Can All Thalassemia Patients be Cured with HSCT?

Suradej Hongeng

Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital,

Mahidol University, Bangkok, Thailand

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?

BMT with MRD in Thalassemia and Lucarelli Classification

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

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 = 21MRD = 28

Bu-Cy-ATG(Bu-Flu-ATG for

class 3)

8292

7182

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 = 40MRD = 20

Treo-TT-Flu- ATG --

8287

MUD = matched unrelated donor, MRD = match related donor

Unrelated donor HSCT in Thalassemia

References Patients (N) Protocols OS(%)

TFS (%)

Ghavamzadeh et al (BBMT 2008)

PBCS = 87BM = 96

Bu-Cy 8389

7676

Iravani et al(Exp Clin Transplant 2010)

PBCS = 20BM = 32(HR =52)

Bu-Cy 80 65

Irfan et al (J Pak Med Assoc 2012)

PBCS = 27BM = 29

LR: Bu-Cy HR: HU-Aza-Flu-

Bu-Cy

6573

5567

Locatelli et al (EBMT)(Blood 2013)

CB = 66BM = 259

Bu-Cy (Bu-Flu)+/TT

- 8086

PBSC = peripheral blood stem cell, BM = bone marrow, CB = cord blood

Sources of HSC for HSCT in Thalassemia

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.

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

Cyclophosphamide Post HSC Infusion

Bolanos-Meade et al, Blood 2012

Haplo-HSCT for sickle cell disease with Cy-Post HSC (Johns Hopkins)

Bolanos-Meade et al, Blood 2012

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)

Sabloff et al. ICBMTR, Blood 2011

Myeloablative (MAC) vs Reduced Toxicity (RTC)Conditioning Regimen

BBMT, 2014

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

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

1 2 30

10

20

30

40

50

60

70

80

CD4 T cells proliferation

No.1No.2No.3

Time of testing

Stim

ulat

ion

inde

xDecreased CD4 cell proliferation

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)

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.

MAC (Age > 10) (n = 76) vs Novel RTC (Age < 10) (n= 22)

OS MAC = 95%

RTC = 90%

EFS MAC = 88% RTC =

93%

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)

Phase of Haplo-SCTPre-transplant immunosuppression (lymphoid depletion)Conditioning regimenCyclophosphamide 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 +5 to +60 Mycophenolate mofetil

Haplo-SCT Platform

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)

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.

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.

Complications

•Mucositis = 9•VOD mild to moderate = 4

•CMV reactivation = 5•BK cystitis = 4

•Adenovirus cystitis = 2•Herpes zoster = 2

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)

OS and EFS for Haplo-SCT for Thal Patients (n=25)

OS = 93%

EFS = 88%

OS Haplo vs Related vs Unrelated HSCT

Haplo (n=25) = 92%

Related (n=65) = 91%

Unrelated (n=33) = 89%

p = 0.45

EFS Haplo vs Related vs Unrelated HSCT

Haplo (n=25)

= 88%

Related (n=65) = 89%

Unrelated (n=33) = 88%

p = 0.47

Immune Reconstitution

0 month = day at starting conditioning regimen

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.

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

Overview of the clinical protocol

Testingand Release

While Frozen

Maximize% Transduced

HSCs

Vector+

Cytokines

Bone MarrowHarvest

MaximizeMyeloablation

WithoutImmunosuppression

Bone MarrowConditioning

Busulfex

IV InfusionTransduced Cells

(> 4x106 CD34+/Kg)(Spontaneous Homing)

CD34+ cells

(2x108 unsorted BM cells/Kgkept for rescue)

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)

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.

Haplo Tx with Cy-Post Tx in Malignant and Non-malignant Diseases

Leukemias 22 pts

Neuroblastoma8 pts

Severe aplastic anemia2 ptsGaucher disease

1 pt

Acknowledgement

Ramathibodi Foundation