transplant in Severe Thalassemia Patients: Time to Transplant](https://reader036.vdocuments.us/reader036/viewer/2022062408/56813c00550346895da55a41/html5/thumbnails/12.jpg)
BMT in Thalassemia
Risk factors for BMT in thalassemia
Chelation Regular vs IrregularHepatomegaly Absent vs PresentLiver fibrosis Absent vs Present
Risk classes for BMT in thalassemia
Chelation Hepatomegaly Fibrosis
Class1 Regular NO NOClass2 Reg/Irreg NO/YES NO/YESClass3 Irregular YES YES
Lucarelli G et al. N Engl J Med 1990
![Page 13: Allogeneic Hematopoietic Stem Cell Transplant in Severe Thalassemia Patients: Time to Transplant](https://reader036.vdocuments.us/reader036/viewer/2022062408/56813c00550346895da55a41/html5/thumbnails/13.jpg)
Dilemma in HSCT in Thalassemia
Searching for a suitable donor
Class 3 (older patients)
![Page 14: Allogeneic Hematopoietic Stem Cell Transplant in Severe Thalassemia Patients: Time to Transplant](https://reader036.vdocuments.us/reader036/viewer/2022062408/56813c00550346895da55a41/html5/thumbnails/14.jpg)
Dilemma 1
Searching a suitable donor
Unrelated donor
Haploidentical donor
![Page 15: Allogeneic Hematopoietic Stem Cell Transplant in Severe Thalassemia Patients: Time to Transplant](https://reader036.vdocuments.us/reader036/viewer/2022062408/56813c00550346895da55a41/html5/thumbnails/15.jpg)
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
![Page 16: Allogeneic Hematopoietic Stem Cell Transplant in Severe Thalassemia Patients: Time to Transplant](https://reader036.vdocuments.us/reader036/viewer/2022062408/56813c00550346895da55a41/html5/thumbnails/16.jpg)
Unrelated Donor BMT in Thalassemia
Class 1 and 230 patients, median age 8 yearsaGVHD gr II-IV 29%cGVHD 11%
Class 338 patients, median age 19 yearsaGVHD gr II-IV 56%cGVHD 27%
La Nasa et al. Ann NY Acad Sci 2005
![Page 17: Allogeneic Hematopoietic Stem Cell Transplant in Severe Thalassemia Patients: Time to Transplant](https://reader036.vdocuments.us/reader036/viewer/2022062408/56813c00550346895da55a41/html5/thumbnails/17.jpg)
Treosulfan, Thiotepa, Fludarabine, ATG (unrelated) Blood; 2012
![Page 18: Allogeneic Hematopoietic Stem Cell Transplant in Severe Thalassemia Patients: Time to Transplant](https://reader036.vdocuments.us/reader036/viewer/2022062408/56813c00550346895da55a41/html5/thumbnails/18.jpg)
![Page 19: Allogeneic Hematopoietic Stem Cell Transplant in Severe Thalassemia Patients: Time to Transplant](https://reader036.vdocuments.us/reader036/viewer/2022062408/56813c00550346895da55a41/html5/thumbnails/19.jpg)
![Page 20: Allogeneic Hematopoietic Stem Cell Transplant in Severe Thalassemia Patients: Time to Transplant](https://reader036.vdocuments.us/reader036/viewer/2022062408/56813c00550346895da55a41/html5/thumbnails/20.jpg)
HSCT in Thalassemia at Ramathibodi
Related n=28, Unrelated n=21 Total 49 patients
Overall survival (OS) and thalassemia free survival (TFS) in Thai children
Hongeng S et al. Biol Blood Marrow Transplant 2006
82%
71%
92%
82%
![Page 21: Allogeneic Hematopoietic Stem Cell Transplant in Severe Thalassemia Patients: Time to Transplant](https://reader036.vdocuments.us/reader036/viewer/2022062408/56813c00550346895da55a41/html5/thumbnails/21.jpg)
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
![Page 22: Allogeneic Hematopoietic Stem Cell Transplant in Severe Thalassemia Patients: Time to Transplant](https://reader036.vdocuments.us/reader036/viewer/2022062408/56813c00550346895da55a41/html5/thumbnails/22.jpg)
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
![Page 23: Allogeneic Hematopoietic Stem Cell Transplant in Severe Thalassemia Patients: Time to Transplant](https://reader036.vdocuments.us/reader036/viewer/2022062408/56813c00550346895da55a41/html5/thumbnails/23.jpg)
0.00
0.25
0.50
0.75
1.00
0 50 100 150 200
analysis time
89% (95%CI:70-93)
TFS 102 Thal Patients at Ramathibodi
(Update 2012) Related = 67, Unrelated = 35
(month)
![Page 24: Allogeneic Hematopoietic Stem Cell Transplant in Severe Thalassemia Patients: Time to Transplant](https://reader036.vdocuments.us/reader036/viewer/2022062408/56813c00550346895da55a41/html5/thumbnails/24.jpg)
0.00
0.25
0.50
0.75
1.00
0 50 100 150 200analysis time
Kaplan-Meier survival estimate
OS 102 Thal Patients at Ramathibodi
(Update 2012) Related 67, Unrelated 35
92 % (95%CI:77-94)
(month)
![Page 25: Allogeneic Hematopoietic Stem Cell Transplant in Severe Thalassemia Patients: Time to Transplant](https://reader036.vdocuments.us/reader036/viewer/2022062408/56813c00550346895da55a41/html5/thumbnails/25.jpg)
TFS (Related and Unrelated) Update 2012
at Ramathibodi (n = 102)
94% (95%CI:72-96) n = 67
81% (95%CI:49-84) n = 35
![Page 26: Allogeneic Hematopoietic Stem Cell Transplant in Severe Thalassemia Patients: Time to Transplant](https://reader036.vdocuments.us/reader036/viewer/2022062408/56813c00550346895da55a41/html5/thumbnails/26.jpg)
OS (Related and Unrelated) Update 2012at Ramathibodi (n=102)
97%(95%CI:81-99) n = 67 84%(95%CI:57-91) n = 35
![Page 27: Allogeneic Hematopoietic Stem Cell Transplant in Severe Thalassemia Patients: Time to Transplant](https://reader036.vdocuments.us/reader036/viewer/2022062408/56813c00550346895da55a41/html5/thumbnails/27.jpg)
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%
![Page 28: Allogeneic Hematopoietic Stem Cell Transplant in Severe Thalassemia Patients: Time to Transplant](https://reader036.vdocuments.us/reader036/viewer/2022062408/56813c00550346895da55a41/html5/thumbnails/28.jpg)
Haploidentical HSCT (34+ selection)
31 pts
Myeloablative regimen; Cyclo, Bu, Flu,Thiotepa and ATG
GVHD prophylaxis
CSA
Sodani et al, Pediatr Rep
2011
![Page 29: Allogeneic Hematopoietic Stem Cell Transplant in Severe Thalassemia Patients: Time to Transplant](https://reader036.vdocuments.us/reader036/viewer/2022062408/56813c00550346895da55a41/html5/thumbnails/29.jpg)
Dilemma 2
Class 3 patients
All class 3 patients are the same?
What should be done for this group?
![Page 30: Allogeneic Hematopoietic Stem Cell Transplant in Severe Thalassemia Patients: Time to Transplant](https://reader036.vdocuments.us/reader036/viewer/2022062408/56813c00550346895da55a41/html5/thumbnails/30.jpg)
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
![Page 31: Allogeneic Hematopoietic Stem Cell Transplant in Severe Thalassemia Patients: Time to Transplant](https://reader036.vdocuments.us/reader036/viewer/2022062408/56813c00550346895da55a41/html5/thumbnails/31.jpg)
BMT in Class 3 Thalassemia
56 children aged < 17 yearsMRD, BU14CY200
95 children aged < 17 yearsMRD, BU14CY<200
Lucarelli G et al. Blood 1996
![Page 32: Allogeneic Hematopoietic Stem Cell Transplant in Severe Thalassemia Patients: Time to Transplant](https://reader036.vdocuments.us/reader036/viewer/2022062408/56813c00550346895da55a41/html5/thumbnails/32.jpg)
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
![Page 33: Allogeneic Hematopoietic Stem Cell Transplant in Severe Thalassemia Patients: Time to Transplant](https://reader036.vdocuments.us/reader036/viewer/2022062408/56813c00550346895da55a41/html5/thumbnails/33.jpg)
High risk; age > 7 and hepatomegaly BBMT; 2007
![Page 34: Allogeneic Hematopoietic Stem Cell Transplant in Severe Thalassemia Patients: Time to Transplant](https://reader036.vdocuments.us/reader036/viewer/2022062408/56813c00550346895da55a41/html5/thumbnails/34.jpg)
Sabloff et al. ICBMTR, Blood 2011
![Page 35: Allogeneic Hematopoietic Stem Cell Transplant in Severe Thalassemia Patients: Time to Transplant](https://reader036.vdocuments.us/reader036/viewer/2022062408/56813c00550346895da55a41/html5/thumbnails/35.jpg)
What Kind of Conditioning Regimen?
Myeloablation
Reduced intensity
Non-ablation
![Page 36: Allogeneic Hematopoietic Stem Cell Transplant in Severe Thalassemia Patients: Time to Transplant](https://reader036.vdocuments.us/reader036/viewer/2022062408/56813c00550346895da55a41/html5/thumbnails/36.jpg)
![Page 37: Allogeneic Hematopoietic Stem Cell Transplant in Severe Thalassemia Patients: Time to Transplant](https://reader036.vdocuments.us/reader036/viewer/2022062408/56813c00550346895da55a41/html5/thumbnails/37.jpg)
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 yrOS 93%, TFS 83% rejection rate 8%
Sodani P et al. Blood 2004
![Page 38: Allogeneic Hematopoietic Stem Cell Transplant in Severe Thalassemia Patients: Time to Transplant](https://reader036.vdocuments.us/reader036/viewer/2022062408/56813c00550346895da55a41/html5/thumbnails/38.jpg)
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
![Page 39: Allogeneic Hematopoietic Stem Cell Transplant in Severe Thalassemia Patients: Time to Transplant](https://reader036.vdocuments.us/reader036/viewer/2022062408/56813c00550346895da55a41/html5/thumbnails/39.jpg)
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
![Page 40: Allogeneic Hematopoietic Stem Cell Transplant in Severe Thalassemia Patients: Time to Transplant](https://reader036.vdocuments.us/reader036/viewer/2022062408/56813c00550346895da55a41/html5/thumbnails/40.jpg)
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
![Page 41: Allogeneic Hematopoietic Stem Cell Transplant in Severe Thalassemia Patients: Time to Transplant](https://reader036.vdocuments.us/reader036/viewer/2022062408/56813c00550346895da55a41/html5/thumbnails/41.jpg)
Treosulfan, Thiotepa, Fludarabine, ATG (unrelated) Blood; 2012
![Page 42: Allogeneic Hematopoietic Stem Cell Transplant in Severe Thalassemia Patients: Time to Transplant](https://reader036.vdocuments.us/reader036/viewer/2022062408/56813c00550346895da55a41/html5/thumbnails/42.jpg)
Our Approach for Patients with Class 3 and Older than 10 yrs
![Page 43: Allogeneic Hematopoietic Stem Cell Transplant in Severe Thalassemia Patients: Time to Transplant](https://reader036.vdocuments.us/reader036/viewer/2022062408/56813c00550346895da55a41/html5/thumbnails/43.jpg)
High Risk Class 3 Patients
Definition
Older patients
Age > 10 yrs
Hepatomegaly
![Page 44: Allogeneic Hematopoietic Stem Cell Transplant in Severe Thalassemia Patients: Time to Transplant](https://reader036.vdocuments.us/reader036/viewer/2022062408/56813c00550346895da55a41/html5/thumbnails/44.jpg)
Class 3 Lucarelli (Age > 10 y and Hepatomegaly) Pre-transplant Management
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
Sodani P et al. Blood 2004Hongeng S et al. Am J Hematol 2007
![Page 45: Allogeneic Hematopoietic Stem Cell Transplant in Severe Thalassemia Patients: Time to Transplant](https://reader036.vdocuments.us/reader036/viewer/2022062408/56813c00550346895da55a41/html5/thumbnails/45.jpg)
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
![Page 46: Allogeneic Hematopoietic Stem Cell Transplant in Severe Thalassemia Patients: Time to Transplant](https://reader036.vdocuments.us/reader036/viewer/2022062408/56813c00550346895da55a41/html5/thumbnails/46.jpg)
Patient Characteristics
Total 24 patients
All patients aged older than 10 yrs.
(median 18; range 11-22)
All have hepatomegaly; > 5 cms
![Page 47: Allogeneic Hematopoietic Stem Cell Transplant in Severe Thalassemia Patients: Time to Transplant](https://reader036.vdocuments.us/reader036/viewer/2022062408/56813c00550346895da55a41/html5/thumbnails/47.jpg)
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
![Page 48: Allogeneic Hematopoietic Stem Cell Transplant in Severe Thalassemia Patients: Time to Transplant](https://reader036.vdocuments.us/reader036/viewer/2022062408/56813c00550346895da55a41/html5/thumbnails/48.jpg)
2 Iannone R, et al. BBMT 2003
3 Horan JT, et al. BMT 2005
4 Jacobsohn DA, et al. Lancet 2004
5 Krishnamurti L, et al. BMT 2006
Am J Hematol, 2007
![Page 49: Allogeneic Hematopoietic Stem Cell Transplant in Severe Thalassemia Patients: Time to Transplant](https://reader036.vdocuments.us/reader036/viewer/2022062408/56813c00550346895da55a41/html5/thumbnails/49.jpg)
TFS and OS of RIT in 24 Thal Patients
0.00
0.25
0.50
0.75
1.00
0 20 40 60 80
time (months)
EFS OS
probability survival estimates
92 % (95%CI:50-96)
![Page 50: Allogeneic Hematopoietic Stem Cell Transplant in Severe Thalassemia Patients: Time to Transplant](https://reader036.vdocuments.us/reader036/viewer/2022062408/56813c00550346895da55a41/html5/thumbnails/50.jpg)
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
![Page 51: Allogeneic Hematopoietic Stem Cell Transplant in Severe Thalassemia Patients: Time to Transplant](https://reader036.vdocuments.us/reader036/viewer/2022062408/56813c00550346895da55a41/html5/thumbnails/51.jpg)
Sequential Immunoablative Program
Fludarabine 40 mg/m2 x 5 days
Dexamethsone 25 mg/m2 x 5 days
28-day cycle prior to conditioning regimen
Ten patients received 1 cycle
Eight patients received 2 cycles
![Page 52: Allogeneic Hematopoietic Stem Cell Transplant in Severe Thalassemia Patients: Time to Transplant](https://reader036.vdocuments.us/reader036/viewer/2022062408/56813c00550346895da55a41/html5/thumbnails/52.jpg)
Conditioning Regimen
Fludarabine 35 mg/m2; d-9,-8,-7,-6,-5,-4
Busulfex 130 mg/m2; d-9,-8,-7,-6
ATG (Thymoglobulin) 1.5 mg/kg; d-3,-2,-1
![Page 53: Allogeneic Hematopoietic Stem Cell Transplant in Severe Thalassemia Patients: Time to Transplant](https://reader036.vdocuments.us/reader036/viewer/2022062408/56813c00550346895da55a41/html5/thumbnails/53.jpg)
GvHD Prophylaxis
CSA or FK506
MMF for 60 days
![Page 54: Allogeneic Hematopoietic Stem Cell Transplant in Severe Thalassemia Patients: Time to Transplant](https://reader036.vdocuments.us/reader036/viewer/2022062408/56813c00550346895da55a41/html5/thumbnails/54.jpg)
Patient Characteristics
Eighteen patients were included in this study.
Two out of 18 had second HSCT.
Homozygous β thal = 4; β thal/HbE = 14
Age; median = 14 yr (10-18 yr)
Male 7; Female 11
Splenectomy = 7 (Referral hospital)
All patients had liver > 5 cm below costal margin
Ferritin level; median = 2892 ng/mL (869-8350)
All were class 3. (High risk class 3)
![Page 55: Allogeneic Hematopoietic Stem Cell Transplant in Severe Thalassemia Patients: Time to Transplant](https://reader036.vdocuments.us/reader036/viewer/2022062408/56813c00550346895da55a41/html5/thumbnails/55.jpg)
Graft
17 patients received PBSC
1 patient received BM
Median CD34+ dose 9.43 cells/kg (4.67-19.26)
MRD 11 MMRD 2 (DRB1)
MUD 3 MMUD 2 (C)
![Page 56: Allogeneic Hematopoietic Stem Cell Transplant in Severe Thalassemia Patients: Time to Transplant](https://reader036.vdocuments.us/reader036/viewer/2022062408/56813c00550346895da55a41/html5/thumbnails/56.jpg)
Engraftment
All were engrafted.
PMN engraftment; median d+12 (11-18)
Platelet engraftment; median d+18 (12-47)
![Page 57: Allogeneic Hematopoietic Stem Cell Transplant in Severe Thalassemia Patients: Time to Transplant](https://reader036.vdocuments.us/reader036/viewer/2022062408/56813c00550346895da55a41/html5/thumbnails/57.jpg)
GvHD
Acute GvHD
gr II-IV 4 patients (22%)
Gr III-IV none
Chronic GvHD
Mild 5 patients (28%)
Extensive none
![Page 58: Allogeneic Hematopoietic Stem Cell Transplant in Severe Thalassemia Patients: Time to Transplant](https://reader036.vdocuments.us/reader036/viewer/2022062408/56813c00550346895da55a41/html5/thumbnails/58.jpg)
Complications
Mild VOD 3 patients (16%)
Mucositis gr 1 3 patients (16%)
![Page 59: Allogeneic Hematopoietic Stem Cell Transplant in Severe Thalassemia Patients: Time to Transplant](https://reader036.vdocuments.us/reader036/viewer/2022062408/56813c00550346895da55a41/html5/thumbnails/59.jpg)
Infections
CMV reactivation 3 patients
BK reactivation 1 patient
BK cystitis 1 patient
Herpes zoster 1 patient
Chicken pox 1 patient
![Page 60: Allogeneic Hematopoietic Stem Cell Transplant in Severe Thalassemia Patients: Time to Transplant](https://reader036.vdocuments.us/reader036/viewer/2022062408/56813c00550346895da55a41/html5/thumbnails/60.jpg)
Sequential Immunoablative Concept
We have tested T cell function by PHA stimulation before and after Flu Dex administration.
![Page 61: Allogeneic Hematopoietic Stem Cell Transplant in Severe Thalassemia Patients: Time to Transplant](https://reader036.vdocuments.us/reader036/viewer/2022062408/56813c00550346895da55a41/html5/thumbnails/61.jpg)
CSFE CD4 cell proliferation
Stimulation index (SI)Percentage of CFSElowCD4 cells (PHA)
Percentage of CFSElowCD4 cells (Neg control = no PHA)
Venken et al.Journal of Immunological Methods 322 (2007) 1–11
![Page 62: Allogeneic Hematopoietic Stem Cell Transplant in Severe Thalassemia Patients: Time to Transplant](https://reader036.vdocuments.us/reader036/viewer/2022062408/56813c00550346895da55a41/html5/thumbnails/62.jpg)
No.1 = KCNo.2 = AKNo.3 = AS
![Page 63: Allogeneic Hematopoietic Stem Cell Transplant in Severe Thalassemia Patients: Time to Transplant](https://reader036.vdocuments.us/reader036/viewer/2022062408/56813c00550346895da55a41/html5/thumbnails/63.jpg)
Outcome
Two patients died.
1Cerebellar hemorrhage from motorcycle accident.
2IPA
16/18 patients survived without thalassemia symptom. Median follow up time 30 months
![Page 64: Allogeneic Hematopoietic Stem Cell Transplant in Severe Thalassemia Patients: Time to Transplant](https://reader036.vdocuments.us/reader036/viewer/2022062408/56813c00550346895da55a41/html5/thumbnails/64.jpg)
0.0
00.2
50.5
00.7
51.0
0P
rob
ab
ility
0 2 4 6Years
Overall survival Thalassemia Free-survival
Survival and Thalassemia-Free Survivals of Patients Treated with Novel Reduced Toxicity HSCT (unpublished data)
88% (95% CI, 0.5327 - 0.9621)
![Page 65: Allogeneic Hematopoietic Stem Cell Transplant in Severe Thalassemia Patients: Time to Transplant](https://reader036.vdocuments.us/reader036/viewer/2022062408/56813c00550346895da55a41/html5/thumbnails/65.jpg)
Source of HSC for HSCT in Thal
• BM
• PBSC
• CB
![Page 66: Allogeneic Hematopoietic Stem Cell Transplant in Severe Thalassemia Patients: Time to Transplant](https://reader036.vdocuments.us/reader036/viewer/2022062408/56813c00550346895da55a41/html5/thumbnails/66.jpg)
Related Donor CBT for Thalassemia
• Multicenter study (Eurocord group)
• 33 patients with thal major (11 SCD)
• Class1 = 20, class2 = 13
• Full matched HLA (32), 5/6 (1)
• Conditioning regimen: BU16CY200, ATG/ALG BUCY+/-FLU+/-TT
• Median TNC 4 x 10^7/kg
• Engraftment: 7/33 primary graft failure 3 persistent MC
Locatelli F et al. Blood 2003
![Page 67: Allogeneic Hematopoietic Stem Cell Transplant in Severe Thalassemia Patients: Time to Transplant](https://reader036.vdocuments.us/reader036/viewer/2022062408/56813c00550346895da55a41/html5/thumbnails/67.jpg)
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
![Page 68: Allogeneic Hematopoietic Stem Cell Transplant in Severe Thalassemia Patients: Time to Transplant](https://reader036.vdocuments.us/reader036/viewer/2022062408/56813c00550346895da55a41/html5/thumbnails/68.jpg)
Unrelated Donor CBT for Thalassemia( n= 35)
Jaing et al, BMT 2012
![Page 69: Allogeneic Hematopoietic Stem Cell Transplant in Severe Thalassemia Patients: Time to Transplant](https://reader036.vdocuments.us/reader036/viewer/2022062408/56813c00550346895da55a41/html5/thumbnails/69.jpg)
UCBT in Thal and SCD
Cell dose > 5 x 10(7) /kg; Better outcome
Ruggeri et al. EBMT data, BBMT 2011
![Page 70: Allogeneic Hematopoietic Stem Cell Transplant in Severe Thalassemia Patients: Time to Transplant](https://reader036.vdocuments.us/reader036/viewer/2022062408/56813c00550346895da55a41/html5/thumbnails/70.jpg)
Post HSCT Management to Prevent Rejection
![Page 71: Allogeneic Hematopoietic Stem Cell Transplant in Severe Thalassemia Patients: Time to Transplant](https://reader036.vdocuments.us/reader036/viewer/2022062408/56813c00550346895da55a41/html5/thumbnails/71.jpg)
Mixed Chimerism After BMTLucarelli Group
BMT 335 thalassemic patients
Chimerism status at 2 months
Complete chimerism227 (67.8%)
Mixed chimerism108 (32.2%)
CC218 (96%)
PMC9 (4%)
PMC73 (67.6%)
GR35 (32.4%)
Andreani M, BMT 2000
![Page 72: Allogeneic Hematopoietic Stem Cell Transplant in Severe Thalassemia Patients: Time to Transplant](https://reader036.vdocuments.us/reader036/viewer/2022062408/56813c00550346895da55a41/html5/thumbnails/72.jpg)
Mixed Chimerism After BMTLucarelli Group
108 mixed chimerism
MC1 (RHCs<10%)61 (56.5%)
MC2 (RHCs 10-25%)27 (25%)
MC3 (RHCs>25%)20 (18.5%)
CC57%
CC44%
CC0%
PMC30%
PMC15%
PMC10%
GR13%
GR41%
GR90%
Andreani M, BMT 2000
![Page 73: Allogeneic Hematopoietic Stem Cell Transplant in Severe Thalassemia Patients: Time to Transplant](https://reader036.vdocuments.us/reader036/viewer/2022062408/56813c00550346895da55a41/html5/thumbnails/73.jpg)
Management for Mixed Chimerism
Chimerism study weekly after engraftment for 3 months
If MC with recipient > 10-25%
Decrease immunosuppressive agents
MC with recipient > 25%
Donor lymphocyte infusion
or
Minimal conditioning regimen: fludarabine
+ busulfan followed by PBSC infusion
![Page 74: Allogeneic Hematopoietic Stem Cell Transplant in Severe Thalassemia Patients: Time to Transplant](https://reader036.vdocuments.us/reader036/viewer/2022062408/56813c00550346895da55a41/html5/thumbnails/74.jpg)
Pediatr Transplantation, 2011
![Page 75: Allogeneic Hematopoietic Stem Cell Transplant in Severe Thalassemia Patients: Time to Transplant](https://reader036.vdocuments.us/reader036/viewer/2022062408/56813c00550346895da55a41/html5/thumbnails/75.jpg)
Effect of Splenectomy in HSCT for Thalassemia
Mathew V, et al. BBMT 2007
![Page 76: Allogeneic Hematopoietic Stem Cell Transplant in Severe Thalassemia Patients: Time to Transplant](https://reader036.vdocuments.us/reader036/viewer/2022062408/56813c00550346895da55a41/html5/thumbnails/76.jpg)
Conclusion
Outcomes of both related- and unrelated-donor HSCT with severe thalassemia seemed to be favorable.
Favorable result in unrelated transplantation patients is due to high resolution HLA matching (8/8; ABC and DRB1)
![Page 77: Allogeneic Hematopoietic Stem Cell Transplant in Severe Thalassemia Patients: Time to Transplant](https://reader036.vdocuments.us/reader036/viewer/2022062408/56813c00550346895da55a41/html5/thumbnails/77.jpg)
ConclusionConditioning regimen:
Bu Cy (Full dose)
Bu Cy (Reduced dose) Flu Thiotepa
Bu Flu (Full dose)
Treo Flu Thiotepa
+ ATG (unrelated or PBSC)
High risk class 3: age > 7 and hepatomegaly
Bu Flu ATG plus sequential immunoablation with
Flu Dex
Bu Cy (Reduced dose) Flu Thiotepa + ATG (unrelated)
Treo Flu Thiotepa + ATG (unrelated)
![Page 78: Allogeneic Hematopoietic Stem Cell Transplant in Severe Thalassemia Patients: Time to Transplant](https://reader036.vdocuments.us/reader036/viewer/2022062408/56813c00550346895da55a41/html5/thumbnails/78.jpg)
ConclusionMixed chimerism management program seems to help to maintain sustainable engraftment.
Related CBTHigh graft failure rateNo MTX for GVHD prophylaxisAdequate cell dose (> 5 x 107/kg nucleated cell)
Unrelated CBT and Haploidentical TxHigh TRM and graft failureUncertain role in thalassemia
Cord blood expansion for future useNew approach for haploidentical HSCT
![Page 79: Allogeneic Hematopoietic Stem Cell Transplant in Severe Thalassemia Patients: Time to Transplant](https://reader036.vdocuments.us/reader036/viewer/2022062408/56813c00550346895da55a41/html5/thumbnails/79.jpg)
AcknowledgementSamart Pakakasama
Ampaiwan Chuansumrit
Nongnuch Sirachainan
Usanarat Anurathapan
Duanthida Songdej
HLA lab and BMT nurses
Somtawain Sirirueng
Wanpen Pantangkool
Saengsuree Jootar
Artit Ungkanont
Vinai Suvattee
Suthat Fucharoen
Surapol Issaragrisil
Borje Andrersson
Srinakarind Hospital
Suandok Hospital
Songklanakarin Hospital
![Page 80: Allogeneic Hematopoietic Stem Cell Transplant in Severe Thalassemia Patients: Time to Transplant](https://reader036.vdocuments.us/reader036/viewer/2022062408/56813c00550346895da55a41/html5/thumbnails/80.jpg)