A B D U L L A H H . A L J E F R I , M D , C A B P , F A A P

K I N G F A I S A L S P E C I A L I S T H O S P I T A L

R I Y A D H , S A U D I A R A B I A

Hematopoietic Stem Cell Transplantation in children with β-Thalassemia at KFSH- Riyadh:

An Overview and experience over the years

Introduction

Allogeneic stem cell transplantation is the only potential cure for thalassemia.

Replacing the ineffective /defective erythropoiesis with functioning and effective hematopoiesis.

Correction of anemia , stop transfusion.

Correct consequences of the disease on physical disability ,deformities and resumption of normal growth.

Survival, thalassemia-free survival,

Rejection and non-rejection mortality

Lucarelli G et a. Ann N Y Acad Sci. 1998 Jun 30;850:270-5.

Survival, thalassemia-free survival, rejection and non-rejection mortality

291 Class 2 thalassemia patients aged <17 years transplanted using Protocol 6

Survival, thalassemia-free survival,

Rejection and non-rejection mortality

Outcomes for SCT for β-thalassemia

Angelucci, E. et al. Haematologica 2008;93:1780-1784

Results of hemopoietic stem cell transplantation in 900 consecutive patients, aged 1-35 years, transplanted from an HLA identical sibling in Pesaro since December 1981

Lucarelli G & Gaziev J. Blood Rev.

2008;22:53-63

Thalassemia – Patient Characteristics

Time Frame : 1 Jan 1994 – Dec 2016

Total Transplants : 196 Transplants

Total Eligible : 161 Single Transplants

Total patients : 161 Patients

Exclusion:

• Patients having multiple transplants

(n=34).

• One patient received double CB.

Thalassemia – Patient Characteristics (All Transplants, n=161)

Age at Diagnosis:

Mean, SD: 2.1, 2.4 Years

Range: 4 months – 11.88 Years

Median: 1.1 Years

Age at Infusion:

Mean, SD: 6.3, 3.5 Years

Range: 1.0 – 15.8 Years

Median: 5.3 Years

Gender:

Male: 78 (48.4%)

Females: 83 (51.6%)

Thalassemia – Patient Characteristics (All Transplants Patients=161)

1. Hepatitis B:

Positive (Hbs Ag+):…………….… None

2. Hepatitis C (Not Done=41):

Positive:……………………………. Five (3%)

3. EBV (Not Done=42):

Positive:……………………………. Twelve (7%)

4. CMV (Not Done=2):

Positive:……………………………. One Hundred Twenty (75%)

Thalassemia – Patient Characteristics (n=161)

Donors (n=161):

HLA Identical - Siblings:……………………………141 (87.6%)

HLA Identical – Other Relatives:…………….…… 16 (9.9%)

Related 1-AG Mismatch:…………………………… 4 (2.5%)

Thalassemia – Patient Characteristics

Transplants (n=161):

Source of HSCT:

Bone Marrow :………………………………..…157 (97.5%)

PBSC :…………………………………………… 1 (0.6%)

PBSC + BM :.…………………………………… 3 (1.9%)

CD 34+ Cells (X106 Dose/Kg):

Mean, SD: 7.2, 3.5

Range: 0.8 – 17.1

Median: 6.8

Thalassemia – Patient Characteristics

Conditioning Regimens (n=161):

BU / CY:………………………………..… 45 (28%)

BU/CY/ATG :…………………………..… 75 (46.6%)

BU/CY/FLU :…………………………..… 41 (25.5%)

Thalassemia – Time to Recovery at Day 100

Time to ANC Recovery* (0.5X109/L) Evaluated at D-100:

Transplants :…………………………. 161 (All recovered)

Mean, SD :………….………………… 17.6, 4.2 Days

Range :………………………………... 9 – 40 Days

Median :……………………………….. 17 Days

Time to Platelets Recovery** (20X109/L) Evaluated at D-100:

Transplants :…………………………. 150 (92.3%)

Mean, SD :……………….…………… 35.7, 13.4 Days

Range :…………………………..……. 17 – 103 Days

Median :……………………………….. 33 Days

Thalassemia – Transplant Results

Sustained Donor Chimerism (%Myeloid) Evaluated at Day 100:

Done :………………………………….. 126 (78.3%) out of 161

Mean, SD :………………..…………… 83.0%, 29.9%

Range :………………………………… 0 – 100%

Median :……………………………….. 100%

Thalassemia – Transplant Results

Sustained Donor Chimerism (%Lymphoid) Evaluated at Day 100 :

Done :………………………………….. 126 (78.3%) out of 161

Mean, SD :…………………..………… 77.9%, 29.6%

Range :………………………………… 0 – 100%

Median :……………………………….. 90.1%

Thalassemia – Transplant Results

Transfusion Free Status With Respect To Known Donor’s Cell on D-100

PRBC > 75% (D-100) 75% (D-100) Total Evaluable

Transfusions Donor Cells* Donor Cells* Patients

Transf. free 72 (93.5%) 25 (75.8%) 97 (88.2%)

Transf. dpndt. 5 (6.5%) 8 (24.2%) 13 (11.8%)

77 (70%) 33 (30%) 110

P-Value: 0.020

* Both %Myeloid and %Lymphoid

Thalassemia – Transplant Results

P-Value: 0.020

Thalassemia – Outcome of Transplants

Reviewing Our Data By Two Types of Conditioning used

Conditioning Regimen (Total Evaluable Transplants = 161):

BU/CY :…………………………………. 45 Transplants

BU/CY/ATG :……..…………………….. 75 Transplants

BU/CY/FLU :……………………………. 41 Transplants

Thalassemia – Thalassemia Free Outcome By Conditioning Regimens

Events (at Last Update April 2017) BU/CY (n=45)

BU/CY/ATG (n=75)

BU/CY/FLU (n=41)

Whole Cohort (n=161)

Alive and No Evidence of Disease 32 (71.1%) 57 (76%) 36 (87.8%) 125 (77.6%)

Rejected after D -100 2 (4.4%) 7 (9.3%) None 9 (5.6%)

Graft Failure within D-100 4 (8.9%) 4 (5.3%) None 8 (5%)

Expired 6 (13.3%) 6 (8%) 4 (9.8%) 16 (9.9%)

P-Value: 0.027

Thalassemia – Overall Survival Analysis

10 Years Overall Survival: 0.898±0.024

90%

Total Patients :……..……………………… 161

Total Evaluable :…………………………... 161

Total Events :….…………………………... 16 Deaths

Median Follow-up Time :…………………. 77.2 (63-91) months

Thalassemia – Thalassemia Free Survival

Total Patients :……..……………………… 161

Total Evaluable :…………………………... 161

Median Follow-up Time :…………………. 77.2 (63-91) months

Events: Graft Failures, Post Transplant PRBC Transfusion & Death

77%

10 Year Thalassemia Free Survival: 0.774±0.033

Thalassemia – Thalassemia Free Survival

Total Patients :……..……………………… 161

Total Evaluable :…………………………... 161

Median Follow-up Time :…………………. 72.3 (60.3-84.2) months

Event: Graft Failures, Post Transplant PRBC Transfusion & Death

10 Years Overall Survival: 0.897±0.024

10 Year Thalassemia Free Survival: 0.774±0.033

Rejection: 15 of 161 (9.3%)

Non-Rejection Mortality Rate: 12 of 146(8.2%)

Overall Survival

Thalassemia Free Survival

Non-Rejection Mortality

90%

77%

8%

Rejection : 9%

Thalassemia – Thalassemia Free Survival By Eras of Chemo-Conditioning

Thalassemia Free Survival (P-Value: 0.205) Total Patients :……..……………………… 161

Total Evaluable :…………………………... 161

Median Follow-up Time :…………………. 77.2 (63-91) months

Event: Graft Failures, Post Transplant PRBC Transfusion & Death

Bu/Cy/Flu vs. Bu/Cy/ATG: P-Value: 0.180

Bu/Cy/Flu vs. Bu/Cy: P-Value: 0.078

Median Follow-Up Time (months):

Bu/Cy: 129.6 (112.7 – 146.4)

Bu/Cy/ATG: 84.2 (69.6 – 98.8)

Bu/Cy/Flu: 39.5 (29.1 – 49.9)

88%

76%

71%

Thalassemia – Thalassemia Free Survival By Risk Factors

Factors Investigated Whole Cohort (n=141)

BU/CY (n=39)

BU/CY/ATG

(n=66)

BU/CY/FLU (n=36)

Age at SCT (≤7 Yrs vs. >7 Yrs) 0.965 0.147 0.998 0.320

Donor Gender (Male vs. Female) 0.377 0.246 0.791 0.667

Donor Age at SCT (≤14 Yrs vs. >14 Yrs) 0.662 0.048 0.771 0.539

Donor Relationship (Father, Mother, Brother, Sister) 0.574 0.183 0.858 0.774

Donor Relationship (Siblings vs. Parents) 0.824 0.224 0.479 0.620

Recipient Donor Relationship (FF, MM, MF, FM) 0.667 0.328 0.928 0.819

Recipient Donor Relationship (Same vs. Different Gender) 0.701 0.149 0.551 0.977

D-100 Donor Cells (≤75% vs. >75%) * 0.001 0.407 <0.001 0.172

aGVHD Grade 3 and Above 0.002 <0.001 0.069 0.537

Ferritin Level at SCT (≤3000 vs. >3000) 0.111 0.140 0.229 0.469

* Both %Myeloid and %Lymphoid

• Listed are the P-Values resulting from the Kaplan-Meier Thalassemia Free Survival Analysis.

• Values in Red are P-Values that are statistically significant.

Thalassemia – Thalassemia Free Survival By Donor Cells on D-100

Thalassemia Free Survival

P-Value: <0.001

* Both %Myeloid and %Lymphoid

Total Patients :……..……………………… 161

Total Evaluable :…………………………... 161

Median Follow-up Time :…………………. 77.2 (63-91) months

Event: Graft Failures, Post Transplant PRBC Transfusion & Death

87%

61%

Thalassemia – Thalassemia Free Survival By aGVHD (3 and above)

Thalassemia Free Survival

P-Value: 0.021

(Full Cohort)

Total Patients :……..……………………… 161

Total Evaluable :…………………………... 161

Median Follow-up Time :…………………. 77.2 (63-91) months

Event: Graft Failures, Post Transplant PRBC Transfusion & Death

80%

50%

Thalassemia – Outcome

Complications:

Around Day 100:

GVHD – Acute Grade 3 or 4 :…………..…………………….... 12 of 141 (8.5%)

Skin :……………………. 5 (3.5%)

Liver :…………………… 5 (3.5%)

Gut :…………………….. 6 (4.3%)

VOD (D-100) :…………………….….…………………………….. 13 of 141 (9.2%)

Hemorrhage Cystitis (D-100) :………………………..………….. 11 of 140 (7.9%)

Post Day 100:

GVHD - Chronic :……………………….……... 9 of 117 (7.7%)

cGVHD Extensive :…………………. 3 of 8 (37.5%)

cGVHD Limited :……………….……. 5 of 8 (62.2%)

VOD :…………………………………..……….. None

Hemorrhage Cystitis :……….……….………... None

(For one patient data on cGVHD assessment was not available.)

Self Limiting

Thalassemia – Transplant Results

Impact of Pre-Transplant Iron Overload

Cardiac Siderosis Levels on Outcome By MRI T2*

Cardiac Siderosis Levels Thalassemia Free

Survival

No. of patients with available data

P-value

None 85.3% 34

0.579

Mild 100% 6

Thalassemia – Transplant Results

Impact of Pre-Transplant Iron Overload

Hepatic Iron Overload on Outcome By MRI T2*

Hepatic Siderosis Thalassemia Free Survival No. of patients with

available data P-value

None 100% 11

0.091

Mild 100% 10

Moderate 73.7% 19

Severe 100% 1

Conclusion

HSCT is an effective modality for potential cure from the disease.

KFSHRC experience is similar to other international institutions using standard modalities of care

OS : 90%, TFS : 77 % are acceptable results, but with the use of the new modalities of preparative regimen the outcome improved

( TFS : 88%).

Good donor’s chimerism >75% at D-100 is a strong predictor of

sustained engraftment.

Severe aGVHD has a major impact on survival and outcome.

Using the classic ( BU/CY) contributed to VOD and Hemorrhagic Cystitis before D-100.

Best conditions for patients at time of HSCT are young children recipients ( Preschool) who have no organ dysfunction and the graft from fully HLA-match sibs.

Advancement in Thalassemia Transplant

Improved preparative and conditioning regimens.

Reduced toxicity regimens

Alternative source of stem cell transplantation

such as cord blood

Alternative best match ( extended haploidentical testing )

Improved High Risk GVHD prevention strategies

Expansion of BMT Donor’s registries on regional basis.

Reduced toxicity regimen

Fludarabine

Theotepa

Treosulafan

Survival, thalassemia-free survival,

Rejection and non-rejection mortality

HSCT Preparation/Conditioning

Reduction of hematopoietic tissue mass:

2-6 months prior to transplant

Repeated transfusion ( maintain high RBC/HGB)

Intensive chelation (SC/IV)

Hydroxyurea, Immuran, EPO, G-CSF

Conditioning:

Myeloablation

Myelosuppression

Treatment protocol developed for transplantation

for advanced disease in thalassemia

Estimates of survival, thalassemia-free survival

non-rejection mortality and rejection

Alternative donor/source

Matched

Mis-match

Unrelated

Haploidentical

Matched Unrelated Donor

GITMO study ( Italian Bone Marrow Transplant Group)

68 pts. , M 15 yr ( 2- 37 )

Immunogenetic compatibility

( stringent high resolution molecular typing )

OS : 79% TFS : 66%

Extended haplotype identity ( HLA-A ---- HLA-Dq )

Limitation is donor availability (ancestral, ethnic identity)

La Nasa et al ( AnnNY Acad 2005)

Unrelated Cord Blood

EBMT, CIBMTR

51 patients

13 died

16 sustained engraftment

Ruggeri et al ( BMT 2010)

Mismatch Related Donor

Gasiev et al ( BMT 2000 )

Limited experience

29 patients

Poor outcome

OS : 65% , TFS : 21%

Sodani et al ( Blood 2010)

Haploidentical , limited pts. 20

2 died

6 rejection

14 disease free

Acceptable source of HSCT :

Match Related

Related cord blood

Match unrelated (extended haploidentical, high resolution molecular typing)

E. Angelucci ( American Society of Hematolgy, ASH 2010)

Angelucci et al, Haematologica, 2014