Can all thalassemis patients be cured with HSCT? suradej hongeng

1. Can All Thalassemia Patients be Cured with HSCT?
Suradej Hongeng
Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital,
Mahidol University, Bangkok, Thailand

2. Background
Currently, thalassemia free survival rates after matched
related (MRD) and unrelated (MUD) donors HSCT were
75-90%.
The probability of finding a suitable donor (MRD and MUD)
is around 30-60%.
Is a haploidenitcal donor HSCT suitable for a thalassemia
patient?

3. BMT with MRD in Thalassemia and Lucarelli Classification
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

4. References Patients (N) Protocols for
MUD
OS
(%)
TFS
(%)
La nasa et al
(Ann NY Acad Sci 2005)
MUD = 68 Bu-Cy
(Bu-Flu)+/TT
79.3 65.8
Hongeng et al
(BBMT 2006)
MUD = 21
MRD = 28
Bu-Cy-ATG
(Bu-Flu-ATG for
class 3)
82
92
71
82
Li et al
(Blood 2012)
MUD = 52
(PBSC)
MRD = 30
(BM/CB/PBSC)
Bu-Cy-TT-Flu 92.3
90.0
90.4
83.3
Bernardo et al
(Blood 2012)
MUD = 40
MRD = 20
Treo-TT-Flu- ATG -
-
82
87
MUD = matched unrelated donor, MRD = match related donor
Unrelated donor HSCT in Thalassemia

5. References Patients (N) Protocols OS
(%)
TFS
(%)
Ghavamzadeh et al
(BBMT 2008)
PBCS = 87
BM = 96
Bu-Cy 83
89
76
76
Iravani et al
(Exp Clin Transplant 2010)
PBCS = 20
BM = 32
(HR =52)
Bu-Cy 80 65
Irfan et al
(J Pak Med Assoc 2012)
PBCS = 27
BM = 29
LR: Bu-Cy
HR: HU-Aza-Flu-
Bu-Cy
65
73
55
67
Locatelli et al (EBMT)
(Blood 2013)
CB = 66
BM = 259
Bu-Cy
(Bu-Flu)+/TT
- 80
86
PBSC = peripheral blood stem cell, BM = bone marrow, CB = cord blood
Sources of HSC for HSCT in Thalassemia

6. References Patients (N) Protocols OS
(%)
TFS
(%)
Jaing et al
(BMT 2012)
MUD CBT
35
Bu-Cy-ATG 88 74
Ruggeri et al (EBMT)
(BBMT 2011)
MUD CBT
35
Bu-Cy +/ ATG 62 21
MUD = matched unrelated donor, CBT = cord blood transplantaiton
Sources of HSC for HSCT in Thalassemia
Factors associated with better survival were a higher TNC/kg of >5 × 107 and
better HLA matching.

7. Haploidentical HSCT in Thalassemia
(34+ Selection by Clinimac) (Italian Group)
• Five of 22 pts had graft rejection.
• Two of 22 pts died of viral infection.
• Fifteen of 22 pts survived without thalassemia.
Sodani et al, Blood 2010
• 22 pts
• Myeloablative regimen;
Cy, Bu, Flu, Thiotepa & ATG
• GVHD prophylaxis: CSA

8. Cyclophosphamide Post HSC Infusion
Bolanos-Meade et al, Blood 2012

9. Haplo-HSCT for sickle cell disease with
Cy-Post HSC (Johns Hopkins)
Bolanos-Meade et al, Blood 2012

10. Haplo-HSCT for Sickle Cell Disease with Cy-Post HSCT
• Six of 14 pts (40%) had graft failure.
• Two of 14 pts could not stop immunosuppressive drugs (IS)
because of poor donor chimerism.
• Only 6 of 14 (42%) pts were free of both transfusion &
immunosuppression.
Bolanos-Meade et al, Blood 2012
Haplo-HSCT for sickle cell disease with
Cy-Post HSCT (Johns Hopkins)

11. Sabloff et al. ICBMTR, Blood 2011

12. Myeloablative (MAC) vs Reduced Toxicity (RTC)
Conditioning Regimen
BBMT, 2014

13. Novel RTC Approach for High Risk Class 3 Patients
(Age > 10 and Hepatomegaly)
• Pre transplant management
–Hypertransfusion, chelation and hydroxyurea
• Pretransplant immunosuppression (PTIS)
–Flu + Dex (2 cycles; 28 days/cycle)
• Conditioning regimen
–Bu + Flu + ATG

14. Pre-transplant Immunosuppression (PTIS)
(Lymphoid Depletion)
• Fludarabine 40 mg/m2 x 5 days
• Dexamethasone 25 mg/m2 x 5 days
• 1-2 cycles; 28-day cycle
• PTIS is given prior to conditioning regimen

15. 0
20
40
60
80
100
120
140
1 2 3 4
Stimulationindex
Time of testing
CD4 T cells proliferation
No.1
No.2
No.3
Decreased CD4 cell proliferation

16. Novel RTC regimen and GVHD prophylaxis
• 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
• CSA or FK506 and MMF (60 days)

17. Patient characteristics
MAC (Age < 10 years)
Related n= 50 , Unrelated n=26 (34%)
Mismatched HLA (1 Ag or 1 Allele) 12/76 (15%)
Novel RTC (Age > 10 years)
Related n=15 , Unrelated n=7 (32%)
Mismatched HLA (1 Ag or 1 Allele) 5/22 (22%)
All received BM or PBSC.

18. MAC (Age > 10) (n = 76) vs
Novel RTC (Age < 10) (n= 22)
OS MAC = 95%
RTC = 90%
EFS MAC = 88%
RTC = 93%

19. Haplo-HSCT for Thal Patients
Study Population
• 142 thalassemia patients undergoing HSCT
(1989 – July 2015)
• Exclude non-protocol patients n = 12
• Exclude cord blood transplant n = 7
• Related n = 65; Unrelated n = 33; Haplo = 25 (Total n = 123)

20. Phase of Haplo-SCT
Pre-transplant immunosuppression (lymphoid depletion)
Conditioning regimen
Cyclophosphamide post stem cell infusion
• D -68 to -64 Fludarabine 40mg/m2/d & Dexamethasone 25mg/m2/d
• D -40 to -36 Fludarabine 40mg/m2/d & Dexamethasone 25mg/m2/d
• D -12 to -10 Thymoglobulin 1.5mg/kg/d
• D -8 to -3 Fludarabine 35mg/m2/d
• D -8 to -5 Busulfan IV 130mg/m2/d
• D 0 PBSC
• D +3 to +4 Cyclophosphamide 50mg/kg/d
• D +5 FK 506 or sirolimus until 6-12 months
• D +5to +60 Mycophenolate mofetil

21. Haplo-SCT Platform

22. Patients
• Jan 2013 – July 2015
• 25 patients; 12 male : 13 female
• Age 2-20 yrs (median = 14); 12 pts age > 10 yrs (high risk)
• 1 pt underwent Haplo-HSCT for 2nd HSCT (1st HSCT; MRD)
• Donor; Mother = 16, Father = 7
• HLA matching A B C DRB1 and DQ;5/10 = 13,6/10 = 7, 7/10 = 5
• Graft: PBSC CD34+ = 4-19 x 106 cells/kg (median 11.6 x106)

23. Results
• Median time of neutrophil engraftment was d+14 (11-18 days).
• aGVHD II = 7, aGVHD IV = 1
• Three pts had limited cGVHD.
• Two of 18 had graft failure.
• Both 2 pts received additional HSC with minimal conditioning
regimen.
• One had engraftment but died of GVHD and multiorgan failure
and 1 had autologous cells recovery.

24. Results
All pts had anti HLA antibody testing.
Three pts had positive anti HLA antibody with high titers.
Two of 3 pts with positive anti HLA antibody had graft failure.

25. Complications
• Mucositis = 9
• VOD mild to moderate = 4
• CMV reactivation = 5
• BK cystitis = 4
• Adenovirus cystitis = 2
• Herpes zoster = 2

26. Outcome
• Twenty three of 25 pts who had full donor chimerism at the
time of engraftment still had sustainable full donor
chimersim.
• Two pts (8%) had graft failure.
• One died of GVHD and multi-organ failure.
• Median follow up time is 11 months (5 – 29 months)

27. OS and EFS for Haplo-SCT for Thal
Patients (n=25)
OS = 93%
EFS = 88%

28. OS Haplo vs Related vs Unrelated HSCT
Haplo (n=25) = 92%
Related (n=65) = 91%
Unrelated (n=33) = 89%
p = 0.45

29. EFS Haplo vs Related vs Unrelated HSCT
Haplo (n=25) = 88%
Related (n=65) = 89%
Unrelated (n=33) = 88%
p = 0.47

30. Immune Reconstitution
0 month = day at starting conditioning regimen

31. Conclusions
• The Haplo-HSCT for thalassemia patients is feasible.
• The outcome of Haplo-HSCT is comparable to MRD and
MUD.
• We need to modify transplant regime for patients who have
anti HLA antibody.

32. Can all thalassemia patients be cured with HSCT ?
MRD, MUD, Haplo or Autologous HSC with gene
therapy?

34. Overview of the clinical protocol
Testing
and Release
While Frozen
Maximize
% Transduced
HSCs
Vector
+
Cytokines
Bone Marrow
Harvest
Maximize
Myeloablation
Without
Immunosuppression
Bone Marrow
Conditioning
Busulfex
IV Infusion
Transduced Cells
(> 4x106 CD34+/Kg)
(Spontaneous Homing)
CD34+ cells
(2x108 unsorted BM cells/Kg
kept for rescue)

35. 35
Initial results from the Northstar Study (HGB-204):
A Phase 1/2 Study of Gene Therapy for
β-Thalassemia Major via Transplantation of
Autologous Hematopoietic Stem Cells Transduced
Ex-Vivo with a Lentiviral βA-T87Q-Globin Vector
Alexis A. Thompson, John E. J. Rasko, Suradej Hongeng, Janet
L. Kwiatkowski, Gary Schiller, Christof von Kalle, Marina
Cavazzana, Philippe Leboulch, Alexandria Petrusich, Sandeep
Soni, Mark C. Walters
ASH Abstract # 549 (2014)

36. Thai Patients in HBG-204
Three Thai patients were enrolled. (3/18 pts)
First pt had been treated already for 1 year.
She is transfusion independence for 8 months.
The last two patients are now in the process of
mobilization and gene transfection.
Both of them will return to Ramathibodi Hospital from
Children’s Hospital Oakland Research Institute for
transplant process in October and November 2015.

37. Haplo Tx with Cy-Post Tx in
Malignant and Non-malignant Diseases
Leukemias 22 pts
Neuroblastoma 8 pts
Severe aplastic anemia 2 pts
Gaucher disease 1 pt

38. Acknowledgement
Ramathibodi Foundation