hematopoietic stem cell transplantation in children with β...
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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