BMT for Hemoglobinopathies

Hemoglobinopathies burden
 >330,000 yearly births: - ¾ Sickle cell diseases
- ¼ Thalassemia major
 Hemoglobinopathies are the most common life-threatening non-
communicable diseases in the pediatric age group globally
 In many countries they are a substantial burden on national health care
expense and blood consumption
 Global burden on the rise as childhood mortality decreases

“It has been estimated that if the survival rate of children

with SCD in Africa increases to only 50% the African
norm, more than 6 million Africans will be living with
SCD”
Weatherall D.: Blood 2010: 115:4331
hemoglobinophaties
The thalassemia belt
The thalassemia belt vs. global population <15y

http://sasi.group.shef.ac.uk/worldmapper
Thalassemia
 Thalassemia survival in Pakistan

120

100

80
1996
60
2006
40

20

0
2 4 6 8 10 12 14 16 18 20 22 24 25

1996: data from HBB Karachi, 2006: data from BTIHS, Karachi
Bone marrow transplantation
for severe thalassemia
BMT in thalasemia mayor
BMT in thalasemia mayor
 Matched-related HCT (BMT) for hemoglobinopathies
Thalassemia vs. Sickle Cell Disease

Thalassemia Sickle cell disease

New cases/year > 80,000 > 250,000
Total BMTs done ~ 4,000 ~ 1000
Risk group
Good Poor
identification
Transplant related
5-40% 5-10%
mortality
Chelation effective but Hydroxyurea inexpensive
Medical therapy
expensive but partially effective

Quality of life Potentially good Variable

Highly dependent on Variable depending on

Life expectancy
medical care medical care
 1.00
Survival Probability

0.75 Birth cohort

1985–1997
1980–1984
0.50 1975–1979
1970–1974
1965–1969
0.25 1960–1964

P < .00005

0
0 5 10 15 20 25 30
Age (years)
Borgna-Pignatti C, et al. Haematologica. 2004;891:187
Hemoglobinopathies Registry of the European Group for Blood and Marrow
Transplantation

Angelucci and Baronciani 2010

 Thalassemia: Life-long supportive care

Open issues
• Drug/transfusion tollerance
• Blood-borne infections
• Ospeoporosis and pain
• Pulmonary hypertension
• Quality of life
• Financial burden
 BMT in Thalassemia
Standard preparation with Busulfan-Cyclophosphamide (BuCy)

Chelation Hepatomegaly Fibrosis

Class 1 Regular No No
Class 2 Reg/Irreg No/yes No/Yes
Class 3 Irregular Yes yes

Patients < 17 year

OS TFS
Class 1 94% 87%
Class 2 84% 81%
Class 3 70% 58%

Adults
OS TFS
67% 63%

Emanuele Angelucci: Hematopoietic stem cell transplantation for Thalassemia. ASH Educational Book 2010
 HR BMT in Thalassemia (class 3)
Modified conditining with Hydroxyurea+Azathioprine from day -45, Fludarabine,
Bu and reduced Cy (protocol 26) in class 3 pts < 17 yrs old

OS TFS
93% 85%

Sodani et al. Blood. 2004;104(4):1201-1203

 Quality of life post-BMT

La Nasa et al. Blood 2013

109 patients (44 females and 65 males) assessed > 20 yrs from BMT (BuCy), mean age
at BMT 12 yrs (1-36) and 34 yrs (21-48) at time of study.

Long-term health-related quality of life, employment status and birth rate similar to the
general population

Relevant variables affecting HRQoL:

 Extensive chronic GVHD (6%)
 Age at BMT (better if less than 15 yrs)
 Comorbidities (risk group at BMT)

Matched cohort of 124 thalassemia patients receiving conventional treatment

showed poorer QoL outcomes
 Bone marrow transplantation for thalassemia

Risk group assignment independent of liver biopsy

Children <7 years with liver ≤2cm below

the costal margin may enjoy cure rates
greater than 85%

Sabloff et al. Blood. 2011

 BMT for thalassemia

 Splenectomy prior to BMT may increase TRM (Bhatia et al.

Pediatr.Transplant. 2009)

 VOD incidence <10% (DFB prophylaxis probably not justified unless HCV+
or abnormal LFTs)

 HCV positivity not a contraindication (Erer et al. Bone Marrow

Transplant. 1994)
 Conditioning for thalassemia BMT

 Standard regimen: Busulfan & Cyclophosphamide

(BuCy)

 Significant rejection rates, particularly in younger

children (~30%)

 The addition of thiotepa (Tt) 10 mg/kg has reduced

rejection rates (5-10%) but at the cost of infertility
 Use of ATG for thalassemia BMT
Both in the Greek and French experience (183 total pts)
ATG can substantially reduce rejection rates (5-10%)
when added to BuCy

ATG-Busulfan-Cyclophosphamide with MTX & CSA ± PDN x 6-9 months for

GVHD/Rejection prophylaxis is probably the current most consolidated strategy for
matched-relatd BMT which is associated with acceptable (and well known) cure rates,
acute toxicities and late effects

Goussetis et al. Bone Marrow Transplantation 2012

Galambrun et al. Biology of Blood and Marrow Transplantation 2013
Cure2Children currently recommended regime for low-risk MRD
BMT for
severe thalassemia and sickle cell disease

ATG (Rabbit-Fresenius) total dose of 16mg/kg from day -12 to -10

Busulfan oral total dose 14 mg/kg from day -9 to -6

Cyclophosphamide total dose 200 mg/kg from day -5 to -2

Day 0: GCSF-primed bone marrow

GVHD/Rejection prophylaxis
Methotrexate 10mg/m2 at day +1, 8mg/m2 at +3, +6 & +11
Cyclosporin A 5 mg/kg/day at days -2 to +5 then 3mg/kg/day till day +22, then
oral dose of 10mg/kg/day, blood level-adjusted. Tapered at day +180
Methylprednisolone 0.5 mg/kg/day from day -1 to +30 then tapered gradually
over 15 days
 Timing of ATG for thalassemia BMT

 For doses of ATG Fresenius in the 10-15 mg/kg range from day -6 to -2 the peak
level is on day 0 and decrease with a half life of 3-5 days

↓ Rejection
↑ GVHD (?)
↑ Immune recovery
↓ EBV-LPD

ATG day -9 to -7 ATG day -6 to -2

Day -10 Day 0
 The Cure2Children Experience
Thiotepa-Bu-Cy (35 pts) vs. ATG-Bu-Cy (13 pts)

Overall survival: 94.2% vs. 92.3%

Thalassemia-free survival: 91.3% vs. 92.3%

No statistically significant difference by log-rank test.

This is why we don’t favour regimens including thiotepa and IV

busulfan/treosulfan
 Unrelated transplantation for thalassemia

Unrelated BMT (La Nasa et al. Ann.N.Y.Acad.Sci. 2005)

 Extended compatibility required (<30% find 10/10 donor)

 (Class 1-2) 96% OS

 (Class 1-2) 80% TFS
 cGVHD 18%

Unrelated CBT (Ruggeri et al. Biol. Blood Marrow Transplant. 2011)

 62% OS
 21% TFS
 Indirect positive effects of BMT
 Increases awareness about thalassemia

 Attracts families for screening

 Generates resources for supportive care and prevention

 Increase compliance with chelation and safe blood use

 Attracts and motivates professionals

 Empowers medical centers and paves the way for the cure of related disorders

 Fosters research and higher medical education

The realistic hope for a cure may involve
families in prevention programs

 2.800 extended family members screened for free

 50 mothers of thalassemic children offered free

prenatal testing for subsequent pregnancies
 BMT Prospects
Transplantation in the “New thalassemia era”

 Any transplantation-related mortality (TRM) is

increasingly unacceptable

 BMT has to provide a normal quality of life

 Fertility preservation

 Rejection is relatively more acceptable than TRM or

cGVHD
 BMT Prospects
Downstaging higher risk patients

Advances in supportive care (chelation,

hydroxyurea, etc…) may allow negative
iron balances, organ damage reversal and
reduce TRM
 BMT Prospects
The post-BMT cyclophosphamide (PTCy) revolution

Donors’s T-cells Recipient’s T-cells

unshared histompatibility antigens unshared histompatibility antigens

Post-BMT Cy
clonal selection bidirectional clonal selection
allo-depletion

GVHD Rejection
T-reg resistance to Cy through expression of aldehyde
dehydrogenase, the major in vivo mechanism of Cy
resistance, may contribute to the clinical activity of
PTCy in preventing GVHD
 Prospects

Bashey et al.: T-Cell–Replete HLA-Haploidentical Hematopoietic Transplantation for

Hematologic Malignancies Using Post-Transplantation Cyclophosphamide Results in
Outcomes Equivalent to Those of Contemporaneous HLA-Matched Related and Unrelated
Donor Transplantation.

Journal of Clinical Oncology 31, no. 10 (April 1, 2013): 1310–1316.

 Prospects
Double unrelated cord blood vs. Haploidentical marrow
Results of 2 parallel phase 2 trials (adult leukemia/lymphoma pts )

1-yr non- d100 Median Median Graft Stem cell

relapse II-IV ANC plt failure source
mortality GVHD recovery recovery cost
(>500) (>20K)
dUCB >60K
(50 pts) 24% 40% d15 d30 12%
USD
Haplo BMT
(50 pts)
7% 32% d16 d24 2% 0

Brunstein et al. Blood 2011;118:282

 Partially matched related (haploidentical) BMT for
sickle cell disease

Mortality III-IV GVHD Graft failure

Haplo BMT
(14 pts: 15-42 yrs)
0% 0% 43%

Bolanos-Meade et al. Blood 2012;118:282

 Prospects
Use of post-BMT Cy for 2nd BMT in thalassemia

Time to second BMT

First BMT Second BMT

Days of RBC Tx

Days of RBC Tx
independency

independency
Second BMT
neutropenic

neutropenic
prophylaxis

prophylaxis
Age at first

First BMT

rejection

rejection
regimen

regimen
Plt Tx

Plt Tx
GVHD

GVHD
Total

Total
days

days
BMT

Bu 14 mg/kg CSA TT 10 mg/kg

12 Cy 50 mg/kg
1.7 y TT 10 mg/kg PDN 18 30 2 Bu 14 mg/kg
(day +3 & +4)
21 2yrs+ 6
Cy 200 mg/kg MTX mo Cy 100 mg/kg

Bu 14 mg/kg CSA
13 TT 10 mg/kg Cy 50 mg/kg
1.6 y TT 10 mg/kg PDN 15 240 5 Bu 14 mg/kg (day +3 & +4)
20 2yrs+ 5
Cy 200 mg/kg MTX mo

Yaqub at al. Bone Marrow Transplantation 2014

 Conclusions

 BMT for low-risk children with thalassemia (or SCD) with

a compatible donor might be simpler, less expensive and
more accessible than generally perceived.

 It can cure over 90% of children with a suitable donor

and improve their health-related quality of life.

 HLA-typing should be offered whenever a healthy sibling

is available (hemoglobinopathy carriers included)